Title of Invention

"HIV PROTEASE INHIBITOR PHOSPHONATE ANALOGUES"

Abstract The present invention provides HIV protease inhibitor phosphonate analogues of the formula: wherein A' is -P(O)R1R2 wherein in the above radical, R1 and R2 are independently selected from hydroxy, methoxy, ethoxy, trifluoroethoxy, isopropoxy, phenoxy, benzvloxv and O- pivaloyloxymethyl; and the enantiomers and diastereomers as well as physiologically acceptable salts, hydrates and prodrugs thereof
Full Text CELLULAR ACCUMULATION OF PHQSPHONATE ANALOGS OF HIV PROTEASE INHIBITOR COMPOUNDS
This non-provisional application claims the benefit of Provisional Applications 60/375,622, filed April 26, 2002; Provisional Application No. 60/375,779 filed April 26, 2002; Provisional Application No. 60/375,834, filed April 26, 2002, and Provisional Application No. 60/375,665 filed April 26, 2002, all of which are incorporated herein by reference. Additionally, copending applications Attorney Docket Nos. 259.PC and 260.PC filed concurrently with this application are also incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
The invention relates generally to compounds with antiviral activity and more specifically with anti-HIV protease properties.
BACKGROUND OF THE INVENTION
ADDS is a major public health problem worldwide. Although drugs targeting HIV viruses are in wide use and have shown effectiveness, toxicity and development of resistant strains have limited their usefulness. Assay methods capable of determining the presence, absence or amounts of HIV viruses are of practical utility in the search for inhibitors as well as for diagnosing the presence of HIV.
Human immunodeficiency virus (HIV) infection and related disease is a major public health problem worldwide. The retrovirus human immunodeficiency virus type 1 (HIV-1), a member of the primate lentivirus family (DeClercq E (1994) Annals of the New York Academy of Sciences, 724:438-456; Barre-Sinoussi F (1996) Lancet, 348:31-35), is generally accepted to be the causative agent of acquired immunodeficiency syndrome (AIDS) Tarrago etal FASEB Journal 1994, 8:497-503). AIDS is the result of repeated replication of HIV-1 and a decrease in immune capacity, most prominently a fall in the number of CD4+ lymphocytes. The mature virus has a single stranded RNA genome that encodes 15 proteins (Frankel etal (1998) Annual Review of Biochemistry, 67:1-25; Katz etal (1994) Annual Review of Biochemistry, 63:133-173), including three key enzymes: (i) protease (Pit) (von der Helm K (1996) Biological Chemistry, 377:765-774); (ii) reverse transcriptase (RT) (Hottiger etal (1996) Biological Chemistry Hoppe-Seyler, 377:97-120), an enzyme unique to retroviruses; and (iii) integrase (Asante etal (1999) Advances in Virus Research 52:351-369; Wlodawer A (1999) Advances in Virus Research 52:335-350; Esposito etal (1999) Advances in Virus Research 52:319-333). Protease is responsible for processing the viral precursor polyproteins, integrase is responsible for the integration of the double stranded DNA form of the viral genome into host DNA and RT is the key enzyme in the replication of the viral genome. In viral replication, RT acts as both an RNA- and a DNA-dependent DNA polymerase, to convert the single stranded RNA genome into double stranded DNA. Since virally encoded Reverse Transcriptase (RT) mediates specific reactions during the natural reproduction of the virus, inhibition of HIV RT is an important therapeutic target for treatment of HTV infection and related disease.
Sequence analysis of the complete genomes from several infective and non-infective HIV-isolates has shed considerable light on the make-up of the virus and the types of molecules that are essential for its replication and maturation to an infective species. The HIV protease is essential for the processing of the viral gag and gag-pol polypeptides into mature virion proteins. L. Ratner, et al., Nature, 313:277-284 (1985); L. H. Pearl and W. R. Taylor, Nature, 329:351 (1987). HIV exhibits the same gag/pol/env organization seen in other retroviruses. L. Ratner, et al., above; S. Wain-Hobson, et al., Cell, 40:9-17 (1985); R. Sanchez-Pescador, et al., Science, 227:484-492 (1985); and M. A. Mussing, et al., Nature, 313:450-458(1985).
A therapeutic target in AIDS involves inhibition of the viral protease (or proteinase)
that is essential for processing HlV-fusion polypeptide precursors. In HTV and several other retroviruses, the proteolytic maturation of the gag and gag/pol fusion polypeptides (a process indispensable for generation of infective viral particles) has been shown to be mediated by a protease that is, itself, encoded by the pol region of the viral genome. Y. Yoshinaka, et al., Proc. Natl. Acad. Sci. USA, 82:1618-1622 (1985); Y. Yoshinaka, et al., J. ViroL, 55:870-873 (1985); Y. Yoshinaka, et al., J. ViroL, 57:826-832 (1986); and K. von der Helm, Proc. Natl. Acad. Sci., USA, 74:911-915 (1977). Inhibition of the protease has been shown to inhibit the processing of the HIV p55 in mammalian cell and HTV replication in T lymphocytes. T. J. McQuade, et al., Science, 247:454 (1990).
Drugs approved in the United States for AIDS therapy include nucleoside inhibitors of RT (Smith et al (1994) Clinical Investigator, 17:226-243), protease inhibitors and non-nucleoside RT inhibitors (NNRTI), (Johnson et al (2000) Advances in Internal Medicine, 45 (1-40; Porche DJ (1999) Nursing Clinics of North America, 34:95-112).
The protease (or proteinase), consisting of only 99 amino acids, is among the smallest enzymes known, and its demonstrated homology to aspartyl proteases such as pepsin and renin (L. H. Pearl and W. R. Taylor, Nature, 329:351-354 (1987); and I. Katoh, et al., Nature, 329:654-656 (1987)), led to inferences regarding the three-dimensional structure and mechanism of the enzyme (L. H. Pearl and W. R. Taylor, above) that have since been borne out experimentally. Active HTV protease has been expressed in bacteria (see, e.g., P. L. Darke, et al., J. Biol. Chem., 264:2307-2312 (1989)) and chemically synthesized (J. Schneider and S. B. Kent, Cell, 54:363-368 (1988); and R. F. Nutt, et al., Proc. Natl. Acad. Sci., USA, 85:7129-7133 (1988)). Site directed mutagenesis (P. L. Darke, et aL, above); and N. E. Kohl, et al., Proc. Natl. Acad. Sci., USA, 85:4686-4690 (1988)) and pepstatin inhibition (P. L. Darke, et al., J. Biol. Chem., 264:2307-2312 (1989); S. Seelmeier, et al., Proc. Natl. Acad. Sci., USA, 85:6612-6616 (1988); C.-Z. Giam and L Borsos, J. Biol. Chem., 263:14617-14720 (1988); and J. Hansen, et al., EMBO L, 7:1785-1791 (1988)) have provided evidence for HIV protease's mechanistic function as an aspartyl protease. A study has demonstrated that the protease cleaves at the sites expected in peptides modeled after the regions actually cleaved by the enzyme in the gag and pol precursor proteins during viral maturation. P. L. Darke, et al., Biochem. Biophys. Res. Communs., 156:297-303 (1988). X-ray crystallographic analysis of the HTV-protease (M. A. Navia, et al., Nature, 337:615-620 (1989)) and a related retroviral enzyme fromRous sarcoma virus (M. Miller, et al., Nature,
337:576-579 (1989)) reveal an active site in the protease dimer that is identical to that seen in other aspartyl proteases, thus supporting the supposition (L. H. Pearl and W. R. Taylor, above) that the HIV enzyme is active as a dimer. See also Joseph A. Martin, "Recent Advances in the Design of HIV Proteinase Inhibitors," Antiviral Research, 17 (1992) 265-278.
Inhibitors of HIV protease are useful to limit the establishment and progression of infection by therapeutic administration as well as in diagnostic assays for HIV. Protease inhibitor drugs approved by the FDA include:
• saquinavir (Invirase®, Fortovase®, Hoffman-La Roche, EP-00432695 and EP-
00432694)
• ritonavir (Norvir®, Abbott Laboratories)
• indinavir (Crixivan®, Merck & Co.)
• nelfinavir (Viracept®, Pfizer)
• amprenavir (Agenerase®, GlaxoSmithKline, Vertex Pharmaceuticals)
• lopinavir/ritonavir (Kaletra®, Abbott Laboratories)
Experimental protease inhibitor drugs include:
• fosamprenavir (GlaxoSmithKline, Vertex Pharmaceuticals)
• tipranavir (Boehringer Ingelheim)
• atazanavir (Bristol-Myers Squibb).
There is a need for anti-HTV therapeutic agents, i.e. drugs having improved antiviral and pharmacokinetic properties with enhanced activity against development of HTV resistance, improved oral bioavailability, greater potency and extended effective half-life in vivo. New HIV protease inhibitors (PI) should be active against mutant HTV strains, have distinct resistance profiles, fewer side effects, less complicated dosing schedules, and orally active. In particular, there is a need for a less onerous dosage regimen, such as one pill, once per day. Although drugs targeting HTV protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al AT. Engl. J. Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001).
Combination therapy of PI and RT inhibitors has proven to be highly effective in suppressing viral replication to unquantifiable levels for a sustained period of time. Also,
combination therapy with RT and protease inhibitors have shown synergistic effects in suppressing HTV replication. Unfortunately, many patients currently fail combination therapy due to the development of drug resistance, non-compliance with complicated dosing regimens, pharmacokinetic interactions, toxicity, and lack of potency. Therefore, there is a need for new HIV protease inhibitors that are synergistic in combination with other HIV inhibitors.
Improving the delivery of drugs and other agents to target cells and tissues has been the focus of considerable research for many years. Though many attempts have been made to develop effective methods for importing biologically active molecules into cells, both in vivo and in vitro, none has proved to be entirely satisfactory. Optimizing the association of the inhibitory drug with its intracellular target, while minimizing intercellular redistribution of the drug, e.g. to neighboring cells, is often difficult or inefficient.
Most agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., cytotoxic agents and other anti-cancer or anti-viral drugs) that can be administered. By comparison, although oral administration of drugs is generally recognized as a convenient and economical method of administration, oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g. blood/brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract. Accordingly, a major goal has been to develop methods for specifically targeting agents to cells and tissues. Benefits of such treatment includes avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells. Intracellular targeting may be achieved by methods and compositions which allow accumulation or retention of biologically active agents inside cells.
SUMMARY OF THE INVENTION
The present invention provides novel compounds with HIV protease activity, i.e. novel human retroviral protease inhibitors. Therefore, the compounds of the invention may inhibit retroviral proteases and thus inhibit the replication of the virus. They are useful for treating human patients infected with a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and/or related diseases. The present invention includes novel phosphonate HIV protease inhibitor (PI) compounds and phosphonate analogs of known approved and experimental protease inhibitors. The compounds of the invention optionally provide cellular accumulation as set forth below.
The present invention relates generally to the accumulation or retention of therapeutic compounds inside cells. The invention is more particularly related to attaining high concentrations of phosphonate-containing molecules in HTV infected cells. Intracellular targeting may be achieved by methods and compositions which allow accumulation or retention of biologically active agents inside cells. Such effective targeting may be applicable to a variety of therapeutic formulations and procedures.
Compositions of the invention include new PI compounds having at least one phosphonate group. The invention includes all known approved and experimental protease inhibitors with at least one phosphonate group.
In one aspect, the invention includes compounds having Formulas I, n, HI, IV, V, VI, VH and Vnia-d:
here a wavy line indicates the other structural moieties of the compounds.
Formulas I- VIE are substituted with one or more covalently attached groups, including at least one phosphonate group. Formulas I-Vm are "scaffolds", i.e. substructures which are common to the specific compounds encompassed therein.
Another aspect of the invention provides a pharmaceutical combination comprising an effective amount of a compound selected from Formulas I-VEI and a second compound having anti-HIV properties.
Another aspect of the invention provides a method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected annual which comprises administering to, i.e. treating, said animal with a pharmaceutical combination comprising an effective amount of a compound selected from Formulas I-VIE and a second compound having anti-HIV properties.
The invention provides a pharmaceutical composition comprising an effective amount of a compound selected from Formulas I-VIII, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
This invention pertains to a method of increasing cellular accumulation and retention of drug compounds, thus improving their therapeutic and diagnostic value.
The invention also provides a method of inhibiting HIV, comprising administering to a mammal infected with HIV (HIV positive) an amount of a compound of Formulas I-VEI, effective to inhibit the growth of said HIV infected cells.
The invention also provides a compound selected from Formulas I-VEI for use in medical therapy (preferably for use in treating cancer, e.g. solid tumors), as well as the use of a compound of Formulas I-VEI for the manufacture of a medicament useful for the treatment of cancer, e.g. solid tumors.
The invention also provides processes and novel intermediates disclosed herein which are useful for preparing compounds of the invention. Some of the compounds of Formulas I-
Vin are useful to prepare other compounds of Formulas I-VHI.
In another aspect of the invention, the activity of HIV protease is inhibited by a method comprising the step of treating a sample suspected of containing HIV virus with a compound or composition of the invention.
Another aspect of the invention provides a method for inhibiting the activity of HIV protease comprising the step of contacting a sample suspected of containing HIV virus with a composition of the invention.
In other aspects, novel methods for synthesis analysis, separation, isolation, purification, characterization, and testing of the compounds of this invention are provided.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying description, structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.
DEFINITIONS
Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:
The terms "phosphonate" and "phosphonate group" mean a functional group or moiety within a molecule that comprises at least one phosphorus-carbon bond, and at least one phosphorus-oxygen double bond. The phosphorus atom is further substituted with oxygen, sulfur, and nitrogen substituents. These substituents may be part of a prodrug moiety. As defined herein, "phosphonate" and "phosphonate group" include molecules with phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, phosphondiamidate and phosphonthioate functional groups.
The term "prodrug" as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or
metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically-active compound.
"Pharmaceutically acceptable prodrug" refers to a compound that is metabolized in the host, for example hydrolyzed or oxidized, by either enzymatic action or by general acid or base soIvolysis, to form an active ingredient. Typical examples of prodrugs of the compounds of the invention have biologically labile protecting groups on a functional moiety of the compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, esterified, deesterified, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, photolyzed, hydrolyzed, or other functional group change or conversion involving forming or breaking chemical bonds on the prodrug.
"Prodrug moiety" means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Prodrugs" in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters -CH2OC(=O)R9 and acyloxymethyl carbonates -CH2OC(=O)OR9 where R9 is Q-Ce alkyl, Ci-Ce substituted alkyl, Ce-C2o aryl or Ce-C2o substituted aryl. The acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al (1983) J. Pharm. Sci. 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756. In certain compounds of the invention, a prodrug moiety is part of a phosphonate group. Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) -CH2OC(=O)C(CH3)3. An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) -CH2OC(=O)OC(CH3)3.
The phosphonate group may be a phosphonate prodrug moiety. The prodrug moiety may be sensitive to hydrolysis, such as, but not limited to a pivaloyloxymethyl carbonate (POC) or POM group. Alternatively, the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group.
Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem. 37:498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) /. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-or para-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenal may generate the phenolic compound through the action of enzymes, e.g. esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to generate the phosphoric acid and the quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al (1992) J. Chem. Soc. Perkin Trans. 12345; Brook et al WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier et al WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al (1993) Antiviral Res., 22: 155-174; Benzaria et al (1996) /. Med. Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion et al, US Patent No. 6312662).
"Protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of a protecting group varies widely. One function of a protecting group is to serve as intermediates in the synthesis of the parental drug substance. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See: "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound
alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.
Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodmgs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
Any reference to any of the compounds of the invention also includes a reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4+ (wherein X is Q-C4 alkyl). Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfarnic acids. Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NX/ (wherein X is independently selected from H or a Ci-C4 alkyl group).
For therapeutic use, salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable
compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
"Alky!" is Q-Cig hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CHs), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CHs)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3.
"Alkenyl" is C2-Cig hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp2 double bond. Examples include, but are not limited to: ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2 CH2CH2CH2CH=CH2)
"Alkynyl" is C2-Cig hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to: acetylenic (-C=CH) and propargyl (-CH2G=CH),
"Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to: methylene (-CH2-) 1,2-ethyI (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.
"Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Typical
alkenyleue radicals include, but are not limited to: 1,2-ethylene (-CH=CH-).
"Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but are not limited to: acetylene (-G=C-), propargyl (-CH2C=C-), and 4-pentynyl (-CH2CH2CH2GCH-).
"Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
" Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like. The arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
"Substituted alkyl", "substituted aryl", and "substituted arylalkyl" mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a substituent. Typical substituents include, but are not limited to, -X, -R, -O-, -OR, -SR, -S", -NR2, -NR3, =NR, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2) =N2, -N3, NC(=0)R, -C(=O)R, -C(=O)NRR -S(=O)2O-, -S(=O)2OH, -S(=O)2R, -OS(=O)2OR, -S(=0)2NR, -S(=0)R, -OP(=O)O2RR,-P(=O)O2RR-P(=O)(O")2, -P(=O)(OH)2, -C(=0)R, -C(=0)X, -C(S)R, -C(0)OR, -C(O)O-, -C(S)OR, -C(O)SR, -C(S)SR, -C(O)NRR, -C(S)NRR, -C(NR)NRR, where each X is independently a halogen: F, Cl, Br, or I; and each R is independently -H, alkyl, aryl, heterocycle, protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may also be similarly substituted.
"Heterocycle" as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3,4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and /. Am. Chem. Soc. (1960) 82:5566.
Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyL, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofiiranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinoLinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-l,2,5-thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, IH-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, |3-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.
One embodiment of the bis-tetrahydrofuranyl group is:



By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3,4, 5, or 6 of a pyridine, position 3, 4,5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3,5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
By way of example and not limitation, nitrogen bonded heterocycles are bonded at
position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or p-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
"Carbocycle" means a saturated, unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g. arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
"Linker" or "link" means a chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches a phosphonate group to a drug. Linkers include portions of substituents A1 and A3 enumerated in Formula I, or substituents AI and As enumerated in Formula n, which include moieties such as: repeating units of alkyloxy (e.g. polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, Jeffamine™); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.
The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
"Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1, D and L, or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
HIV Protease Inhibitor Compounds
The compounds of the invention include those with HTV protease inhibitory activity. In particular, the compounds include HTV protease inhibitors. The compounds of the inventions bear a phosphonate group, which may be a prodrug moiety.
In various embodiments of the invention one identifies compounds that may fall within the generic scope of the documents cited under the definition of the terms ILPPI (Indinavir-like phosphonate protease inhibitors, Formula I); AMLPPI (Amprenavir-like phosphonate protease inhibitors, Formula II); KNILPPI (KNI-like phosphonate protease inhibitors, Formula III); RLPPI (Ritonavir-like phosphonate protease inhibitors, Formula IV); LLPPI (Lopinavir-like phosphonate protease inhibitors, Formula IV); NLPPI (Nelfinavir-like phosphonate protease inhibitors, Formula V); SLPPI (Saquinavir-like phosphonate protease inhibitors, Formula V); ATLPPI (Atanzavir-like phosphonate protease inhibitors, Formula VI); TLPPI (Tipranavir-like phosphonate protease inhibitors, Formula VET); and CCLPPI (Cyclic carbonyl-like phosphonate protease inhibitors, Formula Vllla-d) all of which comprise a phosphonate group, e.g. a phosphonate diester, phosphonamidate-ester prodrug, or a phosphondiamidate-ester (Jiang et al, US 2002/0173490 Al).
Whenever a compound described herein is substituted with more than one of the same
designated group, e.g., "R1" or "R6a", then it will be understood that the groups may be the
same or different, i.e., each group is independently selected. Wavy lines indicate the site of
covalent bond attachments to the adjoining groups, moieties, or atoms. *
Compounds of the invention are set forth in the schemes, examples, descriptions and claims below and include the invention includes compounds having Formulas I, H, ELI, IV, V, VI, VII and Vffla-d:


where a wavy line indicates the other structural moieties of the compounds.
Formula I compounds have a 3-hydroxy-5-amino-pentamide core. Formula II compounds have a 2-hydroxy-l, 3-amino-propylamide or 2-hydroxy-l,3-arnino-propylaminosulfone core. Formula m compounds have a 2-hydroxy-3-amino-propylamide core. Formula IV compounds have a 2-hydroxy-4-amino-butylamine core. Formula V compounds have a acylated 1,3-diaminopropane core. Formula VI compounds have a 2-hydroxy-3-diaza-propylamide core. Formula Vn compounds have a sulfonamide 5,6-dihydro-4-hydroxy-2-pyrone core. Formula VTHa-d compounds have a six or seven-membered ring, and a cyclic carbonyl, sulfhydryl, sulfoxide or sulfone core, where Y1 is oxygen, sulfur, or substituted nitrogen and m2 is 0, 1 or 2.
Formulas I, n, IE, IV, V, VI, Vn and VlHa-d are substituted with one or more covalently attached groups, including at least one phosphonate group. Formulas I, n, ffl, IV, V, VI, VH and VEHa-d are substituted with one or more covalently attached A° groups, including simultaneous substitutions at any or all A°. A° is A1, A2 or W3. Compounds of Formulas I, H, m, IV, V, VI, VH and VIHa-d include at least one A1.
Y1 is independently O, S, N(RX), N(O)(RX), N(ORX), N(O)(ORX), or N(N(RX)( Rx)). Y2 is independently a bond, O, N(RX), N(O)(RX), N(ORX), N(O)(ORX), N(N(RX)( Rx)),
-S(0)M2-, or -S(O)M2-S(O)M2-.
Rx is independently H, W3, a protecting group, or the formula:
wherein:
Mla, Mlc, and Mid are independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and Ry is independently H, W3, R2 or a protecting group. Alternatively, Rx is a group of the formula:
wherein:
mla, mlb, mlc, mid and mle are independently 0 or 1;
m!2c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Ry is H, W3, R2 or a protecting group; provided that:
if mla, m!2c, and mid are 0, then mlb, mlc and mle are 0;
if mla and m!2c are 0 and mid is not 0, then mlb and mlc are 0;
if mla and mid are 0 and m!2c is not 0, then mlb and at least one of mlc and mle areO;
if mla is 0 and m!2c and mid are not 0, then mlb is 0;
if m!2c and mid are 0 and mla is not 0, then at least two of mlb, mlc and mle are 0;
if m!2c is 0 and mla and mid are not 0, then at least one of mlb and mlc are 0; and
if mid is 0 and mla and m!2c are not 0, then at least one of mlc and mle are 0.
R1 is independently H or alkyl of 1 to 18 carbon atoms.
R2 is independently H, R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups. Alternatively, taken together at a carbon atom, two R2 groups form a ring, i.e. a spiro carbon. The ring may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The ring may be substituted with 0 to 3 R3 groups.
R3 is R3a, R3b, R3c or R3d, provided that when R3 is bound to a heteroatom, then R3 is R3c or R3d.
R3a is F, Cl, Br, I, -CN, N3 or -NO2.
R3b is Y1.
R3c is -Rx, -N(RX)(RX), -SRX, -S(O)RX, -S(O)2RX, -S(O)(ORX), -S(O)2(ORX), -OC(Y1)RX, -OCCY^OR", -OC(Y1XN(RXXRX)), -SCCY^R", -SC(Y1)ORX, -SCCY'XNCR'XR*)), -NCR^CXY^R*, -N(RX)C(Y1)ORX, or -NCR^CCY^NCR^CR')).
R3d is -CXY^R", -CCY^OR" or -CCY^WXR*)).
R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms.
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups.
R5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups.
W3 is W4 or W5.
W4 is R5, -CCY^R3, -C(Yl)W5, -S02R5, or -SO2W5.
W5 is carbocycle or heterocycle wherein W° is independently substituted with 0 to 3 R2 groups.
W3a is W42 or W5a.
W43 is R5a, -CCY^R58, -CCY^W5', -S02R5a, or -SO2W5a.
W°a is a multivalent substituted carbocycle or heterocycle wherein W a is independently substituted with 0 to 3 R2 groups.
W6 is W3 independently substituted with 1, 2, or 3 A3 groups.
M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
W5 and W5a carbocycles and W5 and W5a heterocycles may be independently substituted with 0 to 3 R2 groups. W5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. W may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms. The W5 rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or di-unsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms.
A W5 or W5a heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected fromN, O, P, and S). W5 and W5a heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). W5 and W5a heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system. The W5 heterocycle may be bonded to Y2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.
W5 and W5a heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl. W5 also includes, but is not limited to, examples such as:
W5 and W5a carbocycles and heterocycles may be independently substituted with 0 to 3 R2 groups, as defined above. For example, substituted W5 carbocycles include:
where W3a is a carbocycle or a heterocycle and W3a is independently substituted with 0 or 1 R" groups.
Embodiments of A1 also include:



where n is an integer from 1 to 18.
Embodiments of A3 include where M2 is 0, such as:

and where M12b is 1, Y1 is oxygen, and Y2b is oxygen (O) or nitrogen (N(RX)) such as:
An embodiment of A3 includes:

where Y2c is O, N(Ry) or S. For example, R1 may be H and n may be 1.
Another embodiment of A includes:
M12b where W5 is a carbocycle such as phenyl or substituted phenyl. Such embodiments include:

where Y2b is O or N(RX); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; and the phenyl carbocycle is substituted with 0 to 3 R2 groups. Such embodiments of A3 include phenyl phosphonamidate amino acid, e.g. alanate esters and phenyl phosphonate-lactate esters:
The chiral carbon of the amino acid and lactate moieties may be either the R or S configuration or the racemic mixture.
Embodiments of Rx include esters, carbamates, carbonates, thioesters, amides, thioamides, and urea groups:
Embodiments of A include where
Alternatively, A2 is phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl or substituted pyridyl.
Exemplary embodiments of Formula I compounds include, but are not limited to, structures:

Exemplary embodiments of Formula Vllta compounds include structures:


Exemplary embodiments of Formula VITIb compounds include structures:

N
Exemplary embodiments of Formula VIIIc compounds include structures:

Exemplary embodiments of Formula Vllld compounds include structures:
where A1 denotes a covalent attachment site of a phosphonate group.
A Cellular Accumulation Embodiment
Another embodiment of the invention is directed toward an HTV protease inhibitor compound capable of accumulating in human PBMCs. Accumulation in human PBMCs is described in the examples herein. Typically, the compounds of this embodiment further comprise a phosponate or phosphonate prodrug. More typically, the phosphonate or phosphonate prodrug has the structure A3 as described herein. Each of the preferred embodiments of A3 described herein is a preferred embodiment of A3 in the present embodiment.
Optionally, the compounds of this embodiment demonstrate improved intracellular half-life of the compounds or intracellular metabolites of the compounds in human PBMCs when compared to analogs of the compounds not having the phosphonate or phosphonate prodrug. Typically, the half-life is improved by at least about 50%, more typically at least in the range 50-100%, still more typically at least about 100%, more typically yet greater than about 100%.
In a preferred embodiment, the intracellular half-life of a metabolite of the compound in human PBMCs is improved when compared to an analog of the compound not having the phosphonate or phosphonate prodrug. In such embodiments, the metabolite is typically generated intracellularly, more typically, it is generated within human PBMCs. Still more typically, the metabolite is a product of the cleavage of a phosphonate prodrug within human PBMCs. More typically yet, the phosphonate prodrug is cleaved to form a metabolite having at least one negative charge at physiological pH. Most typically, the phosphonate prodrug is enzymatically cleaved within human PBMCs to form a phosphonate having at least one active hydrogen atom of the form P-OH.
Not withstanding other disclosure herein which describes the role or presents of phosphonates in the compounds of the invention, in another embodiment of the invention A

,3a
is A which is of the formula:

In this embodiment of the invention, any A3 group may be A3a. In another aspect of the invention, A3 is of the formula:
M12a is other than 0 and at least one phosphonate group present in the compound is not bonded directly to W3. More typically, the phosphonate is not bonded directly to W5. In such an embodiment, the phosphorous atom of the phosphonate is not bonded directly to a carbon atom of a ring.
In another aspect of the invention an Amprenavir like phosphonate protease inhibitor, as described above in the description and below in the claims, contains an A3 group of the formula:
M12a is other than 0 and at least one phosphonate group present in the compound is not bonded directly to W3. More typically, the phosphonate is not bonded directly to W5. In
such an embodiment, the phosphorous atom of the phosphonate is not bonded directly to a carbon atom of a ring.
One embodiment of Amprenavir like phosphonate protease inhibitors as described above in the description and below in the claims excludes compounds of the formulas:
In another aspect of the invention, A3 is of the formula:


M12a is 0 and at least one phosphonate group present in the compound is bonded directly to W3. More typically, the phosphonate is bonded directly to W5. In such an embodiment, the phosphorous atom of the phosphonate is bonded directly to a carbon atom of a ring.
In another aspect of the invention an Amprenavir like phosphonate protease inhibitor, as described above in the description and below in the claims, contains an A3 group of the formula:

VR2 R
M12a is 0 and at least one phosphonate group present in the compound is bonded directly to W3. More typically, the phosphonate is bonded directly to W5. In such an embodiment, the phosphorous atom of the phosphonate is bonded directly to a carbon atom of a ring.
One embodiment of Amprenavir like phosphonate protease inhibitors as described above in the description and below in the claims is directed to compounds of the formulas:

Exemplary Enumerated Compounds.
By way of example and not limitation, embodiments of the invention are named below in tabular format (Table 100). These embodiments are of the general formula "MBF':
O
Pd1 MBF
Each embodiment of MBF is depicted as a substituted nucleus (Sc) hi which the nucleus is designated by a number and each substituent is designated in order by letter or number. Tables 1.1 to 1.5 are a schedule of nuclei used in forming the embodiments of Table 100. Each nucleus (Sc) is given a number designation from Tables 1.1 to 1.5, and this designation appears first in each embodiment name. Similarly, Tables 10.1 to 10.19 and 20.1 to 20.36 list the selected linking groups (Lg) and prodrug (Pd1 and Pd2) substituents, again by letter or number designation, respectively.
Accordingly, each named embodiment of Table 100 is depicted by a number designating the nucleus from Table 1.1-1.5, followed by a letter designating the Unking group (Lg) from Table 10.1-10.19, and two numbers designating the two prodrug groups (Pd1 and Pd2) from Table 20. 1-20.36. In graphical tabular form, each embodiment of Table 100 appears as a name having the syntax:
Sc.Lg.Pd'.Pd2
Thus, ignoring stereochemistry, structure 10, Scheme 2, Scheme Section A, is represented by 12.AH.247.247.
Each Sc group is shown having a tilda The tilda is the point of covalent attachment of Sc to Lg. Q1 and Q2 of the linking groups (Lg), it should be understood, do not represent groups or atoms but are simply connectivity designations. Q1 is the site of the covalent bond to the nucleus (Sc) and Q2 is the site of the covalent bond to the phosphorous atom of formula MBF. Each prodrug group (Pd1 and Pd2) are covalently bonded to the phosphorous atom of MBF at the tilda symbol ("~"). Some embodiments of Tables 10.1-10.19 and 20.1-20.36 may be designated as a combination of letters and numbers (Table 10.1-10.19) or number and letter (Table 20.1-20.36). For example there are Table 10 entries for BJ1 and BJ2. In any event, entries of Table 10.1-10.19 always begin with a letter and those of Table 20.1-20.36 always begin with a number. When a nucleus (Sc) is shown enclosed within square brackets ("[]") and a covalent bond extends outside the brackets, the point of covalent attachment of Sc to Lg may be at any substitutable site on SC. Selection of the point of attachment is described herein. By way of example and not limitation, the point of attachment is selected from those depicted in the schemes and examples.
l.D.229.154; l.D.229.157; l.D.229.166; l.D.229.169; l.D.229.172; l.D.229.175; l.D.229.240; l.D.229.244; l.D.230.228; l.D.230.229; l.D.230.230; l.D.230.231; l.D.230.236; l.D.230.237; l.D.230.238; l.D.230.239; l.D.230.154; l.D.230.157; l.D.230.166; l.D.230.169; l.D.230.172; l.D.230.175; l.D.230.240; l.D.230.244; l.D.231.228; l.D.231.229; l.D.231.230; l.D.231.231; l.D.231.236; l.D.231.237; l.D.231.238; l.D.231.239; l.D.231.154; l.D.231.157; l.D.231.166; l.D.231.169; l.D.231.172; l.D.231.175; l.D.231.240; l.D.231.244; l.D.236.228; l.D.236.229; l.D.236.230; l.D.236.231; l.D.236.236; l.D.236.237; l.D.236.238; l.D.236.239; l.D.236.154; l.D.236.157; l.D.236.166; l.D.236.169; l.D.236.172; l.D.236.175; l.D.236.240; l.D.236.244; l.D.237.228; l.D.237.229; l.D.237.230; l.D.237.231; l.D.237.236; l.D.237.237; l.D.237.238; l.D.237.239; l.D.237.154; l.D.237.157; l.D.237.166; l.D.237.169; l.D.237.172; l.D.237.175; l.D.237.240; l.D.237.244; l.D.238.228; l.D.238.229; l.D.238.230; l.D.238.231; l.D.238.236; l.D.238.237; l.D.238.238; l.D.238.239; l.D.238.154; l.D.238.157; l.D.238.166; l.D.238.169; l.D.238.172; l.D.238.175; l.D.238.240; l.D.238.244; l.D.239.228; l.D.239.229; l.D.239.230; l.D.239.231; l.D.239.236; l.D.239.237; l.D.239.238; l.D.239.239; l.D.239.154; l.D.239.157; l.D.239.166; l.D.239.169; l.D.239.172; l.D.239.175; l.D.239.240; l.D.239.244; l.D.154.228; l.D.154.229; l.D.154.230; l.D.154.231; l.D.154.236; l.D.154.237; l.D.154.238; l.D.154.239; l.D.154.154; l.D.154.157; l.D.154.166; l.D.154.169; l.D.154.172; l.D.154.175; l.D.154.240; l.D.154.244; l.D.157.228; l.D.157.229; l.D.157.230; l.D.157.231; l.D.157.236; l.D.157.237; l.D.157.238; l.D.157.239; l.D.157.154; l.D.157.157; l.D.157.166; l.D.157.169; l.D.157.172; l.D.157.175; l.D.157.240; l.D.157.244; l.D.166.228; l.D.166.229; l.D.166.230; l.D.166.231; l.D.166.236; l.D.166.237; l.D.166.238; l.D.166.239; l.D.166.154; l.D.166.157; l.D.166.166; l.D.166.169; l.D.166.172; l.D.166.175; l.D.166.240; l.D.166.244; l.D.169.228; l.D.169.229; l.D.169.230; l.D.169.231; l.D.169.236; l.D.169.237; l.D.169.238; l.D.169.239; l.D.169.154; l.D.169.157; l.D.169.166; l.D.169.169; l.D.169.172; l.D.169.175; l.D.169.240; l.D.169.244; l.D.172.228; l.D.172.229; l.D.172.230; l.D.172.231; l.D.172.236; l.D.172.237; l.D.172.238; l.D.172.239; l.D.172.154; l.D.172.157; l.D.172.166; l.D.172.169; l.D.172.172; l.D.172.175; l.D.172.240; l.D.172.244; l.D.175.228; l.D.175.229; l.D.175.230; l.D.175.231; l.D.175.236; l.D.175.237; l.D.175.238; l.D.175.239; l.D.175.154; l.D.175.157; l.D.175.166; l.D.175.169; l.D.175.172; l.D.175.175; l.D.175.240; l.D.175.244; l.D.240.228; l.D.240.229; l.D.240.230; l.D.240.231; l.D.240.236; l.D.240.237; l.D.240.238; l.D.240.239; l.D.240.154; l.D.240.157; l.D.240.166; l.D.240.169; l.D.240.172; l.D.240.175; l.D.240.240; l.D.240.244; l.D.244.228; l.D.244.229; l.D.244.230; l.D.244.231; l.D.244.236; l.D.244.237; l.D.244.238; l.D.244.239; l.D.244.154; l.D.244.157; l.D.244.166; l.D.244.169; l.D.244.172; l.D.244.175; l.D.244.240; l.D.244.244;
Prodrugs of l.E
l.E.228.228; l.E.228.229; l.E.228.230; l.E.228.231; l.E.228.236; l.E.228.237; l.E.228.238; l.E.228.239; l.E.228.154; l.E.228.157; l.E.228.166; l.E.228.169; l.E.228.172; l.E.228.175; l.E.228.240; l.E.228.244; l.E.229.228; l.E.229.229; l.E.229.230; l.E.229.231; l.E.229.236; l.E.229.237; l.E.229.238; l.E.229.239; l.E.229.154; l.E.229.157; l.E.229.166; l.E.229.169; l.E.229.172; l.E.229.175; l.E.229.240; l.E.229.244; l.E.230.228; l.E.230.229;
l.E.230.230; l.E.230.231; l.E.230.236; l.E.230.237; l.E.230.238; l.E.230.239; l.E.230.154; l.E.230.157; l.E.230.166; l.E.230.169; l.E.230.172; l.E.230.175; l.E.230.240; l.E.230.244; l.E.231.228; l.E.231.229; l.E.231.230; l.E.231.231; l.E.231.236; l.E.231.237; l.E.231.238; l.E.231.239; l.E.231.154; l.E.231.157; l.E.231.166; l.E.231.169; l.E.231.172; l.E.231.175; l.E.231.240; l.E.231.244; l.E.236.228; l.E.236.229; l.E.236.230; l.E.236.231; l.E.236.236; l.E.236.237; l.E.236.238; l.E.236.239; l.E.236.154; l.E.236.157; l.E.236.166; l.E.236.169; l.E.236.172; l.E.236.175; l.E.236.240; l.E.236.244; l.E.237.228; l.E.237.229; l.E.237.230; l.E.237.231; l.E.237.236; l.E.237.237; l.E.237.238; l.E.237.239; l.E.237.154; l.E.237.157; l.E.237.166; l.E.237.169; l.E.237.172; l.E.237.175; l.E.237.240; l.E.237.244; l.E.238.228; l.E.238.229; l.E.238.230; l.E.238.231; l.E.238.236; l.E.238.237; l.E.238.238; l.E.238.239; l.E.238.154; l.E.238.157; l.E.238.166; l.E.238.169; l.E.238.172; l.E.238.175; l.E.238.240; l.E.238.244; l.E.239.228; l.E.239.229; l.E.239.230; l.E.239.231; l.E.239.236; l.E.239.237; l.E.239.238; l.E.239.239; l.E.239.154; l.E.239.157; l.E.239.166; l.E.239.169; l.E.239.172; l.E.239.175; l.E.239.240; l.E.239.244; l.E.154.228; l.E.154.229; l.E.154.230; l.E.154.231; l.E.154.236; l.E.154.237; l.E.154.238; l.E.154.239; l.E.154.154; l.E.154.157; l.E.154.166; l.E.154.169; l.E.154.172; l.E.154.175; l.E.154.240; l.E.154.244; l.E.157.228; l.E.157.229; l.E.157.230; l.E.157.231; l.E.157.236; l.E.157.237; l.E.157.238; l.E.157.239; l.E.157.154; l.E.157.157; l.E.157.166; l.E.157.169; l.E.157.172; l.E.157.175; l.E.157.240; l.E.157.244; l.E.166.228; l.E.166.229; l.E.166.230; l.E.166.231; l.E.166.236; l.E.166.237; l.E.166.238; l.E.166.239; l.E.166.154; l.E.166.157; l.E.166.166; l.E.166.169; l.E.166.172; l.E.166.175; l.E.166.240; l.E.166.244; l.E.169.228; l.E.169.229; l.E.169.230; l.E.169.231; l.E.169.236; l.E.169.237; l.E.169.238; l.E.169.239; l.E.169.154; l.E.169.157; l.E.169.166; l.E.169.169; l.E.169.172; l.E.169.175; l.E.169.240; l.E.169.244; l.E.172.228; l.E.172.229; l.E.172.230; l.E.172.231; l.E.172.236; l.E.172.237; l.E.172.238; l.E.172.239; l.E.172.154; l.E.172.157; l.E.172.166; l.E.172.169; l.E.172.172; l.E.172.175; l.E.172.240; l.E.172.244; l.E.175.228; l.E.175.229; l.E.175.230; l.E.175.231; l.E.175.236; l.E.175.237; l.E.175.238; l.E.175.239; l.E.175.154; l.E.175.157; l.E.175.166; l.E.175.169; l.E.175.172; l.E.175.175; l.E.175.240; l.E.175.244; l.E.240.228; i:E.240.229; l.E.240.230; l.E.240.231; l.E.240.236; l.E.240.237; l.E.240.238; l.E.240.239; l.E.240.154; l.E.240.157; l.E.240.166; l.E.240.169; l.E.240.172; l.E.240.175; l.E.240.240; l.E.240.244; l.E.244.228; l.E.244.229; l.E.244.230; l.E.244.231; l.E.244.236; l.E.244.237; l.E.244.238; l.E.244.239; l.E.244.154; l.E.244.157; l.E.244.166; l.E.244.169; l.E.244.172; l.E.244.175; l.E.244.240; l.E.244.244;
Prodrugs of l.G
l.G.228.228; l.G.228.229; l.G.228.230; l.G.228.231; l.G.228.236; l.G.228.237; l.G.228.238; l.G.228.239; l.G.228.154; l.G.228.157; l.G.228.166; l.G.228.169; l.G.228.172; l.G.228.175; l.G.228.240; l.G.228.244; l.G.229.228; l.G.229.229; l.G.229.230; l.G.229.231; l.G.229.236; l.G.229.237; l.G.229.238; l.G.229.239; l.G.229.154; l.G.229.157; l.G.229.166; l.G.229.169; l.G.229.172; l.G.229.175; l.G.229.240; l.G.229.244; l.G.230.228; l.G.230.229; l.G.230.230; l.G.230.231; l.G.230.236; l.G.230.237; l.G.230.238; l.G.230.239; l.G.230.154; l.G.230.157; l.G.230.166; l.G.230.169; l.G.230.172; l.G.230.175; l.G.230.240; l.G.230.244; l.G.231.228; l.G.231.229; l.G.231.230; l.G.231.231; l.G.231.236; l.G.231.237; l.G.231.238; l.G.231.239; l.G.231.154; l.G.231.157; l.G.231.166; l.G.231.169; l.G.231.172; l.G.231.175; l.G.231.240; l.G.231.244; l.G.236.228; l.G.236.229; l.G.236.230; l.G.236.231; l.G.236.236; l.G.236.237; l.G.236.238; l.G.236.239;
l.G.236.154; l.G.236.157; l.G.236.166; l.G.236.169; l.G.236.172; l.G.236.175; l.G.236.240; l.G.236.244; l.G.237.228; l.G.237.229; l.G.237.230; l.G.237.231; l.G.237.236; l.G.237.237; l.G.237.238; l.G.237.239; l.G.237.154; l.G.237.157; l.G.237.166; l.G.237.169; l.G.237.172; l.G.237.175; l.G.237.240; l.G.237.244; l.G.238.228; l.G.238.229; l.G.238.230; l.G.238.231; l.G.238.236; l.G.238.237; l.G.238.238; l.G.238.239; l.G.238.154; l.G.238.157; l.G.238.166; l.G.238.169; l.G.238.172; l.G.238.175; l.G.238.240; l.G.238.244; l.G.239.228; l.G.239.229; l.G.239.230; l.G.239.231; l.G.239.236; l.G.239.237; l.G.239.238; l.G.239.239; l.G.239.154; l.G.239.157; l.G.239.166; i.G.239.169; l.G.239.172; l.G.239.175; l.G.239.240; l.G.239.244; l.G.154.228; l.G.154.229; l.G.154.230; l.G.154.231; l.G.154.236; l.G.154.237; l.G.154.238; l.G.154.239; l.G.154.154; l.G.154.157; l.G.154.166; l.G.154.169; l.G.154.172; l.G.154.175; l.G.154.240; l.G.154.244; l.G.157.228; l.G.157.229; l.G.157.230; l.G.157.231; l.G.157,236; l.G.157.237; l.G.157.238; l.G.157.239; l.G.157.154; l.G.157.157; l.G.157.166; l.G.157.169; l.G.157.172; l.G.157.175; l.G.157.240; l.G.157.244; l.G.166.228; l.G.166.229; l.G.166.230; l.G.166.231; l.G.166.236; l.G.166.237; l.G.166.238; l.G.166.239; l.G.166.154; l.G.166.157; l.G.166.166; l.G.166.169; l.G.166.172; l.G.166.175; l.G.166.240; l.G.166.244; l.G.169.228; l.G.169.229; l.G.169.230; l.G.169.231; l.G.169.236; l.G.169.237; l.G.169.238; l.G.169.239; l.G.169.154; l.G.169.157; l.G.169.166; l.G.169.169; l.G.169.172; l.G.169.175; l.G.169.240; l.G.169.244; l.G.172.228; l.G.172.229; l.G.172.230; l.G.172.231; l.G.172.236; l.G.172.237; l.G.172.238; l.G.172.239; l.G.172.154; l.G.172.157; l.G.172.166; l.G.172.169; l.G.172.172; l.G.172.175; l.G.172.240; l.G.172.244; l.G.175.228; l.G.175.229; l.G.175.230; l.G.175.231; l.G.175.236; l.G.175.237; l.G.175.238; l.G.175.239; l.G.175.154; l.G.175.157; l.G.175.166; l.G.175.169; l.G.175.172; l.G.175.175; l.G.175.240; l.G.175.244; l.G.240.228; l.G.240.229; l.G.240.230; l.G.240.231; l.G.240.236; l.G.240.237; l.G.240.238; l.G.240.239; l.G.240.154; l.G.240.157; l.G.240.166; l.G.240.169; l.G.240.172; l.G.240.175; l.G.240.240; l.G.240.244; l.G:244.228; l.G.244.229; l.G.244.230; l.G.244.231; l.G.244.236; l.G.244.237; l.G.244.238; l.G.244.239; l.G.244.154; l.G.244.157; l.G.244.166; l.G.244.169; l.G.244.172; l.G.244.175; l.G.244.240; l.G.244.244;
Prcxirugs of I.I
1.1.228.228; 1.1.228.229; 1.1.228.230; 1.1.228.231; 1.1.228.236; 1.1.228.237; 1.1.228.238; 1.1.228.239; 1.1.228.154; 1.1.228.157; 1.1.228.166; 1.1.228.169; 1.L228.172; 1.1.228.175; 1.1.228.240; 1.1.228.244; 1.1.229.228; 1.1.229.229; 1.1.229.230; 1.1.229.231; 1.1.229.236; 1.1.229.237; 1.1.229.238; 1.1.229.239; 1.L229.154; 1.1.229.157; 1.1.229.166; 1.1.229.169; 1.1.229.172; 1.1.229.175; 1.1.229.240; 1.1.229.244; 1.1.230.228; 1.1.230.229; 1.1.230.230; 1.1.230.231; 1.1.230.236; 1.1.230.237; 1.1.230.238; 1.1.230.239; 1.1.230.154; 1.1.230.157; 1.1.230.166; 1.1.230.169; 1.1230.172; 1.1.230.175; 1.1.230.240; 1.1.230.244; 1.1.231.228; 1.1.231.229; 1.1.231.230; 1.1.231.231; 1.1.231.236; 1.1.231.237; 1.1.231.238; 1.1.231.239; 1.1.231.154; 1.1.231.157; 1.1.231.166; 1.1.231.169; 1.1.231.172; 1.1.231.175; 1.1.231.240; 1.1.231.244; 1.1.236.228; 1.1.236.229; 1.1.236.230; 1.1.236.231; 1.1.236.236; 1.1.236.237; 1.1.236.238; 1.1.236.239; 1.1.236.154; 1.1.236.157; 1.1.236.166; 1.1.236.169; 1.1.236.172; 1.1.236.175; 1.1.236.240; 1.1.236.244; 1.1.237.228; 1.1.237.229; 1.1.237.230; 1.1.237.231; 1.1.237.236; 1.1.237.237; 1.1.237.238; 1.1.237.239; 1.1.237.154; 1.1.237.157; 1.1.237.166;
1.1.237.169; 1.1.237.172; 1.1.237.175; 1.1.237.240; 1.1.237.244; 1.1.238.228; 1.1.238.229; 1.1.238.230; 1.1.238.231; 1.1.238.236; 1.1.238.237; 1.1.238.238; 1.1.238.239; 1.1.238.154; 1.1.238.157; 1.1.238.166; 1.1.238.169; 1.1.238.172; 1.1.238.175; 1.1.238.240; 1.1.238.244; 1.1.239.228; 1.1.239.229; 1.1.239.230; 1.1.239.231; 1.1.239.236; 1.1.239.237; 1.1.239.238; 1.1.239.239; 1.1.239.154; 1.1.239.157; 1.1.239.166; 1.1.239.169; 1.1.239.172; 1.1.239.175; 1.1.239.240; 1.1.239.244; 1.1.154.228; 1.1.154.229; 1.1.154.230; 1.1.154.231; 1.1.154.236; 1.1.154.237; 1.1.154.238; 1.1.154.239; 1.1.154.154; 1.1.154.157; 1.1.154.166; 1.1.154.169; 1.1.154.172; 1.1.154.175; 1.1.154.240; 1.1.154.244; 1.1.157.228; 1.1.157.229; 1.1.157.230; 1.1.157.231; 1.1.157.236; 1.1.157.237; 1.1.157.238; 1.1.157.239; 1.1.157.154; 1.1.157.157; 1.1.157.166; 1.1.157.169; 1.1.157.172; 1.1.157.175; 1.1.157.240; 1.1.157.244; 1.1.166.228; 1.1.166.229; 1.1.166.230; 1.1.166.231; 1.1.166.236; 1.1.166.237; 1.1.166.238; 1.1.166.239; 1.1.166.154; 1.1.166.157; 1.1.166.166; 1.1.166.169; 1.1.166.172; 1.1.166.175; 1.1.166.240; 1.1.166.244; 1.1.169.228; 1.1.169.229; 1.1.169.230; 1.1.169.231; 1.1.169.236; 1.1.169.237; 1.1.169.238; 1.1.169.239; 1.1.169.154; 1.1.169.157; 1.1.169.166; 1.1.169.169; 1.1.169.172; 1.1.169.175; 1.1.169.240; 1.1.169.244; 1.1.172.228; 1.1.172.229; 1.1.172.230; 1.1.172.231; 1.1.172.236; 1.1.172.237; 1.1.172.238; 1.1.172.239; 1.1.172.154; 1.1.172.157; 1.1.172.166; 1.1.172.169; 1.1.172.172; 1.1.172.175; 1.1.172.240; 1.1172.244; 1.1.175.228; 1.1.175.229; 1.1.175.230; 1.1.175.231; 1.1.175.236; 1.1.175.237; 1.1.175.238; 1.1.175.239; 1.1.175.154; 1.1.175.157; 1.1.175.166; 1.1.175.169; 1.1.175.172; 1.1.175.175; 1.1.175.240; 1.1.175.244; 1.1.240.228; 1.1.240.229; 1.1.240.230; 1.1.240.231; 1.1.240.236; 1.1.240.237; 1.1.240.238; 1.1.240.239; 1.1.240.154; 1.1.240.157; 1.1.240,166; 1.1.240.169; 1.1.240.172; 1.1.240.175; 1.1.240.240; 1.1.240.244; 1.1.244.228; 1.1.244.229; 1.1.244.230; 1.1.244.231; 1.1.244.236; 1.1.244.237; 1.1.244.238; 1.1.244.239; 1.1.244.154; 1.1.244.157; 1.1.244.166; 1.1.244.169; 1.1.244.172; 1.1.244.175; 1.1.244.240; 1.1.244.244;
Prodrugs of l.T
l.J.228.228; l.J.228.229; l.J.228.230; l.J.228.231; l.J.228.236; l.J.228.237; l.J.228.238; l.J.228.239; l.J.228.154; l.J.228.157; l.J.228.166; l.J.228.169; l.J.228.172; l.J.228.175; l.J.228.240; l.J.228.244; 1J.229.228; l.J.229.229; l.J.229.230; l.J.229.231; 1J.229.236; 1J.229.237; l.J.229.238; l.J.229.239; l.J.229.154; l.J.229.157; l.J.229.166; l.J.229.169; l.J.229.172; l.J.229.175; l.J.229.240; l.J.229.244; l.J.230.228; l.J.230.229; l.J.230.230; l.J.230.231; l.J.230.236; l.J.230.237; l.J.230.238; l.J.230.239; l.J.230.154; l.J.230.157; l.J.230.166; l.J.230.169; l.J.230.172; l.J.230.175; l.J.230.240; l.J.230.244; l.J.231.228; l.J.231.229; l.J.231.230; l.J.231.231; l.J.231.236; l.J.231.237; l.J.231.238; l.J.231.239; l.J.231.154; l.J.231.157; l.J.231.166; l.J.231.169; l.J.231.172; l.J.231.175; l.J.231.240; l.J.231.244; l.J.236.228; l.J.236.229; l.J.236.230; l.J.236.231; 1J.236.236; l.J.236.237; l.J.236.238; l.J.236.239; l.J.236.154; l.J.236.157; l.J.236.166; l.J.236.169; l.J.236.172; l.J.236.175; l.J.236.240; l.J.236.244; l.J.237.228; l.J.237.229; l.J.237.230; l.J.237.231; l.J.237.236; l.J.237.237; l.J.237.238; l.J.237.239; l.J.237.154; l.J.237.157; l.J.237.166; l.J.237.169; l.J.237.172; l.J.237.175; l.J.237.240; l.J.237.244; l.J.238.228; l.J.238.229; l.J.238.230; l.J.238.231; l.J.238.236; l.J.238.237; l.J.238.238; l.J.238.239; l.J.238.154; l.J.238.157; l.J.238.166; l.J.238.169; l.J.238.172; 1J.238.175; l.J.238.240; l.J.238.244; l.J.239.228; l.J.239.229; l.J.239.230; l.J.239.231; l.J.239.236; l.J.239.237; l.J.239.238; l.J.239.239; l.J.239.154; l.J.239.157; l.J.239.166; l.J.239.169; l.J.239.172; l.J.239.175; l.J.239.240; l.J.239.244; l.J.154.228; l.J.154.229; l.J.154.230; l.J.154.231; l.J.154.236; l.J.154.237; l.J.154.238; 1J.154.239; l.J.154.154; l.J.154.157; l.J.154.166; l.J.154.169;
l.J.154.172; l.J.154.175; l.J.154.240; l.J.154.244; l.J.157.228; l.J.157.229; l.J.157.230; l.J.157.231; l.J.157.236; l.J.157.237; l.J.157.238; l.J.157.239; l.J.157.154; l.J.157.157; l.J.157.166; l.J.157.169; l.J.157.172; l.J.157.175; l.J.157.240; l.J.157.244; l.J.166.228; l.J.166.229; l.J.166.230; l.J.166.231; l.J.166.236; l.J.166.237; l.J.166.238; l.J.166.239; l.J.166.154; l.J.166.157; l.J.166.166; l.J.166.169; l.J.166.172; l.J.166.175; l.J.166.240; l.J.166.244; l.J.169.228; l.J.169.229; l.J.169.230; l.J.169.231; l.J.169.236; l.J.169.237; l.J.169.238; l.J.169.239; l.J.169.154; l.J.169.157; l.J.169.166; l.J.169.169; l.J.169.172; l.J.169.175; l.J.169.240; l.J.169.244; l.J.172.228; l.J.172.229; l.J.172.230; l.J.172.231; l.J.172.236; l.J.172.237; l.J.172.238; l.J.172.239; l.J.172.154; l.J.172.157; 1J.172.166; l.J.172.169; l.J.172.172; l.J.172.175; l.J.172.240; l.J.172.244; l.J.175.228; l.J.175.229; l.J.175.230; 1J.175.231; l.J.175.236; l.J.175.237; l.J.175.238; l.J.175.239; l.J.175.154; l.J.175.157; l.J.175.166; l.J.175.169; l.J.175.172; 1J.175.175; l.J.175.240; l.J.175.244; l.J.240.228; l.J.240.229; l.J.240.230; l.J.240.231; l.J.240.236; l.J.240.237; l.J.240.238; l.J.240.239; l.J.240.154; l.J.240.157; l.J.240.166; l.J.240.169; 1J.240.172; l.J.240.175; l.J.240.240; l.J.240.244; l.J.244.228; l.J.244.229; l.J.244.230; l.J.244.231; l.J.244.236; l.J.244.237; l.J.244.238; l.J.244.239; l.J.244.154; l.J.244.157; l.J.244.166; l.J.244.169; l.J.244.172; l.J.244.175; l.J.244.240; l.J.244.244;
Prodrugs of l.L
l.L.228.228; l.L.228.229; l.L.228.230; l.L.228.231; l.L.228.236; l.L.228.237; l.L.228.238; l.L.228.239; l.L.228.154; l.L.228.157; l.L.228.166; l.L.228.169; l.L.228.172; l.L.228.175; l.L.228.240; l.L.228.244; l.L.229.228; l.L.229.229; l.L.229.230; l.L.229.231; l.L.229.236; l.L.229.237; l.L.229.238; l.L.229.239; l.L.229.154; l.L.229.157; l.L.229.166; l.L.229.169; l.L.229.172; l.L.229.175; l.L.229.240; l.L.229.244; l.L.230.228; l.L.230.229; l.L.230.230; l.L.230.231; l.L.230.236; l.L.230.237; l.L.230.238; l.L.230.239; l.L.230.154; l.L.230.157; l.L.230.166; l.L.230.169; l.L.230.172; l.L.230.175; l.L.230.240; l.L.230.244; l.L.231.228; l.L.231.229; l.L.231.230; l.L.231.231; l.L.231.236; l.L.231.237; l.L.231.238; l.L.231.239; l.L.231.154; l.L.231.157; l.L.231.166; l.L.231.169; l.L.231.172; l.L.231.175; l.L.231.240; l.L.231.244; l.L.236.228; l.L.236.229; l.L.236.230; l.L.236.231; l.L.236.236; l.L.236.237; l.L.236.238; l.L.236.239; l.L.236.154; l.L.236.157; l.L.236.166; l.L.236.169; l.L.236.172; l.L.236.175; l.L.236.240; l.L.236.244; l.L.237.228; l.L.237.229; l.L.237.230; l.L.237.231; 1.1.237.236; l.L.237.237; l.L.237.238; l.L.237.239; l.L.237.154; l.L.237.157; l.L.237.166; l.L.237.169; l.L.237.172; l.L.237.175; l.L.237.240; l.L.237.244; l.L.238.228; l.L.238.229; l.L.238.230; l.L.238.231; l.L.238.236; l.L.238.237; l.L.238.238; l.L.238.239; l.L.238.154; l.L.238.157; l.L.238.166; l.L.238.169; l.L.238.172; l.L.238.175; l.L.238.240; l.L.238.244; l.L.239.228; l.L.239.229; l.L.239.230; l.L.239.231; l.L.239.236; l.L.239.237; l.L.239.238; l.L.239.239; l.L.239.154; l.L.239.157; l.L.239.166; l.L.239.169; l.L.239.172; l.L.239.175; l.L.239.240; l.L.239.244; l.L.154.228; l.L.154.229; l.L.154.230; l.L.154.231; l.L.154.236; l.L.154.237; l.L.154.238; l.L.154.239; l.L.154.154; l.L.154.157; l.L.154.166; l.L.154.169; l.L.154.172; l.L.154.175; l.L.154.240; l.L.154.244; l.L.157.228; l.L.157.229; l.L.157.230; l.L.157.231; l.L.157.236; l.L.157.237; l.L.157.238; l.L.157.239; l.L.157.154; l.L.157.157; l.L.157.166; l.L.157.169; l.L.157.172; l.L.157.175; l.L.157.240; l.L.157.244; l.L.166.228; l.L.166.229; l.L.166.230; l.L.166.231; l.L.166.236; l.L.166.237; l.L.166.238; l.L.166.239; l.L.166.154; l.L.166.157; l.L.166.166; l.L.166.169; l.L.166.172; l.L.166.175; l.L.166.240; l.L.166.244; l.L.169.228; l.L.169.229; l.L.169.230; l.L.169.231; l.L.169.236; l.L.169.237; l.L.169.238; l.L.169.239; l.L.169.154; l.L.169.157; l.L.169.166; l.L.169.169;
l.L.169.172; l.L.169.175; l.L.169.240; l.L.169.244; l.L.172.228; l.L.172.229; l.L.172.230; l.L.172.231; l.L.172.236; l.L.172.237; l.L.172.238; l.L.172.239; l.L.172.154; l.L.172.157; l.L.172.166; l.L.172.169; l.L.172.172; l.L.172.175; l.L.172.240; l.L.172.244; l.L.175.228; l.L.175.229; l.L.175.230; l.L.175.231; l.L.175.236; l.L.175.237; l.L.175.238; l.L.175.239; l.L.175.154; l.L.175.157; l.L.175.166; l.L.175.169; l.L.175.172; l.L.175.175; l.L.175.240; l.L.175.244; l.L.240.228; l.L.240.229; l.L.240.230; l.L.240.231; l.L.240.236; l.L.240.237; l.L.240.238; l.L.240.239; l.L.240.154; l.L.240.157; l.L.240.166; l.L.240.169; l.L.240.172; l.L.240.175; l.L.240.240; l.L.240.244; l.L.244.228; l.L.244.229; l.L.244.230; l.L.244.231; l.L.244.236; l.L.244.237; l.L.244.238; l.L.244.239; l.L.244.154; l.L.244.157; l.L.244.166; l.L.244.169; l.L.244.172; l.L.244.175; l.L.244.240; l.L.244.244;
Frodrugs of l.O
1.O.228.228; 1.O.228.229; 1.O.228.230; 1.O.228.231; 1.O.228.236; 1.O.228.237; 1.0.228.238; 1.O.228.239; 1.O.228.154; 1.O.228.157; 1.O.228.166; 1.O.228.169; 1.O.228.172; 1.O.228.175; 1.O.228.240; 1.O.228.244; 1.O.229.228; 1.O.229.229; 1.O.229.230; 1.O.229.231; 1.O.229.236; 1.O.229.237; 1.O.229.238; 1.O.229.239; 1.O.229.154; 1.O.229.157; 1.O.229.166; 1.O.229.169; 1.O.229.172; 1.O.229.175; 1.O.229.240; 1.O.229.244; 1.O.230.228; 1.O.230.229; 1.O.230.230; 1.O.230.231; 1.O.230.236; 1.O.230.237; 1.O.230.238; 1.O.230.239; 1.O.230.154; 1.O.230.157; 1.O.230.166; 1.O.230.169; 1.O.230.172; 1.O.230.175; 1.O.230.240; 1.O.230.244; 1.O.231.228; 1.O.231.229; 1.O.231.230; 1.O.231.231; 1.O.231.236; 1.O.231.237; 1.O.231.238; 1.O.231.239; 1.O.231.154; 1.O.231.157; 1.O.231.166; 1.O.231.169; 1.O.231.172; 1.O.231.175; 1.O.231.240; 1.O.231.244; 1.O.236.228; 1.O.236.229; 1.O.236.230; 1.O.236.231; 1.O.236.236; 1.O.236.237; 1.O.236.238; 1.O.236.239; 1.O.236.154; 1.O.236.157; 1.O.236.166; 1.O.236.169; 1.O.236.172; 1.O.236.175; 1.O.236.240; 1.O.236.244; 1.O.237.228; 1.O.237.229; 1.O.237.230; 1.O.237.231; 1.O.237.236; 1.O.237.237; 1.O.237.238; 1.O.237.239; 1.O.237.154; 1.O.237.157; 1.O.237.166; 1.O.237.169; 1.O.237.172; 1.O.237.175; 1.O.237.240; 1.O.237.244; 1.O.238.228; 1.O.238.229; 1.O.238.230; 1.O.238.231; 1.O.238.236; 1.O.238.237; 1.O.238.238; 1.O.238.239; 1.O.238.154; 1.O.238.157; 1.O.238.166; 1.O.238.169; 1.O.238.172; 1.O.238.175; 1.O.238.240; 1.O.238.244; 1.O.239.228; 1.O.239.229; 1.O.239.230; 1.O.239.231; 1.O.239.236; 1.O.239.237; 1.O.239.238; 1.O.239.239; 1.O.239.154; 1.O.239.157; 1.O.239.166; 1.O.239.169; 1.O.239.172; 1.O.239.175; 1.O.239.240; 1.O.239.244; l.O. 154.228; 1.O.154.229; l.O. 154.230; 1.O.154.231; 1.O.154.236; 1.O.154.237; 1.O.154.238; 1.O.154.239; 1.O.154.154; 1.O.154.157; 1.O.154.166; 1.O.154.169; 1.O.154.172; 1.O.154.175; 1.O.154.240; 1.O.154.244; 1.O.157.228; 1.O.157.229; 1.O.157.230; 1.O.157.231; 1.O.157.236; 1.O.157.237; 1.O.157.238; 1.O.157.239; 1.O.157.154; 1.O.157.157; 1.O.157.166; 1.O.157.169; 1.O.157.172; 1.O.157.175; 1.O.157.240; 1.O.157.244; 1.O.166.228; 1.O.166.229; 1.O.166.230; 1.O.166.231; 1.O.166.236; 1.O.166.237; 1.O.166.238; 1.O.166.239; 1.O.166.154; 1.O.166.157; 1.O.166.166; 1.O.166.169; 1.O.166.172; 1.O.166.175; 1.O.166.240; 1.O.166.244; 1.O.169.228; 1.O.169.229; 1.O.169.230; 1.O.169.231; 1.O.169.236; 1.O.169.237; 1.O.169.238; 1.O.169.239; 1.O.169.154; 1.O.169.157; 1.O.169.166; 1.O.169.169; 1.O.169.172; 1.O.169.175; 1.O.169.240; 1.O.169.244; 1.O.172.228; 1.O.172.229; 1.O.172.230; 1.O.172.231; 1.O.172.236; 1.O.172.237; 1.O.172.238; 1.O.172.239; 1.O.172.154; 1.O.172.157; 1.O.172.166; 1.O.172.169;
1.O.172.172; 1.O.172.175; 1.O.172.240; 1.O.172.244; 1.O.175.228; 1.O.175.229; 1.O.175.230; 1.O.175.231; 1.O.175.236; 1.O.175.237; 1.O.175.238; 1.O.175.239; 1.O.175.154; 1.O.175.157; 1.O.175.166; 1.O.175.169; 1.O.175.172; 1.O.175.175; 1.O.175.240; 1.O.175.244; 1.O.240.228; 1.O.240.229; 1.O.240.230; 1.O.240.231; 1.O.240.236; 1.O.240.237; 1.O.240.238; 1.O.240.239; 1.O.240.154; 1.O.240.157; 1.O.240.166; 1.O.240.169; 1.O.240.172; 1.O.240.175; 1.O.240.240; 1.O.240.244; 1.O.244.228; 1.O.244.229; 1.O.244.230; 1.O.244.231; 1.O.244.236; 1.O.244.237; 1.O.244.238; 1.O.244.239; 1.O.244.154; 1.O.244.157; 1.O.244.166; 1.O.244.169; 1.O.244.172; 1.O.244.175; i.O.244.240; 1.O.244.244;
Prodrugs of l.P
l.P.228.228; l.P.228.229; l.P.228.230; l.P.228.231; l.P.228.236; l.P.228.237; 1.P228.238; l.P.228.239; l.P.228.154; l.P.228.157; l.P.228.166; l.P.228.169; l.P.228.172; l.P.228.175; l.P.228.240; l.P.228.244; l.P.229.228; l.P.229.229; l.P.229.230; l.P.229.231; l.P.229.236; l.P.229.237; l.P.229.238; l.P.229.239; l.P.229.154; l.P.229.157; l.P.229.166; l.P.229.169; l.P.229.172; l.P.229.175; l.P.229.240; l.P.229.244; l.P.230.228; l.P.230.229; l.P.230.230; l.P.230.231; l.P.230.236; l.P.230.237; l.P.230.238; l.P.230.239; l.P.230.154; l.P.230.157; l.P.230.166; l.P.230.169; l.P.230.172; l.P.230.175; l.P.230.240; l.P.230.244; l.P.231.228; l.P.231.229; l.P.231.230; l.P.231.231; l.P.231.236; l.P.231.237; l.P.231.238; l.P.231.239; l.P.231.154; l.P.231.157; l.P.231.166; l.P.231.169; l.P.231.172; l.P.231.175; l.P.231.240; l.P.231.244; l.P.236.228; l.P.236.229; l.P.236.230; l.P.236.231; l.P.236.236; l.P.236.237; l.P.236.238; l.P.236.239; l.P.236.154; l.P.236.157; l.P.236.166; l.P.236.169; l.P.236.172; l.P.236.175; 1.P236.240; l.P.236.244; l.P.237.228; l.P.237.229; l.P.237.230; l.P.237.231; l.P.237.236; l.P.237.237; l.P.237.238; l.P.237.239; l.P.237.154; l.P.237.157; l.P.237.166; l.P.237.169; l.P.237.172; l.P.237.175; l.P.237.240; l.P.237.244; l.P.238.228; l.P.238.229; l.P.238.230; l.P.238.231; l.P.238.236; l.P.238.237; l.P.238.238; l.P.238.239; l.P.238.154; l.P.238.157; l.P.238.166; l.P.238.169; l.P.238.172; l.P.238.175; l.P.238.240; l.P.238.244; l.P.239.228; l.P.239.229; l.P.239.230; l.P.239.231; l.P.239.236; l.P.239.237; l.P.239.238; l.P.239.239; l.P.239.154; l.P.239.157; l.P.239.166; l.P.239.169; l.P.239.172; l.P.239.175; l.P.239.240; l.P.239.244; l.P.154.228; l.P.154.229; l.P.154.230; l.P.154.231; l.P.154.236; l.P.154.237; l.P.154.238; l.P.154.239; l.P.154.154; l.P.154.157; l.P.154.166; l.P.154.169; l.P.154.172; l.P.154.175; l.P.154.240; l.P.154.244; l.P.157.228; l.P.157.229; l.P.157.230; l.P.157.231; l.P.157.236; l.P.157.237; LP.157.238; l.P.157.239; l.P.157.154; l.P.157.157; l.P.157.166; l.P.157.169; l.P.157.172; l.P.157.175; l.P.157.240; l.P.157.244; l.P.166.228; l.P.166.229; l.P.166.230; l.P.166.231; l.P.166.236; l.P.166.237; l.P.166.238; l.P.166.239; l.P.166.154; l.P.166.157; l.P.166.166; l.P.166.169; l.P.166.172; l.P.166.175; l.P.166.240; l.P.166.244; l.P.169.228; l.P.169.229; l.P.169.230; l.P.169.231; l.P.169.236; l.P.169.237; l.P.169.238; l.P.169.239; l.P.169.154; l.P.169.157; l.P.169.166; l.P.169.169; l.P.169.172; l.P.169.175; l.P.169.240; l.P.169.244; l.P.172.228; l.P.172.229; l.P.172.230; l.P.172.231; l.P.172.236; l.P.172.237; l.P.172.238; l.P.172.239; l.P.172.154; l.P.172.157; l.P.172.166; l.P.172.169; l.P.172.172; l.P.172.175; l.P.172.240; l.P.172.244; l.P.175.228; l.P.175.229; l.P.175.230; l.P.175.231; l.P.175.236; l.P.175.237; l.P.175.238; l.P.175.239; l.P.175.154; l.P.175.157; l.P.175.166; l.P.175.169; l.P.175.172; l.P.175.175; l.P.175.240; l.P.175.244; l.P.240.228; l.P.240.229; l.P.240.230; l.P.240.231; l.P.240.236; l.P.240.237; l.P.240.238; l.P.240.239; l.P.240.154; l.P.240.157; l.P.240.166; l.P.240.169; l.P.240.172; l.P.240.175; l.P.240.240; l.P.240.244; l.P.244.228; l.P.244.229; l.P.244.230; l.P.244.231;
l.P.244.236; l.P.244.237; l.P.244.238; l.P.244.239; l.P.244.154; l.P.244.157; l.P.244.166; l.P.244.169; l.P.244.172; l.P.244.175; l.P.244.240; l.P.244.244;
Prodrugs of l.U
l.U.228.228; l.U.228.229; l.U.228.230; l.U.228.231; l.U.228.236; l.U.228.237; l.U.228.238; l.U.228.239; l.U.228.154; l.U.228.157; l.U.228.166; l.U.228.169; l.U.228.172; l.U.228.175; l.U.228.240; l.U.228.244; l.U.229.228; l.U.229.229; l.U.229.230; l.U.229.231; l.U.229.236; l.U.229.237; l.U.229.238; l.U.229.239; l.U.229.154; l.U.229.157; l.U.229.166; l.U.229.169; l.U.229.172; i.U.229.175; l.U.229.240; l.U.229.244; l.U.230.228; l.U.230.229; l.U.230.230; l.U.230.231; l.U.230.236; l.U.230.237; l.U.230.238; l.U.230.239; l.U.230.154; l.U.230.157; l.U.230.166; l.U.230.169; l.U.230.172; l.U.230.175; l.U.230.240; l.U.230.244; l.U.231.228; l.U.231.229; l.U.231.230; l.U.231.231; l.U.231.236; l.U.231.237; l.U.231.238; l.U.231.239; l.U.231.154; l.U.231.157; l.U.231.166; l.U.231.169; l.U.231.172; l.U.231.175; l.U.231.240; l.U.231.244; l.U.236.228; l.U.236.229; l.U.236.230; l.U.236.231; l.U.236.236; l.U.236.237; l.U.236.238; l.U.236.239; l.U.236.154; l.U.236.157; l.U.236.166; l.U.236.169; l.U.236.172; l.U.236.175; l.U.236.240; l.U.236.244; l.U.237.228; l.U.237.229; l.U.237.230; l.U.237.231; l.U.237.236; l.U.237.237; l.U.237.238; l.U.237.239; l.U.237.154; l.U.237.157; l.U.237.166; l.U.237.169; l.U.237.172; l.U.237.175; l.U.237.240; l.U.237.244; l.U.238.228; l.U.238.229; l.U.238.230; l.U.238.231; l.U.238.236; l.U.238.237; l.U.238.238; l.U.238.239; l.U.238.154; l.U.238.157; l.U.238.166; l.U.238.169; l.U.238.172; l.U.238.175; l.U.238.240; l.U.238.244; l.U.239.228; l.U.239.229; l.U.239.230; l.U.239.231; l.U.239.236; l.U.239.237; l.U.239.238; l.U.239.239; l.U.239.154; l.U.239.157; l.U.239.166; l.U.239.169; l.U.239.172; l.U.239.175; l.U.239.240; l.U.239.244; l.U.154.228; l.U.154.229; l.U.154.230; l.U.154.231; l.U.154.236; l.U.154.237; l.U.154.238; l.U.154.239; l.U.154.154; l.U.154.157; l.U.154.166; l.U.154.169; l.U.154.172; l.U.154.175; l.U.154.240; l.U.154.244; l.U.157.228; l.U.157.229; l.U.157.230; l.U.157.231; l.U.157.236; l.U.157.237; l.U.157.238; l.U.157.239; l.U.157.154; l.U.157.157; l.U.157.166; l.U.157.169; l.U.157.172; l.U.157.175; l.U.157.240; l.U.157.244; l.U.166.228; l.U.166.229; l.U.166.230; l.U.166.231; l.U.166.236; l.U.166.237; l.U.166.238; l.U.166.239; l.U.166.154; l.U.166.157; l.U.166.166; l.U.166.169; l.U.166.172; l.U.166.175; l.U.166.240; l.U.166.244; l.U.169.228; l.U.169.229; l.U.169.230; l.U.169.231; l.U.169.236; l.U.169.237; l.U.169.238; l.U.169.239; l.U.169.154; l.U.169.157; l.U.169.166; l.U.169.169; l.U.169.172; l.U.169.175; l.U.169.240; l.U.169.244; l.U.172.228; l.U.172.229; l.U.172.230; l.U.172.231; l.U.172.236; l.U.172.237; l.U.172.238; l.U. 172.239; l.U.172.154; l.U.172.157; l.U.172.166; l.U.172.169; l.U.172.172; l.U.172.175; l.U.172.240; l.U.172.244; l.U.175.228; l.U.175.229; l.U.175.230; l.U.175.231; l.U.175.236; l.U.175.237; l.U.175.238; l.U.175.239; l.U.175.154; l.U.175.157; l.U.175.166; l.U.175.169; l.U.175.172; l.U.175.175; l.U.175.240; l.U.175.244; l.U.240.228; l.U.240.229; l.U.240.230; l.U.240.231; l.U.240.236; l.U.240.237; l.U.240.238; l.U.240.239; l.U.240.154; l.U.240.157; l.U.240.166; l.U.240.169; l.U.240.172; l.U.240.175; l.U.240.240; l.U.240.244; l.U.244.228; l.U.244.229; l.U.244.230; l.U.244.231; l.U.244.236; l.U.244.237;
l.U.244.238; l.U.244.239; l.U.244.154; l.U.244.157; l.U.244.166; l.U.244.169; l.U.244.172; l.U.244.175; l.U.244.240; l.U.244.244;
Prodrugs of l.W
l.W.228.228; l.W.228.229; l.W.228.230; l.W.228.231; l.W.228.236; l.W.228.237; l.W.228.238; l.W.228.239; l.W.228.154; l.W.228.157; l.W.228.166; l.W.228.169; l.W.228.172; l.W.228.175; l.W.228.240; l.W.228.244; l.W.229.228; l.W.229.229; l.W.229.230; l.W.229.231; l.W.229.236; l.W.229.237; l.W.229.238; l.W.229.239; l.W.229.154; l.W.229.157; 1.^.229.166; l.W.229.169; l.W.229.172; l.W.229.175; l.W.229.240; l.W.229.244; l.W.230.228; l.W.230.229; l.W.230.230; l.W.230.231; l.W.230.236; l.W.230.237; l.W.230.238; l.W.230.239; l.W.230.154; l.W.230.157; l.W.230.166; l.W.230.169; l.W.230.172; l.W.230.175; l.W.230.240; l.W.230.244; l.W.231.228; l.W.231.229; l.W.231.230; l.W.231.231; l.W.231.236; l.W.231.237; l.W.231.238; l.W.231.239; l.W.231.154; l.W.231.157; l.W.231.166; l.W.231.169; l.W.231.172; l.W.231.175; l.W.231.240; l.W.231.244; l.W.236.228; l.W.236.229; l.W.236.230; l.W.236.231; l.W.236.236; l.W.236.237; l.W.236.238; l.W.236.239; l.W.236.154; l.W.236.157; l.W.236.166; l.W.236.169; l.W.236.172; l.W.236.175; l.W.236.240; l.W.236.244; l.W.237.228; l.W.237.229; l.W.237.230; l.W.237.231; l.W.237.236; l.W.237.237; l.W.237.238; l.W.237.239; l.W.237.154; l.W.237.157; l.W.237.166; l.W.237.169; l.W.237.172; l.W.237.175; l.W.237.240; l.W.237.244; l.W.238.228; l.W.238.229; l.W.238.230; l.W.238.231; l.W.238.236; l.W.238.237; l.W.238.238; l.W.238.239; l.W.238.154; l.W.238.157; l.W.238.166; l.W.238.169; l.W.238.172; l.W.238.175; l.W.238.240; l.W.238.244; l.W.239.228; l.W.239.229; l.W.239.230; l.W.239.231; l.W-239.236; l.W.239.237; l.W.239.238; l.W.239.239; l.W.239.154; l.W.239.157; l.W.239.166; l.W.239.169; l.W.239.172; l.W.239.175; l.W.239.240; l.W.239.244; l.W.154.228; l.W.154.229; l.W.154.230; l.W.154.231; l.W.154.236; l.W.154.237; l.W.154.238; l.W.154.239; l.W.154.154; l.W.154.157; l.W.154.166; l.W.154.169; l.W.154.172; l.W.154.175; l.W.154.240; l.W.154.244; l.W.157.228; l.W.157.229; l.W.157.230; l.W.157.231; l.W.157.236; l.W.157.237; l.W.157.238; l.W.157.239; l.W.157.154; l.W.157.157; l.W.157.166; l.W.157.169; l.W.157.172; l.W.157.175; l.W.157.240; l.W.157.244; l.W.166.228; l.W.166.229; l.W.166.230; l.W.166.231; l.W.166.236; l.W.166.237; l.W.166.238; l.W.166.239; l.W.166.154; l.W.166.157; l.W.166.166; l.W.166.169; l.W.166.172; l.W.166.175; l.W.166.240; l.W.166.244; l.W.169.228; l.W.169.229; l.W.169.230; l.W.169.231; l.W.169.236; l.W.169.237; l.W.169.238; l.W.169.239; l.W.169.154; l.W.169.157; l.W.169.166; l.W.169.169; l.W.169.172; l.W.169.175; l.W.169.240; l.W.169.244; l.W.172.228; l.W.172.229; l.W.172.230; l.W.172.231; l.W.172.236; l.W.172.237; l.W.172.238; l.W.172.239; l.W.172.154; l.W.172.157; l.W.172.166; l.W.172.169; l.W.172.172; l.W.172.175; l.W.172.240; l.W.172.244; l.W.175.228; l.W.175.229; l.W.175.230; l.W.175.231; l.W.175.236; l.W.175.237; l.W.175.238; l.W.175.239; l.W.175.154; l.W.175.157; l.W.175.166; l.W.175.169; l.W.175.172; l.W.175.175; l.W.175.240; l.W.175.244; l.W.240.228; l.W.240.229; l.W.240.230; l.W.240.231; l.W.240.236; l.W.240.237; l.W.240.238; l.W.240.239; l.W.240.154; l.W.240.157; l.W.240.166; l.W.240.169; l.W.240.172; l.W.240.175; l.W.240.240; l.W.240.244; l.W.244.228; l.W.244.229; l.W.244.230; l.W.244.231; l.W.244.236; l.W.244.237;
l.W.244.238; l.W.244.239; l.W.244.154; l.W.244.157; l.W.244.166; l.W.244.169; l.W.244.172; l.W.244.175; l.W.244.240; l.W.244.244;
Prodrugs of l.Y
l.Y.228.228; l.Y.228.229; l.Y.228.230; l.Y.228.231; l.Y.228.236; l.Y.228.237; l.Y.228.238; l.Y.228.239; l.Y.228.154; l.Y.228.157; l.Y.228.166; l.Y.228.169; l.Y.228.172; l.Y.228.175; l.Y.228.240; l.Y.228.244; l.Y.229.228; l.Y.229.229; l.Y.229.230; l.Y.229.231; l.Y.229.236; l.Y.229.237; l.Y.229.238; l.Y.229.239; l.Y.229.154; l.Y.229.157; l.Y.229.166; l.Y.229.169; l.Y.229.172; l.Y.229.175; l.Y.229.240; l.Y.229.244; l.Y.230.228; l.Y.230.229; l.Y.230.230; l.Y.230.231; l.Y.230.236; l.Y.230.237; l.Y.230.238; l.Y.230.239; l.Y.230.154; l.Y.230.157; l.Y.230.166; 1.Y.230169; l.Y.230.172; l.Y.230.175; l.Y.230.240; l.Y.230.244; l.Y.231.228; l.Y.231.229; l.Y.231.230; l.Y.231.231; l.Y.231.236; l.Y.231.237; l.Y.231.238; l.Y.231.239; l.Y.231.154; l.Y.231.157; l.Y.231.166; l.Y.231.169; l.Y.231.172; l.Y.231.175; l.Y.231.240; l.Y.231.244; l.Y.236.228; l.Y.236.229; l.Y.236.230; l.Y.236.231; l.Y.236.236; l.Y.236.237; l.Y.236.238; l.Y.236.239; l.Y.236.154; l.Y.236.157; l.Y.236.166; l.Y.236.169; l.Y.236.172; l.Y.236.175; l.Y.236.240; l.Y.236.244; l.Y.237.228; l.Y.237.229; l.Y.237.230; l.Y.237.231; l.Y.237.236; l.Y.237.237; l.Y.237.238; l.Y.237.239; l.Y.237.154; l.Y.237.157; l.Y.237.166; l.Y.237.169; l.Y.237.172; l.Y.237.175; l.Y.237.240; l.Y.237.244; l.Y.238.228; l.Y.238.229; l.Y.238.230; l.Y.238.231; l.Y.238.236; l.Y.238.237; l.Y.238.238; l.Y.238.239; l.Y.238.154; l.Y.238.157; l.Y.238.166; l.Y.238.169; l.Y.238.172; l.Y.238.175; l.Y.238.240; l.Y.238.244; l.Y.239.228; l.Y.239.229; l.Y.239.230; l.Y.239.231; l.Y.239.236; l.Y.239.237; l.Y.239.238; l.Y.239.239; l.Y.239.154; l.Y.239.157; l.Y.239.166; l.Y.239.169; l.Y.239.172; l.Y.239.175; l.Y.239.240; l.Y.239.244; l.Y.154.228; l.Y.154.229; l.Y.154.230; l.Y.154.231; l.Y.154.236; l.Y.154.237; l.Y.154.238; l.Y.154.239; l.Y.154.154; l.Y.154.157; l.Y.154.166; l.Y.154.169; l.Y.154.172; l.Y.154.175; l.Y.154.240; l.Y.154.244; l.Y.157.228; l.Y.157.229; l.Y.157.230; l.Y.157.231; l.Y.157.236; l.Y.157.237; l.Y.157.238; l.Y.157.239; l.Y.157.154; l.Y.157.157; l.Y.157.166; l.Y.157.169; l.Y.157.172; l.Y.157.175; l.Y.157.240; l.Y.157.244; l.Y.166.228; l.Y.166.229; l.Y.166.230; l.Y.166.231; l.Y.166.236; l.Y.166.237; l.Y.166.238; l.Y.166.239; l.Y.166.154; l.Y.166.157; l.Y.166.166; l.Y.166.169; l.Y.166.172; l.Y.166.175; l.Y.166.240; l.Y.166.244; l.Y.169.228; l.Y.169.229; l.Y.169.230; l.Y.169.231; l.Y.169.236; l.Y.169.237; l.Y.169.238; l.Y.169.239; l.Y.169.154; l.Y.169.157; l.Y.169.166; l.Y.169.169; l.Y.169.172; l.Y.169.175; l.Y.169.240; l.Y.169.244; l.Y.172.228; l.Y.172.229; l.Y.172.230; l.Y.172.231; l.Y.172.236; l.Y.172.237; l.Y.172.238; l.Y.172.239; l.Y.172.154; l.Y.172.157; l.Y.172.166; l.Y.172.169; l.Y.172.172; l.Y.172.175; l.Y.172.240; l.Y.172.244; l.Y.175.228; l.Y.175.229; l.Y.175.230; l.Y.175.231; l.Y.175.236; l.Y.175.237; l.Y.175.238; l.Y.175.239; l.Y.175.154; l.Y.175.157; l.Y.175.166; l.Y.175.169; l.Y.175.172; l.Y.175.175; l.Y.175.240; l.Y.175.244; l.Y.240.228; l.Y.240.229; l.Y.240.230; l.Y.240.231; l.Y.240.236; l.Y.240.237; l.Y.240.238; l.Y.240.239; l.Y.240.154; l.Y.240.157; l.Y.240.166; l.Y.240.169; l.Y.240.172; l.Y.240.175; l.Y.240.240; l.Y.240.244; l.Y.244.228; l.Y.244.229; l.Y.244.230; l.Y.244.231; l.Y.244.236; l.Y.244.237;
l.Y.244.238; l.Y.244.239; l.Y.244.154; l.Y.244.157; l.Y.244.166; l.Y.244.169; l.Y.244.172; l.Y.244.175; l.Y.244.240; l.Y.244.244;
Prodrugs of 2.B
2.B.228.228; 2.B.228.229; 2.B.228.230; 2.B.228.231; 2.B.228.236; 2.B.228.237; 2.B.228.238; 2.B.228.239; 2.B.228.154; 2.B.228.157; 2.B.228.166; 2.B.228.169; 2.B.228.172; 2.B.228.175; 2.B.228.240; 2.B.228.244; 2.B.229.228; 2.B.229.229; 2.B.229.230; 2.B.229.231; 2.B.229.236; 2.B.229.237; 2.B.229.238; 2.B.229.239; 2.B.229.154; 2.B.229.157; 2.B.229.166; 2.B.229.169; 2.B.229.172; 2.B.229.175; 2.B.229.240; 2.B.229.244; 2.B.230.228; 2.B.230.229; 2.B.230.230; 2.B.230.231; 2.B.230.236; 2.B.230.237; 2.B.230.238; 2.B.230.239; 2.B.230.154; 2.B.230.157; 2.B.230.166; 2.B.230.169; 2.B.230.172; 2.B.230.175; 2.B.230.240; 2.B.230.244; 2.B.231.228; 2.B.231.229; 2.B.231.230; 2.B.231.231; 2.B.231.236; 2.B.231.237; 2.B.231.238; 2.B.231.239; 2.B.231.154; 2.B.231.157; 2.B.231.166; 2.B.231.169; 2.B.231.172; 2.B.231.175; 2.B.231.240; 2.B.231.244; 2.B.236.228; 2.B.236.229; 2.B.236.230; 2.B.236.231; 2.B.236.236; 2.B.236.237; 2.B.236.238; 2.B.236.239; 2.B.236.154; 2.B.236.157; 2.B.236.166; 2.B.236.169; 2.B.236.172; 2.B.236.175; 2.B.236.240; 2.B.236.244; 2.B.237.228; 2.B.237.229; 2.B.237.230; 2.B.237.231; 2.B.237.236; 2.B.237.237; 2.B.237.238; 2.B.237.239; 2.B.237.154; 2.B.237.157; 2.B.237.166; 2.B.237.169; 2.B.237.172; 2.B.237.175; 2.B.237.240; 2.B.237.244; 2.B.238.228; 2.B.238.229; 2.B.238.230; 2.B.238.231; 2.B.238.236; 2.B.238.237; 2.B.238.238; 2.B.238.239; 2.B.238.154; 2.B.238.157; 2.B.238.166; 2.B.238.169; 2.B.238.172; 2.B.238.175; 2.B.238.240; 2.B.238.244; 2.B.239.228; 2.B.239.229; 2.B.239.230; 2.B.239.231; 2.B.239.236; 2.B.239.237; 2.B.239.238; 2.B.239.239; 2.B.239.154; 2.B.239.157; 2.B.239.166; 2.B.239.169; 2.B.239.172; 2.B.239.175; 2.B.239.240; 2.B.239.244; 2.B.154.228; 2.B.154.229; 2.B.154.230; 2.B.154231; 2.B.154.236; 2.B.154.237; 2.B.154.238; 2.B.154.239; 2.B.154.154; 2.B.154.157; 2.B.154.166; 2.B.154.169; 2.B.154.172; 2.B.154.175; 2.B.154.240; 2.B.154.244; 2.B.157.228; 2.B.157.229; 2.B.157.230; 2.B.157.231; 2.B.157.236; 2.B.157.237; 2.B.157.238; 2.B.157.239; 2.B.157.154; 2.B.157.157; 2.B.157.166; 2.B.157.169; 2.B.157.172; 2.B.157.175; 2.B.157.240; 2.B.157.244; 2.B.166.228; 2.B.166.229; 2.B.166.230; 2.B.166.231; 2.B.166.236; 2.B.166.237; 2.B.166.238; 2.B.166.239; 2.B.166.154; 2.B.166.157; 2.B.166.166; 2.B.166.169; 2.B.166.172; 2.B.166.175; 2.B.166.240; 2.B.166.244; 2.B.169.228; 2.B.169.229; 2.B.169.230; 2.B.169.231; 2.B.169.236; 2.B.169.237; 2.B.169.238; 2.B.169.239; 2.B.169.154; 2.B.169.157; 2.B.169.166; 2.B.169.169; 2.B.169.172; 2.B.169.175; 2.B.169.240; 2.B.169.244; 2.B.172.228; 2.B.172.229; 2.B.172.230; 2.B.172.231; 2.B.172.236; 2.B.172.237; 2.B.172.238; 2.B.172.239; 2.B.172.154; 2.B.172.157; 2.B.172.166; 2.B.172.169; 2.B.172.172; 2.B.172.175; 2.B.172.240; 2.B.172.244; 2.B.175.228; 2.B.175.229; 2.B.175.230; 2.B.175.231; 2.B.175.236; 2.B.175.237; 2.B.175.238; 2.B.175.239; 2.B.175.154; 2.B.175.157; 2.B.175.166; 2.B.175.169; 2.B.175.172; 2.B.175.175; 2.B.175.240; 2.B.175.244; 2.B.240.228; 2.B.240.229; 2.B.240.230; 2.B.240.231; 2.B.240.236; 2.B.240.237; 2.B.240.238; 2.B.240.239; 2.B.240.154; 2.B.240.157; 2.B.240.166; 2.B.240.169; 2.B.240.172; 2.B.240.175; 2.B.240.240; 2.B.240.244; 2.B.244.228; 2.B.244.229; 2.B.244.230; 2.B.244.231; 2.B.244.236; 2.B.244.237; 2.B.244.238; 2.B.244.239; 2.B.244.154; 2.B.244.157; 2.B.244.166; 2.B.244.169; 2.B.244.172; 2.B.244.175; 2.B.244.240; 2.B.244.244;
Prodrugs of 2.D
2.D.228.228; 2.D.-228.229; 2.D.228.230; 2.D.228.231; 2.D.228.236; 2.D.228.237; 2.D.228.238; 2.D.228.239; 2.D.228.154; 2.D.228.157; 2.D.228.166; 2.D.228.169; 2.D.228.172; 2.D.228.175; 2.D.228.240; 2.D.228.244; 2.D.229.228; 2.D.229.229;
2.D.229.230; 2.D.229.231; 2.D.229.236; 2.D.229.237; 2.D.229.238; 2.D.229.239; 2.D.229.154; 2.D.229.157; 2.D.229.166; 2.D.229.169; 2.D.229.172; 2.D.229.175; 2.D.229.240; 2.D.229.244; 2.D.230.228; 2.D.230.229; 2.D.230.230; 2.D.230.231; 2.D.230.236; 2.D.230.237; 2.D.230.238; 2.D.230.239; 2.D.230.154; 2.D.230.157; 2.D.230.166; 2.D.230.169; 2.D.230.172; 2.D.230.175; 2.D.230.240; 2.D.230.244; 2.D.231.228; 2.D.231.229; 2.D.231.230; 2.D.231.231; 2.D.231.236; 2.D.231.237; 2.D.231.238; 2.D.231.239; 2.D.231.154; 2.D.231.157; 2.D.231.166; 2.D.231.169; 2.D.231.172; 2.D.231.175; 2.D.231.240; 2.D.231.244; 2.D.236.228; 2.D.236.229; 2.D.236.230; 2.D.236.23I; 2.D.236.236; 2.D.236.237; 2.D.236.238; 2.D.236.239; 2.D.236.154; 2.D.236.157; 2.D.236.166; 2.D.236.169; 2.D.236.172; 2.D.236.175; 2.D.236.240; 2.D.236.244; 2.D.237.228; 2.D.237.229; 2.D.237.230; 2.D.237.231; 2.D.237.236; 2.D.237.237; 2.D.237.238; 2.D.237.239; 2.D.237.154; 2.D.237.157; 2.D.237.166; 2.D.237.169; 2.D.237.172; 2.D.237.175; 2.D.237.240; 2.D.237.244; 2.D.238.228; 2.D.238.229; 2.D.238.230; 2.D.238.231; 2.D.238.236; 2.D.238.237; 2.D.238.238; 2.D.238.239; 2.D.238.154; 2.D.238.157; 2.D.238.166; 2.D.238.169; 2.D.238.172; 2.D.238.175; 2.D.238.240; 2.D.238.244; 2.D.239.228; 2.D.239.229; 2.D.239.230; 2.D.239.231; 2.D.239.236; 2.D.239.237; 2.D.239.238; 2.D.239.239; 2.D.239.154; 2.D.239.157; 2.D.239.166; 2.D.239.169; 2.D.239.172; 2.D.239.175; 2.D.239.240; 2.D.239.244; 2.D.154.228; 2.D.154.229; 2.D.154.230; 2.D.154.231; 2.D.154.236; 2.D.154.237; 2.D.154.238; 2.D.154.239; 2.D.154.154; 2.D.154.157; 2.D.154.166; 2.D.154.169; 2.D.154.172; 2.D.154.175; 2.D.154.240; 2.D.154.244; 2.D.157.228; 2.D.157.229; 2.D.157.230; 2.D.157.231; 2.D.157.236; 2.D.157.237; 2.D.157.238; 2.D.157.239; 2.D.157.154; 2.D.157.157; 2.D.157.166; 2.D.157.169; 2.D.157.172; 2.D.157.175; 2.D.157.240; 2.D.157.244; 2.D.166.228; 2.D.166.229; 2.D.166.230; 2.D.166.231; 2.D.166.236; 2.D.166.237; 2.D.166.238; 2.D.166.239; 2.D.166.154; 2.D.166.157; 2.D.166.166; 2.D.166.169; 2.D.166.172; 2.D.166.175; 2.D.166.240; 2.D.166.244; 2.D.169.228; 2.D.169.229; 2.D.169.230; 2.D.169.231; 2.D.169.236; 2.D.169.237; 2.D.169.238; 2.D.169.239; 2.D.169.154; 2.D.169.157; 2.D.169.166; 2.D.169.169; 2.D.169.172; 2.D.169.175; 2.D.169.240; 2.D.169.244; 2.D.172.228; 2.D.172.229; 2.D.172.230; 2.D.172.231; 2.D.172.236; 2.D.172.237; 2.D.172.238; 2.D.172.239; 2.D.172.154; 2.D.172.157; 2.D.172.166; 2.D.172.169; 2.D.172.172; 2.D.172.175; 2.D.172.240; 2.D.172.244; 2.D.175.228; 2.D.175.229; 2.D.175.230; 2.D.175.231; 2.D.175.236; 2.D.175.237; 2.D.175.238; 2.D.175.239; 2.D.175.154; 2.D.175.157; 2.D.175.166; 2.D.175.169; 2.D.175.172; 2.D.175.175; 2.D.175.240; 2.D.175.244; 2.D.240.228; 2.D.240.229; 2.D.240.230; 2.D.240.231; 2.D.240.236; 2.D.240.237; 2.D.240.238; 2.D.240.239; 2.D.240.154; 2.D.240.157; 2.D.240.166; 2.D.240.169; 2.D.240.172; 2.D.240.175; 2.D.240.240; 2.D.240.244; 2.D.244.228; 2.D.244.229; 2.D.244.230; 2.D.244.231; 2.D.244.236; 2.D.244.237; 2.D.244.238; 2.D.244.239; 2.D.244.154; 2.D.244.157; 2.D.244.166; 2.D.244.169; 2.D.244.172; 2.D.244.175; 2.D.244.240; 2.D.244.244;
Prodrugs of 2.E
2.E.228.228; 2.E.228.229; 2.E.228.230; 2.E.228.231; 2.E.228.236; 2.E.228.237; 2.E.228.238; 2.E.228.239; 2.E.228.154; 2.E.228.157; 2.E.228.166; 2.E.228.169; 2.E.228.172; 2.E.228.175; 2.E.228.240; 2.E.228.244; 2.E.229.228; 2.E.229.229; 2.E.229.230; 2.E.229.231; 2.E.229.236; 2.E.229.237; 2.E.229.238; 2.E.229.239; 2.E.229.154; 2.E.229.157; 2.E.229.166;
2.E.229.169; 2.E.229.172; 2.E.229.175; 2.E.229.240; 2.E.229.244; 2.E.230.228; 2.E.230.229; 2.E.230.230; 2.E.230.231; 2.E.230.236; 2.E.230.237; 2.E.230.238; 2.E.230.239; 2.E.230.154; 2.E.230.157; 2.E.230.166; 2.E.230.169; 2.E.230.172; 2.E.230.175; 2.E.230.240; 2.E.230.244; 2.E.231.228; 2.E.231.229; 2.E.231.230; 2.E.231.231; 2.E.231.236; 2.E.231.237; 2.E.231.238; 2.E.231.239; 2.E.231.154; 2.E.231.157; 2.E.231.166; 2.E.231.169; 2.E.231.172;2.E.231.175; 2.E.231.240; 2.E.231.244; 2.E.236.228; 2.E.236.229; 2.E.236.230; 2.E.236.231; 2.E.236.236; 2.E.236.237; 2.E.236.238; 2.E.236.239; 2.E.236.154; 2.E.236.157; 2.E.236.166; 2.E.236.169; 2.E.236.172; 2.E.236.175; 2.E.236.240; 2.E.236.244; 2.E.237.228; 2.E.237.229; 2.E.237.230; 2.E.237.231; 2.E.237.236; 2.E.237.237; 2.E.237.238; 2.E.237.239; 2.E.237.154; 2.E.237.157; 2.E.237.166; 2.E.237.169; 2.E.237.172; 2.E.237.175; 2.E.237.240; 2.E.237.244; 2.E.238.228; 2.E.238.229; 2.E.238.230; 2.E.238.231; 2.E.238.236; 2.E.238.237; 2.E.238.238; 2.E.238.239; 2.E.238.154; 2.E.238.157; 2.E.238.166; 2.E.238.169; 2.E.238.172; 2.E.238.175; 2.E.238.240; 2.E.238.244; 2.E.239.228; 2.E.239.229; 2.E.239.230; 2.E.239.231; 2.E.239.236; 2.E.239.237; 2.E.239.238; 2.E.239.239; 2.E.239.154; 2.E.239.157; 2.E.239.166; 2.E.239.169; 2.E.239.172; 2.E.239.175; 2.E.239.240; 2.E.239.244; 2.E.154.228; 2.E.154.229; 2.E.154.230; 2.E.154.231; 2.E.154.236; 2.E.154.237; 2.E.154.238; 2.E.154.239; 2.E.154.154; 2.E.154.157; 2.E.154.166; 2.E.154.169; 2.E.154.172; 2.E.154.175; 2.E.154.240; 2.E.154.244; 2.E.157.228; 2.E.157.229; 2.E.157.230; 2.E.157.231; 2.E.157.236; 2.E.157.237; 2.E.157.238; 2.E.157.239; 2.E.157.154; 2.E.157.157; 2.E.157.166; 2.E.157.169; 2.E.157.172; 2.E.157.175; 2.E.157.240; 2.E.157.244; 2.E.166.228; 2.E.166.229; 2.E.166.230; 2.E.166.231; 2.E.166.236; 2.E.166.237; 2.E.166.238; 2.E.166.239; 2.E.166.154; 2.E.166.157; 2.E.166.166; 2.E.166.169; 2.E.166.172; 2.E.166.175; 2.E.166.240; 2.E.166.244; 2.E.169.228; 2.E.169.229; 2.E.169.230; 2.E. 169.231; 2.E.169.236; 2.E.169.237; 2.E.169.238; 2.E.169.239; 2.E.169.154; 2.E.169.157; 2.E.169.166; 2.E.169.169; 2.E.169.172; 2.E.169.175; 2.E.169.240; 2.E.169.244; 2.E.172.228; 2.E.172.229; 2.E.172.230; 2.E.172.231; 2.E.172.236; 2.E.172.237; 2.E.172.238; 2.E.172.239; 2.E.172.154; 2.E.172.157; 2.E.172.166; 2.E.172.169; 2.E.172.172; 2.E.172.175; 2.E.172.240; 2.E.172.244; 2.E.175.228; 2.E.175.229; 2.E.175.230; 2.E.175.231; 2.E.175.236; 2.E.175.237; 2.E.175.238; 2.E.175.239; 2.E.175.154; 2.E.175.157; 2.E.175.166; 2.E.175.169; 2.E.175.172; 2.E.175.175; 2.E.175.240; 2.E.175.244; 2.E.240.228; 2.E.240.229; 2.E.240.230; 2.E.240.231; 2.E.240.236; 2.E.240.237; 2.E.240.238; 2.E.240.239; 2.E.240.154; 2.E.240.157; 2.E.240.166; 2.E.240.169; 2.E.240.172; 2.E.240.175; 2.E.240.240; 2.E.240.244; 2.E.244.228; 2.E.244.229; 2.E.244.230; 2.E.244.231; 2.E.244.236; 2.E.244.237; 2.E.244.238; 2.E.244.239; 2.E.244.154; 2.E.244.157; 2.E.244.166; 2.E.244.169; 2.E.244.172; 2.E.244.175; 2.E.244.240; 2.E.244.244;
Frodrugs of 2.G
2.G.228.228; 2.G.228.229; 2.G.228.230; 2.G.228.231; 2.G.228.236; 2.G.228.237; 2.G.228.238; 2.G.228.239; 2.G.228.154; 2.G.228.157; 2.G.228.166; 2.G.228.169; 2.G.228.172; 2.G.228.175; 2.G.228.240; 2.G.228.244; 2.G.229.228; 2.G.229.229; 2.G.229.230; 2.G.229.231; 2.G.229.236; 2.G.229.237; 2.G.229.238; 2.G.229.239; 2.G.229.154; 2.G.229.157; 2.G.229.166; 2.G.229.169; 2.G.229.172; 2.G.229.175; 2.G.229.240; 2.G.229.244; 2.G.230.228; 2.G.230.229; 2.G.230.230; 2.G.230.231; 2.G.230.236; 2.G.230.237; 2.G.230.238; 2.G.230.239; 2.G.230.154; 2.G.230.157; 2.G.230.166; 2.G.230.169; 2.G.230.172; 2.G.230.175; 2.G.230.240; 2.G.230.244; 2.G.231.228; 2.G.231.229; 2.G.231.230; 2.G.231.231; 2.G.231.236; 2.G.231.237; 2.G.231.238; 2.G.231.239; 2.G.231.154; 2.G.231.157; 2.G.231.166; 2.G.231.169; 2.G.231.172; 2.G.231.175; 2.G.231.240; 2.G.231.244; 2.G.236.228; 2.G.236.229;
2.G.236.230; 2.G.236.231; 2.G.236.236; 2.G.236.237; 2.G.236.238; 2.G.236.239; 2.G.236.154; 2.G.236.157; 2.G.236.166; 2.G.236.169; 2.G.236.172; 2.G.236.175; 2.G.236.240; 2.G.236.244; 2.G.237.228; 2.G.237.229; 2.G.237.230; 2.G.237.231; 2.G.237.236; 2.G.237.237; 2.G.237.238; 2.G.237.239; 2.G.237.154; 2.G.237.157; 2.G.237.166; 2.G.237.169; 2.G.237.172; 2.G.237.175; 2.G.237.240; 2.G.237.244; 2.G.238.228; 2.G.238.229; 2.G.238.230; 2.G.238.231; 2.G.238.236; 2.G.238.237; 2.G.238.238; 2;G.238.239; 2.G.238.154; 2.G.238.157; 2.G.238.166; 2.G.238.169; 2.G.238.172; 2.G.238.175; 2.G.238.240; 2.G.238.244; 2.G.239.228; 2.G.239.229; 2.G.239.230; 2.G.239.231; 2.G.239.236; 2.G.239.237; 2.G.239.238; 2.G.239.239; 2.G.239.154; 2.G.239.157; 2.G.239.166; 2.G.239.169; 2.G.239.172; 2.G.239.175; 2.G.239.240; 2.G.239.244; 2.G.154.228; 2.G.154.229; 2.G.154.230; 2.G.154.231; 2.G.154.236; 2.G.154.237; 2.G.154.238; 2.G.154.239; 2.G.154.154; 2.G.154.157; 2.G.154.166; 2.G.154.169; 2.G.154.172; 2.G.154.175; 2.G.154.240; 2.G.154.244; 2.G.157.228; 2.G.157.229; 2.G.157.230; 2.G.157.231; 2.G.157.236; 2.G.157.237; 2.G.157.238; 2.G.157.239; 2.G.157.154; 2.G.157.157; 2.G.157.166; 2.G.157.169; 2.G.157.172; 2.G.157.175; 2.G.157.240; 2.G.157.244; 2.G.166.228; 2.G.166.229; 2.G.166.230; 2.G.166.231; 2.G.166.236; 2.G.166.237; 2.G.166.238; 2.G.166.239; 2.G.166.154; 2.G.166.157; 2.G.166.166; 2.G.166.169; 2.G.166.172;2.G.166.175; 2.G.166.240; 2.G.166.244; 2.G.169.228; 2.G.169.229; 2.G.169.230; 2.G.169.231; 2.G.169.236; 2.G.169.237; 2.G.169.238; 2.G.169.239; 2.G.169.154; 2.G.169.157; 2.G.169.166; 2.G.169.169; 2.G.169.172; 2.G.169.175; 2.G.169.240; 2.G.169.244; 2.G.172.228; 2.G.172.229; 2.G.172.230; 2.G.172.231^ 2.G.172.236; 2.G.172.237; 2.G.172.238; 2.G.172.239; 2.G.172.154; 2.G.172.157; 2.G.172.166; 2.G.172.169; 2.G.172.172; 2.G.172.175; 2.G.172.240; 2.G.172.244; 2.G.175.228; 2.G.175.229; 2.G.175.230; 2.G.175.231; 2.G.175.236; 2.G.175.237; 2.G.175.238; 2.G.175.239; 2.G.175.154; 2.G.175.157; 2.G.175.166; 2.G.175.169; 2.G.175.172; 2.G.175.175; 2.G.175.240; 2.G.175.244; 2.G.240.228; 2.G.240.229; 2.G.240.230; 2.G.240.231; 2.G.240.236; 2.G.240.237; 2.G.240.238; 2.G.240.239; 2.G.240.154; 2.G.240.157; 2.G.240.166; 2.G.240.169; 2.G.240.172; 2.G.240.175; 2.G.240.240; 2.G.240.244; 2.G.244.228; 2.G.244.229; 2.G.244.230; 2.G.244.231; 2.G.244.236; 2.G.244.237; 2.G.244.238; 2.G.244.239; 2.G.244.154; 2.G.244.157; 2.G.244.166; 2.G.244.169; 2.G.244.172; 2.G.244.175; 2.G.244.240; 2.G.244.244;
Prodrugs of 2.1
2.1.228.228; 2.1.228.229; 2.1.228.230; 2.1.228.231; 2.1.228.236; 21.228.237; 2.1.228.238; 2.1.228.239; 2.1.228.154; 2.1.228.157; 2.1.228.166; 2.1.228.169; 2.1.228.172; 2.1.228.175; 2.1.228.240; 2.1.228.244; 2.1.229.228; 2.1.229.229; 2.1.229.230; 2.1.229.231; 2.1.229.236; 2.1.229.237; 2.1.229.238; 2.1.229.239; 2.1.229.154; 2.1.229.157; 2.1.229.166; 2.1.229.169; 2.1.229.172; 2.1.229.175; 2.1.229.240; 2.1.229.244; 2.1.230.228; 2.1.230.229; 2.1.230.230; 2.1.230.231; 2.1.230.236; 2.1.230.237; 2.1.230.238; 2.1.230.239; 2.1.230.154; 2.1.230.157; 2.1.230.166; 2.1.230.169; 2.1.230.172; 2.1.230.175; 2.1.230.240; 2.1.230.244; 2.1.231.228; 2.1.231.229; 2.1.231.230; 2.1.231.231; 2.1.231.236; 2.1.231.237; 2.1.231.238; 2.1.231.239; 2.1.231.154; 2.1.231.157; 2.1.231.166; 2.1.231.169; 2.1.231.172; 2.1.231.175; 2.1.231.240; 2.1.231.244; 2.1.236.228; 2.1.236.229; 2.1.236.230; 2.1.236.231; 2.1.236.236; 2.1.236.237; 2.1.236.238; 2.1.236.239; 2.1.236.154; 2.1.236.157; 2.1.236.166; 2.1.236.169; 2.1.236.172; 2.1.236.175; 2.1.236.240; 2.1.236.244; 2.1.237.228; 2.1.237.229; 2.1.237.230; 2.1.237.231;
2.1.237.236; 2.1.237.237; 2.1.237.238; 2.1.237.239; 2.1.237.154; 2.1.237.157; 2.1.237.166; 2.1.237.169; 2.1.237.172; 2.1.237.175; 2.1.237.240; 2.1.237.244; 2.1.238.228; 2.1.238.229; 2.1.238.230; 2.1.238.231; 2.1.238.236; 2.1.238.237; 2.1.238.238; 2.1.238.239; 2.1.238.154; 2.1.238.157; 2.1.238.166; 2.1.238.169; 2.1.238.172; 2.1.238.175; 2.1.238.240; 2.1.238.244; 2.1.239.228; 2.1.239.229; 2.1.239.230; 2.1.239.231; 2.1.239.236; 2.1.239.237; 2.1.239.238; 2.1.239.239; 2.1.239.154; 2.1.239.157; 2.1.239.166; 2.1.239.169; 2.1.239.172; 2.1.239.175; 2.1.239.240; 2.1.239.244; 2.1.154.228; 2.1.154.229; 2.1.154.230; 2.1.154.231; 2.1.154.236; 2.1.154.237; 2.1.154.238; 2.1.154.239; 2.1.154.154; 2.1.154.157; 2.1.154.166; 2.1.154.169; 2.1.154.172; 2.1.154.175; 2.1.154.240; 2.1.154.244; 2.1.157.228; 2.1.157.229; 2.1.157.230; 2.1.157.231; 2.1.157.236; 2.1.157.237; 2.1.157.238; 2.1.157.239; 2.1.157.154; 2.1.157.157; 2.1.157.166; 2.1.157.169; 2.1.157.172; 2.1.157.175; 2.1.157.240; 2.1.157.244; 2.1.166.228; 2.1.166.229; 2.1.166.230; 2.1.166.231; 2.1.166.236; 2.1.166.237; 2.1.166.238; 2.1.166.239; 2.1.166.154; 2.1.166.157; 2.1.166.166; 2.1.166.169; 2.1.166.172; 2.1.166.175; 2.1.166.240; 2.1.166.244; 2.1.169.228; 2.1.169.229; 2.1.169.230; 2.1.169.231; 2.1.169.236; 2.1.169.237; 2.1.169.238; 2.1.169.239; 2.1.169.154; 2.1.169.157; 2.1.169.166; 2.1.169.169; 2.1.169.172; 2.1.169.175; 2.1.169.240; 2.1.169.244; 2.1.172.228; 2.1.172.229; 2.1.172.230; 2.1.172.231; 2.1.172.236; 2.1.172.237; 2.1.172.238; 2.1.172.239; 2.1.172.154; 2.1.172.157; 2.1.172.166; 2.1.172.169; 2.1.172.172; 2.1.172.175; 2.1.172.240; 2.1.172.244; 2.1.175.228; 2.1.175.229; 2.1.175.230; 2.1.175.231; 2.1.175.236; 2.1.175.237; 2.1.175.238; 2.1.175.239; 2.1.175.154; 2.1.175.157; 2.1.175.166; 2.1.175.169; 2.1.175.172; 2.1.175.175; 2.1.175.240; 2.1.175.244; 2.1.240.228; 2.1.240.229; 2.1.240.230; 2.1.240.231; 2.1.240.236; 2.1.240.237; 2.1.240.238; 2.1.240.239; 2.1.240.154; 2.1.240.157; 2.1.240.166; 2.1.240.169; 2.1.240.172; 2.1.240.175; 2.1.240.240; 2.1.240.244; 2.1.244.228; 2.1.244.229; 2.1.244.230; 2.1.244.231; 2.1.244.236; 2.1.244.237; 2.1.244.238; 2.1.244.239; 2.1.244.154; 2.1.244.157; 2.1.244.166; 2.1.244.169; 2.1.244.172; 2.1.244.175; 2.1.244.240; 2.1.244.244;
Prodrugs of 2.T
2J.228.228; 2.J.228.229; 2.J.228.230; 2.J.228.231; 2.J.228.236; 2J.228.237; 2.J.228.238; 2J.228.239; 2J.228.154; 2J.228.157; 2J.228.166; 2.J.228.169; 2J.228.172; 2.J.228.175; 2J.228.240; 2J.228.244; 2J.229.228; 2J.229.229; 2 J.229.230; 2J.229.231; 2J.229.236; 2J.229.237; 2J.229.238; 2J.229.239; 2J.229.154; 2J.229.157; 2J.229.166; 2.J.229.169; 2J.229.172; 2J.229.175; 2J.229.240; 2J.229.244; 2J.230.228; 2J.230.229; 2.J.230.230; 2J.230.231; 2J.230.236; 2J.230.237; 2J.230.238; 2J.230.239; 2.J.230.154; 2J.230.157; 2.J.230.166; 2J.230.169; 2.J.230.172; 2J.230.175; 2J.230.240; 2J.230.244; 2J.231.228; 2J.231.229; 2.J.231.230; 2J.231.231; 2J.231.236; 2J.231.237; 2.J.231.238; 2J.231.239; 2J.231.154; 2J.231.157; 2.J.231.166; 2J.231.169; 2J.231.172; 2.J.231.175; 2J.231.240; 2.J.231.244; 2.J.236.228; 2.J.236.229; 2 J.236.230; 2.J.236.231; 2 J.236.236; 2.J.236.237; 2J.236.238; 2J.236.239; 2J.236.154; 2J.236.157; 2J.236.166; 2J.236.169; 2.J.236.172; 2 J.236.175; 2J.236.240; 2.J.236.244; 2J.237.228; 2J.237.229; 2J.237.230; 2J.237.231; 2.J.237.236; 2J.237.237; 2J.237.238; 2J.237.239; 2.J.237.154; 2J.237.157; 2.J.237.166; 2J.237.169; 2J.237.172; 2J.237.175; 2.J.237.240; 2J.237.244; 2J.238.228; 2.J.238.229; 2.J.238.230; 2.J.238.231; 2J.238.236; 2J.238.237; 2.J.238.238; 2J.238.239; 2.J.238.154; 2J.238.157; 2.J.238.166; 2.J.238.169; 2J.238.172; 2J.238.175; 2.J.238.240; 2J.238.244; 2.J.239.228; 2J.239.229; 2.J.239.230; 2J.239.231; 2J.239.236; 2.J.239.237; 2J.239.238; 2J.239.239; 2J.239.154; 2.J.239.157; 2.J.239.166; 2.J.239.169; 2J.239.172; 2.J.239.175; 2.J.239.240; 2J.239.244; 2.J.154.228; 2.J.154.229; 2.J.154.230; 2.J.154.231; 2J.154.236;
2.J.154.237; 2J.154.238; 2.J.154.239; 2.J.154.154; 2J.154.157; 2J.154.166; 2J.154.169; 2.J.154.172; 2J.154.175; 2.J.154.240; 2.J.154.244; 2J.157.228; 2J.157.229; 2J.157.230; ' 2J.157.231; 2J.157.236; 2.J.157.237; 2J.157.238; 2J.157.239; 2J.157.154; 2J.157.157; 2J.157.166; 2.J.157.169; 2.J.157.172; 2J.157.175; 2J.157.240; 2J.157.244; 2J.166.228; 2.J.166.229; 2J.166.230; 2J.166.231; 2J.166.236; 2J.166.237; 2J.166.238; 2J.166.239; 2J.166.154; 2J.166.157; 2J.166.166; 2J.166.169; 2J.166.172; 2J.166.175; 2J.166.240; 2J.166.244; 2J.169.228; 2.J.169.229; 2.J.169.230; 2J.169.231; 2J.169.236; 2J.169.237; 2J.169.238; 2J.169.239; 2.J.169.154; 2J.169.157; 2J.169.166; 2J.169.169; 2J.169.172; 2J.169.175; 2J.169.240; 2J.169.244; 2.J.172.228; 2J.172.229; 2J.172.230; 2.J.172.231; 2J.172.236; 2J.172.237; 2J.172.238; 2.J.172.239; 2J.172.154; 2J.172.157; 2J.172.166; 2J.172.169; 2.J.172.172; 2J.172.175; 2J.172.240; 2J.172.244; 2J.175.228; 2J.175.229; 2J.175.230; 2.J.175.231; 2.J.175.236; 2.J.175.237; 2J.175.238; 2J.175.239; 2J.175.154; 2.J.175.157; 2J.175.166; 2J.175.169; 2J.175.172; 2J.175.175; 2J.175.240; 2J.175.244; 2 J.240.228; 2J.240.229; 2J.240.230; 2J.240.231; 2 J.240.236; 2J.240.237; 2J.240.238; 2J.240.239; 2J.240.154; 2J.240.157; 2J.240.166; 2J.240.169; 2J.240.172; 2J.240.175; 2J.240.240; 2 J.240.244; 2 J.244.228; 2J.244.229; 2J.244.230; 2J.244.231; 2J.244.236; 2J.244.237; 2J.244.238; 2J.244.239; 2J.244.154; 2J.244.157; 2J.244.166; 2J.244.169; 2J.244.172; 2.J.244.175; 2J.244.240; 2J.244.244;
Prodrugs of 2.L
2.L.228.228; 2.L.228.229; 2.L.228.230; 2.L.228.231; 2.L.228.236; 2.L.228.237; 2.L.228.238; 2.L.228.239; 2.L.228.154; 2.L.228.157; 2.L.228.166; 2.L.228.169; 2.L.228.172; 2.L.228.175; 2.L.228.240; 2.L.228.244; 2.L.229.228; 2.L.229.229; 2.L.229.230; 2.L.229.231; 2.L.229.236; 2.L.229.237; 2.L.229.238; 2.L.229.239; 2.L.229.154; 2.L.229.157; 2.L.229.166; 2.L.229.169; 2.L.229.172; 2.L.229.175; 2.L.229.240; 2.L.229.244; 2.L.230.228; 2.L.230.229; 2.L.230.230; 2.L.230.231; 2.L.230.236; 2.L.230.237; 2.L.230.238; 2.L.230.239; 2.L.230.154; 2.L.230.157; 2.L.230.166; 2.L.230.169; 2.L.230.172; 2.L.230.175; 2.L.230.240; 2.L.230.244; 2.L.231.228; 2.L.231.229; 2.L.231.230; 2.L.231.231; 2.L.231.236; 2.L.231.237; 2.L.231.238; 2.L.231.239; 2.L.231.154; 2.L.231.157; 2.L.231.166; 2.L.231.169; 2.L.231.172; 2.L.231.175; 2.L.231.240; 2.L.231.244; 2.L.236.228; 2.L.236.229; 2.L.236.230; 2.L.236.231; 2.L.236.236; 2.L.236.237; 2.L.236.238; 2.L.236.239; 2.L.236.154; 2.L.236.157; 2.L.236.166; 2.L.236.169; 2.L.236.172; 2.L.236.175; 2.L.236.240; 2.L.236.244; 2.L.237.228; 2.L.237.229; 2.L.237.230; 2.L.237.231; 2.L.237.236; 2.L.237.237; 2.L.237.238; 2.L.237.239; 2.L.237.154; 2.L.237.157; 2.L.237.166; 2.L.237.169; 2X.237.172; 2.L.237.175; 2.L.237.240; 2.L.237.244; 2.L.238.228; 2.L.238.229; 2.L.238.230; 2.L.238.231; 2.L.238.236; 2.L.238.237; 2.L.238.238; 2.L.238.239; 2.L.238.154; 2.L.238.157; 2.L.238.166; 2.L.238.169; 2.L.238.172; 2.L.238.175; 2.L.238.240; 2.L.238.244; 2.L.239.228; 2.L.239.229; 2.L.239.230; 2.L.239.231; 2.L.239.236; 2.L.239.237; 2.L.239.238; 2.L.239.239; 2.L.239.154; 2.L.239.157; 2.L.239.166; 2.L.239.169; 2.L.239.172; 2.L.239.175; 2.L.239.240; 2.L.239.244; 2.L.154.228; 2.L.154.229; 2.L.154.230; 2.L.154.231; 2.L.154.236; 2.L.154.237; 2.L.154.238; 2.L.154.239; 2.L.154.154; 2.L.154.157; 2.L.154.166; 2.L.154.169; 2.L.154.172; 2.L.154.175; 2.L.154.240; 2.L.154.244; 2.L.157.228; 2.L.157.229; 2.L.157.230; 2.L.157.231; 2.L.157.236; 2.L.157.237; 2.L.157.238; 2.L.157.239; 2.L.157.154; 2.L.157.157; 2.L.157.166; 2.L.157.169; 2.L.157.172; 2.L.157.175; 2.L.157.240; 2.L.157.244; 2.L.166.228; 2.L.166.229; 2.L.166.230; 2.L.166.231; 2.L.166.236; 2.L.166.237; 2.L.166.238; 2.L.166.239; 2.L.166.154; 2.L.166.157; 2.L.166.166; 2.L.166.169; 2.L.166.172; 2.L.166.175; 2.L.166.240; 2.L.166.244; 2.L.169.228; 2.L.169.229; 2.L.169.230; 2.L.169.231; 2.L.169.236;
2.L.169.237; 2.L.169.238; 2.L.169.239; 2.L.169.154; 2.L.169.157; 2.L.169.166; 2.L.169.169; 2.L.169.172; 2.L.169.175; 2.L.169.240; 2.L.169.244; 2.L.172.228; 2.L.172.229; 2.L.172.230; 2.L.172.231; 2.L.172.236; 2.L.172.237; 2.L.172.238; 2.L.172.239; 2.L.172.154; 2.L.172.157; 2.L.172.166; 2.L.172.169; 2.L.172.172; 2.L.172.175; 2.L.172.240; 2.L.172.244; 2.L.175.228; 2.L.175.229; 2.L.175.230; 2.L.175.231; 2.L.175.236; 2.L.175.237; 2.L.175.238; 2.L.175.239; 2.L.175.154; 2.L.175.157; 2.L.175.166; 2.L.175.169; 2.L.175.172; 2.L.175.175; 2.L.175.240; 2.L.175.244; 2.L.240.228; 2.L.240.229; 2.L.240.230; 2.L.240.231; 2.L.240.236; 2.L.240.237; 2.L.240.238; 2.L.240.239; 2.L.240.154; 2.L.240.157; 2.L.240.166; 2.L.240.169; 2.L.240.172; 2.L.240.175; 2.L.240.240; 2.L.240.244; 2.L.244.228; 2.L.244.229; 2.L.244.230; 2.L.244.231; 2.L.244.236; 2.L.244.237; 2.L.244.238; 2.L.244.239; 2.L.244.154; 2.L.244.157; 2.L.244.166; 2.L.244.169; 2.L.244.172; 2.L.244.175; 2.L.244.240; 2.L.244.244;
Prodrugs of 2.O
2.O.228.228; 2.O.228.229; 2.O.228.230; 2.O.228.231; 2.O.228.236; 2.O.228.237; 2.O.228.238; 2.O.228.239; 2.O.228.154; 2.O.228.157; 2.O.228.166; 2.O.228.169; 2.O.228.172; 2.O.228.175; 2.O.228.240; 2.O.228.244; 2.O.229.228; 2.O.229.229; 2.O.229.230; 2.O.229.231; 2.O.229.236; 2.O.229.237; 2.O.229.238; 2.O.229.239; 2.O.229.154; 2.O.229.157; 2.O.229.166; 2.O.229.169; 2.O.229.172; 2.O.229.175; 2.O.229.240; 2.O.229.244; 2.O.230.228; 2.O.230.229; 2.O.230.230; 2.O.230.231; 2.O.230.236; 2.O.230.237; 2.O.230.238; 2.O.230.239; 2.O.230.154; 2.O.230.157; 2.O.230.166; 2.O.230.169; 2.O.230.172; 2.O.230.175; 2.O.230.240; 2.O.230.244; 2.O.231.228; 2.O.231.229; 2.O.231.230; 2.O.231.231; 2.O.231.236; 2.O.231.237; 2.O.231.238; 2.O.231.239; 2.O.231.154; 2.O.231.157; 2.O.231.166; 2.O.231.169; 2.O.231.172; 2.O.231.175; 2.O.231.240; 2.O.231.244; 2.O.236.228; 2.O.236.229; • 2.O.236.230; 2.O.236.231; 2.O.236.236; 2.O.236.237; 2.O.236.238; 2.O.236.239; 2.O.236.154; 2.O.236.157; 2.O.236.166; 2.O.236.169; 2.O.236.172; 2.O.236.175; 2.O.236.240; 2.O.236.244; 2.O.237.228; 2.O.237.229; 2.O.237.230; 2.O.237.231; 2.O.237.236; 2.O.237.237; 2.O.237.238; 2.O.237.239; 2.O.237.154; 2.O.237.157; 2.0:237.166; 2.O.237.169; 2.O.237.172; 2.O.237.175; 2.O.237.240; 2.O.237.244; 2.O.238.228; 2.O.238.229; 2.O.238.230; 2.O.238.231; 2.O.238.236; 2.O.238.237; 2.O.238.238; 2.O.238.239; 2.O.238.154; 2.O.238.157; 2.O.238.166; 2.O.238.169; 2.O.238.172; 2.O.238.175; 2.O.238.240; 2.O.238.244; 2.O.239.228; 2.O.239.229; 2.O.239.230; 2.O.239.231; 2.O.239.236; 2.O.239.237; 2.O.239.238; 2.O.239.239; 2.O.239.154; 2.O.239.157; 2.O.239.166; 2.O.239.169; 2.O.239.172; 2.O.239.175; 2.O.239.240; 2.O.239.244; 2.0.154.228; 2.0.154.229; 2.O.154.230; 2.O.154.231; 2.O.154.236; 2.O.154.237; 2.O.154.238; 2.O.154.239; 2.O.154.154; 2.O.154.157; 2.O.154.166; 2.O.154.169; 2.O.154.172; 2.O.154.175; 2.O.154.240; 2.O.154.244; 2.O.157.228; 2.O.157.229; 2.O.157.230; 2.O.157.231; 2.O.157.236; 2.O.157.237; 2.O.157.238; 2.O.157.239; 2.O.157.154; 2.O.157.157; 2.O.157.166; 2.O.157.169; 2.0.157.172; 2.O.157.175; 2.O.157.240; 2.O.157.244; 2.O.166.228; 2.O.166.229; 2.O.166.230; 2.O.166.231; 2.O.166.236; 2.O.166.237; 2.O.166.238; 2.O.166.239; 2.O.166.154; 2.O.166.157; 2.O.166.166; 2.O.166.169; 2.O.166.172; 2.O.166.175; 2.O.166.240; 2.O.166.244; 2.O.169.228; 2.O.169.229; 2.O.169.230; 2.O.169.231; 2.O.169.236; 2.O.169.237; 2.O.169.238; 2.O.169.239; 2.O.169.154; 2.O.169.157; 2.O.169.166; 2.O.169.169; 2.O.169.172; 2.O.169.175; 2.O.169.240; 2.O.169.244; 2.O.172.228; 2.O.172.229; 2.O.172.230; 2.O.172.231; 2.O.172.236; 2.O.172.237;
2.O.172.238; 2.O.172.239; 2.O.172.154; 2.O.172.157; 2.O.172.166; 2.O.172.169; 2.O.172.172; 2.O.172.175; 2.O.172.240; 2.O.172.244; 2.O.175.228; 2.O.175.229; 2.O.175.230; 2.O.175.231; 2.O.175.236; 2.O.175.237; 2.O.175.238; 2.O.175.239; 2.O.175.154; 2.O.175.157; 2.O.175.166; 2.O.175.169; 2.O.175.172; 2.O.175.175; 2.O.175.240; 2.O.175.244; 2.O.240.228; 2.O.240.229; 2.O.240.230; 2.O.240.231; 2.O.240.236; 2.O.240.237; 2.O.240.238; 2.O.240.239; 2.O.240.154; 2.O.240.157; 2.O.240.166; 2.O.240.169; 2.O.240.172; 2.O.240.175; 2.O.240.240; 2.O.240.244; 2.O.244.228; 2.O.244.229; 2.O.244.230; 2.O.244.231; 2.O.244.236; 2.O.244.237; 2.O.244.238; 2.O.244.239; 2.O.244.154; 2.O.244.I57; 2.O.244.166; 2.O.244.169; 2.O.244.172; 2.O.244.175; 2.O.244.240; 2.O.244.244;
Prodrugs of 2.P
2.P.228.228; 2.P.228.229; 2.P.228.230; 2.P.228.231; 2.P.228.236; 2.P.228.237; 2.P.228.238; 2.P.228.239; 2.P.228.154; 2.P.228.157; 2.P.228.166; 2.P.228.169; 2.P.228.172; 2.P.228.175; 2.P.228.240; 2.P.228.244; 2.P.229.228; 2.P.229.229; 2.P.229.230; 2.P.229.231; 2.P.229.236; 2.P.229.237; 2.P.229.238; 2.P.229.239; 2.P.229.154; 2.P.229.157; 2.P.229.166; 2.P.229.169; 2.P.229.172; 2.P.229.175; 2.P.229.240; 2.P.229.244; 2.P.230.228; 2.P.230.229; 2.P.230.230; 2.P.230.231; 2.P.230.236; 2.P.230.237; 2.P.230.238; 2.P.230.239; 2.P.230.154; 2.P.230.157; 2.P.230.166; 2.P.230.169; 2.P.230.172; 2.P.230.175; 2.P.230.240; 2.P.230.244; 2.P.231.228; 2.P.231.229; 2.P.231.230; 2.P.231.231; 2.P.231.236; 2.P.231.237; 2.P.231.238; 2.P.231.239; 2.P.231.154; 2.P.231.157; 2.P.231.166; ZP.231.169; 2.P.231.172; 2.P.231.175; 2.P.231.240; 2.P.231.244; 2.P.236.228; 2.P.236.229; 2.P.236.230; 2.P.236.231; 2.P.236.236; 2.P.236.237; 2.P.236.238; 2.P.236.239; 2.P.236.154; 2.P.236.157; 2.P.236.166; 2.P.236.169; 2.P.236.172; 2.P.236.175; 2.P.236.240; 2.P.236.244; 2.P.237.228; 2.P.237.229; 2.P.237.230; 2.P.237.231; 2.P.237.236; 2.P.237.237; 2.P.237.238; 2.P.237.239; 2.P.237.154; 2.P.237.157; 2.P.237.166; 2.P.237.169; 2.P.237.172; 2.P.237.175; 2.P.237.240; 2.P.237.244; 2.P.238.228; 2.P.238.229; 2.P.238.230; 2.P.238.231; 2.P.238.236; 2.P.238.237; 2.P.238.238; 2.P.238.239; 2.P.238.154; 2.P.238.157; 2.P.238.166; 2.P.238.169; 2.P.238.172; 2.P.238.175; 2.P.238.240; 2.P.238.244; 2.P.239.228; 2.P.239.229; 2.P.239.230; 2.P.239.231; 2.P.239.236; 2.P.239.237; 2.P.239.238; 2.P.239.239; 2.P.239.154; 2.P.239.157; 2.P.239.166; 2.P.239.169; 2.P.239.1'/2; 2.P.239.175; 2.P.239.240; 2.P.239.244; 2.P.154.228; 2.P.154.229; 2.P.154.230; 2.P.154.231; 2.P.154.236; 2.P.154.237; 2.P.154.238; 2.P.154.239; 2.P.154.154; 2.P.154.157; 2.P.154.166; 2.P.154.169; 2.P.154.172; 2.P.154.175; 2.P.154.240; 2.P.154.244; 2.P.157.228; 2.P.157.229; 2P.157.230; 2.P.157.231; 2.P.157.236; 2.P.157.237; 2.P.157.238; 2.P.157.239; 2.P.157.154; 2.P.157.157; 2.P.157.166; 2.P.157.169; 2.P.157.172; 2.P.157.175; 2.P.157.240; 2.P.157.244; 2.P.166.228; 2.P.166.229; 2.P.166.230; 2.P.166.231; 2.P.166.236; 2.P.166.237; 2.P.166.238; 2.P.166.239; 2.P.166.154; 2.P.166.157; 2.P.166.166; 2.P.166.169; 2.P.166.172; 2.P.166.175; 2.P.166.240; 2.P.166.244; 2.P.169.228; 2.P.169.229; 2.P.169.230; 2.P.169.231; 2.P.169.236; 2.P.169.237; 2.P.169.238; 2.P.169.239; 2.P.169.154; 2.P.169.157; 2.P.169.166; 2.P.169.169; 2.P.169.172; 2.P.169.175; 2.P.169.240; 2.P.169.244; 2.P.172.228; 2.P.172.229; 2.P.172.230; 2.P.172.231; 2.P.172.236; 2.P.172.237; 2.P.172.238; 2.P.172.239; 2.P.172.154; 2.P.172.157; 2.P.172.166; 2.P.172.169; 2.P.172.172; 2.P.172.175; 2.P.172.240; 2.P.172.244; 2.P.175.228; 2.P.175.229; 2.P.175.230; 2.P.175.231; 2.P.175.236; 2.P.175.237; 2.P.175.238; 2.P.175.239; 2.P.175.154; 2.P.175.157; 2.P.175.166; 2.P.175.169; 2.P.175.172; 2.P.175.175; 2.P.175.240; 2.P.175.244; 2.P.240.228; 2.P.240.229; 2.P.240.230; 2.P.240.231; 2.P.240.236; 2.P.240.237; 2.P.240.238; 2.P.240.239; 2.P.240.154; 2.P.240.157; 2.P.240.166; 2.P.240.169; 2.P.240.172;
2.P.240.175- 2.P.240.240; 2.P.240.244; 2.P.244.228; 2.P.244.229; 2.P.244.230; 2.P.244.231; 2.P.244.236'; 2.P.244.237; 2.P.244.238; 2.P.244.239; 2.P.244.154; 2.P.244.157; 2.P.244.166; 2.P.244.169; 2.P.244.172; 2.P.244.175; 2.P.244.240; 2.P.244.244;
Prodrugs of 2.U
2.U.228.228; 2.U.228.229; 2.U.228.230; 2.U.228.231; 2.U.228.236; 2.U.228.237; 2.U.228.238; 2.U.228.239; 2.U.228.154; 2.U.228.157; 2.U.228.166; 2.U.228.169; 2.U.228.172; 2.U.228.175; 2.U.228.240; 2.U.228.244; 2.U.229.228; 2.U.229.229; 2.U.229.230; 2.U.229.231; 2.U.229.236; 2.U.229.237; 2.U.229.238; 2.U.229.239; 2.U.229.154; 2.U.229.157; 2.U.229.166; 2.U.229.169; 2.U.229.172; 2.U.229.175; 2.U.229.240; 2.U.229.244; 2.U.230.228; 2.U.230.229; 2.U.230.230; 2.U.230.231; 2.U.230.236; 2.U.230.237; 2.U.230.238; 2.U.230.239; 2.U.230.154; 2.U.230.157; 2.U.230.166; 2.U.230.169; 2.U.230.172; 2.U.230.175; 2.U.230.240; 2.U.230.244; 2.U.231.228; 2.U.231.229; 2.U.231.230; 2.U.231.231; 2.U.231.236; 2.U.231.237; 2.U.231.238; 2.U.231.239; 2.U.231.154; 2.U.231.157; 2.U.231.166; 2.U.231.169; 2.U.231.172; 2.U.231.175; 2.U.231.240; 2.U.231.244; 2.U.236.228; 2.U.236.229; 2.U.236.230; 2.U.236.231; 2.U.236.236; 2.U.236.237; 2.U.236.238; 2.U.236.239; 2.U.236.154; 2.U.236.157; 2.U.236.166; 2.U.236.169; 2.U.236.172; 2.U.236.175; 2.U.236.240; 2.U.236.244; 2.U.237.228; 2.U.237.229; 2.U.237.230; 2.U.237.231; 2.U.237.236; 2.U.237.237; 2.U.237.238; 2.U.237.239; 2.U.237.154; 2.U.237.157; 2.U.237.166; 2.U.237.169; 2.U.237.172; 2.U.237.175; 2.U.237.240; 2.U.237.244; 2.U.238.228; 2.U.238.229; 2.U.238.230; 2.U.238.231; 2.U.238.236; 2.U.238.237; 2.U.238.238; 2.U.238.239; 2.U.238.154; 2.U.238.157; 2.U.238.166; 2.U.238.169; 2.U.238.172; 2.U.238.175; 2.U.238.240; 2.U.238.244; 2.U.239.228; 2.U.239.229; 2.U.239.230; 2.U.239.231; 2.U.239.236; 2.U.239.237; 2.U.239.238; 2.U.239.239; 2.U.239.154; 2.U.239.157; 2.U.239.166; 2.U.239.169; 2.U.239.172; 2.U.239.175; 2.U.239.240; 2.U.239.244; 2.U.154.228; 2.U.154.229; 2.U.154.230; 2.U.154.231; 2.U.154.236; 2.U.154.237; 2.U.154.238; 2.U.154.239; 2.U.154.154; 2.U.154.157; 2.U.154.166; 2.U.154.169; 2.U.154.172; 2.U.154.175; 2.U.154.240; 2.U.154.244; 2.U.157.228; 2.U.157.229; 2.U.157.230; 2.U.157.231; 2.U.157.236; 2.U.157.237; 2.U.157.238; 2.U.157.239; 2.U.157.154; 2.U.157.157; 2.U.157.166; 2.U.157.169; 2.U.157.172; 2.U.157.175; 2.U.157.240; 2.U.157.244; 2.U.166.228; 2.U.166.229; 2.U.166.230; 2.U.166.231; 2.U.166.236; 2.U.166.237; 2.U.166.238; 2.U.166.239; 2.U.166.154; 2.U.166.157; 2.U.166.166; 2.U.166.169; 2.U.166.172; 2.U.166.175; 2.U.166.240; 2.U.166.244; 2.U.169.228; 2.U.169.229; 2.U.169.230; 2.U.169.231; 2.U.169.236; 2.U.169.237; 2.U.169.238; 2.U.169.239; 2.U.169.154; 2.U.169.157; 2.U.169.166; 2.U.169.169; 2.U.169.172; 2.U.169.175; 2.U.169.240; 2.U.169.244; 2.U.172.228; 2.U.172.229; 2.U.172.230; 2.U.172.231; 2.U.172.236; 2.U.172.237; 2.U.172.238; 2.U.172.239; 2.U.172.154; 2.U.172.157; 2.U.172.166; 2.U.172.169; 2.U.172.172; 2.U.172.175; 2.U.172.240; 2.U .172.244; 2.U.175.228; 2.U.175.229; 2.U.175.230; 2.U.175.231; 2.U.175.236; 2.U.175.237; 2.U.175.238; 2.U.175.239; 2.U.175.154; 2.U.175.157; 2.U.175.166; 2.U.175.169; 2.U.175.172; 2.U.175.175; 2.U.175.240; 2.U.175.244; 2.U.240.228; 2.U.240.229; 2.U.240.230; 2.U.240.231; 2.U.240.236; 2.U.240.237; 2.U.240.238; 2.U.240.239; 2.U.240.154; 2.U.240.157; 2.U.240.166; 2.U.240.169; 2.U.240.172; 2.U.240.175; 2.U.240.240; 2.U.240.244; 2.U.244.228; 2.U.244.229; 2.U.244.230; 2.U.244.231; 2.U.244.236; 2.U.244.237;
2.U.244.238; 2.U.244.239; 2.U.244.154; 2.U.244.157; 2.U.244.166; 2.U.244.169; 2.U.244.172J 2.U.244.175; 2.U.244.240; 2.U.244.244;
Prodrugs of 2.W
2.W.228.228; 2.W.228.229; 2.W.228.230; 2.W.228.231; 2.W.228.236; 2.W.228.237; 2.W.228.238; 2.W.228.239; 2.W.228.154; 2.W.228.157; 2.W.228.166; 2.W.228.169; 2.W.228.172; 2.W.228.175; 2.W.228.240; 2.W.228.244; 2.W.229.228; 2.W.229.229; 2.W.229.230; 2.W.229.231; 2.W.229.236; 2.W.229.237; 2.W.229.238; 2.W.229.239; 2.W.229.154; 2.W.229.157; 2.W.229.166; 2.W.229.169; 2.W.229.172; 2.W.229.175; 2.W.229.240; 2.W.229.244; 2.W.230.228; 2.W.230.229; 2.W.230.230; 2.W.230.231; 2.W.230.236; 2.W.230.237; 2.W.230.238; 2.W.230.239; 2.W.230.154; 2.W.230.157; 2.W.230.166; 2.W.230.169; 2.W.230.172; 2.W.230.175; 2.W.230.240; 2.W.230.244; 2.W.231.228; 2.W.231.229; 2.W.23L230; 2.W.231.231; 2.W.231.236; 2.W.231.237; 2.W.231.238; 2.W.231.239; 2.W.231.154; 2.W.231.157; 2.W.231.166; 2.W.231.169; 2.W.231.172; 2.W.231.175; 2.W.231.240; 2.W.231.244; 2.W.236.228; 2.W.236.229; 2.W.236.230; 2.W.236.231; 2.W.236.236; 2.W.236.237; 2.W.236.238; 2.W.236.239; 2.W.236.154; 2.W.236.157; 2.W.236.166; 2.W.236.169; 2.W.236.172; 2.W.236.175; 2.W.236.240; 2.W.236.244; 2.W.237.228; 2.W.237.229; 2.W.237.230; 2.W.237.231; 2.W.237.236; 2.W.237.237; 2.W.237.238; 2.W.237.239; 2.W.237.154; 2.W.237.157; 2.W.237.166; 2.W.237.169; 2.W.237.172; 2.W.237.175; 2.W.237.240; 2.W.237.244; 2.W.238.228; 2.W.238.229; 2.W.238.230; 2.W.238.231; 2.W.238.236; 2.W.238.237; 2.W.238.238; 2.W.238.239; 2.W.238.154; 2.W.238.157; 2.W.238.166; 2.W.238.169; 2.W.238.172; 2.W.238.175; 2.W.238.240; 2.W.238.244; 2.W.239.228; 2.W.239.229; 2.W.239.230; 2.W.239.231; 2.W.239.236; 2.W.239.237; 2.W.239.238; 2.W.239.239; 2.W.239.154; 2.W.239.157; 2.W.239.166; 2.W.239.169; 2.W.239.172; 2.W.239.175; 2.W.239.240; 2.W.239.244; 2.W.154.228; 2.W.154.229; 2.W.154.230; 2.W.154.231; 2.W.154.236; 2.W.154.237; 2.W.154.238; 2.W.154.239; 2.W.154.154; 2.W.154.157; 2.W.154.166; 2.W.154.169; 2.W.154.172; 2.W.154.175; 2.W.154.240; 2.W.154.244; 2.W.157.228; 2.W.157.229; 2.W.157.230; 2.W.157.231; 2.W.157.236; 2.W.157.237; 2.W.157.238; 2.W.157.239; 2.W.157.154; 2.W.157.157; 2.W.157.166; 2.W.157.169; 2.W.157.172; 2.W.157.175; 2.W.157.240; 2.W.157.244; 2.W.166.228; 2.W.166.229; 2.W.166.230; 2.W.166.231; 2.W.166.236; 2.W.166.237; 2.W.166.238; 2.W.166.239; 2.W.166.154; 2.W.166.157; 2.W.166.166; 2.W.166.169; 2.W.166.172; 2.W.166.175; 2.W.166.240; 2.W.166.244; 2.W.169.228; 2.W.169.229; 2.W.169.230; 2.W.169.231; 2.W.169.236; 2.W.169.237; 2.W.169.238; 2.W.169.239; 2.W.169.154; 2.W.169.157; 2.W.169.166; 2.W.169.169; 2.W.169.172; 2.W.169.175; 2.W.169.240; 2.W.169.244; 2.W.172.228; 2.W.172.229; 2.W.172.230; 2.W.172.231; 2.W.172.236; 2.W.172.237; 2.W.172.238; 2.W.172.239; 2.W.172.154; 2.W.172.157; 2.W.172.166; 2.W.172.169; 2.W.172.172; 2.W.172.175; 2.W.172.240; 2.W.172.244; 2.W.175.228; 2.W.175.229; 2.W.175.230; 2.W.175.231; 2.W.175.236; 2.W.175.237; 2.W.175.238; 2.W.175.239; 2.W.175.154; 2.W.175.157; 2.W.175.166; 2.W.175.169; 2.W.175.172; 2.W.175.175; 2.W. 175.240; 2.W.175.244; 2.W.240.228; 2.W.240.229; 2.W.240.230; 2.W.240.231; 2.W.240.236; 2.W.240.237; 2.W.240.238; 2.W.240.239; 2.W.240.154; 2.W.240.157; 2.W.240.166; 2.W.240.169; 2.W.240.172; 2.W.240.175; 2.W.240.240; 2.W.240.244; 2.W.244.228; 2.W.244.229; 2.W.244.230; 2.W.244.231; 2.W.244.236; 2.W.244.237;
2.W.244.238; 2.W.244.239; 2.W.244.154; 2.W.244.157; 2.W.244.166; 2.W.244.169; 2.W.244.172; 2.W.244.175; 2.W.244.240; 2.W.244.244;
Frodrugs of 2.Y
2.Y.228.228; 2.Y.228.229; 2.Y.228.230; 2.Y.228.231; 2.Y.228.236; 2.Y.228.237; 2.Y.228.238; 2.Y.228.239; 2.Y.228.154; 2.Y.228.157; 2.Y.228.166; 2.Y.228.169; 2.Y.228.172; 2.Y.228.175; 2.Y.228.240; 2.Y.228.244; 2.Y.229.228; 2.Y.229.229; 2.Y.229.230; 2.Y.229.231; 2.Y.229.236; 2.Y.229.237; 2.Y.229.238; 2.Y.229.239; 2.Y.229.154; 2.Y.229.157; 2.Y.229.166; 2.Y.229.169; 2.Y.229.172; 2.Y.229.175; 2.Y.229.240; 2.Y.229.244; 2.Y.230.228; 2.Y.230.229; 2.Y.230.230; 2.Y.230.231; 2.Y.230.236; 2.Y.230.237; 2.Y.230.238; 2.Y.230.239; 2.Y.230.154; 2.Y.230.157; 2-Y.230.166; 2.Y.230.169; 2.Y.230.172; 2.Y.230.175; 2.Y.230.240; 2.Y.230.244; 2.Y.231.228; 2.Y.231.229; 2.Y.231.230; 2.Y.231.231; 2.Y.231.236; 2.Y.231.237; 2.Y.231.238; 2.Y.231.239; 2.Y.231.154; 2.Y.231.157; 2.Y.231.166; 2.Y.231.169; 2.Y.231.172; 2.Y.231.175; 2.Y.231.240; 2.Y.231.244; 2.Y.236.228; 2.Y.236.229; 2.Y.236.230; 2.Y.236.231; 2.Y.236.236; 2.Y.236.237; 2.Y.236.238; 2.Y.236.239; 2.Y.236.154; 2.Y.236.157; 2.Y.236.166; 2.Y.236.169; 2.Y.236.172; 2.Y.236.175; 2.Y.236.240; 2.Y.236.244; 2.Y.237.228; 2.Y.237.229; 2.Y.237.230; 2.Y.237.231; 2.Y.237.236; 2.Y.237.237; 2.Y.237.238; 2.Y.237.239; 2.Y.237.154; 2.Y.237.157; 2.Y.237.166; 2.Y.237.169; 2.Y.237.172; 2.Y.237.175; 2.Y.237.240; 2.Y.237.244; 2.Y.238.228; 2.Y.238.229; 2.Y.238.230; 2.Y.238.231; 2.Y.238.236; 2.Y.238.237; 2.Y.238.238; 2.Y.238.239; 2.Y.238.154; 2.Y.238.157; 2.Y.238.166; 2.Y.238.169; 2.Y.238.172; 2.Y.238.175; 2.Y.238.240; 2.Y.238.244; 2.Y.239.228; 2.Y.239.229; 2.Y.239.230; 2.Y.239.231; 2.Y.239.236; 2.Y.239.237; 2.Y.239.238; 2.Y.239.239; 2.Y.239.154; 2.Y.239.157; 2.Y.239.166; 2.Y.239.169; 2.Y.239.172; 2.Y.239.175; 2.Y.239.240; 2.Y.239.244; 2.Y.154.228; 2.Y.154.229; 2.Y.154.230; 2.Y.154.231; 2.Y.154.236; 2.Y.154.237; 2.Y.154.238; 2.Y.154.239; 2.Y.154.154; 2.Y.154.157; 2.Y.154.166; 2.Y.154.169; 2.Y.154.172; 2.Y.154.175; 2.Y.154.240; 2.Y.154.244; 2.Y.157.228; 2.Y.157.229; 2.Y.157.230; 2.Y.157.231; 2.Y.157.236; 2.Y.157.237; 2.Y.157.238; 2.Y.157.239; 2.Y.157.154; 2.Y.157.157; 2.Y.157.166; 2.Y.157.169; 2.Y.157.172; 2.Y.157.175; 2.Y.157.240; 2.Y.157.244; 2.Y.166.228; 2.Y.166.229; 2.Y.166.230; 2.Y.166.231; 2.Y.166.236; 2.Y.166.237; 2.Y.166.238; 2.Y.166.239; 2.Y.166.154; 2.Y.166.157; 2.Y.166.166; 2.Y.166.169; 2.Y.166.172; 2.Y.166.175; 2.Y.166.240; 2.Y.166.244; 2.Y.169.228; 2.Y.169.229; 2.Y.169.230; 2.Y.169.231; 2.Y.169.236; 2.Y.169.237; 2.Y.169.238; 2.Y.169.239; 2.Y.169.154; 2.Y.169.157; 2.Y.169.166; 2.Y.169.169; 2.Y.169.172; 2.Y.169.175; 2.Y.169.240; 2.Y.169.244; 2.Y.172.228; 2.Y.172.229; 2.Y.172.230; 2.Y.172.231; 2.Y.172.236; 2.Y.172.237; 2.Y.172.238;2.Y.172.239; 2.Y.172.154; 2.Y.172.157; 2.Y.172.166; 2.Y.172.169; 2.Y.172.172; 2.Y.172.175; 2.Y.172.240; 2.Y.172.244; 2.Y.175.228; 2.Y.175.229; 2.Y.175.230; 2.Y.175.231; 2.Y.175.236; 2.Y.175.237; 2.Y.175.238; 2.Y.175.239; 2.Y.175.154; 2.Y.175.157; 2.Y.175.166; 2.Y.175.169; 2.Y.175.172; 2.Y.175.175; 2.Y.175.240; 2.Y.175.244; 2.Y.240.228; 2.Y.240.229; 2.Y.240.230; 2.Y.240.231; 2.Y.240.236; 2.Y.240.237; 2.Y.240.238; 2.Y.240.239; 2.Y.240.154; 2.Y.240.157; 2.Y.240.166; 2.Y.240.169; 2.Y.240.172; 2.Y.240.175; 2.Y.240.240; 2.Y.240.244; 2.Y.244.228; 2.Y.244.229; 2.Y.244.230; 2.Y.244.231; 2.Y.244.236; 2.Y.244.237;
2.Y.244.238; 2.Y.244.239; 2.Y.244.154; 2.Y.244.157; 2.Y.244.166; 2.Y.244.169; 2.Y.244.172; 2.Y.244.175; 2.Y.244.240; 2.Y.244.244;
Prodrugs of 3.B
3.B.228.228; 3.B.228.229; 3.B.228.230; 3.B.228.231; 3.B.228.236; 3.B.228.237; 3.B.228.238; 3.B.228.239; 3.B.228.154; 3.B.228.157; 3.B.228.166; 3.B.228.169; 3.B.228.172; 3.B.228.175; 3.B.228.240; 3.B.228.244; 3.B.229.228; 3.B.229.229; 3.B.229.230; 3.B.229.231; 3.B.229.236; 3.B.229.237; 3.B.229.238; 3.B.229.239; 3.B.229.154; 3.B.229.157; 3.B.229.166; 3.B.229.169; 3.B.229.172; 3.B.229.175; 3.B.229.240; 3.B.229.244; 3.B .230.228; 3.B.230.229; 3.B.230.230; 3.B.230.231; 3.B.230.236; 3.B.230.237; 3.B.230.238; 3.B.230.239; 3.B.230.154; 3.B.230.157; 3.B.230.166; 3.B.230.169; 3.B.230.172; 3.B.230.175; 3.B.230.240; 3.B.230.244; 3.B.231.228; 3.B.231.229; 3.B.231.230; 3.B.231.231; 3.B.231.236; 3.B.231.237; 3.B.231.238; 3.B.231.239; 3.B.231.154; 3.B.231.157; 3.B.231.166; 3.B.231.169; 3.B.231.172; 3.B.231.175; 3.B.231.240; 3.B.231.244; 3.B.236.228; 3.B.236.229; 3.B.236.230; 3.B.236.231; 3.B.236.236; 3.B.236.237; 3.B.236.238; 3.B.236.239; 3.B.236.154; 3.B.236.157; 3.B.236.166; 3.B.236.169; 3.B.236.172; 3.B.236.175; 3.B.236.240; 3.B.236.244; 3.B.237.228; 3.B.237.229; 3.B.237.230; 3.B.237.231; 3.B.237.236; 3.B.237.237; 3.B.237.238; 3.B.237.239; 3.B.237.154; 3.B.237.157; 3.B.237.166; 3.B.237.169; 3.B.237.172; 3.B.237.175; 3.B.237.240; 3.B.237.244; 3.B.238.228; 3.B.238.229; 3.B.238.230; 3.B.238.231; 3.B.238.236; 3.B.238.237; 3.B.238.238; 3.B.238.239; 3.B.238.154; 3.B.238.157; 3.B.238.166; 3.B.238.169; 3.B.238.172; 3.B.238.175; 3.B.238.240; 3.B.238.244; 3.B.239.228; 3.B.239.229; 3.B.239.230; 3.B.239.231; 3.B.239.236; 3.B.239.237; 3.B.239.238; 3.B.239.239; 3.B.239.154; 3.B.239.157; 3.B.239.166; 3.B.239.169; 3.B.239.172; 3.B.239.175; 3.B.239.240; 3.B.239.244; 3.B.154.228; 3.B.154.229; 3.B.154.230; 3.B.154.231; 3.B.154.236; 3.B.154.237; 3.B.154.238; 3.B.154.239; 3.B.154.154; 3.B.154.157; 3.B.154.166; 3.B.154.169; 3.B.154.172; 3.B.154.175; 3.B.154.240; 3.B.154.244; 3.B.157.228; 3.B.157.229; 3.B.157.230; 3.B.157.231; 3.B.157.236; 3.B.157.237; 3.B.157.238; 3.B.157.239; 3.B.157.154; 3.B.157.157; 3.B.157.166; 3.B.157.169; 3.B.157.172; 3.B.157.175; 3.B.157.240; 3.B.157.244; 3.B.166.228; 3.B.166.229; 3.B.166.230; 3.B.166.231; 3.B.166.236; 3.B.166.237; 3.B.166.238; 3.B.166.239; 3.B.166.154; 3.B.166.157; 3.B.166.166; 3.B.166.169; 3.B.166.172; 3.B.166.175; 3.B.166.240; 3.B.166.244; 3.B.169.228; 3.B.169.229; 3.B.169.230; 3.B.169.231; 3.B.169.236; 3.B.169.237; 3.B.169.238; 3.B.169.239; 3.B.169.154; 3.B.169.157; 3.B.169.166; 3.B.169.169; 3.B.169.172; 3.B.169.175; 3.B.169.240; 3.B.169.244; 3.B.172.228; 3.B.172.229; 3.B.172.230; 3.B.172.231; 3.B.172.236; 3.B.172.237; 3.B.172.238; 3.B.172.239; 3.B.172.154; 3.B.172.157; 3.B.172.166; 3.B.172.169; 3.B.172.172; 3.B.172.175; 3.B.172.240; 3.B.172.244; 3.B.175.228; 3.B.175.229; 3.B.175.230; 3.B.175.231; 3.B.175.236; 3.B.175.237; 3.B.175.238; 3.B.175.239; 3.B.175.154; 3.B.175.157; 3.B.175.166; 3.B.175.169; 3.B.175.172; 3.B.175.175; 3.B.175.240; 3.B.175.244; 3.B.240.228; 3.B.240.229; 3.B.240.230; 3.B.240.231; 3.B.240.236; 3.B.240.237; 3.B.240.238; 3.B.240.239; 3.B.240.154; 3.B.240.157; 3.B.240.166; 3.B.240.169; 3.B.240.172; 3.B.240.175; 3.B.240.240; 3.B.240.244; 3.B.244.228; 3.B.244.229; 3.B.244.230; 3.B.244.231; 3.B.244.236; 3.B.244.237; 3.B.244.238; 3.B.244.239; 3.B.244.154; 3.B.244.157; 3.B.244.166; 3.B.244.169; 3.B.244.172; 3.B.244.175; 3.B.244.240; 3.B.244.244;
Prodrugs of 3.D
3.D.228.228; 3.D.228.229; 3.D.228.230; 3.D.228.231; 3.D.228.236; 3.D.228.237; 3.D.228.238; 3.D.228.239; 3.D.228.154; 3.D.228.157; 3.D.228.166; 3.D.228.169; 3.D.228.172; 3.D.228.175; 3.D.228.240; 3.D.228.244; 3.D.229.228; 3.D.229.229;
3.D.229.230; 3.D.229.231; 3.D.229.236; 3.D.229.237; 3.D.229.238; 3.D.229.239; 3.D.229.154; 3.D.229.157; 3.D.229.166; 3.D.229.169; 3.D.229.172; 3.D.229.175; 3.D.229.240; 3.D.229.244; 3.D.230.228; 3.D.230.229; 3.D.230.230; 3.D.230.231; 3.D.230.236; 3.D.230.237; 3.D.230:238; 3.D.230.239; 3.D.230.154; 3.D.230.157; 3.D.230.166; 3.D.230.169; 3.D.230.172; 3.D.230.175; 3.D.230.240; 3.D.230.244; 3.D.231.228; 3.D.231.229; 3.D.231.230; 3.D.231.231; 3.D.231.236; 3.D.231.237; 3.D.231.238; 3.D.231.239; 3.D.231.154; 3.D.231.157; 3.D.231.166; 3.D.231.169; 3.D.231.172; 3.D.231.175; 3.D.231.240; 3.D.231.244; 3.D.236.228; 3.U236.229; 3.D.236.230; 3.D.236.231; 3.D.236.236; 3.D.236.237; 3.D.236.238; 3.D.236.239; 3.D.236.154; 3.D.236.157; 3.D.236.166; 3.D.236.169; 3.D.236.172; 3.D.236.175; 3.D.236.240; 3.D.236.244; 3.D.237.228; 3.D.237.229; 3.D.237.230; 3.D.237.231; 3.D.237.236; 3.D.237.237; 3.D.237.238; 3.D.237.239; 3.D.237.154; 3.D.237.157; 3.D.237.166; 3.D.237.169; 3.D.237.172; 3.D.237.175; 3.D.237.240; 3.D.237.244; 3.D.238.228; 3.D.238.229; 3.D.238.230; 3.D.238.231; 3.D.238.236; 3.D.238.237; 3.D.238.238; 3.D.238.239; 3.D.238.154; 3.D.238.157; 3.D.238.166; 3.D.238.169; 3.D.238.172; 3.D.238.175; 3.D.238.240; 3.D.238.244; 3.D.239.228; 3.D.239.229; 3.D.239.230; 3.D.239.231; 3.D.239.236; 3.D.239.237; 3.D.239.238; 3.D.239.239; 3.D.239.154; 3.D.239.157; 3.D.239.166; 3.D.239.169; 3.D.239.172; 3.D.239.175; 3.D.239.240; 3.D.239.244; 3.D.154.228; 3.D.154.229; 3.D.154.230; 3.D.154.231; 3.D.154.236; 3.D.154.237; 3.D.154.238; 3.D.154.239; 3.D.154.154; 3.D.154.157; 3.D.154.166; 3.D.154.169; 3.D.154.172; 3.D.154.175; 3.D.154.240; 3.D.154.244; 3.D.157.228; 3.D.157.229; 3.D.157.230; 3.D.157.231; 3.D.157.236; 3.D.157.237; 3.D.157.238; 3.D.157.239; 3.D.157.154; 3.D.157.157; 3.D.157.166; 3.D.157.169; 3.D.157.172; 3.D.157.175; 3.D.157.240; 3.D.157.244; 3.D.166.228; 3.D.166.229; 3.D.166.230; 3.D.166.231; 3.D.166.236; 3.D.166.237; 3.D.166.238; 3.D.166.239; 3.D.166.154; 3.D.166.157; 3.D.166.166; 3.D.166.169; 3.D.166.172; 3.D.166.175; 3.D.166.240; 3.D.166.244; 3.D.169.228; 3.D.169.229; 3.D.169.230; 3.D.169.231; 3.D.169.236; 3.D.169.237; 3.D.169.238; 3.D.169.239; 3.D.169.154; 3.D.169.157; 3.D:i69.166; 3.D.169.169; 3.D.169.172; 3.D.169.175; 3.D.169.240; 3.D.169.244; 3.D.172.228; 3.D.172.229; 3.D.172.230; 3.D.172.231; 3.D.172.236; 3.D.172.237; 3.D.172.238; 3.D.172.239; 3.D.172.154; 3.D.172.157; 3.D.172.166; 3.D.172.169; 3.D.172.172; 3.D.172.175; 3.D.172.240; 3.D.172.244; 3.D.175.228; 3.D.175.229; 3.D.175.230; 3.D.175.231; 3.D.175.236; 3.D.175.237; 3.D.175.238; 3.D.175.239; 3.D.175.154; 3.D.175.157; 3.D.175.166; 3.D.175.169; 3.D.175.172; 3.D.175.175; 3.D.175.240; 3.D.175.244; 3.D.240.228; 3.D.240.229; 3.D.240.230; 3.D.240.231; 3.D .240.236; 3.D.240.237; 3.D.240.238; 3.D.240.239; 3.D.240.154; 3.D.240.157; 3.D.240.166; 3.D.240.169; 3.D.240.172; 3.D.240.175; 3.D.240.240; 3.D.240.244; 3.D.244.228; 3.D.244.229; 3.D.244.230; 3.D.244.231; 3.D.244.236; 3.D.244.237; 3.D.244.238; 3.D.244.239; 3.D.244.154; 3.D.244.157; 3.D.244.166; 3.D.244.169; 3.D.244.172; 3.D.244.175; 3.D.244.240; 3.D.244.244;
Prodrugs of 3.E
3.E.228.228; 3.E.228.229; 3.E.228.230; 3.E.228.231; 3.E.228.236; 3.E.228.237; 3.E.228.238; 3.E.228.239; 3.E.228.154; 3.E.228.157; 3.E.228.166; 3.E.228.169; 3.E.228.172; 3.E.228.175; 3.E.228.240; 3.E.228.244; 3.E.229.228; 3.E.229.229; 3.E.229.230; 3.E.229.231; 3.E.229.236; 3.E.229.237; 3.E.229.238; 3.E.229.239; 3.E.229.154; 3.E.229.157; 3.E.229.166;
3.E.229.169; 3.E.229.172; 3.E.229.175; 3.E.229.240; 3.E.229.244; 3.E.230.228; 3.E.230.229; 3.E.230.230; 3.E.230.231; 3.E.230.236; 3.E.230.237; 3.E.230.238; 3.E.230.239; 3.E.230.154; 3.E.230.157; 3.E.230.166; 3.E.230.169; 3.E.230.172; 3.E.230.175; 3.E.230.240; 3.E.230.244; 3.E.231.228; 3.E.231.229; 3.E.231.230; 3.E.231.231; 3.E.231.236; 3.E.231.237; 3.E.231.238; 3.E.231.239; 3.E.231.154; 3.E.231.157; 3.E.231.166; 3.E.231.169; 3.E.231.172; 3.E.231.175; 3.E.231.240; 3.E.231.244; 3.E.236.228; 3.E.236.229; 3.E.236.230; 3.E.236.231; 3.E.236.236; 3.E.236.237; 3.E.236.238; 3.E.236.239; 3.E.236.154; 3.E.236.157; 3.E.236.166; 3.E.236.169; 3.E.236.172; 3.E.236.175; 3.E.236.240; 3.E.236.244; 3.E.237.228; 3.E.237.229; 3.E.237.230; 3.E.237.231; 3.E.237.236; 3.E.237.237; 3.E.237.238; 3.E.237.239; 3.E.237.154; 3.E.237.157; 3.E.237.166; 3.E.237.169; 3.E.237.172; 3.E.237.175; 3.E.237.240; 3.E.237.244; 3.E.238.228; 3.E.238.229; 3.E.238.230; 3.E.238.231; 3.E.238.236; 3.E.238.237; 3.E.238.238; 3.E.238.239; 3.E.238.154; 3.E.238.157; 3.E.238.166; 3.E.238.169; 3.E.238.172; 3.E.238.175; 3.E.238.240; 3.E.238.244; 3.E.239.228; 3.E.239.229; 3.E.239.230; 3.E.239.231; 3.E.239.236; 3.E.239.237; 3.E.239.238; 3.E.239.239; 3.E.239.154; 3.E.239.157; 3.E.239.166; 3.E.239.169; 3.E.239.172; 3.E.239.175; 3.E.239.240; 3.E.239.244; 3.E.154.228; 3.E.154.229; 3.E.154.230; 3.E.154.231; 3.E.154.236; 3.E.154.237; 3.E.154.238; 3.E.154.239; 3.E.154.154; 3.E.154.157; 3.E.154.166; 3.E.154.169; 3.E.154.172; 3.E.154.175; 3.E.154.240; 3.E.154.244; 3.E.157.228; 3.E.157.229; 3.E.157.230; 3.E.157.231; 3.E.157.236; 3.E.157.237; 3.E.157.238; 3.E.157.239; 3.E.157.154; 3.E.157.157; 3.E.157.166; 3.E.157.169; 3.E.157.172; 3.E.157.175; 3.E.157.240; 3.E.157.244; 3.E.166.228; 3.E.166.229; 3.E.166.230; 3.E.166.231; 3.E.166.236; 3.E.166.237; 3.E.166.238; 3.E.166.239; 3.E.166.154; 3.E.166.157; 3.E.166.166; 3.E.166.169; 3.E.166.172; 3.E.166.175; 3.E.166.240; 3.E.166.244; 3.E.169.228; 3.E.169.229; 3.E.169.230; 3.E.169.231; 3.E.169.236; 3.E.169.237; 3.E.169.238; 3.E.169.239; 3.E.169.154; 3.E.169.157; 3.E.169.166; 3.E.169.169; 3.E.169.172; 3.E.169.175; 3.E.169.240; 3.E.169.244; 3.E.172.228; 3.E.172.229; 3.E.172.230; 3.E.172.231; 3.E.172.236; 3.E.172.237; 3.E.172.238; 3.E.172.239; 3.E.172.154; 3.E.172.157; 3.E.172.166; 3.E.172.169; 3.E.172.172; 3.E.172.175; 3.E.172.240; 3.E.172.244; 3.E.175.228; 3.E.175.229; 3.E-175.230; 3.E.175.231; 3.E.175.236; 3.E.175.237; 3.E.175.238; 3.E.175.239; 3.E.175.154; 3.E.175.157; 3.E.175.166; 3.E.175.169; 3.E.175.172; 3.E.175.175; 3.E.175.240; 3.E.175.244; 3.E.240.228; 3.E.240.229; 3.E.240.230; 3.E.240.231; 3.E.240.236; 3.E.240.237; 3.E.240.238; 3.E.240.239; 3.E.240.154; 3.E.240.157; 3.E.240.166; 3.E.240.169; 3.E.240.172; 3.E.240.175; 3.E.240.240; 3.E.240.244; 3.E.244.228; 3.E.244.229; 3.E.244.230; 3.E.244.231; 3.E.244.236; 3.E.244.237; 3.E.244.238; 3.E.244.239; 3.E.244.154; 3.E.244.157; 3.E.244.166; 3.E.244.169; 3.E.244.172; 3.E.244.175; 3.E.244.240; 3.E.244.244;
Prodrugs of 3.G
3.G.228.228; 3.G.228.229; 3.G.228.230; 3.G.228.231; 3.G.228.236; 3.G.228.237; 3.G.228.238; 3.G.228.239; 3.G.228.154; 3.G.228.157; 3.G.228.166; 3.G.228.169; 3.G.228.172; 3.G.228.175; 3.G.228.240; 3.G.228.244; 3.G.229.228; 3.G.229.229; 3.G.229.230; 3.G.229.231; 3.G.229.236; 3.G.229.237; 3.G.229.238; 3.G.229.239; 3.G.229.154; 3.G.229.157; 3.G.229.166; 3.G.229.169; 3.G.229.172; 3.G.229.175; 3.G.229.240; 3.G.229.244; 3.G.230.228; 3.G.230.229; 3.G.230.230; 3.G.230.231; 3.G.230.236; 3.G.230.237; 3.G.230.238; 3.G.230.239; 3.G.230.154; 3.G.230.157; 3.G.230.166; 3.G.230.169; 3.G.230.172; 3.G.230.175; 3.G.230.240; 3.G.230.244; 3.G.231.228; 3.G.231.229; 3.G.231.230; 3.G.231.231; 3.G.231.236; 3.G.231.237; 3.G.231.238; 3.G.231.239; 3.G.231.154; 3.G.231.157; 3.G.231.166; 3.G.231.169; 3.G.231.172; 3.G.231.175; 3.G.231.240; 3.G.231.244; 3.G.236.228; 3.G.236.229;
3.G.236.230; 3.G.236.231; 3.G.236.236; 3.G.236.237; 3.G.236.238; 3.G.236.239; 3.G.236.154; 3.G.236.157; 3.G.236.166; 3.G.236.169; 3.G.236.172; 3.G.236.175; 3.G.236.240; 3.G.236.244; 3.G.237.228; 3.G.237.229; 3.G.237.230; 3.G.237.231; 3.G.237.236; 3.G.237.237; 3.G.237.238; 3.G.237.239; 3.G.237.154; 3.G.237.157; 3.G.237.166; 3.G.237.169; 3.G.237.172; 3.G.237.175; 3.G.237.240; 3.G.237.244; 3.G.238.228; 3.G.238.229; 3.G.238.230; 3.G.238.231; 3.G.238.236; 3.G.238.237; 3.G.238.238; 3.G.238.239; 3.G.238.154; 3.G.238.157; 3.G.238.166; 3.G.238.169; 3.G.238.172; 3.G.238.175; 3.G.238.240; 3.G.238.244; 3.G.239.228; 3.G.239.229; 3.G.239.230; 3.G.239.231; 3.G.239.236; 3.G.239.237; 3.G.239.238; 3.G.239.239; 3.G.239.154; 3.G.239.157; 3.G.239.166; 3.G.239.169; 3.G.239.172; 3.G.239.175; 3.G.239.240; 3.G.239.244; 3.G.154.228; 3.G.154.229; 3.G.154.230; 3.G.154.231; 3.G.154.236; 3.G.154.237; 3.G.154.238; 3.G.154.239; 3.G.154.154; 3.G.154.157; 3.G.154.166; 3.G.154.169; 3.G.154.172; 3.G.154.175; 3.G.154.240; 3.G.154.244; 3.G.157.228; 3.G.157.229; 3.G.157.230; 3.G.157.231; 3.G.157.236; 3.G.157.237; 3.G.157.238; 3.G.157.239; 3.G.157.154; 3.G.157.157; 3.G:i57.166; 3.G.157.169; 3.G.157.172; 3.G.157175; 3.G.157.240; 3.G.157.244; 3.G.166.228; 3.G.166.229; 3.G.166.230; 3.G.166.231; 3.G.166.236; 3.G.166.237; 3.G.166.238; 3.G.166.239; 3.G.166.154; 3.G.166.157; 3.G.166.166; 3.G.166.169; 3.G.166.172; 3.G.166.175; 3.G.166.240; 3.G.166.244; 3.G.169.228; 3.G.169.229; 3.G.169.230; 3.G.169.231; 3.G.169.236; 3.G.169.237; 3.G.169.238; 3.G.169.239; 3.G.169.154; 3.G.169.157; 3.G.169.166; 3.G.169.169; 3.G.169.172; 3.G.169.175; 3.G.169.240; 3.G.169.244; 3.G.172.228; 3.G.172.229; 3.G.172.230; 3.G.172.231; 3.G.172.236; 3.G.172.237; 3.G.172.238; 3.G.172.239; 3.G.172.154; 3.G.172.157; 3.G.172.166; 3.G.172.169; 3.G.172.172; 3.G.172.175; 3.G.172.240; 3.G.172.244; 3.G.175.228; 3.G.175.229; 3.G.175.230; 3.G.175.231; 3.G.175.236; 3.G.175.237; 3.G.175.238; 3.G.175.239; 3.G.175.154; 3.G.175.157; 3.G.175.166; 3.G.175.169; 3.G.175.172; 3.G.175.175; 3.G.175.240; 3.G.175.244; 3.G.240.228; 3.G.240.229; 3.G.240.230; 3.G.240.231; 3.G.240.236; 3.G.240.237; 3.G.240.238; 3.G.240.239; 3.G.240.154; 3.G.240.157; 3.G.240.166; 3.G.240.169; 3.G.240.172; 3.G.240.175; 3.G.240.240; 3.G.240.244; 3.G.244.228; 3.G.244.229; 3.G.244.230; 3.G.244.231; 3.G.244.236; 3.G.244.237; 3.G.244.238; 3.G.244.239; 3.G.244.154; 3.G.244.157; 3.G.244.166; 3.G.244.169; 3.G.244.172; 3.G.244.175; 3.G.244.240; 3.G.244.244;
Prodrugs of 3.1
3.1.228.228; 3.1.228.229; 3.1.228.230; 3.1.228.231; 3.1.228.236; 3.1.228.237; 3.1.228.238; 3.1.228.239; 3.1.228.154; 3.1.228.157; 3.1.228.166; 3.1.228.169; 3.1.228.172; 3.1.228.175; 3.1.228.240; 3.1.228.244; 3.1.229.228; 3.1.229.229; 3.1.229.230; 3.1.229.231; 3.1.229.236; 3.1.229.237; 3.1.229.238; 3.1.229.239; 3.1.229.154; 3.1.229.157; 3.1.229.166; 3.1.229.169; 3.1.229.172; 3.1.229.175; 3.1.229.240; 3.1.229.244; 3.1.230.228; 3.1.230.229; 3.1.230.230; 3.1.230.231; 3.1.230.236; 3.1.230.237; 3.1.230.238; 3.1.230.239; 3.1.230.154; 3.1.230.157; 3.1.230.166; 3.1.230.169; 3.1.230.172; 3.1.230.175; 3.1.230.240; 3.1.230.244; 3.1.231.228; 3.1.231.229; 3.1.231.230; 3.1.231.231; 3.1.231.236; 3.1.231.237; 3.1.231.238; 3.1.231.239; 3.1.231.154; 3.1.231.157; 3.1.231.166; 3.1.231.169; 3.1.231.172; 3.1.231.175; 3.1.231.240; 3.1.231.244; 3.1.236.228; 3.1.236.229; 3.1.236.230; 3.1.236.231; 3.1.236.236; 3.1.236.237; 3.1.236.238; 3.1.236.239; 3.1.236.154; 3.1.236.157; 3.1.236.166; 3.1.236.169; 3.1.236.172; 3.1.236.175; 3.1.236.240; 3.1.236.244; 3.1.237.228; 3.1.237.229; 3.1.237.230; 3.1.237.231;
3.1.237.236; 3.1.237.237; 3.1.237.238; 3.1.237.239; 3.1.237.154; 3.1.237.157; 3.1.237.166; 3.1.237.169; 3.1.237.172; 3.1.237.175; 3.1.237.240; 3.1.237.244; 3.1.238.228; 3.1.238.229; 3.1.238.230; 3.1.238.231; 3.1.238.236; 3.1.238.237; 3.1.238.238; 3.1.238.239; 3.1.238.154; 3.1.238.157; 3.1.238.166; 3.1.238.169; 3.1.238.172; 3.1.238.175; 3.1.238.240; 3.1.238.244; 3.1.239.228; 3.1.239.229; 3.1.239.230; 3.1.239.231; 3.1.239.236; 3.1.239.237; 3.1.239.238; 3.1.239.239; 3.1.239.154; 3.1.239.157; 3.1.239.166; 3.1.239.169; 3.1.239.172; 3.1.239.175; 3.1.239.240; 3.1.239.244; 3.1.154.228; 3.1.154.229; 3.1.154.230; 3.1.154.231; 3.1.154.236; 3.1.154.237; 3.1.154.238; 3.1.154.239; 3.1.154.154; 3.1.154.157; 3.1.154.166; 3.1.154.169; 3.1.154.172; 3.1.154.175; 3.1.154.240; 3.1.154.244; 3.1.157.228; 3.1.157.229; 3.1.157.230; 3.1.157.231; 3.1.157.236; 3.1.157.237; 3.1.157.238; 3.1.157.239; 3.1.157.154; 3.1.157.157; 3.1.157.166; 3.1.157.169; 3.1.157-172; 3.1.157.175; 3.1.157.240; 3.1.157.244; 3.1.166.228; 3.1.166.229; 3.1.166.230; 3.1.166.231; 3.1.166.236; 3.1.166.237; 3.1.166.238; 3.1.166.239; 3.1.166.154; 3.1.166.157; 3.1.166.166; 3.1.166.169; 3.1.166.172; 3.1.166.175; 3.1.166.240; 3.1.166.244; 3.1.169.228; 3.1.169.229; 3.1.169.230; 3.1.169.231; 3.1.169.236; 3.1.169.237; 3.1.169.238; 3.1.169.239; 3.1.169.154; 3.1.169.157; 3.1.169.166; 3.1.169.169; 3.1.169.172; 3.1.169.175; 3.1.169.240; 3.1.169.244; 3.1.172.228; 3.1.172.229; 3.1.172.230; 3.1.172.231; 3.1.172.236; 3.1.172.237; 3.1.172.238; 3.1.172.239; 3.1.172.154; 3.1.172.157; 3.1.172.166; 3.1.172.169; 3.1.172.172; 3.1.172.175; 3.1.172.240; 3.1.172.244; 3.1.175.228; 3.1.175.229; 3.1.175.230; 3.1.175.231; 3.1.175.236; 3.1.175.237; 3.1.175.238; 3.1.175.239; 3.1.175.154; 3.1.175.157; 3.1.175.166; 3.1.175.169; 3.1.175.172; 3.1.175.175; 3.1.175.240; 3.1.175.244; 3.1.240.228; 3.1.240.229; 3.1.240.230; 3.1.240.231; 3.1.240.236; 3.1.240.237; 3.1.240.238; 3.1.240.239; 3.1.240.154; 3.1.240.157; 3.1.240.166; 3.1.240.169; 3.1.240.172; 3.L240.175; 3.1.240.240; 3.1.240.244; 3.1.244.228; 3.1.244.229; 3.1.244.230; 3,1.244.231; 3.1.244.236; 3.1.244.237; 3.1.244.238; 3.1.244.239; 3.1.244.154; 3.1.244.157; 3.1.244.166; 3.1.244.169; 3.1.244.172; 3.1.244.175; 3.1.244.240; 3.1.244.244;
Prodrugs of 3.T
3.J.228.228; 3J.228.229; 3.J.228.230; 3.J.228.231; 3.J.228.236; 3.J.228.237; 3.J.228.238; 3J.228.239; 3.J.228.154; 3J.228.157; 3J.228.166; 3J.228.169; 3J.228.172; 3J.228.175; 3J.228.240; 3J.228.244; 3.J.229.228; 3J.229.229; 3J.229.230; 3J.229.231; 3J.229.236; 3J.229.237; 3J.229.238; 3J.229.239; 3J.229.154; 3J.229.157; 3J.229.166; 3.J.229.169; 3.J.229.172; 3.J.229.175; 3J.229.240; 3.J.229.244; 3J.230.228; 3J.230.229; 3.J.230.230; 3.J.230.231; 3J.230.236; 3J.230.237; 3J.230.238; 3J.230.239; 3J.230.154; 3J.230.157; 3J.230.166; 3.J.230.169; 3J.230.172; 3.J.230.175; 3.J.230.240; 3J.230.244; 3J.231.228; 3J.231.229; 3J.231.230; 3J.231.231; 3J.231.236; 3J.231.237; 3J.231.238; 3J.231.239; 3J.231.154; 3.J.231.157; 3.J.231.166; 3.J.231.169; 3J.231.172; 3J.231.175; 3J.231.240; 3J.231.244; 3J.236.228; 3.J.236.229; 3J.236.230; 3J.236.231; 3J.236.236; 3J.236.237; 3.J.236.238; 3J.236.239; 3J.236.154; 3 J.236.157; 3.J.236.166; 3 J.236.169; 3.J.236.172; 3J.236.175; 3.J.236.240; 3J.236.244; 3J.237.228; 3.J.237.229; 3J.237.230; 3J.237.231; 3.J.237.236; 3.J.237.237; 3J.237.238; 3J.237.239; 3J.237.154; 3J.237.157; 3.J.237.166; 3.J.237.169; 3.J.237.172; 3J.237.175; 3.J.237.240; 3.J.237.244; 3J.238.228; 3.J.238.229; 3J.238.230; 3.J.238.231; 3J.238.236; 3.J.238.237; 3.J.238.238; 3J.238.239; 3J.238.154; 3.J.238.157; 3.J.238.166; 3J.238.169; 3J.238.172; 3.J.238.175; 3J.238.240; 3J.238.244; 3J.239.228; 3.J.239.229; 3J.239.230; 3.J.239.231; 3J.239.236; 3J.239.237; 3J.239.238; 3.J.239.239; 3J.239.154; 3J.239.157; 3.J.239.166; 3J.239.169; 3J.239.172; 3J.239.175; 3.J.239.240; 3.J.239.244; 3J.154.228; 3.J.154.229; 3.J.154.230; 3.J.154.231; 3J.154.236;
3J.154.237; 3.J.154.238; 3J.154.239; 3J.154.154; 3J.154.157; 3J.154.166; 3J.154.169; 3J.154.172; 3J.154.175; 3J.154.240; 3J.154.244; 3J.157.228; 3J.157.229; 3.J.157.230; 3J.157.231; 3J.157.236; 3J.157.237; 3J.157.238; 3J.157.239; 3J.157.154; 3J.157.157; 3J.157.166; 3J.157.169; 3J.157.172; 3J.157.175; 3J.157.240; 3J.157.244; 3J.166.228; 3J.166.229; 3J.166.230; 3J.166.231; 3J.166.236; 3J.166.237; 3J.166.238; 3J.166.239; 3J.166.154; 3J.166.157; 3J.166.166; 3J.166.169; 3J.166.172; 3J.166.175; 3J.166.240; 3J.166.244; 3J.169.228; 3J.169.229; 3J.169.230; 3J.169.231; 3J.169.236; 3J.169.237; 3J.169.238; 3J.169.239; 3J.169.154; 3.J.169.157; 3J.169.166; 3J.169.169; 3J.169.172; 3J.i69.175; 3J.169.240; 3J.169.244; 3.J.172.228; 3J.172.229; 3.J.172.230; 3J.172.231; 3J.172.236; 3J.172.237; 3J.172.238; 3J.172.239; 3.J.172.154; 3J.172.157; 3.J.172.166; 3J.172.169; 3J.172.172; 3.J.172.175; 3.J.172.240; 3J.172.244; 3J.175.228; 3.J..175.229; 3J.175.230; 3.J.175.231; 3 J.175.236; 3.J.175.237; 3.J.175.238; 3J.175.239; 3J.175.154; 3.J.175.157; 3.J.175.166; 3.J.175.169; 3.J.175.172; 3.J.175.175; 3J.175.240; 3.J.175.244; 3J.240.228; 3 J.240.229; 3 J.240.230; 3J.240.231; 3.J.240.236; 3.J.240.237; 3J.240.238; 3J.240.239; 3J.240.154; 3.J.240.157; 3.J.240.166; 3.J.240.169; 3J.240.172; 3.J.240.175; 3 J.240.240; 3.J.240.244; 3J.244.228; 3.J.244.229; 3J.244.230; 3.J.244.231; 3.J.244.236; 3.J.244.237; 3.J.244.238; 3.J.244.239; 3.J.244.154; 3.J.244.157; 3.J.244.166; 3J.244.169; 3 J.244.172; 3.J.244.175; 3.J.244.240; 3.J.244.244;
Prodrugs of 3.L
3.L.228.228; 3.L.228.229; 3.L.228.230; 3.L.228.231; 3.L.228.236; 3.L.228.237; 3.L.228.238; 3.L.228.239; 3.L.228.154; 3.L.228.157; 3.L.228.166; 3.L.228.169; 3.L.228.172; 3.L.228.175; 3.L.228.240; 3.L.228.244; 3.L.229.228; 3.L.229.229; 3.L.229.230; 3.L.229.231; 3.L.229.236; 3.L.229.237; 3.L.229.238; 3.L.229.239; 3.L.229.154; 3.L.229.157; 3.L.229.166; 3.L.229.169; 3.L.229.172; 3.L.229.175; 3.L.229.240; 3.L.229.244; 3.L.230.228; 3.L.230.229; 3.L.230.230; 3.L.230.231; 3.L.230.236; 3.L.230.237; 3.L.230.238; 3.L.230.239; 3.L.230.154; 3.L.230.157; 3.L.230.166; 3.L.230.169; 3.L.230.172; 3.L.230.175; 3.L.230.240; 3.L.230.244; 3.L.231.228; 3.L.231.229; 3.L.231.230; 3.L.231.231; 3.L.231.236; 3.L.231.237; 3.L.231.238; 3.L1231.239; 3.L.231.154; 3.L.231.157; 3.L.231.166; 3.L.231.169; 3.L.231.172; 3.L.231.175; 3.L.231.240; 3.L.231.244; 3.L.236.228; 3.L.236.229; 3.L.236.230; 3.L.236.231; 3.L.236.236; 3.L.236.237; 3.L.236.238; 3.L.236.239; 3.L.236.154; 3.L.236.157; 3.L.236.166; 3.L.236.169; 3.L.236.172; 3.L.236.175; 3.L.236.240; 3.L.236.244; 3.L.237.228; 3.L.237.229; 3.L.237.230; 3.L.237.231; 3.L.237.236; 3.L.237.237; 3.L.237.238; 3.L.237.239; 3.L.237.154; 3.L.237.157; 3.L.237.166; 3.L.237.169; 3.L.237.172; 3.L.237.175; 3.L.237.240; 3.L.237.244; 3.L.238.228; 3.L.238.229; 3.L.238.230; 3.L.238.231; 3.L.238.236; 3.L.238.237; 3.L.238.238; 3.L.238.239; 3.L.238.154; 3.L.238.157; 3.L.238.166; 3.L.238.169; 3.L.238.172; 3.L.238.175; 3.L.238.240; 3.L.238.244; 3.L.239.228; 3.L.239.229; 3.L.239.230; 3.L.239.231; 3.L.239.236; 3.L.239.237; 3.L.239.238; 3.L.239.239; 3.L.239.154; 3.L.239.157; 3.L.239.166; 3.L.239.169; 3.L.239.172; 3.L.239.175; 3.L.239.240; 3.L.239.244; 3.L.154.228; 3.L.154.229; 3.L.154.230; 3.L.154.231; 3.L.154.236; 3.L.154.237; 3.L.154.238; 3.L.154.239; 3.L.154.154; 3.L.154.157; 3.L.154.166; 3.L.154.169; 3.L.154.172; 3.L.154.175; 3.L.154.240; 3.L.154.244; 3.L.157.228; 3.L.157.229; 3.L.157.230; 3.L.157.231; 3.L.157.236; 3.L.157.237; 3.L.157.238; 3.L.157.239; 3.L.157.154; 3.L.157.157; 3.L.157.166; 3.L.157.169; 3.L.157.172; 3.L.157.175; 3.L.157.240; 3.L.157.244; 3.L.166.228; 3.L.166.229; 3.L.166.230; 3.L.166.231; 3.L.166.236; 3.L.166.237; 3.L.166.238; 3.L.166.239; 3.L.166.154; 3.L.166.157; 3.L.166.166; 3.L.166.169; 3.L.166.172; 3.L.166.175; 3.L.166.240; 3.L.166.244; 3.L.169.228; 3.L.169.229; 3.L.169.230; 3.L.169.231; 3.L.169.236;
3.L.169.237; 3.L.169.238; 3.L.169.239; 3.L.169.154; 3.L.169.157; 3.L.169.166; 3.L.169.169; 3.L.169.172; 3.L.169.175; 3.L.169.240; 3.L.169.244; 3.L.172.228; 3.L.172.229; 3.L.172.230; 3.L.172.231; 3.L.172.236; 3.L.172.237; 3.L.172.238; 3.L.172.239; 3.L.172.154; 3.L.172.157; 3.L.172.166; 3.L.172.169; 3.L.172.172; 3.L.172.175; 3.L.172.240; 3.L.172.244; 3.L.175.228; 3.L.175.229; 3.L.175.230; 3.L.175.231; 3.L.175.236; 3.L.175.237; 3.L.175.238; 3.L.175.239; 3.L.175.154; 3.L.175.157; 3.L.175.166; 3.L.175.169; 3.L.175.172; 3.L.175.175; 3.L.175.240; 3.L.175.244; 3.L.240.228; 3.L.240.229; 3.L.240.230; 3.L.240.231; 3.L.240.236; 3.L.240.237; 3.L.240.238; 3.L.240.239; 3.L.240.154; 3.L.240.157; 3.L.240.166; 3.L.240.169; 3.L.240.172; 3.L.240.175; 3.L.240.240; 3.L.240.244; 3.L.244.228; 3.L.244.229; 3.L.244.230; 3.L.244.231; 3.L.244.236; 3.L.244.237; 3.L.244.238; 3.L.244.239; 3.L.244.154; 3.L.244.157; 3.L.244.166; 3.L.244.169; 3.L.244.172; 3.L.244.175; 3.L.244.240; 3.L.244.244;
Prodrugs of 3.O
3.O.228.228; 3.O.228.229; 3.O.228.230; 3.O.228.231; 3.O.228.236; 3.O.228.237; 3.O.228.238; 3.O.228.239; 3.O.228.154; 3.O.228.157; 3.O.228.166; 3.O.228.169; 3.O.228.172; 3.O.228.175; 3.O.228.240; 3.O.228.244; 3.O.229.228; 3.O.229.229; 3.O.229.230; 3.O.229.231; 3.O.229.236; 3.O.229.237; 3.O.229.238; 3.O.229.239; 3.O.229.154; 3.O.229.157; 3.O.229.166; 3.O.229.169; 3.O.229.172; 3.O.229.175; 3.O.229.240; 3.O.229.244; 3.O.230.228; 3.O.230.229; 3.O.230.230; 3.O.230.231; 3.O.230.236; 3.O.230.237; 3.O.230.238; 3.O.230.239; 3.O.230.154; 3.O.230.157; 3.O.230.166; 3.O.230.169; 3.O.230.172; 3.O.230.175; 3.O.230.240; 3.O.230.244; 3.O.231.228; 3.O.231.229; 3.O.231.230; 3.O.231.231; 3.O.231.236; 3.O.231.237; 3.O.231.238; 3.O.231.239; 3.O.231.154; 3.O.231.157; 3.O.231.166; 3.O.231.169; 3.O.231.172; 3.O.231.175; 3.O.231.240; 3.O.231.244; 3.O.236.228; 3.O.236.229; 3.O.236.230; 3.O.236.231; 3.O.236.236; 3.O.236.237; 3.O.236.238; 3.O.236.239; 3.O.236.154; 3.O.236.157; 3.O.236.166; 3.O.236.169; 3.O.236.172; 3.O.236.175; 3.O.236.240; 3.O.236.244; 3.O.237.228; 3.O.237.229; 3.O.237.230; 3.O.237.231; 3.O.237.236; 3.O.237.237; 3.O.237.238; 3.O.237.239; 3.O.237.154; 3.O.237.157; 3.O.237.166; 3.O.237.169; 3.O.237.172; 3.O.237.175; 3.O.237.240; 3.O.237.244; 3.O.238.228; 3.O.238.229; 3.O.238.230; 3.O.238.231; 3.O.238.236; 3.O.238.237; 3.O.238.238; 3.O.238.239; 3.O.238.154; 3.O.238.157; 3.O.238.166; 3.O.238.169; 3.O.238.172; 3.O.238.175; 3.O.238.240; 3.O.238.244; 3.O.239.228; 3.O.239.229; 3.0.239.230; 3.O.239.231; 3.O.239.236; 3.O.239.237; 3.O.239.238; 3.O.239.239; 3.O.239.154; 3.O.239.157; 3.O.239.166; 3.O.239.169; 3.O.239.172; 3.O.239.175; 3.O.239.240; 3.O.239.244; 3.O.154.228; 3.O.154.229; 3.O.154.230; 3.O.154.231; 3.O.154.236; 3.O.154.237; 3.O.154.238; 3.O.154.239; 3.O.154.154; 3.O.154.157; 3.O.154.166; 3.O.154.169; 3.O.154.172; 3.O.154.175; 3.O.154.240; 3.O.154.244; 3.O.157.228; 3.O.157.229; 3.O.157.230; 3.O.157.231; 3.O.157.236; 3.O.157.237; 3.O.157.238; 3.O.157.239; 3.O.157.154; 3.O.157.157; 3.O.157.166; 3.O.157.169; 3.O.157.172; 3.O.157.175; 3.0.157.240; 3.0.157.244; 3.O.166.228; 3.O.166.229; 3.O.166.230; 3.O.166.231; 3.O.166.236; 3.O.166.237; 3.O.166.238; 3.O.166.239; 3.O.166.154; 3.O.166.157; 3.O.166.166; 3.O.166.169; 3.O.166.172; 3.O.166.175; 3.O.166.240; 3.O.166.244; 3.O.169.228; 3.O.169.229; 3.O.169.230; 3.O.169.231; 3.O.169.236; 3.O.169.237; 3.O.169.238; 3.O.169.239; 3.O.169.154; 3.O.169.157; 3.O.169.166; 3.O.169.169; 3.O.169.172; 3.O.169.175; 3.O.169.240; 3.O.169.244; 3.O.172.228; 3.O.172.229; 3.O.172.230; 3.O.172.231; 3.O.172.236; 3.O.172.237;
3.0.172.238; 3.O.172.239; 3.O.172.154; 3.O.172.157; 3.O.172.166; 3.O.172.169; 3.O.172.172; 3.O.172.175; 3.O.172.240; 3.O.172.244; 3.O.175.228; 3.O.175.229; 3.0.175.230; 3.O.175.231; 3.O.175.236; 3.O.175.237; 3.O.175.238; 3.O.175.239; 3.0.175.154; 3.O.175.157; 3.O.175.166; 3.O.175.169; 3.O.175.172; 3.O.175.175; 3.O.175.240; 3.O.175.244; 3.O.240.228; 3.O.240.229; 3.O.240.230; 3.O.240.231; 3.O.240.236; 3.O.240.237; 3.O.240.238; 3.O.240.239; 3.O.240.154; 3.O.240.157; 3.0.240.166; 3.O.240.169; 3.O.240.172; 3.O.240.175; 3.O.240.240; 3.O.240.244; 3.O.244.228; 3.O.244.229; 3.O.244.230; 3.O.244.231; 3.O.244.236; 3.O.244.237; 3.O.244.238; 3.O.244.239; 3.O.244.154; 3.O.244.157; 3.O.244.166; 3.O.244.169; 3.O.244.172; 3.O.244.175; 3.O.244.240; 3.O.244.244;
Prodrugs of 3.P
3.P.228.228; 3.P.228.229; 3.P.228.230; 3.P.228.231; 3.P.228.236; 3.P.228.237; 3.P.228.238; 3.P.228.239; 3.P.228.154; 3.P.228.157; 3.P.228.166; 3.P.228.169; 3.P.228.172; 3.P.228.175; 3.P.228.240; 3.P.228.244; 3.P.229.228; 3.P.229.229; 3.P.229.230; 3.P.229.231; 3.P.229.236; 3.P.229.237; 3.P.229.238; 3.P.229.239; 3.P.229.154; 3.P.229.157; 3.P.229.166; 3.P.229.169; 3.P.229.172; 3.P.229.175; 3.P.229.240; 3.P.229.244; 3.P.230.228; 3.P.230.229; 3.P.230.230; 3.P.230.231; 3.P.230.236; 3.P.230.237; 3.P.230.238; 3.P.230.239; 3.P.230.154; 3.P.230.157; 3.P.230.166; 3.P.230.169; 3.P.230.172; 3.P.230.175; 3.P.230.240; 3.P.230.244; 3.P.231.228; 3.P.231.229; 3.P.231.230; 3.P.231.231; 3.P.231.236; 3.P.231.237; 3.P.231.238; 3.P.231.239; 3.P.231.154; 3.P.231.157; 3.P.231.166; 3.P.231.169; 3.P.231.172; 3.P.231.175; 3.P.231.240; 3.P.231.244; 3.P.236.228; 3.P.236.229; 3.P.236.230; 3.P.236.231; 3.P.236.236; 3.P.236.237; 3.P.236.238; 3.P.236.239; 3.P.236.154; 3.P.236.157; 3.P.236.166; 3.P.236.169; 3.P.236.172; 3.P.236.175; 3.P.236.240; 3.P.236.244; 3.P.237.228; 3.P.237.229; 3.P.237.230; 3.P.237.231; 3.P.237.236; 3.P.237.237; 3.P.237.238; 3.P.237.239; 3.P.237.154; 3.P.237.157; 3.P.237.166; 3.P.237.169; 3.P.237.172; 3.P.237.175; 3.P.237.240; 3.P.237.244; 3.P.238.228; 3.P.238.229; 3.P.238.230; 3.P.238.231; 3.P.238.236; 3.P.238.237; 3.P.238.238; 3.P.238.239; 3.P.238.154; 3.P.238.157; 3.P.238.166; 3.P.238.169; 3.P.238.172; 3.P.238.175; 3.P.238.240; 3.P.238.244; 3.P.239.228; 3.P.239.229; 3.P.239.230; 3.P.239.231; 3.P.239.236; 3.P.239.237; 3.P.239.238; 3.P.239.239; 3.P.239.154; 3.P.239.157; 3.P.239.166; 3.P.239.169; 3.P.239.172; 3.P.239.175; 3.P.239.240; 3.P.239.244; 3.P.154.228; 3.P.154.229; 3.P.154.230; 3.P.154.231; 3.P.154.236; 3.P.154.237; 3.P.154.238; 3.P.154.239; 3.P.154.154; 3.P.154.157; 3.P.154.166; 3.P.154.169; 3.P.154.172; 3.P.154.175; 3.P.154.240; 3.P.154.244; 3.P.157.228; 3.P.157.229; 3.P.157.230; 3.P.157.231; 3.P.157.236; 3.P.157.237; 3.P.157.238; 3.P.157.239; 3.P.157.154; 3.P.157.157; 3.P.157.166; 3.P.157.169; 3.P.157.172; 3.P.157.175; 3.P.157.240; 3.P.157.244; 3.P.166.228; 3.P.166.229; 3.P.166.230; 3.P.166.231; 3.P.166.236; 3.P.166.237; 3.P.166.238; 3.P.166.239; 3.P.166.154; 3.P.166.157; 3.P.166.166; 3.P.166.169; 3.P.166.172; 3.P.166.175; 3.P.166.240; 3.P.166.244; 3.P.169.228; 3.P.169.229; 3.P.169.230; 3.P.169.231; 3.P.169.236; 3.P.169.237; 3.P.169.238; 3.P.169.239; 3.P.169.154; 3.P.169.157; 3.P.169.166; 3.P.169.169; 3.P.169.172; 3.P.169.175; 3.P.169.240; 3.P.169.244; 3.P.172.228; 3.P.172.229; 3.P.172.230; 3.P.172.231; 3.P.172.236; 3.P.172.237; 3.P.172.238; 3.P.172.239; 3.P.172.154; 3.P.172.157; 3.P.172.166; 3.P.172.169; 3.P.172.172; 3.P.172.175; 3.P.172.240; 3.P.172.244; 3.P.175.228; 3.P.175.229; 3.P.175.230; 3.P.175.231; 3.P.175.236; 3.P.175.237; 3.P.175.238; 3.P.175.239; 3.P.175.154; 3.P.175.157; 3.P.175.166; 3.P.175.169; 3.P.175.172; 3.P.175.175; 3.P.175.240; 3.P.175.244; 3.P.240.228; 3.P.240.229; 3.P.240.230; 3.P.240.231; 3.P.240.236; 3.P.240.237; 3.P.240.238; 3.P.240.239; 3.P.240.154; 3.P.240.157; 3.P.240.166; 3.P.240.169; 3.P.240.172;
3.P.240.175; 3.P.240.240; 3.P.240.244; 3.P.244.228; 3.P.244.229; 3.P.244.230; 3.P.244.231; 3.P.244.236; 3.P.244.237; 3.P.244.238; 3.P.244.239; 3.P.244.154; 3.P.244.157; 3.P.244.166; 3.P.244.169; 3.P.244.172; 3.P.244.175; 3.P.244.240; 3.P.244.244;
Prodrugs of 3.U
3.U.228.228; 3.U.228.229; 3.U.228.230; 3.U.228.231; 3.U.228.236; 3.U.228.237; 3.U.228.238; 3.U.228.239; 3.U.228.154; 3.U.228.157; 3.U.228.166; 3.U.228.169; 3.U.228.172; 3.U.228.175; 3.U.228.240; 3.U.228.244; 3.U.229.228; 3.U.229.229; 3.U.229.230; 3.U.229.231; 3.U.229.236; 3.U.229.237; 3.U.229.238; 3.U.229.239; 3.U.229.154; 3.U.229.157; 3.U.229.166; 3.U.229.169; 3.U.229.172; 3.U.229.175; 3.U.229.240; 3.U.229.244; 3.U.230.228; 3.U.230.229; 3.U.230.230; 3.U.230.231; 3.U.230.236; 3.U.230.237; 3.U.230.238; 3.U.230.239; 3.U.230.154; 3.U.230.157; 3.U.230.166; 3.U.230.169; 3.U.230.172; 3.U.230.175; 3.U.230.240; 3.U.230.244; 3.U.231.228; 3.U.231.229; 3.U.231.230; 3.U.231.231; 3.U.231.236; 3.U.231.237; 3.U.231.238; 3.U.231.239; 3.U.231.154; 3.U.231.157; 3.U.231.166; 3.U.231.169; 3.U.231.172; 3.U.231.175; 3.U.231.240; 3.U.231.244; 3.U.236.228; 3.U.236.229; 3.U.236.230; 3.U.236.231; 3.U.236.236; 3.U.236.237; 3.U.236.238; 3.U.236.239; 3.U.236.154; 3.U.236.157; 3.U.236.166; 3.U.236.169; 3.U.236.172; 3.U.236.175; 3.U.236.240; 3.U.236.244; 3.U.237.228; 3.U.237.229; 3.U.237.230; 3.U.237.231; 3.U.237.236; 3.U.237.237; 3.U.237.238; 3.U.237.239; 3.U.237.154; 3.U.237.157; 3.U.237.166; 3.U.237.169; 3.U.237.172; 3.U.237.175; 3.U.237.240; 3.U.237.244; 3.U.238.228; 3.U.238.229; 3.U.238.230; 3.U.238.231; 3.U.238.236; 3.U.238.237; 3.U.238.238; 3.U.238.239; 3.U.238.154; 3.U.238.157; 3.U.238.166; 3.U.238.169; 3.U.238.172; 3.U.238.175; 3.U.238.240; 3.U.238.244; 3.U.239.228; 3.U.239.229; 3.U.239.230; 3.U.239.231; 3.U.239.236; 3.U.239.237; 3.U.239.238; 3.U.239.239; 3.U.239.154; 3.U.239.157; 3.U.239.166; 3.U.239.169; 3.U.239.172; 3.U.239.175; 3.U.239.240; 3.U.239.244; 3.U.154.228; 3.U.154.229; 3.U.154.230; 3.U.154.231; 3.U.154.236; 3.U.154.237; 3.U.154.238; 3.U.154.239; 3.U.154.154; 3.U.154.157; 3.U.154.166; 3.U.154.169; 3.U.154.172; 3.U.154.175; 3.U.154.240; 3.U.154.244; 3.U.157.228; 3.U.157.229; 3.U.157.230; 3.U.157.231; 3.U.157.236; 3.U.157.237; 3.U.157.238; 3.U.157.239; 3.U.157.154; 3.U.157.157; 3.U.157.166; 3.U.157.169; 3.U.157.172; 3.U.157.175; 3.U.157.240; 3.U.157.244; 3.U.166.228; 3.U.166.229; 3.U.166.230; 3.U.166.231; 3.U.166.236; 3.U.166.237; 3.U.166.238; 3.U.166.239; 3.U.166.154; 3.U.166.157; 3.U.166.166; 3.U.166.169; 3.U.166.172; 3.U.166.175; 3.U.166.240; 3.U.166.244; 3.U.169.228; 3.U.169.229; 3.U.169.230; 3.U.169.231; 3.U.169.236; 3.U.169.237; 3.U.169.238; 3.U.169.239; 3.U.169.154; 3.U.169.157; 3.U.169.166; 3.U.169.169; 3.U.169.172; 3.U.169.175; 3.U.169.240; 3.U.169.244; 3.U.172.228; 3.U.172.229; 3.U.172.230; 3.U.172.231; 3.U.172.236; 3.U.172.237; 3.U.172.238; 3.U.172.239; 3.U.172.154; 3.U.172.157; 3.U.172.166; 3.U.172.169; 3.U.172.172; 3.U.172.175; 3.U.172.240; 3.U.172.244; 3.U.175.228; 3.U.175.229; 3.U.175.230; 3.U.175.231; 3.U.175.236; 3.U.175.237; 3.U.175.238; 3.U.175.239; 3.U.175.154; 3.U.175.157; 3.U.175.166; 3.U.175.169; 3.U.175.172; 3.U.175.175; 3.U.175.240; 3.U.175.244; 3.U.240.228; 3.U.240.229; 3.U.240.230; 3.U.240.231; 3.U.240.236; 3.U.240.237; 3.U.240.238; 3.U.240.239; 3.U.240.154; 3.U.240.157; 3.U.240.166; 3.U.240.169; 3.U.240.172; 3.U.240.175; 3.U.240.240; 3.U.240.244; 3.U.244.228; 3.U.244.229; 3.U.244.230; 3.U.244.231; 3.U.244.236; 3.U.244.237;
3.U.244.238; 3.U.244.239; 3.U.244.154; 3.U.244.157; 3.U.244.166; 3.U.244.169; 3.U.244.172; 3.U.244.175; 3.U.244.240; 3.U.244.244;
Prodrugs of 3.W
3.W.228.228; 3.W.228.229; 3.W.228.230; 3.W.228.231; 3.W.228.236; 3.W.228.237; 3.W.228.238; 3.W.228.239; 3.W.228.154; 3.W.228.157; 3.W.228.166; 3.W.228.169; 3.W.228.172; 3.W.228.175; 3.W.228.240; 3.W.228.244; 3.W.229.228; 3.W.229.229; 3.W.229.230; 3.W.229.231; 3.W.229.236; 3.W.229.237; 3.W.229.238; 3.W.229.239; 3.W.229.154; 3.W.229.157; 3.W.229.166; 3.W.229.169; 3.W.229.172; 3.W.229.175; 3.W.229.240; 3.W.229.244; 3.W.230.228; 3.W.230.229; 3.W.230.230; 3.W.230.231; 3.W.230.236; 3.W.230.237; 3.W.230.238; 3.W.230.239; 3.W.230.154; 3.W.230.157; 3.W.230.166; 3.W.230.169; 3.W.230.172; 3.W.230.175; 3.W.230.240; 3.W.230.244; 3.W.231.228; 3.W.231.229; 3.W.231.230; 3.W.231.231; 3.W.231.236; 3.W.231.237; 3.W.231.238; 3.W.231.239; 3.W.231.154; 3.W.231.157; 3.W.231.166; 3.W.231.169; 3.W.231.172; 3.W.231.175; 3.W.231.240; 3.W.231.244; 3.W.236.228; 3.W.236.229; 3.W.236.230; 3.W.236.231; 3.W.236.236; 3.W.236.237; 3.W.236.238; 3.W.236.239; 3.W.236.154; 3.W.236.157; 3.W.236.166; 3.W.236.169; 3.W.236.172; 3.W.236.175; 3.W.236.240; 3.W.236.244; 3.W.237.228; 3.W.237.229; 3.W.237.230; 3.W.237.231; 3.W.237.236; 3.W.237.237; 3.W.237.238; 3.W.237.239; 3.W.237.154; 3.W.237.157; 3.W.237.166; 3.W.237.169; 3.W.237.172; 3.W.237.175; 3.W.237.240; 3.W.237.244; 3.W.238.228; 3.W.238.229; 3.W.238.230; 3.W.238.231; 3.W.238.236; 3.W.238.237; 3.W.238.238; 3.W.238.239; 3.W.238.154; 3.W.238.157; 3.W.238.166; 3.W.238.169; 3.W.238.172; 3.W.238.175; 3.W.238.240; 3.W.238.244; 3.W.239.228; 3.W.239.229; 3.W.239.230; 3.W.239.231; 3.W.239.236; 3.W.239.237; 3.W.239.238; 3.W.239.239; 3.W.239.154; 3.W.239.157; 3.W.239.166; 3.W.239.169; 3.W.239.172; 3.W.239.175; 3.W.239.240; 3.W.239.244; 3.W.154.228; 3.W.154.229; 3.W.154.230; 3.W.154.231; 3.W.154.236; 3.W.154.237; 3.W.154.238; 3.W.154.239; 3.W.154.154;3.W.154.157; 3.W.154.166; 3.W.154.169; 3.W.154.172; 3.W.154.175; 3.W.154.240; 3.W.154.244; 3.W.157.228; 3.W.157.229; 3.W.157.230; 3.W.157.231; 3.W.157.236; 3.W.157.237; 3.W.157.238; 3.W.157.239; 3.W.157.154; 3.W.157.157; 3.W.157.166; 3.W.157.169; 3.W.157.172; 3.W.157.175; 3.W.157.240; 3.W.157.244; 3.W.166.228; 3.W.166.229; 3.W.166.230; 3.W.166.231; 3.W.166.236; 3.W.166.237; 3.W.166.238; 3.W.166.239; 3.W.166.154; 3.W.166.157; 3.W.166.166; 3.W.166.169; 3.W.166.172; 3.W.166.175; 3.W.166.240; 3.W.166.244; 3.W.169.228; 3.W.169.229; 3.W.169.230; 3.W.169.231; 3.W.169.236; 3.W.169.237; 3.W.169.238; 3.W.169.239; 3.W.169.154; 3.W.169.157; 3.W.169.166; 3.W.169.169; 3.W.169.172; 3.W.169.175; 3.W.169.240; 3.W.169.244; 3.W.172.228; 3.W.172.229; 3.W.172.230; 3.W.172.231; 3.W.172.236; 3.W.172.237; 3.W.172.238; 3.W.172.239; 3.W.172.154; 3.W.172.157; 3.W.172.166; 3.W.172.169; 3.W.172.172; 3.W.172.175; 3.W.172.240; 3.W.172.244; 3.W.175.228; 3.W.175.229; 3.W.175.230; 3.W.175.231; 3.W.175.236; 3.W.175.237; 3.W.175.238; 3.W.175.239; 3.W.175.154; 3.W.175.157; 3.W.175.166; 3.W.175.169; 3.W.175.172; 3.W.175.175; 3.W.175.240; 3.W.175.244; 3.W.240.228; 3.W.240.229; 3.W.240.230; 3.W.240.231; 3.W.240.236; 3.W.240.237; 3.W.240.238; 3.W.240.239; 3.W.240.154; 3.W.240.157; 3.W.240.166; 3.W.240.169; 3.W.240.172; 3.W.240.175; 3.W.240.240; 3.W.240.244; 3.W.244.228; 3.W.244.229; 3.W.244.230; 3.W.244.231; 3.W.244.236; 3.W.244.237;
3.W.244.238; 3.W.244.239; 3.W.244.154; 3.W.244.157; 3.W.244.166; 3.W.244.169; 3.W.244.172; 3.W.244.175; 3.W.244.240; 3.W.244.244;
Prodrugs of 3.Y
3.Y.228.228; 3.Y.228.229; 3.Y.228.230; 3.Y.228.231; 3.Y.228.236; 3.Y.228.237; 3.Y.228.238; 3.Y.228.239; 3.Y.228.154; 3.Y.228.157; 3.Y.228.166; 3.Y.228.169; 3.Y.228.172; 3.Y.228.175; 3.Y.228.240; 3.Y.228.244; 3.Y.229.228; 3.Y.229.229; 3.Y.229.230; 3.Y.229.231; 3.Y.229.236; 3.Y.229.237; 3.Y.229.238; 3.Y.229.239; 3.Y.229.154; 3.Y.229.157; 3.Y.229.166; 3.Y.229.169; 3.Y.229.172; 3.Y.229.175; 3.Y.229.240; 3.Y.229.244; 3.Y.230.228; 3.Y.230.229; 3.Y.230.230; 3.Y.230.231; 3.Y.230.236; 3.Y.230.237; 3.Y.230.238; 3.Y.230.239; 3.Y.230.154; 3.Y.230.157; 3.Y.230.166; 3.Y.230.169; 3.Y.230.172; 3.Y.230.175; 3.Y.230.240; 3.Y.230.244; 3.Y.231.228; 3.Y.231.229; 3.Y.231.230; 3.Y.231.231; 3.Y.231.236; 3.Y.231.237; 3.Y.231.238; 3.Y.231.239; 3.Y.231.154; 3.Y.231.157; 3.Y.231.166; 3.Y.231.169; 3.Y.231.172; 3.Y.231.175; 3.Y.231.240; 3.Y.231.244; 3.Y.236.228; 3.Y.236.229; 3.Y.236.230; 3.Y.236.231; 3.Y.236.236; 3.Y.236.237; 3.Y.236.238; 3.Y.236.239; 3.Y.236.154; 3.Y.236.157; 3.Y.236.166; 3.Y.236.169; 3.Y.236.172; 3.Y.236.175; 3.Y.236.240; 3.Y.236.244; 3.Y.237.228; 3.Y.237.229; 3.Y.237.230; 3.Y.237.231; 3.Y.237.236; 3.Y.237.237; 3.Y.237.238; 3.Y.237.239; 3.Y.237.154; 3.Y.237.157; 3.Y.237.166; 3.Y.237.169; 3.Y.237.172; 3.Y.237.175; 3.Y.237.240; 3.Y.237.244; 3.Y.238.228; 3.Y.238.229; 3.Y.238.230; 3.Y.238.231; 3.Y.238.236; 3.Y.238.237; 3.Y.238.238; 3.Y.238.239; 3.Y.238.154; 3.Y.238.157; 3.Y.238.166; 3.Y.238.169; 3.Y.238.172; 3.Y.238.175; 3.Y.238.240; 3.Y.238.244; 3.Y.239.228; 3.Y.239.229; 3.Y.239.230; 3.Y.239.231; 3.Y.239.236; 3.Y.239.237; 3.Y.239.238; 3.Y.239.239; 3.Y.239.154; 3.Y.239.157; 3.Y.239.166; 3.Y.239.169; 3.Y.239.172; 3.Y.239.175; 3.Y.239.240; 3.Y.239.244; 3.Y.154.228; 3.Y.154.229; 3.Y.154.230; 3.Y.154.231; 3.Y.154.236; 3.Y.154.237; 3.Y.154.238; 3.Y.154.239; 3.Y.154.154; 3.Y.154.157; 3.Y.154.166; 3.Y.154.169; 3.Y.154.172; 3.Y.154.175; 3.Y.154.240; 3.Y.154.244; 3.Y.157.228; 3.Y.157.229; 3.Y.157.230; 3.Y.157.231; 3.Y.157.236; 3.Y.157.237; 3.Y.157.238; 3.Y.157.239; 3.Y.157.154; 3.Y.157.157; 3.Y.157.166; 3.Y.157.169; 3.Y.157.172; 3.Y.157.175; 3.Y.157.240; 3.Y.157.244; 3.Y.166.228; 3.Y.166.229; 3.Y.166.230; 3.Y.166.231; 3.Y.166.236; 3.Y.166.237; 3.Y.166.238; 3.Y.166.239; 3.Y.166.154; 3.Y.166.157; 3.Y.166.166; 3.Y.166.169; 3.Y.166.172; 3.Y.166.175; 3.Y.166.240; 3.Y.166.244; 3.Y.169.228; 3.Y.169.229; 3.Y.169.230; 3.Y.169.231; 3.Y.169.236; 3.Y.169.237; 3.Y.169.238; 3.Y.169.239; 3.Y.169.154; 3.Y.169.157; 3.Y.169.166; 3.Y.169.169; 3.Y.169.172; 3.Y.169.175; 3.Y.169.240; 3.Y.169.244; 3.Y.172.228; 3.Y.172.229; 3.Y.172.230; 3.Y.172.231; 3.Y.172.236; 3.Y.172.237; 3.Y.172.238; 3.Y.172.239; 3.Y.172.154; 3.Y.172.157; 3.Y.172.166; 3.Y.172.169; 3.Y.172.172; 3.Y.172.175; 3.Y.172.240; 3.Y.172.244; 3.Y.175.228; 3.Y.175.229; 3.Y.175.230; 3.Y.175.231; 3.Y.175.236; 3.Y.175.237; 3.Y.175.238; 3.Y.175.239; 3.Y.175.154; 3.Y.175.157; 3.Y.175.166; 3.Y.175.169; 3.Y.175.172; 3.Y.175.175; 3.Y.175.240; 3.Y.175.244; 3.Y.240.228; 3.Y.240.229; 3.Y.240.230; 3.Y.240.231; 3.Y.240.236; 3.Y.240.237; 3.Y.240.238; 3.Y.240.239; 3.Y.240.154; 3.Y.240.157; 3.Y.240.166; 3.Y.240.169; 3.Y.240.172; 3.Y.240.175; 3.Y.240.240; 3.Y.240.244; 3.Y.244.228; 3.Y.244.229; 3.Y.244.230; 3.Y.244.231; 3.Y.244.236; 3.Y.244.237;
3.Y.244.238; 3.Y.244.239; 3.Y.244.154; 3.Y.244.157; 3.Y.244.166; 3.Y.244.169; 3.Y.244.172; 3.Y.244.175; 3.Y.244.240; 3.Y.244.244;
Prodrugs of 4.B
4.B.228.228; 4.B.228.229; 4.B.228.230; 4.B.228.231; 4.B.228.236; 4.B.228.237; 4.B.228.238; 4.B.228.239; 4.B.228.154; 4.B.228.157; 4.B.228.166; 4.B.228.169; 4.B.228.172; 4.B.228.175; 4.B.228.240; 4.B.228.244; 4.B.229.228; 4.B.229.229; 4.B.229.230; 4.B.229.231; 4.B.229.236; 4.B.229.237; 4.B.229.238; 4.B.229.239; 4.B.229.154; 4.B.229.157; 4.B.229.166; 4.B.229.169; 4.B.229.172; 4.B.229.175; 4.B.229.240; 4.B.229.244; 4.B.230.228; 4.B.230.229; 4.B.230.230; 4.B.230.231; 4.B.230.236; 4.B.230.237; 4.B.230.238; 4.B.230.239; 4.B.230.154; 4.B.230.157; 4.B.230.166; 4.B.230.169; 4.B.230.172; 4.B.230.175; 4.B.230.240; 4.B.230.244; 4.B.231.228; 4.B.231.229; 4.B.231.230; 4.B.231.231; 4.B.231.236; 4.B.231.237; 4.B.231.238; 4.B.231.239; 4.B.231.154; 4.B.231.157; 4.B.231.166; 4.B.231.169; 4.B.231.172; 4.B.231.175; 4.B.231.240; 4.B.231.244; 4.B.236.228; 4.B.236.229; 4.B.236.230; 4.B.236.231; 4.B.236.236; 4.B.236.237; 4.B.236.238; 4.B.236.239; 4.B.236.154; 4.B.236.157; 4.B.236.166; 4.B.236.169; 4.B.236.172; 4.B.236.175; 4.B.236.240; 4.B.236.244; 4.B.237.228; 4.B.237.229; 4.B.237.230; 4.B.237.231; 4.B.237.236; 4.B.237.237; 4.B.237.238; 4.B.237.239; 4.B.237.154; 4.B.237.157; 4.B.237.166; 4.B.237.169; 4.B.237.172; 4.B.237.175; 4.B.237.240; 4.B.237.244; 4.B.238.228; 4.B.238.229; 4.B.238.230; 4.B.238.231;4.B.238.236; 4.B.238.237; 4.B.238.238; 4.B.238.239; 4.B.238.154; 4.B.238.157; 4.B.238.166; 4.B.238.169; 4.B.238.172; 4.B.238.175; 4.B.238.240; 4.B.238.244; 4.B.239.228; 4.B.239.229; 4.B.239.230; 4.B.239.231; 4.B.239.236; 4.B.239.237; 4.B.239.238; 4.B.239.239; 4.B.239.154; 4.B.239.157; 4.B.239.166; 4.B.239.169; 4.B.239.172; 4.B.239.175; 4.B.239.240; 4.B.239.244; 4.B.154.228; 4.B.154.229; 4.B.154.230; 4.B.154.231; 4.B.154.236; 4.B.154.237; 4.B.154.238; 4.B.154.239; 4.B.154.154; 4.B.154.157; 4.B.154.166; 4.B.154.169; 4.B.154.172; 4.B.154.175; 4.B.154.240; 4.B.154.244; 4.B.157.228; 4.B.157.229; 4.B.157.230; 4.B.157.231; 4.B.157.236; 4.B.157.237; 4.B.157.238; 4.B.157.239; 4.B.157.154; 4.B.157.157; 4.B.157.166; 4.B.157.169; 4.B.157.172; 4.B.157.175; 4.B.157.240; 4.B.157.244; 4.B.166.228; 4.B.166.229; 4.B.166.230; 4.B.166.231; 4.B.166.236; 4.B.166.237; 4.B.166.238; 4.B.166.239; 4.B.166.154; 4.B.166.157; 4.B.166.166; 4.B.166.169; 4.B.166.172; 4.B.166.175; 4.B.166.240; 4.B.166.244; 4.B.169.228; 4.B.169.229; 4.B.169.230; 4.B.169.231; 4.B.169.236; 4.B.169.237; 4.B.169.238; 4.B.169.239; 4.B.169.154; 4.B.169.157; 4.B.169.166; 4.B.169.169; 4.B.169.172; 4.B.169.175; 4.B. 169.240; 4.B. 169.244; 4.B.172.228; 4.B.172.229; 4.B.172.230; 4.B.172.231; 4.B.172.236; 4.B.172.237; 4.B.172.238; 4.B.172.239; 4.B.172.154; 4.B.172.157; 4.B.172.166; 4.B.172.169; 4.B.172.172; 4.B.172.175; 4.B.172.240; 4.B.172.244; 4.B.175.228; 4.B.175.229; 4.B.175.230; 4.B.175.231; 4.B.175.236; 4.B.175.237; 4.B.175.238; 4.B.175.239; 4.B.175.154; 4.B.175.157; 4.B.175.166; 4.B.175.169; 4.B.175.172; 4.B.175.175; 4.B.175.240; 4.B.175.244; 4.B.240.228; 4.B.240.229; 4.B.240.230; 4.B.240.231; 4.B.240.236; 4.B.240.237; 4.B.240.238; 4.B.240.239; 4.B.240.154; 4.B.240.157; 4.B.240.166; 4.B.240.169; 4.B.240.172; 4.B.240.175; 4.B.240.240; 4.B.240.244; 4.B.244.228; 4.B.244.229; 4.B.244.230; 4.B.244.231; 4.B.244.236; 4.B.244.237; 4.B.244.238; 4.B.244.239; 4.B.244.154; 4.B.244.157; 4.B.244.166; 4.B.244.169; 4.B.244.172; 4.B.244.175; 4.B.244.240; 4.B.244.244;
Prodrugs of 4.D
4.D.228.228; 4.D.228.229; 4.D.228.230; 4.D.228.231; 4.D.228.236; 4.D.228.237; 4.D.228.238; 4.D.228.239; 4.D.228.154; 4.D.228.157; 4.D.228.166; 4.D.228.169; 4.D.228.172; 4.D.228.175; 4.D.228.240; 4.D.228.244; 4.D.229.228; 4.D.229.229;
4.D.229.230; 4.D.229.231; 4.D.229.236; 4.D.229.237; 4.D.229.238; 4.D.229.239; 4.D.229.154; 4.D.229.157; 4.D.229.166; 4.D.229.169; 4.D.229.172; 4.D.229.175; 4.D.229.240; 4.D.229.244; 4.D.230.228; 4.D.230.229; 4.D.230.230; 4.D.230.231; 4.D.230.236; 4.D.230.237; 4.D.230.23S; 4.D.230.239; 4.D.230.154; 4.D.230.157; 4.D.230.166; 4.D.230.169; 4.D.230.172; 4.D.230.175; 4.D.230.240; 4.D.230.244; 4.D.231.228; 4.D.231.229; 4.D.231.230; 4.D.231.231; 4.D.231.236; 4.D.231.237; 4.D.231.238; 4.D.231.239; 4.D.231.154; 4.D.231.157; 4.D.231.166; 4.D.231.169; 4.D.231.172; 4.D.231.175; 4.D.231.240; 4.D.231.244; 4.D.236.228; 4.D.236.229; 4.D.236.230; 4.D.236.231; 4.D.236.236; 4.D.236.237; 4.D.236.238; 4.D.236.239; 4.D.236.154; 4.D.236.157; 4.D.236.166; 4.D.236.169; 4.D.236.172; 4.D.236.175; 4.D.236.240; 4.D.236.244; 4.D.237.228; 4.D.237.229; 4.D.237.230; 4.D.237.231; 4.D.237.236; 4.D.237.237; 4.D.237.238; 4.D.237.239; 4.D.237.154; 4.D.237.157; 4.D.237.166; 4.D.237.169; 4.D.237.172; 4.D.237.175; 4.D.237.240; 4.D.237.244; 4.D.238.228; 4.D.238.229; 4.D.238.230; 4.D.238.231; 4.D.238.236; 4.D.238.237; 4.D.238.238; 4.D.238.239; 4.D.238.154; 4.D.238.157; 4.D.238.166; 4.D.238.169; 4.D.238.172; 4.D.238.175; 4.D.238.240; 4.D.238.244; 4.D.239.228; 4.D.239.229; 4.D.239.230; 4.D.239.231; 4.D.239.236; 4.D.239.237; 4.D.239.238; 4.D.239.239; 4.D.239.154; 4.D.239.157; 4.D.239.166; 4.D.239.169; 4.D.239.172; 4.D.239.175; 4.D.239.240; 4.D.239.244; 4.D.154.228; 4.D.154.229; 4.D.154.230; 4.D.154.231; 4.D.154.236; 4.D.154.237; 4.D.154.238; 4.D.154.239; 4.D.154.154; 4.D.154.157; 4.D.154.166; 4.D.154.169; 4.D.154.172; 4.D.154.175; 4.D.154.240; 4.D.154.244; 4.D.157.228; 4.D.157.229; 4.D.157.230; 4.D.157.231; 4.D.157.236; 4.D.157.237; 4.D.157.238; 4.D.157.239; 4.D.157.154; 4.D.157.157; 4.D.157.166; 4.D.157.169; 4.D.157.172; 4.D.157.175; 4.D.157.240; 4.D.157.244; 4.D.166.228; 4.D.166.229; 4.D.166.230; 4.D.166.231; 4.D.166.236; 4.D.166.237; 4.D.166.238; 4.D.166.239; 4.D.166.154; 4.D.166.157; 4.D.166.166; 4.D.166.169; 4.D.166.172; 4.D.166.175; 4.D.166.240; 4.D.166.244; 4.D.169.228; 4.D.169.229; 4.D.169.230; 4.D.169.231; 4.D.169.236; 4.D.169.237; 4.D.169.238; 4.D.169.239; 4.D.169.154; 4.D.169.157; 4.D.169.166; 4.D.169.169; 4.D.169.172; 4.D.169.175; 4.D.169.240; 4.D.169.244; 4.D.172.228; 4.D.172.229; 4.D.172.230; 4.D.172.231; 4.D.172.236; 4.D.172.237; 4.D.172.238; 4.D.172.239; 4.D.172.154; 4.D.172.157; 4.D.172.166; 4.D.172.169; 4.D.172.172; 4.D.172.175; 4.D.172.240; 4.D.172.244; 4.D.175.228; 4.D.175.229; 4.D.175.230; 4.D.175.231; 4.D.175.236; 4.D.175.237; 4.D.175.238; 4.D.175.239; 4.D.175.154; 4.D.175.157; 4.D.175.166; 4.D.175.169; 4.D.175.172; 4.D.175.175; 4.D.175.240; 4.D.175.244; 4.D.240.228; 4.D.240.229; 4.D.240.230; 4.D.240.231; 4.D.240.236; 4.D.240.237; 4.D.240.238; 4.D.240.239; 4.D.240.154; 4.D.240.157; 4.D.240.166; 4.D.240.169; 4.D.240.172; 4.D.240.175; 4.D.240.240; 4.D.240.244; 4.D.244.228; 4.D.244.229; 4.D.244.230; 4.D.244.231; 4.D.244.236; 4.D.244.237; 4.D.244.238; 4.D.244.239; 4.D.244.154; 4.D.244.157; 4.D.244.166; 4.D.244.169; 4.D.244.172; 4.D.244.175; 4.D.244.240; 4.D.244.244;
Prodrugs of 4.E
4.E.228.228; 4.E.228.229; 4.E.228.230; 4.E.228.231; 4.E.228.236; 4.E.228.237; 4.E.228.238; 4.E.228.239; 4.E.228.154; 4.E.228.157; 4.E.228.166; 4.E.228.169; 4.E.228.172; 4.E.228.175; 4.E.228.240; 4.E.228.244; 4.E.229.228; 4.E.229.229; 4.E.229.230; 4.E.229.231; 4.E.229.236; 4.E.229.237; 4.E.229.238; 4.E.229.239; 4.E.229.154; 4.E.229.157; 4.E.229.166;
4.E.229.169; 4.E.229.172; 4.E.229.175; 4.E.229.240; 4.E.229.244; 4.E.230.228; 4.E.230.229; 4.E.230.23oJ 4.E.230.231; 4.E.230.236; 4.E.230.237; 4.E.230.238; 4.E.230.239; 4.E.230.154; 4.E.230.157; 4.E.230.166; 4.E.230.169; 4.E.230.172; 4.E.230.175; 4.E.230.240; 4.E.230.244; 4.E.231.228; 4.E.231.229; 4.E.231.230; 4.E.231.231; 4.E.231.236; 4.E.231.237; 4.E.231.238; 4.E.231.239; 4.E.231.154; 4.E.231.157; 4.E.231.166; 4.E.231.169; 4.E.231.172; 4.E.231.175; 4.E.231.240; 4.E.231.244; 4.E.236.228; 4.E.236.229; 4.E.236.230; 4.E.236.231; 4.E.236.236; 4.E.236.237; 4.E.236.238; 4.E.236.239; 4.E.236.154; 4.E.236.157; 4.E.236.166; 4.E.236.169; 4.E.236.172; 4.E.236.175; 4.E.236.240; 4.E.236.244; 4.E.237.228; 4.E.237.229; 4.E.237.230; 4.E.237.231; 4.E.237.236; 4.E.237.237; 4.E.237.238; 4.E.237.239; 4.E.237.154; 4.E.237.157; 4.E.237.166; 4.E.237.169; 4.E.237.172; 4.E.237.175; 4.E.237.240; 4.E.237.244; 4.E.238.228; 4.E.238.229; 4.E.238.230; 4.E.238.231; 4.E.238.236; 4.E.238.237; 4.E.238.238; 4.E.238.239; 4.E.238.154; 4.E.238.157; 4.E.238.166; 4.E.238.169; 4.E.238.172; 4.E.238.175; 4.E.238.240; 4.E.238.244; 4.E.239.228; 4.E.239.229; 4.E.239.230; 4.E.239.231; 4.E.239.236; 4.E.239.237; 4.E.239.238; 4.E.239.239; 4.E.239.154; 4.E.239.157; 4.E.239.166; 4.E.239.169; 4.E.239.172; 4.E.239.175; 4.E.239.240; 4.E.239.244; 4.E.154.228; 4.E.154.229; 4.E.154.230; 4.E.154.231; 4.E.154.236; 4.E.154.237; 4.E.154.238; 4.E.154.239; 4.E.154.154; 4.E.154.157; 4.E.154.166; 4.E.154.169; 4.E.154.172; 4.E.154.175; 4.E.154.240; 4.E.154.244; 4.E.157.228; 4.E.157.229; 4.E.157.230; 4.E.157.231; 4.E.157.236; 4.E.157.237; 4.E.157.238; 4.E.157.239; 4.E.157.154; 4.E.157.157; 4.E.157.166; 4.E.157.169; 4.E.157.172; 4.E.157.175; 4.E.157.240; 4.E.157.244; 4.E.166.228; 4.E.166.229; 4.E.166.230; 4.E.166.231; 4.E.166.236; 4.E.166.237; 4.E.166.238; 4.E.166.239; 4.E.166.154; 4.E.166.157; 4.E.166:i66; 4.E.166.169; 4.E.166.172; 4.E.166.175; 4.E.166.240; 4.E.166.244; 4.E.169.228; 4.E.169.229; 4.E.169.230; 4.E.169.231; 4.E.169.236; 4.E.169.237; 4.E.169.238; 4.E.169.239; 4.E.169.154; 4.E.169.157; 4.E.169.166; 4.E.169.169; 4.E.169.172; 4.E.169.175; 4.E.169.240; 4.E.169.244; 4.E.172.228; 4.E.172.229; 4.E.172.230; 4.E.172.231; 4.E.172.236; 4.E.172.237; 4.E.172.238; 4.E.172.239; 4.E.172.154; 4.E.172.157; 4.E.172.166; 4.E.172.169; 4.E.172.172; 4.E.172.175; 4.E.172.240; 4.E.172.244; 4.E.175.228; 4.E.175.229; 4.E.175.230; 4.E.175.231; 4.E.175.236; 4.E.175.237; 4.E.175.238; 4.E.175.239; 4.E.175.154; 4.E.175.157; 4.E.175.166; 4.E.175.169; 4.E.175.172; 4.E.175.175; 4.E.175.240; 4.E.175.244; 4.E.240.228; 4.E.240.229; 4.E.240.230; 4.E.240.231; 4.E.240.236; 4.E.240.237; 4.E.240.238; 4.E.240.239; 4.E.240.154; 4.E.240.157; 4.E.240.166; 4.E.240.169; 4.E.240.172; 4.E.240.175; 4.E.240.240; 4.E.240.244; 4.E.244.228; 4.E.244.229; 4.E.244.230; 4.E.244.231; 4.E.244.236; 4.E.244.237; 4.E.244.238; 4.E.244.239; 4.E.244.154; 4.E.244.157; 4.E.244.166; 4.E.244.169; 4.E.244.172; 4.E.244.175; 4.E.244.240; 4.E.244.244;
Prodrugs of 4.G
4.G.228.228; 4.G.228.229; 4.G.228.230; 4.G.228.231; 4.G.228.236; 4.G.228.237; 4'.G.228.238; 4.G.228.239; 4.G.228.154; 4.G.228.157; 4.G.228.166; 4.G.228.169; 4.G.228.172; 4.G.228.175; 4.G.228.240; 4.G.228.244; 4.G.229.228; 4.G.229.229; 4.G.229.230; 4.G.229.231; 4.G.229.236; 4.G.229.237; 4.G.229.238; 4.G.229.239; 4.G.229.154; 4.G.229.157; 4.G.229.166; 4.G.229.169; 4.G.229.172; 4.G.229.175; 4.G.229.240; 4.G.229.244; 4.G.230.228; 4.G.230.229; 4.G.230.230; 4.G.230.231; 4.G.230.236; 4.G.230.237; 4.G.230.238; 4.G.230.239; 4.G.230.154; 4.G.230.157; 4.G.230.166; 4.G.230.169; 4.G.230.172; 4.G.230.175; 4.G.230.240; 4.G.230.244; 4.G.231.228; 4.G.231.229; 4.G.231.230; 4.G.231.231; 4.G.231.236; 4.G.231.237; 4.G.231.238; 4.G.231.239; 4.G.231.154; 4.G.231.157; 4.G.231.166; 4.G.231.169; 4.G.231.172; 4.G.231.175; 4.G.231.240; 4.G.231.244; 4.G.236.228; 4.G.236.229;
4.G.236.230; 4.G.236.231; 4.G.236.236; 4.G.236.237; 4.G.236.238; 4.G.236.239; 4.G.236.154; 4.G.236.157; 4.G.236.166; 4.G.236.169; 4.G.236.172; 4.G.236.175; 4.G.236.240; 4.G.236.244; 4.G.237.228; 4.G.237.229; 4.G.237.230; 4.G.237.231; 4.G.237.236; 4.G.237.237; 4.G.237.238; 4.G.237.239; 4.G.237.154; 4.G.237.157; 4.G.237.166; 4.G.237.169; 4.G.237.172; 4.G.237.175; 4.G.237.240; 4.G.237.244; 4.G.238.228; 4.G.238.229; 4.G.238.230; 4.G.238.231; 4.G.238.236; 4.G.238.237; 4.G.238.238; 4.G.238.239; 4.G.238.154; 4.G.238.157; 4.G.238.166; 4.G.238.169; 4.G.238.172; 4.G.238.175; 4.G.238.240; 4.G.238.244; 4.G.239.228; 4.G.239.229; 4.G.239.230; 4.G.239.231; 4.G.239.236; 4.G.239.237; 4.G.239.238; 4.G.239.239; 4.G.239.154; 4.G.239.157; 4.G.239.166; 4.G.239.169; 4.G.239.172; 4.G.239.175; 4.G.239.240; 4.G.239.244; 4.G.154.228; 4.G.154.229; 4.G.154.230; 4.G.154.231; 4.G.154.236; 4.G.154.237; 4.G.154.238; 4.G.154.239; 4.G.154.154; 4.G.154.157; 4.G.154.166; 4.G.154.169; 4.G.154.172; 4.G.154.175; 4.G.154.240; 4.G.154.244; 4.G.157.228; 4.G.157.229; 4.G.157.230; 4.G.157.231; 4.G.157.236; 4.G.157.237; 4.G.157.238; 4.G.157.239; 4.G.157.154; 4.G.157.157; 4.G.157.166; 4.G.157.169; 4.G.157.172; 4.G.157.175; 4.G.157.240; 4.G.157.244; 4.G.166.228; 4.G.166.229; 4.G.166.230; 4.G.166.231; 4.G.166.236; 4.G.166.237; 4.G.166.238; 4.G.166.239; 4.G.166.154; 4.G.166.157; 4.G.166.166; 4.G.166.169; 4.G.166.172; 4.G.166.175; 4.G.166.240; 4.G.166.244; 4.G.169.228; 4.G.169.229; 4.G.169.230; 4.G.169.231; 4.G.169.236; 4.G.169.237; 4.G.169.238; 4.G.169.239; 4.G.169.154; 4.G.169.157; 4.G.169.166; 4.G.169.169; 4.G.169.172; 4.G.169.175; 4.G.169.240; 4.G.169.244; 4.G.172.228; 4.G.172.229; 4.G.172.230; 4.G.172.231; 4.G.172.236; 4.G.172.237; 4.G.172.238; 4.G.172.239; 4.G.172.154; 4.G.172.157; 4.G.172.166; 4.G.172.169; 4.G.172.172; 4.G.172.175; 4.G.172.240; 4.G.172.244; 4.G.175.228; 4.G.175.229; 4.G.175.230; 4.G.175.231; 4.G.175.236; 4.G.175.237; 4.G.175.238; 4.G.175.239; 4.G.175.154; 4.G.175.157; 4.G.175.166; 4.G.175.169; 4.G.175.172; 4.G.175.175; 4.G. 175.240; 4.G.175.244; 4.G.240.228; 4.G.240.229; 4.G.240.230; 4.G.240.231; 4.G.240.236; 4.G.240.237; 4.G.240.238; 4.G.240.239; 4.G.240.154; 4.G.240.157; 4.G.240.166; 4.G.240.169; 4.G.240.172; 4.G.240.175; 4.G.240.240; 4.G.240.244; 4.G.244.228; 4.G.244.229; 4.G.244.230; 4.G.244.231; 4.G.244.236; 4.G.244.237; 4.G.244.238; 4.G.244.239; 4.G.244.154; 4.G.244.157; 4.G.244.166; 4.G.244.169; 4.G.244.172; 4.G.244.175; 4.G.244.240; 4.G.244.244;
Frodrugs of 4.1
4.1.228.228; 4.1.228.229; 4.1.228.230; 4.1.228.231; 4.1.228.236; 4.1.228.237; 4.1.228.238; 4.1.228.239; 4.1.228.154; 4.1.228.157; 4.1.228.166; 4.1.228.169; 4.1.228.172; 4.1.228.175; 4.1.228.240; 4.1.228.244; 4.1.229.228; 4.1.229.229; 4.1.229.230; 4.1.229.231; 4.1.229.236; 4.1.229.237; 4.1.229.238; 4.1.229.239; 4.1.229.154; 4.1.229.157; 4.1.229.166; 4.1.229.169; 4.1.229.172; 4.1.229.175; 4.1.229.240; 4.1.229.244; 4.1.230.228; 4.1.230.229; 4.1.230.230; 4.1.230.231; 4.1.230.236; 4.1.230.237; 4.1.230.238; 4.1.230.239; 4.1.230.154; 41.230.157; 4.1.230.166; 4.1.230.169; 4.1.230.172; 4.1.230.175; 4.1.230.240; 4.1.230.244; 4.1.231.228; 4.1.231.229; 4.1.231.230; 4.1.231.231; 4.1.231.236; 4.1.231.237; 4.1.231.238; 4.1.231.239; 4.1.231.154; 4.1.231.157; 4.1.231.166; 4.1.231.169; 4.1.231.172; 4.1.231.175; 4.1.231.240; 4.1.231.244; 4.1.236.228; 4.1.236.229; 4.1.236.230; 4.1.236.231; 4.1.236.236; 4.1.236.237; 4.1.236.238; 4.1.236.239; 4.1.236.154; 4.1.236.157; 4.1.236.166; 4.1.236.169; 4.1.236.172; 4.1.236.175; 4.1.236.240; 4.1.236.244; 4.1.237.228; 4.1.237.229; 4.1.237.230; 4.1.237.231;
4.1.237.236; 4.1.237.237; 4.1.237.238; 4.1.237.239; 4.1.237.154; 4.1.237.157; 4.1.237.166; 4.1.237.169; 4.1.237.172; 4.1.237.175; 4.1.237.240; 4.1.237.244; 4.1.238.228; 4.1.238.229; 4.1.238.230; 4.1.238.231; 4.1.238.236; 4.1.238.237; 4.I.23S.238; 4.1.238.239; 4.1.238.154; 4.1.238.157; 4.1.238.166; 4.1.238.169; 4.1.238.172; 4.1.238.175; 4.1.238.240; 4.1.238.244; 4.1.239.228; 4.1.239.229; 4.1.239.230; 4.1.239.231; 4.1.239.236; 4.1.239.237; 4.1.239.238; 4.1.239.239; 4.1.239.154; 4.1.239.157; 4.1.239.166; 4.1.239.169; 4.1.239.172; 4.1.239.175; 4.1.239.240; 4.1.239.244; 4.1.154.228; 4.1.154.229; 4.1.154.230; 4.1.154.231; 4.1.154.236; 4.1.154.237; 4.1.154.238; 4.1.154.239; 4.1.154.154; 4.1.154.157; 4.1.154.166; 4.1.154.169; 4.1.154.172; 4.1.154.175; 4.1.154.240; 4.1.154.244; 4.1.157.228; 4.1.157.229; 4.1.157.230; 4.1.157.231; 4.1.157.236; 4.1.157.237; 4.1.157.238; 4.1.157.239; 4.1.157.154; 4.1.157.157; 4.1.157.166; 4.1.157.169; 4.1.157.172; 4.1.157.175; 4.1.157.240; 4.1.157.244; 4.1.166.228; 4.1.166.229; 4.1.166.230; 4.1.166.231; 4.1.166.236; 4.1.166.237; 4.1.166.238; 4.1.166.239; 4.1.166.154; 4.1.166.157; 4.1.166.166; 4.1.166.169; 4.1.166.172; 4.1.166.175; 4.1.166.240; 4.1.166.244; 4.1.169.228; 4.1.169.229; 4.1.169.230; 4.1.169.231; 4.1.169.236; 4.1.169.237; 4.1.169.238; 4.1.169.239; 4.1.169.154; 4.1.169.157; 4.1.169.166; 4.1.169.169; 4.1.169.172; 4.1.169.175; 4.1.169.240; 4.1.169.244; 4.1.172.228; 4.1.172.229; 4.1.172.230; 4.1.172.231; 4.1.172.236; 4.1.172.237; 4.1.172.238; 4.1.172.239; 4.1.172.154; 4.1.172.157; 4.1.172.166; 4.1.172.169; 4.1.172.172; 4.1.172.175; 4.1.172.240; 4.1.172.244; 4.1.175.228; 4.1.175.229; 4.1.175.230; 4.1.175.231; 4.1.175.236; 4.1.175.237; 4.1.175.238; 4.1.175.239; 4.1.175.154; 4.1.175.157; 4.1.175.166; 4.1.175.169; 4.1.175.172; 4.1.175.175; 4.1.175.240; 4.1.175.244; 4.1.240.228; 4.1.240.229; 4.1.240.230; 4.1.240.231; 4.1.240.236; 4.1.240.237; 4.1.240.238; 4.1.240.239; 4.1.240.154; 4.1.240.157; 4.1.240.166; 4.1.240.169; 4.1.240.172; 4.1.240.175; 4.1.240.240; 4.1.240.244; 4.1.244.228; 4.1.244.229; 4.1.244.230; 4.1.244.231; 4.1.244.236; 4.1.244.237; 4.1.244.238; 4.1.244.239; 4.1.244.154; 4.1.244.157; 4.1.244.166; 4.1.244.169; 4.1.244.172; 4.1.244.175; 4.1.244.240; 4.1.244.244;
Prodrugs of 4.T
4.J.228.228; 4J.228.229; 4.J.228.230; 4.J.228.231; 4.J.228.236; 4.J.228.237; 4J.228.238; 4J.228.239; 4.J.228.154; 4.J.228.157; 4 J.228.166; 4J.228.169; 4J.228.172; 4J.228.175; 4 J.228.240; 4J.228.244; 4J.229.228; 4J.229.229; 4 J.229.230; 4J.229.231; 4J.229.236; 4J.229.237; 4J.229.238; 4J.229.239; 4J.229.154; 4J.229.157; 4J.229.166; 4J.229.169; 4J.229.172; 4J.229.175; 4J.229.240; 4J.229.244; 4J.230.228; 4J.230.229; 4J.230.230; 4J.230.231; 4J.230.236; 4J.230.237; 4J.230.238; 4J.230.239; 4J.230.154; 4J.230.157; 4J.230.166; 4J.230.169; 4J.230.172; 4J.230.175; 4J.230.240; 4J.230.244; 4J.231.228; 4J.231.229; 4J.231.230; 4J.231.231; 4J.231.236; 4J.231.237; 4J.231.238; 4J.231.239; 4J.231.154; 4J.231.157; 4J.231.166; 4J.231.169; 4J.231.172; 4.J.231.175; 4J.231.240; 4J.231.244; 4J.236.228; 4J.236.229; 4J.236.230; 4J.236.231; 4J.236.236; 4J.236.237; 4J.236.238; 4J.236.239; 4.J.236.154; 4J.236.157; 4J.236.166; 4J.236.169; 4J.236.172; 4J.236.175; 4J.236.240; 4J.236.244; 4J.237.228; 4 J.237.229; 4J.237.230; 4J.237.231; 4J.237.23.6; 4J.237.237; 4J.237.238; 4J.237.239; 4J.237.154; 4J.237.157; 4J.237.166; 4J.237.169; 4J.237.172; 4J.237.175; 4.J.237.240; 4J.237.244; 4.J.238.228; 4J.238.229; 4.J.238.230; 4J.238.231; 4J.238.236; 4J.238.237; 4J.238.238; 4J.238.239; 4J.238.154; 4J.238.157; 4J.238.166; 4J.238.169; 4J.238.172; 4J.238.175; 4J.238.240; 4J.238.244; 4.J.239.228; 4J.239.229; 4J.239.230; 4J.239.231; 4J.239.236; 4.J.239.237; 4J.239.238; 4J.239.239; 4.J.239.154; 4J.239.157; 4J.239.166; 4J.239.169; 4J.239.172; 4.J.239.175; 4J.239.240; 4J.239.244; 4J.154.228; 4.J.154.229; 4.J.154.230; 4J.154.231; 4J.154.236;
4J.154.237; 4J.154.238; 4J.154.239; 4J.154.154; 4J.154.157; 4J.154.166; 4J.154.169; 4J.154.172; 4J.154.175; 4J.154.240; 4J.154.244; 4.J.157.228; 4J.157.229; 4J.157.230; 4J.157.231; 4J.157.236; 4J.157.237; 4J.157.238; 4J.157.239; 4J.157.154; 4J.157.157; 4J.157.166; 4J.157.169; 4J.157.172; 4J.157.175; 4.J.157.240; 4J.157.244; 4.J.166.228; 4J.166.229; 4J.166.230; 4J.166.231; 4J.166.236; 4.J.166.237; 4J.166.238; 4J.166.239; 4J.166.154; 4J.166.157; 4J.166.166; 4J.166.169; 4J.166.172; 4J.166.175; 4J.166.240; 4J.166.244; 4J.169.228; 4J.169.229; 4J.169.230; 4J.169.231; 4J.169.236; 4.J.169.237; 4J.169.238; 4J.169.239; 4J.169.154; 4J.169.157; 4J.169.166; 4J.169.169; 4J.169.172; 4J.169.175; 4J.169.240; 4J.169.244; 4J.172.228; 4.J.172.229; 4J.172.230; 4J.172.231; 4J.172.236; 4.J.172.237; 4.J.172.238; 4J.172.239; 4J.172.154; 4J.172.157; 4J.172.166; 4J.172.169; 4J.172.172; 4J.172.175; 4J.172.240; 4J.172.244; 4J.175.228; 4J.175.229; 4J.175.230; 4J.175.231; 4J.175.236; 4J.175.237; 4.J.175.238; 4J.175.239; 4J.175.154; 4J.175.157; 4 J. 175.166; 4J.175.169; 4J.175.172; 4J.175.175; 4J.175.240; 4J.175.244; 4J.240.228; 4J.240.229; 4J.240.230; 4J.240.231; 4.J.240.236; 4J.240.237; 4J.240.238; 4J.240.239; 4J.240.154; 4 J.240.157; 4J.240.166; 4J.240.169; 4J.240.172; 4J.240.175; 4J.240.240;4.J.240.244; 4J.244.228; 4J.244.229; 4.J.244.230; 4J.244.231; 4J.244.236; 4J.244.237; 4J.244.238; 4 J.244.239; 4J.244.154; 4.J.244.157; 4J.244.166; 4J.244.169; 4J.244.172; 4J.244.175; 4J.244.240; 4 J.244244;
Prodrugs of 4.L
4.L.228.228; 4.L.228.229; 4.L.228.230; 4L.228.231; 4.L.228.236; 4L.228.237; 4.L.228.238; 4.L.228.239; 4.L.228.154; 4.L.228.157; 4.L.228.166; 4.L.228.169; 4.L.228.172; 4.L.228.175; 4.L.228.240; 4.L.228.244; 4.L.229.228; 4.L.229.229; 4.L.229.230; 4.L.229.231; 4.L.229.236; 4.L.229.237; 4L.229.238; 4.L.229.239; 4.L.229.154; 4.L.229.157; 4.L.229.166; 4.L.229.169; 4.L.229.172; 4.L.229.175; 4.L.229.240; 4.L.229.244; 4.L.230.228; 4.L.230.229; 4.L.230.230; 4.L.230.231; 4.L.230.236; 4.L.230.237; 4.L.230.238; 4.L.230.239; 4.L.230.154; 4.L.230.157; 4.L.230.166; 4.L.230.169; 4L.230.172; 4.L.230.175; 4.L.230.240; 4.L.230.244; 4.L.231.228; 4.L.231.229; 4L.231.230; 4.L.231.231; 4.L.231.236; 4.L.231.237; 4.L.231.238; 4.L.231.239; 4.L.231.154; 4.L.231.157; 4.L.231.166; 4L.231.169; 4L.231.172; 4.L.231.175; 4.L.231.240; 4.L.231.244; 4.L.236.228; 4.L.236.229; 4.L.236.230; 4.L.236.231; 4.L.236.236; 4.L.236.237; 4.L.236.238; 4.L.236.239; 4.L.236.154; 4.L.236.157; 4.L.236.166; 4.L.236.169; 4.L.236.172; 4.L.236.175; 4.L.236.240; 4.L.236.244; 4.L.237.228; 4.L.237.229; 4.L.237.230; 4.L.237.231; 4.L.237.236; 4.L.237.237; 4.L.237.238; 4.L.237.239; 4.L.237.154; 4.L.237.157; 4.L.237.166; 4.L.237.169; 4.L.237.172; 4.L.237.175; 4.L.237.240; 4.L.237.244; 4.L.238.228; 4.L.238.229; 4.L.238.230; 4.L.238.231; 4.L.238.236; 4.L.238.237; 4.L.238.238; 4.L.238.239; 4.L.238.154; 4.L.238.157; 4.L.238.166; 4.L.238.169; 4.L.238.172; 4.L.238.175; 4.L.238.240; 4.L.238.244; 4.L.239.228; 4.L.239.229; 4.L.239.230; 4.L.239.231; 4.L.239.236; 4.L.239.237; 4.L.239.238; 4.L.239.239; 4.L.239.154; 4.L.239.157; 4.L.239.166; 4.L.239.169; 4.L.239.172; 4.L.239.175; 4.L.239.240; 4.L.239.244; 4.L.154.228; 4.L.154.229; 4.L.154.230; 4.L.154.231; 4.L.154.236; 4.L.154.237; 4.L.154.238; 4.L.154239; 4.L.154.154; 4.L.154.157; 4.L.154.166; 4.L.154.169; 4.L.154.172; 4.L.154.175; 4.L.154.240; 4.L.154.244; 4.L.157.228; 4.L.157.229; 4.L.157.230; 4.L.157.231; 4.L.157.236; 4.L.157.237; 4.L.157.238; 4.L.157.239; 4.L.157.154; 4.L.157.157; 4.L.157.166; 4.L.157.169; 4.L.157.172; 4.L.157.175; 4.L.157.240; 4.L.157.244; 4.L.166.228; 4.L.166.229; 4.L.166.230; 4.L.166.231; 4.L.166.236; 4.L.166.237; 4.L.166.238; 4.L.166.239; 4.L.166.154; 4.L.166.157; 4.L.166.166; 4.L.166.169; 4.L.166.172; 4.L.166.175; 4.L.166.240; 4.L.166.244; 4.L.169.228; 4.L.169.229; 4.L.169.230; 4.L.169.231; 4.L.169.236;
4.L.169.237; 4.L.169.238; 4.L.169.239; 4.L.169.154; 4.L.169.157; 4.L.169.166; 4.L.169.169; 4.L.169.172; 4.L.169.175; 4.L.169.240; 4.L.169.244; 4.L.172.228; 4.L.172.229; 4.L.172.230; 4.L.172.231; 4.L.172.236; 4.L.172.237; 4.L.172.238; 4.L.172.239; 4.L.172.154; 4.L.172.157; 4.L.172.166; 4.L.172.169; 4.L.172.172; 4.L.172.175; 4.L.172.240; 4.L.172.244; 4.L.175.228; 4.L.175.229; 4.L.175.230; 4.L.175.231; 4.L.175.236; 4.L.175.237; 4.L.175.238; 4.L.175.239; 4.L.175.154; 4.L.175.157; 4.L.175.166; 4.L.175.169; 4.L.175.172; 4.L.175.175; 4.L.175.240; 4.L.175.244; 4.L.240.228; 4.L.240.229; 4.L.240.230; 4.L.240.231; 4.L.240.236; 4.L.240.237; 4.L.240.238; 4.L.240.239; 4.L.240.154; 4.L.240.157; 4.L.240.166; 4.L.240.169; 4.L.240.172; 4.L.240.175; 4.L.240.240; 4.L.240.244; 4.L.244.228; 4.L.244.229; 4.L.244.230; 4.L.244.231; 4.L.244.236; 4.L.244.237; 4.L.244.238; 4.L.244.239; 4.L.244.154; 4.L.244.157; 4.L.244.166; 4.L.244.169; 4.L.244.172; 4.L.244.175; 4.L.244.240; 4.L.244.244;
Prodrugs of 4.O
4.O.228.228; 4.O.228.229; 4.O.228.230; 4.O.228.231; 4.O.228.236; 4.O.228.237; 4.O.228.238; 4.O.228.239; 4.O.228.154; 4.O.228.157; 4.O.228.166; 4.O.228.169; 4.O.228.172; 4.O.228.175; 4.O.228.240; 4.O.228.244; 4.O.229.228; 4.O.229.229; 4.O.229.230; 4.O.229.231; 4.O.229.236; 4.O.229.237; 4.O.229.238; 4.O.229.239; 4.O.229.154; 4.O.229.157; 4.O.229.166; 4.O.229.169; 4.O.229.172; 4.O.229.175; 4.O.229.240; 4.O.229.244; 4.O.230.228; 4.O.230.229; 4.O.230.230; 4.O.230.231; 4.O.230.236; 4.O.230.237; 4.O.230.238; 4.O.230.239; 4.O.230.154; 4.O.230.157; 4.O.230.166; 4.O.230.169; 4.O.230.172; 4.O.230.175; 4.O.230.240; 4.O.230.244; 4.O.231.228; 4.O.231.229; 4.O.231.230; 4.O.231.231; 4.O.231.236; 4.O.231.237; 4.O.231.238; 4.O.231.239; 4.O.231.154; 4.O.231.157; 4.O.231.166; 4.O.231.169; 4.O.231.172; 4.O.231.175; 4.O.231.240; 4.O.231.244; 4.O.236.228; 4.O.236.229; 4.O.236.230; 4.O.236.231; 4.O.236.236; 4.O.236.237; 4.O.236.238; 4.O.236.239; 4.O.236.154; 4.O.236.157; 4.O.236.166; 4.O.236.169; 4.O.236.172; 4.O.236.175; 4.O.236.240; 4.O.236.244; 4.O.237.228; 4.O.237.229; 4.O.237.230; 4.O.237.231; 4.O.237.236; 4.O.237.237; 4.O.237.238; 4.O.237.239; 4.O.237.154; 4.O.237.157; 4.O.237.166; 4.O.237.169; 4.O.237.172; 4.O.237.175; 4.O.237.240; 4.O.237.244; 4.O.238.228; 4.O.238.229; 4.O.238.230; 4.O.238.231; 4.O.238.236; 4.O.238.237; 4.O.238.238; 4.O.238.239; 4.O.238.154; 4.O.238.157; 4.O.238.166; 4.O.238.169; 4.O.238.172; 4.O.238.175; 4.O.238.240; 4.O.238.244; 4.O.239.228; 4.O.239.229; 4.O.239.230; 4.O.239.231; 4.O.239.236; 4.O.239.237; 4.O.239.238; 4.O.239.239; 4.O.239.154; 4.O.239.157; 4.O.239.166; 4.O.239.169; 4.O.239.172; 4.O.239.175; 4.O.239.240; 4.O.239.244; 4.O.154.228; 4.O.154.229; 4.O.154.230; 4.O.154.231; 4.O.154.236; 4.O.154.237; 4.O.154.238; 4.O.154.239; 4.O.154.154; 4.O.154.157; 4.O.154.166; 4.O.154.169; 4.O.154.172; 4.O.154.175; 4.O.154.240; 4.O.154.244; 4.0.157.228; 4.O.157.229; 4.O.157.230; 4.O.157.231; 4.O.157.236; 4.O.157.237; 4.O.157.238; 4.O.157.239; 4.O.157.154; 4.O.157.157; 4.O.157.166; 4.O.157.169; 4.O.157.172; 4.O.157.175; 4.O.157.240; 4.O.157.244; 4.O.166.228; 4.O.166.229; 4.O.166.230; 4.O.166.231; 4.O.166.236; 4.O.166.237; 4.O.166.238; 4.O.166.239; 4.0.166.154; 4.O.166.157; 4.O.166.166; 4.O.166.169; 4.O.166.172; 4.O.166.175; 4.O.166.240; 4.O.166.244; 4.O.169.228; 4.O.169.229; 4.O.169.230; 4.O.169.231; 4.O.169.236; 4.O.169.237; 4.O.169.238; 4.O.169.239; 4.O.169.154; 4.O.169.157; 4.O.169.166; 4.O.169.169; 4.O.169.172; 4.O.169.175; 4.O.169.240; 4.O.169.244; 4.O.172.228; 4.O.172.229; 4.O.172.230; 4.O.172.231; 4.O.172.236; 4.O.172.237;
4.O.172.238; 4.O.172.239; 4.O.172.154; 4.O.172.157; 4.O.172.166; 4.O.172.169; 4.O.172.172; 4.O.172.175; 4.O.172.240; 4.O.172.244; 4.O.175.228; 4.O.175.229; 4.O.175.230; 4.O.175.231; 4.O.175.236; 4.O.175.237; 4.O.175.238; 4.O.175.239; 4.O.175.154; 4.O.175.157; 4.O.175.166; 4.O.175.169; .40.175.172; 4O.175.175; 4.O.175.240; 4.O.175.244; 4.O.240.228; 4.O.240.229; 4.O.240.230; 4.O.240.231; 4.O.240.236; 4.O.240.237; 4.O.240.238; 4.O.240.239; 4.O.240.154; 4.O.240.157; 4.O.240.166; 4.O.240.169; 4.O.240.172; 4.O.240.175; 4.O.240.240; 4.O.240.244; 4.O.244.228; 4.O.244.229; 4.O.244.230; 4.O.244.231; 4.O.244.236; 4.O.244.237; 4.O.244.238; 4.O.244.239; 4.O.244.154; 4.O.244.157; 4.O.244.166; 4.O.244.169; 4.O.244.172; 4.O.244.175; 4.O.244.240; 4.O.244.244;
Prodrugs of 4.P
4.P.228.228; 4.P.228.229; 4.P.228.230; 4.P.228.231; 4.P.228.236; 4.P.228.237; 4.P.228.238; 4.P.228.239; 4.P.228.154; 4.P.228.157; 4.P.228.166; 4.P.228.169; 4.P.228.172; 4.P.228.175; 4.P.228.240; 4.P.228.244; 4.P.229.228; 4.P.229.229; 4.P.229.230; 4.P.229.231; 4.P.229.236; 4.P.229.237; 4.P.229.238; 4.P.229.239; 4.P.229.154; 4.P.229.157; 4.P.229.166; 4.P.229.169; 4.P.229.172; 4.P.229.175; 4.P.229.240; 4.P.229.244; 4.P.230.228; 4.P.230.229; 4.P.230.230; 4.P.230.231; 4.P.230.236; 4.P.230.237; 4.P.230.238; 4.P.230.239; 4.P.230.154; 4.P.230.157; 4.P.230.166; 4.P.230.169; 4.P.230.172; 4.P.230.175; 4.P.230.240; 4.P.230.244; 4.P.231.228; 4.P.231.229; 4.P.231.230; 4P.231.231; 4P.231.236; 4.P.231.237; 4.P.231.238; 4.P.231.239; 4P.231.154; 4P.231.157; 4P.231.166; 4P.231.169; 4P.231.172; 4P.231.175; 4.P.231.240; 4.P.231.244; 4.P.236.228; 4.P.236.229; 4.P.236.230; 4.P.236.231; 4.P.236.236; 4.P.236.237; 4.P.236.238; 4.P.236.239; 4.P.236.154; 4.P.236.157; 4.P.236.166; 4.P.236.169; 4.P.236.172; 4.P.236.175; 4.P.236.240; 4.P.236.244; 4.P.237.228; 4.P.237.229; 4.P.237.230; 4.P.237.231; 4.P.237.236; 4.P.237.237; 4.P.237.238; 4.P.237.239; 4.P.237.154; 4.P.237.157; 4.P.237.166; 4.P.237.169; 4.P.237.172; 4.P.237.175; 4.P.237.240; 4.P.237.244; 4.P.238.228; 4.P.238.229; 4.P.238.230; 4.P.238.231; 4.P.238.236; 4.P.238.237; 4.P.238.238; 4.P.238.239; 4.P.238.154; 4.P.238.157; 4.P.238.166; 4.P.238.169; 4.P.238.172; 4.P.238.175; 4.P.238.240; 4.P.238.244; 4.P.239.228; 4.P.239.229; 4.P.239.230; 4.P.239.231; 4.P.239.236; 4.P.239.237; 4.P.239.238; 4.P.239.239; 4.P.239.154; 4P.239.157; 4.P.239.166; 4.P.239.169; 4.P.239.172; 4.P.239.175; 4.P.239.240; 4.P.239.244; 4.P.154.228; 4.P.154.229; 4.P.154.230; 4P.154231; 4.P.154.236; 4.P.154.237; 4.P.154.238; 4.P.154.239; 4P.154154; 4P.154.157; 4P.154166; 4.P.154.169; 4.P.154.172; 4P.154.175; 4.P.154.240; 4.P.154.244; 4.P.157.228; 4.P.157.229; 4.P.157.230; 4P.157.231; 4.P.157.236; 4.P.157.237; 4.P.157.238; 4.P.157.239; 4P.157.154; 4P.157.157; 4P.157.166; 4.P.157.169; 4P.157.172; 4P.157.175; 4.P.157.240; 4.P.157.244; 4.P.166.228; 4.P.166.229; 4.P.166.230; 4P.166.231; 4.P.166.236; 4.P.166.237; 4.P.166.238; 4.P.166.239; 4P.166.154; 4P.166.157; 4P.166.166; 4P.166.169; 4.P.166.172; 4P.166.175; 4.P.166.240; 4.P.166.244; 4.P.169.228; 4.P.169.229; 4.P.169.230; 4.P.169.231; 4.P.169.236; 4.P.169.237; 4.P.169.238; 4.P.169.239; 4.P.169.154; 4P.169.157; 4P.169.166; 4P.169.169; 4.P.169.172; 4P.169.175; 4.P.169.240; 4.P.169.244; 4.P.172.228; 4.P.172.229; 4.P.172.230; 4.P.172.231; 4.P.172.236; 4.P.172.237; 4.P.172.238; 4.P.172.239; 4P.172.154; 4P.172.157; 4P.172.166; 4P.172.169; 4.P.172.172; 4P.172.175; 4.P.172.240; 4.P.172.244; 4.P.175.228; 4.P.175.229; 4.P.175.230; 4P.175.231; 4.P.175.236; 4.P.175.237; 4.P.175.238; 4.P.175.239; 4.P.175.154; 4P.175.157; 4P.175.166; 4P.175.169; 4P.175.172; 4.P.175.175; 4.P.175.240; 4.P.175.244; 4.P.240.228; 4.P.240.229; 4.P.240.230; 4.P.240.231; 4.P.240.236; 4.P.240.237; 4.P.240.238; 4.P.240.239; 4.P.240.154; 4.P.240.157; 4.P.240.166; 4.P.240.169; 4.P.240.172;
4.P.240.175; 4.P.240.240; 4.P.240.244; 4.P.244.228; 4.P.244.229; 4.P.244.230; 4.P.244.231; 4.P.244.236; 4.P.244.237; 4.P.244.238; 4.P.244.239; 4.P.244.154; 4.P.244.157; 4.P.244.166; 4.P.244.169; 4.P.244.172; 4.P.244.175; 4.P.244.240; 4.P.244.244;
Prodrugs of 4.U
4.U.228.228; 4.U.228.229; 4.U.228.230; 4.U.228.231; 4.U.228.236; 4.U.228.237; 4.U.228.238; 4.U.228.239; 4.U.228.154; 4.U.228.157; 4.U.228.166; 4.U.228.169; 4.U.228.172; 4.U.228.175; 4.U.228.240; 4.U.228.244; 4.U.229.228; 4.U.229.229; 4.U.229.230; 4.U.229.231; 4.U.229.236; 4.U.229.237; 4.U.229.238; 4.U.229.239; 4.U.229.154; 4.U.229.157; 4.U.229.166; 4.U.229.169; 4.U.229.172; 4.U.229.175; 4.U.229.240; 4.U.229.244; 4.U.230.228; 4.U.230.229; 4.U.230.230; 4.U.230.231; 4.U.230.236; 4.U.230.237; 4.U.230.238; 4.U.230.239; 4.U.230.154; 4.U.230.157; 4.U.230.166; 4.U.230.169; 4.U.230.172; 4.U.230.175; 4.U.230.240; 4.U.230.244; 4.U.231.228; 4.U.231.229; 4.U.231.230; 4.U.231.231; 4.U.231.236; 4.U.231.237; 4.U.231.238; 4.U.231.239; 4.U.231.154; 4.U.231.157; 4.U.231.166; 4.U.231.169; 4.U.231.172; 4.U.231.175; 4.U.231.240; 4.U.231.244; 4.U.236.228; 4.U.236.229; 4.U.236.230; 4.U.236.231; 4.U.236.236; 4.U.236.237; 4.U.236.238; 4.U.236.239; 4.U.236.154; 4.U.236.157; 4.U.236.166; 4.U.236.169; 4.U.236.172; 4.U.236.175; 4.U.236.240; 4.U.236.244; 4.U.237.228; 4.U.237.229; 4.U.237.230; 4.U.237.231; 4.U.237.236; 4.U.237.237; 4.U.237.238; 4.U.237.239; 4.U.237.154; 4.U.237.157; 4.U.237.166; 4.U.237.169; 4.U.237.172; 4.U.237.175; 4.U.237.240; 4.U.237.244; 4.U.238.228; 4.U.238.229; 4.U.238.230; 4.U.238.231; 4.U.238.236; 4.U.238.237; 4.U.238.238; 4.U.238.239; 4.U.238.154; 4.U.238.157; 4.U.238.166; 4.U.238.169; 4.U.238.172; 4.U.238.175; 4.U.238.240; 4.U.238.244; 4.U.239.228; 4.U.239.229; 4.U.239.230; 4.U.239.231; 4.U.239.236; 4.U.239.237; 4.U.239.238; 4.U.239.239; 4.U.239.154; 4.U.239.157; 4.U.239.166; 4.U.239.169; 4.U.239.172; 4.U.239.175; 4.U.239.240; 4.U.239.244; 4.U.154.228; 4.U.154.229; 4.U.154.230; 4.U.154.231; 4.U.154.236; 4.U.154.237; 4.U.154.238; 4.U.154.239; 4.U.154.154; 4.U.154.157; 4.U.154.166; 4.U.154.169; 4.U.154.172; 4.U.154.175; 4.U.154.240; 4.U.154.244; 4.U.157.228; 4.U.157.229; 4.U.157.230; 4.U.157.231; 4.U.157.236; 4.U.157.237; 4.U.157.238; 4.U.157.239; 4.U.157.154; 4.U.157.157; 4.U.157.166; 4.U.157.169; 4.U.157.172; 4.U.157.175; 4.U.157.240; 4.U.157.244; 4.U.166.228; 4.U.166.229; 4.U.166.230; 4.U.166.231; 4.U.166.236; 4.U.166.237; 4.U.166.238; 4.U.166.239; 4.U.166.154; 4.U.166.157; 4.U.166.166; 4.U.166.169; 4.U.166.172; 4.U.166.175; 4.U.166.240; 4.U.166.244; 4.U169.228; 4.U.169.229; 4.U.169.230; 4.U.169.231; 4.U.169.236; 4.U.169.237; 4.U.169.238; 4.U.169.239; 4.U.169.154; 4.U.169.157; 4.U.169.166; 4.U.169.169; 4.U.169.172; 4.U.169.175; 4.U.169.240; 4.U.169.244; 4.U.172.228; 4.U.172.229; 4.U.172.230; 4.U.172.231; 4.U.172.236; 4.U.172.237; 4.U.172.238; 4.U.172.239; 4.U.172.154; 4.U.172.157; 4.U.172.166; 4.U.172.169; 4.U.172.172; 4.U.172.175; 4.U.172.240; 4.U.172.244; 4.U.175.228; 4.U.175.229; 4.U.175.230; 4.U.175.231; 4.U.175.236; 4.U.175.237; 4.U.175.238; 4.U.175.239; 4.U.175.154; 4.U.175.157; 4.U.175.166; 4.U.175.169; 4.U.175.172; 4.U.175.175; 4.U.175.240; 4.U.175.244; 4.U.240.228; 4.U.240.229; 4.U.240.230; 4.U.240.231; 4.U.240.236; 4.U.240.237; 4.U.240.238; 4.U.240.239; 4.U.240.154; 4.U.240.157; 4.U.240.166; 4.U.240.169; 4.U.240.172; 4.U.240.175; 4.U.240.240; 4.U.240.244; 4.U.244.228; 4.U.244.229; 4.U.244.230; 4.U.244.231; 4.U.244.236; 4.U.244.237;
4.U.244.238; 4.U.244.239; 4.U.244.154; 4.U.244.157; 4.U.244.166; 4.U.244.169; 4.U.244.172; 4.U.244.175; 4.U.244.240; 4.U.244.244;
Prodrugs of 4.W
4.W.228.228; 4.W.228.229; 4.W.228.230; 4.W.228.231; 4.W.228.236; 4.W.228.237; 4.W.228.238; 4.W.228.239; 4.W.228.154; 4.W.228.157; 4.W.228.166; 4.W.228.169; 4.W.228.172; 4.W.228.175; 4.W.228.240; 4.W.228.244; 4.W.229.228; 4.W.229.229; 4.W.229.230; 4.W.229.231; 4.W.229.236; 4.W.229.237; 4.W.229.238; 4.W.229.239; 4.W.229.154; 4.W.229.157; 4.W.229.166; 4.W.229.169; 4.W.229.172; 4.W.229.175; 4.W.229.240; 4.W.229.244; 4.W.230.228; 4.W.230.229; 4.W.230.230; 4.W.230.231; 4.W.230.236; 4.W.230.237; 4.W.230.238; 4.W.230.239; 4.W.230.154; 4.W.230.157; 4.W.230.166; 4.W.230.169; 4.W.230.172; 4.W.230.175; 4.W.230.240; 4.W.230.244; 4.W.231.228; 4.W.231.229; 4.W.231.230; 4.W.231.231; 4.W.231.236; 4.W.231.237; 4.W.231.238; 4.W.231.239; 4.W.231.154; 4.W.231.157; 4.W.231.166; 4.W.231.169; 4.W.231.172; 4.W.231.175; 4.W.231.240; 4.W.231.244; 4.W.236.228; 4.W.236.229; 4.W.236.230; 4.W.236.231; 4.W.236.236; 4. W.236.237; 4.W.236.238; 4.W.236.239; 4.W.236.154; 4.W.236.157; 4.W.236.166; 4W.236.169; 4.W.236.172; 4.W.236.175; 4.W.236.240; 4.W.236.244; 4.W.237.228; 4.W.237.229; 4.W.237.230; 4.W.237.231; 4.W.237.236; 4.W.237.237; 4.W.237.238; 4.W.237.239; 4.W.237.154; 4.W.237.157; 4.W.237.166; 4.W.237.169; 4.W.237.172; 4.W.237.175; 4.W.237.240; 4.W.237.244; 4.W.238.228; 4.W.238.229; 4.W.238.230; 4.W.238.231; 4.W.238.236; 4.W.238.237; 4.W.238.238; 4.W.238.239; 4.W.238.154; 4.W.238.157; 4.W.238.166; 4.W.238.169; 4.W.238.172; 4.W.238.175; 4.W.238.240; 4.W.238.244; 4.W.239.228; 4.W.239.229; 4.W:239.230; 4.W.239.231; 4.W.239.236; 4.W.239.237; 4.W.239.238; 4.W.239.239; 4.W.239.154; 4.W.239.157; 4.W.239.166; 4.W.239.169; 4.W.239.172; 4.W.239.175; 4.W.239.240; 4.W.239.244; 4.W.154.228; 4.W.154.229; 4.W.154.230; 4.W.154.231; 4.W.154.236; 4.W.154.237; 4.W.154.238; 4.W.154.239; 4.W.154.154; 4.W.154.157; 4.W.154.166; 4.W.154.169; 4.W.154.172; 4.W.154.175; 4.W.154.240; 4.W.154.244; 4.W.157.228; 4.W.157.229; 4.W.157.230; 4.W.157.231; 4.W.157.236; 4.W.157.237; 4.W.157.238;4.W.157.239; 4.W.157.154; 4.W.157.157; 4.W.157.166; 4.W.157.169; 4.W.157.172;4.W.157.175; 4.W.157.240; 4.W.157.244; 4.W.166.228; 4.W.166.229; 4.W.166.230; 4.W.166.231; 4.W.166.236; 4.W.166.237; 4.W.166.238; 4.W.166.239; 4.W.166.154; 4.W.166.157; 4.W.166.166; 4.W.166.169; 4.W.166.172; 4.W.166.175; 4.W.166.240; 4.W.166.244; 4.W.169.228; 4.W.169.229; 4.W.169.230; 4.W.169.231; 4.W.169.236; 4.W.169.237; 4.W.169.238; 4.W.169.239; 4.W.169.154; 4.W.169.157; 4.W.169.166; 4.W.169.169; 4.W.169.172; 4.W.169.175; 4.W.169.240; 4.W.169.244; 4.W.172.228; 4.W.172.229; 4.W.172.230; 4.W.172.231; 4.W.172.236; 4.W.172.237; 4.W.172.238; 4.W.172.239; 4.W.172.154; 4.W.172.157; 4.W.172.166; 4.W.172.169; 4.W.172.172; 4.W.172.175; 4.W.172.240; 4.W.172.244; 4.W.175.228; 4.W.175.229; 4.W.175.230; 4.W.175.231; 4.W.175.236; 4.W.175.237; 4.W.175.238; 4.W.175.239; 4.W.175.154; 4.W.175.157; 4.W.175.166; 4.W.175.169; 4.W.175.172; 4.W.175.175; 4.W.175.240; 4.W.175.244; 4.W.240.228; 4.W.240.229; 4.W.240.230; 4.W.240.231; 4.W.240.236; 4.W.240.237; 4.W.240.238; 4.W.240.239; 4.W.240.154; 4.W.240.157; 4.W.240.166; 4.W.240.169; 4.W.240.172; 4.W.240.175; 4.W.240.240; 4.W.240.244; 4.W.244.228; 4.W.244.229; 4.W.244.230; 4.W.244.231; 4.W.244.236; 4.W.244.237;
4.W.244.238; 4.W.244.239; 4.W.244.154; 4.W.244.157; 4.W.244.166; 4.W.244.169; 4.W.244.172; 4.W.244.175; 4.W.244.240; 4.W.244.244;
Prodrugs of 4.Y
4.Y.228.228; 4.Y.228.229; 4.Y.228.230; 4.Y.228.231; 4.Y.228.236; 4.Y.228.237; 4.Y.228.238; 4.Y.228.239; 4.Y.228.154; 4.Y.228.157; 4.Y.228.166; 4.Y.228.169; 4.Y.228.172; 4.Y.228.175; 4.Y.228.240; 4.Y.228.244; 4.Y.229.228; 4.Y.229.229; 4.Y.229.230; 4.Y.229.231; 4.Y.229.236; 4.Y.229.237; 4;Y.229.238; 4.Y.229.239; 4.Y.229.154; 4.Y.229.157; 4.Y.229.166; 4.Y.229.169; 4.Y.229.172; 4.Y.229.175; 4.Y.229.240; 4.Y.229.244; 4.Y.230.228; 4.Y.230.229; 4.Y.230.230; 4.Y.230.231; 4.Y.230.236; 4.Y.230.237; 4.Y.230.238; 4.Y.230.239; 4.Y.230.154; 4.Y.230.157; 4.Y.230.166; 4.Y.230.169; 4.Y.230.172; 4.Y.230.175; 4.Y.230.240; 4.Y.230.244; 4.Y.231.228; 4.Y.231.229; 4.Y.231.230; 4.Y.231.231; 4.Y.231.236; 4.Y.231.237; 4.Y.231.238; 4.Y.231.239; 4.Y.231.154; 4.Y.231.157; 4.Y.231.166; 4.Y.231.169; 4.Y.23L172; 4.Y.231.175; 4.Y.231.240; 4.Y.231.244; 4.Y.236.228; 4.Y.236.229; 4.Y.236.230; 4.Y.236.231; 4.Y.236.236; 4.Y.236.237; 4.Y.236.238; 4.Y.236.239; 4.Y.236.154; 4.Y.236.157; 4.Y.236.166; 4.Y.236.169; 4.Y.236.172; 4.Y.236.175; 4.Y.236.240; 4.Y.236.244; 4.Y.237.228; 4.Y.237.229; 4.Y.237.230; 4.Y.237.231; 4.Y.237.236; 4.Y.237.237; 4.Y.237.238; 4.Y.237.239; 4.Y.237.154; 4.Y.237.157; 4.Y.237.166; 4.Y.237.169; 4.Y.237.172; 4.Y.237.175; 4.Y.237.240; 4.Y.237.244; 4.Y.238.228; 4.Y.238.229; 4.Y.238.230; 4.Y.238.231; 4.Y.238.236; 4.Y.238.237; 4.Y.238.238; 4.Y.238.239; 4.Y.238.154; 4.Y.238.157; 4.Y.238.166; 4.Y.238.169; 4.Y.238.172; 4.Y.238.175; 4.Y.238.240; 4.Y.238.244; 4.Y.239.228; 4.Y.239.229; 4.Y.239.230; 4.Y.239.231; 4.Y.239.236; 4.Y.239.237; 4.Y.239.238; 4.Y.239.239; 4.Y.239.154; 4.Y.239.157; 4.Y.239.166; 4.Y.239.169; 4.Y.239.172; 4.Y.239.175; 4.Y.239.240; 4.Y.239.244; 4.Y.154.228; 4.Y.154.229; 4.Y. 154.230; 4.Y.154.231; 4.Y.154.236; 4.Y.154.237; 4.Y.154.238; 4.Y.154.239; 4.Y.154.154; 4.Y.154.157; 4.Y.154.166; 4.Y.154.169; 4.Y.154.172; 4.Y.154.175; 4.Y.154.240; 4.Y.154.244; 4.Y.157.228; 4.Y.157.229; 4.Y.157.230; 4.Y.157.231; 4.Y.157.236; 4.Y.157.237; 4.Y157.238; 4.Y.157.239; 4.Y.157.154; 4.Y.157.157; 4.Y.157.166; 4.Y.157.169; 4.Y.157.172; 4.Y.157.175; 4.Y.157.240; 4.Y.157.244; 4.Y.166.228; 4.Y.166.229; 4.Y.166.230; 4.Y.166.231; 4.Y.166.236; 4.Y.166.237; 4.Y.166.238; 4.Y.166.239; 4.Y.166.154; 4.Y.166.157; 4.Y.166.166; 4.Y.166.169; 4.Y.166.172; 4.Y.166.175; 4.Y.166.240; 4.Y.166.244; 4.Y.169.228; 4.Y.169.229; 4.Y.169.230; 4.Y.169.231; 4.Y.169.236; 4.Y.169.237; 4.Y.169.238; 4.Y.169.239; 4.Y.169.154; 4.Y.169.157; 4.Y.169.166; 4.Y.169.169; 4.Y.169.172; 4.Y.169.175; 4.Y.169.240; 4.Y.169.244; 4.Y.172.228; 4.Y.172.229; 4.Y.172.230; 4.Y.172.231; 4.Y.172.236; 4.Y.172.237; 4.Y.172.238; 4.Y.172.239; 4.Y.172.154; 4.Y.172.157; 4.Y.172.166; 4.Y.172.169; 4.Y.172.172; 4.Y.172.175; 4.Y.172.240; 4.Y.172.244; 4.Y.175.228; 4.Y.175.229; 4.Y.175.230; 4.Y.175.231; 4.Y.175.236; 4.Y.175.237; 4.Y.175.238; 4.Y.175.239; 4.Y.175.154; 4.Y.175.157; 4.Y.175.166; 4.Y.175.169; 4.Y.175.172; 4.Y.175.175; 4.Y.175.240; 4.Y.175.244; 4.Y.240.228; 4.Y.240.229; 4.Y.240.230; 4.Y.240.231; 4.Y.240.236; 4.Y.240.237; 4.Y.240.238; 4.Y.240.239; 4.Y.240.154; 4.Y.240.157; 4.Y.240.166; 4.Y.240.169; 4.Y.240.172; 4.Y.240.175; 4.Y.240.240; 4.Y.240.244; 4.Y.244.228; 4.Y.244.229; 4.Y.244.230; 4.Y.244.231; 4.Y.244.236; 4.Y.244.237;
4.Y.244.238; 4.Y.244.239; 4.Y.244.154; 4.Y.244.157; 4.Y.244.166; 4.Y.244.169; 4.Y.244.172; 4.Y.244.175; 4.Y.244.240; 4.Y.244.244;
Prodrugs of 5,B
5.B.228.228; 5.B.228.229; 5.B.228.230; 5.B.228.231; 5.B.228.236; 5.B.228.237; 5.B.228.238; 5.B.228.239; 5.B.228.154; 5.B.228.157; 5.B.228.166; 5.B.228.169; 5.B.228.172; 5.B.228.175; 5.B.228.240; 5.B.228.244; 5.B.229.228; 5.B.229.229; 5.B.229.230; 5.B.229.231; 5.B.229.236; 5.B.229.237; 5.B.229.238; 5.B.229.239; 5.B.229.154; 5.B.229.157; 5.B.229.166; 5.B.229.169; 5.B.229.172; 5.B.229.175; 5.B.229.240; 5.B.229.244; 5.B.230.228; 5.B.230.229; 5.B.230.230; 5.B.230.231; 5.B.230.236; 5.B.230.237; 5.B.230.238; 5.B.230.239; 5.B.230.154; 5.B.230.157; 5.B.230.166; 5.B.230.169; 5.B.230.172; 5.B.230.175; 5.B.230.240; 5.B.230.244; 5.B.231.228; 5.B.231.229; 5.B.231.230; 5.B.231.231; 5.B.231.236; 5.B.231.237; 5.B.231.238; 5.B.231.239; 5,6.231,154; 5.B.231.157; 5.B.231.166; 5.B.231.169; 5.B.231.172; 5.B.231.175; 5.B.231.240; 5.B.231.244; 5.B.236.228; 5.B.236.229; 5.B.236.230; 5.B.236.231; 5.B.236.236; 5.B.236.237; 5.B.236.238; 5.B.236.239; 5.B.236.154; 5.B.236.157; 5.B.236.166; 5.B.236.169; 5.B.236.172; 5.B.236.175; 5.B.236.240; 5.B.236.244; 5.B.237.228; 5.B.237.229; 5.B.237.230; 5.B.237.231; 5.B.237.236; 5.B.237.237; 5.B.237.238; 5.B.237.239; 5.B.237.154; 5.B.237.157; 5.B.237.166; 5.B.237.169; 5.B.237.172; 5.B.237.175; 5.B.237.240; 5.B.237.244; 5.B.238.228; 5.B.238.229; 5.B.238.230; 5.B.238.231; 5.B.238.236; 5.B.238.237; 5.B.238.238; 5.B.238.239; 5.B.238.154; 5.B.238.157; 5.B.238.166; 5.B.238.169; 5.B.238.172; 5.B.238.175; 5.B.238.240; 5.B.238.244; 5.B.239.228; 5.B.239.229; 5.B.239.230; 5.B.239.231; 5.B.239.236; 5.B.239.237; 5.B.239.238; 5.B.239.239; 5.B.239.154; 5.B.239.157; 5.B.239.166; 5.B.239.169; 5.B.239.172; 5.B.239.175; 5.B.239.240; 5.B.239.244; 5.B.154.228; 5.B.154.229; 5.B.154.230; 5.B.154.231; 5.B.154.236; 5.B.154.237; 5.B.154.238; 5.B.154.239; 5.B.154.154; 5.B.154.157; 5.B.154.166; 5.B.154.169; 5.B.154.172; 5.B.154.175; 5.B.154.240; 5.B.154.244; 5.B.157.228; 5.B.157.229; 5.B.157.230; 5.B.157.231; 5.B.157.236; 5.B.157.237; 5.B.157.238; 5.B.157.239; 5.B.157.154; 5.B.157.157; 5.B.157.166; 5.B.157.169; 5.B.157.172; 5.B.157.175; 5.B.157.240; 5.B.157.244; 5.B.166.228; 5.B.166.229; 5.B.166.230; 5.B.166.231; 5.B.166.236; 5.B.166.237; 5.B.166.238; 5.B.166.239; 5.B.166.154; 5.B.166.157; 5.B.166.166; 5.B.166.169; 5.B.166.172; 5.B.166.175; 5.B.166.240; 5.B.166.244; 5.B.169.228; 5.B.169.229; 5.B.169.230; 5.B.169.231; 5.B.169.236; 5.B.169.237; 5.B.169.238; 5.B.169.239; 5.B.169.154; 5.B.169.157; 5.B.169.166; 5.B.169.169; 5.B.169.172; 5.B.169.175; 5.B.169.240; 5.B.169.244; 5.B.172.228; 5.B.172.229; 5.B.172.230; 5.B.172.231; 5.B.172.236; 5.B.172.237; 5.B.172.238; 5.B.172.239; 5.B.172.154; 5.B.172.157; 5.B.172.166; 5.B.172.169; 5.B.172.172; 5.B.172.175; 5.B.172.240; 5.B.172.244; 5.B.175.228; 5.B.175.229; 5.B.175.230; 5.B.175.231; 5.B.175.236; 5.B.175.237; 5.B.175.238; 5.B.175.239; 5.B.175.154; 5.B.175.157; 5.B.175.166; 5.B.175.169; 5.B.175.172; 5.B.175.175; 5.B.175.240; 5.B.175.244; 5.B.240.228; 5.B.240.229; 5.B.240.230; 5.B.240.231; 5.B.240.236; 5.B.240.237; 5.B.240.238; 5.B.240.239; 5.B.240.154; 5.B.240.157; 5.B.240.166; 5.B.240.169; 5.B.240.172; 5.B.240.175; 5.B.240.240; 5.B.240.244; 5.B.244.228; 5.B.244.229; 5.B.244.230; 5.B.244.231; 5.B.244.236; 5.B.244.237; 5.B.244.238; 5.B.244.239; 5.B.244.154; 5.B.244.157; 5.B.244.166; 5.B.244.169; 5.B.244.172; 5.B.244.175; 5.B.244.240; 5.B.244.244;
Frodrugs of 5.D
5.D.228.228; 5.D.228.229; 5.D.228.230; 5.D.228.231; 5.D.228.236; 5.D.228.237; 5.D.228.238; 5.D.228.239; 5.D.228.154; 5.D.228.157; 5.D.228.166; 5.D.228.169; 5.D.228.172; 5.D.228.175; 5.D.228.240; 5.D.228.244; 5.D.229.228; 5.D.229.229;
5.D.229.230; 5.D.229.231; 5.D.229.236; 5.D.229.237; 5.D.229.238; 5.D.229.239; 5.D.229.154; 5.D.229.157; 5.D.229.166; 5.D.229.169; 5.D.229.172; 5.D.229.175; 5.D.229.240; 5.D.229.244; 5.D.230.228; 5.D.230.229; 5.D.230.230; 5.D.230.231; 5.D.230.236; 5.D.230.237; 5.D.230.238; 5.D.230.239; 5.D.230.154; 5.D.230.157; 5.D.230.166; 5.D.230.169; 5.D.230.172; 5.D.230.175; 5.D.230.240; 5.D.230.244; 5.D.231.228; 5.D.231.229; 5.D.231.230; 5.D.231.231; 5.D.231.236; 5.D.231.237; 5.D.231.238; 5.D.231.239; 5.D.231.154; 5.D.231.157; 5.D.231.166; 5.D.231.169; 5.D.231.172; 5.D.231.175; 5.D.231.240; 5.D.231.244; 5.D.236.228; 5.D.236.229; 5.D.236.230; 5.D.236.231; 5.D.236.236; 5.D.236.237; 5.D.236.238; 5.D.236.239; 5.D.236.154; 5.D.236.157; 5.D.236.166; 5.D.236.169; 5.D.236.172; 5.D.236.175; 5.D.236.240; 5.D.236.244; 5.D.237.228; 5.D.237.229; 5.D.237.230; 5.D.237.231; 5.D.237.236; 5.D.237.237; 5.D.237.238; 5.D.237.239; 5.D.237.154; 5.D.237.157; 5.D.237.166; 5.D.237.169; 5.D.237.172; 5.D.237.175; 5.D.237.240; 5.D.237.244; 5.D.238.228; 5.D.238.229; 5.D.238.230; 5.D.238.231; 5.D.238.236; 5.D.238.237; 5.D.238.238; 5.D.238.239; 5.D.238.154; 5.D.238.157; 5.D.238.166; 5.D.238.169; 5.D.238.172; 5.D.238.175; 5.D.238.240; 5.D.238.244; 5.D.239.228; 5.D.239.229; 5.D.239.230; 5.D.239.231; 5.D.239.236; 5.D.239.237; 5.D.239.238; 5.D.239.239; 5.D.239.154; 5.D.239.157; 5.D.239.166; 5.D.239.169; 5.D.239.172; 5.D.239.175; 5.D.239.240; 5.D.239.244; 5.D.154.228; 5.D.154.229; 5.D.154.230; 5.D.154.231; 5.D.154.236; 5.D.154.237; 5.D.154.238; 5.D.154.239; 5.D.154.154; 5.D.154.157; 5.D.154.166; 5.D.154.169; 5.D.154.172; 5.D.154.175; 5.D.154.240; 5.D.154.244; 5.D.157.228; 5.D.157.229; 5.D.157.230; 5.D.157.231; 5.D.157.236; 5.D.157.237; 5.D.157.238; 5.D.157.239; 5.D.157.154; 5.D.157.157; 5.D.157.166; 5.D.157.169; 5.D.157.172; 5.D.157.175; 5.D.157.240; 5.D.157.244; 5.D.166.228; 5.D.166.229; 5.D.166.230; 5.D.166.231; 5.D.166.236; 5.D.166.237; 5.D.166.238; 5.D.166.239; 5.D.166.154; 5.D.166.157; 5.D.166.166; 5.D.166.169; 5.D.166.172; 5.D.166.175; 5.D.166.240; 5.D.166.244; 5.D.169.228; 5.D.169.229; 5.D.169.230; 5.D.169.231; 5.D.169.236; 5.D.169.237; 5.D.169.238; 5.D.169.239; 5.D.169.154; 5.D.169.157; 5.D.169.166; 5.D.169.169; 5.D.169.172; 5.D.169.175; 5.D.169.240; 5.D.169.244; 5.D.172.228; 5.D.172.229; 5.D.172.230; 5.D.172.231; 5.D.172.236; 5.D.172.237; 5.D.172.238; 5.D.172.239; 5.D.172.154; 5.D.172.157; 5.D.172.166; 5.D.172.169; 5.D.172.172; 5.D.172.175; 5.D.172.240; 5.D.172.244; 5.D.175.228; 5.D.175.229; 5.D.175.230; 5.D.175.231; 5.D.175.236; 5.D.175.237; 5.D.175.238; 5.D.175.239; 5.D.175.154; 5.D.175.157; 5.D.175.166; 5.D.175.169; 5.D.175.172; 5.D.175.175; 5.D.175.240; 5.D. 175.244; 5.D.240.228; 5.D.240.229; 5.D.240.230; 5.D.240.231; 5.D.240.236; 5.D.240.237; 5.D.240.238; 5.D.240.239; 5.D.240.154; 5.D.240.157; 5.D.240.166; 5.D.240.169; 5.D.240.172; 5.D.240.175; 5.D.240.240; 5.D.240.244; 5.D.244.228; 5.D.244.229; 5.D.244.230; 5.D.244.231; 5.D.244.236; 5.D.244.237; 5.D.244.238; 5.D.244.239; 5.D.244.154; 5.D.244.157; 5.D.244.166; 5.D.244.169; 5.D.244.172; 5.D.244.175; 5.D.244.240; 5.D.244.244;
Prodrugs of 5.E
5.E.228.228; 5.E.228.229; 5.E.228.230; 5.E.228.231; 5.E.228.236; 5.E.228.237; 5.E.228.238; 5.E.228.239; 5.E.228.154; 5.E.228.157; 5.E.228.166; 5.E.228.169; 5.E.228.172; 5.E.228.175; 5.E.228.240; 5.E.228.244; 5.E.229.228; 5.E.229.229; 5.E.229.230; 5.E.229.231; 5.E.229.236; 5.E.229.237; 5.E.229.238; 5.E.229.239; 5.E.229.154; 5.E.229.157; 5.E.229.166;
5.E.229.169; 5.E.229.172; 5.E.229.175; 5.E.229.240; 5.E.229.244; 5.E.230.228; 5.E.230.229; 5.E.230.230; 5.E.230.231; 5.E.230.236; 5.E.230.237; 5.E.230.238; 5.E.230.239; 5.E.230.154; 5.E.230.157; 5.E.230.166; 5.E.230.169; 5.E.230.172; 5.E.230.175; 5.E.230.240; 5.E.230.244; 5.E.231.228; 5.E.231.229; 5.E.231.230; 5.E.231.231; 5.E.231.236; 5.E.231.237; 5.E.231.238; 5.E.231.239; 5.E.231.154; 5.E.231.157; 5.E.231.166; 5.E.231.169; 5.E.231.172; 5.E.231.175; 5.E.231.240; 5.E.231.244; 5.E.236.228; 5.E.236.229; 5.E.236.230; 5.E.236.231; 5.E.236.236; 5.E.236.237; 5.E.236.238; 5.E.236.239; 5.E.236.154; 5.E.236.157; 5.E.236.166; 5.E.236.169; 5.E.236.172; 5.E.236.175; 5.E.236.240; 5.E.236.244; 5.E.237.228; 5.E.237.229; 5.E.237.230; 5.E.237.231; 5.E.237.236; 5.E.237.237; 5.E.237.238; 5.E.237.239; 5.E.237.154; 5.E.237.157; 5.E.237.166; 5.E.237.169; 5.E.237.172; 5.E.237.175; 5.E.237.240; 5.E.237.244; 5.E.238.228; 5.E.238.229; 5.E.238.230; 5.E.238.231; 5.E.238.236; 5.E.238.237; 5.E.238.238; 5.E.238.239; 5.E.238.154; 5.E.238.157; 5.E.238.166; 5.E.238.169; 5.E.238.172; 5.E.238.175; 5.E.238.240; 5.E.238.244; 5.E.239.228; 5.E.239.229; 5.E.239.230; 5.E.239.231; 5.E.239.236; 5.E.239.237; 5.E.239.238; 5.E.239.239; 5.E.239.154; 5.E.239.157; 5.E.239.166; 5.E.239.169; 5.E.239.172; 5.E.239.175; 5.E.239.240; 5.E.239.244; 5.E.154.228; 5.E.154.229; 5.E.154.230; 5.E.154.231; 5.E.154.236; 5.E.154.237; 5.E.154.238; 5.E.154.239; 5.E.154.154; 5.E.154.157; 5.E.154.166; 5.E.154.169; 5.E.154.172; 5.E.154.175; 5.E.154.240; 5.E.154.244; 5.E.157.228; 5.E.157.229; 5.E.157.230; 5.E.157.231; 5.E.157.236; 5.E.157.237; 5.E.157.238; 5.E.157.239; 5.E.157.154; 5.E.157.157; 5.E.157.166; 5.E.157.169; 5.E.157.172; 5.E.157.175; 5.E.157.240; 5.E.157.244; 5.E.166.228; 5.E.166.229; 5.E.166.230; 5.E.166.231; 5.E.166.236; 5.E.166.237; 5.E.166.238; 5.E.166.239; 5.E.166.154; 5.E.166.157; 5.E.166.166; 5.E.166.169; 5.E.166.172; 5.E.166.175; 5.E.166.240; 5.E.166.244; 5.E.169.228; 5.E.169.229; 5.E.169.230; 5.E.169.231; 5.E.169.236; 5.E.169.237; 5.E.169.238; 5.E.169.239; 5.E.169.154; 5.E.169.157; 5.E.169.166; 5.E.169.169; 5.E.169.172; 5.E.169.175; 5.E.169.240; 5.E.169.244; 5.E.172.228; 5.E.172.229; 5.E.172.230; 5.E.172.231; 5.E.172.236; 5.E.172.237; 5.E.172.238; 5.E.172.239; 5.E.172.154; 5.E.172.157; 5.E.172.166; 5.E.172.169; 5.E.172.172; 5.E.172.175; 5.E.172.240; 5.E.172.244; 5.E.175.228; 5.E.175.229; 5.E.175.230; 5.E.175.231; 5.E.175.236; 5.E.175.237; 5.E.175.238; 5.E.175.239; 5.E.175.154; 5.E.175.157; 5.E.175.166; 5.E.175.169; 5.E.175.172; 5.E.175.175; 5.E.175.240; 5.E.175.244; 5.E.240.228; 5.E.240.229; 5.E.240.230; 5.E.240.231; 5.E.240.236; 5.E.240.237; 5.E.240.238; 5.E.240.239; 5.E.240.154; 5.E.240.157; 5.E.240.166; 5.E.240.169; 5.E.240.172; 5.E.240.175; 5.E.240.240; 5.E.240.244; 5.E.244.228; 5.E.244.229; 5.E.244.230; 5.E.244.231; 5.E.244.236; 5.E.244.237; 5.E.244.238; 5.E.244.239; 5.E.244.154; 5.E.244.157; 5.E.244.166; 5.E.244.169; 5.E.244.172; 5.E.244.175; 5.E.244.240; 5.E.244.244;
Prodrugs of 5.G
5.G.228.228; 5.G.228.229; 5.G.228.230; 5.G.228.231; 5.G.228.236; 5.G.228.237; 5.G.228.238; 5.G.228.239; 5.G.228.154; 5.G.228.157; 5.G.228.166; 5.G.228.169; 5.G.228.172; 5.G.228.175; 5.G.228.240; 5.G.228.244; 5.G.229.228; 5.G.229.229; 5.G.229.230; 5.G.229.231; 5.G.229.236; 5.G.229.237; 5.G.229.238; 5.G.229.239; 5.G.229.154; 5.G.229.157; 5.G.229.166; 5.G.229.169; 5.G.229.172; 5.G.229.175; 5.G.229.240; 5.G.229.244; 5.G.230.228; 5.G.230.229; 5.G.230.230; 5.G.230.231; 5.G.230.236; 5.G.230.237; 5.G.230.238; 5.G.230.239; 5.G.230.154; 5.G.230.157; 5.G.230.166; 5.G.230.169; 5.G.230.172; 5.G.230.175; 5.G.230.240; 5.G.230.244; 5.G.231.228; 5.G.231.229; 5.G.231.230; 5.G.231.231; 5.G.231.236; 5.G.231.237; 5.G.231.238; 5.G.231.239; 5.G.231.154; 5.G.231.157; 5.G.231.166; 5.G.231.169; 5.G.231.172; 5.G.231.175; 5.G.231.240; 5.G.231.244; 5.G.236.228; 5.G.236.229;
5.G.236.230; 5.G.236.231; 5.G.236.236; 5.G.236.237; 5.G.236.238; 5.G.236.239; 5.G.236.154; 5.G.236.157; 5.G.236.166; 5.G.236.169; 5.G.236.172; 5.G.236.175; 5.G.236.240; 5.G.236.244; 5.G.237.228; 5.G.237.229; 5.G.237.230; 5.G.237.231; 5.G.237.236; 5.G.237.237; 5.G.237.238; 5.G.237.239; 5.G.237.154; 5.G.237.157; 5.G.237.166; 5.G.237.169; 5.G.237.172; 5.G.237.175; 5.G.237.240; 5.G.237.244; 5.G.238.228; 5.G.238.229; 5.G.238.230; 5.G.238.231; 5.G.238.236; 5.G.238.237; 5.G.238.238; 5.G.238.239; 5.G.238.154; 5.G.238.157; 5.G.238.166; 5.G.238.169; 5.G.238.172; 5.G.238.175; 5.G.238.240; 5.G.238.244; 5.G.239.228; 5.G.239.229; 5.G.239.230; 5.G.239.231; 5.G.239.236; 5.G.239.237; 5.G.239.238; 5.G.239.239; 5.G.239.154; 5.G.239.157; 5.G.239.166; 5.G.239.169; 5.G.239.172; 5.G.239.175; 5.G.239.240; 5.G.239.244; 5.G.154.228; 5.G.154.229; 5.G.154.230; 5.G.154.231; 5.G.154.236; 5.G.154.237; 5.G.154.238; 5.G.154.239; 5.G.154.154; 5.G.154.157; 5.G.154.166; 5.G.154.169; 5.G.154.172; 5.G.154.175; 5.G.154.240; 5.G.154.244; 5.G.157.228; 5.G.157.229; 5.G.157.230; 5.G.157.231; 5.G.157.236; 5.G.157.237; 5.G.157.238; 5.G.157.239; 5.G.157.154; 5.G.157.157; 5.G.157.166; 5.G.157.169; 5.G.157.172; 5.G.157.175; 5.G.157.240; 5.G.157.244; 5.G.166.228; 5.G.166.229; 5.G.166.230; 5.G.166.231; 5.G.166.236; 5.G.166.237; 5.G.166.238; 5.G.166.239; 5.G.166.154; 5.G.166.157; 5.G.166.166; 5.G.166.169; 5.G.166.172; 5.G.166.175; 5.G.166.240; 5.G.166.244; 5.G.169.228; 5.G.169.229; 5.G.169.230; 5.G.169.231; 5.G.169.236; 5.G.169.237; 5.G.169.238; 5.G.169.239; 5.G.169.154; 5.G.169.157; 5.G.169.166; 5.G.169.169; 5.G.169.172; 5.G.169.175; 5.G.169.240; 5.G.169.244; 5.G.172.228; 5.G.172.229; 5.G.172.230; 5.G.172.231; 5.G.172.236; 5.G.172.237; 5.G.172.238; 5.G.172.239; 5.G.172.154; 5.G.172.157; 5.G.172.166; 5.G.172.169; 5.G.172.172; 5.G.172.175; 5.G.172.240; 5.G.172.244; 5.G.175.228; 5.G.175.229; 5.G.175.230; 5.G.175.231; 5.G.175.236; 5.G.175.237; 5.G.175.238; 5.G.175.239; 5.G.175.154; 5.G.175.157; 5.G.175.166; 5.G.175.169; 5.G.175.172; 5.G.175.175; 5.G.175.240; 5.G.175.244; 5.G.240.228; 5.G.240.229; 5.G.240.230; 5.G.240.231; 5.G.240.236; 5.G.240.237; 5.G.240.238; 5.G.240.239; 5.G.240.154; 5.G.240.157; 5.G:240.166; 5.G.240.169; 5.G.240.172; 5.G.240.175; 5.G.240.240; 5.G.240.244; 5.G.244.228; 5.G.244.229; 5.G.244.230; 5.G.244.231; 5.G.244.236; 5.G.244.237; 5.G.244.238; 5.G.244.239; 5.G.244.154; 5.G.244.157; 5.G.244.166; 5.G.244.169; 5.G.244.172; 5.G.244.175; 5.G.244.240; 5.G.244.244;
Prodrugs of 5.1
5.1.228.228; 5.1.228.229; 5.1.228.230; 5.1.228.231; 5.1.228.236; 5.1.228.237; 5.1.228.238; 5.1.228.239; 5.1.228.154; 5.1.228.157; 5.1.228.166; 5.1.228.169; 5.1.228.172; 5.1.228.175; 5.1.228.240; 5.1.228.244; 5.1.229.228; 5.1.229.229; 5.1.229.230; 5.1.229.231; 5.1.229.236; 5.1.229.237; 5.1.229.238; 5.1.229.239; 5.1.229.154; 5.1.229.157; 5.1.229.166; 5.1.229.169; 5.1.229.172; 5.1.229.175; 5.1.229.240; 5.1.229.244; 5.1.230.228; 5.1.230.229; 5.1.230.230; 5.1.230.231; 5.1.230.236; 5.1.230.237; 5.1.230.238; 5.1.230.239; 5.1.230.154; 5.1.230.157; 5.1.230.166; 5.1.230.169; 5.1.230.172; 5.1.230.175; 5.1.230.240; 5.1.230.244; 5.1.231.228; 5.1.231.229; 5.1.231.230; 5.1.231.231; 5.1.231.236; 5.1.231.237; 5.1.231.238; 5.1.231.239; 5.1.231.154; 5.1.231.157; 5.1.231.166; 5.1.231.169; 5.1.231.172; 5.1.231.175; 5.1.231.240; 5.1.231.244; 5.1.236.228; 5.1.236.229; 5.1.236.230; 5.1.236.231; 5.1.236.236; 5.1.236.237; 5.1.236.238; 5.1.236.239; 5.1.236.154; 5.1.236.157; 5.1.236.166; 5.1.236.169; 5.1.236.172; 5.1.236.175; 5.1.236.240; 5.1.236.244; 5.1.237.228; 5.1.237.229; 5.1.237.230; 5.1.237.231;
5.1.237.236; 5.1.237.237; 5.1.237.238; 5.1.237.239; 5.1.237.154; 5.1.237.157; 5.1.237.166; 5.1.237.169; 5.1.237.172; 5.1.237.175; 5.1.237.240; 5.1.237.244; 5.1.238.228; 5.1.238.229; 5.1.238.230; 5.1.238.231; 5.1.238.236; 5.1.238.237; 5.1.238.238; 5.1.238.239; 5.1.238.154; 5.1.238.157; 5.1.238.166; 5.1.238.169; 5.1.238.172; 5.1.238.175; 5.1.238.240; 5.1.238.244; 5.1.239.228; 5.1.239.229; 5.1.239.230; 5.1.239.231; 5.1.239.236; 5.1.239.237; 5.1.239.238; 5.1.239.239; 5.1.239.154; 5.1.239.157; 5.1.239.166; 5.1.239.169; 5.1.239.172; 5.1.239.175; 5.1.239.240; 5.1.239.244; 5.1.154.228; 5.1.154.229; 5.1.154.230; 5.1.154.231; 5.1.154.236; 5.1.154.237; 5.1.154.238; 5.1.154.239; 5.1.154.154; 5.1.154.157; 5.1.154.166; 5.1.154.169; 5.1.154.172; 5.1.154.175; 5.1.154.240; 5.1.154.244; 5.1.157.228; 5.1.157.229; 5.1.157.230; 5.1.157.231; 5.1.157.236; 5.1.157.237; 5.1.157.238; 5.1.157.239; 5.1.157.154; 5.1.157.157; 5.1.157.166; 5.1.157.169; 5.1.157.172; 5.1.157.175; 5.1.157.240; 5.1.157.244; 5.1.166.228; 5.1.166.229; 5.1.166.230; 5.1.166.231; 5.1.166.236; 5.1.166.237; 5.1.166.238; 5.1.166.239; 5.1.166.154; 5.1.166.157; 5.1.166.166; 5.1.166.169; 5.1.166.172; 5.1.166.175; 5.1.166.240; 5.1.166.244; 5.1.169.228; 5.1.169.229; 5.1.169.230; 5.1.169.231; 5.1.169.236; 5.1.169.237; 5.1.169.238; 5.1.169.239; 5.1.169.154; 5.1.169.157; 5.L169.166; 5.1.169.169; 5.1.169.172; 5.1.169.175; 5.1.169.240; 5.1.169.244; 5.1.172.228; 5.1.172.229; 5.1.172.230; 5.1.172.231; 5.1.172.236; 5.1.172.237; 5.1.172.238; 5.1.172.239; 5.1.172.154; 5.1.172.157; 5.1.172.166; 5.1.172.169; 5.1.172.172; 5.1.172.175; 5.1.172.240; 5.1.172.244; 5.1.175.228; 5.1.175.229; 5.1.175.230; 5.1.175.231; 5.1.175.236; 5X175.237; 5.1.175.238; 5.1.175.239; 5X175.154; 5X175.157; 5.1.175.166; 5.1.175.169; 5.1.175.172; 5.1.175.175; 5.1.175.240; 5X175.244; 5X240.228; 5X240.229; 5X240.230; 5.1.240.231; 5.1.240.236; 5.1.240.237; 5X240.238; 5X240.239; 5X240.154; 5.1.240.157; 5.1.240.166; 5X240.169; 5.1.240.172; 5X240.175; 5X240.240; 5.1.240.244; 5X244.228; 5.1.244.229; 5.1.244.230; 5.1.244.231; 5.1.244.236; 5X244.237; 5X244.238; 5.1.244.239; 5.1.244.154; 5.1.244.157; 5.1.244.166; 5.1.244.169; 5X244.172; 5.1.244.175; 5.1.244.240; 5.1.244.244;
Prodrugs of 5.T
5.J.228.228; 5.J.228.229; 5J.228.230; 5.J.228.231; 5J.228.236; 5J.228.237; 5J.228.238; 5.J.228.239; 5J.228.154; 5.J.228.157; 5 J.228.166; 5 J.228.169; 5J.228.172; 5.J.228.175; 5.J.228.240; 5J.228.244; 5.J.229.228; 5J.229.229; 5J.229.230; 5J.229.231; 5J.229.236; 5.J.229.237; 5J.229.238; 5J.229.239; 5J.229.154; 5J.229.157; 5J.229.166; 5.J.229.169; 5J.229.172; 5J.229.175; 5J.229.240; 5 J.229.244; 5 J.230.228; 5J.230.229; 5.J.230.230; 5 J.230.231; 5J.230.236; 5J.230.237; 5 J.230.238; 5J.230.239; 5J.230.154; 5.J.230.157; 5.J.230.166; 5J.230.169; 5J.230.172; 5J.230.175; 5J.230.240; 5.J.230.244; 5J.231.228; 5 J.231.229; 5.J.231.230; 5J.231.231; 5 J.231.236; 5J.231.237; 5J.231.238; 5.J.231.239; 5J.231.154; 5J.231.157; 5J.231.166; 5J.231.169; 5.J.231.172; 5J.231.175; 5.J.231.240; 5 J.231.244; 5.J.236.228; 5J.236.229; 5 J.236.230; 5J.236.231; 5J.236.236; 5J.236.237; 5J.236.238; 5J.236.239; 5J.236.154; 5J.236.157; 5J.236.166; 5.J.236.169; 5.J.236.172; 5.J.236.175; 5J.236.240; 5J.236.244; 5J.237.228; 5J.237.229; 5J.237.230; 5.J.237.231; 5J.237.236; 5J.237.237; 5J.237.238; 5J.237.239; 5J.237.154; 5J.237.157; 5.J.237.166; 5.J.237.169; 5.J.237.172; 5.J.237.175; 5J.237.240; 5.J.237.244; 5J.238.228; 5J.238.229; 5.J.238.230; 5J.238.231; 5J.238.236; 5.J.238.237; 5J.238.238; 5J.238.239; 5.J.238.154; 5.J.238.157; 5.J.238.166; 5J.238.169; 5.J.238.172; 5J.238.175; 5J.238.240; 5.J.238.244; 5.J.239.228; 5.J.239.229; 5.J.239.230; 5J.239.231; 5J.239.236; 5J.239.237; 5J.239.238; 5.J.239.239; 5.J.239.154; 5.J.239.157; 5.J.239.166; 5.J.239.169; 5.J.239.172; 5J.239.175; 5.J.239.240; 5J.239.244; 5J.154.228; 5.J.154.229; 5.J.154.230; 5.J.154.231; 5J.154.236;
5J.154.237; 5.J.154.238; 5.J.154.239; 5.J.154.154; 5.J.154.157; 5.J. 154.166; 5J.154.169; 5J.154.172; 5J.154.175; 5.J.154.240; 5.J.154.244; 5.J.157.228; 5.J.157.229; 5.J.157.230; 5.J.157.231; 5.J.157.236; 5.J.157.237; 5.J.157.238; 5.J.157.239; 5J.157.154; 5J.157.157; 5J.157.166; 5J.157.169; 5J.157.172; 5J.157.175; 5J.157.240; 5J.157.244; 5.J.166.228; 5J.166.229; 5.J.166.230; 5J.166.231; 5J.166.236; 5J.166.237; 5J.166.238; 5J.166.239; 5J.166.154; 5.J.166.157; 5 J.166.166; 5 J.166.169; 5 J.166.172; 5J.166.175; 5J.166.240; 5J.166.244; 5J.169.228; 5J.169.229; 5.J.169.230; 5J.169.231; 5.J.169.236; 5J.169.237; 5J.169.238; 5J.169.239; 5J.169.154; 5J.169.157; 5J.169.166; 5J.169.169; 5J.169.172; 5J.169.175; 5J.169.240; 5J.169.244; 5J.172.228; 5.J.172.229; 5J.172.230; 5J.172.231; 5J.172.236; 5J.172.237; 5J.172.238; 5.J.172.239; 5J.172.154; 5J.172.157; 5J.172.166; 5J.172.169; 5J.172.172; 5J.172.175; 5J.172.240; 5J.172.244; 5J.175.228; 5J.175.229; 5J.175.230; 5J.175.231; 5.J.175.236; 5J.175.237; 5J.175.238; 5J.175.239; 5J.175.154; 5 J.175.157; 5J.175.166; 5J.175.169; 5J.175.172; 5J.175.175; 5J.175.240; 5.J.175.244; 5J.240.228; 5J.240.229; 5.J.240.230; 5J.240.231; 5J.240.236; 5J.240.237; 5J.240.238; 5J.240.239; 5J.240.154; 5J.240.157; 5J.240.166; 5J.240.169; 5J.240.172; 5J.240.175; 5 J.240.240; 5 J.240.244; 5J.244.228; 5J.244.229; 5 J.244.230; 5 J.244.231; 5J.244.236; 5J.244.237; 5 J.244.238; 5J.244.239; 5J.244.154; 5J.244.157; 5J.244.166; 5J.244.169; 5J.244.172; 5J.244.175; 5.J.244.240; 5J.244.244;
Prodrugs of 5.L
5.L.228.228; 5.L.228.229; 5.L.228.230; 5.L.228.231; 5.L.228.236; 5.L.228.237; 5.L.228.238; 5X.228.239; 5.L.228.154; 5.L.228.157; 5.L.228.166; 5.L.228.169; 5.L.228.172; 5.L.228.175; 5.L.228.240; 5.L.228.244; 5.L.229.228; 5.L.229.229; 5.L.229.230; 5.L.229.231; 5.L.229.236; 5.L.229.237; 5.L.229.238; 5.L.229.239; 5.L.229.154; 5.L.229.157; 5X.229.166; 5.L.229.169; 5.L.229.172; 5.L.229.175; 5.L.229.240; 5.L.229.244; 5.L.230.228; 5.L.230.229; 5.L.230.230; 5.L.230.231; 5.L.230.236; 5.L.230.237; 5.L.230.238; 5.L.230.239; 5X.230.154; 5.L.230.157; 5.L.230.166; 5.L.230.169; 5.L.230.172; 5.L.230.175; 5.L.230.240; 5X.230.244; 5.L.231.228; 5.L.231.229; 5.L.231.230; 5.L.231.231; 5X.231.236; 5.L.231.237; 5X.231.238; 5.L.231.239; 5X.231.154; 5X.231.157; 5X.231.166; 5X.231.169; 5X.231.172; 5X.231.175; 5X.231.240; 5X.231.244; 5X.236.228; 5X.236.229; 5X.236.230; 5X.236.231; 5X.236.236; 5X.236.237; 5X.236.238; 5X.236.239; 5X.236.154; 5X.236.157; 5X.236.166; 5X.236.169; 5X.236.172; 5X.236.175; 5X.236.240; 5X.236.244; 5X.237.228; 5X.237.229; 5X.237.230; 5.L.237.231; 5X.237.236; 5X.237.237; 5X.237.238; 5X.237.239; 5X.237.154; 5X.237.157; 5X.237.166; 5X.237.169; 5X.237.172; 5X.237.175; 5.L.237.240; 5.L.237.244; 5X.238.228; 5X.238.229; 5X.238.230; 5X.238.231; 5X.238.236; 5X.238.237; 5X.238.238; 5X.238.239; 5X.238.154; 5X.238.157; 5.L.238.166; 5X.238.169; 5X.238.172; 5X.238.175; 5X.238.240; 5X.238.244; 5X.239.228; 5X.239.229; 5X.239.230; 5X.239.231; 5X.239.236; 5X.239.237; 5X.239.238; 5X.239.239; 5X.239.154; 5X.239.157; 5.L.239.166; 5X.239.169; 5X.239.172; 5X.239.175; 5X.239.240; 5X.239.244; 5X.154.228; 5X.154.229; 5X.154.230; 5.L.154.231; 5X.154.236; 5X.154.237; 5X.154.238; 5X.154.239; 5X.154.154; 5X.154.157; 5X.154.166; 5X.154.169; 5X.154.172; 5X.154.175; 5X.154.240; 5.L.154.244; 5X.157.228; 5X.157.229; 5.L.157.230; 5X.157.231; 5X.157.236; 5X.157.237; 5.L.157.238; 5X.157.239; 5X.157.154; 5X.157.157; 5X.157.166; 5X.157.169; 5X.157.172; 5X.157.175; 5.L.157.240; 5X.157.244; 5.L.166.228; 5X.166.229; 5X.166.230; 5X.166.231; 5X.166.236; 5X.166.237; 5X.166.238; 5.L. 166.239; 5X.166.154; 5X.166.157; 5X.166.166; 5X.166.169; 5X.166.172; 5X.166.175; 5X.166.240; 5.L.166.244; 5.L.169.228; 5X.169.229; 5.L.169.230; 5X.1.69.231; 5X.169.236;
5.L.169.237; 5.L.169.238; 5.L.169.239; 5.L.169.154; 5.L.169.157; 5.L.169.166; 5.L.169.169; 5.L.169.172; 5.L.169.175; 5.L.169.240; 5.L.169.244; 5.L.172.228; 5.L.172.229; 5.L.172.230; 5.L.172.231; 5.L.172.236; 5.L.172.237; 5.L.172.238; 5.L.172.239; 5.L.172.154; 5.L.172.157; 5.L.172.166; 5.L.172.169; 5.L.172.172; 5.L.172.175; 5.L.172.240; 5.L.172.244; 5.L.175.228; 5.L.175.229; 5.L.175.230; 5.L.175.231; 5.L.175.236; 5.L.175.237; 5.L.175.238; 5.L.175.239; 5.L.175.154; 5.L.175.157; 5.L.175.166; 5.L.175.169; 5.L.175.172; 5.L.175.175; 5.L.175.240; 5.L. 175.244; 5.L.240.228; 5.L.240.229; 5.L.240.230; 5.L.240.231; 5.L.240.236; 5.L.240.237; 5.L.240.238; 5.L.240.239; 5.L.240.154; 5.L.240.157; 5.L.240.166; 5.L.240.169; 5.L.240.172; 5.L.240.175; 5.L.240.240; 5.L.240.244; 5.L.244.228; 5.L.244.229; 5.L.244.230; 5.L.244.231; 5.L.244.236; 5.L.244.237; 5.L.244.238; 5.L.244.239; 5.L.244.154; 5.L.244.157; 5.L.244.166; 5.L.244.169; 5.L.244.172; 5.L.244.175; 5.L.244.240; 5.L.244.244;
Prodrugs of 5.O
5.O.228.228; 5.O.228.229; 5.O.228.230; 5.O.228.231; 5.O.228.236; 5.O.228.237; 5.O.228.238; 5.O.228.239; 5.O.228.154; 5.O.228.157; 5.O.228.166; 5.O.228.169; 5.O.228.172; 5.O.228.175; 5.O.228.240; 5.O.228.244; 5.O.229.228; 5.O.229.229; 5.O.229.230; 5.O.229.231; 5.O.229.236; 5.O.229.237; 5.O.229.238; 5.O.229.239; 5.O.229.154; 5.O.229.157; 5.O.229.166; 5.O.229.169; 5.O.229.172; 5.O.229.175; 5.O.229.240; 5.O.229.244; 5.O.230.228; 5.O.230.229; 5.O.230.230; 5.O.230.231; 5.O.230.236; 5.O.230.237; 5.O.230.238; 5.O.230.239; 5.O.230.154; 5.O.230.157; 5.O.230.166; 5.O.230.169; 5.O.230.172; 5.O.230.175; 5.O.230.240; 5.O.230.244; 5.O.231.228; 5.O.231.229; 5.O.231.230; 5.O.231.231; 5.O.231.236; 5.O.231.237; 5.O.231.238; 5.O.231.239; 5.O.231.154; 5.O.231.157; 5.O.231.166; 5.O.231.169; 5.O.231.172; 5.O.231.175; 5.O.231.240; 5.O.231.244; 5.O.236.228; 5.O.236.229; 5.O.236.230; 5.O.236.231; 5.O.236.236; 5.O.236.237; 5.O.236.238; 5.O.236.239; 5.O.236.154; 5.O.236.157; 5.O.236.166; 5.O.236.169; 5.O.236.172; 5.O.236.175; 5.O.236.240; 5.O.236.244; 5.O.237.228; 5.O.237.229; 5.O.237.230; 5.O.237.231; 5.O.237.236; 5.O.237.237; 5.O.237.238; 5.O.237.239; 5.O.237.154; 5.O.237.157; 5.O.237.166; 5.O.237.169; 5.O.237.172; 5.O.237.175; 5.O.237.240; 5.O.237.244; 5.O.238.228; 5.O.238.229; 5.O.238.230; 5.O.238.231; 5.O.238.236; 5.O.238.237; 5.O.238.238; 5.O.238.239; 5.O.238.154; 5.O.238.157; 5.O.238.166; 5.O.238.169; 5.O.238.172; 5.O.238.175; 5.O.238.240; 5.O.238.244; 5.O.239.228; 5.O.239.229; 5.O.239.230; 5.O.239.231; 5.O.239.236; 5.O.239.237; 5.O.239.238; 5.O.239.239; 5.O.239.154; 5.O.239.157; 5.O.239.166; 5.O.239.169; 5.O.239.172; 5.O.239.175; 5.O.239.240; 5.O.239.244; 5.O.154.228; 5.O.154.229; 5.O.154.230; 5.O.154.231; 5.O.154.236; 5.O.154.237; 5.O.154.238; 5.O.154.239; 5.O.154.154; 5.O.154.157; 5.0.154.166; 5.O.154.169; 5.O.154.172; 5.O.154.175; 5.O.154.240; 5.O.154.244; 5.0.157.228; 5.O.157.229; 5.O.157.230; 5.O.157.231; 5.O.157.236; 5.O.157.237; 5.O.157.238; 5.O.157.239; 5.O.157.154; 5.O.157.157; 5.O.157.166; 5.O.157.169; 5.O.157.172; 5.O.157.175; 5.O.157.240; 5.O.157.244; 5.O.166.228; 5.O.166.229; 5.O.166.230; 5.O.166.231; 5.O.166.236; 5.O.166.237; 5.O.166.238; 5.O.166.239; 5.O.166.154; 5.O.166.157; 5.O.166.166; 5.O.166.169; 5.O.166.172; 5.O.166.175; 5.O.166.240; 5.O.166.244; 5.O.169.228; 5.O.169.229; 5.O.169.230; 5.O.169.231; 5.O.169.236; 5.O.169.237; 5.O.169.238; 5.O.169.239; 5.O.169.154; 5.O.169.157; 5.O.169.166; 5.O.169.169; 5.O.169.172; 5.O.169.175; 5.O.169.240; 5.O.169.244; 5.O.172.228; 5.O.172.229; 5.O.172.230; 5.O.172.231; 5.O.172.236; 5.O.172.237;
5.O.172.238; 5.O.172.239; 5.O.172.154; 5.O.172.157; 5.O.172.166; 5.O.172.169; 5.O.172.172; 5.O.172.175; 5.O.172.240; 5.O.172.244; 5.O.175.228; 5.O.175.229; 5.0.175.230; 5.O.175.231; 5.O.175.236; 5.O.175.237; 5.O.175.238; 5.O.175.239; 5.O.175.154; 5.O.175.157; 5.O.175.166; 5.O.175.169; 5.O.175.172; 5.O.175.175; 5.O.175.240; 5.O.175.244; 5.O.240.228; 5.O.240.229; 5.O.240.230; 5.O.240.231; 5.O.240.236; 5.O.240.237; 5.O.240.238; 5.O.240.239; 5.O.240.154; 5.O.240.157; 5.O.240.166; 5.O.240.169; 5.O.240.172; 5.O.240.175; 5.O.240.240; 5.O.240.244; 5.O.244.228; 5.O.244.229; 5.O.244.230; 5.O.244.231; 5.O.244.236; 5.O.244.237; 5.O.244.238; 5.O.244.239; 5.O.244.154; 5.O.244.I57; 5.O.244.166; 5.O.244.169; 5.O.244.172; 5.O.244.175; 5.O.244.240; 5.O.244.244;
Prodrugs of 5.F
5.P.228.228; 5.P.228.229; 5.P.228.230; 5.P.228.231; 5.P.228.236; 5.P.228.237; 5.P.228.238; 5.P.228.239; 5.P.228.154; 5.P.228.157; 5.P.228.166; 5.P.228.169; 5.P.228.172; 5.P.228.175; 5.P.228.240; 5.P.228.244; 5.P.229.228; 5.P.229.229; 5.P.229.230; 5.P.229.231; 5.P.229.236; 5.P.229.237; 5.P.229.238; 5.P.229.239; 5.P.229.154; 5.P.229.157; 5.P.229.166; 5.P.229.169; 5.P.229.172; 5.P.229.175; 5.P.229.240; 5.P.229.244; 5.P.230.228; 5.P.230.229; 5.P.230.230; 5.P.230.231; 5.P.230.236; 5.P.230.237; 5.P.230.238; 5.P.230.239; 5.P.230.154; 5.P.230.157; 5.P.230.166; 5.P.230.169; 5.P.230.172; 5.P.230.175; 5.P.230.240; 5.P.230.244; 5.P.231.228; 5.P.231.229; 5.P.231.230; 5.P.231.231; 5.P.231.236; 5.P.231.237; 5.P.231.238; 5.P.231.239; 5.P.231.154; 5.P.231.157; 5.P.231.166; 5.P.231.169; 5.P.231.172; 5.P.231.175; 5.P.231.240; 5.P.231.244; 5.P.236.228; 5.P.236.229; 5.P.236.230; 5.P.236.231; 5.P.236.236; 5.P.236.237; 5.P.236.238; 5.P.236.239; 5.P.236.154; 5.P.236.157; 5.P.236.166; 5.P.236.169; 5.P.236.172; 5.P.236.175; 5.P.236.240; 5.P.236.244; 5.P.237.228; 5.P.237.229; 5.P.237.230; 5.P.237.231; 5.P.237.236; 5.P.237.237; 5.P.237.238; 5.P.237.239; 5.P.237.154; 5.P.237.157; 5.P.237.166; 5.P.237.169; 5.P.237.172; 5.P.237.175; 5.P.237.240; 5.P.237.244; 5.P.238.228; 5.P.238.229; 5.P.238.230; 5.P.238.231; 5.P.238.236; 5.P.238.237; 5.P.238.238; 5.P.238.239; 5.P.238.154; 5.P.238.157; 5.P.238.166; 5.P.238.169; 5.P.238.172; 5.P.238.175; 5.P.238.240; 5.R238.244; 5.P.239.228; 5.P.239.229; 5.P.239.230; 5.P.239.231; 5.P.239.236; 5.P.239.237; 5.P.239.238; 5.P.239.239; 5.P.239.154; 5.P.239.157; 5.P.239.166; 5.P.239.169; 5.P.239.172; 5.P.239.175; 5.P.239.240; S.P.239,244; 5.P.154.228; 5.P.154.229; 5.P.154.230; 5.P.154.231; 5.P.154.236; 5.P.154.237; 5.P.154.238; 5.P.154.239; 5.P.154.154; 5.P.154.157; 5.P.154.166; 5.P.154.169; 5.P.154.172; 5.P.154.175; 5.P.154.240; 5.P.154.244; 5.P.157.228; 5.P.157.229; 5.P.157.230; 5.P.157.231; 5.P.157.236; 5.P.157.237; 5.P.157.238; 5.P.157.239; 5.P.157.154; 5.P.157.157; 5.P.157.166; 5.P.157.169; 5.P.157.172; 5.P.157.175; 5.P.157.240; 5.P.157.244; 5.P.166.228; 5.P.166.229; 5.P.166.230; 5.P.166.231; 5.P.166.236; 5.P.166.237; 5.P.166.238; 5.P.166.239; 5.P.166.154; 5.P.166.157; 5.P.166.166; 5.P.166.169; 5.P.166.172; 5.P.166.175; 5.P.166.240; 5.P.166.244; 5.P.169.228; 5.P.169.229; 5.P.169.230; 5.P.169.231; 5.P.169.236; 5.P.169.237; 5.P.169.238; 5.P.169.239; 5.P.169.154; 5.P.169.157; 5.P.169.166; 5.P.169.169; 5.P.169.172; 5.P.169.175; 5.P.169.240; 5.P.169.244; 5.P.172.228; 5.P.172.229; 5.P.172.230; 5.P.172.231; 5.P.172.236; 5.P.172.237; 5.P.172.238; 5.P.172.239; 5.P.172.154; 5.P.172.157; 5.P.172.166; 5.P.172.169; 5.P.172.172; 5.P.172.175; 5.P.172.240; 5.P.172.244; 5.P.175.228; 5.P.175.229; 5.P.175.230; 5.P.175.231; 5.P.175.236; 5.P.175.237; 5.P.175.238; 5.P.175.239; 5.P.175.154; 5.P.175.157; S.P.175,166; 5.P.175.169; 5.P.175.172; 5.P.175.175; 5.P.175.240; 5.P.175.244; 5.P.240.228; 5.P.240.229; 5.P.240.230; 5.P.240.231; 5.P.240.236; 5.P.240.237; 5.P.240.238; 5.P.240.239; 5.P.240.154; 5.P.240.157; 5.P.240.166; 5.P.240.169; 5.P.240.172;
5.P.240.175; 5.P.240.240; 5.P.240.244; 5.P.244.228; 5.P.244.229; 5.P.244.230; 5.P.244.231; 5.P.244.236; 5.P.244.237; 5.P.244.238; 5.P.244.239; 5.P.244.154; 5.P.244.157; 5.P.244.166; 5.P.244.169; 5.P.244.172; 5.P.244.175; 5.P.244.240; 5.P.244.244;
Prodrugs of 5.U
5.U.228.228; 5.U.228.229; 5.U.228.230; 5.U.228.231; 5.U.228.236; 5.U.228.237; 5.U.228.238; 5.U.228.239; 5.U.228.154; 5.U.228.157; 5.U.228.166; 5.U.228.169; 5.U.228.172; 5.U.228.175; 5.U.228.240; 5.U.228.244; 5.U.229.228; 5.U.229.229; 5.U.22y.230; 5.U.229.231; 5.U.229.236; 5.U.229.237; 5.LJ.229.238; 5.U.229.239; 5.U.229.154; 5.U.229.157; 5.U.229.166; 5.U.229.169; 5.U.229.172; 5.U.229.175; 5.U.229.240; 5.U.229.244; 5.U.230.228; 5.U.230.229; 5.U.230.230; 5.U.230.231; 5.U.230.236; 5.U.230.237; 5.U.230.238; 5.U.230.239; 5.U.230.154; 5.U.230.157; 5.U.230.166; 5.U.230.169; 5.U.230.172; 5.U.230.175; 5.U.230.240; 5.U.230.244; 5.U.231.228; 5.U.231.229; 5.U.231.230; 5.U.231.231; 5.U.231.236; 5.U.231.237; 5.U.231.238; 5.U.231.239; 5.U.231.154; 5.U.231.157; 5.U.231.166; 5.U.231.169; 5.U.231.172; 5.U.231.175; 5.U.231.240; 5.U.231.244; 5.U.236.228; 5.U.236.229; 5.U.236.230; 5.U.236.231; 5.U.236.236; 5.U.236.237; 5.U.236.238; 5.U.236.239; 5.U.236.154; 5.U.236.157; 5.U.236.166; 5.U.236.169; 5.,U.236.172; 5.U.236.175; 5.U.236.240; 5.U.236.244; 5.U.237.228; 5.U.237.229; 5.U.237.230; 5.U.237.231; 5.U.237.236; 5.U.237.237; 5.U.237.238; 5.U.237.239; 5.U.237.154; 5.U.237.157; 5.U.237.166; 5.U.237.169; 5.U.237.172; 5.U.237.175; 5.U.237.240; 5.U.237.244; 5.U.238.228; 5.U.238.229; 5.U.238.230; 5.U.238.231; 5.U.238.236; 5.U.238.237; 5.U.238.238; 5.U.238.239; 5.U.238.154; 5.U.238.157; 5.U.238.166; 5.U.238.169; 5.U.238.172; 5.U.238.175; 5.U.238.240; 5.U.238.244; 5.U.239.228; 5.U.239.229; 5.U.239.230; 5.U.239.231; 5.U.239.236; 5.U.239.237; 5.U.239.238; 5.U.239.239; 5.U.239.154; 5.U.239.157; 5.U.239.166; 5.U.239.169; 5.U.239.172; 5.U.239.175; 5.U.239.240; 5.U.239.244; 5.U.154.228; 5.U.154.229; 5.U.154.230; 5.U.154.231; 5.U.154.236; 5.U.154.237; 5.U.154.238; 5.U.154.239; 5.U.154.154; 5.U.154.157; 5.U.154.166; 5.U.154.169; 5.U.154.172; 5.U.154.175; 5.U.154.240; 5.U.154.244; 5.U.157.228; 5.U.157.229; 5.U.157.230; 5.U.157.231; 5.U.157.236; 5.U.157.237; 5.U.157.238; 5.U.157.239; 5.U.157.154; 5.U.157.157; 5.U.157.166; 5.U.157.169; 5.U.157.172; 5.U.157.175; 5.U.157.240; 5.U.157.244; 5.U.166.228; 5.U.166.229; 5.U.166.230; 5.U.166.231; 5.U.166.236; 5.U .166.237; 5.U.166.238; 5.U.166.239; 5.U.166.154; 5.U.166.157; 5.U.166.166; 5.U.166.169; 5.U.166.172; 5.U.166.175; 5.U.166.240; 5.U.166.244; 5.U.169.228; 5.U.169.229; 5.U.169.230; 5.U.169.231; 5.U.169.236; 5.U.169.237; 5.U.169.238; 5.U.169.239; 5.U.169.154; 5.U.169.157; 5.U.169.166; 5.U.169.169; 5.U.169.172; 5.U.169.175; 5.U.169.240; 5.U.169.244; 5.U.172.228; 5.U.172.229; 5.U.172.230; 5.U.172.231; 5.U.172.236; 5.U.172.237; 5.U.172.238; 5.U.172.239; 5.U.172.154; 5.U.172.157; 5.U.172.166; 5.U.172.169; 5.U.172.172; 5.U.172.175; 5.U.172.240; 5.U.172.244; 5.U.175.228; 5.U.175.229; 5.U.175.230; 5.U.175.231; 5.U.175.236; 5.U.175.237; 5.U.175.238; 5.U.175.239; 5.U.175.154; 5.U.175.157; 5.U.175.166; 5.U.175.169; 5.U.175.172; 5.U.175.175; 5.U.175.240; 5.U.175.244; 5.U.240.228; 5.U.240.229; 5.U.240.230; 5.U.240.231; 5.U.240.236; 5.U.240.237; 5.U.240.238; 5.U.240.239; 5.U.240.154; 5.U.240.157; 5.U.240.166; 5.U.240.169; 5.U.240.172; 5.U.240.175; 5.U.240.240; 5.U.240.244; 5.U.244.228; 5.U.244.229; 5.1L244.230; 5.U.244.231; 5.U.244.236; 5.U.244.237;

5.U.244.238; 5.U.244.239; 5.U.244.154; 5.U.244.157; 5.U.244.166; 5.U.244.169; 5.U.244.172; 5.U.244.175; 5.U.244.240; 5.U.244.244;
Prodrugs of 5.W
5.W.228.228; 5.W.228.229; 5.W.228.230; 5.W.228.231; 5.W.228.236; 5.W.228.237; 5.W.228.238; 5.W.228.239; 5.W.228.154; 5.W.228.157; 5.W.228.166; 5.W.228.169; 5.W.228.172; 5.W.228.175; 5.W.228.240; 5.W.228.244; 5.W.229.228; 5.W.229.229; 5.W.229.230; 5.W.229.231; 5.W.229.236; 5.W.229.237; 5.W.229.238; 5.W.229.239; 5.W.229.154; 5.W.229.157; 5.W.229.166; 5.W.229.169; 5.W.229.172; 5.W.229.175; 5.W.229.240; 5.W.229.244; 5.W.230.228; 5.W.230.229; 5.W.230.230; 5.W.230.231; 5.W.230.236; 5.W.230.237; 5.W.230.238; 5.W.230.239; 5.W.230.154; 5.W.230.157; 5.W.230.166; 5.W.230.169; 5.W.230.172; 5.W.230.175; 5.W.230.240; 5.W.230.244; 5.W.231.228; 5.W.231.229; 5.W.231.230; 5.W.231.231; 5.W.231.236; 5.W.231.237; 5.W.231.238; 5.W.231.239; 5.W.231.154; 5.W.231.157; 5.W.231.166; 5.W.231.169; 5.W.231.172; 5.W.231.175; 5.W.231.240; 5.W.231.244; 5.W.236.228; 5.W.236.229; 5.W.236.230; 5.W.236.231; 5.W.236.236; 5.W.236.237; 5.W.236.238; 5.W.236.239; 5.W.236.154; 5.W.236.157; 5.W.236.166; 5.W.236.169; 5.W.236.172; 5.W.236.175; 5.W.236.240; 5.W.236.244; 5.W.237.228; 5.W.237.229; 5.W.237.230; 5.W.237.231; 5.W.237.236; 5.W.237.237; 5.W.237.238; 5.W.237.239; 5.W.237.154; 5.W.237.157; 5.W.237.166; 5.W.237.169; 5.W.237.172; 5.W.237.175; 5.W.237.240; 5.W.237.244; 5.W.238.228; 5.W.238.229; 5.W.238.230; 5.W.238.231; 5.W.238.236; 5.W.238.237; 5.W.238.238; 5.W.238.239; 5.W.238.154; 5.W.238.157; 5.W.238.166; 5.W.238.169; 5.W.238.172; 5.W.238.175; 5.W.238.240; 5.W.238.244; 5.W.239.228; 5.W.239.229; 5.W.239.230; 5.W.239.231; 5.W.239.236; 5.W.239.237; 5.W.239.238; 5.W.239.239; 5.W.239.154; 5.W.239.157; 5.W.239.166; 5.W.239.169; 5.W.239.172; 5.W.239.175; 5.W.239.240; 5.W.239.244; 5.W.154.228; 5.W.154.229; 5.W.154.230; 5.W.154.231; 5.W.154.236; 5.W.154.237; 5.W.154.238; 5.W.154.239; 5.W.154.154; 5.W.154.157; 5.W.154.166; 5.W.154.169; 5.W.154.172; 5.W.154.175; 5.W.154.240; 5.W.154.244; 5.W.157.228; 5.W.157.229; 5.W.157.230; 5.W.157.231; 5.W.157.236; 5.W.157.237; 5.W.157.238; 5.W.157.239; 5.W.157.154; 5.W.157.157; 5.W.157.166; 5.W.157.169; 5.W.157.172; 5.W.157.175; 5.W.157.240; 5.W.157.244; 5.W.166.228; 5.W.166.229; 5.W.166.230; 5.W.166.231; 5.W.166.236; 5.W.166.237; 5.W.166.238; 5.W.166.239; 5.W.166.154; 5.W.166.157; 5.W.166.166; 5.W.166.169; 5.W.166.172; 5.W.166.175; 5.W.166.240; 5.W.166.244; 5.W.169.228; 5.W.169.229; 5.W.169.230; 5.W.169.231; 5.W.169.236; 5.W.169.237; 5.W.169.238; 5.W.169.239; 5.W.169.154; 5.W.169.157; 5.W.169.166; 5.W.169.169; 5.W.169.172; 5.W.169.175; 5.W.169.240; 5.W.169.244; 5.W.172.228; 5.W.172.229; 5.W.172.230; 5.W.172.231; 5.W.172.236; 5.W.172.237; 5.W.172.238; 5.W.172.239; 5.W.172.154; 5.W.172.157; 5.W.172.166; 5.W.172.169; 5.W.172.172; 5.W.172.175; 5.W.172.240; 5.W.172.244; 5.W.175.228; 5.W.175.229; 5.W.175.230; 5.W.175.231; 5.W.175.236; 5.W.175.237; 5.W.175.238; 5.W.175.239; 5.W.175.154; 5.W.175.157; 5.W.175.166; 5.W.175.169; 5.W.175.172; 5.W.175.175; 5.W.175.240; 5.W.175.244; 5.W.240.228; 5.W.240.229; 5.W.240.230; 5.W.240.231; 5.W.240.236; 5.W.240.237; 5.W.240.238; 5.W.240.239; 5.W.240.154; 5.W.240.157; 5.W.240.166; 5.W.240.169; 5.W.240.172; 5.W.240.175; 5.W.240.240; 5.W.240.244; 5.W.244.228; 5.W.244.229; 5.W.244.230; 5.W.244.231; 5.W.244.236; 5.W.244.237;
5.W.244.238; 5.W.244.239; 5.W.244.154; 5.W.244.157; 5.W.244.166; 5.W.244.169; 5.W.244.172; 5.W.244.175; 5.W.244.240; 5.W.244.244;
Prodrugs of 5.Y
5.Y.228.228; 5.Y.228.229; 5.Y.228.230; 5.Y.228.231; 5.Y.228.236; 5.Y.228.237; 5.Y.228.238; 5.Y.228.239; 5.Y.228.154; 5.Y.228.157; 5.Y.228.166; 5.Y.228.169; 5.Y.228.172; 5.Y.228.175; 5.Y.228.240; 5.Y.228.244; 5.Y.229.228; 5.Y.229.229; 5.Y.229.230; 5.Y.229.231; 5.Y.229.236; 5.Y.229.237; 5.Y.229.238; 5.Y.229.239; 5.Y.229.154; 5.Y.229.157; 5.Y.229.166; 5.Y.229.169; 5.Y.229.172; 5.Y.229.175; 5.Y.229.240; 5.Y.229.244; 5.Y.230.228; 5.Y.230.229; 5.Y.230.230; 5.Y.230.231; 5.Y.230.236; 5.Y.230.237; 5.Y.230.238; 5.Y.230.239; 5.Y.230.154; 5.Y.230.157; 5.Y.230.166; 5.Y.230.169; 5.Y.230.172; 5.Y.230.175; 5.Y.230.240; 5.Y.230.244; 5.Y.231.228; 5.Y.231.229; 5.Y.231.230; 5.Y.231.231; 5.Y.231.236; 5.Y.231.237; 5.Y.231.238; 5.Y.231.239; 5.Y.231.154; 5.Y.231.157; 5.Y.231.166; 5.Y.231.169; 5.Y.231.172; 5.Y.231.175; 5.Y.231.240; 5.Y.231.244; 5.Y.236.228; 5.Y.236.229; 5.Y.236.230; 5.Y.236.231; 5.Y.236.236; 5.Y.236.237; 5.Y.236.238; 5.Y.236.239; 5.Y.236.154; 5.Y.236.157; 5.Y.236.166; 5.Y.236.169; 5.Y.236.172; 5.Y.236.175; 5.Y.236.240; 5.Y.236.244; 5.Y.237.228; 5.Y.237.229; 5.Y.237.230; 5.Y.237.231; 5.Y.237.236; 5.Y.237.237; 5.Y.237.238; 5.Y.237.239; 5.Y.237.154; 5.Y.237.157; 5.Y.237.166; 5.Y.237.169; 5.Y.237.172; 5.Y.237.175; 5.Y.237.240; 5.Y.237.244; 5.Y.238.228; 5.Y.238.229; 5.Y.238.230; 5.Y.238.231; 5.Y.238.236; 5.Y.238.237; 5.Y.238.238; 5.Y.238.239; 5.Y.238.154; 5.Y.238.157; 5.Y.238.166; 5.Y.238.169; 5.Y.238.172; 5.Y.238.175; 5.Y.238.240; 5.Y.238.244; 5.Y.239.228; 5.Y.239.229; 5.Y.239.230; 5.Y.239.231; 5.Y.239.236; 5.Y.239.237; 5.Y.239.238; 5.Y.239.239; 5.Y.239.154; 5.Y.239.157; 5.Y.239.166; 5.Y.239.169; 5.Y.239.172; 5.Y.239.175; 5.Y.239.240; 5.Y.239.244; 5.Y.154.228; 5.Y.154.229; 5.Y.154.230; 5.Y.154.231; 5.Y.154.236; 5.Y.154.237; 5.Y.154.238; 5.Y.154.239; 5.Y.154.154; 5.Y.154.157; 5.Y.154.166; 5.Y.154.169; 5.Y.154.172; 5.Y.154.175; 5.Y.154.240; 5.Y.154.244; 5.Y.157.228; 5.Y.157.229; 5.Y.157.230; 5.Y.157.231; 5.Y.157.236; 5.Y.157.237; 5.Y.157.238; 5.Y.157.239; 5.Y.157.154; 5.Y.157.157; 5.Y.157.166; 5.Y.157.169; 5.Y.157.172; 5.Y.157.175; 5.Y.157.240; 5.Y.157.244; 5.Y.166.228; 5.Y.166.229; 5.Y.166.230; 5.Y.166.231; 5.Y.166.236; 5.Y.166.237; 5.Y.166.238; 5.Y.166.239; 5.Y.166.154; 5.Y.166.157; 5.Y.166.166; 5.Y.166.169; 5.Y.166.172; 5.Y.166.175; 5.Y.166.240; 5.Y.166.244; 5.Y.169.228; 5.Y.169.229; 5.Y.169.230; 5.Y.169.231; 5.Y.169.236; 5.Y.169.237; 5.Y.169.238; 5.Y.169.239; 5.Y.169.154; 5.Y.169.157; 5.Y.169.166; 5.Y.169.169; 5.Y.169.172; 5.Y.169.175; 5.Y.169.240; 5.Y.169.244; 5.Y.172.228; 5.Y.172.229; 5.Y.172.230; 5.Y.172.231; 5.Y.172.236; 5.Y.172.237; 5.Y.172.238; 5.Y.172.239; 5.Y.172.154; 5.Y.172.157; 5.Y.172.166; 5.Y.172.169; 5.Y.172.172; 5.Y.172.175; 5.Y.172.240; 5.Y.172.244; 5.Y.175.228; 5.Y.175.229; 5.Y.175.230; 5.Y.175.231; 5.Y.175.236; 5.Y.175.237; 5.Y.175.238; 5.Y.175.239; 5.Y.175.154; 5.Y.175.157; 5.Y.175.166; 5.Y.175.169; 5.Y.175.172; 5.Y.175.175; 5.Y.175.240; 5.Y.175.244; 5.Y.240.228; 5.Y.240.229; 5.Y.240.230; 5.Y.240.231; 5.Y.240.236; 5.Y.240.237; 5.Y.240.238; 5.Y.240.239; 5.Y.240.154; 5.Y.240.157; 5.Y.240.166; 5.Y.240.169; 5.Y.240.172; 5.Y.240.175; 5.Y.240.240; 5.Y.240.244; 5.Y.244.228; 5.Y.244.229; 5.Y.244.230; 5.Y.244.231; 5.Y.244.236; 5.Y.244.237;
5.Y.244.238; 5.Y.244.239; 5.Y.244.154; 5.Y.244.157; 5.Y.244166; 5.Y.244.169; 5.Y.244.172; 5.Y.244.175; 5.Y.244.240; 5.Y.244.244;
Prodrugs of 6.B
6.B.228.228; 6.B.228.229; 6.B.228.230; 6.B.228.231; 6.B.228.236; 6.B.228.237; 6.B.228.238; 6.B.228.239; 6.B.228.154; 6.B.228.157; 6.B.228.166; 6.B.228.169; 6.B.228.172; 6.B.228.175; 6.B.228.240; 6.B.228.244; 6.B.229.228; 6.B.229.229; 6.B.229.230; 6.B.229.231; 6.B.229.236; 6.B.229.237; 6.B.229.238; 6.B.229.239; 6.B.229.154; 6.B.229.157; 6.B.229.166; 6.B.229.169; 6.B.229.172; 6.B.229.175; 6.B.229.240; 6.B.229.244; 6.B.230.228; 6.B.230.229; 6.B.230.230; 6.B.230.231; 6.B.230.236; 6.B.230.237; 6.B.230.238; 6.B.230.239; 6.B.230.154; 6.B.230.157; 6.B.230.166; 6.B.230.169; 6.B.230.172; 6.B.230.175; 6.B.230.240; 6.B.230.244; 6.B.231.228; 6.B.231.229; 6.B.231.230; 6.B.231.231; 6.B.231.236; 6.B.231.237; 6.B.231.238; 6.B.231.239; 6.B.231.154; 6.B.231.157; 6.B.231.166; 6.B.231.169; 6.B.231.172; 6.B.231.175; 6.B.231.240; 6.B.231.244; 6.B.236.228; 6.B.236.229; 6.B.236.230; 6.B.236.231; 6.B.236.236; 6.B.236.237; 6.B.236.238; 6.B.236.239; 6.B.236.154; 6.B.236.157; 6.B.236.166; 6.B.236.169; 6.B.236.172; 6.B.236.175; 6.B.236.240; 6.B.236.244; 6.B.237.228; 6.B.237.229; 6.B.237.230; 6.B.237.231; 6.B.237.236; 6.B.237.237; 6.B.237.238; 6.B.237.239; 6.B.237.154; 6.B.237.157; 6.B.237.166; 6.B.237.169; 6.B.237.172; 6.B.237.175; 6.B.237.240; 6.B.237.244; 6.B.238.228; 6.B.238.229; 6.B.238.230; 6.B.238.231; 6.B.238.236; 6.B.238.237; 6.B.238.238; 6.B.238.239; 6.B.238.154; 6.B.238.157; 6.B.238.166; 6.B.238.169; 6.B.238.172; 6.B.238.175; 6.B.238.240; 6.B.238.244; 6.B.239.228; 6.B.239.229; 6.B.239.230; 6.B.239.231; 6.B.239.236; 6.B.239.237; 6.B.239.238; 6.B.239.239; 6.B.239.154; 6.B.239.157; 6.B.239.166; 6.B.239.169; 6.B.239.172; 6.B.239.175; 6.B.239.240; 6.B.239.244; 6.B.154.228; 6.B.154.229; 6.B.154.230; 6.B.154.231; 6.B.154.236; 6.B.154.237; 6.B.154.238; 6.B.154.239; 6.B.154.154; 6.B.154.157; 6.B.154.166; 6.B.154.169; 6.B.154.172; 6.B.154.175; 6.B.154.240; 6.B.154.244; 6.B.157.228; 6.B.157.229; 6.B.157.230; 6.B.157.231; 6.B.157.236; 6.B.157.237; 6.B.157.238; 6.B.157.239; 6.B.157.154; 6.B.157.157; 6.B.157.166; 6.B.157.169; 6.B.157.172; 6.B.157.175; 6.B.157.240; 6.B.157.244; 6.B.166.228; 6.B.166.229; 6.B.166.230; 6.B.166.231; 6.B.166.236; 6.B.166.237; 6.B.166.238; 6.B'.166.239; 6.B.166.154; 6.B.166.157; 6.B.166.166; 6.B.166.169; 6.B.166.172; 6.B.166.175; 6.B.166.240; 6.B.166.244; 6.B.169.228; 6.B.169.229; 6.B.169.230; 6.B.169.231; 6.B.169.236; 6.B.169.237; 6.B.169.238; 6.B.169.239; 6.B.169.154; 6.B.169.157; 6.B.169.166; 6.B.169.169; 6.B.169.172; 6.B.169.175; 6.B.169.240; 6.B.169.244; 6.B.172.228; 6.B.172.229; 6.B.172.230; 6.B.172.231; 6.B.172.236; 6.B.172.237; 6.B.172.238; 6.B.172.239; 6.B.172.154; 6.B.172.157; 6.B.172.166; 6.B.172.169; 6.B.172.172; 6.B.172.175; 6.B.172.240; 6.B.172.244; 6.B.175.228; 6.B.175.229; 6.B.175.230; 6.B.175.231; 6.B.175.236; 6.B.175.237; 6.B.175.238; 6.B.175.239; 6.B.175.154; 6.B.175.157; 6.B.175.166; 6.B.175.169; 6.B.175.172; 6.B.175.175; 6.B.175.240; 6.B.175.244; 6.B.240.228; 6.B.240.229; 6.B.240.230; 6.B.240.231; 6.B.240.236; 6.B.240.237; 6.B.240.238; 6.B.240.239; 6.B.240.154; 6.B.240.157; 6.B.240.166; 6.B.240.169; 6.B.240.172; 6.B.240.175; 6.B.240.240; 6.B.240.244; 6.B.244.228; 6.B.244.229; 6.B.244.230; 6.B.244.231; 6.B.244.236; 6.B.244.237; 6.B.244.238; 6.B.244.239; 6.B.244.154; 6.B.244.157; 6.B.244.166; 6.B.244.169; 6.B.244.172; 6.B.244.175; 6.B.244.240; 6.B.244.244;
Prodrugs of 6.D
6.D.228.228; 6.D.228.229; 6.D.228.230; 6.D.228.231; 6.D.228.236; 6.D.228.237; 6.D.228.238; 6.D.228.239; 6.D.228.154; 6.D.228.157; 6.D.228.166; 6.D.228.169; 6.D.228.172; 6.D.228.175; 6.D.228.240; 6.D.228.244; 6.D.229.228; 6.D.229.229;
6.0.2^9.230; 6.D.229.231; 6.D.229.236; 6.D.229.237; 6.D.229.238; 6.D.229.239; 6.D.229.154; 6.D.229.157; 6.D.229.166; 6.D.229.169; 6.D.229.172; 6.D.229.175; 6.D.229.240; 6.D.229.244; 6.D.230.228; 6.D.230.229; 6.D.230.230; 6.D.230.231; 6.D.230.236; 6.D.230.237; 6.D.230.238; 6.D.230.239; 6.D.230.154; 6.D.230.157; 6.D.230.166; 6.D.230.169; 6.D.230.172; 6.D.230.175; 6.D.230.240; 6.D.230.244; 6.D.231.228; 6.D.231.229; 6.D.231.230; 6.D.231.231; 6.D.231.236; 6.D.231.237; 6.D.231.238; 6.D.231.239; 6.D.231.154; 6.D.231.157; 6.D.231.166; 6.D.231.169; 6.D.231.172; 6.D.231.175; 6.D.231.240; 6.D.231.244; 6.D.236.228; 6.D.236.229; 6.D.236.230; 6.D.236.231; 6.D.236.236; 6.D.236.237; 6.D.236.238; 6.D.236.239; 6.D.236.154; 6.D.236.157; 6.D.236.166; 6.D.236.169; 6.D.236.172; 6.D.236.175; 6.D.236.240; 6.D.236.244; 6.D.237.228; 6.D.237.229; 6.D.237.230; 6.D.237.231; 6.D.237.236; 6.D.237.237; 6.D.237.238; 6.D.237.239; 6.D.237.154; 6.D.237.157; 6.D.237.166; 6.D.237.169; 6.D.237.172; 6.D.237.175; 6.D.237.240; 6.D.237.244; 6.D.238.228; 6.D.238.229; 6.D.238.230; 6.D.238.231; 6.D.238.236; 6.D.238.237; 6.D.238.238; 6.D.238.239; 6.D.238.154; 6.D.238.157; 6.D.238.166; 6.D.238.169; 6.D.238.172; 6.D.238.175; 6.D.238.240; 6.D.238.244; 6.D.239.228; 6.D.239.229; 6.D.239.230; 6.D.239.231; 6.D.239.236; 6.D.239.237; 6.D.239.238; 6.D.239.239; 6.D.239.154; 6.D.239.157; 6.D.239.166; 6.D.239.169; 6.D.239.172; 6.D.239.175; 6.D.239.240; 6.D.239.244; 6.D.154.228; 6.D.154.229; 6.D.154.230; 6.D.154.231; 6.D.154.236; 6.D.154.237; 6.D.154.238; 6.D.154.239; 6.D.154.154; 6.D.154.157; 6.D.154.166; 6.D.154.169; 6.D.154.172; 6.D.154.175; 6.D.154.240; 6.D.154.244; 6.D.157.228; 6.D.157.229; 6.D.157.230; 6.D.157.231; 6.D.157.236; 6.D.157.237; 6.D.157.238; 6.D.157.239; 6.D.157.154; 6.D.157.157; 6.D.157.166; 6.D.157.169; 6.D.157.172; 6.D.157.175; 6.D.157.240; 6.D.157.244; 6.D.166.228; 6.D.166.229; 6.D.166.230; 6.D.166.231; 6.D.166.236; 6.D.166.237; 6.D.166.238; 6.D.166.239; 6.D.166.154; 6.D.166.157; 6.D.166.166; 6.D.166.169; 6.D.166.172; 6.D.166.175; 6.D.166.240; 6.D.166.244; 6.D.169.228; 6.D.169.229; 6.D.169.230; 6.D.169.231; 6.D.169.236; 6.D.169.237; 6.D.169.238; 6.D.169.239; 6.D.169.154; 6.D.169.157; 6.D.169.166; 6.D.169.169; 6.D.169.172; 6.D.169.175; 6.D.169.240; 6.D.169.244; 6.D.172.228; 6.D.172.229; 6.D.172.230; 6.D.172.231; 6.D.172.236; 6.D.172.237; 6.D.172.238; 6.D.172.239; 6.D.172.154; 6.D.172.157; 6.D.172.166; 6.D.172.169; 6.D.172.172; 6.D.172.175; 6.D.172.240; 6.D.172.244; 6.D.175.228; 6.D.175.229; 6.D.175.230; 6.D.175.231; 6.D.175.236; 6.D.175.237; 6.D.175.238; 6.D.175.239; 6.D.175.154; 6.D.175.157; 6.D.175.166; 6.D.175.169; 6.D.175.172; 6.D.175.175; 6.D.175.240; 6.D.175.244; 6.D.240.228; 6.D.240.229; 6.D.240.230; 6.D.240.231; 6.D.240.236; 6.D.240.237; 6.D.240.238; 6.D.240.239; 6.D.240.154; 6.D.240.157; 6.D.240.166; 6.D.240.169; 6.D.240.172; 6.D.240.175; 6.D.240.240; 6.D.240.244; 6.D.244.228; 6.D.244.229; 6.D.244.230; 6.D.244.231; 6.D.244.236; 6.D.244.237; 6.D.244.238; 6.D.244.239; 6.D.244.154; 6.D.244.157; 6.D.244.166; 6.D.244.169; 6.D.244.172; 6.D.244.175; 6.D.244.240; 6.D.244.244;
Prodrugs of 6.E
6.E.228.228; 6.E.228.229; 6.E.228.230; 6.E.228.231; 6.E.228.236; 6.E.228.237; 6.E.228.238; 6.E.228.239; 6.E.228.154; 6.E.228.157; 6.E.228.166; 6.E.228.169; 6.E.228.172; 6.E.228.175; 6.E.228.240; 6.E.228.244; 6.E.229.228; 6.E.229.229; 6.E.229.230; 6.E.229.231; 6.E.229.236; 6.E.229.237; 6.E.229.238; 6.E.229.239; 6.E.229.154; 6.E.229.157; 6.E.229.166;
6.E.229.169; 6.E.229.172; 6.E.229.175; 6.E.229.240; 6.E.229.244; 6.E.230.228; 6.E.230.229; 6.E.230.230; 6.E.230.231; 6.E.230.236; 6.E.230.237; 6.E.230.238; 6.E.230.239; 6.E.230.154; 6.E.230.157; 6.E.230.166; 6.E.230.169; 6.E.230.172; 6.E.230.175; 6.E.230.240; 6.E.230.244; 6.E.231.228; 6.E.231.229; 6.E.231.230; 6.E.231.231; 6.E.231.236; 6.E.231.237; 6.E.231.238; 6.E.231.239; 6.E.231.154; 6.E.231.157; 6.E.231.166; 6.E.231.169; 6.E.231.172; 6.E.231.175; 6.E.231.240; 6.E.231.244; 6.E.236.228; 6.E.236.229; 6.E.236.230; 6.E.236.231; 6.E.236.236; 6.E.236.237; 6.E.236.238; 6.E.236.239; 6.E.236.154; 6.E.236.157; 6.E.236.166; 6.E.236.169; 6.E.236.172; 6.E.236.175; 6.E.236.240; 6.E.236.244; 6.E.237.228; 6.E.237.229; 6.E.237.230; 6.E.237.231; 6.E.237.236; 6.E.237.237; 6.E.237.238; 6.E.237.239; 6.E.237.154; 6.E.237.157; 6.E.237.166; 6.E.237.169; 6.E.237.172; 6.E.237.175; 6.E.237.240; 6.E.237.244; 6.E.238.228; 6.E.238.229; 6.E.238.230; 6.E.238.231; 6.E.238.236; 6.E.238.237; 6.E.238.238; 6.E.238.239; 6.E.238.154; 6.E.238.157; 6.E.238.166; 6.E.238.169; 6.E.238.172; 6.E.238.175; 6.E.238.240; 6.E.238.244; 6.E.239.228; 6.E.239.229; 6.E.239.230; 6.E.239.231; 6.E.239.236; 6.E.239.237; 6.E.239.238; 6.E.239.239; 6.E.239.154; 6.E.239.157; 6.E.239.166; 6.E.239.169; 6.E.239.172; 6.E.239.175; 6.E.239.240; 6.E.239.244; 6.E.154.228; 6.E.154.229; 6.E.154.230; 6.E.154.231; 6.E.154.236; 6.E.154.237; 6.E.154.238; 6.E.154.239; 6.E.154.154; 6.E.154.157; 6.E.154.166; 6.E.154.169; 6.E.154.172; 6.E.154.175; 6.E.154.240; 6.E.154.244; 6.E.157.228; 6.E.157.229; 6.E.157.230; 6.E.157.231; 6.E.157.236; 6.E.157.237; 6.E.157.238; 6.E.157.239; 6.E.157.154; 6.E.157.157; 6.E.157.166; 6.E.157.169; 6.E.157.172; 6.E.157.175; 6.E.157.240; 6.E.157.244; 6.E.166.228; 6.E.166.229; 6.E.166.230; 6.E.166.231; 6.E.166.236; 6.E.166.237; 6.E.166.238; 6.E.166.239; 6.E.166.154; 6.E.166.157; 6.E.166.166; 6.E.166.169; 6.E.166.172; 6.E.166.175; 6.E.166.240; 6.E.166.244; 6.E.169.228; 6.E.169.229; 6.E.169.230; 6.E.169.231; 6.E.169.236; 6.E.169.237; 6.E.169.238; 6.E.169.239; 6.E.169.154; 6J.169.157; 6.E.169.166; 6.E.169.169; 6.E.169.172; 6.E.169.175; 6.E.169.240; 6.E.169.244; 6.E.172.228; 6.E. 172.229; 6.E.172.230; 6.E.172.231; 6.E.172.236; 6.E.172.237; 6.E.172.238; 6.E.172.239; 6.E.172.154; 6.E.172.157; 6.E.172.166; 6.E.172.169; 6.E.172.172; 6.E.172.175; 6.E.172.240; 6.E.172.244; 6.E.175.228; 6.E.175.229; 6.E.175.230; 6.E.175.231; 6.E.175.236; 6.E.175.237; 6.E.175.238; 6.E.175.239; 6.E.175.154; 6.E.175.157; 6.E.175.166; 6.E.175.169; 6.E.175.172; 6.E.175.175; 6.E.175.240; 6.E.175.244; 6.E.240.228; 6.E.240.229; 6.E.240.230; 6.E.240.231; 6.E.240.236; 6.E.240.237; 6.E.240.238; 6.E.240.239; 6.E.240.154; 6.E.240.157; 6.E.240.166; 6.E.240.169; 6.E.240.172; 6.E.240.175; 6.E.240.240; 6.E.240.244; 6.E.244.228; 6.E.244.229; 6.E.244.230; 6.E.244.231; 6.E.244.236; 6.E.244.237; 6.E.244.238; 6.E.244.239; 6.E.244.154; 6.E.244.157; 6.E.244.166; 6.E.244.169; 6.E.244.172; 6.E.244.175; 6.E.244.240; 6.E.244.244;
Prodrugs of 6.G
6.G.228.228; 6.G.228.229; 6.G.228.230; 6.G.228.231; 6.G.228.236; 6.G.228.237; 6.G.228.238; 6.G.228.239; 6.G.228.154; 6.G.228.157; 6.G.228.166; 6.G.228.169; 6.G.228.172; 6.G.228.175; 6.G.228.240; 6.G.228.244; 6.G.229.228; 6.G.229.229; 6.G.229.230; 6.G.229.231; 6.G.229.236; 6.G.229.237; 6.G.229.238; 6.G.229.239; 6.G.229.154; 6.G.229.157; 6.G.229.166; 6.G.229.169; 6.G.229.172; 6.G.229.175; 6.G.229.240; 6.G.229.244; 6.G.230.228; 6.G.230.229; 6.G.230.230; 6.G.230.231; 6.G.230.236; 6.G.230.237; 6.G.230.238; 6.G.230.239; 6.G.230.154; 6.G.230.157; 6.G.230.166; 6.G.230.169; 6.G.230.172; 6.G.230.175; 6.G.230.240; 6.G.230.244; 6.G.231.228; 6.G.231.229; 6.G.231.230; 6.G.231.231; 6.G.231.236; 6.G.231.237; 6.G.231.238; 6.G.231.239; 6.G.231.154; 6.G.231.157; 6.G.231.166; 6.G.231.169; 6.G.231.172; 6.G.231.175; 6.G.231.240; 6.G.231.244; 6.G.236.228; 6.G.236.229;
6.G.236.230; 6.G.236.231; 6.G.236.236; 6.G.236.237; 6.G.236.238; 6.G.236.239; 6.G.236.154; 6.G.236.157; 6.G.236.166; 6.G.236.169; 6.G.236.172; 6.G.236.175; 6.G.236.240; 6.G.236.244; 6.G.237.228; 6.G.237.229; 6.G.237.230; 6.G.237.231; 6.G.237.236; 6.G.237.237; 6.G.237.238; 6.G.237.239; 6.G.237.154; 6.G.237.157; 6.G.237.166; 6.G.237.169; 6.G.237.172; 6.G.237.175; 6.G.237.240; 6.G.237.244; 6.G.238.228; 6.G.238.229; 6.G.238.230; 6.G.238.231; 6.G.238.236; 6.G.238.237; 6.G.238.238; 6.G.238.239; 6.G.238.154; 6.G.238.157; 6.G.238.166; 6.G.238.169; 6.G.238.172; 6.G.238.175; 6.G.238.240; 6.G.238.244; 6.G.239.228; 6.G.239.229; 6.G.239.230; 6.G.239.231; 6.G.239.236; 6.G.239.237; 6.G.239.238; 6.G.239.239; 6.G.239.154; 6.G.239.157; 6.G.239.166; 6.G.239.169; 6.G.239.172; 6.G.239.175; 6.G.239.240; 6.G.239.244; 6.G.154.228; 6.G.154.229; 6.G.154.230; 6.G.154.231; 6.G.154.236; 6.G.154.237; 6.G.154.238; 6.G.154.239; 6.G.154.154; 6.G.154.157; 6.G.154.166; 6.G.154.169; 6.G.154.172; 6.G.154.175; 6.G.154.240; 6.G.154.244; 6.G.157.228; 6.G.157.229; 6.G.157.230; 6.G.157.231; 6.G.157.236; 6.G.157.237; 6.G.157.238; 6.G.157.239; 6.G.157.154; 6.G.157.157; 6.G.157.166; 6.G.157.169; 6.G.157.172; 6.G.157.175; 6.G.157.240; 6.G.157.244; 6.G.166.228; 6.G.166.229; 6.G.166.230; 6.G.166.231; 6.G.166.236; 6.G.166.237; 6.G.166.238; 6.G.166.239; 6.G.166.154; 6.G.166.157; 6.G.166.166; 6.G.166.169; 6.G.166.172; 6.G.166.175; 6.G.166.240; 6.G.166.244; 6.G.169.228; 6.G.169.229; 6.G.169.230; 6.G.169.231; 6.G.169.236; 6.G.169.237; 6.G.169.238; 6.G.169.239; 6.G.169.154; 6.G.169.157; 6.G.169.166; 6.G.169.169; 6.G.169.172; 6.G.169.175; 6.G.169.240; 6.G.169.244; 6.G.172.228; 6.G.172.229; 6.G.172.230; 6.G.172.231; 6.G.172.236; 6.G.172.237; 6.G.172.238; 6.G.172.239; 6.G.172.154; 6.G.172.157; 6.G.172.166; 6.G.172.169; 6.G.172.172; 6.G.172.175; 6.G.172.240; 6.G.172.244; 6.G.175.228; 6.G.175.229; 6.G.175.230; 6.G.175.231; 6.G.175.236; 6.G.175.237; 6.G.175.238; 6.G.175.239; 6.G.175.154; 6.G.175.157; 6.G.175.166; 6.G.175.169; 6.G.175.172; 6.G.175.175; 6.G.175.240; 6.G.175.244; 6.G.240.228; 6.G.240.229; 6.G.240.230; 6.G.240.231; 6.G.240.236; 6.G.240.237; 6.G.240.238; 6.G.240.239; 6.G.240.154; 6.G.240.157; 6.G.240.166; 6.G.240.169; 6.G.240.172; 6.G.240.175; 6.G.240.240; 6.G.240.244; 6.G.244.228; 6.G.244.229; 6.G.244.230; 6.G.244.231; 6.G.244.236; 6.G.244.237; 6.G.244.238; 6.G.244.239; 6.G.244.154; 6.G.244.157; 6.G.244.166; 6.G.244.169; 6.G.244.172; 6.G.244.175; 6.G.244.240; 6.G.244.244;
Prodrugs of 6.1
6.L228.228; 6.1.228.229; 6.1.228.230; 6.1.228.231; 6.1.228.236; 6.1.228.237; 6.1.228.238; 6.1.228.239; 6.1.228.154; 6.1.228.157; 6.1.228.166; 6.1.228.169; 6.1.228.172; 6.1.228.175; 6.1.228.240; 6.1.228.244; 6.1.229.228; 6.1.229.229; 6.1.229.230; 6.1.229.231; 6.1.229.236; 6.1.229.237; 6.1.229.238; 6.1.229.239; 6.1.229.154; 6.1.229.157; 6.1.229.166; 6.1.229.169; 6.1.229.172; 6.1.229.175; 6.1.229.240; 6.1.229.244; 6.1.230.228; 6.1.230.229; 6.1.230.230; 6.1.230.231; 6.1.230.236; 6.1.230.237; 6.1.230.238; 6.1.230.239; 6.1.230.154; 6.1.230.157; 6.1.230.166; 6.1.230.169; 6.1.230.172; 6.1.230.175; 6.1.230.240; 6.1.230.244; 6.1.231.228; 6.1.231.229; 6.1.231.230; 6.1.231.231; 6.1.231.236; 6.1.231.237; 6.1.231.238; 6.1.231.239; 6.1.231.154; 6.1.231.157; 6.1.231.166; 6.1.231.169; 6.1.231.172; 6.1.231.175; 6.1.231.240; 6.1.231.244; 6.1.236.228; 6.1.236.229; 6.1.236.230; 6.1.236.231; 6.1.236.236; 6.1.236.237; 6.1.236.238; 6.1.236.239; 6.1.236.154; 6.1.236.157; 6.1.236.166; 6.1.236.169; 6.1.236.172; 6.1.236.175; 6.1.236.240; 6.1.236.244; 6.1.237.228; 6.1.237.229; 6.1.237.230; 6.1.237.231;
6.L237.236; 6.1.237.237; 6.1.237.238; 6.1.237.239; 6.1.237.154; 6.1.237.157; 6.1.237.166; 6.1.237.169; 6.1.237.172; 6.1.237.175; 6.1.237.240; 6.1.237.244; 6.1.238.228; 6.1.238.229; 6.1.238.230; 6.1.238.231; 6.1.238.236; 6.1.238.237; 6.1.238.238; 6.1.238.239; 6.1.238.154; 6.1.238.157; 6.1.238.166; 6.1.238.169; 6.1.238.172; 6.1.238.175; 6.1.238.240; 6.1.238.244; 6.1.239.228; 6.1.239.229; 6.1.239.230; 6.1.239.231; 6.1.239.236; 6.1.239.237; 6.1.239.238; 6.1.239.239; 6.1.239.154; 6.1.239.157; 6.1.239.166; 6.1.239.169; 6.1.239.172; 6.1.239.175; 6.1.239.240; 6.1.239.244; 6.1.154.228; 6.1.154.229; 6.1.154.230; 6.1.154.231; 6.1.154.236; 6.1.154.237; 6.1.154.238; 6.1.154.239; 6.1.154.154; 6.1.154.157; 6.1.154.166; 6.1.154.169; 6.1.154.172; 6.1.154.175; 6.1.154.240; 6.1.154.244; 6.1.157.228; 6.1.157.229; 6.1.157.230; 6.1.157.231; 6.1.157.236; 6.1.157.237; 6.1.157.238; 6.1.157.239; 6.1.157.154; 6.1.157.157; 6.1.157.166; 6.1.157.169; 6.1.157.172; 6.1.157.175; 6.1.157.240; 6.1.157.244; 6.1.166.228; 6.1.166.229; 6.1.166.230; 6.1.166.231; 6.1.166.236; 6.1.166.237; 6.1.166.238; 6.1.166.239; 6.1.166.154; 6.1.166.157; 6.1.166.166; 6.1.166.169; 6.1.166.172; 6.1.166.175; 6.1.166.240; 6.1.166.244; 6.1.169.228; 6.1.169.229; 6.1.169.230; 6.1.169.231; 6.1.169.236; 6.1.169.237; 6.1.169.238; 6.1.169.239; 6.1.169.154; 6.1.169.157; 6.1.169.166; 6.1.169.169; 6.1.169.172; 6.1.169.175; 6.1.169.240; 6.1.169.244; 6.1.172.228; 6.1.172.229; 6.1.172.230; 6.1.172.231; 6.1.172.236; 6.1.172.237; 6.1.172.238; 6.1.172.239; 6.1.172.154; 6.1.172.157; 6.1.172.166; 6.1.172.169; 6.1.172.172; 6.1.172.175; 6.1.172.240; 6.1.172.244; 6.1.175.228; 6.1.175.229; 6.1.175.230; 6.1.175.231; 6.1.175.236; 6.1.175.237; 6.1.175.238; 6.1.175.239; 6.1.175.154; 6.1.175.157; 6.1.175.166; 6.L175.169; 6.1.175.172; 6.1.175.175; 6.1.175.240; 6.1.175.244; 6.1.240.228; 6.1.240.229; 6.1.240.230; 6.1.240.231; 6.1.240.236; 6.1.240.237; 6.1.240.238; 6.1.240.239; 6.1.240.154; 6.1.240.157; 6.1.240.166; 6.1.240.169; 6.1.240.172; 6.1.240.175; 6.1.240.240; 6.1.240.244; 6.1.244.228; 6.1.244.229; 6.1.244.230; 6.1.244.231; 6.1.244.236; 6.1.244.237; 6.1.244.238; 6.1.244.239; 6.1.244.154; 6.1.244.157; 6.1.244.166; 6.1.244.169; 6.1.244.172; 6.1.244.175; 6.1.244.240; 6.1.244.244;
Prodrugs of 6.T
6.J.228.228; 6.J.228.229; 6.J.228.230; 6.J.228.231; 6J.228.236; 6.J.228.237; 6J.228.238; 6J.228.239; 6J.228.154; 6 J.228.157; 6J.228.166; 6J.228.169; 6.J.228.172; 6J.228.175; 6J.228.240; 6.J.228.244; 6 J.229.228; 6J.229.229; 6J.229.230; 6.J.229.231; 6J.229.236; 6J.229.237; 6J.229.238; 6J.229.239; 6J.229.154; 6J.229.157; 6J.229.166; 6J.229.169; 6J.229.172; 6.J.229.175; 6J.229.240; 6.J.229.244; 6J.230.228; 6J.230.229; 6J.230.230; 6J.230.231; 6.J.230.236; 6.J.230.237; 6J.230.238; 6J.230.239; 6J.230.154; 6J.230.157; 6J.230.166; 6J.230.169; 6J.230.172; 6J.230.175; 6J.230.240; 6J.230.244; 6J.231.228; 6J.231.229; 6J.231.230; 6J.231.231; 6J.231.236; 6.J.231.237; 6J.231.238; 6.J.231.239; 6.J.231.154; 6J.231.157; 6J.231.166; 6j.231.169; 6J.231.172; 6J.231.175; 6J.231.240; 6J.231.244; 6 J.236.228; 6.J.236.229; 6.J.236.230; 6J.236.231; 6J.236.236; 6J.236.237; 6J.236.238; 6J.236.239; 6.J.236.154; 6J.236.157; 6 J.236.166; 6.J.236.169; 6J.236.172; 6J.236.175; 6.J.236.240; 6J.236.244; 6J.237.228; 6J.237.229; 6J.237.230; 6J.237.231; 6.J.237.236; 6.J.237.237; 6J.237.238; 6J.237.239; 6J.237.154; 6.J.237.157; 6J.237.166; 6.J.237.169; 6.J.237.172; 6.J.237.175; 6.J.237.240; 6J.237.244; 6J.238.228; 6J.238.229; 6J.238.230; 6J.238.231; 6.J.238.236; 6.J.238.237; 6.J.238.238; 6.J.238.239; 6J.238.154; 6J.238.157; 6.J.238.166; 6J.238.169; 6J.238.172; 6.J.238.175; 6J.238.240; 6J.238.244; 6J.239.228; 6J.239.229; 6J.239.230; 6J.239.231; 6J.239.236; 6.J.239.237; 6J.239.238; 6J.239.239; 6J.239.154; 6J.239.157; 6J.239.166; 6.J.239.169; 6J.239.172; 6.J.239.175; 6.J.239.240; 6.J.239.244; 6J.154.228; 6J.154.229; 6.J.154.230; 6.J.154.231; 6J.154.236;
6.J.154.237; 6.J.154.238; 6.J.154.239; 6J.154.154; 6J.154.157; 6J.154.166; 6J.154.169; 6J.154.172; 6J.154.175; 6.J.154.240; 6J.154.244; 6J.157.228; 6J.157.229; 6J.157.230; 6J.157.231; 6J.157.236; 6.J.157.237; 6J.157.238; 6J.157.239; 6J.157.154; 6J.157.157; 6J.157.166; 6J.157.169; 6J.157.172; 6J.157.175; 6J.157.240; 6J.157.244; 6J.166.228; 6J.166.229; 6.J.166.230; 6J.166.231; 6J.166.236; 6J.166.237; 6J.166.238; 6J.166.239; 6J.166.154; 6J.166.157; 6J.166.166; 6J.166.169; 6J.166.172; 6J.166.175; 6J.166.240; 6J.166.244; 6J.169.228; 6J.169.229; 6J.169.230; 6J.169.231; 6J.169.236; 6J.169.237; 6J:169.238; 6J.169.239; 6J.169.154; 6J.169.157; 6J.169.166; 6J.169.169; 6J.169.172; 6J.169.175; 6J.169.240; 6J.169.244; 6J.172.228; 6J.172.229; 6J.172.230; 6J.172.231; 6J.172.236; 6J.172.237; 6J.172.238; 6J.172.239; 6J.172.154; 6J.172.157; 6J.172.166; 6J.172.169; 6J.172.172; 6J.172.175; 6J.172.240; 6J.172.244; 6J.175.228; 6J.175.229; 6J.175.230; 6J.175.231; 6J.175.236; 6J.175.237; 6J.175.238; 6J.175.239; 6J.175.154; 6J.175.157; 6J.175.166; 6J.175.169; 6J.175.172; 6J.175.175; 6J.175.240; 6J.175.244; 6J-240.228; 6J.240.229; 6J.240.230; 6J.240.231; 6J.240.236; 6J.240.237; 6J.240.238; 6J.240.239; 6J.240.154; 6J.240.157; 6J.240.166; 6J.240.169; 6J.240.172; 6J.240.175; 6J.240.240; 6J.240.244; 6J.244.228; 6J.244.229; 6J.244.230; 6J.244.231; 6J.244.236; 6J.244.237; 6J.244.238; 6J.244.239; 6J.244.154; 6J.244.157; 6J.244.166; 6J.244.169; 6J.244.172; 6.J.244.175; 6.J.244.240; 6J.244.244;
Prodrugs of 6.L
6.L.228.228; 6.L.228.229; 6.L.228.230; 6.L.228.231; 6.L.228.236; 6.L.228.237; 6.L.228.238; 6.L.228.239; 6.L.228.154; 6.L.228.157; 6.L.228.166; 6.L.228.169; 6.L.228.172; 6.L.228.175; 6.L.228.240; 6.L.228.244; 6.L.229.228; 6.L.229.229; 6.L.229.230; 6.L.229.231; 6.L.229.236; 6.L.229.237; 6.L.229.238; 6.L.229.239; 6.L.229.154; 6.L.229.157; 6.L.229.166; 6.L.229.169; 6.L.229.172; 6.L.229.175; 6.L.229.240; 6.L.229.244; 6.L.230.228; 6.L.230.229; 6.L.230.230; 6.L.230.231; 6.L.230.236; 6.L.230.237; 6.L.230.238; 6.L.230.239; 6.L.230.154; 6.L.230.157; 6.L.230.166; 6.L.230.169; 6.L.230.172; 6.L.230.175; 6.L.230.240; 6.L.230.244; 6.L.231.228; 6.L.231.229; 6.L.231.230; 6.L.231.231; 6.L.231.236; 6.L.231.237; 6.L.231.238; 6.L.231.239; 6.L.231.154; 6.L.231.157; 6.L.231.166; 6.L.231.169; 6.L.231.172; 6.L.231.175; 6.L.231.240; 6.L.231.244; 6.L.236.228; 6.L.236.229; 6.L.236.230; 6.L.236.231; 6.L.236.236; 6.L.236.237; 6.L.236.238; 6.L.236.239; 6.L.236.154; 6.L.236.157; 6.L.236.166; 6.L.236.169; 6.L.236.172; 6.L.236.175; 6.L.236.240; 6.L.236.244; 6.L.237.228; 6.L.237.229; 6.L.237.230; 6.L.237.231; 6.L.237.236; 6.L.237.237; 6.L.237.238; 6.L.237.239; 6.L.237.154; 6.L.237.157; 6.L.237.166; 6.L.237.169; 6.L.237.172; 6.L.237.175; 6.L.237.240; 6.L.237.244; 6.L.238.228; 6.L.238.229; 6.L.238.230; 6.L.238.231; 6.L.238.236; 6.L.238.237; 6.L.238.238; 6.L.238.239; 6.L.238.154; 6.L.238.157; 6.L.238.166; 6.L.238.169; 6.L.238.172; 6.L.238.175; 6.L.238.240; 6.L.238.244; 6.L.239.228; 6.L.239.229; 6.L.239.230; 6.L.239.231; 6.L.239.236; 6.L.239.237; 6.L.239.238; 6.L.239.239; 6.L.239.154; 6.L.239.157; 6.L.239.166; 6.L.239.169; 6.L.239.172; 6.L.239.175; 6.L.239.240; 6.L.239.244; 6.L.154.228; 6.L.154.229; 6.L.154.230; 6.L.154.231; 6.L.154.236; 6.L.154.237; 6.L.154.238; 6.L.154.239; 6.L.154.154; 6.L.154.157; 6.L.154.166; 6.L.154.169; 6.L.154.172; 6.L.154.175; 6.L.154.240; 6.L.154.244; 6.L.157.228; 6.L.157.229; 6.L.157.230; 6.L.157.231; 6.L.157.236; 6.L.157.237; 6.L.157.238; 6.L.157.239; 6.L.157.154; 6.L.157.157; 6.L.157.166; 6.L.157.169; 6.L.157.172; 6.L.157.175; 6.L.157.240; 6.L.157.244; 6.L.166.228; 6.L.166.229; 6.L.166.230; 6.L.166.231; 6.L.166.236; 6.L.166.237; 6.L.166.238; 6.L.166.239; 6.L.166.154; 6.L.166.157; 6.L.166.166; 6.L.166.169; 6.L.166.172; 6.L.166.175; 6.L.166.240; 6.L.166.244; 6.L.169.228; 6.L.169.229; 6.L.169.230; 6.L.169.231; 6.L.169.236;
6.L.169.237; 6.L.169.238; 6.L.169.239; 6.L.169.154; 6.L.169.157; 6.L.169.166; 6.L.169.169; 6.L.169.172; 6.L.169.175; 6.L.169.240; 6.L.169.244; 6.L.172.228; 6.L.172.229; 6.L.172.230; 6.L.172.231; 6.L.172.236; 6.L.172.237; 6.L.172.238; 6.L.172.239; 6.L.172.154; 6.L.172.157; 6.L.172.166; 6.L.172.169; 6.L.172.172; 6.L.172.175; 6.L.172.240; 6.L.172.244; 6.L.175.228; 6.L.175.229; 6.L.175.230; 6.L.175.231; 6.L.175.236; 6.L.175.237; 6.L.175.238; 6.L.175.239; 6.L.175.154; 6.L.175.157; 6.L.175.166; 6.L.175.169; 6.L.175.172; 6.L.175.175; 6.L.175.240; 6.L.175.244; 6.L.240.228; 6.L.240.229; 6.L.240.230; 6.L.240.231; 6.L.240.236; 6.L.240.237; 6.L.240.238; 6.L.240.239; 6.L.240.154; 6.L.240.157; 6.L.240.166; 6.L.240.169; 6.L.240.172; 6.L.240.175; 6.L.240.240; 6.L.240.244; 6.L.244.228; 6.L.244.229; 6.L.244.230; 6.L.244.231; 6.L.244.236; 6.L.244.237; 6.L.244.238; 6.L.244.239; 6.L.244.154; 6.L.244.157; 6.L.244.166; 6.L.244.169; 6.L.244.172; 6.L.244.175; 6.L.244.240; 6.L.244.244;
Prodrugs of 6.O
6.O.228.228; 6.O.228.229; 6.O.228.230; 6.O.228.231; 6.O.228.236; 6.O.228.237; 6.O.228.238; 6.O.228.239; 6.O.228.154; 6.O.228.157; 6.O.228.166; 6.O.228.169; 6.O.228.172; 6.O.228.175; 6.O.228.240; 6.O.228.244; 6.O.229.228; 6.O.229.229; 6.O.229.230; 6.O.229.231; 6.O.229.236; 6.O.229.237; 6.O.229.238; 6.O.229.239; 6.O.229.154; 6.O.229.157; 6.O.229.166; 6.O.229.169; 6.O.229.172; 6.O.229.175; 6.0.229.240; 6.O.229.244; 6.O.230.228; 6.O.230.229; 6.O.230.230; 6.O.230.231; 6.O.230.236; 6.O.230.237; 6.O.230.238; 6.O.230.239; 6.O.230.154; 6.O.230.157; 6.O.230.166; 6.O.230.169; 6.O.230.172; 6.O.230.175; 6.O.230.240; 6.O.230.244; 6.O.231.228; 6.O.231.229; 6.O.231.230; 6.O.231.231; 6.O.231.236; 6.O.231.237; 6.O.231.238; 6.O.231.239; 6.O.231.154; 6.O.231.157; 6.O.231.166; 6.O.231.169; 6.O.231.172; 6.O.231.175; 6.O.231.240; 6.O.231.244; 6.O.236.228; 6.O.236.229; 6.O.236.230; 6.O.236.231; 6.O.236.236; 6.O.236.237; 6.O.236.238; 6.O.236.239; 6.O.236.154; 6.O.236.157; 6.O.236.166; 6.O.236.169; 6.O.236.172; 6.O.236.175; 6.O.236.240; 6.O.236.244; 6.O.237.228; 6.O.237.229; 6.O.237.230; 6.O.237.231; 6.O.237.236; 6.O.237.237; 6.O.237.238; 6.O.237.239; 6.O.237.154; 6.O.237.157; 6.0:237.166; 6.O.237.169; 6.O.237.172; 6.O.237.175; 6.O.237.240; 6.O.237.244; 6.O.238.228; 6.O.238.229; 6.O.238.230; 6.O.238.231; 6.O.238.236; 6.O.238.237; 6.O.238.238; 6.O.238.239; 6.O.238.154; 6.O.238.157; 6.O.238.166; 6.O.238.169; 6.O.238.172; 6.O.238.175; 6.O.238.240; 6.O.238.244; 6.O.239.228; 6.O.239.229; 6.O.239.230; 6.Q.239.231; 6.O.239.236; 6.O.239.237; 6.O.239.238; 6.O.239.239; 6.O.239.154; 6.O.239.157; 6.O.239.166; 6.O.239.169; 6.O.239.172; 6.O.239.175; 6.O.239.240; 6.O.239.244; 6.O.154.228; 6.O.154.229; 6.O.154.230; 6.O.154.231; 6.O.154.236; 6.O.154.237; 6.O.154.238; 6.O.154.239; 6.O.154.154; 6.O.154.157; 6.O.154.166; 6.O.154.169; 6.O.154.172; 6.O.154.175; 6.O.154.240; 6.O.154.244; 6.O.157.228; 6.O.157.229; 6.O.157.230; 6.O.157.231; 6.O.157.236; 6.O.157.237; 6.O.157.238; 6.O.157.239; 6.O.157.154; 6.O.157.157; 6.O.157.166; 6.O.157.169; 6.O.157.172; 6.O.157.175; 6.O.157.240; 6.O.157.244; 6.O.166.228; 6.O.166.229; 6.O.166.230; 6.O.166.231; 6.O.166.236; 6.O.166.237; 6.O.166.238; 6.O.166.239; 6.O.166.154; 6.O.166.157; 6.O.166.166; 6.O.166.169; 6.O.166.172; 6.O.166.175; 6.O.166.240; 6.O.166.244; 6.O.169.228; 6.O.169.229; 6.O.169.230; 6.O.169.231; 6.O.169.236; 6.O.169.237; 6.O.169.238; 6.O.169.239; 6.O.169.154; 6.O.169.157; 6.O.169.166; 6.O.169.169; 6.O.169.172; 6.O.169.175; 6.O.169.240; 6.O.169.244; 6.O.172.228; 6.O.172.229; 6.O.172.230; 6.O.172.231; 6.O.172.236; 6.O.172.237;
6.O.172.238; 6.O.172.239; 6.O.172.154; 6.O.172.157; 6.O.172.166; 6.O.172.169; 6.O.172.172; 6.O.172.175; 6.O.172.240; 6.O.172.244; 6.O.175.228; 6.O.175.229; 6.O.175.230; 6.O.175.231; 6.O.175.236; 6.O.175.237; 6.O.175.238; 6.O.175.239; 6.O.175.154; 6.O.175.157; 6.O.175.166; 6.O.175.169; 6.O.175.172; 6.O.175.175; 6.O.175.240; 6.O.175.244; 6.O.240.228; 6.O.240.229; 6.O.240.230; 6.O.240.231; 6.O.240.236; 6.O.240.237; 6.O.240.238; 6.O.240.239; 6.O.240.154; 6.O.240.157; 6.O.240.166; 6.O.240.169; 6.O.240.172; 6.O.240.175; 6.O.240.240; 6.O.240.244; 6.O.244.228; 6.O.244.229; 6.O.244.230; 6.O.244.231; 6.O.244.236; 6.O.244.237; 6.O.244.238; 6.O.244.239; 6.O.244.154; 6.O.244.157; 6.O.244.166; 6.O.244.169; 6.O.244.172; 6.O.244.175; 6.O.244.240; 6.O.244.244;
Prod rugs of 6.P
6.P.228.228; 6.P.228.229; 6.P.228.230; 6.P.228.231; 6.P.228.236; 6.P.228.237; 6.P.228.238; 6.P.228.239; 6.P.228.154; 6.P.228.157; 6.P.228.166; 6.P.228.169; 6.P.228.172; 6.P.228.175; 6.P.228.240; 6.P.228.244; 6.P.229.228; 6.P.229.229; 6.P.229.230; 6.P.229.231; 6.P.229.236; 6.P.229.237; 6.P.229.238; 6.P.229.239; 6.P.229.154; 6.P.229.157; 6.P.229.166; 6.P.229.169; 6.P.229.172; 6.P.229.175; 6.P.229.240; 6.P.229.244; 6.P.230.228; 6.P.230.229; 6.P.230.230; 6.P.230.231; 6.P.230.236; 6.P.230.237; 6.P.230.238; 6.P.230.239; 6.P.230.154; 6.P.230.157; 6.P.230.166; 6.P.230.169; 6.P.230.172; 6.P.230.175; 6.P.230.240; 6.P.230.244; 6.P.231.228; 6.P.231.229; 6.P.231.230; 6.P.231.231; 6.P.231.236; 6.P.231.237; 6.P.231.238; 6.P.231.239; 6.P.231.154; 6.P.231.157; 6.P.231.166; 6.P.231.169; 6.P.231.172; 6.P.231.175; 6.P.231.240; 6.P.231.244; 6.P.236.228; 6.P.236.229; 6.P.236.230; 6.P.236.231; 6.P.236.236; 6.P.236.237; 6.P.236.238; 6.P.236.239; 6.P.236.154; 6.P.236.157; 6.P.236.166; 6.P.236.169; 6.P.236.172; 6.P.236.175; 6.P.236.240; 6.P.236.244; 6.P.237.228; 6.P.237.229; 6.P.237.230; 6.P.237.231; 6.P.237.236; 6.P.237.237; 6.P.237.238; 6.P.237.239; 6.P.237.154; 6.P.237.157; 6.P.237.166; 6.P.237.169; 6.P.237.172; 6.P.237.175; 6.P.237.240; 6.P.237.244; 6.P.238.228; 6.P.238.229; 6.P.238.230; 6.P.238.231; 6.P.238.236; 6.P.238.237; 6.P.238.238; 6.P.238.239; 6.P.238.154; 6.P.238.157; 6.P.238.166; 6.P.238.169; 6.P.238.172; 6.P.238.175; 6.P.238.240; 6.P.238.244; 6.P.239.228; 6.P.239.229; 6.P.239.230; 6.P.239.231; 6.P.239.236; 6.P.239.237; 6.P.239.238; 6.P.239.239; 6.P.239.154; 6.P.239.157; 6.P.239.166; 6.P.239.169; 6.P.239.172; 6.P.239.175; 6.P.239.240; 6.P.239.244; 6.P.154.228; 6.P.154.229; 6.P.154.230; 6.P.154.231; 6.P.154.236; 6.P.154.237; 6.P.154.238; 6.P.154.239; 6.P.154.154; 6.P.154.157; 6.P.154.166; 6.P.154.169; 6.P.154172; 6.P.154.175; 6.P.154.240; 6.P.154.244; 6.P.157.228; 6.P.157.229; 6.P.157.230; 6.P.157.231; 6.P.157.236; 6.P.157.237; 6.P.157.238; 6.P.157.239; 6.P.157.154; 6.P.157.157; 6.P.157.166; 6.P.157.169; 6.P.157.172; 6.P.157.175; 6.P.157.240; 6.P.157.244; 6.P.166.228; 6.P.166.229; 6.P.166.230; 6.P.166.231; 6.P.166.236; 6.P.166.237; 6.P.166.238; 6.P.166.239; 6.P.166.154; 6.P.166.157; 6.P.166.166; 6.P.166.169; 6.P.166.172; 6.P.166.175; 6.P.166.240; 6.P.166.244; 6.P.169.228; 6.P.169.229; 6.P.169.230; 6.P.169.231; 6.P.169.236; 6.P.169.237; 6.P.169.238; 6.P.169.239; 6.P.169.154; 6.P.169.157; 6.P.169.166; 6.P.169.169; 6.P.169.172; 6.P.169.175; 6.P.169.240; 6.P.169.244; 6.P.172.228; 6.P.172.229; 6.P.172.230; 6.P.172.231; 6.P.172.236; 6.P.172.237; 6.P.172.238; 6.P.172.239; 6.P.172.154; 6.P.172.157; 6.P.172.166; 6.P.172.169; 6.P.172.172; 6.P.172.175; 6.P.172.240; 6.P.172.244; 6.P.175.228; 6.P.175.229; 6.P.175.230; 6.P.175.231; 6.P.175.236; 6.P.175.237; 6.P.175.238; 6.P.175.239; 6.P.175.154; 6.P.175.157; 6.P.175.166; 6.P.175.169; 6.P.175.172; 6.P.175.175; 6.P.175.240; 6.P.175.244; 6.P.240.228; 6.P.240.229; 6.P.240.230; 6.P.240.231; 6.P.240.236; 6.P.240.237; 6.P.240.238; 6.P.240.239; 6.P.240.154; 6.P.240.157; 6.P.240.166; 6.P.240.169; 6.P.240.172;
6.P.240.175; 6.P.240.240; 6.P.240.244; 6.P.244.228; 6.P.244.229; 6.P.244.230; 6.P.244.231; 6.P.244.236; 6.P.244.237; 6.P.244.238; 6.P.244.239; 6.P.244.154; 6.P.244.157; 6.P.244.166; 6.P.244.169; 6.P.244.172; 6.P.244.175; 6.P.244.240; 6.P.244.244;
Prodrugs of 6.U
6.U.228.228; 6.U.228.229; 6.U.228.230; 6.U.228.231; 6.U.228.236; 6.U.228.237; 6.U.228.238; 6.U.228.239; 6.U.228.154; 6.U.228.157; 6.U.228.166; 6.U.228.169; 6.U.228.172; 6.U.228.175; 6.U.228.240; 6.U.228.244; 6.U.229.228; 6.U.229.229; 6.U.229.230; 6.U.229.231; 6.U.229.236; 6.U.229.237; 6.U.229.238; 6.U.229.239; 6.U.229.154; 6.U.229.157; 6.U.229.166; 6.U.229.169; 6.U.229.172; 6.U.229.175; 6.U.229.240; 6.U.229.244; 6.U.230.228; 6.U.230.229; 6.U.230.230; 6.U.230.231; 6.U.230.236; 6.U.230.237; 6.U.230.238; 6.U.230.239; 6.U.230.154; 6.U.230.157; 6.U.230.166; 6.U.230.169; 6.U.230.172; 6.U.230.175; 6.U.230.240; 6.U.230.244; 6.U.231.228; 6.U.231.229; 6.U.231.230; 6.U.231.231; 6.U.231.236; 6.U.231.237; 6.U.231.238; 6.U.231.239; 6.U.231.154; 6.U.231.157; 6.U.231.166; 6.U.231.169; 6.U.231.172; 6.U.231.175; 6.U.231.240; 6.U.231.244; 6.U.236.228; 6.U.236.229; 6.U.236.230; 6.U.236.231; 6.U.236.236; 6.U.236.237; 6.U.236.238; 6.U.236.239; 6.U.236.154; 6.U.236.157; 6.U.236.166; 6.U.236.169; 6.U.236.172; 6.U.236.175; 6.U.236.240; 6.U.236.244; 6.U.237.228; 6.U.237.229; 6.U.237.230; 6.U.237.231; 6.U.237.236; 6.U.237.237; 6.U.237.238; 6.U.237.239; 6.U.237.154; 6.U.237.157; 6.U.237.166; 6.U.237.169; 6.U.237.172; 6.U.237.175; 6.U.237.240; 6.U.237.244; 6.U.238.228; 6.U.238.229; 6.U.238.230; 6.U.238.231; 6.U.238.236; 6.U.238.237; 6.U.238.238; 6.U.238.239; 6.U.238.154; 6.U.238.157; 6.U.238.166; 6.U.238.169; 6.U.238.172; 6.U.238.175; 6.U.238.240; 6.U.238.244; 6.U.239.228; 6.U.239.229; 6.U.239.230; 6.U.239.231; 6.U.239.236; 6.U.239.237; 6.U.239.238; 6.U.239.239; 6.U.239.154; 6.U.239.157; 6.U.239.166; 6.U.239.169; 6.U.239.172; 6.U.239.175; 6.U.239.240; 6.U.239.244; 6.U.154.228; 6.U.154.229; 6.U.154.230; 6.U.154.231; 6.U.154.236; 6.U.154.237; 6.U.154.238; 6.U.154.239; 6.U.154.154; 6.U.154157; 6.U.154.166; 6.U.154.169; 6.U.154.172; 6.U.154.175; 6.U.154.240; 6.U.154.244; 6.U.157.228; 6.U.157.229; 6.U.157.230; 6.U.157.231; 6.U.157.236; 6.U.157.237; 6.U.157.238; 6.U.157.239; 6.U.157.154; 6.U.157.157; 6.U.157.166; 6.U.157.169; 6.U.157.172; 6.U.157.175; 6.U.157.240; 6.U.157.244; 6.U.166.228; 6.U.166.229; 6.U.166.230; 6.U.166.231; 6.U.166.236; 6.U.166.237; 6.U.166.238; 6.U.166.239; 6.U.166.154; 6.U.166.157; 6.U.166.166; 6.U.166.169; 6.U.166.172; 6.U.166.175; 6.U.166.240; 6.U.166.244; 6.U.169.228; 6.U.169.229; 6.U.169.230; 6.U.169.231; 6.U.169.236; 6.U.169.237; 6.U.169.238; 6.U.169.239; 6.U.169.154; 6.U.169.157; 6.U.169.166; 6.U.169.169; 6.U.169.172; 6.U.169.175; 6.U.169.240; 6.U.169.244; 6.U.172.228; 6.U.172.229; 6.U.172.230; 6.U.172.231; 6.U.172.236; 6.U.172.237; 6.U.172.238; 6.U.172.239; 6.U.172.154; 6.U.172.157; 6.U.172.166; 6.U.172.169; 6.U.172.172; 6.U.172.175; 6.U.172.240; 6.U.172.244; 6.U.175.228; 6.U.175.229; 6.U.175.230; 6.U.175.231; 6.U.175.236; 6.U.175.237; 6.U.175.238; 6.U.175.239; 6.U.175.154; 6.U.175.157; 6.U.175.166; 6.U.175.169; 6.U.175.172; 6.U.175.175; 6.U.175.240; 6.U.175.244; 6.U.240.228; 6.U.240.229; 6.U.240.230; 6.U.240.231; 6.U.240.236; 6.U.240.237; 6.U.240.238; 6.U.240.239; 6.U.240.154; 6.U.240.157; 6.U.240.166; 6.U.240.169; 6.U.240.172; 6.U.240.175; 6.U.240.240; 6.U.240.244; 6.U.244.228; 6.U.244.229; 6.U.244.230; 6.U.244.231; 6.U.244.236; 6.U.244.237;
6.U.244.238; 6.U.244.239; 6.U.244.154; 6.U.244.157; 6.U.244.166; 6.U.244.169; 6.U.244.172; 6.U.244.175; 6.U.244.240; 6.U.244.244;
Frodrugs of 6.W
6.W.228.228; 6.W.228.229; 6.W.228.230; 6.W.228.231; 6.W.228.236; 6.W.228.237; 6.W.228.238; 6.W.228.239; 6.W.228.154; 6.W.228.157; 6.W.228.166; 6.W.228.169; 6.W.228.172; 6.W.228.175; 6.W.228.240; 6.W.228.244; 6.W.229.228; 6.W.229.229; 6.W.229.230; 6.W.229.231; 6.W.229.236; 6.W.229.237; 6.W.229.238; 6.W.229.239; 6.W.229.154; 6.W.229.157; 6.VV.229.I66; 6.W.229.169; 6.W.229.172; 6.W.229.175; 6.W.229.240; 6.W.229.244; 6.W.230.228; 6.W.230.229; 6.W.230.230; 6.W.230.231; 6.W.230.236; 6.W.230.237; 6.W.230.238; 6.W.230.239; 6.W.230.154; 6.W.230.157; 6.W.230.166; 6.W.230.169; 6.W.230.172; 6.W.230.175; 6.W.230.240; 6.W.230.244; 6.W.231.228; 6.W.231.229; 6.W.231.230; 6.W.231.231; 6.W.231.236; 6.W.231.237; 6.W.231.238; 6.W.231.239; 6.W.231.154; 6.W.231.157; 6.W.231.166; 6.W.231.169; 6.W.231.172; 6.W.231.175; 6.W.231.240; 6.W.231.244; 6.W.236.228; 6.W.236.229; 6.W.236.230; 6.W.236.231; 6.W.236.236; 6.W.236.237; 6.W.236.238; 6.W.236.239; 6.W.236.154; 6.W.236.157; 6.W.236.166; 6.W.236.169; 6.W.236.172; 6.W.236.175; .6.W.236.240; 6.W.236.244; 6.W.237.228; 6.W.237.229; 6.W.237.230; 6.W.237.231; 6.W.237.236; 6.W.237.237; 6.W.237.238; 6.W.237.239; 6.W.237.154; 6.W.237.157; 6.W.237.166; 6.W.237.169; 6.W.237.172; 6.W.237.175; 6.W.237.240; 6.W.237.244; 6.W.238.228; 6.W.238.229; 6.W.238.230; 6.W.238.231; 6.W.238.236; 6.W.238.237; 6.W.238.238; 6.W.238.239; 6.W.238.154; 6.W.238.157; 6.W.238.166; 6.W.238.169; 6.W.238.172; 6.W.238.175; 6.W.238.240; 6.W.238.244; 6.W.239.228; 6.W.239.229; 6.W.239.230; 6.W.239.231; 6.W.239.236; 6.W.239.237; 6.W.239.238; 6.W.239.239; 6.W.239.154; 6.W.239.157; 6.W.239.166; 6.W.239.169; 6.W.239.172; 6.W.239.175; 6.W.239.240; 6.W.239.244; 6.W.154.228; 6.W.154.229; 6.W.154.230; 6.W.154.231; 6.W.154.236; 6.W.154.237; 6.W.154.238; 6.W.154.239; 6.W.154.154; 6.W.154.157; 6.W.154.166; 6.W.154.169; 6.W.154.172; 6.W.154.175; 6.W.154.240; 6.W.154.244; 6.W.157.228; 6.W.157.229; 6.W.157.230; 6.W.157.231; 6.W.157.236; 6.W.157.237; 6.W.157.238; 6.W.157.239; 6.W.157.154; 6.W.157.157; 6.W.157.166; 6.W.157.169; 6.W.157.172;6.W.157.175; 6.W.157.240; 6.W.157.244; 6.W.166.228; 6.W.166.229; 6.W.166.230; 6.W.166.231; 6.W.166.236; 6.W.166.237; 6.W.166.238; 6.W.166.239; 6.W.166.154; 6.W.166.157; 6.W.166.166; 6.W.166.169; 6.W.166.172; 6.W.166.175; 6.W.166.240; 6.W.166.244; 6.W.169.228; 6.W.169.229; 6.W.169.230; 6.W.169.231; 6.W.169.236; 6.W.169.237; 6.W.169.238; 6.W.169.239; 6.W.169.154; 6.W.169.157; 6.W.169.166; 6.W.169.169; 6.W.169.172; 6.W.169.175; 6.W.169.240; 6.W.169.244; 6.W.172.228; 6.W.172.229; 6.W.172.230; 6.W.172.231; 6.W.172.236; 6.W.172.237; 6.W.172.238; 6.W.172.239; 6.W.172.154; 6.W.172.157; 6.W.172.166; 6.W.172.169; 6.W.172.172; 6.W.172.175; 6.W.172.240; 6.W.172.244; 6.W.175.228; 6.W.175.229; 6.W.175.230; 6.W.175.231; 6.W.175.236; 6.W.175.237; 6.W.175.238; 6.W.175.239; 6.W.175.154; 6.W.175.157; 6.W.175.166; 6.W.175.169; 6.W.175.172; 6.W.175.175; 6.W.175.240; 6.W.175.244; 6.W.240.228; 6.W.240.229; 6.W.240.230; 6.W.240.231; 6.W.240.236; 6.W.240.237; 6.W.240.238; 6.W.240.239; 6.W.240.154; 6.W.240.157; 6.W.240.166; 6.W.240.169; 6.W.240.172; 6.W.240.175; 6.W.240.240; 6.W.240.244; 6.W.244.228; 6.W.244.229; 6.W.244.230; 6.W.244.231; 6.W.244.236; 6.W.244.237;
6.W.244.238; 6.W.244.239; 6.W.244.154; 6.W.244.157; 6.W.244.166; 6.W.244.169; 6.W.244.172; 6.W.244.175; 6.W.244.240; 6.W.244.244;
Prodrugs of 6.Y
6.Y.228.228; 6.Y.228.229; 6.Y.228.230; 6.Y.228.231; 6.Y.228.236; 6.Y.228.237; 6.Y.228.238; 6.Y.228.239; 6.Y.228.154; 6.Y.228.157; 6.Y.228.166; 6.Y.228.169; 6.Y.228.172; 6.Y.228.175; 6.Y.228.240; 6.Y.228.244; 6.Y.229.228; 6.Y.229.229; 6.Y.229.230; 6.Y.229.231; 6.Y.229.236; 6.Y.229.237; 6.Y.229.238; 6.Y.229.239; 6.Y.229.154; 6.Y.229.157; 6.Y.229.166; 6.Y.229.169; 6.Y.229.172; 6.Y.229.175; 6.Y.229.240; 6.Y.229.244; 6.Y.230.228; 6.Y.230.229; 6.Y.230.230; 6.Y.230.231; 6.Y.230.236; 6.Y.230.237; 6.Y.230.238; 6.Y.230.239; 6.Y.230.154; 6.Y.230.157; 6.Y.230.166; 6.Y.230.169; 6.Y.230.172; 6.Y.230.175; 6.Y.230.240; 6.Y.230.244; 6.Y.231.228; 6.Y.231.229; 6.Y.231.230; 6.Y.231.231; 6.Y.231.236; 6.Y.231.237; 6.Y.231.238; 6.Y.231.239; 6.Y.231.154; 6.Y.231.157; 6.Y.231.166; 6.Y.231.169; 6.Y.231.172; 6.Y.231.175; 6.Y.231.240; 6.Y.231.244; 6.Y.236.228; 6.Y.236.229; 6.Y.236.230; 6.Y.236.231; 6.Y.236.236; 6.Y.236.237; 6.Y.236.238; 6.Y.236.239; 6.Y.236.154; 6.Y.236.157; 6.Y.236.166; 6.Y.236.169; 6.Y.236.172; 6.Y.236.175; 6.Y.236.240; 6.Y.236.244; 6.Y.237.228; 6.Y.237.229; 6.Y.237.230; 6.Y.237.231; 6.Y.237.236; 6.Y.237.237; 6.Y.237.238; 6.Y.237.239; 6.Y.237.154; 6.Y.237.157; 6.Y.237.166; 6.Y.237.169; 6.Y.237.172; 6.Y.237.175; 6.Y.237.240; 6.Y.237.244; 6.Y.238.228; 6.Y.238.229; 6.Y.238.230; 6.Y.238.231; 6.Y.238.236; 6.Y.238.237; 6.Y.238.238; 6.Y.238.239; 6.Y.238.154; 6.Y.238.157; 6.Y.238.166; 6.Y.238.169; 6.Y.238.172; 6.Y.238.175; 6.Y.238.240; 6.Y.238.244; 6.Y.239.228; 6.Y.239.229; 6.Y.239.230; 6.Y.239.231; 6.Y.239.236; 6.Y.239.237; 6.Y.239.238; 6.Y.239.239; 6.Y.239.154; 6.Y.239.157; 6.Y.239.166; 6.Y.239.169; 6.Y.239.172; 6.Y.239.175; 6.Y.239.240; 6.Y.239.244; 6.Y.154.228; 6.Y.154.229; 6.Y.154.230; 6.Y.154.231; 6.Y. 154.236; 6.Y. 154.237; 6.Y. 154.238; 6.Y. 154.239; 6.Y. 154.154; 6.Y.154.157; 6.Y.154.166; 6.Y.154.169; 6.Y.154.172; 6.Y.154.175; 6.Y.154.240; 6.Y.154.244; 6.Y.157.228; 6.Y.157.229; 6.Y.157.230; 6.Y.157.231; 6.Y.157.236; 6.Y.157.237; 6.Y: 157.238; 6.Y. 157.239; 6.Y. 157.154; 6.Y. 157.157; 6.Y. 157.166; 6.Y. 157.169; 6.Y.157.172; 6.Y.157.175; 6.Y.157.240; 6.Y.157.244; 6.Y.166.228; 6.Y.166.229; 6.Y.166.230; 6.Y.166.231; 6.Y.166.236; 6.Y.166.237; 6.Y.166.238; 6.Y.166.239; 6. Y. 166.154; 6. Y. 166.157; 6.Y.166.166; 6.Y.166.169; 6.Y.166.172; 6.Y.166.175; 6.Y.166.240; 6.Y.166.244; 6.Y.169.228; 6.Y.169.229; 6.Y.169.230; 6.Y.169.231; 6.Y. 169.236; 6.Y. 169.237; 6.Y. 169.238; 6.Y. 169.239; 6.Y. 169.154; 6.Y. 169.157; 6.Y.169.166; 6.Y.169.169; 6.Y.169.172; 6.Y.169.175; 6.Y.169.240; 6.Y.169.244; 6.Y.172.228; 6.Y.172.229; 6.Y.172.230; 6.Y.172.231; 6.Y.172.236; 6.Y.172.237; 6.Y.172.238; 6.Y.172.239; 6.Y.172.154; 6.Y.172.157; 6.Y.172.166; 6.Y.172.169; 6.Y. 172.172; 6.Y. 172.175; 6.Y. 172.240; 6.Y. 172.244; 6.Y. 175.228; 6.Y. 175.229; 6.Y.175.230; 6.Y.175.231; 6.Y.175.236; 6.Y.175.237; 6.Y.175.238; 6.Y.175.239; 6.Y.175.154; 6.Y.175.157; 6.Y.175.166; 6.Y.175.169; 6.Y.175.172; 6.Y.175.175; 6.Y.175.240; 6.Y.175.244; 6.Y.240.228; 6.Y.240.229: 6.Y.240.230; 6.Y.240.231; 6.Y.240.236; 6.Y.240.237; 6.Y.240.238; 6.Y.240.239; 6.Y.240.154; 6.Y.240.157; 6.Y.240.166; 6.Y.240.169; 6.Y.240.172; 6.Y.240.175; 6.Y.240.240; 6.Y.240.244; 6.Y.244.228; 6.Y.244.229; 6.Y.244.230; 6.Y.244.231; 6.Y.244.236; 6.Y.244.237; 6.Y.244.238; 6.Y.244.239; 6.Y.244.154; 6.Y.244.157; 6.Y.244.166; 6.Y.244.169; 6.Y.244.172; 6.Y.244.175; 6.Y.244.240; 6.Y.244.244;
Prodrugs of 7.AH
7.AH.4.157; 7.AH.4.158; 7.AH.4.L96; 7.AH.4.223; 7.AH.4.240; 7.AH.4.244; 7.AH.4.243; 7.AH.4.247; 7.AH.5.157; 7.AH.5.158; 7.AH.5.196; 7.AH.5.223; 7.AH.5.240; 7.AH.5.244; 7.AH.5.243; 7.AH.5.247; 7.AH.7.157; 7.AH.7.158; 7.AH.7.196; 7.AH.7.223; 7.AH.7.240; 7.AH.7.244; 7.AH.7.243; 7.AH.7.247; 7.AH.15.157; 7.AH.15.158; 7.AH. 15.196; 7.AH.15.223; 7.AH.15.240; 7.AH.15.244; 7.AH.15.243; 7.AH.15.247; 7.AH.16.157; 7.AH.16.158; 7.AH.16.196; 7.AH.16.223; 7.AH.16.240; 7.AH.16.244; 7.AH.16.243; 7.AH.16.247; 7.AH.18.157; 7.AH.18.158; 7.AH.18.196; 7.AH.18.223; 7.AH.18.240; 7.AH.18.244; 7.AH.18.243; 7.AH. 18.247; 7.AH.26.157; 7.AH.26.158; 7.AH.26.196; 7.AH.26.223; 7.AH.26.240; 7.AH.26.244; 7.AH.26.243; 7.AH.26.247; 7.AH.27.157; 7.AH.27.158; 7.AH.27.196; 7.AH.27.223; 7.AH.27.240; 7.AH.27.244; 7.AH.27.243; 7.AH.27.247; 7.AH.29.157; 7.AH.29.158; 7.AH.29.196; 7.AH.29.223; 7.AH.29.240; 7.AH.29.244; 7.AH.29.243; 7.AH.29.247; 7.AH.54.157; 7.AH.54.158; 7.AH.54.196; 7.AH.54.223; 7.AH.54.240; 7.AH.54.244; 7.AH.54.243; 7.AH.54.247; 7.AH.55.157; 7.AH.55.158; 7.AH.55.196; 7.AH.55.223; 7.AH.55.240; 7.AH.55.244; 7.AH.55.243; 7.AH.55.247; 7.AH.56.157; 7.AH.56.158; 7.AH.56.196; 7.AH.56.223; 7.AH.56.240; 7.AH.56.244; 7.AH.56.243; 7.AH.56.247; 7.AH.157.157; 7.AH.157.158; 7.AH.157.196; 7.AH. 157.223; 7.AH. 157.240; 7.AH. 157.244; 7.AH. 157.243; 7.AH. 157.247; 7.AH.196.157; 7.AH.196.158; 7.AH.196.196; 7.AH. 196.223; 7.AH. 196.240; 7.AH. 196.244; 7.AH. 196.243; 7.AH.196.247; 7.AH.223.157; 7.AH.223.158; 7.AH.223.196; 7.AH.223.223; 7.AH.223.240; 7.AH.223.244; 7.AH.223.243; 7.AH.223.247; 7.AH.240.157; 7.AH.240.158; 7.AH.240.196; 7.AH.240.223; 7.AH.240.240; 7.AH.240.244; 7.AH.240.243; 7.AH.240.247; 7.AH.244.157; 7.AH.244.158; 7.AH.244.196; 7.AH.244.223; 7.AH.244.240; 7.AH.244.244; 7.AH.244.243; 7.AH.244.247; 7.AH.247.157; 7.AH.247.158; 7.AH.247.196; 7.AH.247.223; 7.AH.247.240; 7.AH.247.244; 7.AH.247.243; 7.AH.247.247;
Prodrugs of 7.AT
7.AJ.4.157; 7.AJ.4.158; 7.AJ.4.196; 7.AJ.4.223; 7.AJ.4.240; 7.AJ.4.244; 7.AJ.4.243; 7.AJ.4.247; 7.AJ.5.157; 7.AJ.5.158; 7.AJ.5.196; 7.AJ.5.223; 7.AJ.5.240; 7.AJ.5.244; 7.AJ.5.243; 7.AJ.5.247; 7.AJ.7.157; 7.AJ.7.158; 7.AJ.7.196; 7.AJ.7.223; 7.AJ.7.240; 7.AJ.7.244; 7.AJ.7.243; 7.AJ.7.247; 7.AJ.15.157; 7.AJ.15.158; 7.AJ.15.196; 7.AJ.15.223; 7.AJ. 15.240; 7.AJ. 15.244; 7.AJ. 15.243; 7.AJ. 15.247; 7.AJ.16.157; 7.AJ.16.158; 7.AJ.16.196; 7.AJ. 16.223; 7.AJ. 16.240; 7.AJ. 16.244; 7.AJ. 16.243; 7.AJ. 16.247; 7.AJ.18.157; 7.AJ.18.158; 7.AJ.18.196; 7.AJ.18.223; 7.AJ.18.240; 7.AJ.18.244; 7.AJ.18.243; 7.AJ.18.247; 7.AJ.26.157; 7.AJ.26.158; 7.AJ.26.196; 7.AJ.26.223; 7.AJ.26.240; 7.AJ.26.244; 7.AJ.26.243; 7.AJ.26.247; 7.AJ.27.157; 7.AJ.27.158; 7.AJ.27.196; 7.AJ.27.223; 7.AJ.27.240; 7.AJ.27.244; 7.AJ.27.243; 7.AJ.27.247; 7.AJ.29.157; 7.AJ.29.158; 7.AJ.29.196; 7.AJ.29.223; 7.AJ.29.240; 7.AJ.29.244; 7.AJ.29.243; 7.AJ.29.247; 7.AJ.54.157; 7.AJ.54.158; 7.AJ.54.196; 7.AJ.54.223; 7.AJ.54.240; 7.AJ.54.244; 7.AJ.54.243; 7.AJ.54.247; 7.AJ.55.157; 7.AJ.55.158; 7.AJ.55.196; 7.AJ.55.223; 7.AJ.55.240; 7.AJ.55.244; 7.AJ.55.243; 7.AJ.55.247; 7.AJ.56.157; 7.AJ.56.158; 7.AJ.56.196; 7.AJ.56.223; 7.AJ.56.240; 7.AJ.56.244; 7.AJ.56.243; 7.AJ.56.247; 7.AJ.157.157; 7.AJ. 157.158; 7.AJ. 157.196; 7.AJ. 157.223; 7.AJ. 157.240; 7.AJ. 157.244; 7.AJ. 157.243; 7.AJ. 157.247; 7.AJ. 196.157; 7.AJ. 196.158; 7.AJ.196.196; 7.AJ. 196.223; 7.AJ. 196.240; 7.AJ. 196.244; 7.AJ. 196.243; 7.AJ. 196.247; 7.AJ.223.157;7.AJ.223.158; 7.AJ.223.196; 7.AJ.223.223; 7.AJ.223.240; 7.AJ.223.244; 7.AJ.223.243; 7.AJ.223.247; 7.AJ.240.157; 7.AJ.240.158; 7.AJ.240.196; 7.AJ.240.223; 7.AJ.240.240; 7.AJ.240.244; 7.AJ.240.243; 7.AJ.240.247; 7.AJ.244.157; 7.AJ.244.158; 7.AJ.244.196; 7.AJ.244.223; 7.AJ.244.240;
7.AJ.244.244; 7.AJ.244.243; 7.AJ.244.247; 7.AJ.247.157; 7.AL247.158; 7.AJ.247.196; 7.AJ.247.223; 7.AJ.247.240; 7.AJ.247.244; 7.AJ.247.243; 7.AJ.247.247;
Prodrugs of 7.AN
7.AN.4.157; 7.AN.4.158; 7.ANA 196; 7.AN.4.223; 7.AN.4.240; 7.AN.4.244; 7.AN.4.243; 7.AN.4.247; 7.AN.5.157; 7.AN.5.158; 7.AN.5.196; 7.AN.5.223; 7.AN.5.240; 7.AN.5.244; 7.AN.5.243; 7.AN.5.247; 7.AN.7.157; 7.AN.7.158; 7.AN.7.196; 7.AN.7.223; 7.AN.7.240; 7.AN.7.244; 7.AN.7.243; 7.AN.7.247; 7.AN. 15.157; 7.AN.15.158; 7.AN.15.196; 7.AN. 15.223; 7.AN. 15.240; 7.AN. 15.244; 7.AN. 15.243; 7.AN. 15.247; 7.AN. 16.157; 7.AN.16.158; 7.AN.16.196; 7.AN.16.223; 7.AN.16.240; 7.AN.16.244; 7.AN.16.243; 7.AN.16.247; 7.AN.18.157; 7.AN.18.158; 7.AN.18.196; 7.AN.18.223; 7.AN.18.240; 7.AN.18.244; 7.AN.18.243; 7.AN.18.247; 7.AN.26.157; 7.AN.26.158; 7.AN.26.196; 7.AN.26.223; 7.AN.26.240; 7.AN.26.244; 7.AN.26.243; 7.AN.26.247; 7.AN.27.157; 7.AN.27.158; 7.AN.27.196; 7.AN.27.223; 7.AN.27.240; 7.AN.27.244; 7.AN.27.243; 7.AN.27.247; 7.AN.29.157; 7.AN.29.158; 7.AN.29.196; 7.AN.29.223; 7.AN.29.240; 7.AN.29.244; 7.AN.29.243; 7.AN.29.247; 7.AN.54.157; 7.AN.54.158; 7.AN.54.196; 7.AN.54.223; 7.AN.54.240; 7.AN.54.244; 7.AN.54.243; 7.AN.54.247; 7.AN.55.157; 7.AN.55.158; 7.AN.55.196; 7.AN.55.223; 7.AN.55.240; 7.AN.55.244; 7.AN.55.243; 7.AN.55.247; 7.AN.56.157; 7.AN.56.158; 7.AN.56.196; 7.AN.56.223; 7.AN.56.240; 7.AN.56.244; 7.AN.56.243; 7.AN.56.247; 7.AN.157.157; 7.AN.157.158; 7.AN.157.196; 7.AN.157.223; 7.AN.157.240; 7.AN.157.244; 7.AN.157.243; 7.AN.157.247; 7.AN.196.157; 7.AN.196.158; 7.AN.196.196; 7.AN.196.223; 7.AR196.240; 7.AN.196.244; 7.AN.196.243; 7.AN. 196.247; 7.AN.223.157; 7.AN.223.158; 7.AN.223.196; 7.AN.223.223; 7.AN.223.240; 7.AN.223.244; 7.AN.223.243; 7.AN.223.247; 7.AN.240.157; 7.AN.240.158; 7.AN.240.196; 7.AN.240.223; 7.AN.240.240; 7.AN.240.244; 7.AN.240.243; 7.AN.240.247; 7.AN.244.157; 7.AN.244.158; 7.AN.244.196; 7.AN.244.223; 7.AN.244.240; 7.AN.244.244; 7.AN.244.243; 7.AN.244.247; 7.AN.247.157; 7.AN.247.158; 7.AN.247.196; 7.AN.247.223; 7.AN.247.240; 7.AN.247.244; 7.AN.247.243; 7.AN.247.247;
Prodrugs of 7. AP
7.AP.4.157; 7.AP.4.158; 7.AP.4.196; 7.AP.4.223; 7.AP.4.240; 7.AP.4.244; 7.AP.4.243; 7.AP.4.247; 7.AP.5.157; 7.AP.5.158; 7.AP.5.196; 7.AP.5.223; 7.AP.5.240; 7.AP.5.244; 7.AP.5.243; 7.AP.5.247; 7.AP.7.157; 7.AP.7.158; 7.AP.7.196; 7.AP.7.223; 7.AP.7.240; 7.AP.7.244; 7.AP.7.243; 7.AP.7.247; 7.AP.15.157; 7.AP. 15.158; 7.AP.15.196; 7.AP. 15.223; 7.AP.15.240; 7.AP.15.244; 7.AP.15.243; 7.AP.15.247; 7.AP.16.157; 7.AP.16.158; 7.AP.16.196; 7.AP.16.223; 7.AP.16.240; 7.AP.16.244; 7.AP.16.243; 7.AP.16.247; 7.AP.18.157;7.AP.18.158; 7.AP.18.196; 7.AP. 18.223; 7.AP. 18.240; 7.AP.18.244; 7.AP.18.243; 7.AP.18.247; 7.AP.26.157; 7.AP.26.158; 7.AP.26.196; 7.AP.26.223; 7.AP.26.240; 7.AP.26.244; 7.AP.26.243; 7.AP.26.247; 7.AP.27.157; 7.AP.27.158; 7.AP.27.196; 7.AP.27.223; 7.AP.27.240; 7.AP.27.244; 7.AP.27.243; 7.AP.27.247; 7.AP.29.157; 7.AP.29.158; 7.AP.29.196; 7.AP.29.223; 7.AP.29.240; 7.AP.29.244; 7.AP.29.243; 7.AP.29.247; 7.AP.54.157; 7.AP.54.158; 7.AP.54.196; 7.AP.54.223; 7.AP.54.240; 7.AP.54.244; 7.AP.54.243; 7.AP.54.247; 7.AP.55.157; 7.AP.55.158; 7.AP.55.196; 7.AP.55.223; 7.AP.55.240; 7.AP.55.244; 7.AP.55.243; 7.AP.55.247; 7.AP.56.157; 7.AP.56.158; 7.AP.56.196; 7.AP.56.223; 7.AP.56.240; 7.AP.56.244; 7.AP.56.243; 7.AP.56.247; 7.AP.157.157; 7.AP.157.158; 7.AP.157.196; 7.AP.157.223; 7.AP.157.240; 7.AP.157.244; 7.AP.157.243; 7.AP.157.247; 7.AP.196.157; 7.AP.196.158; 7.AP.196.196; 7.AP.196.223; 7.AP.196.240; 7.AP.196.244; 7.AP.196.243; 7.AP.196.247;
7.AP.223.157; 7.AP.223.158; 7.AP.223.196; 7.AP.223.223; 7.AP.223.240; 7.AP.223.244; 7.AP.223.243; 7.AP.223.247; 7.AP.240.157; 7.AP.240.158; 7.AP.240.196; 7.AP.240.223; 7.AP.240.240; 7.AP.240.244; 7.AP.240.243; 7.AP.240.247; 7.AP.244.157; 7.AP.244.158; 7.AP.244.196; 7.AP.244.223; 7.AP.244.240; 7.AP.244.244; 7.AP.244.243; 7.AP.244.247; 7.AP.247.157; 7.AP.247.158; 7.AP:247.196; 7.AP.247.223; 7.AP.247.240; 7.AP.247.244; 7.AP.247.243; 7.AP.247.247;
Prodrugs of 7.AZ
7.AZ.4.157; 7.AZ.4.158; 7.AZ.4.196; 7.AZ.4.223; 7.AZ.4.240; 7.AZ.4.244; 7.AZ.4.243; 7.AZ.4.247; 7.AZ.5.157; 7.AZ.5.158; 7.AZ.5.196; 7.AZ.5.223; 7.AZ.5.240; 7.AZ.5.244; 7.AZ.5.243; 7.AZ.5.247; 7.AZ.7.157; 7.AZ.7.158; 7.AZ.7.196; 7.AZ.7.223; 7.AZ.7.240; 7.AZ.7.244; 7.AZ.7.243; 7.AZ.7.247; 7.AZ.15.157; 7.AZ.15.158; 7.AZ.15.196; 7.AZ.15.223; 7.AZ. 15.240; 7.AZ. 15.244; 7.AZ. 15.243; 7.AZ. 15.247; 7.AZ.16.157; 7.AZ.16.158; 7.AZ.16.196; 7.AZ. 16.223; 7.AZ. 16.240; 7.AZ. 16.244; 7.AZ. 16.243; 7.AZ. 16.247; 7.AZ.18.157; 7.AZ.18.158; 7.AZ.18.196; 7.AZ.18.223; 7.AZ.18.240; 7.AZ.18.244; 7.AZ.18.243; 7.AZ.18.247; 7.AZ.26.157; 7.AZ.26.158; 7.AZ.26.196; 7.AZ.26.223; 7.AZ.26.240; 7.AZ.26.244; 7.AZ.26.243; 7.AZ.26.247; 7.AZ.27.157; 7.AZ.27.158; 7.AZ.27.196; 7.AZ.27.223; 7.AZ.27.240; 7.AZ.27.244; 7.AZ.27.243; 7.AZ.27.247; 7.AZ.29.157; 7.AZ.29.158; 7.AZ.29.196; 7.AZ.29.223; 7.AZ.29.240; 7.AZ.29.244; 7.AZ.29.243; 7.AZ.29.247; 7.AZ.54.157; 7.AZ.54.158; 7.AZ.54.196; 7.AZ.54.223; 7.AZ.54.240; 7.AZ.54.244; 7.AZ.54.243; 7.AZ.54.247; 7.AZ.55.157; 7.AZ.55.158; 7.AZ.55.196; 7.AZ.55.223; 7.AZ.55.240; 7.AZ.55.244; 7.AZ.55.243; 7.AZ.55.247; 7.AZ.56.157; 7.AZ.56.158; 7.AZ.56.196; 7.AZ.56.223; 7.AZ.56.240; 7.AZ.56.244; 7.AZ.56.243; 7.AZ.56.247; 7.AZ.157.157; 7.AZ.157.158; 7.AZ.157.196; 7.AZ.157.223; 7.AZ.157.240; 7.AZ.157.244; 7.AZ.157.243; 7.AZ.157.247; 7.AZ.196.157; 7.AZ.196.158; 7.AZ.196.196; 7.AZ.196.223; 7.AZ.196.240; 7.AZ.196.244; 7.AZ.196.243; 7.AZ.196.247; 7.AZ.223.157; 7.AZ.223.158; 7.AZ.223.196; 7.AZ.223.223; 7.AZ.223.240; 7.AZ.223.244; 7.AZ.223.243; 7.AZ.223.247; 7.AZ.240.157; 7.AZ.240.158; 7.AZ.240.196; 7.AZ.240.223; 7.AZ.240.240; 7.AZ.240.244; 7.AZ.240.243; 7.AZ.240.247; 7.AZ.244.157; 7.AZ.244.158; 7.AZ.244.196; 7.AZ.244.223; 7.AZ.244.240; 7.AZ.244.244; 7.AZ.244.243; 7.AZ.244.247; 7.AZ.247.157; 7.AZ.247.158; 7.AZ.247.196; 7.AZ.247.223; 7.AZ.247.240; 7.AZ.247.244; 7.AZ.247.243; 7.AZ.247.247;
Prodrugs of 7.BF
7.BF.4.157; 7.BF.4.158; 7.BF.4.196; 7.BF.4.223; 7.BF.4.240; 7.BF.4.244; 7.BF.4.243; 7.BF.4.247; 7.BF.5.157; 7.BF.5.158; 7.BF.5.196; 7.BF.5.223; 7.BF.5.240; 7.BF.5.244; 7.BF.5.243; 7.BF.5.247; 7.BF.7.157; 7.BF.7.158; 7.BF.7.196; 7.BF.7.223; 7.BF.7.240; 7.BF.7.244; 7.BF.7.243; 7.BF.7.247; 7.BF.15.157; 7.BF.15.158; 7.BF.15.196; 7.BF.15.223; 7.BF.15.240; 7.BF.15.244; 7.BF.15.243; 7.BF.15.247; 7.BF.16.157; 7.BF.16.158; 7.BF.16.196; 7.BF. 16.223; 7.BF. 16.240; 7.BF. 16.244; 7.BF. 16.243; 7.BF. 16.247; 7.BF.18.157; 7.BF.18.158; 7.BF.18.196; 7.BF.18.223; 7.BF.18.240; 7.BF.18.244; 7.BF. 18.243; 7.BF. 18.247; 7.BF.26.157; 7.BF.26.158; 7.BF.26.196; 7.BF.26.223; 7.BF.26.240; 7.BF.26.244; 7.BF.26.243; 7.BF.26.247; 7.BF.27.157; 7.BF.27.158; 7.BF.27.196; 7.BF.27.223; 7.BF.27.240; 7.BF.27.244; 7.BF.27.243; 7.BF.27.247; 7.BF.29.157; 7.BF.29.158; 7.BF.29.196; 7.BF.29.223; 7.BF.29.240; 7.BF.29.244; 7.BF.29.243; 7.BF.29.247; 7.BF.54.157; 7.BF.54.158; 7.BF.54.196; 7.BF.54.223; 7.BF.54.240; 7.BF.54.244; 7.BF.54.243; 7.BF.54.247; 7.BF.55.157; 7.BF.55.158; 7.BF.55.196; 7.BF.55.223; 7.BF.55.240; 7.BF.55.244; 7.BF.55.243; 7.BF.55.247;
7.BF.56.157; 7.BF.56.158; 7.BF.56.196; 7.BF.56.223; 7.BF.56.240; 7.BF.56.244; 7.BF.56.243; 7.BF.56.247; 7.BF.157.157; 7.BF.157.158; 7.BF.157.196; 7.BF. 157.223; 7.BF.157.240; 7.BF.157.244; 7.BF.157.243; 7.BF.157.247; 7.BF.196.157; 7.BF.196.158; 7.BF.196.196; 7.BF.196.223; 7.BF.196.240; 7.BF.196.244; 7.BF.196.243; 7.BF.196.247; 7.BF.223.157; 7.BF.223.158; 7.BF.223.196; 7.BF.223.223; 7.BF.223.240; 7.BF.223.244; 7.BF.223.243; 7.BF.223.247; 7.BF.240.157; 7.BF.240.158; 7.BF.240.196; 7.BF.240.223; 7.BF.240.240; 7.BF.240.244; 7.BF.240.243; 7.BF.240.247; 7.BF.244.157; 7.BF.244.158; 7.BF.244.196; 7.BF.244.223; 7.BF.244.240; 7.BF.244.244; 7.BF.244.243; 7.BF.244.247; 7.BF.247.157; 7.BF.247.158: 7.BF.247.196; 7.BF.247.223; 7.BF.247.240; 7.BF.247.244; 7.BF.247.243; 7.BF.247.247;
Frodrugs of 7.CI
7.CI.4.157; 7.CI.4.158; 7.CI.4.196; 7.CI.4.223; 7.CI.4.240; 7.CI.4.244; 7.CI.4.243; 7.CI.4.247; 7.CI.5.157; 7.CI.5.158; 7.CI.5.196; 7.CI.5.223; 7.CI.5.240; 7.CI.5.244; 7.CI.5.243; 7.CI.5.247; 7.CI.7.157; 7.CI.7.158; 7.CI.7.196; 7.CI.7.223; 7.CI.7.240; 7.CI.7.244; 7.CI.7.243; 7.CI.7.247; 7.CI.15.157; 7.CI.15.158; 7.CI.15.196; 7.CI. 15.223; 7.CI. 15.240; 7.CI. 15.244; 7.CI. 15.243; 7.CI. 15.247; 7.CI.16.157; 7.CI.16.158; 7.CI.16.196; 7.CI. 16.223; 7.CI. 16.240; 7.CI. 16.244; 7.CI. 16.243; 7.CI. 16.247; 7.CI.18.157; 7.CI.18.158; 7.CI.18.196; 7.CI.18.223; 7.CI.18.240; 7.CI.18.244; 7.CI.18.243; 7.CI.18.247; 7.CI.26.157; 7.CI.26.158; 7.CI.26.196; 7.CI.26.223; 7.CI.26.240; 7.CI.26.244; 7.CI.26.243; 7.CI.26.247; 7.CI.27.157; 7.CI.27.158; 7.CI.27.196; 7.CI.27.223; 7.CI.27.240; 7.CI.27.244; 7.CI.27.243; 7.CI.27.247; 7.CI.29.157; 7.CI.29.158; 7.CI.29.196; 7.CI.29.223; 7.CI.29.240; 7.CI.29.244; 7.CI.29.243; 7.CI.29.247; 7.CI.54.157; 7.CI.54.158; 7.CI.54.196; 7.CI.54.223; 7.CI.54.240; 7.CI.54.244; 7.CI.54.243; 7.CI.54.247; 7.CI.55.157; 7.CI.55.158; 7.CI.55.196; 7.CI.55.223; 7.CI.55.240; 7.CI.55.244; 7.CI.55.243; 7.CI.55.247; 7.CI.56.157; 7.CI.56.158; 7.CI.56.196; 7.CI.56.223; 7.CI.56.240; 7.CI.56.244; 7.CI.56.243; 7.CI.56.247; 7.CI.157.157; 7.CI.157.158; 7.CI.157.196; 7.CI.157.223; 7.CI.157.240; 7.CI.157.244; 7.CI.157.243; 7.CI.157.247; 7.CI.196.157; 7.CI.196.158; 7.CI.196.196; 7.CL196.223; 7.CI.196.240; 7.CI.196.244; 7.CI.196.243; 7.CI.196.247; 7.CI.223.157; 7.CI.223.158; 7.CI.223.196; 7.CL223.223; 7.CI.223.240; 7.CI.223.244; 7.CI.223.243; 7.CL223.247; 7.CI.240.157; 7.CI.240.158; 7.CI.240.196; 7.CI.240.223; 7.CI.240.240; 7.CL240.244; 7.CI.240.243; 7.CI.240.247; 7.CI.244.157; 7.CI.244.158; 7.CI.244.196; 7.CL244.223; 7.CI.244.240; 7.CI.244.244; 7.CI.244.243; 7.CI.244.247; 7.CI.247.157; 7.CI.247.158; 7.CI.247.196; 7.CI.247.223; 7.CI.247.240; 7.CI.247.244; 7.CI.247.243; 7.CI.247.247;
Prodrugs of 7.CO
7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.C0.4.243; 7.CO.4.247; 7.CO.5.157; 7.CO.5.158; 7.CO.5.196; 7.CO.5.223; 7.CO.5.240; 7.CO.5.244; 7.CO.5.243; 7.CO.5.247; 7.CO.7.157; 7.CO.7.158; 7.CO.7.196; 7.CO.7.223; 7.CO.7.240; 7.CO.7.244; 7.CO.7.243; 7.CO.7.247; 7.CO.15.157; 7.CO.15.158; 7.CO.15.196; 7.CO.15.223; 7.CO.15.240; 7.CO. 15.244; 7.CO. 15.243; 7.CO.15.247; 7.CO.16.157; 7.CO.16.158; 7.CO.16.196; 7.CO.16.223; 7.CO.16.240; 7.CO.16.244; 7.CO.16.243; 7.CO.16.247; 7.CO.18.157; 7.CO.18.158; 7.CO.18.196; 7.CO.18.223; 7.CO.18.240; 7.CO.18.244; 7.CO.18.243; 7.CO.18.247; 7.CO.26.157; 7.CO.26.158; 7.CO.26.196; 7.C0.26.223; 7.CO.26.240; 7.CO.26.244; 7.CO.26.243; 7.CO.26.247; 7.CO.27.157; 7.CO.27.158; 7.CO.27.196; 7.CO.27.223; 7.CO.27.240; 7.CO.27.244; 7.CO.27.243; 7.CO.27.247; 7.CO.29.157; 7.CO.29.158; 7.CO.29.196; 7.CO.29.223; 7.CO.29.240; 7.CO.29.244; 7.CO.29.243; 7.CO.29.247; 7.CO.54.157; 7.CO.54.158; 7.CO.54.196;
7.C0.54.223; 7.CO.54.240; 7.CO.54.244; 7.CO.54.243; 7.CO.54.247; 7.CO.55.157; 7.C0.55.158; 7.CO.55.196; 7.CO.55.223; 7.C0.55.240; 7.CO.55.244; 7.CO.55.243; 7.C0.55.247; 7.CO.56.157; 7.CO.56.158; 7.CO.56.196; 7.CO.56.223; 7.CO.56.240; 7.C0.56.244; 7.CO.56.243; 7.CO.56.247; 7.CO.157.157; 7.CO.157.158; 7.CO.157.196; 7.C0.157.223; 7.CO.157.240; 7.CO.157.244; 7.CO.157.243; 7.CO.157.247; 7.CO.196.157; 7.C0.196.158; 7.CO.196.196; 7.CO. 196.223; 7.CO. 196.240; 7.CO. 196.244; 7.CO. 196.243; 7.CO. 196.247; 7.CO.223.157; 7.CO.223.158; 7.CO.223.196; 7.CO.223.223; 7.CO.223.240; 7.C0.223.244; 7.CO.223.243; 7.CO.223.247; 7.CO.240.157; 7.CO.240.158; 7.CO.240.196; 7.CO.240.223; 7.CO.240.240; 7.CO.240.244; 7.CO.240.243; 7.CO.240.247; 7.CO.244.157; 7.C0.244.158; 7.CO.244.196; 7.CO.244.223; 7.CO.244.240; 7.CO.244.244; 7.CO.244.243; 7.CO.244.247; 7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247;
Prodrugs of 8. AH
8.AH.4.157; 8.AH.4.158; 8.AH.4.196; 8.AH.4.223; 8.AH.4.240; 8.AH.4.244; 8.AH.4.243; 8.AH.4.247; 8.AH.5.157; 8.AH.5.158; 8.AH.5.196; 8.AH.5.223; 8.AH.5.240; 8.AH.5.244; 8.AH.5.243; 8.AH.5.247; 8.AH.7.157; 8.AH.7.158; 8.AH.7.196; 8.AH.7.223; 8.AH.7.240; 8.AH.7.244; 8.AH.7.243; 8.AH.7.247; 8.AH.15.157; 8.AH.15.158; 8.AH.15.196; 8.AH. 15.223; 8.AH.15.240; 8.AH.15.244; 8.AH.15.243; 8.AH.15.247; 8.AH.16.157; 8.AH.16.158; 8.AH.16.196; 8.AH.16.223; 8.AH.16.240; 8.AH.16.244; 8.AH.16.243; 8.AH.16.247; 8.AH.18.157; 8.AH.18.158; 8.AH.18.196; 8.AH.18.223; 8.AH.18.240; 8.AH.18.244; 8.AH.18.243; 8.AH.18.247; 8.AH.26.157; 8.AH.26.158; 8.AH.26.196; 8.AH.26.223; 8.AH.26.240; 8.AH.26.244; 8.AH.26.243; 8.AH.26.247; 8.AH.27.157; 8.AH.27.158; 8.AH.27.196; 8.AH.27.223; 8.AH.27.240; 8.AH.27.244; 8.AH.27.243; 8.AH.27.247; 8.AH.29.157; 8.AH.29.158; 8.AH.29.196; 8.AH.29.223; 8.AH.29.240; 8.AH.29.244; 8.AH.29.243; 8.AH.29.247; 8.AH.54.157; 8.AH.54.158; 8.AH.54.196; 8.AH.54.223; 8.AH.54.240; 8.AH.54.244; 8.AH.54.243; 8.AH.54.247; 8.AH.55.157; 8.AH.55.158; 8.AH.55.196; 8.AH.55.223; 8.AH.55.240; 8.AH.55.244; 8.AH.55.243; 8.AH.55.247; 8.AH.56.157; 8.AH.56.158; 8.AH.56.196; 8.AH.56.223; 8.AH.56.240; 8.AH.56.244; 8.AH.56.243; 8.AH.56.247; 8.AH.157.157; 8.AH.157.158; 8.AH.157.196; 8.AH.157.223; 8.AH.157.240; 8.AH.157.244; 8.AH.157.243; 8.AH.157.247; 8.AH.196.157; 8.AH.196.158; 8.AH.196.196; 8.AH.196.223; 8.AH.196.240; 8.AH.196.244; 8.AH.196.243; 8.AH. 196.247; 8.AH.223.157; 8.AH.223.158; 8.AH.223.196; 8.AH.223.223; 8.AH.223.240; 8.AH.223.244; 8.AH.223.243; 8.AH.223.247; 8.AH.240.157; 8.AH.240.158; 8.AH.240.196; 8.AH.240.223; 8.AH.240.240; 8.AH.240.244; 8.AH.240.243; 8.AH.240.247; 8.AH.244.157; 8.AH.244.158; 8.AH.244.196; 8.AH.244.223; 8.AH.244.240; 8.AH.244.244; 8.AH.244.243; 8.AH.244.247; 8.AH.247.157; 8.AH.247.158; 8.AH.247.196; 8.AH.247.223; 8.AH.247.240; 8.AH.247.244; 8.AH.247.243; 8.AH.247.247;
Prodrugs of 8.AT
8.AJ.4.157; 8.AJ.4.158; 8.AJ.4.196; 8.AJ.4.223; 8.AJ.4.240; 8.AJ.4.244; 8.AJ.4.243; 8.AJ.4.247; 8.AJ.5.157; 8.AJ.5.158; 8.AJ.5.196; 8.AJ.5.223; 8.AJ.5.240; 8.AJ.5.244; 8.AJ.5.243; 8.AJ.5.247; 8.AJ.7.157; 8.AJ.7.158; 8.AJ.7.196; 8.AJ.7.223; 8.AJ.7.240; 8.AJ.7.244; 8.AJ.7.243; 8.AJ.7.247; 8.AJ.15.157; 8:AJ.15.158; 8.AJ.15.196; 8.AJ.15.223; 8.AJ.15.240; 8.AJ.15.244; 8.AJ.15.243; 8.AJ.15.247; 8.AJ.16.157; 8.AJ.16.158; 8.AJ.16.196; 8.AJ.16.223; 8.AJ.16.240; 8.AJ.16.244; 8.AJ.16.243; 8.AJ.16.247; 8.AJ.18.157; 8.AJ.18.158; 8.AJ.18.196; 8.AJ.18.223; 8.AJ.18.240; 8.AJ.18.244; 8.AJ.18.243; 8.AJ.18.247; 8.AJ.26.157; 8.AJ.26.158; 8.AJ.26.196; 8.AJ.26.223; 8.AJ.26.240; 8.AJ.26.244; 8.AJ.26.243; 8.AJ.26.247;
S.AJ.27.157; 8.AJ.27.158; 8.AJ.27.196; 8.AJ.27.223; 8.AJ.27.240; 8.AJ.27.244; 8.AJ.27.243; 8.AJ.27.247; 8.AJ.29.157; 8.AJ.29.158; 8.AJ.29.196; 8.AJ.29.223; 8.AJ.29.240; 8.AJ.29.244; 8.AJ.29.243; 8.AJ.29.247; 8.AJ.54.157; 8.AJ.54.158; 8.AJ.54.196; 8.AJ.54.223; 8.AJ.54.240; 8.AJ.54.244; 8.AJ.54.243; 8.AJ.54.247; 8.AJ.55.157; 8.AJ.55.158; 8.AJ.55.196; 8.AJ.55.223; 8.AJ.55.240; 8.AJ.55.244; 8.AJ.55.243; 8.AJ.55.247; 8.AJ.56.157; 8.AJ.56.158; 8.AJ.56.196; 8.AJ.56.223; 8.AJ.56.240; 8.AJ.56.244; 8.AJ.56.243; 8.AJ.56.247; 8.AJ.157.157; 8.AJ.157.158; 8.AJ.157.196; 8.AJ.157.223; 8.AJ.157.240; 8.AJ.157.244; 8.AJ.157.243; 8.AJ.157.247; 8.AJ.196.157; 8.AJ.196.158; 8.AJ.196.196; 8.AJ.196.223; 8.AJ. 196.240; 8.AJ. 196.244; 8.AJ. 196.243; S.AJ. 196.247; 8.AJ.223.157; 8.AJ.223.158; 8.AJ.223.196; 8.AJ.223.223; 8.AJ.223.240; 8.AJ.223.244; 8.AJ.223.243; 8.AJ.223.247; 8.AJ.240.157; 8.AJ.240.158; 8.AJ.240.196; 8.AJ.240.223; 8.AJ.240.240; 8.AJ.240.244; 8.AJ.240.243; 8.AJ.240.247; 8.AJ.244.157; 8.AJ.244.158; 8.AJ.244.196; 8.AJ.244.223; 8.AJ.244.240; 8.AJ.244.244; 8.AJ.244.243; 8.AJ.244.247; 8.AJ.247.157; 8.AJ.247.158; 8.AJ.247.196; 8.AJ.247.223; 8.AJ.247.240; 8.AJ.247.244; 8.AJ.247.243; 8.AJ.247.247;
Prodrugs of 8. AN
8.AN.4.157; 8.AN.4.158; 8.AN.4.196; 8.AN.4.223; 8.AN.4.240; 8.AN.4.244; 8.AN.4.243; 8.AN.4.247; 8.AN.5.157; 8.AN.5.158; 8.AN.5.196; 8.AN.5.223; 8.AN.5.240; 8.AN.5.244; 8.AN.5.243; 8.AN.5.247; 8.AN.7.157; 8.AN.7.158; 8.AN.7.196; 8.AN.7.223; 8.AN.7.240; 8.AN.7.244; 8.AN.7.243; 8.AN.7.247; 8.AN.15.157; 8.AN.15.158; 8.AN.15.196; 8.AN. 15.223; 8.AN. 15.240; 8.AN. 15.244; 8.AN. 15.243; 8.AN. 15.247; 8.AN.16.157; 8.AN.16.158; 8.AN.16.196; 8.AN.16.223; 8.AN.16.240; 8.AN.16.244; 8.AN.16.243; 8.AN.16.247; 8.AN.18.157; 8.AN.18.158; 8.AN.18.196; 8.AN.18.223; 8.AN.18.240; 8.AN.18.244; 8.AN.18.243; 8.AN.18.247; 8.AN.26.157; 8.AN.26.158; 8.AN.26.196; 8.AN.26.223; 8.AN.26.240; 8.AN.26.244; 8.AN.26.243; 8.AN.26.247; 8.AN.27.157; 8.AN.27.158; 8.AN.27.196; 8.AN.27.223; 8.AN.27.240; 8.AN.27.244; 8.AN.27.243; 8.AN.27.247; 8.AN.29.157; 8.AN.29.158; 8.AN.29.196; 8.AN.29.223; 8.AN.29.240; 8.AN.29.244; 8.AN.29.243; 8.AN.29.247; 8.AN.54.157; 8.AN.54.158; 8.AN.54.196; 8.AN.54.223; 8.AN.54.240; 8.AN.54.244; 8.AN.54.243; 8.AN.54.247; 8.AN.55.157; 8.AN.55.158; 8.AN.55.196; 8.AN.55.223; 8.AN.55.240; 8.AN.55.244; 8.AN.55.243; 8.AN.55.247; 8.AN.56.157; 8.AN.56.158; 8.AN.56.196; 8.AN.56.223; 8.AN.56.240; 8.AN.56.244; 8.AN.56.243; 8.AN.56.247; 8.AN.157.157; 8.AN.157.158; 8.AN.157.196; 8.AN.157.223; 8.AN.157.240; 8.AN.157.244; 8.AN. 157.243; 8.AN. 157.247; 8.AN.196.157; 8.AN.196.158; 8.AN. 196.196; 8.AN. 196.223; 8.AN. 196.240; 8.AN. 196.244; 8.AN. 196.243; 8.AN.196.247; 8.AN.223.157; 8.AN.223.158; 8.AN.223.196; 8.AN.223.223; 8.AN.223.240; 8.AN.223.244; 8.AN.223.243; 8.AN.223.247; 8.AN.240.157; 8.AN.240.158; 8.AN.240.196; 8.AN.240.223; 8.AN.240.240; 8.AN.240.244; 8.AN.240.243; 8.AN.240.247; 8.AN.244.157; 8.AN.244.158; 8.AN.244.196; 8.AN.244.223; 8.AN.244.240; 8.AN.244.244; 8.AN.244.243; 8.AN.244.247; 8.AN.247.157; 8.AN.247.158; 8.AN.247.196; 8.AN.247.223; 8.AN.247.240; 8.AN.247.244; 8.AN.247.243; 8.AN.247.247;
Prodrugs of 8.AP
8.AP.4.157; 8.AP.4.158; 8.AP.4.196; 8.AP.4.223; 8.AP.4.240; 8.AP.4.244; 8.AP.4.243; 8.AP.4.247; 8.AP.5.157; 8.AP.5.158; 8.AP.5.196; 8.AP.5.223; 8.AP.5.240; 8.AP.5.244; 8.AP.5.243; 8.AP.5.247; 8.AP.7.157; 8.AP.7.158; 8.AP.7.196; 8.AP.7.223; 8.AP.7.240; 8.AP.7.244; 8.AP.7.243; 8.AP.7.247; 8.AP. 15.157; 8.AP.15.158; 8.AP.15.196; 8.AP.15.223; 8.AP.15.240; 8.AP.15.244; 8.AP.15.243; 8.AP.15.247; 8.AP.16.157; 8.AP.16.158; 8.AP.16.196; 8.AP.16.223; 8.AP.16.240; 8.AP.16.244; 8.AP.16.243; 8.AP.16.247;
8.AP.18.157; 8.AP.18.158; 8.AP.18.196; 8.AP.18.223; 8.AP.18.240; 8.AP.18.244; 8.AP. 18.243; 8.AP. 18.247; 8.AP.26.157; 8.AP.26.158; 8.AP.26.196; 8.AF.26.223; 8.AP.26.240; 8.AP.26.244; 8.AP.26.243; 8.AP.26.247; 8.AP.27.157; 8.AP.27.158; 8.AP.27.196; 8.AP.27.223; 8.AP.27.240; 8.AP.27.244; 8.AP.27.243; 8.AP.27.247; 8.AP.29.157; 8.AP.29.158; 8.AP.29.196; 8.AP.29.223; 8.AP.29.240; 8.AP.29.244; 8.AP.29.243; 8.AP.29.247; 8.AP.54.157; 8.AP.54.158; 8.AP.54.196; 8.AP.54.223; 8.AP.54.240; 8.AP.54.244; 8.AP.54.243; 8.AP.54.247; 8.AP.55.157; 8.AP.55.158; 8.AP.55.196; 8.AP.55.223; 8.AP.55.240; 8.AP.55.244; 8.AP.55.243; 8.AP.55.247; 8.AP.56.157; 8.AP.56.158; 8.AP.56.196; 8.AP.56.223; 8.AP.56.240; 8.AP.56.244; 8.AP.56.243; 8.AP.56.247; 8.AP.157.157; 8.AP.157.158; 8.AP.157.196; 8.AP.157.223; 8.AP.157.240; 8.AP.157.244; 8.AP.157.243; 8.AP.157.247; 8.AP.196.157; 8.AP.196.158; 8.AP.196.196; 8.AP. 196.223; 8.AP. 196.240; 8.AP. 196.244; 8.AP. 196.243; 8.AP. 196.247; 8.AP.223.157; 8.AP.223.158; 8.AP.223.196; 8.AP.223.223; 8.AP.223.240; 8.AP.223.244; 8.AP.223.243; 8.AP.223.247; 8.AP.240.157; 8.AP.240.158; 8.AP.240.196; 8.AP.240.223; 8.AP.240.240; 8.AP.240.244; 8.AP.240.243; 8.AP.240.247; 8.AP.244.157; 8.AP.244.158; 8.AP.244.196; 8.AP.244.223; 8.AP.244.240; 8.AP.244.244; 8.AP.244.243; 8.AP.244.247; 8.AP.247.157; 8.AP.247.158; 8.AP.247.196; 8.AP.247.223; 8.AP.247.240; 8.AP.247.244; 8.AP.247.243; 8.AP.247.247;
Prodrugs of 8.AZ
8.AZ.4.157; 8.AZ.4.158; 8.AZ.4.196; 8.AZ.4.223; 8.AZ.4.240; 8.AZ.4.244; 8.AZ.4.243; 8.AZ.4.247; 8.AZ.5.157; 8.AZ.5.158; 8.AZ.5.196; 8.AZ.5.223; 8.AZ.5.240; 8.AZ.5.244; 8.AZ.5.243; 8.AZ.5.247; 8.AZ.7.157; 8.AZ.7.158; 8.AZ.7.196; 8.AZ.7.223; 8.AZ.7.240; 8.AZ.7.244; 8.AZ.7.243; 8.AZ.7.247; 8.AZ.15.157; 8.AZ.15.158; 8.AZ.15.196; 8.AZ. 15.223; 8.AZ. 15.240; 8.AZ. 15.244; 8.AZ. 15.243; 8.AZ. 15.247; 8.AZ.16.157; 8.AZ.16.158; 8.AZ.16.196; 8.AZ. 16.223; 8.AZ. 16.240; 8.AZ. 16.244; 8.AZ. 16.243; 8.AZ. 16.247; 8.AZ.18.157; 8.AZ.18.158; 8.AZ.18.196; 8.AZ.18.223; 8.AZ.18.240; 8.AZ.18.244; 8.AZ.18.243; 8.AZ.18.247; 8.AZ.26.157; 8.AZ.26.158; 8.AZ.26.196; 8.AZ.26.223; 8.AZ.26.240; 8.AZ.26.244; 8.AZ.26.243; 8.AZ.26.247; 8.AZ.27.157; 8.AZ.27.158; 8.AZ.27.196; 8.AZ.27.223; 8.AZ.27.240; 8.AZ.27.244; 8.AZ.27.243; 8.AZ.27.247; 8.AZ.29.157; 8.AZ.29.158; 8.AZ.29.196; 8.AZ.29.223; 8.AZ.29.240; 8.AZ.29.244; 8.AZ.29.243; 8.AZ.29.247; 8.AZ.54.157; 8.AZ.54.158; 8.AZ.54.196; 8.AZ.54.223; 8.AZ.54.240; 8.AZ.54.244; 8.AZ.54.243; 8.AZ.54.247; 8.AZ.55.157; 8.AZ.55.158; 8.AZ.55.196; 8.AZ.55.223; 8.AZ.55.240; 8.AZ.55.244; 8.AZ.55.243; 8.AZ.55.247; 8.AZ.56.157; 8.AZ.56.158; 8.AZ.56.196; 8.AZ.56.223; 8.AZ.56.240; 8.AZ.56.244; 8.AZ.56.243; 8.AZ.56.247; 8.AZ.157.157; 8.AZ.157.158; 8.AZ.157.196; 8.AZ. 157.223; 8.AZ.157.240; 8.AZ.157.244; 8.AZ.157.243; 8.AZ.157.247; 8.AZ.196.157; 8.AZ.196.158; 8.AZ.196.196; 8.AZ. 196.223; 8.AZ. 196.240; 8.AZ. 196.244; 8.AZ. 196.243; 8.AZ. 196.247; 8.AZ.223.157; 8.AZ.223.158; 8.AZ.223.196; 8.AZ.223.223; 8.AZ.223.240; 8.AZ.223.244; 8.AZ.223.243; 8.AZ.223.247; 8.AZ.240.157; 8.AZ.240.158; 8.AZ.240.196; 8.AZ.240.223; 8.AZ.240.240; 8.AZ.240.244; 8.AZ.240.243; 8.AZ.240.247; 8.AZ.244.157; 8.AZ.244.158; 8.AZ.244.196; 8.AZ.244.223; 8.AZ.244.240; 8.AZ.244.244; 8.AZ.244.243; 8.AZ.244.247; 8.AZ.247.157; 8.AZ.247.158; 8.AZ.247.196; 8.AZ.247.223; 8.AZ.247.240; 8.AZ.247.244; 8.AZ.247.243; 8.AZ.247.247;
Prodrugs of 8.BF
8.BF.4.157; 8.BF.4.158; 8.BF.4.196; 8.BF.4.223; 8.BF.4.240; 8.BF.4.244; 8.BF.4.243; 8.BF.4.247; 8.BF.5.157; 8.BF.5.158; 8.BF.5.196; 8.BF.5.223; 8.BF.5.240; 8.BF.5.244;
8.BF.5.243; 8.BF.5.247; 8.BF.7.157; 8.BF.7.158; 8.BF.7.196; 8.BF.7.223; 8.BF.7.240; 8.BF.7.244; 8.BF.7.243; 8.BF.7.247; 8.BF.15.157; 8.BF.15.158; 8.BF.15.196; 8.BF. 15.223; 8.BF. 15.240; 8.BF. 15.244; 8.BF. 15.243; 8.BF. 15.247; 8.BF.16.157; 8.BF.16.158; 8.BF.16.196; 8.BF. 16.223; 8.BF. 16.240; 8.BF. 16.244; 8.BF. 16.243; 8.BF. 16.247; 8.BF.18.157; 8.BF.18.158; 8.BF.18.196; 8.BF.18.223; 8.BF.18.240; 8.BF.18.244; 8.BF. 18.243; 8.BF. 18.247; 8.BF.26.157; 8.BF.26.158; 8.BF.26.196; 8.BF.26.223; 8.BF.26.240; 8.BF.26.244; 8.BF.26.243; 8.BF.26.247; 8.BF.27.157; 8.BF.27.158; 8.BF.27.196; 8.BF.27.223; 8.BF.27.240; 8.BF.27.244; 8.BF.27.243; 8.BF.27.247; 8.BF.29.157; 8.BF.29.158; 8.BF.29.196; 8.BF.29.223; 8.BF.29.240; 8.BF.29.244; 8.BF.29.243; 8.BF.29.247; 8.BF.54.157; 8.BF.54.158; 8.BF.54.196; 8.BF.54.223; 8.BF.54.240; 8.BF.54.244; 8.BF.54.243; 8.BF.54.247; 8.BF.55.157; 8.BF.55.158; 8.BF.55.196; 8.BF.55.223; 8.BF.55.240; 8.BF.55.244; 8.BF.55.243; 8.BF.55.247; 8.BF.56.157; 8.BF.56.158; 8.BF.56.196; 8.BF.56.223; 8.BF.56.240; 8.BF.56.244; 8.BF.56.243; 8.BF.56.247; 8.BF.157.157; 8.BF.157.158; 8.BF.157.196; 8.BF.157.223; 8.BF. 157.240; 8.BF. 157.244; 8.BF. 157.243; 8.BF. 157.247; 8.BF.196.157; 8.BF.196.158; 8.BF.196.196; 8.BF. 196.223; 8.BF. 196.240; 8.BF. 196.244; 8.BF. 196.243; 8.BF. 196.247; 8.BF.223.157; 8.BF.223.158; 8.BF.223.196; 8.BF.223.223; 8.BF.223.240; 8.BF.223.244; 8.BF.223.243; 8.BF.223.247; 8.BF.240.157; 8.BF.240.158; 8.BF.240.196; 8.BF.240.223; 8.BF.240.240; 8.BF.240.244; 8.BF.240.243; 8.BF.240.247; 8.BF.244.157; 8.BF.244.158; 8.BF.244.196; 8.BF.244.223; 8.BF.244.240; 8.BF.244.244; 8.BF.244.243; 8.BF.244.247; 8.BF.247.157; 8.BF.247.158; 8.BF.247.196; 8.BF.247.223; 8.BF.247.240; 8.BF.247.244; 8.BF.247.243; 8.BF.247.247;
Prodrugs of 8.CI
8.CI.4.157; 8.CI.4.158; 8.CI.4.196; 8.CI.4.223; 8.CI.4.240; 8.CI.4.244; 8.CI.4.243; 8.CI.4.247; 8.CI.5.157; 8.CI.5.158; 8.CI.5.196; 8.CI.5.223; 8.CI.5.240; 8.CI.5.244; 8.CI.5.243; 8.a.5.247; 8.CI.7.157; 8.CI.7.158; 8.CL7.196; 8.CL7.223; 8.CI.7.240; 8.CI.7.244; 8.CI.7.243; 8.CL7.247; 8.a.l5.157; 8.CL15.158; 8.CL15.196; 8.CL15.223; 8.CI.15.240; 8.CI.15.244; 8.CI.15.243; 8.CL15.247; 8.CL16.157; 8.CI.16.158; 8.CL16.196; 8.CI.16.223; 8.CI.16.240; 8.CI.16.244; 8:CI.16.243; 8.CL16.247; 8.CL18.157; 8.CI.18.158; 8.CI.18.196; 8.CI.18.223; 8.CI.18.240; 8.CI.18.244; 8.CL18.243; 8.CI.18.247; 8.CL26.157; 8.CI.26.158; 8.CI.26.196; 8.CL26.223; 8.CL26.240; 8.CI.26.244; 8.CI.26.243; 8.CL26.247; 8.CI.27.157; 8.CI.27.158; 8.CI.27.196; 8.CI.27.223; 8.CI.27.240; 8.CI.27.244; 8.CI.27.243; 8.CI.27.247; 8.CI.29.157; 8.CI.29.158; 8.CI.29.196; 8.CI.29.223; 8.CI.29.240; 8.CI.29.244; 8.CI.29.243; 8.CI.29.247; 8.CI.54.157; 8.CI.54.158; 8.CI.54.196; 8.CI.54.223; 8.CI.54.240; 8.CI.54.244; 8.CI.54.243; 8.CI.54.247; 8.CI.55.157; 8.CI.55.158; 8.CI.55.196; 8.CI.55.223; 8.CI.55.240; 8.CI.55.244; 8.CI.55.243; 8.CI.55.247; 8.CI.56.157; 8.CI.56.158; 8.CI.56.196; 8.CI.56.223; 8.CI.56.240; 8.CI.56.244; 8.CI.56.243; 8.CI.56.247; 8.CI.157.157; 8.CI.157.158; 8.CI.157.196; 8.CI. 157.223; 8.CI. 157.240; 8.CI. 157.244; 8.CI. 157.243; 8.CI. 157.247; 8.CI.196.157; 8.CI.196.158; 8.CI.196.196; 8.CI. 196.223; 8.CI. 196.240; 8.CI. 196.244; 8.CI. 196.243; 8.CI. 196.247; 8.CI.223.157; 8.CI.223.158; 8.a.223.196; 8.CI.223.223; 8.CI.223.240; 8.CI.223.244; 8.CI.223.243; 8.CI.223.247; 8.CI.240.157; 8.CI.240.158; S.CI.240.196; 8.CI.240.223; 8.CI.240.240; 8.CI.240.244; 8.CI.240.243; 8.CI.240.247; 8.CI.244.157; 8.CI.244.158; 8.CI.244.196; 8.CI.244.223; 8.CI.244.240; 8.CI.244.244; 8.CI.244.243; 8.CI.244.247; 8.CI.247.157; 8.CI.247.158; 8.CI.247.196; 8.CI.247.223; 8.CI.247.240; 8.CI.247.244; 8.CI.247.243; 8.CI.247.247;
Prodrugs of 8.CO
8.C0.4.157; 8.CO.4.158; 8.CO.4.196; 8.CO.4.223; 8.CO.4.240; 8.CO.4.244; 8.CO.4.243; 8.CO.4.247; 8.CO.5.157; 8.CO.5.158; 8.CO.5.196; 8.CO.5.223; 8.CO.5.240; 8.CO.5.244; 8.C0.5.243; 8.CO.5.247; 8.CO.7.157; 8.CO.7.158; 8.CO.7.196; 8.CO.7.223; 8.CO.7.240; 8.CO.7.244; 8.CO.7.243; 8.CO.7.247; 8.CO.15.157; 8.CO.15.158; 8.CO.15.L96; 8.CO.15.223; 8.CO.15.240; 8.CO.15.244; 8.CO.15.243; 8.CO.15.247; 8.CO.16.157; 8.CO.16.158; 8.CO.16.196; 8.CO.16.223; 8.CO.16.240; 8.CO.16.244; 8.C0.16.243; 8.CO.16.247; 8.CO.18.157; 8.CO.18.158; 8.CO.18.196; 8.CO.18.223; 8.CO.18.240; 8.CO.18.244; 8.CO.18.243; 8.CO.18.247; 8.CO.26.157; 8.CO.26.158; 8.CO.26.196; 8.CO.26.223; 8.CO.26.240; 8.CO.26.244; 8.CO.26.243; 8.CO.26.247; 8.CO.27.157; 8.CO.27.158; 8.CO.27.196; 8.CO.27.223; 8.CO.27.240; 8.CO.27.244; 8.CO.27.243; 8.CO.27.247; 8.CO.29.157; 8.CO.29.158; 8.CO.29.196; 8.CO.29.223; 8.CO.29.240; 8.CO.29.244; 8.CO.29.243; 8.CO.29.247; 8.CO.54.157; 8.CO.54.158; 8.CO.54.196; 8.CO.54.223; 8.CO.54.240; 8.CO.54.244; 8.CO.54.243; 8.CO.54.247; 8.CO.55.157; 8.CO.55.158; 8.CO.55.196; 8.CO.55.223; 8.CO.55.240; 8.CO.55.244; 8.CO.55.243; 8.CO.55.247; 8.CO.56.157; 8.CO.56.158; 8.CO.56.196; 8.CO.56.223; 8.CO.56.240; 8.CO.56.244; 8.CO.56.243; 8.CO.56.247; 8.CO.157.157; 8.CO.157.158; 8.CO.157.196; 8.CO.157.223; 8.CO.157.240; 8.CO.157.244; 8.CO.157.243; 8.C0.157.247; 8.CO.196.157; 8.CO.196.158; 8.CO.196.196; 8.CO. 196.223; 8.CO. 196.240; 8.CO. 196.244; 8.CO. 196.243; 8.CO.196.247; 8.CO.223.157; 8.CO.223.158; 8.CO.223:i96; 8.CO.223.223; 8.CO.223.240; 8.CO.223.244; 8.CO.223.243; 8.CO.223.247; 8.CO.240.157; 8.C0.240.158; 8.CO.240.196; 8.CO.240.223; 8.CO.240.240; 8.CO.240.244; 8.CO.240.243; 8.C0.240.247; 8.CO.244.157; 8.CO.244.158; 8.CO.244.196; 8.CO.244.223; 8.CO.244.240; 8.C0.244.244; 8.CO.244.243; 8.CO.244.247; 8.CO.247.157; 8.CO.247.158; 8.CO.247.196; 8.CO.247.223; 8.CO.247.240; 8.CO.247.244; 8.CO.247.243; 8.CO.247.247;
Prodrugs of 9.AH
9.AH.4.157; 9.AH.4.158; 9.AH.4.196; 9.AH.4.223; 9.AH.4.240; 9.AH.4.244; 9.AH.4.243; 9.AH.4.247; 9.AH.5.157; 9.AH.5.158; 9.AH.5.196; 9.AH.5.223; 9.AH.5.240; 9.AH.5.244; 9.AH.5.243; 9.AH.5.247; 9.AH.7.157; 9.AH.7.158; 9.AH.7.196; 9.AH.7.223; 9.AH.7.240; 9.AH.7.244; 9.AH.7.243; 9.AH.7.247; 9.AH.15.157; 9.AH.15.158; 9.AH.15.196; 9.AH.15.223; 9.AH.15.240; 9.AH.15.244; 9.AH.15.243; 9.AH.15.247; 9.AH.16.157; 9.AH.16.158; 9.AH.16.196; 9.AH.16.223; 9.AH.16.240; 9.AH.16.244; 9.AH.16.243; 9.AH.16.247; 9.AH.18.157; 9.AH.18.158; 9.AH.18.196; 9.AH.18.223; 9.AH.18.240; 9.AH. 18.244; 9.AH. 18.243; 9.AH. 18.247; 9.AH.26.157; 9.AH.26.158; 9.AH.26.196; 9.AH.26.223; 9.AH.26.240; 9.AH.26.244; 9.AH.26.243; 9.AH.26.247; 9.AH.27.157; 9.AH.27.158; 9.AH.27.196; 9.AH.27.223; 9.AH.27.240; 9.AH.27.244; 9.AH.27.243; 9.AH.27.247; 9.AH.29.157; 9.AH.29.158; 9.AH.29.196; 9.AH.29.223; 9.AH.29.240; 9.AH.29.244; 9.AH.29.243; 9.AH.29.247; 9.AH.54.157; 9.AH.54.158; 9.AH.54.196; 9.AH.54.223; 9.AH.54.240; 9.AH.54.244; 9.AH.54.243; 9.AH.54.247; 9.AH.55.157; 9.AH.55.158; 9.AH.55.196; 9.AH.55.223; 9.AH.55.240; 9.AH.55.244; 9.AH.55.243; 9.AH.55.247; 9.AH.56.157; 9.AH.56.158; 9.AH.56.196; 9.AH.56.223; 9.AH.56.240; 9.AH.56.244; 9.AH.56.243; 9.AH.56.247; 9.AH.157.157; 9.AH.157.158; 9.AH.157.196; 9.AH. 157.223; 9.AH. 157.240; 9.AH. 157.244; 9.AH. 157.243; 9.AH. 157.247; 9.AH.196.157; 9.AH.196.158; 9.AH.196.196; 9.AH.196.223; 9.AH.196.240; 9.AH.196.244; 9.AH.196.243; 9.AH.196.247; 9.AH.223.157; 9.AH.223.158; 9.AH.223.196; 9.AH.223.223; 9.AH.223.240; 9.AH.223.244; 9.AH.223.243; 9.AH.223.247; 9.AH.240.157; 9.AH.240.158; 9.AH.240.196; 9.AH.240.223; 9.AH.240.240; 9.AH.240.244; 9.AH.240.243; 9.AH.240.247; 9.AH.244.157; 9.AH.244.158; 9.AH.244.196; 9.AH.244.223; 9.AH.244.240; 9.AH.244.244; 9.AH.244.243;
9.AH.244.247; 9.AH.247.157; 9.AH.247.158; 9.AH.247.196; 9.AH.247.223; 9.AH.247.240; 9.AH.247.244; 9.AH.247.243; 9.AH.247.247;
Prodrugs of 9.AT
9.AJ.4.157; 9.AJ.4.158; 9.AJ.4.196; 9.AJ.4.223; 9.AJ.4.240; 9.AJ.4.244; 9.AJ.4.243; 9.AJ.4.247; 9.AJ.5.157; 9.AJ.5.158; 9.AJ.5.196; 9.AJ.5.223; 9.AJ.5.240; 9.AJ.5.244; 9.AJ.5.243; 9.AJ.5.247; 9.AJ.7.157; 9.AJ.7.158; 9.AJ.7.196; 9.AJ.7.223; 9.AJ.7.240; 9.AJ.7.244; 9.AJ.7.243; 9.AJ.7.247; 9.AJ.15.157; 9.AJ.15.158; 9.AJ.15.196; 9.AJ.15.223; . 9.AJ. 15.240; 9.AJ. 15.244; 9.AJ. 15.243; 9.AJ. 15.247; 9.AJ.16.157; 9.AJ.16.158; 9.AJ.16.196; 9.AJ.16.223; 9.AJ.16.240; 9.AJ.16.244; 9.AJ.16.243; 9.AJ.16.247; 9.AJ.18.157; 9.AJ.18.158; 9.AJ.18.196; 9.AJ.18.223; 9.AJ.18.240; 9.AJ.18.244; 9.AJ.18.243; 9.AJ.18.247; 9.AJ.26.157; 9.AJ.26.158; 9.AJ.26.196; 9.AJ.26.223; 9.AJ.26.240; 9.AJ.26.244; 9.AJ.26.243; 9.AJ.26.247; 9.AJ.27.157; 9.AJ.27.158; 9.AJ.27.196; 9.AJ.27.223; 9.AJ.27.240; 9.AJ.27.244; 9.AJ.27.243; 9.AJ.27.247; 9.AJ.29.157; 9.AJ.29.158; 9.AJ.29.196; 9.AJ.29.223; 9.AJ.29.240; 9.AJ.29.244; 9.AJ.29.243; 9.AJ.29.247; 9.AJ.54.157; 9.AJ.54.158; 9.AJ.54.196; 9.AJ.54.223; 9.AJ.54.240; 9.AJ.54.244; 9.AJ.54.243; 9.AJ.54.247; 9.AJ.55.157; 9.AJ.55.158; 9.AJ.55.196; 9.AJ.55.223; 9.AJ.55.240; 9.AJ.55.244; 9..AJ.55.243; 9.AJ.55.247; 9.AJ.56.157; 9.AJ.56.158; 9.AJ.56.196; 9.AJ.56.223; 9.AJ.56.240; 9.AJ.56.244; 9.AJ.56.243; 9.AJ.56.247; 9.AJ.157.157; 9.AJ.157.158; 9.AJ.157.196; 9.AJ.157.223; 9.AJ.157.240; 9.AJ.157.244; 9.AJ.157.243; 9.AJ. 157.247; 9.AJ. 196.157; 9.AJ.196.158; 9.AJ.196.196; 9.AJ. 196.223; 9.AJ. 196.240; 9.AJ.196.244; 9.AJ.196.243; 9.AJ.196.247; 9.AJ.223.157; 9.AJ.223.158; 9.AJ.223.196; 9.AJ.223.223; 9.AJ.223.240; 9.AJ.223.244; 9.AJ.223.243; 9.AJ.223.247; 9.AJ.240.157; 9.AJ.240.158; 9.AJ.240.196; 9.AJ.240.223; 9.AJ.240.240; 9.AJ.240.244; 9.AJ.240.243; 9.AJ.240.247; 9.AJ.244.157; 9.AJ.244.158; 9.AJ.244.196; 9.AJ.244.223; 9.AJ.244.240; 9.AJ.244.244; 9.AJ.244.243; 9.AJ.244.247; 9.AJ.247.157; 9.AJ.247.158; 9.AJ.247.196; 9.AJ.247.223; 9.AJ.247.240; 9.AJ.247.244; 9.AJ.247.243; 9.AJ.247.247;
Prodrugs of 9.AN
9.AN.4.157; 9.ANA 158; 9.AN.4.196; 9.AN.4.223; 9.AN.4.240; 9.AN.4.244; 9.AN.4.243; 9.AN.4.247; 9.AN.5.157; 9.AN.5.158; 9.AN.5.196; 9.AN.5.223; 9.AN.5.240; 9.AN.5.244; 9.AN.5.243; 9.AN.5.247; 9.AN.7.157; 9.AN.7.158; 9.AN.7.196; 9.AN.7.223; 9.AN.7.240; 9.AN.7.244; 9.AN.7.243; 9.AN.7.247; 9.AN.15.157; 9.AN. 15.158; 9.AN. 15.196; 9.AN. 15.223; 9.AN. 15.240; 9.AN. 15.244; 9.AN. 15.243; 9.AN. 15.247; 9.AN.16.157; 9.AN.16.158; 9.AN.16.196; 9.AN.16.223; 9.AN.16.240; 9.AN.16.244; 9.AN.16.243; 9.AN. 16.247; 9.AN.18.157; 9.AN.18.158; 9.AN.18.196; 9.AN.18.223; 9.AN.18.240; 9.AN. 18.244; 9.AN.18.243; 9.AN.18.247; 9.AN.26.157; 9.AN.26.158; 9.AN.26.196; 9.AN.26.223; 9.AN.26.240; 9.AN.26.244; 9.AN.26.243; 9.AN.26.247; 9.AN.27.157; 9.AN.27.158; 9.AN.27.196; 9.AN.27.223; 9.AN.27.240; 9.AN.27.244; 9.AN.27.243; 9.AN.27.247; 9.AN.29.157; 9.AN.29.158; 9.AN.29.196; 9.AN.29.223; 9.AN.29.240; 9.AN.29.244; 9.AN.29.243; 9.AN.29.247; 9.AN.54.157; 9.AN.54.158; 9.AN.54.196; 9.AN.54.223; 9.AN.54.240; 9.AN.54.244; 9.AN.54.243; 9.AN.54.247; 9.AN.55.157; 9.AN.55.158; 9.AN.55.196; 9.AN.55.223; 9.AN.55.240; 9.AN.55.244; 9.AN.55.243; 9.AN.55.247; 9.AN.56.157; 9.AN.56.158; 9.AN.56.196; 9.AN.56.223; 9.AN.56.240; 9.AN.56.244; 9.AN.56.243; 9.AN.56.247; 9.AN.157.157; 9.AN.157.158; 9.AN.157.196; 9.AN. 157.223; 9.AN. 157.240; 9.AN. 157.244; 9.AN. 157.243; 9.AN. 157.247; 9.AN. 196.157; 9.AN.196.158; 9.AN.196.196; 9.AN.196.223; 9.AN.196.240; 9.AN.196.244; 9.AN.196.243; 9.AN.196.247; 9.AN.223.157; 9.AN.223.158; 9.AN.223.196; 9.AN.223.223:9.AN.223.240; 9.AN.223.244; 9.AN.223.243: 9.AN.223.247; 9.AN.240.157; 9.AN.240.158; 9.AN.240.196;
9.AN.240.223; 9.AN.240.240; 9.AN.240.244; 9.AN.240243; 9.AN.240.247; 9.AN.244.157; 9 AN.244.158; 9.AN.244.196; 9.AN.244.223; 9.AN.244.240; 9.AN.244.244; 9.AN.244.243; 9.AN.244.247; 9.AN.247.157; 9.AN.247.158; 9.AN.247.196; 9.AN.247.223; 9.AN.247.240; 9.AN.247.244; 9.AN.247.243; 9.AN.247.247;
Prodrugs of 9.AF
9.AP.4.157: 9.AP.4.158; 9.AP.4.196; 9.AP.4.223; 9.AP.4.240; 9.AP.4.244; 9.AP.4.243; 9.AP.4.247; 9.AP.5.157; 9.AP.5.158; 9.AP.5.196; 9.AP.5.223; 9.AP.5.240; 9.AP.5.244; 9.AP.5.243; 9.AP.5.247; 9.AP.7.157; 9.AP.7.158; 9.AP.7.196; 9.AP.7.223; 9.AP.7.240; 9.AP.7.244; 9.AP.7.243; 9.AP.7.247; 9.AP.15.157; 9.AP.15.158; 9.AP.15.196; 9.AP.15.223; 9.AP. 15.240; 9.AP. 15.244; 9.AP. 15.243; 9.AP. 15.247; 9.AP.16.157; 9.AP.16.158; 9.AP.16.196; 9.AP.16.223; 9.AP.16.240; 9.AP.16.244; 9.AP.16.243; 9.AP.16.247; 9.AP.18.157; 9.AP.18.158; 9.AP.18.196; 9.AP.18.223; 9.AP.18.240; 9.AP.18.244; 9.AP.18.243; 9.AP.18.247; 9.AP.26.157; 9.AP.26.158; 9.AP.26.196; 9.AP.26.223; 9.AP.26.240; 9.AP.26.244; 9.AP.26.243; 9.AP.26.247; 9.AP.27.157; 9.AP.27.158; 9.AP.27.196; 9.AP.27.223; 9.AP.27.240; 9.AP.27.244; 9.AP.27.243; 9.AP.27.247; 9.AP.29.157; 9.AP.29.158; 9.AP.29.196; 9.AP.29.223; 9.AP.29.240; 9.AP.29.244; 9.AP.29.243; 9.AP.29.247; 9.AP.54.157; 9.AP.54.158; 9.AP.54.196; 9.AP.54.223; 9.AP.54.240; 9.AP.54.244; 9.AP.54.243; 9.AP.54.247; 9.AP.55.157; 9.AP.55.158; 9.AP.55.196; 9.AP.55.223; 9.AP.55.240; 9.AP.55.244; 9.AP.55.243; 9.AP.55.247; 9.AP.56.157; 9.AP.56.158; 9.AP.56.196; 9.AP.56.223; 9.AP.56.240; 9.AP.56.244; 9.AP.56.243; 9.AP.56.247; 9.AP.157.157; 9.AP.157.158; 9.AP.157.196; 9.AP.157.223; 9.AP.157.240; 9.AP.157.244; 9.AP.157.243; 9.AP.157.247; 9.AP.196.157; 9.AP.196.158; 9.AP.196.196; 9.AP. 196.223; 9.AP. 196.240; 9.AP. 196.244; 9.AP. 196.243; 9.AP. 196.247; 9.AP.223.157; 9.AP.223.158; 9.AP.223.196; 9.AP.223.223; 9.AP.223.240; 9.AP.223.244; 9.AP.223.243; 9.AP.223.247; 9.AP.240.157; 9.AP.240.158; 9.AP.240.196; 9.AP.240.223; 9.AP.240.240; 9.AP.240.244; 9.AP.240.243; 9.AP.240.247; 9.AP.244.157; 9.AP.244.158; 9.AP.244.196; 9.AP.244.223; 9.AP.244.240; 9.AP.244.244; 9.AP.244.243; 9.AP.244.247; 9.AP.247.157; 9.AP.247.158; 9.AP.247.196; 9.AP.247.223; 9.AP.247.240; 9.AP.247.244; 9.AP.247.243; 9.AP.247.247;
Prodrugs of 9. AZ
9.AZ.4.157; 9.AZ.4.158; 9.AZ.4.196; 9.AZ.4.223; 9.AZ.4.240; 9.AZ.4.244; 9.AZ.4.243; 9.AZ.4.247; 9.AZ.5.157; 9.AZ.5.158; 9.AZ.5.196; 9.AZ.5.223; 9.AZ.5.240; 9.AZ.5.244; 9.AZ.5.243; 9.AZ.5.247; 9.AZ.7.157; 9.AZ.7.158; 9.AZ.7.196; 9.AZ.7.223; 9.AZ.7.240; 9.AZ.7.244; 9.AZ.7.243; 9.AZ.7.247; 9.AZ. 15.157; 9.AZ.15.158; 9.AZ.15.196; 9.AZ. 15.223; 9.AZ.15.240; 9.AZ.15.244; 9.AZ.15.243; 9.AZ.15.247; 9.AZ.16.157; 9.AZ.16.158; 9.AZ. 16.196; 9.AZ. 16.223; 9.AZ. 16.240; 9.AZ. 16.244; 9.AZ. 16.243; 9.AZ. 16.247; 9.AZ.18.157; 9.AZ.18.158; 9.AZ.18.196; 9.AZ.18.223; 9.AZ.18.240; 9.AZ.18.244; 9.AZ. 18.243; 9.AZ. 18.247; 9.AZ.26.157; 9.AZ.26.158; 9.AZ.26.196; 9.AZ.26.223; 9.AZ.26.240; 9.AZ.26.244; 9.AZ.26.243; 9.AZ.26.247; 9.AZ.27.157; 9.AZ.27.158; 9.AZ.27.196; 9.AZ.27.223; 9.AZ.27.240; 9.AZ.27.244; 9.AZ.27.243; 9.AZ.27.247; 9.AZ.29.157; 9.AZ.29.158; 9.AZ.29.196; 9.AZ.29.223; 9.AZ.29.240; 9.AZ.29.244; 9.AZ.29.243; 9.AZ.29.247; 9.AZ.54.157; 9.AZ.54.158; 9.AZ.54.196; 9.AZ.54.223; 9.AZ.54.240; 9.AZ.54.244; 9.AZ.54.243; 9.AZ.54.247; 9.AZ.55.157; 9.AZ.55.158; 9.AZ.55.196; 9.AZ.55.223; 9.AZ.55.240; 9.AZ.55.244; 9.AZ.55.243; 9.AZ.55.247; 9.AZ.56.157; 9.AZ.56.158; 9.AZ.56.196; 9.AZ.56.223; 9.AZ.56.240; 9.AZ.56.244; 9.AZ.56.243; 9.AZ.56.247; 9.AZ. 157.157; 9.AZ. 157.158; 9.AZ. 157.196; 9.AZ.157.223;
9.AZ.157.240; 9.AZ.157.244; 9.AZ.157.243; 9.AZ.157.247; 9.AZ.196.157; 9.AZ.196.158; . 9.AZ.196.196; 9.AZ. 196.223; 9.AZ. 196.240; 9.AZ. 196.244; 9.AZ. 196.243; 9.AZ. 196.247; 9.AZ.223.157; 9.AZ.223.158; 9.AZ.223.196; 9.AZ.223.223; 9.AZ.223.240; 9.AZ.223.244; 9.AZ.223.243; 9.AZ.223.247; 9.AZ.240.157; 9.AZ.240.158; 9.AZ.240.196; 9.AZ.240.223; 9.AZ.240.240; 9.AZ.240.244; 9.AZ.240.243; 9.AZ.240.247; 9.AZ.244.157; 9.AZ.244.158; 9.AZ.244.196; 9.AZ.244.223; 9.AZ.244.240; 9.AZ.244.244; 9.AZ.244.243; 9.AZ.244.247; 9.AZ.247.157; 9.AZ.247.158; 9.AZ.247.196; 9.AZ.247.223; 9.AZ.247.240; 9.AZ.247.244; 9.AZ.247.243; 9.AZ.247.247;
Prodrugs of 9.BF
9.BF.4.157; 9.BF.4.158; 9.BF.4.196; 9.BF.4.223; 9.BF.4.240; 9.BF.4.244; 9.BF.4.243; 9.BF.4.247; 9.BF.5.157; 9.BF.5.158; 9.BF.5.196; 9.BF.5.223; 9.BF.5.240; 9.BF.5.244; 9.BF.5.243; 9.BF.5.247; 9.BF.7.157; 9.BF.7.158; 9.BF.7.196; 9.BF.7.223; 9.BF.7.240; 9.BF.7.244; 9.BF.7.243; 9.BF.7.247; 9.BF.15.157; 9.BF.15.158; 9.BF.15.196; 9.BF. 15.223; 9.BF. 15.240; 9.BF. 15.244; 9.BF. 15.243; 9.BF. 15.247; 9.BF.16.157; 9.BF.16.158; 9.BF.16.196; 9.BF.16.223; 9.BF.16.240; 9.BF.16.244; 9.BF.16.243; 9.BF.16.247; 9.BF.18.157; 9.BF.18.158; 9.BF.18.196; 9.BF.18.223; 9.BF.18.240; 9.BF.18.244; 9.BF.18.243; 9.BF.18.247; 9.BF.26.157; 9.BF.26.158; 9.BF.26.196; 9.BF.26.223; 9.BF.26.240; 9.BF.26.244; 9.BF.26.243; 9.BF.26.247; 9.BF.27.157; 9.BF.27.158; 9.BF.27.196; 9.BF.27.223; 9.BF.27.240; 9.BF.27.244; 9JBF.27.243; 9.BF.27.247; 9.BF.29.157; 9.BF.29.158; 9.BF.29.196; 9.BF.29.223; 9.BF.29.240; 9.BF.29.244; 9.BF.29.243; 9.BF.29.247; 9.BF.54.157; 9.BF.54.158; 9.BF.54.196; 9.BF.54.223; 9.BF.54.240; 9.BF.54.244; 9.BF.54.243; 9.BF.54.247; 9.BF.55.157; 9JBF.55.158; 9.BF.55.196; 9.BF.55.223; 9.BF.55.240; 9.BF.55.244; 9.BF.55.243; 9.BF.55.247; 9.BF.56.157; 9.BF.56.158; 9.BF.56.196; 9.BF.56.223; 9.BF.56.240; 9.BF.56.244; 9.BF.56.243; 9.BF.56.247; 9.BF.157.157; 9.BF.157.158; 9.BF.157.196; 9.BF.157.223; 9.BF.157.240; 9.BF.157.244; 9.BF.157.243; 9.BF.157.247; 9.BF.196.157; 9.BF.196.158; 9.BF.196.196; 9.BF. 196.223; 9.BF. 196.240; 9.BF. 196.244; 9.BF. 196.243; 9.BF. 196.247; 9.BF.223.157; 9.BF.223.158; 9.BF.223.196; 9.BF.223.223; 9.BF.223.240; 9.BF.223.244; 9.BF.223.243; 9.BF.223.247; 9.BF.240.157; 9.BF.240.158; 9.BF.240.196; 9.BF.240.223; 9.BF.240.240; 9.BF.240.244; 9.BF.240.243; 9.BF.240.247; 9.BF.244.157; 9.BF.244.158; 9.BF.244.196; 9.BF.244.223; 9.BF.244.240; 9.BF.244.244; 9.BF.244.243; 9.BF.244.247; 9.BF.247.157; 9.BF.247.158; 9.BF.247.196; 9.BF.247.223; 9.BF.247.240; 9.BF.247.244; 9.BF.247.243; 9.BF.247.247;
Prodrugs of 9.CI
9.CI.4.157; 9.CI.4.158; 9.CI.4.196; 9.CI.4.223; 9.CI.4.240; 9.CI.4.244; 9.CI.4.243; 9.CI.4.247; 9.CI.5.157; 9.CL5.158; 9.CI.5.196; 9.CI.5.223; 9.CI.5.240; 9.CI.5.244; 9.CI.5.243; 9.CI.5.247; 9.CI.7.157; 9.CI.7.158; 9.CI.7.196; 9.CI.7.223; 9.CI.7.240; 9.CI.7.244; 9.CI.7.243; 9.CI.7.247; 9.CI.15.157; 9.CI.15.158; 9.CI.15.196; 9.CI. 15.223; 9.CI.15.240; 9.CI.15.244; 9.CI.15.243; 9.CI.15.247; 9.CI.16.157; 9.CI.16.158; 9.CI.16.196; 9.CI.16.223; 9.CL16.240; 9.CI.16.244; 9.CI.16.243; 9.CI.16.247; 9.CI.18.157; 9.CI.18.158; 9.CI.18.196; 9.CI.18.223; 9.CI.18.240; 9.CI.18.244; 9.CI.18.243; 9.CI.18.247; 9.CI.26.157; 9.CI.26.158; 9.CI.26.196; 9.CI.26.223; 9.CI.26.240; 9.CI.26.244; 9.CI.26.243; 9.CI.26.247; 9.CI.27.157; 9.CI.27.158; 9.CI.27.196; 9.CI.27.223; 9.CI.27.240; 9.CI.27.244; 9.CI.27.243; 9.CI.27.247; 9.CI.29.157; 9.CI.29.158; 9.CI.29.196; 9.CI.29.223; 9.CI.29.240; 9.CI.29.244; 9.CI.29.243; 9.CL29.247; 9.CI.54.157; 9.CI.54.158; 9.CI.54.196; 9.CI.54.223; 9.CI.54.240; 9.CI.54.244; 9.CL54.243; 9.CI.54.247; 9.CI.55.157; 9.CI.55.158; 9.CI.55.196; 9.CI.55.223;
9.CI 55.240; 9.CI.55.244; 9.CI.55.243; 9.CI.55.247; 9.CI.56.157; 9.CI.56.158; 9.CI.56.196; 9.CI.56.223; 9.CI.56.240; 9.CI.56.244; 9.CI.56.243; 9.CI.56.247; 9.CI.157.157; 9.CI.157.158; 9.CI.157.196; 9.CI.157.223; 9.CI.157.240; 9.CI.157.244; 9.CI.157.243; 9.CI.157.247; 9.CI.196.157; 9.CI.196.158; 9.CI.196.196; 9.CI.196.223; 9.CI.196.240; 9.CI.196.244; 9.CI.196.243; 9.CI.196.247; 9.CI.223.157; 9.CI.223.158; 9.CI.223.196; 9.CI.223.223; 9.CI.223.240; 9.CI.223.244; 9.CI.223.243; 9.CI.223.247; 9.CI.240.157; 9.CI.240.158; 9.CI.240.196; 9.CI.240.223; 9.CI.240.240; 9.CI.240.244; 9.CI.240.243; 9.CI.240.247; 9.CI.244.157; 9.CI.244.158; 9.CI.244.196; 9.CI.244.223; 9.CI.244.240;; 9.CI.244.244; 9.CI.244.243; 9.CI.244.247; 9.CI.247.157; 9.CI.247.158; 9.CI.247.196; 9.CI.247.223; 9.CI.247.240; 9.CI.247.244; 9.CI.247.243; 9.CI.247.247;
Prodrugs of 9.CO
9.CO.4.157; 9.CO.4.158; 9.C0.4.196; 9.CO.4.223; 9.C0.4.240; 9.CO.4.244; 9.CO.4.243; 9.CO.4.247; 9.CO.5.157; 9.CO.5.158; 9.CO.5.196; 9.CO.5.223; 9.CO.5.240; 9.CO.5.244; 9.CO.5.243; 9.CO.5.247; 9.CO.7.157; 9.CO.7.158; 9.CO.7.196; 9.CO.7.223; 9.CO.7.240; 9.CO.7.244; 9.CO.7.243; 9.CO.7.247; 9.CO.15.157; 9.CO.15.158; 9.CO.15.196; 9.CO.15.223; 9.CO.15.240; 9.CO.15.244; 9.CO.15.243; 9.CO.15.247; 9.CO.16.157; 9.CO.16.158; 9.CO.16.196; 9.CO.16.223; 9.CO.16.240; 9.CO.16.244; 9.CO.16.243; 9.CO.16.247; 9.CO.18.157; 9.CO.18.158; 9.CO.18.196; 9.CO.18.223; 9.CO.18.240; 9.CO.18.244; 9.CO.18.243; 9.CO.18.247; 9.CO.26.157; 9.CO.26.158; 9.CO.26.196; 9.CO.26.223; 9.CO.26.240; 9.CO.26.144; 9.CO.26.243; 9.CO.26.247; 9.CO.27.157; 9.CO.27.158; 9.CO.27.196; 9.CO.27.223; 9.CO.27.240; 9.CO.27.244; 9.CO.27.243; 9.CO.27.247; 9.CO.29.157; 9.CO.29.158; 9.CO.29.196; 9.CO.29.223; 9.CO.29.240; 9.CO.29.244; 9.CO.29.243; 9.CO.29.247; 9.CO.54.157; 9.CO.54.158; 9.CO.54.196; 9.CO.54.223; 9.CO.54.240; 9.CO.54.244; 9.CO.54.243; 9.CO.54.247; 9.CO.55.157; 9.CO.55.158; 9.CO.55.196; 9.CO.55.223; 9.CO.55.240; 9.CO.55.244; 9.CO.55.243; 9.CO.55.247; 9.CO.56.157; 9.CO.56.158; 9.CO.56.196; 9.CO.56.223; 9.CO.56.240; 9.CO.56.244; 9.CO.56.243; 9.CO.56.247; 9.CO.157.157; 9.CO.157.158; 9.CO.157.196; 9.CO. 157.223; 9.CO. 157.240; 9.CO. 157.244; 9.CO. 157.243; 9.CO. 157.247; 9.CO.196.157; 9.CO.196.158; 9.CO.196.196; 9.CO. 196.223; 9.CO. 196.240; 9.CO. 196.244; 9.CO. 196.243; 9.CO. 196.247; 9.CO.223.157; 9.CO.223.158; 9.CO.223.196; 9.CO.223.223; 9.CO.223.240; 9.CO.223.244; 9.CO.223.243; 9.CO.223.247; 9.CO.240.157; 9.C0.240.158; 9.CO.240.196; 9.CO.240.223; 9.CO.240.240; 9.CO.240.244; 9.CO.240.243; 9.CO.240.247; 9.CO.244.157; 9.CO.244.158; 9.CO.244.196; 9.CO.244.223; 9.CO.244.240; 9.C0.244.244; 9.CO.244.243; 9.CO.244.247; 9.CO.247.157; 9.CO.247.158; 9.CO.247.196; 9.CO.247.223; 9.CO.247.240; 9.CO.247.244; 9.CO.247.243; 9.CO.247.247;
Prodrugs of 10.AH
10.AH.4.157; 10.AH.4.158; 10.AH.4.196; 10.AH.4.223; 10.AH.4.240; 10.AH.4.244; 10.AH.4.243; 10.AH.4.247; 10.AH.5.157; 10.AH.5.158; 10.AH.5.196; 10.AH.5.223; 10.AH.5.240; 10.AH.5.244; 10.AH.5.243; 10.AH.5.247; 10.AH.7.157; 10.AH.7.158; 10.AH.7.196; 10.AH.7.223; 10.AH.7.240; 10.AH.7.244; 10.AH.7.243; 10.AH.7.247; 10.AH.15.157; 10.AH.15.158; 10.AH.15.196; 10.AH. 15.223; 10.AH. 15.240; 10.AH. 15.244; 10.AH.15.243; 10.AH.15.247; 10.AH.16.157; 10.AH.16.158; 10.AH.16.196; 10.AH.16.223; 10.AH. 16.240; 10.AH. 16.244; 10.AH. 16.243; 10.AH. 16.247; 10.AH.18.157; 10.AH.18.158; 10.AH.18.196; 10.AH.18.223; 10.AH.18.240; 10.AH.18.244; 10.AH.18.243; 10.AH.18.247; 10.AH.26.157; 10.AH.26.158; 10.AH.26.196; 10.AH.26.223: 10.AH.26.240; 10.AH.26.244; 10.AH.26.243; 10.AH.26.247; 10.AH.27.157; 10.AH.27.158; 10.AH.27.196; 10.AH.27.223;
10 AH.27.240; 10.AH.27.244; 10.AH.27.243; 10.AH.27.247; 10.AH.29.157; 10.AH.29.158; 10.AH.29.196; 10.AH.29.223; 10.AH.29.240; 10.AH.29.244; 10.AH.29.243; 10.AH.29.247; 10.AH.54.157; 10.AH.54.158; 10.AH.54.196; 10.AH.54.223; 10.AH.54.240; 10.AH.54.244; 10.AH.54.243; 10.AH.54.247; 10.AH.55.157; 10.AH.55.158; 10.AH.55.196; 10.AH.55.223; 10.AH.55.240; 10.AH.55.244; 10.AH.55.243; 10.AH.55.247; 10.AH.56.157; 10.AH.56.158; IO.AH.56.196; IO.AH.56.223; IO.AH.56.240; IO.AH.56.244; IO.AH.56.243; IO.AH.56.247; 10.AH.157.157; 10.AH.157.158; 10.AH. 157.196; 10.AH. 157.223; 10.AH. 157.240; 10. AH. 157.244; 10. AH. 157.243; 10.AH. 157.247; 10. AH. 196.157; 10.AH.196.158; 10. AH. 196.196; 10.AH. 196.223; 10. AH. 196.240; 10. AH. 196.244; 10. AH. 196.243; 10. AH. 196.247; 10.AH.223.157; 10.AH.223.158; 10.AH.223.196; 10.AH.223.223; 10.AH.223.240; 10.AH.223.244; 10.AH.223.243; 10.AH.223.247; 10.AH.240.157; 10.AH.240.158; 10.AH.240.196; 10.AH.240.223; 10.AH.240.240; 10.AH.240.244; 10.AH.240.243; 10.AH.240.247; 10.AH.244.157; 10.AH.244.158; 10.AH.244.196; 10.AH.244.223; 10.AH.244.240; 10.AH.244.244; 10.AH.244.243; 10.AH.244.247; 10.AH.247.157; 10.AH.247.158; 10.AH.247.196; 10.AH.247.223; 10.AH.247.240; 10.AH.247.244; 10.AH.247.243; 10.AH.247.247;
Prodrugs of 10. AT
10.AJ.4.157; 10.AJ.4.158; 10.AJ.4.196; 10.AJ.4.223; 10.AJ.4.240; 10.AJ.4.244; IO.AJ.4.243; IO.AJ.4.247; IO.AJ.5.157; IO.AJ.5.158; IO.AJ.5.196; IO.AJ.5.223; IO.AJ.5.240; IO.AJ.5.244; IO.AJ.5.243; IO.AJ.5.247; IO.AJ.7.157; IO.AJ.7.158; IO.AJ.7.196; IO.AJ.7.223; 10.AJ.7.240; 10.AJ.7.244; 10.AJ.7.243; 10.AJ.7.247; 10.AJ.15.157; 10.AJ.15.158; 10.AJ.15.196; 10.AJ.15.223; 10. AJ. 15.240; 10.AJ.15.244; 10.AJ.15.243; 10.AJ.15.247; 10.AJ.16.157; 10.AJ.16.158; 10.AJ.16.196; 10.AJ. 16.223; 10.AJ. 16.240; 10.AJ. 16.244; 10.AJ.16.243; 10.AJ.16.247; 10.AJ.18.157; 10.AJ.18.158; 10.AJ.18.196; 10.AJ.18.223; 10.AJ. 18.240; 10.AJ. 18.244; 10.AJ. 18.243; 10.AJ. 18.247; 10.AJ.26.157; 10.AJ.26.158; 10.AJ.26.196; 10.AJ.26.223; 10.AJ.26.240; 10.AJ.26.244; 10.AJ.26.243; 10.AJ.26.247; 10.AJ.27.157; 10.AJ.27.158; 10.AJ.27.196; 10.AJ.27.223; 10.AJ.27.240; 10.AJ.27.244; 10.AJ.27.243; 10.AJ.27.247; 10.AJ.29.157; 10.AJ.29.158; 10.AJ.29.196; 10.AJ.29.223; IO.AJ.29.240; 10.AJ.29.244; 10.AJ.29.243; 10.AJ.29.247; 10.AJ.54.157; 10.AJ.54.158; 10.AJ.54.196; 10.AJ.54.223; 10.AJ.54.240; 10.AJ.54.244; 10.AJ.54.243; 10.AJ.54.247; 10.AJ.55.157; 10.AJ.55.158; 10.AJ.55.196; 10.AJ.55.223; 10.AJ.55.240; 10.AJ.55.244; 10.AJ.55.243; 10.AJ.55.247; 10.AJ.56.157; 10.AJ.56.158; 10.AJ.56.196; 10.AJ.56.223; IO.AJ.56.240; IO.AJ.56.244; IO.AJ.56.243; IO.AJ.56.247; IO.AJ.157.157; IO.AJ.157.158; 10. AJ. 157.196; 10.AJ. 157.223; 10.AJ. 157.240; 10.AJ. 157.244; 10.AJ. 157.243; 10. AJ. 157.247; 10.AJ.196.157; 10.AJ.196.158; 10.AJ.196.196; 10.AJ. 196.223; 10. AJ. 196.240; 10.AJ. 196.244; 10.AJ. 196.243; 10. AJ. 196.247; 10.AJ.223.157; 10.AJ.223.158; 10.AJ.223.196; 10.AJ.223.223; 10.AJ.223.240; 10.AJ.223.244; 10.AJ.223.243; 10.AJ.223.247; 10.AJ.240.157; 10.AJ.240.158; 10.AJ.240.196; 10.AJ.240.223; 10.AJ.240.240; 10.AJ.240.244; 10.AJ.240.243; 10.AJ.240.247; 10.AJ.244.157; 10.AJ.244.158; 10.AJ.244.196; 10.AJ.244.223; 10.AJ.244.240; 10.AJ.244.244; 10.AJ.244.243; 10.AJ.244.247; 10.AJ.247.157; 10.AJ.247.158; 10.AJ.247.196; 10.AJ.247.223; 10.AJ.247.240; 10.AJ.247.244; 10.AJ.247.243; 10.AJ.247.247;
Prodrugs of 10.AN
10.AN.4.157; 10.AN.4.158; 10.AN.4.196; 10.AN.4.223; 10.AN.4.240; 10.AN.4.244; 10.AN.4.243; 10.AN.4.247; 10.AN.5.157; 10.AN.5.158; 10.AN.5.196; 10.AN.5.223;
O.AN.5.240; 10.AN.5.244; 10.AN.5.243; 10.AN.5.247; 10.AN.7.157; 10.AN.7.158;
O.AN.7.196; 10.AN.7.223; 10.AN.7.240; 10.AN.7.244; 10.AN.7.243; 10.AN.7.247;
.0. AN. 15.157; 10.AN.15.158; 10.AN.15.196; 10.AN. 15.223; 10.AN. 15.240; 10.AN. 15.244;
.O.AN. 15.243; 10.AN. 15.247; 10.AN.16.157; 10.AN.16.158; 10.AN.16.196; 10.AN. 16.223; LO.AN.16.240; 10.AN.16.244; 10.AN.16.243; 10.AN.16.247; 10.AN.18.157; 10.AN.18.158; LO.AN.18.196; 10.AN. 18.223; 10.AN. 18.240; 10.AN. 18.244; 10.AN. 18.243; 10.AN. 18.247; LO.AN.26.157; 10.AN.26.158; 10.AN.26.196; 10.AN.26.223; 10.AN.26.240; 10.AN.26.244; LO.AN.26.243; 10.AN.26.247; 10.AN.27.157; 10.AN.27.158; 10.AN.27.196; 10.AN.27.223; 10.AN.27.240; 10.AN.27.244; 10.AN.27.243; 10.AN.27.247; 10.AN.29.157; 10.AN.29.158; 10.AN.29.196; 10.AN.29.223; 10.AN.29.240; 10.AN.29.244; 10.AN.29.243; 10.AN.29.247; 10.AN.54.157; 10.AN.54.158; 10.AN.54.196; 10.AN.54.223; 10.AN.54.240; 10.AN.54.244; IO.AN.54.243; IO.AN.54.247; IO.AN.55.157; IO.AN.55.158; IO.AN.55.196; IO.AN.55.223; IO.AN.55.240; IO.AN.55.244; IO.AN.55.243; IO.AN.55.247; IO.AN.56.157; IO.AN.56.158; 10.AN.56.196; 10.AN.56.223; 10.AN.56.240; 10.AN.56.244; 10.AN.56.243; 10.AN.56.247; 10.AN.157.157; 10.AN.157.158; 10.AN.157.196; 10.AN. 157.223; 10.AN. 157.240; 10.AN. 157.244; 10.AN. 157.243; 10.AN.157.247; 10.AN.196.157; 10.AN.196.158; 10.AN.196.196; 10. AN. 196.223; 10.AN. 196.240; 10.AN. 196.244; 10. AN. 196.243; 10. AN. 196.247; 10.AN.223.157; 10.AN.223.158; 10.AN.223.196; 10.AN.223.223; 10.AN.223.240; 10.AN.223.244; 10.AN.223.243; 10.AN.223.247; 10.AN.240.157; 10.AN.240.158; 10.AN.240.196; 10.AN.240.223; 10.AN.240.240; 10.AN.240.244; 10.AN.240.243; 10.AN.240.247; 10.AN.244.157; 10.AN.244.158; 10.AN.244.196; 10.AN.244.223; 10.AN.244.240; 10.AN.244.244; 10.AN.244.243; 10.AN.244.247; 10.AN.247.157; 10.AN.247.158; 10.AN.247.196; 10.AN.247.223; 10.AN.247.240; 10.AN.247.244; 10.AN.247.243; 10.AN.247.247;
Prodrugs of 10.AP
10.AP.4.157; 10.AP.4.158; 10.AP.4.196; 10.AP.4.223; 10.AP.4.240; 10.AP.4.244; 10.AP.4.243; 10.AP.4.247; 10.AP.5.157; 10.AP.5.158; 10.AP.5.196; 10.AP.5.223; 10.AP.5.240; 10.AP.5.244; 10.AP.5.243; 10.AP.5.247; 10.AP.7.157; 10.AP.7.158; 10.AP.7.196; 10.AP.7.223; 10.AP.7.240; 10.AP.7.244; 10.AP.7.243; 10.AP.7.247; IO.AP.15.157; IO.AP.15.158; IO.AP.15.196; IO.AP.15.223; IO.AP.15.240; IO.AP.15.244; 10.AP.15.243; 10.AP.15.247; 10.AP.16.157; 10.AP.16.158; 10.AP.16.196; 10.AP.16.223; 10.AP.16.240; 10.AP.16.244; 10.AP.16.243; 10.AP.16.247; 10.AP.18.157; 10.AP.18.158; 10.AP.18.196; 10.AP.18.223; 10.AP.18.240; 10.AP.18.244; 10.AP.18.243; 10.AP.18.247; 10.AP.26.157; 10.AP.26.158; 10.AP.26.196; 10.AP.26.223; 10.AP.26.240; 10.AP.26.244; IO.AP.26.243; IO.AP.26.247; IO.AP.27.157; IO.AP.27.158; IO.AP.27.196; IO.AP.27.223; 10.AP.27.240; 10.AP.27.244; 10.AP.27.243; 10.AP.27.247; 10.AP.29.157; 10.AP.29.158; 10.AP.29.196; 10.AP.29.223; 10.AP.29.240; 10.AP.29.244; 10.AP.29.243; 10.AP.29.247; 10.AP.54.157; 10.AP.54.158; 10.AP.54.196; 10.AP.54.223; 10.AP.54.240; 10.AP.54.244; 10.AP.54.243; 10.AP.54.247; 10.AP.55.157; 10.AP.55.158; 10.AP.55.196; 10.AP.55.223; 10.AP.55.240; 10.AP.55.244; 10.AP.55.243; 10.AP.55.247; 10.AP.56.157; 10.AP.56.158; 10.AP.56.196; 10.AP.56.223; 10.AP.56.240; 10.AP.56.244; 10.AP.56.243; 10.AP.56.247; 10.AP.157.157; 10.AP.157.158; 10.AP.157.196; 10.AP.157.223; 10.AP. 157.240; 10. AP. 157.244; 10.AP.157.243; 10. AP. 157.247; 10.AP.196.157; 10.AP.196.158; 10.AP.196.196; 10. AP. 196.223; 10.AP. 196.240; 10.AP. 196.244; 10. AP. 196.243; 10.AP. 196.247; 10.AP.223.157; 10.AP.223.158; 10.AP.223.196; 10.AP.223.223; 10.AP.223.240; 10.AP.223.244; 10.AP.223.243; 10.AP.223.247; 10.AP.240.157; 10.AP.240.158; 10.AP.240.196; 10.AP.240.223; 10.AP.240.240; 10.AP.240.244;
10.AP.240.243; 10.AP.240.247; 10.AP.244.157; 10.AP.244.158; 10.AP.244.196; 10.AP.244.223; 10.AP.244.240; 10.AP.244.244; 10.AP.244.243; 10.AP.244.247; 10.AP.247.157; 10.AP.247.158; 10.AP.247.196; 10.AP.247.223; 10.AP.247.240; 10.AP.247.244; 10.AP.247.243; 10.AP.247.247;
Prodrugs of 10.AZ
10.AZ.4.157; 10.AZ.4.158; 10.AZ.4.196; 10.AZ.4.223; 10.AZ.4.240; 10.AZ.4.244; 10.AZ.4.243; 10.AZ.4.247; 10.AZ.5.157; 10.AZ.5.158; 10.AZ.5.196; 10.AZ.5.223; 10.AZ.5.240; 10.AZ.5.244; 10.AZ.5.243; 10.AZ.5.247; 10.AZ.7.157; 10.AZ.7.158; 10.AZ.7.196; 10.AZ.7.223; 10.AZ.7.240; 10.AZ.7.244; 10.AZ.7.243; 10.AZ.7.247; 10.AZ.15.157; 10.AZ.15.158; 10.AZ.15.196; 10.AZ.15.223; 10.AZ.15.240; 10.AZ.15.244; 10.AZ.15.243; 10.AZ.15.247; 10.AZ.16.157; 10.AZ.16.158; 10.AZ.16.196; 10.AZ.16.223; 10.AZ.16.240; 10.AZ. 16.244; 10.AZ.16.243; 10.AZ.16.247; 10.AZ.18.157; 10.AZ.18.158; 10.AZ.18.196; 10.AZ.18.223; 10.AZ.18.240; 10.AZ.18.244; 10.AZ.18.243; 10.AZ.18.247; 10.AZ.26.157; 10.AZ.26.158; 10.AZ.26.196; 10.AZ.26.223; 10.AZ.26.240; 10.AZ.26.244; 10.AZ.26.243; 10.AZ.26.247; 10.AZ.27.157; 10.AZ.27.158; 10.AZ.27.196; 10.AZ.27.223; 10.AZ.27.240; 10.AZ.27.244; 10.AZ.27.243; 10.AZ.27.247; 10.AZ.29.157; 10.AZ.29.158; 10.AZ.29.196; 10.AZ.29.223; 10.AZ.29.240; 10.AZ.29.244; 10.AZ.29.243; 10.AZ.29.247; IO.AZ.54.157; IO.AZ.54.158; IO.AZ.54.196; IO.AZ.54.223; IO.AZ.54.240; IO.AZ.54.244; IO.AZ.54.243; IO.AZ.54.247; IO.AZ.55.157; IO.AZ.55.158; IO.AZ.55.196; IO.AZ.55.223; IO.AZ.55.240; IO.AZ.55.244; IO.AZ.55.243; IO.AZ.55.247; IO.AZ.56.157; IO.AZ.56.158; IO.AZ.56.196; IO.AZ.56.223; IO.AZ.56.240; IO.AZ.56.244; IO.AZ.56.243; IO.AZ.56.247; 10.AZ.157.157; 10.AZ.157.158; 10.AZ.157.196; 10. AZ. 157.223; 10.AZ.157.240; 10.AZ. 157.244; 10.AZ.157.243; 10.AZ. 157.247; 10.AZ.196.157; 10.AZ.196.158; 10.AZ.196.196; 10.AZ. 196.223; 10.AZ. 196.240; 10. AZ. 196.244; 10. AZ. 196.243; 10.AZ. 196.247; 10.AZ.223.157; 10.AZ.223.158; 10.AZ.223.196; 10.AZ.223.223; 10.AZ.223.240; 10.AZ.223.244; 10.AZ.223.243; 10.AZ.223.247; 10.AZ.240.157; 10.AZ.240.158; 10.AZ.240.196; 10.AZ.240.223; 10.AZ.240.240; 10.AZ.240.244; 10.AZ.240.243; 10.AZ.240.247; 10.AZ.244.157; 10.AZ.244.158; 10.AZ.244.196; 10.AZ.244.223; 10.AZ.244.240; 10.AZ.244.244; 10.AZ.244.243; 10.AZ.244.247; 10.AZ.247.157; 10.AZ.247.158; 10.AZ.247.196; 10.AZ.247.223; 10.AZ.247.240; 10.AZ.247.244; 10.AZ.247.243; 10.AZ.247.247;
Prodrugs of 1Q.BF
10.BF.4.157; 10.BF.4.158; 10.BF.4.196; 10.BF.4.223; 10.BF.4.240; 10.BF.4.244; 10.BF.4.243; 10.BF.4.247; 10.BF.5.157; 10.BF.5.158; 10.BF.5.196; 10.BF.5.223; 10.BF.5.240; 10.BF.5.244; 10.BF.5.243; 10.BF.5.247; 10.BF.7.157; 10.BF.7.158; 10.BF.7.196; 10.BF.7.223; 10.BF.7.240; 10.BF.7.244; 10.BF.7.243; 10.BF.7.247; 10.BF.15.157; 10.BF.15.158; 10.BF.15.196; 10.BF.15.223; 10.BF.15.240; 10.BF.15.244; 10.BF.15.243; 10.BF.15.247; 10.BF.16.157; 10.BF.16.158; 10.BF.16.196; 10.BF.16.223; 10.BF. 16.240; 10.BF. 16.244; 10.BF. 16.243; 10.BF. 16.247; 10.BF.18.157; 10.BF.18.158; 10.BF.18.196; 10.BF.18.223; 10.BF.18.240; 10.BF.18.244; IO.BF.18,243; 10.BF.18.247; 10.BF.26.157; 10.BF.26.158; 10.BF.26.196; 10.BF.26.223; 10.BF.26.240; 10.BF.26.244; 10.BF.26.243; 10.BF.26.247; 10.BF.27.157; 10.BF.27.158; 10.BF.27.196; 10.BF.27.223; 10.BF.27.240; 10.BF.27.244; 10.BF.27.243; 10.BF.27.247; 10.BF.29.157; 10.BF.29.158; 10.BF.29.196; 10.BF.29.223; 10.BF.29.240; 10.BF.29.244; 10.BF.29.243; 10.BF.29.247; 10.BF.54.157; 10.BF.54.158; 10.BF.54.196; 10.BR54.223; 10.BF.54.240; 10.BF.54.244; 10.BF.54.243; 10.BF.54.247; 10.BF.55.157; 10.BF.55.158; 10.BF.55.196; 10.BF.55.223;
10.BF.55.240; 10.BF.55.244; 10.BF.55.243; 10.BF.55.247; IO.BF.56,157; 10.BF.56.158; 10.BF.56.196; 10.BF.56.223; 10.BF.56.240; 10.BF.56.244; 10.BF.56.243; 10.BF.56.247; 10.BF.157.157; 10.BF.157.158; 10.BF.157.196; 10.BF. 157.223; 10.BF. 157.240; 10.BF. 157.244; 10.BF. 157.243; 10.BF. 157.247; 10.BF.196.157; 10.BF.196.158; 10.BF.196.196; 10.BF. 196.223; 10.BF. 196.240; 10.BF. 196.244; 10.BF. 196.243; 10.BF. 196.247; 10.BF.223.157; 10.BF.223.158; 10.BF.223.196; 10.BF.223.223; 10.BF.223.240; 10.BF.223.244; 10.BF.223.243; 10.BF.223.247; 10.BF.240.157; 10.BF.240.158; 10.BF.240.196; 10.BF.240.223; 10.BF.240.240; 10.BF.240.244; 10.BF.240.243; 10.BF.240.247; 10.BF.244.157; 10.BF.244.158; 10.BF.244.196; 10.BF.244.223; 10.BF.244.240; 10.BF.244.244; 10.BF.244.243; 10.BF.244.247; 10.BF.247.157; 10.BF.247.158; 10.BF.247.196; 10.BF.247.223; 10.BF.247.240; 10.BF.247.244; 10.BF.247.243; 10.BF.247.247;
Prodrugs of 10.CI
10.CI.4.157; 10.CI.4.158; 10.CI.4.196; 10.CI.4.223; 10.CI.4.240; 10.CI.4.244; 10.CI.4.243; 10.CI.4.247; 10.CI.5.157; 10.CI.5.158; 10.CI.5.196; 10.CI.5.223; 10.CI.5.240; 10.CI.5.244; 10.CI.5.243; 10.CI.5.247; 10.CI.7.157; 10.CI.7.158; 10.CI.7.196; 10.CI.7.223; 10.CI.7.240; 10.CI.7.244; 10.CI.7.243; 10.CI.7.247; 10.CI.15.157; 10.CI.15.158; 10.CI.15.196; 10.CI. 15.223; 10.CI. 15.240; 10.CI. 15.244; 10.CI. 15.243; 10.CI. 15.247; 10.CI.16.157; 10.CI.16.158; 10.CI.16.196; 10.CI.16.223; 10.CI.16.240; 10.CI.16.244; 10.CI.16.243; 10.CI.16.247; 10.CI.18.157; 10.CI.18.158; 10.CI.18.196; 10.CI.18.223; lO.a.18.240; 10.CI.18.244; 10.CI.18.243; 10.CI.18.247; 10.CI.26.157; 10.CI.26.158; 10.CI.26.196; 10.CI.26.223; 10.CI.26.240; 10.CI.26.244; 10.CI.26.243; 10.CI.26.247; 10.CI.27.157; 10.CI.27.158; 10.CI.27.196; 10.CI.27.223; 10.CI.27.240; 10.CI.27.244; 10.CI.27.243; 10.CI.27.247; 10.CI.29.157; 10.CI.29.158; 10.CI.29.196; 10.CI.29.223; 10.CI.29.240; 10.CI.29.244; 10.CI.29.243; 10.CI.29.247; 10.CI.54.157; 10.CI.54.158; 10.CI.54.196; 10.CI.54.223; 10.CI.54.240; 10.CI.54.244; 10.CI.54.243; 10.CI.54.247; 10.CI.55.157; 10.CI.55.158; 10.CI.55.196; 10.CI.55.223; 10.CI.55.240; 10.CI.55.244; 10.CI.55.243; 10.CI.55.247; 10.CI.56.157; 10.CI.56.158; 10.CI.56.196; 10.CI.56.223; 10.CI.56.240; 10.CI.56.244; 10.CI.56.243; 10.CI.56.247; 10.CI.157.157; 10.CI.157.158; IO.CI.157.196; 10.CI. 157.223; 10.CI. 157.240; 10.CI. 157.244; 10.CI. 157.243; 10.CI. 157.247; IO.CI.196.157; IO.CI.196.158; IO.CI.196.196; 10.CI. 196.223; 10.CI. 196.240; 10.CI. 196.244; lO.a.196.243; 10.CI. 196.247; 10.CI.223.157; 10.CI.223.158; 10.CI.223.196; 10.CI.223.223; IO.CI.223.240; IO.CI.223.244; IO.CI.223.243; IO.CI.223.247; 10.CI.240.157; 10.CI.240.158; 10.CI.240.196; IO.CI.240.223; IO.CI.240.240; IO.CI.240.244; IO.CI.240.243; IO.CI.240.247; 10.CI.244.157; 10.CI.244.158; 10.CI.244.196; 10.CI.244.223; 10.CI.244.240; 10.CI.244.244; 10.CI.244.243; 10.CI.244.247; 10.CI.247.157; 10.CI.247.158; 10.CI.247.196; 10.CI.247.223; 10.CI.247.240; 10.CI.247.244; 10.CI.247.243; 10.CI.247.247;
Prodrugs of 10.CO
10.CO.4.157; 10.CO.4.158; 10.CO.4.196; 10.CO.4.223; 10.CO.4.240; 10.CO.4.244; 10.C0.4.243; 10.CO.4.247; 10.CO.5.157; 10.CO.5.158; 10.CO.5.196; 10.CO.5.223; 10.C0.5.240; 10.CO.5.244; 10.CO.5.243; 10.CO.5.247; 10.CO.7.157; 10.CO.7.158; 10.CO.7.196; 10.CO.7.223; 10.CO.7.240; 10.CO.7.244; 10.CO.7.243; 10.CO.7.247; 10.CO.15.157; 10.CO.15.158; 10.CO.15.196; 10.CO. 15.223; 10.CO. 15.240; 10.CO. 15.244; 10.CO.15.243; 10.CO.15.247; 10.CO.16.157; 10.CO.16.158; 10.CO.16.196; 10.CO.16.223; 10.C0.16.240; 10.CO. 16.244; 10.CO.16.243; 10.CO.16.247; 10.C0.18.157; 10.CO.18.158; 10.CO.18.196; 10.CO.18.223; 10.CO.18.240; 10.CO.18.244; 10.CO.18.243; 10.CO.18.247;
10C0.26.157; 10.CO.26.15S; 10.CO.26.196; 10.CO.26.223; 10.CO.26.240; 10.CO.26.244; 10.C0.26.243; 10.CO.26.247; 10.CO.27.157; 10.CO.27.158; 10.CO.27.196; 10.CO.27.223; 10.C0.27.240; 10.CO.27.244; 10.CO.27.243; 10.CO.27.247; 10.CO.29.157; 10.CO.29.158; 10.CO.29.196; 10.CO.29.223; 10.CO.29.240; 10.CO.29.244; 10.CO.29.243; 10.CO.29.247; 10.C0.54.157; 10.CO.54.158; 10.CO.54.196; 10.CO.54.223; 10.CO.54.240; 10.CO.54.244; 10.C0.54.243; 10.CO.54.247; 10.CO.55.157; 10.CO.55.158; 10.CO.55.196; 10.CO.55.223; 10.C0.55.240; 10.CO.55.244; 10.CO.55.243; 10.CO.55.247; 10.CO.56.157; 10.CO.56.158; 10.CO.56.196; 10.CO.56.223; 10.CO.56.240; 10.CO.56.244; 10.CO.56.243; 10.CO.56.247; 10.CO.157.157; 10.CO. 157.158; 10.CO.157.196; 10.CO.157.223; 10.CO. 157.240; 10.CO. 157.244; 10.CO. 157.243; 10.CO. 157.247; 10.CO.196.157; 10.CO.196.158; 10.CO.196.196; 10.CO. 196.223; 10.CO. 196.240; 10.CO. 196.244; 10.CO. 196.243; 10.CO. 196.247; 10.CO.223.157; 10.CO.223.158; 10.CO.223.196; 10.CO.223.223; 10.CO.223.240; 10.CO.223.244; 10.CO.223.243; 10.CO.223.247; 10.CO.240.157; 10.C0.240.158; 10.CO.240.196; 10.CO.240.223; 10.CO.240.240; 10.CO.240.244; 10.CO.240.243; 10.CO.240.247; 10.CO.244.157; 10.CO.244.158; 10.CO.244.196; 10.CO.244.223; 10.CO.244.240; 10.CO.244.244; 10.CO.244.243; 10.CO.244.247; 10.CO.247.157; 10.CO.247.158; 10.CO.247.196; 10.CO.247.223; 10.CO.247.240; 10.CO.247.244; 10.CO.247.243; 10.CO.247.247;
Prodrugs of ll.AH
ll.AH.4.157; ll.AH.4.158; ll.AH.4.196; ll.AH.4.223; ll.AH.4.240; ll.AH.4.244; ll.AH.4.243; ll.AH.4.247; ll.AH.5.157; ll.AH.5.158; ll.AH.5.196; ll.AH.5.223; ll.AH.5.240; ll.AH.5.244; ll.AH.5.243; ll.AH.5.247; ll.AH.7.157; ll.AH.7.158; ll.AH.7.196; ll.AH.7.223; ll.AH.7.240; ll.AH.7.244; ll.AH.7.243; ll.AH.7.247; ll.AH.15.157; ll.AH.15.158; ll.AH. 15.196; ll.AH.15.223; ll.AH.15.240; ll.AH.15.244; 11.AH. 15.243; ll.AH. 15.247; ll.AH.16.157; ll.AH.16.158; ll.AH.16.196; 11.AH. 16.223; ll.AH.16.240; ll.AH.16.244; ll.AH.16.243; ll.AH.16.247; ll.AH.18.157; ll.AH.18.158; ll.AH.18.196; ll.AH.18.223; ll.AH.18.240; ll.AH.18.244; ll.AH.18.243; ll.AH.18.247; ll.AH.26.157; ll.AH.26.158; ll.AH.26.196; ll.AH.26.223; ll.AH.26.240; ll.AH.26.244; ll.AH.26.243; ll.AH.26.247; ll.AH.27.157; ll.AH.27.158; ll.AH.27.196; ll.AH.27.223; ll.AH.27.240; ll.AH.27.244; ll.AH.27.243; ll.AH.27.247; ll.AH.29.157; ll.AH.29.158; ll.AH.29.196; ll.AH.29.223; ll.AH.29.240; ll.AH.29.244; ll.AH.29.243; 1 l.AH.29.247; ll.AH.54.157; ll.AH.54.158; ll.AH.54.196; ll.AH.54.223; ll.AH.54.240; ll.AH.54.244; ll.AH.54.243; ll.AH.54.247; ll.AH.55.157; ll.AH.55.158; ll.AH.55.196; ll.AH.55.223; ll.AH.55.240; ll.AH.55.244; ll.AH.55.243; ll.AH.55.247; ll.AH.56.157; ll.AH.56.158; ll.AH.56.196; ll.AH.56.223; ll.AH.56.240; ll.AH.56.244; ll.AH.56.243; ll.AH.56.247; 11.AH. 157.157; ll.AH. 157.158; ll.AH.157.196; 11.AH. 157.223; ll.AH. 157.240; ll.AH.157.244; 11.AH. 157.243; ll.AH. 157.247; ll.AH. 196.157; ll.AH. 196.158; ll.AH.196.196; ll.AH. 196.223; 11.AH. 196.240; ll.AH. 196.244; ll.AH. 196.243; 11.AH. 196.247; ll.AH.223.157; ll.AH.223.158; ll.AH.223.196; ll.AH.223.223; ll.AH.223.240; ll.AH.223.244; ll.AH.223.243; ll.AH.223.247; ll.AH.240.157; ll.AH.240.158; ll.AH.240.196; ll.AH.240.223; ll.AH.240.240; ll.AH.240.244; ll.AH.240.243; 11.AH.240.247; ll.AH.244.157; ll.AH.244.158; ll.AH.244.196; ll.AH.244.223; ll.AH.244.240; ll.AH.244.244; ll.AH.244.243; ll.AH.244.247; ll.AH.247.157; ll.AH.247.158; ll.AH.247.196; ll.AH.247.223; ll.AH.247.240; ll.AH.247.244; ll.AH.247.243; ll.AH.247.247;
Frodrugs of 11.A]
11 AJ4 157- ll.AJ.4.158; ll.AJ.4.196; ll.AJ.4.223; ll.AJ.4.240; ll.AJ.4.244; 11.AJ.4243- ll.AJ.4.247; ll.AJ.5.157; ll.AJ.5.158; ll.AJ.5.196; ll.AJ.5.223; ll.AJ.5.240; ll.AJ.5.244; ll.AJ.5.243; ll.AJ.5.247; ll.AJ.7.157; ll.AJ.7.158; ll.AJ.7.196; ll.AJ.7.223; ll.AJ.7.240; ll.AJ.7.244; ll.AJ.7.243; ll.AJ.7.247; ll.AJ.15.157; ll.AJ.15.158; ll.AJ.15.196; ll.AJ.15.223; ll.AJ.15.240; ll.AJ.15.244; ll.AJ.15.243; ll.AJ.15.247; ll.AJ.16.157; ll.AJ.16.158; ll.AJ.16.196; ll.AJ.16.223; ll.AJ.16.240; ll.AJ.16.244; ll.AJ.16.243; ll.AJ.16.247; ll.AJ.18.157; ll.AJ.18.158; ll.AJ.18.196; ll.AJ.18.223; ll.AJ. 18.240; 11.AJ. 18.244; ll.AJ. 18.243; ll.AJ. 18.247; ll.AJ.26.157; ll.AJ.26.158; ll.AJ.26.196; ll.AJ.26.223; ll.AJ.26.240; ll.AJ.26.244; ll.AJ.26.243; ll.AJ.26.247; ll.AJ.27.157; ll.AJ.27.158; ll.AJ.27.196; ll.AJ.27.223; ll.AJ.27.240; ll.AJ.27.244; ll.AJ.27.243; ll.AJ.27.247; ll.AJ.29.157; ll.AJ.29.158; ll.AJ.29.196; ll.AJ.29.223; ll.AJ.29.240; ll.AJ.29.244; ll.AJ.29.243; ll.AJ.29.247; ll.AJ.54.157; ll.AJ.54.158; ll.AJ.54.196; ll.AJ.54.223; ll.AJ.54.240; ll.AJ.54.244; ll.AJ.54.243; ll.AJ.54.247; ll.AJ.55.157; ll.AJ.55.158; ll.AJ.55.196; ll.AJ.55.223; ll.AJ.55.240; ll.AJ.55.244; ll.AJ.55.243; ll.AJ.55.247; ll.AJ.56.157; ll.AJ.56.158; ll.AJ.56.196; ll.AJ.56.223; ll.AJ.56.240; ll.AJ.56.244; ll.AJ.56.243; ll.AJ.56.247; ll.AJ.157.157; ll.AJ. 157.158; ll.AJ.157.196; ll.AJ. 157.223; ll.AJ. 157.240; ll.AJ. 157.244; ll.AJ. 157.243; 11.AJ. 157.247; ll.AJ. 196.157; ll.AJ. 196.158; ll.AJ. 196.196; ll.AJ. 196.223; 11.AJ. 196.240; ll.AJ. 196.244; ll.AJ.196.243; ll.AJ. 196.247; ll.AJ.223.157; ll.AJ.223.158; ll.AJ.223.196; ll.AJ.223.223; ll.AJ.223.240; ll.AJ.223.244; ll.AJ.223.243; ll.AJ.223.247; ll.AJ.240.157; ll.AJ.240.158; ll.AJ.240.196; ll.AJ.240.223; ll.AJ.240.240; ll.AJ.240.244; ll.AJ.240.243; ll.AJ.240.247; ll.AJ.244.157; ll.AJ.244.158; ll.AJ.244.196; ll.AJ.244.223; ll.AJ.244.240; ll.AJ.244.244; ll.AJ.244.243; ll.AJ.244.247; ll.AJ.247.157; ll.AJ.247.158; ll.AJ.247.196; ll.AJ.247.223; ll.AJ.247.240; ll.AJ.247.244; ll.AJ.247.243; ll.AJ.247.247;
Prodrugs of 11. AN
ll.AN.4.157; ll.AN.4.158; ll.AN.4.196; ll.AN.4.223; ll.AN.4.240; ll.AN.4.244; ll.AN.4.243; ll.AN.4.247; ll.AN.5.157; ll.AN.5.158; ll.AN.5.196; ll.AN.5.223; ll.AN.5.240; ll.AN.5.244; ll.AN.5.243; ll.AN.5.247; ll.AN.7.157; ll.AN.7.158; ll.AN.7.196; ll.AN.7.223; ll.AN.7.240; ll.AN.7.244; ll.AN.7.243; ll.AN.7.247; ll.AN.15.157; ll.AN.15.158; ll.AN.15.196; ll.AN.15.223; ll.AN.15.240; ll.AN.15.244; ll.AN.15.243; ll.AN.15.247; ll.AN.16.157; ll.AN.16.158; ll.AN.16.196; ll.AN.16.223; ll.AN.16.240; ll.AN.16.244; ll.AN.16.243; ll.AN.16.247; ll.AN.18.157; ll.AN.18.158; ll.AN.18.196; ll.AN.18.223; ll.AN.18.240; ll.AN.18.244; ll.AN.18.243; ll.AN.18.247; ll.AN.26.157; ll.AN.26.158; ll.AN.26.196; ll.AN.26.223; ll.AN.26.240; ll.AN.26.244; ll.AN.26.243; ll.AN.26.247; ll.AN.27.157; ll.AN.27.158; ll.AN.27.196; ll.AN.27.223; ll.AN.27.240; ll.AN.27.244; ll.AN.27.243; ll.AN.27.247; ll.AN.29.157; ll.AN.29.158; ll.AN.29.196; ll.AN.29.223; ll.AN.29.240; ll.AN.29.244; ll.AN.29.243; ll.AN.29.247; ll.AN.54.157; ll.AN.54.158; ll.AN.54.196; ll.AN.54.223; ll.AN.54.240; ll.AN.54.244; ll.AN.54.243; ll.AN.54.247; ll.AN.55.157; ll.AN.55.158; ll.AN.55.196; ll.AN.55.223; ll.AN.55.240; ll.AN.55.244; ll.AN.55.243; ll.AN.55.247; 1LAN.56.157; ll.AN.56.158; ll.AN.56.196; ll.AN.56.223; ll.AN.56.240; ll.AN.56.244; ll.AN.56.243; ll.AN.56.247; ll.AN.157.157; 1 LAN. 157.158; ll.AN.157.196; 1 LAN. 157.223; 1 LAN. 157.240; ll.AN.157.244; 1 LAN. 157.243; 1 LAN. 157.247; 1 LAN. 196.157; 1 LAN. 196.158; 1 LAN. 196.196; ll.AN.196.223; ll.AN.196.240; 1 LAN. 196.244; 1 LAN. 196.243; ll.AN.196.247; ll.AN.223.157; ll.AN.223.158; ll.AN.223.196; ll.AN.223.223;
ll.AN.223.240; ll.AN.223.244; ll.AN.223.243; ll.AN.223.247; ll.AN.240.157; ll.AN.240.158; ll.AN.240.196; 11.AN.240.223; ll.AN.240.240; ll.AN.240.244; ll.AN.240.243; ll.AN.240.247; ll.AN.244.157; ll.AN.244.158; ll.AN.244.196; ll.AN.244.223; ll.AN.244.240; ll.AN.244.244; ll.AN.244.243; ll.AN.244.247; ll.AN.247.157; ll.AN.247.158; ll.AN.247.196; ll.AN:247.223; ll.AN.247.240; ll.AN.247.244; 1I.AN.247.243; ll.AN.247.247;
Prodrugs of 11.AF
ll.AP.4.157, iI.AP.4.158; ll.AP.4.196; ll.AP.4.223; ll.AP.4.240; ll.AP.4.244; ll.AP.4.243; ll.AP.4.247; 1LAP.5.157; ll.AP.5.158; ll.AP.5.196; ll.AP.5.223; ll.AP.5.240;ll.AP.5.244; ll.AP.5.243; ll.AP.5.247; ll.AP.7.157; ll.AP.7.158; ll.AP.7.196; ll.AP.7.223; ll.AP.7.240; ll.AP.7.244; ll.AP.7.243; ll.AP.7.247; ll.AP.15.157; ll.AP.15.158; ll.AP.15.196; ll.AP.15.223; ll.AP.15.240; ll.AP.15.244; ll.AP.15.243; ll.AP.15.247; ll.AP.16.157; ll.AP.16.158; ll.AP.16.196; ll.AP.16.223; ll.AP.16.240; ll.AP.16.244; ll.AP.16.243; ll.AP.16.247; ll.AP.18.157; ll.AP.18.158; ll.AP.18.196; ll.AP.18.223; ll.AP.18.240; ll.AP.18.244; ll.AP.18.243; ll.AP.18.247; ll.AP.26.157; ll.AP.26.158; ll.AP.26.196; ll.AP.26.223; 1LAP.26.240; ll.AP.26.244; ll.AP.26.243; ll.AP.26.247; ll.AP.27.157; ll.AP.27.158; ll.AP.27.196; ll.AP.27.223; ll.AP.27.240; ll.AP.27.244; ll.AP.27.243; ll.AP.27.247; ll.AP.29.157; ll.AP.29.158; ll.AP.29.196; Il.AP.29.223; ll.AP.29.240; ll.AP.29.244; ll.AP.29.243; ll.AP.29.247; ll.AP.54.157; ll.AP.54.158; ll.AP.54.196; ll.AP.54.223; ll.AP.54.240; ll.AP.54.244; 1LAP.54.243; ll.AP.54.247; ll.AP.55.157; ll.AP.55.158; ll.AP.55.196; ll.AP.55.223; ll.AP.55.240; ll.AP.55.244; ll.AP.55.243; ll.AP.55.247; ll.AP.56.157; ll.AP.56.158; ll.AP.56.196; ll.AP.56.223; ll.AP.56.240; ILAP.56.244; ll.AP.56.243; ll.AP.56.247; 1 LAP. 157.157; 1 LAP. 157.158; ll.AP.157.196; 1 LAP. 157.223; 1 LAP. 157.240; ll.AP.157.244; ll.AP.157.243; ll.AP.157.247; ll.AP.196.157; ll.AP.196.158; ll.AP.196.196; ll.AP.196.223; 1 LAP. 196.240; ll.AP.196.244; 1 LAP. 196.243; ll.AP.196.247; ll.AP.223.157; ll.AP.223.158; 1LAP.223.196; ll.AP.223.223; ll.AP.223.240; ll.AP.223.244; ll.AP.223.243; 1 l.AP.223.247; ll.AP.240.157; ll.AP.240.158; 1LAP.240.196; ll.AP.240.223; 1 LAP.240.240; 11.AP.240.244; 1LAP.240.243; ll.AP.240.247; 1LAP.244.157; ll.AP.244.158; 11.AP.244.196; ll.AP.244.223; 1 l.AP.244.240; 11.AP.244.244; ll.AP.244.243; ll.AP.244.247; 1LAP.247.157; ll.AP.247.158; ll.AP.247.196; 1LAP.247.223; 11.AP.247.240; 1LAP.247.244; ll.AP.247.243; ll.AP.247.247;
Prodrugs of ll.AZ
ll.AZ.4.157; ll.AZ.4.158; ll.AZ.4.196; ll.AZ.4.223; ll.AZ.4.240; ll.AZ.4.244; ll.AZ.4.243; ll.AZ.4.247; ll.AZ.5.157; 1LAZ.5.158; 1LAZ.5.196; ll.AZ.5.223; ll.AZ.5.240; ll.AZ.5.244; ll.AZ.5.243; ll.AZ.5.247; ll.AZ.7.157; ll.AZ.7.158; ll.AZ.7.196; ll.AZ.7.223; ll.AZ.7.240; ll.AZ.7.244; ll.AZ.7.243; ll.AZ.7.247; ll.AZ.15.157; ll.AZ.15.158; ll.AZ.15.196; ll.AZ.15.223; ll.AZ.15.240; ll.AZ.15.244; ll.AZ.15.243; ll.AZ.15.247; ll.AZ.16.157; ll.AZ.16.158; ll.AZ.16.196; ll.AZ.16.223; ll.AZ.16.240; ll.AZ.16.244; ll.AZ.16.243; ll.AZ.16.247; ll.AZ.18.157; ll.AZ.18.158; ll.AZ.18.196; ll.AZ.18.223; ll.AZ.18.240; ll.AZ.18.244; ILAZ.18.243; ll.AZ.18.247; ll.AZ.26.157; ll.AZ.26.158; ll.AZ.26.196; ll.AZ.26.223; ll.AZ.26.240; ll.AZ.26.244; ll.AZ.26.243; ll.AZ.26.247; ll.AZ.27.157; ll.AZ.27.158; 1LAZ.27.196; ll.AZ.27.223; ll.AZ.27.240; 1LAZ.27.244; ll.AZ.27.243; ll.AZ.27.247; ll.AZ.29.157; ll.AZ.29.158; ll.AZ.29.196; ll.AZ.29.223; ll.AZ.29.240; ll.AZ.29.244; ll.AZ.29.243; ll.AZ.29.247;
ll.AZ.54.157; ll.AZ.54.158; ll.AZ.54.196; ll.AZ.54.223; ll.AZ.54.240; ll.AZ.54.244; ll.AZ.54.243; ll.AZ.54.247; ll.AZ.55.157; ll.AZ.55.158; ll.AZ.55.196; ll.AZ.55.223; ll.AZ.55.240; ll.AZ.55.244; ll.AZ.55.243; ll.AZ.55.247; ll.AZ.56.157; ll.AZ.56.158; ll.AZ.56.196; ll.AZ.56.223; ll.AZ.56.240; ll.AZ.56.244; ll.AZ.56.243; ll.AZ.56.247; ll.AZ.157.157; ll.AZ.157.158; ll.AZ.157.196; ll.AZ. 157.223; ll.AZ. 157.240; 11.AZ. 157.244; ll.AZ. 157.243; ll.AZ. 157.247; ll.AZ. 196.157; ll.AZ. 196.158; ll.AZ. 196.196; ll.AZ. 196.223; 1 l.AZ. 196.240; ll.AZ. 196.244; ll.AZ. 196.243; 11.AZ. 196.247; ll.AZ.223.157; ll.AZ.223.158; ll.AZ.223.196; ll.AZ.223.223; ll.AZ.223.240; ll.AZ.223.244; ll.AZ.223.243; ll.AZ.223.247; ll.AZ.240.157; ll.AZ.240.158; ll.AZ.240.196; ll.AZ.240.223; ll.AZ.240.240; ll.AZ.240.244; ll.AZ.240.243; ll.AZ.240.247; ll.AZ.244.157; ll.AZ.244.158; ll.AZ.244.196; ll.AZ.244.223; ll.AZ.244.240; ll.AZ.244.244; ll.AZ.244.243; ll.AZ.244.247; ll.AZ.247.157; ll.AZ.247.158; ll.AZ.247.196; ll.AZ.247.223; ll.AZ.247.240; ll.AZ.247.244; ll.AZ.247.243; ll.AZ.247.247;
Prodrugs of 11.BF
ll.BF.4.157; ll.BF.4.158; ll.BF.4.196; ll.BF.4.223; ll.BF.4.240; ll.BF.4.244; ll.BF.4.243; ll.BF.4.247; ll.BF.5.157; ll.BF.5.158; ll.BF.5.196; ll.BF.5.223; ll.BF.5.240; ll.BF.5.244; ll.BF.5.243; ll.BF.5.247; ll.BF.7.157; ll.BF.7.158; ll.BF.7.196; ll.BF.7.223; ll.BF.7.240; ll.BF.7.244; ll.BF.7.243; ll.BF.7.247; ll.BF.15.157; ll.BF.15.158; ll.BF.15.196; ll.BF.15.223; ll.BF.15.240; ll.BF.15.244; 11.BF. 15.243; ll.BF. 15.247; ll.BF.16.157; ll.BF.16.158; ll.BF.16.196; 11.BF. 16.223; ll.BF.16.240; ll.BF.16.244; ll.BF.16.243; ll.BF.16.247; ll.BF.18.157; ll.BF.18.158; ll.BF.18.196; ll.BF.18.223; ll.BF.18.240; ll.BF.18.244; ll.BF.18.243; ll.BF.18.247; ll.BF.26.157; ll.BF.26.158; ll.BF.26.196; ll.BF.26.223; ll.BF.26.240; ll.BF.26.244; ll.BF.26.243; ll.BF.26.247; ll.BF.27.157; ll.BF.27.158; ll.BF.27.196; ll.BF.27.223; ll.BF.27.240; ll.BF.27.244; ll.BF.27.243; ll.BF.27.247; ll.BF.29.157; ll.BF.29.158; ll.BF.29.196; ll.BF.29.223; ll.BF.29.240; ll.BF.29.244; ll.BF.29.243; ll.BF.29.247; ll.BF.54.157; ll.BF.54.158; ll.BF.54.196; ll.BF.54.223; ll.BF.54.240; ll.BF.54.244; ll.BF.54.243; ll.BF.54.247; ll.BF.55.157; ll.BF.55.158; ll.BF.55.196; ll.BF.55.223; ll.BF.55.240; ll.BF.55.244; ll.BF.55.243; 1 l.BF.55.247; ll.BF.56.157; ll.BF.56.158; ll.BF.56.196; ll.BF.56.223; ll.BF.56.240; ll.BF.56.244; ll.BF.56.243; ll.BF.56.247; ll.BF. 157.157; ll.BF. 157.158; ll.BF. 157.196; ll.BF. 157.223; ll.BF. 157.240; ll.BF. 157.244; ll.BF.157.243; ll.BF. 157.247; ll.BF. 196.157; ll.BF. 196.158; ll.BF.196.196; ll.BF. 196.223; ll.BF. 196.240; ll.BF. 196.244; ll.BF. 196.243; ll.BF. 196.247; ll.BF.223.157; ll.BF.223.158; ll.BF.223.196; ll.BF.223.223; ll.BF.223.240; ll.BF.223.244; ll.BF.223.243; ll.BF.223.247; ll.BF.240.157; ll.BF.240.158; ll.BF.240.196; ll.BF.240.223; ll.BF.240.240; ll.BF.240.244; ll.BF.240.243; ll.BF.240.247; ll.BF.244.157; ll.BF.244.158; ll.BF.244.196; ll.BF.244.223; ll.BF.244.240; ll.BF.244.244; ll.BF.244.243; ll.BF.244.247; ll.BF.247.157; ll.BF.247.158; ll.BF.247.196; ll.BF.247.223; ll.BF.247.240; ll.BF.247.244; ll.BF.247.243; ll.BF.247.247;
Prodrugs of ll.CI
ll.CI.4.157; ll.CI.4.158; ll.CI.4.196; ll.CI.4.223; ll.CI.4.240; ll.CI.4.244; ll.CI.4.243; ll.CI.4.247; ll.CI.5.157; ll.CI.5.158; ll.CI.5.196; ll.CI.5.223; ll.CI.5.240; ll.CI.5.244; ll.CI.5.243; ll.CI.5.247; ll.CI.7.157; ll.CI.7.158; ll.CI.7.196; ll.CI.7.223; ll.CI.7.240; ll.CI.7.244; ll.CI.7.243; ll.CI.7.247; 11.CI.15.157; ll.CI.15.158;
ll.CI. 15.196; ll.CI.15.223; ll.CI. 15.240; ll.CI. 15.244; ll.CI.15.243; ll.CI.15.247; ll.CI.16.157; ll.CI.16.158; ll.CI.16.196; ll.CI.16.223; ll.CI.16.240; ll.CI.16.244; ll.CI.16.243; ll.CI.16.247; ll.CI.18.157; 11.CI.18.158; ll.CI.18.196; ll.CI.18.223; ll.CI.18.240; ll.CI.18.244; ll.CI.18.243; ll.CI.18.247; ll.CI.26.157; ll.CI.26.158; ll.CI.26.196; ll.CI.26.223; ll.CI.26.240; ll.CI.26.244; ll.CI.26.243; ll.CI.26.247; ll.CI.27.157; ll.CI.27.158; ll.CI.27.196; ll.CI.27.223; ll.CI.27.240; ll.CI.27.244; ll.CI.27.243; ll.CI.27.247; 11.CI.29.157; 11.CI.29.158; 11.CI.29.196; ll.CI.29.223; ll.CI.29.240; ll.CI.29.244; ll.CI.29.243; ll.CI.29.247; ll.CI.54.157; ll.CI.54.158; 11.CI.54.196; ll.CI.54.223; ll.CI.54.240: ll.CI.54.244; ll.CI.54.243; ll.CI.54.247; 11.CI.55.157; 11.CI.55.158; 11.CL55.196; ll.CI.55.223; ll.CI.55.240; ll.CI.55.244; ll.CI.55.243; ll.CI.55.247; ll.CI.56.157; ll.CI.56.158; ll.CI.56.196; ll.CI.56.223; ll.CI.56.240; ll.CI.56.244; 1LCI.56.243; ll.CI.56.247; ll.CI. 157.157; ll.CI. 157.158; ll.CI. 157.196; ll.CI.157.223; ll.CI. 157.240; 1 LCI. 157.244; ll.CI. 157.243; ll.CI.157.247; ll.CI. 196.157; ll.CI. 196.158; ll.CI.196.196; ll.CI. 196.223; ll.CI. 196.240; ll.CI. 196.244; ll.CI. 196.243; ll.CI. 196.247; ll.CI.223.157; 11.CI.223.158; 11.CI.223.196; ll.CI.223.223; ll.CI.223.240; ll.CI.223.244; ll.a.223.243; ll.CI.223.247; 11.CI.240.157; ll.CI.240.158; 11.CI.240.196; ll.CI.240.223; ll.CI.240.240; ll.CI.240.244; ll.CI.240.243; ll.CI.240.247; 11.CI.244.157; 11.CI.244.158; ll.a.244.196; ll.CI.244.223; ll.CI.244.240; ll.CI.244.244; ll.CI.244.243; ll.CI.244.247; 11.CI.247.157; 11.CI.247.158; 11.CI.247.196; ll.CI.247.223; ll.CI.247.240; ll.CI.247.244; ll.CI.247.243; ll.CI.247.247;
Prodrugs of ll.CO
ll.CO.4.157; ll.CO.4.158; ll.CO.4.196; ll.CO.4.223; ll.CO.4.240; ll.CO.4.244; ll.CO.4.243; ll.CO.4.247; ll.CO.5.157; ll.CO.5.158; ll.CO.5.196; ll.CO.5.223; ll.CO.5.240; ll.CO.5.244; ll.CO.5.243; ll.CO.5.247; ll.CO.7.157; ll.CO.7.158; ll.CO.7.196; ll.CO.7.223; ll.CO.7.240; ll.CO.7.244; ll.CO.7.243; ll.CO.7.247; ll.CO.15.157; ll.CO.15.158; ll.CO.15.196; ll.CO.15.223; ll.CO.15.240; ll.CO.15.244; ll.CO.15.243; ll.CO.15.247; ll.CO.16.157; ll.CO.16.158; ll.CO.16.196; ll.CO.16.223; ll.CO.16.240; ll.CO.16.244; ll.CO.16.243; ll.CO.16.247; ll.CO.18.157; ll.CO.18.158; ll.CO.18.196; ll.CO.18.223; ll.CO.18.240; ll.CO.18.244; ll.CO.18.243; ll.CO.18.247; ll.CO.26.157; ll.CO.26.158; ll.CO.26.196; 1 l.CO.26.223; ll.CO.26.240; ll.CO.26.244; ll.CO.26.243; ll.CO.26.247; ll.CO.27.157; ll.CO.27.158; ll.CO.27.196; ll.CO.27.223; ll.CO.27.240; ll.CO.27.244; ll.CO.27.243; ll.CO.27.247; ll.CO.29.157; ll.CO.29.158; ll.CO.29.196; ll.CO.29.223; ll.CO.29.240; 1 l.CO.29.244; ll.CO.29.243; ll.CO.29.247; ll.CO.54.157; ll.CO.54.158; ll.CO.54.196; ll.CO.54.223; ll.CO.54.240; ll.CO.54.244; ll.CO.54.243; ll.CO.54.247; ll.CO.55.157; ll.CO.55.158; ll.CO.55.196; ll.CO.55.223; ll.CO.55.240; ll.CO.55.244; ll.CO.55.243; ll.CO.55.247; ll.CO.56.157; ll.CO.56.158; ll.CO.56.196; ll.CO.56.223; ll.CO.56.240; ll.CO.56.244; ll.CO.56.243; ll.CO.56.247; 11.CO. 157.157; ll.CO. 157.158; ll.CO.157.196; 11.CO. 157.223; ll.CO. 157.240; 11.CO. 157.244; ll.CO. 157.243; ll.CO.157.247; ll.CO. 196.157; ll.CO. 196.158; ll.CO.196.196; ll.CO. 196.223; 11.CO. 196.240; 11.CO. 196.244; 11.CO. 196.243; 11.CO. 196.247; ll.CO.223.157; ll.CO.223.158; ll.CO.223.196; ll.CO.223.223; ll.CO.223.240; ll.CO.223.244; 11.CO.223.243; ll.CO.223.247; 11.CO.240.157; 11.CO.240.158; 11.CO.240.196; ll.CO.240.223; ll.CO.240.240; ll.CO.240.244; ll.CO.240.243; ll.CO.240.247; 11.CO.244.157; 11.CO.244.158; 11.CO.244.196; ll.CO.244.223; ll.CO.244.240; ll.CO.244.244; ll.CO.244.243; ll.CO.244.247; 11.C0.247.157; 11.CO.247.158; ll.CO.247.196; ll.CO.247.223; ll.CO.247.240; ll.CO.247.244; ll.CO.247.243; ll.CO.247.247;
Prodrugs of 12.AH
12.AH.4.157; 12. AHA 158; 12.AH.4.196; 12.AH.4.223; 12.AH.4.240; 12.AH.4.244; 12.AHA243; 12.AHA247; 12.AH.5.157; 12.AH.5.158; 12.AH.5.196; 12.AH.5.223; 12.AH.5.240; 12.AH.5.244; 12.AH.5.243; 12.AH.5.247; 12.AH.7.157; 12.AH.7.158; 12.AH.7.196; 12.AH.7.223; 12.AH.7.240; 12.AH.7.244; 12.AH.7.243; 12.AH.7.247; 12.AH.15.157; 12.AH.15.158: 12. AH. 15.196; 12.AH. 15.223; 12. AH. 15.240; 12. AH. 15.244; 12.AH.15.243; 12.AH.15.247; 12.AH.16.157; 12.AH.16.158; 12.AH.16.196; 12.AH.16.223; 12.AH.16.240; 12.AH.16.244; 12.AH.16.243; 12.AH.16.247; 12.AH.18.157; 12.AH.18.158; 12.AH.18.196; 12.AH.18.223; 12.AH.18.240; 12.AH.18.244; 12.AH.18.243; 12.AH.18.247; 12.AH.26.157; 12.AH.26.158; 12.AH.26.196; 12.AH.26.223; 12.AH.26.240; 12.AH.26.244; 12.AH.26.243; 12.AH.26.247; 12.AH.27.157; 12.AH.27.158; 12.AH.27.196; 12.AH.27.223; 12.AH.27.240; 12.AH.27.244; 12.AH.27.243; 12.AH.27.247; 12.AH.29.157; 12.AH.29.158; 12.AH.29.196; 12.AH.29.223; 12.AH.29.240; 12.AH.29.244; 12.AH.29.243; 12.AH.29.247; 12.AH.54.157; 12.AH.54.158; 12.AH.54.196; 12.AH.54.223; 12.AH.54.240; 12.AH.54.244; 12.AH.54.243; 12.AH.54.247; 12.AH.55.157; 12.AH.55.158; 12.AH.55.196; 12.AH.55.223; 12.AH.55.240; 12.AH.55.244; 12.AH.55.243; 12.AH.55.247; 12. AH.56.157; 12.AH.56.158; 12.AH.56.196; 12.AH.56.223; 12.AH.56.240; 12.AH.56.244; 12.AH.56.243; 12.AH.56.247; 12.AH.157.157; 12. AH. 157.158; 12.AH.157.196; 12. AH. 157.223; 12. AH. 157.240; 12.AH.157.244; 12. AH. 157.243; 12. AH. 157.247; 12.AH.196.157; 12.AH.196.158; 12. AH. 196.196; 12. AH. 196.223; 12. AH. 196.240; 12. AH. 196.244; 12.AH. 196.243; 12.AH. 196.247; 12.AH.223.157; 12.AH.223.158; 12.AH.223.196; 12.AH.223.223; 1ZAH.223.240; 12.AH.223.244; 12.AH.223.243; 12.AH.223.247; 12.AH.240.157; 12.AH.240.158; 12.AH.240.196; 12.AH.240.223; 12.AH.240.240; 12.AH.240.244; 12.AH.240.243; 12.AH.240.247; 12.AH.244.157; 12.AH.244.158; 12.AH.244.196; 12.AH.244.223; 12.AH.244.240; 12.AH.244.244; 12.AH.244.243; 12.AH.244.247; 12.AH.247.157; 12.AH.247.158; 12.AH.247.196; 12.AH.247.223; 12.AH.247.240; 12.AH.247.244; 12.AH.247.243; 12.AH.247.247;
Prodrugs of 12.AT
12.AJ.4.157; 12.AJA158; 12.AJ.4.196; 12.AJ.4.223; 12.AJ.4.240; 12.AJ.4.244; 12.AJ.4.243; 12.AJ.4.247; 12.AJ.5.157; 12.AJ.5.158; 12.AJ.5.196; 12.AJ.5.223; 12.AJ.5.240; 12.AJ.5.244; 12.AJ.5.243; 12.AJ.5.247; 12.AJ.7.157; 12.AJ.7.158; 12.AJ.7.196; 12.AJ.7.223; 12.AJ.7.240; 12.AJ.7.244; 12.AJ.7.243; 12.AJ.7.247; 12.AJ.15.157; 12.AJ.15.158; 12.AJ.15.196; 12.AJ. 15.223; 12.AJ. 15.240; 12.AJ. 15.244; 12.AJ. 15.243; 12.AJ. 15.247; 12.AJ.16.157; 12.AJ.16.158; 12. AJ. 16.196; 12.AJ. 16.223; 12.AJ. 16.240; 12.AJ. 16.244; 12.AJ.16.243; 12.AJ.16.247; 12.AJ.18.157; 12.AJ.18.158; 12.AJ.18.196; 12.AJ.18.223; 12.AJ.18.240; 12.AJ.18.244; 12.AJ.18.243; 12.AJ.18.247; 12.AJ.26.157; 12.AJ.26.158; 12.AJ.26.196; 12.AJ.26.223; 12.AJ.26.240; 12.AJ.26.244; 12.AJ.26.243; 12.AJ.26.247; 12.AJ.27.157; 12.AJ.27.158; 12.AJ.27.196; 12.AJ.27.223; 12.AJ.27.240; 12.AJ.27.244; 12.AJ.27.243; 12.AJ.27.247; 12.AJ.29.157; 12.AJ.29.158; 12.AJ.29.196; 12.AJ.29.223; 12.AJ.29.240; 12.AJ.29.244; 12.AJ.29.243; 12.AJ.29.247; 12.AJ.54.157; 12.AJ.54.158; 12.AJ.54.196; 12.AJ.54.223; 12.AJ.54.240; 12.AJ.54.244; 12.AJ.54.243; 12.AJ.54.247; 12.AJ.55.157; 12.AJ.55.158; 12.AJ.55.196; 12.AJ.55.223; 12.AJ.55.240; 12.AJ.55.244; 12.AJ.55.243; 12.AJ.55.247; 12.AJ.56.157; 12.AJ.56.158; 12.AJ.56.196; 12.AJ.56.223; 12.AJ.56.240; 12.AJ.56.244; 12.AJ.56.243; 12.AJ.56.247; 12. AJ. 157.157; 12.AJ.157.158; 12.AJ.157.196; 12. AJ. 157.223; 12.AJ.157.240; 12.AJ. 157.244; 12.AJ.157.243; 12.AJ. 157.247; 12. AJ. 196.157; 12.AJ.196.158; 12.AJ.196.196; 12.AJ. 196.223;
12. AJ. 196.240; 12.AJ. 196.244; 12.AJ. 196.243; 12.AJ. 196.247; 12.AJ.223.157; 12.AJ.223.158; 12.AJ.223.196; 12.AJ.223.223; 12.AJ.223.240; 12.AJ.223.244; 12.AJ.223.243; 12.AJ.223.247; 12.AJ.240.157; 12.AJ.240.158; 12.AJ.240.196; 12.AJ.240.223; 12.AJ.240.240; 12.AJ.240.244; 12.AJ.240.243; 12.AJ.240.247; 12.AJ.244.157; 12.AJ.244.158; 12.AJ.244.196; 12.AJ.244.223; 12.AJ.244.240; 12.AJ.244.244; 12.AJ.244.243; 12.AJ.244.247; 12.AJ.247.157; 12.AJ.247.158; 12.AJ.247.196; 12.AJ.247.223; 12.AJ.247.240; 12.AJ.247.244; 12.AJ.247.243; 12.AJ.247.247;
Prodrugs of 12.AN
12.AN.4.157; 12.AN.4.158; 12.AN.4.196; 12.AN.4.223; 12.AN.4.240; 12.AN.4.244; 12.AN.4.243; 12.AN.4.247; 12.AN.5.157; 12.AN.5.158; 12.AN.5.196; 12.AN.5.223; 12.AN.5.240; 12.AN.5.244; 12.AN.5.243; 12.AN.5.247; 12.AN.7.157; 12.AN.7.158; 12.AN.7.196; 12.AN.7.223; 12.AN.7.240; 12.AN.7.244; 12.AN.7.243; 12.AN.7.247; 12.AN.15.157; 12.AN.15.158; 12.AN.15.196; 12.AN.15.223; 12.AN.15.240; 12.AN.15.244; 12.AN.15.243; 12.AN.15.247; 12.AN.16.157; 12.AN.16.158; 12.AN.16.196; 12.AN.16.223; 12.AN.16.240; 12.AN.16.244; 12. AN. 16.243; 12.AN.16.247; 12.AN.18.157; 12.AN.18.158; 12. AN. 18.196; 12.AN. 18.223; 12. AN. 18.240; 12.AN. 18.244; 12.AN. 18.243; 12.AN. 18.247; 12.AN.26.157; 12.AN.26.158; 12.AN.26.196; 12.AN.26.223; 12.AN.26.240; 12.AN.26.244; 12.AN.26.243; 12.AN.26.247; 12.AN.27.157; 12.AN.27.158; 12.AN.27.196; 12.AN.27.223; 12.AN.27.240; 12.AN.27.244; 12.AN.27.243; 12.AN.27.247; 12.AN.29.157; 12.AN.29.158; 12.AN.29.196; 12.AN.29.223; 12.AN.29.240; 12.AN.29.244; 12.AN.29.243; 12.AN.29.247; 12.AN.54.157; 12.AN.54.158; 12.AN.54.196; 12.AN.54.223; 12.AN.54.240; 12.AN.54.244; 12.AN.54.243; 12.AN.54.247; 12.AN.55.157; 12.AN.55.158; 12.AN.55.196; 12.AN.55.223; 12.AN.55.240; 12.AN.55.244; 12.AN.55.243; 12.AN.55.247; 12.AN.56.157; 12.AN.56.158; 12.AN.56.196; 12.AN.56.223; 12.AN.56.240; 12.AN.56.244; 12.AN.56.243; 12.AN.56.247; 12. AN. 157.157; 12.AN.157.158; 12.AN.157.196; 12.AN. 157.223; 12. AN. 157.240; 12. AN. 157.244; 12.AN. 157.243; 12.AN. 157.247; 12. AN. 196.157; 12. AN. 196.158; 12. AN. 196.196; 12.AN. 196.223; 12.AN. 196.240; 12. AN. 196.244; 12. AN. 196.243; 12.AN. 196.247; 12.AN.223.157; 12.AN.223.158; 12.AN.223.196; 12.AN.223.223; 12.AN.223.240; 12.AN.223.244; 12.AN.223.243; 12.AN.223.247; 12.AN.240.157; 12.AN.240.158; 12.AN.240.196; 12.AN.240.223; 12.AN.240.240; 12.AN.240.244; 12.AN.240.243; 12.AN.240.247; 12.AN.244.157; 12.AN.244.158; 12.AN.244.196; 12.AN.244.223; 12.AN.244.240; 12.AN.244.244; 12.AN.244.243; 12.AN.244.247; 12.AN.247.157; 12.AN.247.158; 12.AN.247.196; 12.AN.247.223; 12.AN.247.240; 12.AN.247.244; 12.AN.247.243; 12.AN.247.247;
Prodrugs of 12.AP
12.AP.4.157; 12.AP.4.158; 12.AP.4.196; 12.AP.4.223; 12.AP.4.240; 12.AP.4.244; 12.AP.4.243; 12.AP.4.247; 12.AP.5.157; 12.AP.5.158; 12.AP.5.196; 12.AP.5.223; 12.AP.5.240; 12.AP.5.244; 12.AP.5.243; 12.AP.5.247; 12.AP.7.157; 12.AP.7.158; 12.AP.7.196; 12.AP.7.223; 12.AP.7.240; 12.AP.7.244; 12.AP.7.243; 12.AP.7.247; 12.AP.15.157; 12.AP.15.158; 12.AP.15.196; 12.AP.15.223; 12.AP.15.240; 12.AP.15.244; 12.AP.15.243; 12.AP.15.247; 12.AP.16.157; 12.AP.16.158; 12.AP.16.196; 12.AP.16.223; 12.AP.16.240; 12.AP.16.244; 12.AP.16.243; 12.AP.16.247; 12.AP.18.157; 12.AP.18.158; 12.AP.18.196; 12.AP.18.223; 12.AP.18.240; 12.AP.18.244; 12.AP.18.243; 12.AP.18.247; 12.AP.26.157; 12.AP.26.158; 12.AP.26.196; 12.AP.26.223; 12.AP.26.240; 12.AP.26.244; 12.AP.26.243; 12.AP.26.247; 12.AP.27.157; 12.AP.27.158; 12.AP.27.196; 12.AP.27.223;
12.AP.27.240; 12.AP.27.244; 12.AP.27.243; 12.AP.27.247; 12.AP.29.157; 12.AP.29.158; 12.AP.29.196; 12.AP.29.223; 12.AP.29.240; 12.AP.29.244; 12.AP.29.243; 12.AP.29.247; 12.AP.54.157; 12.AP.54.158; 12.AP.54.196; 12.AP.54.223; 12.AP.54.240; 12.AP.54.244; 12.AP.54.243; 12.AP.54.247; 12.AP.55.157; 12.AP.55.158; 12.AP.55.196; 12.AP.55.223; 12.AP.55.240; 12.AP.55.244; 12.AP.55.243; 12.AP.55.247; 12.AP.56.157; 12.AP.56.158; 12.AP.56.196; 12.AP.56.223; 12.AP.56.240; 12.AP.56.244; 12.AP.56.243; 12.AP.56.247; 12.AP. 157.157; 12.AP.157.158; 12.AP.157.196; 12.AP. 157.223; 12.AP. 157.240; 12.AP. 157.244; 12.AP. 157.243; 12.AP. 157.247; 12.AP.196.157; 12. AP. 196.158; 12.AP.196.196; 12. AP. 196.223; 12. AP. 196.240; 12.AP. 196.244; 12. AP. 196.243; 12.AP. 196.247; 12.AP.223.157; 12.AP.223.158; 12.AP.223.196; 12.AP.223.223; 12.AP.223.240; 12. AP.223.244; 12.AP.223.243; 12.AP.223.247; 12.AP.240.157; 12.AP.240.158; 12.AP.240.196; 12.AP.240.223; 12.AP.240.240; 12.AP.240.244; 12.AP.240.243; 12.AP.240.247; 12.AP.244.157; 12.AP.244.158; 12.AP.244.196; 12.AP.244.223; 12.AP.244.240; 12.AP.244.244; 12.AP.244.243; 12.AP.244.247; 12.AP.247.157; 12.AP.247.158; 12.AP.247.196; 12.AP.247.223; 12.AP.247.240; 12.AP.247.244; 12.AP.247.243; 12.AP.247.247;
Prodrugs of 12.AZ
12.AZ.4.157; 12.AZ.4.158; 12.AZ.4.196; 12.AZ.4.223; 12.AZ.4.240; 12.AZ.4.244; 12.AZ.4.243; 12.AZ.4.247; 12.AZ.5.157; 12.AZ.5.158; 12.AZ.5.196; 12.AZ.5.223; 12.AZ.5.240; 12.AZ.5.244; 12.AZ.5.243; 12.AZ.5.247; 12.AZ.7.157; 12.AZ.7.158; 12.AZ.7.196; 12.AZ.7.223; 12.AZ.7.240; 12.AZ.7.244; 12.AZ.7.243; 12.AZ.7.247; 12.AZ.15.157; 12.AZ.15.158; 12.AZ.15.196; 12.AZ. 15.223; 12.AZ. 15.240; 12.AZ. 15.244; 12.AZ.15.243; 12.AZ.15.247; 12.AZ.16.157; 12.AZ.16.158; 12.AZ.16.196; 12.AZ.16.223; 12.AZ.16.240; 12.AZ.16.244; 12.AZ.16.243; 12.AZ.16.247; 12.AZ.18.157; 12.AZ.18.158; 12.AZ.18.196; 12.AZ.18.223; 12.AZ.18.240; 12.AZ.18.244; 12.AZ.18.243; 12.AZ.18.247; 12.AZ.26.157; 12.AZ.26.158; 12.AZ.26.196; 12.AZ.26.223; 12.AZ.26.240; 12.AZ.26.244; 12.AZ.26.243; 12.AZ.26.247; 12.AZ.27.157; 12.AZ.27.158; 12.AZ.27.196; 12.AZ.27.223; 12.AZ.27.240; 12.AZ.27.244; 12.AZ.27.243; 12.AZ.27.247; 12.AZ.29.157; 12.AZ.29.158; 12.AZ.29.196; 12.AZ.29.223; 12.AZ.29.240; 12.AZ.29.244; 12.AZ.29.243; 12.AZ.29.247; 12.AZ.54.157; 12.AZ.54.158; 12.AZ.54.196; 12.AZ.54.223; 12.AZ.54.240; 12.AZ.54.244; 12.AZ.54.243; 12.AZ.54.247; 12.AZ.55.157; 12.AZ.55.158; 12.AZ.55.196; 12.AZ.55.223; 12.AZ.55.240; 12.AZ.55.244; 12.AZ.55.243; 12.AZ.55.247; 12.AZ.56.157; 12.AZ.56.158; 12.AZ.56.196; 12.AZ.56.223; 12.AZ.56.240; 12.AZ.56.244; 12.AZ.56.243; 12.AZ.56.247; 12. AZ. 157.157; 12.AZ.157.158; 12. AZ. 157.196; 12.AZ. 157.223; 12.AZ.157.240; 12.AZ. 157.244; 12.AZ.157.243; 12.AZ. 157.247; 12.AZ.196.157; 12. AZ. 196.158; 12.AZ.196.196; 12. AZ. 196.223; 12.AZ. 196.240; 12.AZ. 196.244; 12.AZ. 196.243; 12.AZ. 196.247; 12.AZ.223.157; 12.AZ.223.158; 12.AZ.223.196; 12.AZ.223.223; 12.AZ.223.240; 12.AZ.223.244; 12.AZ.223.243; 12.AZ.223.247; 12.AZ.240.157; 12.AZ.240.158; 12.AZ.240.196; 12.AZ.240.223; 12.AZ.240.240; 12.AZ.240.244; 12.AZ.240.243; 12.AZ.240.247; 12.AZ.244.157; 12.AZ.244.158; 12.AZ.244.196; 12.AZ.244.223; 12.AZ.244.240; 12.AZ.244.244; 12.AZ.244.243; 12.AZ.244.247; 12.AZ.247.157; 12.AZ.247.158; 12.AZ.247.196; 12.AZ.247.223; 12.AZ.247.240; 12.AZ.247.244; 12.AZ.247.243; 12.AZ.247.247;
Frodrugs of 12.BF
12.BF.4.157; 12.BF.4.158; 12.BF.4.196; 12.BF.4.223; 12.BF.4.240; 12.BF.4.244; 12.BF.4.243; 12.BF.4.247; 12.BF.5.157; 12.BF.5.158; 12.BF.5.196; 12.BF.5.223;
12.BF.5.240; 12.BF.5.244; 12.BF.5.243; 12.BF.5.247; 12.BF.7.157; 12.BF.7.158; 12.BF.7.196; 12.BF.7.223; 12.BF.7.240; 12.BF.7.244; 12.BF.7.243; 12.BF.7.247; 12.BF.15.157; 12.BF.15.158; 12.BF.15.196; 12.BF.15.223; 12.BF.15.240; 12.BF.15.244; 12.BF.15.243; 12.BF.15.247; 12.BF.16.157; 12.BF.16.158; 12.BF.16.196; 12.BF.16.223; 12.BF. 16.240; 12.BF. 16.244; 12.BF. 16.243; 12.BF. 16.247; 12.BF.18.157; 12.BF.18.158; 12.BF.18.196; 12.BF.18.223; 12.BF.18.240; 12.BF.18.244; 12.BF.18.243; 12.BF.18.247; 12.BF.26.157; 12.BF.26.158; 12.BF.26.196; 12.BF.26.223; 12.BF.26.240; 12.BF.26.244; 12.BF.26.243; 12.BF.26.247; 12.BF.27.157; 12.BF.27.158; 12.BF.27.196; 12.BF.27.223; 12.BF.27.240; 12.BF.27.244; 12.BF.27.243; 12.BF.27.247; 12.BF.29.157; 12.BF.29.158; 12.BF.29.196; 12.BF.29.223; 12.BF.29.240; 12.BF.29.244; 12.BF.29.243; 12.BF.29.247; 12.BF.54.157; 12.BF.54.158; 12.BF.54.196; 12.BF.54.223; 12.BF.54.240; 12.BF.54.244; 12.BF.54.243; 12.BF.54.247; 12.BF.55.157; 12.BF.55.158; 12.BF.55.196; 12.BF.55.223; 12.BF.55.240; 12.BF.55.244; 12.BF.55.243; 12.BF.55.247; 12.BF.56.157; 12.BF.56.158; 12.BF.56.196; 12.BF.56.223; 12.BF.56.240; 12.BF.56.244; 12.BF.56.243; 12.BF.56.247; 12.BF.157.157; 12.BF.157.158; 12.BF.157.196; 12.BF. 157.223; 12.BF. 157.240; 12.BF. 157.244; 12.BF. 157.243; 12.BF. 157.247; 12.BF.196.157; 12.BF.196.158; 12.BF.196.196; 12.BF. 196.223; 12.BF. 196.240; 12.BF. 196.244; 12.BF. 196.243; 12.BF. 196.247; 12.BF.223.157; 12.BF.223.158; 12.BF.223.196; 12.BF.223.223; 12.BF.223.240; 12.BF.223.244; 12.BF.223.243; 12.BF.223.247; 12.BF.240.157; 12.BF.240.158; 12.BF.240.196; 12.BF.240.223; 12.BF.240.240; 12.BF.240.244; 12.BF.240.243; 12.BF.240.247; 12.BF.244.157; 12.BF.244.158; 12.BF.244.196; 12.BF.244.223; 12.BF.244.240; 12.BF.244.244; 12.BF.244.243; 12.BF.244.247; 12.BF.247.157; 12.BF.247.158; 12.BF.247.196; 12.BF.247.223; 12.BF.247.240; 12.BF.247.244; 12.BF.247.243; 12.BF.247.247;
Prodrugs of 12.CI
12.CI.4.157; 12.CI.4.158; 12.CI.4.196; 12.CI.4.223; 12.CL4.240; 12.CL4.244; 12.CI.4.243; 12.CI.4.247; 12.CI.5.157; 12.CI.5.158; 12.CI.5.196; 12.CI.5.223; 12.CI.5.240; 12.CI.5.244; 12.CI.5.243; 12.CI.5.247; 12.CI.7.157; 12.CI.7.158; 12.CI.7.196; 12.CL7.223; 12.CI.7.240; 12.CI.7.244; 12.CI.7.243; 12.CI.7.247; 12.a.l5.157; 12.CI.15.158; 12.CI.15.196; 12.CI.15.223; 12.CI.15.240; 12.CI.15.244; 12.CI.15.243; 12.CL15.247; 12.CI.16.157; 12.CI.16.158; 12.CI.16.196; 12.CI.16.223; 12.CI.16.240; 12.CL16.244; 12.CI.16.243; 12.CI.16.247; 12.CI.18.157; 12.CI.18.158; 12.CI.18.196; 12.CL18.223; 12.CI.18.240; 12.CI.18.244; 12.CI.18.243; 12.CI.18.247; 12.CI.26.157; 12.CL26.158; 12.CI.26.196; 12.CI.26.223; 12.CI.26.240; 12.CI.26.244; 12.CI.26.243; 12.CL26.247; 12.CI.27.157; 12.CI.27.158; 12.CI.27.196; 12.CI.27.223; 12.CI.27.240; 12.CI.27.244; 12.CI.27.243; 12.CI.27.247; 12.CI.29.157; 12.CI.29.158; 12.CI.29.196; 12.CI.29.223; 12.CI.29.240; 12.CI.29.244; 12.CI.29.243; 12.CI.29.247; 12.CI.54.157; 12.CI.54.158; 12.CI.54.196; 12.CI.54.223; 12.CI.54.240; 12.CI.54.244; 12.CI.54.243; 12.CI.54.247; 12.CI.55.157; 12.CI.55.158; 12.CI.55.196; 12.CI.55.223; 12.CI.55.240; 12.CI.55.244; 12.CI.55.243; 12.CI.55.247; 12.CI.56.157; 12.CI.56.158; 12.CI.56.196; 12.CI.56.223; 12.CI.56.240; 12.CI.56.244; 12.CI.56.243; 12.CI.56.247; 12.CI.157.157; 12.CI.157.158; 12.CI.157.196; 12.CI. 157.223; 12.CI. 157.240; 12.CI. 157.244; 12.CI. 157.243; 12.CI.157.247; 12.CI.196.157; 12.CI.196.158; 12.CI.196.196; 12.CI. 196.223; 12.CI.196.240; 12.CI. 196.244; 12.CI. 196.243; 12.CI. 196.247; 12.CI.223.157; 12.CI.223.158; 12.CI.223.196; 12.CI.223.223; 12.CI.223.240; 12.CI.223.244; 12.CI.223.243; 12.CI.223.247; 12.CI.240.157; 12.CI.240.158; 12.CI.240.196; 12.CI.240.223; 12.CI.240.240; 12.CI.240.244; 12.CI.240.243; 12.CI.240.247; 12.CI.244.157; 12.CI.244.158; 12.CI.244.196; 12.CI.244.223; 12.CI.244.240; 12.CI.244.244;
12.CI.244.243; 12.CI.244.247; 12.CI.247.157; 12.CI.247.158; 12.CI.247.196; 12.CI.247.223; 12.CI.247.240; 12.CI.247.244; 12.CI.247.243; 12.CI.247.247;
Prodrugs of 12.CQ
12.CO.4.157; 12.CO.4.158; 12.CO.4.196; 12.CO.4.223; 12.CO.4.240; 12.CO.4.244; 12.CO.4.243; 12.C0.4.247; 12.CO.5.157; 12.CO.5.158; 12.CO.5.196; 12.CO.5.223; 12.CO.5.240; 12.CO.5.244; 12.C0.5.243; 12.CO.5.247; 12.CO.7.157; 12.C0.7.158; 12.CO.7.196; 12.CO.7.223; 12.C0.7.240; 12.CO.7.244; 12.CO.7.243; 12.C0.7.247; 12.CO.15.157; 12.CO.15.158; 12.CO.15.196; 12.CO. 15.223; 12.CO. 15.240; 12.CO. 15.244; 12.C0.15.243; 12.CO.15.247; 12.CO.16.157; 12.CO.16.158; 12.CO.16.196; 12.CO.16.223; 12.CO.16.240; 12.CO.16.244; 12.CO.16.243; 12.CO.16.247; 12.CO.18.157; 12.CO.18.158; 12.C0.18.196; 12.CO.18.223; 12.CO.18.240; 12.CO.18.244; 12.CO.18.243; 12.CO.18.247; 12.CO.26.157; 12.CO.26.158; 12.CO.26.196; 12.CO.26.223; 12.CO.26.240; 12.CO.26.244; 12.CO.26.243; 12.CO.26.247; 12.CO.27.157; 12.CO.27.158; 12.CO.27.196; 12.CO.27.223; 12.CO.27.240; 12.CO.27.244; 12.CO.27.243; 12.CO.27.247; 12.CO.29.157; 12.CO.29.158; 12.CO.29.196; 12.CO.29.223; 12.CO.29.240; 12.CO.29.244; 12.CO.29.243; 12.CO.29.247; 12.CO.54.157; 12.CO.54.158; 12.CO.54.196; 12.CO.54.223; 12.CO.54.240; 12.CO.54.244; 12.CO.54.243; 12.CO.54.247; 12.CO.55.157; 12.CO.55.158; 12.CO.55.196; 12.CO.55.223; 12.CO.55.240; 12.CO.55.244; 12.CO.55.243; 12.CO.55.247; 12.CO.56.157; 12.CO.56.158; 12.C0.56.196; 12.CO.56.223; 12.CO.56.240; 12.CO.56.244; 12.CO.56.243; 12.CO.56.247; 12.C0.157.157; 12.CO. 157.158; 12.CO.157.196; 12.CO. 157.223; 12.CO. 157.240; 12.CO. 157.244; 12.CO. 157.243; 12.CO. 157.247; 12.CO.196.157; 12.CO.196.158; 12.CO.196.196; 12.CO. 196.223; 12.CO. 196.240; 12.CO. 196.244; 12.CO. 196.243; 12.CO. 196.247; 12.CO.223.157; 12.CO.223.158; 12.CO.223.196; 12.CO.223.223; 12.C0.223.240; 12.CO.223.244; 12.CO.223.243; 12.CO.223.247; 12.CO.240.157; 12.CO.240.158; 12.CO.240.196; 12.CO.240.223; 12.CO.240.240; 12.CO.240.244; 12.CO.240.243; 12.CO.240.247; 12.CO.244.157; 12.CO.244.158; 12.CO.244.196; 12.C0.244.223; 12.CO.244.240; 12.C0.244.244; 12.CO.244.243; 12.CO.244.247; 12.CO.247.157; 12.CO.247.158; 12.CO.247.196; 12.CO.247.223; 12.CO.247.240; 12.CO.247.244; 12.CO.247.243; 12.CO.247.247.Prodrugs of 13.B
13.B.228.228; 13.B.228.229; 13.B.228.230; 13.B.228.231; 13.B.228.236; 13.B.228.237; 13.B.228.238; 13.B.228.239; 13.B.228.154; 13.B.228.157; 13.B.228.166; 13.B.228.169; 13.B.228.172; 13.B.228.175; 13.B.228.240; 13.B.228.244; 13.B.229.228; 13.B.229.229; 13.B.229.230; 13.B.229.231; 13.B.229.236; 13.B.229.237; 13.B.229.238; 13.B.229.239; 13.B.229.154; 13.B.229.157; 13.B.229.166; 13.B.229.169; 13.B.229.172; 13.B.229.175; 13.B.229.240; 13.B.229.244; 13.B.230.228; 13.B.230.229; 13.B.230.230; 13.B.230.231; 13.B.230.236; 13.B.230.237; 13.B.230.238; 13.B.230.239; 13.B.230.154; 13.B.230.157; 13.B.230.166; 13.B.230.169; 13.B.230.172; 13.B.230.175; 13.B.230.240; 13.B.230.244; 13.B.231.228; 13.B.231.229; 13.B.231.230; 13.B.231.231; 13.B.231.236; 13.B.231.237; 13.B.231.238; 13.B.231.239; 13.B.231.154; 13.B.231.157; 13.B.231.166; 13.B.231.169; 13.B.231.172; 13.B.231.175; 13.B.231.240; 13.B.231.244; 13.B.236.228; 13.B.236.229; 13.B.236.230; 13.B.236.231; 13.B.236.236; 13.B.236.237; 13.B.236.238; 13.B.236.239; 13.B.236.154; 13.B.236.157; 13.B.236.166; 13.B.236.169; 13.B.236.172; 13.B.236.175; 13.B.236.240; 13.B.236.244; 13.B.237.228; 13.B.237.229; 13.B.237.230; 13.B.237.231; 13.B.237.236; 13.B.237.237; 13.B.237.238; 13.B.237.239; 13.B.237.154; 13.B.237.157; 13.B.237.166; 13.B.237.169; 13.B.237.172; 13.B.237.175; 13.B.237.240; 13.B.237.244; 13.B.238.228; 13.B.238.229; 13.B.238.230; 13.B.238.231; 13.B.238.236; 13.B.238.237; 13.B.238.238; 13.B.238.239; 13.B.238.154; 13.B.238.157; 13.B.238.166; 13.B.238.169; 13.B.238.172; 13.B.238.175; 13.B.238.240; 13.B.238.244; 13.B.239.228; 13.B.239.229; 13.B.239.230; 13.B.239.231; 13.B.239.236; 13.B.239.237; 13.B.239.238; 13.B.239.239; 13.B.239.154; 13.B.239.157; 13.B.239.166; 13.B.239.169; 13.B.239.172; 13.B.239.175; 13.B.239.240; 13.B.239.244; 13.B.154.228; 13.B.154.229; 13.B.154.230; 13.B.154.231; 13.B.154.236; 13.B.154.237; 13.B.154.238; 13.B.154.239; 13.B.154.154; 13.B.154.157; 13.B.154.166; 13.B.154.169; 13.B.154.172; 13.B.154175; 13.B.154.240; 13.B.154.244; 13.B.157.228; 13.B.157.229; 13.B.157.230; 13.B.157.231; 13.B.157.236; 13.B.157.237; 13.B.157.238; 13.B.157.239; 13.B.157.154; 13.B.157.157; 13.B.157.166; 13.B.157.169; 13.B.157.172; 13.B.157.175; 13.B.157.240; 13.B.157.244; 13.B.166.228; 13.B.166.229; 13.B.166.230; 13.B.166.231; 13.B.166.236; 13.B.166.237; 13.B.166.238; 13.B.166.239; 13.B.166.154; 13.B.166.157; 13.B.166.166; 13.B.166.169; 13.B.166.172; 13.B.166.175; 13.B.166.240; 13.B.166.244; 13.B.169.228; 13.B.169.229; 13.B.169.230; 13.B.169.231; 13.B.169.236; 13.B.169.237; 13.B.169.238; 13.B.169.239; 13.B.169.154; 13.B.169.157; 13.B.169.166; 13.B.169.169; 13.B.169.172; 13.B.169.175; 13.B.169.240; 13.B.169.244; 13.B.172.228; 13.B.172.229; 13.B.172.230; 13.B.172.231; 13.B.172.236; 13.B.172.237; 13.B.172.238; 13.B.172.239; 13.B.172.154; 13.B.172.157; 13.B.172.166; 13.B.172.169; 13.B.172.172; 13.B.172.175; 13.B.172.240; 13.B.172.244; 13.B.175.228; 13.B.175.229; 13.B.175.230; 13.B.175.231; 13.B.175.236; 13.B.175.237; 13.B.175.238; 13.B.175.239; 13.B.175.154; 13.B.175.157; 13.B.175.166; 13.B.175.169; 13.B.175.172; 13.B.175.175; 13.B.175.240; 13.B.175.244; 13.B.240.228; 13.B.240.229; 13.B.240.230; 13.B.240.231; 13.B.240.236; 13.B.240.237; 13.B.240.238; 13.B.240.239; 13.B.240.154; 13.B.240.157; 13.B.240.166; 13.B.240.169; 13.B.240.172; 13.B.240.175; 13.B.240.240; 13.B.240.244; 13.B.244.228; 13.B.244.229; 13.B.244.230; 13.B.244.231; 13.B.244.236; 13.B.244.237; 13.B.244.238; 13.B.244.239; 13.B.244.154; 13.B.244.157; 13.B.244.166; 13.B.244.169; 13.B.244.172; 13.B.244.175; 13.B.244.240; 13.B.244.244;
Prodrugs of 13.D
13.D.228.228; 13.D.228.229; 13.D.228.230; 13.D.228.231; 13.D.228.236; 13.D.228.237; 13.D.228.238; 13.D.228.239; 13.D.228.154; 13.D.228.157; 13.D.228.166; 13.D.228.169; 13.D.228.172; 13.D.228.175; 13.D.228.240; 13.D.228.244; 13.D.229.228; 13.D.229.229; 13.D.229.230; 13.D.229.231; 13.D.229.236; 13.D.229.237; 13.D.229.238; 13.D.229.239; 13.D.229.154; 13.D.229.157; 13.D.229.166; 13.D.229.169; 13.D.229.172; 13.D.229.175; 13.D.229.240; 13.D.229.244; 13.D.230.228; 13.D.230.229; 13.D.230.230; 13.D.230.231; 13.D.230.236; 13.D.230.237; 13.D.230.238; 13.D.230.239; 13.D.230.154; 13.D.230.157; 13.D.230.166; 13.D.230.169; 13.D.230.172; 13.D.230.175; 13.D.230.240; 13.D.230.244; 13.D.231.228; 13.D.231.229; 13.D.231.230; 13.D.231.231; 13.D.231.236; 13.D.231.237; 13.D.231.238; 13.D.231.239; 13.D.231.154; 13.D.231.157; 13.D.231.166; 13.D.231.169; 13.D.231.172; 13.D.231.175; 13.D.231.240; 13.D.231.244; 13.D.236.228; 13.D.236.229; 13.D.236.230; 13.D.236.231; 13.D.236.236; 13.D.236.237; 13.D.236.238; 13.D.236.239; 13.D.236.154; 13.D.236.157; 13.D.236.166; 13.D.236.169; 13.D.236.172; 13.D.236.175; 13.D.236.240; 13.D.236.244; 13.D.237.228; 13.D.237.229; 13.D.237.230; 13.D.237.231; 13.D.237.236; 13.D.237.237; 13.D.237.238; 13.D.237.239; 13.D.237.154; 13.D.237.157; 13.D.237.166; 13.D.237.169; 13.D.237.172; 13.D.237.175; 13.D.237.240; 13.D.237.244; 13.D.238.228; 13.D.238.229; 13.D.238.230; 13.D.238.231; 13.D.238.236; 13.D.238.237; 13.D.238.238; 13.D.238.239; 13.D.238.154; 13.D.238.157; 13.D.238.166; 13.D.238.169; 13.D.238.172; 13.D.238.175; 13.D.238.240; 13.D.238.244; 13.D.239.228; 13.D.239.229; 13.D.239.230; 13.D.239.231; 13.D.239.236; 13.D.239.237; 13.D.239.238; 13.D.239.239; 13.D.239.154; 13.D.239.157; 13.D.239.166; 13.D.239.169; 13.D.239.172; 13.D.239.175; 13.D.239.240; 13.D.239.244; 13.D.154.228; 13.D.154.229; 13.D.154.230; 13.D.154.231; 13.D.154.236; 13.D.154.237; 13.D.154.238; 13.D.154.239; 13.D.154.154; 13.D.154.157; 13.D.154.166; 13.D.154.169; 13.D.154.172; 13.D.154.175; 13.D.154.240; 13.D.154.244; 13.D.157.228; 13.D.157.229; 13.D.157.230; 13.D.157.231; 13.D.157.236; 13.D.157.237; 13.D.157.238; 13.D.157.239; 13.D.157.154; 13.D.157.157; 13.D.157.166; 13.D.157.169; 13.D.157.172; 13.D.157.175; 13.D.157.240; 13.D.157.244; 13.D.166.228; 13.D.166.229; 13.D.166.230; 13.D.166.231; 13.D.166.236; 13.D.166.237; 13.D.166.238; 13.D.166.239; 13.D.166.154; 13.D.166.157; 13.D.166.166; 13.D.166.169; 13.D.166.172; 13.D.166.175; 13.D.166.240; 13.D.166.244; 13.D.169.228; 13.D.169.229; 13.D.169.230; 13.D.169.231; 13.D.169.236; 13.D.169.237; 13.D.169.238; 13.D.169.239; 13.D.169.154; 13.D.169.157; 13.D.169.166; 13.D.169.169; 13.D.169.172; 13.D.169.175; 13.D.169.240; 13.D.169.244; 13.D.172.228; 13.D.172.229; 13.D.172.230; 13.D.172.231; 13.D.172.236; 13.D.172.237; 13.D.172.238; 13.D.172.239; 13.D.172.154; 13.D.172.157; 13.D.172.166; 13.D.172.169; 13.D.172.172; 13.D.172.175; 13.D.172.240; 13.D.172.244; 13.D.175.228; 13.D.175.229; 13.D.175.230; 13.D.175.231; 13.D.175.236; 13.D.175.237; 13.D.175.238; 13.D.175.239; 13.D.175.154; 13.D.175.157; 13.D.175.166; 13.D.175.169; 13.D.175.172; 13.D.175.175; 13.D.175.240; 13.D.175.244; 13.D.240.228; 13.D.240.229; 13.D.240.230; 13.D.240.231; 13.D.240.236; 13.D.240.237; 13.D.240.238; 13.D.240.239; 13.D.240.154; 13.D.240.157; 13.D.240.166; 13.D.240.169; 13.D.240.172; 13.D.240.175; 13.D.240.240; 13.D.240.244; 13.D.244.228; 13.D.244.229; 13.D.244.230; 13.D.244.231; 13.D.244.236; 13.D.244.237; 13.D.244.238; 13.D.244.239; 13.D.244.154; 13.D.244.157; 13.D.244.166; 13.D.244.169; 13.D.244.172; 13.D.244.175; 13.D.244.240; 13.D.244.244;
Prodrugs of 13.E
13.E.228.228; 13.E.228.229; 13.E.228.230; 13.E.228.231; 13.E.228.236; 13.E.228.237; 13.E.228.238; 13.E.228.239; 13.E.228.154; 13.E.228.157; 13.E.228.166; 13.E.228.169; 13.E.228.172; 13.E.228.175; 13.E.228.240; 13.E.228.244; 13.E.229.228; 13.E.229.229; 13.E.229.230; 13.E.229.231; 13.E.229.236; 13.E.229.237; 13.E.229.238; 13.E.229.239; 13.E.229.154; 13.E.229.157; 13.E.229.166; 13.E.229.169; 13.E.229.172; 13.E.229.175; 13.E.229.240; 13.E.229.244; 13.E.230.228; 13.E.230.229; 13.E.230.230; 13.E.230.231; 13.E.230.236; 13.E.230.237; 13.E.230.238; 13.E.230.239; 13.E.230.154; 13.E.230.157; 13.E.230.166; 13.E.230.169; 13.E.230.172; 13.E.230.175; 13.E.230.240; 13.E.230.244; 13.E.231.228; 13.E.231.229; 13.tl.23l.230; 13.E.231.231; 13.E.231.236; 13.E.231.237; 13.E.231.238; 13.E.231.239; 13.E.231.154; 13.E.231.157; 13.E.231.166; 13.E.231.169; 13.E.231.172; 13.E.231.175; 13.E.231.240; 13.E.231.244; 13.E.236.228; 13.E.236.229; 13.E.236.230; 13.E.236.231; 13.E.236.236; 13.E.236.237; 13.E.236.238; 13.E.236.239; 13.E.236.154; 13.E.236.157; 13.E.236.166; 13.E.236.169; 13.E.236.172; 13.E.236.175; 13.E.236.240; 13.E.236.244; 13.E.237.228; 13.E.237.229; 13.E.237.230; 13.E.237.231; 13.E.237.236; 13.E.237.237; 13.E.237.238; 13.E.237.239; 13.E.237.154; 13.E.237.157; 13.E.237.166; 13.E.237.169; 13.E.237.172; 13.E.237.175; 13.E.237.240; 13.E.237.244; 13.E.238.228; 13.E.238.229; 13.E.238.230; 13.E.238.231; 13.E.238.236; 13.E.238.237; 13.E.238.238; 13.E.238.239; 13.E.238.154; 13.E.238.157; 13.E.238.166; 13.E.238.169; 13.E.238.172; 13.E.238.175; 13.E.238.240; 13.E.238.244; 13.E.239.228; 13.E.239.229; 13.E.239.230; 13.E.239.231; 13.E.239.236; 13.E.239.237; 13.E.239.238; 13.E.239.239; 13.E.239.154; 13.E.239.157; 13.E.239.166; 13.E.239.169; 13.E.239.172; 13.E.239.175; 13.E.239.240; 13.E.239.244; 13.E.154.228; 13.E.154.229; 13.E.154.230; 13.E.154.231; 13.E.154.236; 13.E.154.237; 13.E.154.238; 13.E.154.239; 13.E.154.154; 13.E.154.157; 13.E.154.166; 13.E.154.169; 13.E.154.172; 13.E.154.175; 13.E.154.240; 13.E.154.244; 13.E.157.228; 13.E.157.229; 13.E.157.230; 13.E.157.231; 13.E.157.236; 13.E.157.237; 13.E.157.238; 13.E.157.239; 13.E.157.154; 13.E.157.157; 13.E.157.166; 13.E.157.169; 13.E.157.172; 13.E.157.175; 13.E.157.240; 13.E.157.244; 13.E.166.228; 13.E.166.229; 13.E.166.230; 13.E.166.231; 13.E.166.236; 13.E.166.237; 13.E.166.238; 13.E.166.239; 13.E.166.154; 13.E.166.157; 13.E.166.166; 13.E.166.169; 13.E.166.172; 13.E.166.175; 13.E.166.240; 13.E.166.244; 13.E.169.228; 13.E.169.229; 13.E.169.230; 13.E.169.231; 13.E.169.236; 13.E.169.237; 13.E.169.238; 13.E.169.239; 13.E.169.154; 13.E.169.157; 13.E.169.166; 13.E.169.169; 13.E.169.172; 13.E.169.175; 13.E.169.240; 13.E.169.244; 13.E.172.228; 13.E.172.229; 13.E.172.230; 13.E.172.231; 13.E.172.236; 13.E.172.237; 13.E.172.238; 13.E.172.239; 13.E.172.154; 13.E.172.157; 13.E.172.166; 13.E.172.169; 13.E.172.172; 13.E.172.175; 13.E.172.240; 13.E.172.244; 13.E.175.228; 13.E.175.229; 13.E.175.230; 13.E.175.231; 13.E.175.236; 13.E.175.237; 13.E.175.238; 13.E.175.239; 13.E.175.154; 13.E.175.157; 13.E.175.166; 13.E.175.169; 13.E.175.172; 13.E.175.175; 13.E.175.240; 13.E.175.244; 13.E.240.228; 13.E.240.229; 13.E.240.230; 13.E.240.231; 13.E.240.236; 13.E.240.237; 13.E.240.238; 13.E.240.239; 13.E.240.154; 13.E.240.157; 13.E.240.166; 13.E.240.169; 13.E.240.172; 13.E.240.175; 13.E.240.240; 13.E.240.244; 13.E.244.228; 13.E.244.229; 13.E.244.230; 13.E.244.231; 13.E.244.236; 13.E.244.237; 13.E.244.238; 13.E.244.239; 13.E.244.154; 13.E.244.157; 13.E.244.166; 13.E.244.169; 13.E.244.172; 13.E.244.175; 13.E.244.240; 13.E.244.244;
Prodrugs of 13.G
13.G.228.228; 13.G.228.229; 13.G.228.230; 13.G.228.231; 13.G.228.236; 13.G.228.237; 13.G.228.238; 13.G.228.239; 13.G.228.154; 13.G.228.157; 13.G.228.166; 13.G.228.169; 13.G.228.172; 13.G.228.175; 13.G.228.240; 13.G.228.244; 13.G.229.228; 13.G.229.229; 13.G.229.230; 13.G.229.231; 13.G.229.236; 13.G.229.237; 13.G.229.238; 13.G.229.239; 13.G.229.154; 13.G.229.157; 13.G.229.166; 13.G.229.169; 13.G.229.172; 13.G.229.175; 13.G.229.240; 13.G.229.244; 13.G.230.228; 13.G.230.229; 13.G.230.230; 13.G.230.231; 13.G.230.236; 13.G.230.237; 13.G.230.238; 13.G.230.239; 13.G.230.154; 13.G.230.157; 13.G.230.166; 13.G.230.169; 13.G.230.172; 13.G.230.175; 13.G.230.240; 13.G.230.244; 13.G.231.228; 13.G.231.229; 13.G.231.230; 13.G.231.231; 13.G.231.236; I3.G.231.237; 13.G.231.238; 13.G.231.239; 13.G.231.154; 13.G.231.157; 13.G.231.166; 13.G.231.169; 13.G.231.172; 13.G.231.175; 13.G.231.240; 13.G.231.244; 13.G.236.228; 13.G.236.229; 13.G.236.230; 13.G.236.231; 13.G.236.236; 13.G.236.237; 13.G.236.238; 13.G.236.239; 13.G.236.154; 13.G.236.157; 13.G.236.166; 13.G.236.169; 13.G.236.172; 13.G.236.175; 13.G.236.240; 13.G.236.244; 13.G.237.228; 13.G.237.229; 13.G.237.230; 13.G.237.231; 13.G.237.236; 13.G.237.237; 13.G.237.238; 13.G.237.239; 13.G.237.154; 13.G.237.157; 13.G.237.166; 13.G.237.169; 13.G.237.172; 13.G.237.175; 13.G.237.240; 13.G.237.244; 13.G.238.228; 13.G.238.229; 13.G.238.230; 13.G.238.231; 13.G.238.236; 13.G.238.237; 13.G.238.238; 13.G.238.239; 13.G.238.154; 13.G.238.157; 13.G.238.166; 13.G.238.169; 13.G.238.172; 13.G.238.175; 13.G.238.240; 13.G.238.244; 13.G.239.228; 13.G.239.229; 13.G.239.230; 13.G.239.231; 13.G.239.236; 13.G.239.237; 13.G.239.238; 13.G.239.239; 13.G.239.154; 13.G.239.157; 13.G.239.166; 13.G.239.169; 13.G.239.172; 13.G.239.175; 13.G.239.240; 13.G.239.244; 13.G.154.228; 13.G.154.229; 13.G.154.230; 13.G.154.231; 13.G.154.236; 13.G.154.237; 13.G.154.238; 13.G.154.239; 13.G.154.154; 13.G.154.157; 13.G.154.166; 13.G.154.169; 13.G.154.172; 13.G.154.175; 13.G.154.240; 13.G.154.244; 13.G.157.228; 13.G.157.229; 13.G.157.230; 13.G.157.231; 13.G.157.236; 13.G.157.237; 13.G.157.238; 13.G.157.239; 13.G.157.154; 13.G.157.157; 13.G.157.166; 13.G.157.169; 13.G.157.172; 13.G.157.175; 13.G.157.240; 13.G.157.244; 13.G.166.228; 13.G.166.229; 13.G.166.230; 13.G.166.231; 13.G.166.236; 13.G.166.237; 13.G.166.238; 13.G.166.239; 13.G.166.154; 13.G.166.157; 13.G.166.166; 13.G.166.169; 13.G.166.172; 13.G.166.175; 13.G.166.240; 13.G.166.244; 13.G.169.228; 13.G.169.229; 13.G.169.230; 13.G.169.231; 13.G.169.236; 13.G.169.237; 13.G.169.238; 13.G.169.239; 13.G.169.154; 13.G.169.157; 13.G.169.166; 13.G.169.169; 13.G.169.172; 13.G.169.175; 13.G.169.240; 13.G.169.244; 13.G.172.228; 13.G.172.229; 13.G.172.230; 13.G.172.231; 13.G.172.236; 13.G.172.237; 13.G.172.238; 13.G.172.239; 13.G.172.154; 13.G.172.157; 13.G.172.166; 13.G.172.169; 13.G.172.172; 13.G.172.175; 13.G.172.240; 13.G.172.244; 13.G.175.228; 13.G.175.229; 13.G.175.230; 13.G.175.231; 13.G.175.236; 13.G.175.237; 13.G.175.238; 13.G.175.239; 13.G.175.154; 13.G.175.157; 13.G.175.166; 13.G.175.169; 13.G.175.172; 13.G.175.175; 13.G.175.240; 13.G.175.244; 13.G.240.228; 13.G.240.229; 13.G.240.230; 13.G.240.231; 13.G.240.236; 13.G.240.237; 13.G.240.238; 13.G.240.239; 13.G.240.154; 13.G.240.157; 13.G.240.166; 13.G.240.169; 13.G.240.172; 13.G.240.175; 13.G.240.240; 13.G.240.244; 13.G.244.228; 13.G.244.229; 13.G.244.230; 13.G.244.231; 13.G.244.236; 13.G.244.237; 13.G.244.238; 13.G.244.239; 13.G.244.154; 13.G.244.157; 13.G.244.166; 13.G.244.169; 13.G.244.172; 13.G.244.175; 13.G.244.240; 13.G.244.244;
Prodrugs of j.3.1
13.1.228.228; 13.1.228.229; 13.1.228.230; 13.1.228.231; 13.1.228.236; 13.1.228.237; 13.1.228.238; 13.1.228.239; 13.1.228.154; 13.1.228.157; 13.1.228.166; 13.1.228.169; 13.1.228.172; 13.1.228.175; 13.1.228.240; 13.1.228.244; 13.1.229.228; 13.1.229.229; 13.1.229.230; 13.1.229.231; 13.1.229.236; 13.1.229.237; 13.1.229.238; 13.1.229.239; 13.1.229.154; 13.1.229.157; 13.1.229.166; 13.1.229.169; 13.1.229.172; 13.1.229.175; 13.1.229.240; 13.1.229.244; 13.1.230.228; 13.1.230.229; 13.1.230.230; 13.1.230.231; 13.1.230.236; 13.1.230.237; 13.1.230.238; 13.1.230.239; 13.1.230.154; 13.1.230.157; 13.1.230.166; 13.1.230.169; 13.1.230.172; 13.1.230.175; 13.1.230.240; 13.1.230.244; 13.1.231.228; 13.1.231.229; 13.1.231.230; 13.1.231.231; 13.1.231.236; 13.1.231.237; 13.1.231.238; 13.1.231.239; 13.1.231.154; 13.1.231.157; 13.1.231.166; 13.1.231.169; 13.1.231.172; 13.1.231.175; 13.1.231.240; 13.1.231.244; 13.1.236.228; 13.1.236.229; 13.1.236.230; 13.1.236.231; 13.1.236.236; 13.1.236.237; 13.1.236.238; 13.1.236.239; 13.1.236.154; 13.1.236.157; 13.1.236.166; 13.1.236.169; 13.1.236.172; 13.1.236.175; 13.1.236.240; 13.1.236.244; 13.1.237.228; 13.1.237.229; 13.1.237.230; 13.1.237.231; 13.1.237.236; 13.1.237.237; 13.1.237.238; 13.1.237.239; 13.1.237.154; 13.1.237.157; 13.1.237.166; 13.1.237.169; 13.1.237.172; 13.1.237.175; 13.1.237.240; 13.1.237.244; 13.1.238.228; 13.1.238.229; 13.1.238.230; 13.1.238.231; 13.1.238.236; 13.1.238.237; 13.1.238.238; 13.L238.239; 13.1.238.154; 13.1.238.157; 13.1.238.166; 13.1.238.169; 13.1.238.172; 13.1.238.175; 13.1.238.240; 13.1.238.244; 13.1.239.228; 13.L239.229; 13.1.239.230; 13.L239.231; 13.1.239.236; 13.1.239.237; 13.1.239.238; 13.1.239.239; 13.1.239.154; 13.1.239.157; 13.1.239.166; 13.1.239.169; 13.1.239.172; 13.1.239.175; 13.1.239.240; 13.L239.244; 13.1.154.228; 13.1.154.229; 13.1.154.230; 13.1.154.231; 13.1.154.236; 13.1.154.237; 13.1.154.238; 13.1.154.239; 13.1.154.154; 13.1.154.157; 13.1.154.166; 13.1.154.169; 13.L154.172; 13.1.154.175; 13.1.154.240; 13.L154.244; 13.1.157.228; 13.1.157.229; 13.1.157.230; 13.1.157.231; 13.1.157.236; 13.1.157.237; 13.1.157.238; 13.1.157.239; 13.L157.154; 13.1.157.157; 13.1.157.166; 13.1.157.169; 13.1.157.172; 13.1.157.175; 13.1.157.240; 13.1.157.244; 13.1.166.228; 13.1.166.229; 13.1.166.230; 13.1.166.231; 13.1.166.236; 13.1.166.237; 13.1.166.238; 13.L166.239; 13.1.166.154; 13.1.166.157; 13.1.166.166; 13.1.166.169; 13.1.166.172; 13.1.166.175; 13.1.166.240; 13.1.166.244; 13.1.169.228; 13.1.169.229; 13.1.169.230; 13.1.169.231; 13.1.169.236; 13.1.169.237; 13.1.169.238; 13.1.169.239; 13.1.169.154; 13.1.169.157; 13.1.169.166; 13.1.169.169; 13.1.169.172; 13.1.169.175; 13.1.169.240; 13.1.169.244; 13.1.172.228; 13.1.172.229; 13.1.172.230; 13.1.172.231; 13.1.172.236; 13.1.172.237; 13.1.172.238; 13.1.172.239; 13.1.172.154; 13.1.172.157; 13.1.172.166; 13.1.172.169; 13.1.172.172; 13.1.172.175; 13.1.172.240; 13.1.172.244; 13.1.175.228; 13.1.175.229; 13.1.175.230; 13.1.175.231; 13.1.175.236; 13.1.175.237; 13.1.175.238; 13.1.175.239; 13.1.175.154; 13.1.175.157; 13.1.175.166; 13.1.175.169; 13.1.175.172; 13.1.175.175; 13.1.175.240; 13.1.175.244; 13.1.240.228; 13.1.240.229; 13.1.240.230; 13.1.240.231; 13.1.240.236; 13.1.240.237; 13.1.240.238; 13.1.240.239; 13.1.240.154; 13.1.240.157; 13.1.240.166; 13.1.240.169; 13.1.240.172; 13.1.240.175; 13.1.240.240; 13.1.240.244; 13.1.244.228; 13.1.244.229; 13.1.244.230; 13.1.244.231; 13.1.244.236; 13.1.244.237; 13.1.244.238; 13.1.244.239; 13.1.244.154; 13.1.244.157; 13.1.244.166; 13.1.244.169; 13.1.244.172; 13.1.244.175; 13.1.244.240; 13.1.244.244;
Frodrugs of 13.T
13.J.228.228; 13.J.228.229; 13J.228.230; 13J.228.231; 13J.228.236; 13J.228.237; 13J.228.238; 13J.228.239; 13J.228.154; 13.J.228.157; 13J.228.166; 13J.228.169; 13J.228.172; 13J.228.175; 13J.228.240; 13J.228.244; 13J.229.228; 13J.229.229; 13J.229.230; 13.J.229.231; 13J.229.236; 13.J.229.237; 13.J.229.238; 13J.229.239; 13J.229.154; 13J.229.157; 13J.229.166; 13J.229.169; 13J.229.172; 13.J.229.175; 13J.229.240; 13J.229.244; 13J.230.228; 13.J.230.229; 13 J.230.230; 13J.230.231; 13J.230.236; 13J.230.237; 13J.230.238; 13.J.230.239; 13J.230.154; 13.J.230.157; 13J.230.166; 13J.230.169; 13J.230.172; 13.J.230.175; 13J.230.240; 13.J.230.244; 13J.231.228; 13J.231.229; 13.J.231.230; 13J.231.231; 13J.231.236; 13J.231.237; 13.J.231.238; 13.J.231.239; 13.J.231.154; 13J.231.157; 13J.231.166; 13.J.231.169; 13J.231.172; 13J.231.175; 13J.231.240; 13.J.231.244; 13J.236.228; 13.J.236.229; 13J.236.230; 13 J.236.231; 13J.236.236; 13.J.236.237; 13J.236.238; 13.J.236.239; 13J.236.154; 13.J.236.157; 13.J.236.166; 13.J.236.169; 13J.236.172; 13.J.236.175; 13.J.236.240; 13J.236.244; 13 J.237.228; 13J.237.229; 13 J.237.230; 13.J.237.231; 13J.237.236; 13 J.237.237; 13J.237.238; 13J.237.239; 13.J.237.154; 13.J.237.157; 13J.237.166; 13.J.237.169; 13.J.237.172; 13.J.237.175; 13J.237.240; 13J.237.244; 13J.238.228; 13J.238.229; 13J.238.230; 13J.238.231; 13 J.238.236; 13J.238.237; 13.J.238.238; 13J.238.239; 13J.238.154; 13.J.238.157; 13.J.238.166; 13.J.238.169; 13J.238.172; 13.J.238.175; 13.J.238.240; 13.J.238.244; 13.J.239.228; 13J.239.229; 13.J.239.230; 13.J.239.231; 13J.239.236; 13J.239.237; 13J.239.238; 13.J.239.239; 13J.239.154; 13J.239.157; 13J.239.166; 13J.239.169; 13J.239.172; 13.J.239.175; 13J.239.240; 13.J.239.244; 13J.154.228; 13.J.154.229; 13.J.154.230; 13.J.154.231; 13.J.154.236; 13.J.154.237; 13.J.154.238; 13J.154.239; 13.J.154.154; 13.J.154.157; 13J.154.166; 13.J.154.169; 13.J.154.172; 13.J.154.175; 13J.154.240; 13.J.154.244; 13.J.157.228; 13J.157.229; 13.J.157.230; 13.J.157.231; 13J.157.236; 13J.157.237; 13.J.157.238; 13.J.157.239; 13.J.157.154; 13.J.157.157; 13.J.157.166; 13.J.157.169; 13.J.157.172; 13.J.157.175; 13.J.157.240; 13 J.157.244; 13.J.166.228; 13.J.166.229; 13.J.166.230; 13J.166.231; 13 J.166.236; 13.J.166.237; 13J.166.238; 13.J.166.239; 13.J.166.154; 13.J.166.157; 13.J.166.166; 13J.166.169; 13.J.166.172; 13.J.166.175; 13.J.166.240; 13.J.166.244; 13J.169.228; 13.J.169.229; 13.J.169.230; 13J.169.231; 13.J.169.236; 13J.169.237; 13.J.169.238; 13J.169.239; 13J.169.154; 13.J.169.157; 13.J.169.166; 13.J.169.169; 13.J.169.172; 13J.169.175; 13J.169.240; 13.J.169.244; 13J.172.228; 13.J.172.229; 13J.172.230; 13 J.172.231; 13.J.172.236; 13.J.172.237; 13J.172.238; 13J.172.239; 13.J.172.154; 13.J.172.157; 13J.172.166; 13.J.172.169; 13J.172.172; 13J.172.175; 13J.172.240; 13.J.172.244; 13J.175.228; 13J.175.229; 13.J.175.230; 13.J.175.231; 13.J.175.236; 13.J.175.237; 13.J.175.238; 13.J.175.239; 13J.175.154; 13J.175.157; 13J.175.166; 13.J.175.169; 13.J.175.172; 13.J.175.175; 13.J.175.240; 13.J.175.244; 13.J.240.228; 13.J.240.229; 13J.240.230; 13.J.240.231; 13.J.240.236; 13J.240.237; 13J.240.238; 13.J.240.239; 13.J.240.154; 13.J.240.157; 13.J.240.166; 13.J.240.169; 13J.240.172; 13.J.240.175; 13.J.240.240; 13.J.240.244; 13.J.244.228; 13J.244.229; 13.J.244.230; 13.J.244.231; 13.J.244.236; 13.J.244.237; 13.J.244.238; 13 J.244.239; 13.J.244.154; 13.J.244.157; 13J.244.166; 13.J.244.169; 13.J.244.172; 13.J.244.175; 13.J.244.240; 13.J.244.244;
Prodrues of 13.L
13.L.228.228; 13.L.228.229; 13.L.228.230; 13.L.228.231; 13.L.228.236; 13.L.228.237;
3.L.228.238; 13.L.228.239; 13.L.228.154; 13.L.228.157; 13.L.228.166; 13.L.228.169;
3.L.228.172; 13.L.228.175; 13.L.228.240; 13.L.228.244; 13.L.229.228; 13.L.229.229;
.3.L.229.230; 13.L.229.231; 13.L.229.236; 13.L.229.237; 13.L.229.238; 13.L.229.239;
.3.L.229.154; 13.L.229.157; 13.L.229.166; 13.L.229.169; 13.L.229.172; 13.L.229.175;
.3.L.229.240; 13.L.229.244; 13.L.230.228; 13.L.230.229; 13.L.230.230; 13.L.230.231;
.3.L.230.236; 13.L.230.237; 13.L.230.238; 13.L.230.239; 13.L.230.154; 13.L.230.157;
.3.L.230.166; 13.L.230.169; 13.L.230.172; 13.L.230.175; 13.L.230.240; 13.L.230.244;
.3.L.231.228; 13.L.231.229; 13.L.231.230; 13.L.231.231; 13.L.231.236; 13.L.231.237;
.3.L.231.238; 13.L.231.239; 13.L.231.154; 13.L.231.157; 13.L.231.166; 13.L.231.169;
L3.L.231.172; 13.L.231.175; 13.L.231.240; 13.L.231.244; 13.L.236.228; 13.L.236.229;
13.L.236.230; 13.L.236.231; 13.L.236.236; 13.L.236.237; 13.L.236.238; 13.L.236.239;
L3.L.236.154; 13.L.236.157; 13.L.236.166; 13.L.236.169; 13.L.236.172; 13.L.236.175;
L3.L.236.240; 13.L.236.244; I3.L.237.228; 13.L.237.229; 13.L.237.230; 13.L.237.231;
L3.L.237.236; 13.L.237.237; 13.L.237.238; 13.L.237.239; 13.L.237.154; 13.L.237.157;
L3.L.237.166; 13.L.237.169; 13.L.237.172; 13.L.237.175; 13.L.237.240; 13.L.237.244;
L3.L.238.228; 13.L.238.229; 13.L.238.230; 13.L.238.231; 13.L.238.236; 13.L.238.237;
L3.L.238.238; 13.L.238.239; 13.L.238.154; 13.L.238.157; 13.L.238.166; 13.L.238.169;
L3.L.238.172; 13.L.238.175; 13.L.238.240; 13.L.238.244; 13.L.239.228; 13.L.239.229;
L3.L.239.230; 13.L.239.231; 13.L.239.236; 13.L.239.237; 13.L.239.238; 13.L.239.239;
13.L.239.154; 13.L.239.157; 13.L.239.166; 13.L.239.169; 13.L.239.172; 13.L.239.175;
L3.L.239.240; 13.L.239.244; 13.L.154.228; 13.L.154.229; 13.L.154.230; 13.L.154.231;
13.L.154.236; 13.L.154.237; 13.L.154.238; 13.L.154.239; 13.L.154.154; 13.L.154.157;
13.L.154.166; 13.L.154.169; 13.L.154.172; 13.L.154.175; 13.L.154.240; 13.L.154.244;
13.L.157.228; 13.L.157.229; 13.L.157.230; 13.L.157.231; 13.L.157.236; 13.L.157.237;
13.L.157.238; 13.L.157.239; 13.L.157.154; 13.L.157.157; 13.L.157.166; 13.L.157.169;
13.L.157.172; 13.L.157.175; 13.L.157.240; 13.L.157.244; 13.L.166.228; 13.L.166.229;
13.L.166.230; 13.L.166.231; 13.L.166.236; 13.L.166.237; 13.L.166.238; 13.L.166.239;
13.L.166.154; 13.L.166.157; 13.L.166.166; 13.L.166.169; 13.L.166.172; 13.L.166.175;
13.L.166.240; 13.L.166.244; 13.L.169.228; 13.L.169.229; 13.L.169.230; 13.L.169.231;
13.L.169.236; 13.L.169.237; 13.L.169.238; 13.L.169.239; 13.L.169.154; 13.L.169.157;
13.L.169.166; 13.L.169.169; 13.L.169.172; 13.L.169.175; 13.L.169.240; 13.L.169.244;
13.L.172.228; 13.L.172.229; 13.L.172.230; 13.L.172.231; 13.L.172.236; 13.L.172.237;
13.L.172.238; 13.L.172.239; 13.L.172.154; 13.L.172.157; 13.L.172.166; 13.L.172.169;
13.L.172.172; 13.L.172.175; 13.L.172.240; 13.L.172.244; 13.L.175.228; 13.L.175.229;
13.L.175.230; 13.L.175.231; 13.L.175.236; 13.L.175.237; 13.L.175.238; 13.L.175.239;
13.L.175.154; 13.L.175.157; 13.L.175.166; 13.L.175.169; 13.L.175.172; 13.L.175.175;
13.L.175.240; 13.L.175.244; 13.L.240.228; 13.L.240.229; 13.L.240.230; 13.L.240.231;
13.L.240.236; 13.L.240.237; 13.L.240.238; 13.L.240.239; 13.L.240.154; 13.L.240.157;
13.L.240.166; 13.L.240.169; 13.L.240.172; 13.L.240.175; 13.L.240.240; 13.L.240.244;
13.L.244.228; 13.L.244.229; 13.L.244.230; 13.L.244.231; 13.L.244.236; 13.L.244.237;
13.L.244.238; 13.L.244.239; 13.L.244.154; 13.L.244.157; 13.L.244.166; 13.L.244.169;
13.L.244.172; 13.L.244.175; 13.L.244.240; 13.L.244.244;
Prodrugs of 13.O
13.O.228.228; 13.O.228.229; 13.O.228.230; 13.O.228.231; 13.O.228.236; 13.O.228.237; 13.O.228.238; 13.O.228.239; 13.O.228.154; 13.O.228.157; 13.O.228.166; 13.O.228.169; 13.0.228.172; 13.O.228.175; 13.O.228.240; 13.O.228.244; 13.O.229.228; 13.O.229.229; 13.O.229.230; 13.O.229.231; 13.O.229.236; 13.O.229.237; 13.O.229.238; 13.O.229.239; 13.O.229.154; 13.O.229.157; 13.O.229.166; 13.O.229.169; 13.O.229.172; 13.O.229.175; 13.O.229.240; 13.O.229.244; 13.O.230.228; 13.O.230.229; 13.O.230.230; 13.O.230.231; 13.O.230.236; 13.O.230.237; 13.O.230.238; 13.O.230.239; 13.O.230.154; 13.O.230.157; 13.O.230.166; 13.O.230.169; 13.O.230.172; 13.O.230.175; 13.O.230.240; 13.O.230.244; 13.O.231.228; 13.O.231.229; 13.O.231.230; 13.O.231.231; 13.O.231.236; 13.O.231.237; 13.O.231.238; 13.O.231.239; 13.O.231.154; 13.O.231.157; 13.O.231.166; 13.O.231.169; 13.O.231.172; 13.O.231.175; 13.O.231.240; 13.O.231.244; 13.O.236.228; 13.O.236.229; 13.O.236.230; 13.O.236.231; 13.O.236.236; 13.O.236.237; 13.O.236.238; 13.O.236.239; 13.O.236.154; 13.O.236.157; 13.O.236.166; 13.O.236.169; 13.O.236.172; 13.O.236.175; 13.O.236.240; 13.O.236.244; 13.O.237.228; 13.O.237.229; 13.O.237.230; 13.O.237.231; 13.O.237.236; 13.O.237.237; 13.O.237.238; 13.O.237.239; 13.O.237.154; 13.O.237.157; 13.O.237.166; 13.O.237.169; 13.O.237.172; 13.O.237.175; 13.O.237.240; 13.O.237.244; 13.O.238.228; 13.O.238.229; 13.O.238.230; 13.O.238.231; 13.O.238.236; 13.O.238.237; 13.O.238.238; 13.O.238.239; 13.O.238.154; 13.O.238.157; 13.O.238.166; 13.O.238.169; 13.O.238.172; 13.O.238.175; 13.O.238.240; 13.O.238.244; 13.O.239.228; 13.O.239.229; 13.O.239.230; 13.O.239.231; 13.O.239.236; 13.O.239.237; 13.O.239.238; 13.O.239.239; 13.O.239.154; 13.O.239.157; 13.O.239.166; 13.O.239.169; 13.O.239.172; 13.O.239.175; 13.O.239.240; 13.O.239.244; 13.O.154.228; 13.O.154.229; 13.O.154.230; 13.O.154.231; 13.O.154.236; 13.O.154.237; 13.O.154.238; 13.O.154.239; 13.O.154.154; 13.O.154.157; 13.O.154.166; 13.O.154.169; 13.O.154.172; 13.O.154.175; 13.O.154.240; 13.O.154.244; 13.O.157.228; 13.O.157.229; 13.O.157.230; 13.O.157.231; 13.O.157.236; 13.O.157.237; 13.O.157.238; 13.O.157.239; 13.O.157.154; 13.O.157.157; 13.O.157.166; 13.O.157.169; 13.O.157.172; 13.O.157.175; 13.O.157.240; 13.O.157.244; 13.O.166.228; 13.O.166.229; 13.O.166.230; 13.O.166.231; 13.O.166.236; 13.O.166.237; 13.O.166.238; 13.O.166.239; 13.0.166.154; 13.O.166.157; 13.O.166.166; 13.O.166.169; 13.O.166.172; 13.O.166.175; 13.O.166.240; 13.O.166.244; 13.O.169.228; 13.O.169.229; 13.O.169.230; 13.O.169.231; 13.O.169.236; 13.O.169.237; 13.O.169.238; 13.O.169.239; 13.O.169.154; 13.O.169.157; 13.O.169.166; 13.O.169.169; 13.O.169.172; 13.O.169.175; 13.0.169.240; 13.O.169.244; 13.O.172.228; 13.O.172.229; 13.O.172.230; 13.O.172.231; 13.O.172.236; 13.O.172.237; 13.O.172.238; 13.O.172.239; 13.O.172.154; 13.O.172.157; 13.O.172.166; 13.O.172.169; 13.O.172.172; 13.O.172.175; 13.O.172.240; 13.O.172.244; 13.O.175.228; 13.O.175.229; 13.O.175.230; 13.O.175.231; 13.O.175.236; 13.O.175.237; 13.O.175.238; 13.O.175.239; 13.O.175.154; 13.O.175.157; 13.O.175.166; 13.O.175.169; 13.O.175.172; 13.O.175.175; 13.O.175.240; 13.O.175.244; 13.O.240.228; 13.O.240.229; 13.O.240.230; 13.O.240.231; 13.O.240.236; 13.O.240.237; 13.O.240.238; 13.O.240.239; 13.O.240.154; 13.O.240.157; 13.O.240.166; 13.O.240.169; 13.O.240.172; 13.O.240.175; 13.O.240.240; 13.O.240.244; 13.O.244.228; 13.O.244.229; 13.O.244.230; 13.O.244.231; 13.O.244.236; 13.O.244.237; 13.O.244.238; 13.O.244.239; 13.O.244.154; 13.O.244.157; 13.O.244.166; 13.O.244.169; 13.O.244.172; 13.O.244.175; 13.O.244.240; 13.O.244.244;
Prodrugs of 13.P
13.P.228.228; 13.P.228.229; 13.P.228.230; 13.P.228.231; 13.P.228.236; 13.P.228.237; 13.P.228.238; 13.P.228.239; 13.P.228.154; 13.P.228.157; 13.P.228.166; 13.P.228.169; 13.P.228.172; 13.P.228.175; 13.P.228.240; 13.P.228.244; 13.P.229.228; 13.P.229.229; 13.P.229.230; 13.P.229.231; 13.P.229.236; 13.P.229.237; 13.P.229.238; 13..P.229.239; 13.P.229.154; 13.P.229.157; 13.P.229.166; 13.P.229.169; 13.P.229.172; 13.P.229.175; 13.P.229.240; 13.P.229.244; 13.P.230.228; 13.P.230.229; 13.P.230.230; 13.P.230.231; 13.P.230.236; 13.P.230.237; 13.P.230.238; 13.P.230.239; 13.P.230.154; 13.P.230.157; 13.P.230.166; 13.P.230.169; 13.P.230.172; 13.P.230.175; 13.P.230.240; 13.P.230.244; 13.P231.228; 13.P.231.229; 13.P.231.230; 13.P.231.231; 13.P.231.236; 13.P.231.237; 13.P.231.238; 13.P.231.239; 13.P.231.154; 13.P.231.157; 13.P.231.166; 13.P.231.169; 13.P231.172; 13.P.231.175; 13.P.231.240; 13.P.231.244; 13.P.236.228; 13.P.236.229; 13.P.236.230; 13.P.236.231; 13.P.236.236; 13.P.236.237; 13.P.236.238; 13P.236.239; 13.P236.154; 13.P.236.157; 13.P.236.166; 13.P.236.169; 13.P.236.172; 13.P.236.175; 13.P.236.240; 13.P.236.244; 13.P.237.228; 13.P237.229; 13.P.237.230; 13.P.237231; 13.P.237.236; 13.P.237.237; 13.P.237.238; 13.P.237.239; 13.P237.154; 13.P237.157; 13.P237.166; 13.P237.169; 13.P237.172; 13.P237.175; 13.P237240; 13.P237244; 13.P238.228; 13.P238.229; 13.P238230; 13.P238231; 13.P238236; 13.P238237; 13.P238238; 13.P238239; 13.P238.154; 13.P238.157; 13.P238.166; 13.P238.169; 13.P238.172; 13.P238.175; 13.P238240; 13.P238244; 13.P239228; 13.P239229; 13.P239230; 13.P239231; 13.P239236; 13.P239237; 13.P239238; 13.P239239; 13.P239.154; 13.P239.157; 13.P.239.166; 13.P239.169; 13.P239.172; 13.P239.175; 13.P239240; 13.P239244; 13.P.154228; 13.P.154229; 13.P.154230; 13P.154.231; 13.P.154.236; 13.P.154237; 13.P.154238; 13.P.154239; 13P.154.154; 13P.154.157; 13.P.154.166; 13.P.154.169; 13P.154.172; 13P.154.175; 13P.154.240; 13P.154.244; 13.P.157.228; 13P.157.229; 13.P.157.230; 13P.157.231; 13P.157.236; 13P.157.237; 13P.157.238; 13.P.157239; 13P.157.154; 13.P.157.157; 13.P.157.166; 13P.157.169; 13P.157.172; 13P.157.175; 13P.157.240; 13.P.157244; 13.P.166228; 13P.166.229; 13P.166.230; 13.P.166231; 13.P.166.236; 13.P.166237; 13.P.166238; 13.P.166239; 13P.166.154; 13P.166.157; 13.P.166.166; 13.P.166.169; 13.P.166.172; 13P.166.175; 13.P.166.240; 13.P.166244; 13.P.169228; 13.P.169229; 13.P.169230; 13.P.169231; 13P.169.236; 13.P.169237; 13.P.169238; 13.P.169239; 13P.169.154; 13.P.169.157; 13P.169.166; 13P.169.169; 13.P.169.172; 13P.169.175; 13P.169.240; 13P.169.244; 13.P.172.228; 13.P.172.229; 13P.172.230; 13P.172.231; 13P.172.236; 13P.172.237; 13P.172.238; 13.P.172239; 13P.172.154; 13P.172.157; 13P.172.166; 13P.172.169; 13.P. 172.172; 13.P.172.175; 13.P.172.240; 13P.172.244; 13P.175.228; 13.P.175.229; 13.P. 175230; 13.P.175231; 13.P.175236; 13P.175.237; 13P.175.238; 13P.175.239; 13P.175.154; 13P.175.157; 13P.175.166; 13.P.175.169; 13P.175.172; 13P.175.175; 13.P. 175240; 13.P. 175244; 13.P.240228; 13.P240229; 13.P240230; 13.P240231; 13.P240236; 13.P240237; 13.P.240238; 13.P240.239; 13.P240.154; 13.P.240.157; 13.P240.166; 13.P240.169; 13.P240.172; 13.P240.175; 13.P240240; 13.P.240244; 13.P.244228; 13.P244.229; 13.P244.230; 13P.244.231; 13.P244236; 13.P.244.237; 13.P.244.238; 13.P.244.239; 13.P244.154; 13.P.244.157; 13.P244.166; 13.P.244.169; 13.P.244.172; 13.P244.175; 13.P244.240; 13.P244244;
Prodrugs of 13.U
13.U.228.228; 13.U.228.229; 13.U.228.230; 13.U.228.231; 13.U.228.236; 13.U.228.237; 13.U.228.238; 13.U.228.239; 13.U.228.154; 13.U.228.157; 13.U.228.166; 13.U.228.169; 13.U.228.172; 13.U.228.175; 13.U.228.240; 13.U.228.244; 13.U.229.228; 13.U.229.229; 13.U.229.230; 13.U.229.231; 13.U.229.236; 13.U.229.237; 13.U.229.238; 13.U.229.239; 13.U.229.154; 13.U.229.157; 13.U.229.166; 13.U.229.169; 13.,U. 229.172; 13.U.229.175; 13.U.229.240; 13.U.229.244; 13.U.230.228; 13.U.230.229; 13.U.230.230; 13.U.230.231; 13.U.230.236; 13.U.230.237; 13.U.230.238; 13.U.230.239; 13.U.230.154; 13.U.230.157; 13.U.230.166; 13.U.230.169; 13.U.230.172; 13.U.230.175; 13.U.230.240; 13.U.230.244; 13.U.231.228; 13.U.231.229; 13.U.231.230; 13.U.231.231; 13.U.231.236; 13.U.231.237; 13.U.231.238; 13.U.231.239; 13.U.231.154; 13.U.231.157; 13.U.231.166; 13.U.231.169; 13.U.231.172; 13.U.231.175; 13.U.231.240; 13.U.231.244; 13.U.236.228; 13.U.236.229; 13.U.236.230; 13.U.236.231; 13.U.236.236; 13.U.236.237; 13.U.236.238; 13.U.236.239; 13.U.236.154; 13.U.236.157; 13.U.236.166; 13.U.236.169; 13.U.236.172; 13.U.236.175; 13.U.236.240; 13.U.236.244; 13.U.237.228; 13.U.237.229; 13.U.237.230; 13.U.237.231; 13.U.237.236; 13.U.237.237; 13.U.237.238; 13.U.237.239; 13.U.237.154; 13.U.237.157; 13.U.237.166; 13.U.237.169; 13.U.237.172; 13.U.237.175; 13.U.237.240; 13.U.237.244; 13.U.238.228; 13.U.238.229; 13.U.238.230; 13.U.238.231; 13.U.238.236; 13.U.238.237; 13.U.238.238; 13.U.238.239; 13.U.238.154; 13.U.238.157; 13.U.238.166; 13.U.238.169; 13.U.238.172; 13.U.238.175; 13.U.238.240; 13.U.238.244; 13.U.239.228; 13.U.239.229; 13.U.239.230; 13.U.239.231; 13.U.239.236; 13.U.239.237; 13.U.239.238; 13.U.239.239; 13.U.239.154; 13.U.239.157; 13.U.239.166; 13.U.239.169; 13.U.239.172; 13.U.239.175; 13.U.239.240; 13.U.239.244; 13.U.154.228; 13.U.154.229; 13.U.154.230; 13.U.154.231; 13.U.154.236; 13.U.154.237; 13.U.154.238; 13.U.154.239; 13.U.154.154; 13.U.154.157; 13.U.154.166; 13.U.154.169; 13.U.154.172; 13.U.154.175; 13.U.154.240; 13.U.154.244; 13.U.157.228; 13.U.157.229; 13.U.157.230; 13.U.157.231; 13.U.157.236; 13.U.157.237; 13.U.157.238; 13.U.157.239; 13.U.157.154; 13.U.157.157; 13.U.157.166; 13.U.157.169; 13.U.157.172; 13.U.157.175; 13.U.157.240; 13.U.157.244; 13.U.166.228; 13.U.166.229; 13.U.166.230; 13.U.166.231; 13.U.166.236; 13.U.166.237; 13.U.166.238; 13.U.166.239; 13.U.166.154; 13.U.166.157; 13.U.166.166; 13.U.166.169; 13.U.166.172; 13.U.166.175; 13.U.166.240; 13.U.166.244; 13.U.169.228; 13.U.169.229; 13.U.169.230; 13.U.169.231; 13.U.169.236; 13.U.169.237; 13.U.169.238; 13.U.169.239; 13.U.169.154; 13.U.169.157; 13.U.169.166; 13.U.169.169; 13.U.169.172; 13.U.169.175; 13.U.169.240; 13.U.169.244; 13.U.172.228; 13.U.172.229; 13.U.172.230; 13.U.172.231; 13.U.172.236; 13.U.172.237; 13.U.172.238; 13.U.172.239; 13.U.172.154; 13.U.172.157; 13.U.172.166; 13.U.171169; 13.U.172.172; 13.U.172.175; 13.U.172.240; 13.U.172.244; 13.U.175.228; 13.U.175.229; 13.U.175.230; 13.U.175.231; 13.U.175.236; 13.U.175.237; 13.U.175.238; 13.U.175.239; 13.U.175.154; 13.U.175.157; 13.U.175.166; 13.U.175.169; 13.U.175.172; 13.U.175.175; 13.U.175.240; 13.U.175.244; 13.U.240.228; 13.U.240.229; 13.U.240.230; 13.U.240.231; 13.U.240.236; 13.U.240.237; 13.U.240.238; 13.U.240.239; 13.U.240.154; 13.U.240.157; 13.U.240.166; 13.U.240.169; 13.U.240.172; 13.U.240.175; 13.U.240.240; 13.U.240.244; 13.U.244.228; 13.U.244.229; 13.U.244.230; 13.U.244.231; 13.U.244.236; 13.U.244.237; 13.U.244.238; 13.U.244.239; 13.U.244.154; 13.U.244.157; 13.U.244.166; 13.U.244.169; 13.U.244.172; 13.U.244.175; 13.U.244.240; 13.U.244.244;
Prodrugs of 13.W
13.W.228.228; 13.W.228.229; 13.W.228.230; 13.W.228.231; 13.W.228.236; 13.W.228.237; 13.W.228.238; 13.W.228.239; 13.W.22S.154; 13.W.228.157; 13.W.228.166; 13.W.228.169; 13.W.228.172; 13.W.228.175; 13.W.228.240; 13.W.228.244; 13.W.229.228; 13.W.229.229; 13.W.229.230; 13.W.229.231; 13.W.229.236; 13.W.229.237; 13.W.229.238; 13.W.229.239; 13.W.229.154; 13.W.229.157; 13.W.229.166; 13.W.229.169; 13.W.229.172; 13.W.229.175; 13.W.229.240; 13.W.229.244; 13.W.230.228; 13.W.230.229; 13.W.230.230; 13.W.230.231; 13.W.230.236; 13.W.230.237; 13.W.230.238; 13.W.230.239; 13.W.230.154; 13.W.230.157; 13.W.230.166; 13.W.230.169; 13.W.230.172; 13.W.230.175; 13.W.230.240; 13.W.230.244; 13.W.231.228; 13.W.231.229; 13.W.231.230; 13.V/.231.231; 13.W.231.236; 13.W.231.237; 13.W.231.238; 13.W.231.239; 13.W.231.154; 13.W.231.157; 13.W.231.166; 13:W.231.169; 13.W.231.172; 13.W.231.175; 13.W.231.240; 13.W.231.244; 13.W.236.228; 13.W.236.229; 13.W.236.230; 13.W236.231; 13.W.236.236; 13.W.236.237; 13.W.236.238; 13.W.236.239; 13.W.236.154; 13.W.236.157; 13.W.236.166; 13.W.236.169; 13.W.236.172; 13.W.236.175; 13.W.236.240; 13.W.236.244; 13.W.237.228; 13.W.237.229; 13.W.237.230; 13.W.237.231; 13.W.237.236; 13.W.237.237; 13.W.237.238; 13.W.237.239; 13.W.237.154; 13.W.237.157; 13.W.237.166; 13.W.237.169; 13.W.237.172; 13.W.237.175; 13.W.237.240; 13.W.237.244; 13.W.238.228; 13.W.238.229; 13.W.238.230; 13.W.238.231; 13.W.238.236; 13.W.238.237; 13.W.238.238; 13.W.238.239; 13.W.238.154; 13.W.238.157; 13.W.238.166; 13.W.238.169; 13.W.238.172; 13.W.238.175; 13.W.238.240; 13.W.238.244; 13.W.239.228; 13.W.239.229; 13.W.239.230; 13.W.239.231; 13.W.239.236; 13.W.239.237; 13.W.239.238; 13.W.239.239; 13.W.239.154; 13.W.239.157; 13.W.239.166; 13.W.239.169; 13.W.239.172; 13.W.239.175; 13.W.239.240; 13.W.239.244; 13.W.154.228; 13.W.154.229; 13.W.154.230; 13.W.154.231; 13.W.154.236; 13.W.154.237; 13.W.154.238; 13.W.154.239; 13.W.154.154; 13.W.154.157; 13.W.154.166; 13.W.154.169; 13.W.154.172; 13.W.154.175; 13.W.154.240; 13.W.154.244; 13.W.157.228; 13.W.157.229; 13.W.157.230; 13.W.157.231; 13.W.157.236; 13.W.157.237; 13.W.157.238; 13.W.157.239; 13.W.157.154; 13.W.157.157; 13.W.157.166; 13.W.157.169; 13.W.157.172; 13.W.157.175; 13.W.157.240; 13.W.157.244; 13.W.166.228; 13.W.166.229; 13.W.166.230; 13.W.166.231; 13.W.166.236; 13.W.166.237; 13.W.166.238; 13.W.166.239; 13.W.166.154; 13.W.166.157; 13.W.166.166; 13.W.166.169; 13.W.166.172; 13.W.166.175; 13.W.166.240; 13.W.166.244; 13.W.169.228; 13.W.169.229; 13.W.169.230; 13.W.169.231; 13.W.169.236; 13.W.169.237; 13.W.169.238; 13.W.169.239; 13.W.169.154; 13.W.169.157; 13.W.169.166; 13.W.169.169; 13.W.169.172; 13.W.169.175; 13.W.169.240; 13.W.169.244; 13.W.172.228; 13.W.172.229; 13.W.172.230; 13.W.172.231; 13.W.172.236; 13.W.172.237; 13.W.172.238; 13.W.172.239; 13.W.172.154; 13.W.172.157; 13. W. 172.166; 13iW.172.169; 13.W.172.172; 13.W.172.175; 13.W.172.240; 13.W.172.244; 13.W.175.228; 13.W.175.229; 13.W.175.230; 13.W.175.231; 13.W.175.236; 13.W.175.237; 13.W.175.238; 13.W.175.239; 13.W.175.154; 13.W.175.157; 13.W.175.166; 13.W.175.169; 13.W.175.172; 13.W.175.175; 13.W.175.240; 13.W.175.244; 13.W.240.228; 13.W.240.229; 13.W.240.230; 13.W.240.231; 13.W.240.236; 13.W.240.237; 13.W.240.238; 13.W.240.239; 13.W.240.154; 13.W.240.157; 13.W.240.166; 13.W.240.169; 13.W.240.172; 13.W.240.175; 13.W.240.240; 13.W.240.244; 13.W.244.228; 13.W.244.229; 13.W.244.230; 13.W.244.231; 13.W.244.236; 13.W.244.237; 13.W.244.238; 13.W.244.239; 13.W.244.154; 13.W.244.157; 13.W.244.166; 13.W.244.169; 13.W.244.172; 13.W.244.175; 13.W.244.240; 13.W.244.244;
Prodrugs of 13.Y
13.Y.228.228; 13.Y.228.229; 13.Y.228.230; 13.Y.228.231; 13.Y.228.236; 13.Y.228.237; 13.Y.228.238; 13.Y.228.239; 13.Y.228.154; 13.Y.228.157; 13.Y.228.166; 13.Y.228.169; 13.Y.228.172; 13.Y.228.175; 13.Y.228.240; 13.Y.228.244; 13.Y.229.228; 13.Y.229.229; 13.Y.229.230; 13.Y.229.231; 13.Y.229.236; 13.Y.229.237; 13.Y.229.238; 13.Y.229.239; 13.Y.229.154; 13.Y.229.157; 13.Y.229.166; 13.Y.229.169; 13.Y.229.172; 13.Y.229.175; 13.Y.229.240; 13.Y.229.244; 13.Y.230.228; 13.Y.230.229; 13.Y.230.230; 13.Y.230.231; 13.Y.230.236; 13.Y.230.237; 13.Y.230.238; 13.Y.230.239; 13.Y.230.154; 13.Y.230.157; 13.Y.230.166; 13.Y.230.169; 13.Y.230.172; 13.Y.230.175; 13.Y.230.240; 13.Y.230.244; > 13.Y.231.228; 13.Y.231.229; 13.Y.231.230; 13.Y.231.23I; I3.Y.231.236; 13.Y.231.237; 13.Y.231.238; 13.Y.231.239; 13.Y.231.154; 13.Y.231.157; 13.Y.231.166; 13.Y.231.169; 13.Y.231.172; 13.Y.231.175; 13.Y.231.240; 13.Y.231.244; 13.Y.236.228; 13.Y.236.229; 13.Y.236.230; 13.Y.236.231; 13.Y.236.236; 13.Y.236.237; 13.Y.236.238; 13.Y.236.239; 13.Y.236.154; 13.Y.236.157; 13.Y.236.166; 13.Y.236.169; 13.Y.236.172; 13.Y.236.175; 13.Y.236.240; 13.Y.236.244; 13.Y.237.228; 13.Y.237.229; 13.Y.237.230; 13.Y.237.231; 13.Y.237.236; 13.Y.237.237; 13.Y.237.238; 13.Y.237.239; 13.Y.237.154; 13.Y.237.157; 13.Y.237.166; 13.Y.237.169; 13.Y.237.172; 13.Y.237.175; 13.Y.237.240; 13.Y.237.244; 13.Y.238.228; 13.Y.238.229; 13.Y.238.230; 13.Y.238.231; 13.Y.238.236; 13.Y.238.237; 13.Y.238.238; 13.Y.238.239; 13.Y.238.154; 13.Y.238.157; 13.Y.238.166; 13.Y.238.169; 13.Y.238.172; 13.Y.238.175; 13.Y.238.240; 13.Y.238.244; 13.Y.239.228; 13.Y.239.229; 13.Y.239.230; 13.Y.239.231; 13.Y.239.236; 13.Y.239.237; 13.Y.239.238; 13.Y.239.239; 13.Y.239.154; 13.Y.239.157; 13.Y.239.166; 13.Y.239.169; 13.Y.239.172; 13.Y.239.175; 13.Y.239.240; 13.Y.239.244; 13.Y.154.228; 13.Y.154.229; 13.Y.154.230; 13.Y.154.231; 13.Y.154.236; 13.Y.154.237; 13.Y.154.238; 13.Y.154.239; 13.Y.154.154; 13.Y.154.157; 13.Y.154.166; 13.Y.154.169; 13.Y.154.172; 13.Y.154.175; 13.Y.154.240; 13.Y.154.244; 13.Y.157.228; 13.Y.157.229; 13.Y.157.230; 13.Y.157.231; 13.Y.157.236; 13.Y.157.237; 13.Y.157.238; 13.Y.157.239; 13.Y.157.154; 13.Y.157.157; 13.Y.157.166; 13.Y.157.169; 13.Y.157.172; 13.Y.157.175; 13.Y.157.240; 13.Y.157.244; 13.Y.166.228; 13.Y.166.229; 13.Y.166.230; 13.Y.166.231; 13.Y.166.236; 13.Y.166.237; 13.Y.166.238; 13.Y.166.239; 13.Y.166.154; 13.Y.166.157; 13.Y.166.166; 13.Y.166.169; 13.Y.166.172; 13.Y.166.175; 13.Y.166.240; 13.Y.166.244; 13.Y.169.228; 13.Y.169.229; 13.Y.169.230; 13.Y.169.231; 13.Y.169.236; 13.Y.169.237; 13.Y.169.238; 13.Y.169.239; 13.Y.169.154; 13.Y.169.157; 13.Y.169.166; 13.Y.169.169; 13.Y.169.172; 13.Y.169.175; 13.Y.169.240; 13.Y.169.244; 13.Y.172.228; 13.Y.172.229; 13.Y.172.230; 13.Y.172.231; 13.Y.172.236; 13.Y.172.237; 13.Y.172.238; 13.Y.172.239; 13.Y.172.154; 13.Y.172.157; 13.Y.172.166; 13.Y.172.169; 13.Y.172.172; 13.Y.172.175; 13.Y.172.240; 13.Y.172.244; 13.Y.175.228; 13.Y.175.229; 13.Y.175.230; 13.Y.175.231; 13.Y.175.236; 13.Y.175.237; 13.Y.175.238; 13.Y.175.239; 13.Y.175.154; 13.Y.175.157; 13.Y.175.166; 13.Y.175.169; 13.Y.175.172; 13.Y.175.175; 13.Y.175.240; 13.Y.175.244; 13.Y.240.228; 13.Y.240.229; 13.Y.240.230; 13.Y.240.231; 13.Y.240.236; 13.Y.240.237; 13.Y.240.238; 13.Y.240.239; 13.Y.240.154; 13.Y.240.157; 13.Y.240.166; 13.Y.240.169; 13.Y.240.172; 13.Y.240.175; 13.Y.240.240; 13.Y.240.244; 13.Y.244.228; 13.Y.244.229; 13.Y.244.230; 13.Y.244.231; 13.Y.244.236; 13.Y.244.237; 13.Y.244.238; 13.Y.244.239; 13.Y.244.154; 13.Y.244.157; 13.Y.244.166; 13.Y.244.169; 13.Y.244.172; 13.Y.244.175; 13.Y.244.240; 13.Y.244.244;
Prodrugs of 14.AH
14.AH.4.157; 14.AH.4.158; 14.AH.4.196; 14.AH.4.223; 14.AH.4.240; 14.AH.4.244; 14.AH.4.243; 14.AH.4.247; 14.AH.5.157; 14.AH.5.158; 14.AH.5.196; 14.AH.5.223; 14.AH.5.240; 14.AH.5.244; 14.AH.5.243; 14.AH.5.247; 14.AH.7.157; 14.AH.7.158; 14.AH.7.196; 14.AH.7.223; 14.AH.7.240; 14.AH.7.244; 14.AH.7.243; 14.AH.7.247; 14.AH.15.157; 14.AH.15.158; 14.AH.15.196; 14.AH.15.223; 14.AH.15.240; 14.AH.15.244; 14.AH.15.243; 14.AH.15.247; 14.AH.16.157; 14.AH.16.158; 14.AH.16.196; 14.AH.16.223; 14.AH. 16.240; 14.AH. 16.244; 14.AH. 16.243; 14.AH. 16.247; 14.AH.18.157; RAH. 18.158; 14.AH.18.196; 14.AH.18.223; 14.AH.18.240; 14.AH.18.244; 14.AH.18.243; 14.AH.18.247; 14.AH.26.157; 14.AH.26.158; 14.AH.26.196; 14.AH.26.223; 14.AH.26.240; 14.AH.26.244; 14.AH.26.243; 14.AH.26.247; 14.AH.27.157; 14.AH.27.158; 14.AH.27.196; 14.AH.27.223; 14.AH.27.240; 14.AH.27.244; 14.AH.27.243; 14.AH.27.247; 14.AH.29.157; 14.AH.29.158; 14.AH.29.196; 14.AH.29.223; 14.AH.29.240; 14.AH.29.244; 14.AH.29.243; 14.AH.29.247; 14.AH.54.157; 14.AH.54.158; 14.AH.54.196; 14.AH.54.223; 14.AH.54.240; 14.AH.54.244; 14.AH.54.243; 14.AH.54.247; 14.AH.55.157; 14.AH.55.158; 14.AH.55.196; RAH.55.223; 14.AH.55.240; 14.AH.55.244; 14.AH.55.243; 14.AH.55.247; 14.AH.56.157; 14.AH.56.158; 14.AH.56.196; 14.AH.56.223; 14.AH.56.240; 14.AH.56.244; 14.AH.56.243; 14.AH.56.247; 14.AH.157.157; 14. AH. 157.158; 14. AH. 157.196; 14. AH. 157.223; 14.AH. 157.240; 14. AH. 157.244; 14.AH. 157.243; 14. AH. 157.247; 14. AH. 196.157; 14. AH. 196.158; 14.AH.196.196; 14.AH.196.223; 14. AH. 196.240; 14.AH. 196.244; 14. AH. 196.243; 14.AH. 196.247; 14.AH.223.157; 14.AH.223.158; 14.AH.223.196; 14.AH.223.223; 14.AH.223.240; 14.AH.223.244; 14.AH.223.243; 14.AH.223.247; 14.AH.240.157; 14.AH.240.158; 14.AH.240.196; 14.AH.240.223; 14.AH.240.240; 14.AH.240.244; 14.AH.240.243; 14.AH.240.247; 14.AH.244.157; 14.AH.244.158; 14.AH.244.196; 14.AH.244.223; 14.AH.244.240; 14.AH.244.244; 14.AH.244.243; 14.AH.244.247; 14.AH.247.157; 14.AH.247.158; 14.AH.247.196; 14.AH.247.223; 14.AH.247.240; 14.AH.247.244; 14.AH.247.243; 14.AH.247.247;
Frodrugs of 14.AT
14.AJ.4.157; 14.AJ.4.158; 14.AJ.4.196; 14.AJ.4.223; 14.AJ.4.240; 14.AJ.4.244; 14.AJ.4.243; 14.AJ.4.247; 14.AJ.5.157; 14.AJ.5.158; 14.AJ.5.196; 14.AJ.5.223; 14.AJ.5.240; 14.AJ.5.244; 14.AJ.5.243; 14.AJ.5.247; 14.AJ.7.157; 14.AJ.7.158; 14.AJ.7.196; 14.AJ.7.223; 14.AJ.7.240; 14.AJ.7.244; 14.AJ.7.243; 14.AJ.7.247; 14.AJ.15.157; 14.AJ.15.158; 14.AJ.15.196; 14.AJ.15.223; 14.AJ.15.240; 14.AJ.15.244; 14.AJ.15.243; 14.AJ. 15.247; 14.AJ.16.157; 14.AJ.16.158; 14.AJ.16.196; 14.AJ.16.223; 14.AJ. 16.240; 14.AJ. 16.244; 14.AJ. 16.243; 14.AJ. 16.247; 14.AJ.18.157; 14.AJ.18.158; 14.AJ.18.196; 14.AJ. 18.223; 14.AJ.18.240; 14.AJ.18.244; 14.AJ.18.243; 14.AJ.18.247; 14.AJ.26.157; 14.AJ.26.158; 14.AJ.26.196; 14.AJ.26.223; 14.AJ.26.240; 14.AJ.26.244; 14.AJ.26.243; 14.AJ.26.247; 14.AJ.27.157; 14.AJ.27.158; 14.AJ.27.196; 14.AJ.27.223; 14.AJ.27.240; 14.AJ.27.244; 14.AJ.27.243; 14.AJ.27.247; 14.AJ.29.157; 14.AJ.29.158; 14. AJ.29.196; 14.AJ.29.223; 14.AJ.29.240; 14.AJ.29.244; 14.AJ.29.243; 14.AJ.29.247; 14.AJ.54.157; 14.AJ.54.158; 14.AJ.54.196; 14.AJ.54.223; 14.AJ.54.240; 14.AJ.54.244; 14.AJ.54.243; 14.AJ.54.247; 14.AJ.55.157; 14.AJ.55.158; 14.AJ.55.196; 14.AJ.55.223; 14.AJ.55.240; 14.AJ.55.244; 14.AJ.55.243; 14.AJ.55.247; 14.AJ.56.157; 14.AJ.56.158; 14.AJ.56.196; 14.AJ.56.223; 14.AJ.56.240; 14.AJ.56.244; 14.AJ.56.243; 14.AJ.56.247; 14.AJ.157.157; 14. AJ. 157.158; 14.AJ.157.196; 14. AJ. 157.223; 14. AJ. 157.240; 14.AJ.157.244; 14.AJ. 157.243; 14.AJ. 157.247; 14.AJ. 196.157; RAJ. 196.158; RAJ.196.196; 14.AJ. 196.223;
14.AJ. 196.240; 14. AJ. 196.244; 14. AJ. 196.243; 14. AJ. 196.247; 14.AJ.223.157; 14.AJ.223.158; 14.AJ.223.196; 14.AJ.223.223; 14.AJ.223.240; 14.AJ.223.244; 14.AJ.223.243; 14.AJ.223.247; 14.AJ.240.157; 14.AJ.240.158; 14.AJ.240.196; 14.AJ.240.223; 14.AJ.240.240; 14.AJ.240.244; 14.AJ.240.243; 14.AJ.240.247; 14.AJ.244.157; 14.AJ.244.158; 14.AJ.244.196; 14.AJ.244.223; 14.AJ.244.240; 14.AJ.244.244; 14.AJ.244.243; 14.AJ.244.247; 14.AJ.247.157; 14.AJ.247.158; 14.AJ.247.196; 14.AJ.247.223; 14.AJ.247.240; 14.AJ.247.244; 14.AJ.247.243; 14.AJ.247.247;
Prodrugs of 14.AN
14.AN.4.157; 14.AN.4.158; 14.AN.4.196; 14.AN.4.223; 14.AN.4.240; 14.AN.4.244; 14.AN.4.243; 14.AN.4.247; 14.AN.5.157; 14.AN.5.158; 14.AN.5.196; 14.AN.5.223; 14.AN.5.240; 14.AN.5.244; 14.AN.5.243; 14.AN.5.247; 14.AN.7.157; 14.AN.7.158; 14.AN.7.196; 14.AN.7.223; 14.AN.7.240; 14.AN.7.244; 14.AN.7.243; 14.AN.7.247; 14.AN.15.157; 14.AN.15.158; 14.AN.15.196; 14.AN.15.223; 14.AN.15.240; 14.AN.15.244; 14.AN. 15.243; 14.AN. 15.247; 14.AN.16.157; 14.AN.16.158; 14.AN.16.196; 14.AN. 16.223; 14.AN.16.240; 14.AN.16.244; 14.AN.16.243; 14.AN.16.247; 14.AN.18.157; 14.AN.18.158; 14.AN.18.196; 14.AN.18.223; 14.AN.18.240; 14.AN.18.244; 14.AN.18.243; 14.AN.18.247; 14.AN.26.157; 14.AN.26.158; 14.AN.26.196; 14.AN.26.223; 14.AN.26.240; 14.AN.26.244; 14.AN.26.243; 14.AN.26.247; 14.AN.27.157; 14.AN.27.158; 14.AN.27.196; 14.AN.27.223; 14.AN.27.240; 14.AN.27.244; 14.AN.27.243; 14.AN.27.247; 14.AN.29.157; 14.AN.29.158; 14.AN.29.196; 14.AN.29.223; 14.AN.29.240; 14.AN.29.244; 14.AN.29.243; 14.AN.29.247; 14.AN.54.157; 14.AN.54.158; 14.AN.54.196; 14.AN.54.223; 14.AN.54.240; 14.AN.54.244; 14.AN.54.243; 14.AN.54.247; 14.AN.55.157; 14.AN.55.158; 14.AN.55.196; 14.AN.55.223; 14.AN.55.240; 14.AN.55.244; 14.AN.55.243; 14.AN.55.247; 14.AN.56.157; 14.AN.56.158; 14.AN.56.196; 14.AN.56.223; 14.AN.56.240; 14.AN.56.244; 14.AN.56.243; 14.AN.56.247; 14.AN.157.157; 14.AN.157.158; 14. AN. 157.196; 14.AN. 157.223; 14.AN. 157.240; 14. AN. 157.244; 14.AN. 157.243; 14.AN. 157.247; 14.AN.196.157; 14.AN.196.158; 14. AN. 196.196; 14.AN. 196.223; 14.AN. 196.240; 14.AN. 196.244; 14. AN. 196.243; 14.AN. 196.247; 14.AN.223.157; 14.AN.223.158; 14.AN.223.196; 14.AN.223.223; 14.AN.223.240; 14.AN.223.244; 14.AN.223.243; 14.AN.223.247; 14.AN.240.157; 14.AN.240.158; 14.AN.240.196; 14.AN.240.223; 14.AN.240.240; 14.AN.240.244; 14.AN.240.243; 14.AN.240.247; 14.AN.244.157; 14.AN.244.158; 14.AN.244.196; 14.AN.244.223; 14.AN.244.240; 14.AN.244.244; 14.AN.244.243; 14.AN.244.247; 14.AN.247.157; 14.AN.247.158; 14.AN.247.196; 14.AN.247.223; 14.AN.247.240; 14.AN.247.244; 14.AN.247.243; 14.AN.247.247;
Prodrugs of 14. AP
14.AP.4.157; 14.AP.4.158; 14.AP.4.196; 14.AP.4.223; 14.AP.4.240; 14.AP.4.244; 14.AP.4.243; 14.AP.4.247; 14.AP.5.157; 14.AP.5.158; 14.AP.5.196; 14.AP.5.223; 14.AP.5.240; 14.AP.5.244; 14.AP.5.243; 14.AP.5.247; 14.AP.7.157; 14.AP.7.158; 14.AP.7.196; 14.AP.7.223; 14.AP.7.240; 14.AP.7.244; 14.AP.7.243; 14.AP.7.247; 14.AP.15.157; 14.AP.15.158; 14.AP.15.196; 14.AP.15.223; 14.AP.15.240; 14.AP.15.244; 14.AP. 15.243; 14.AP. 15.247; 14.AP.16.157; RAP. 16.158; 14.AP.16.196; 14.AP. 16.223; 14.AP.16.240; 14.AP.16.244; 14.AP.16.243; 14.AP.16.247; 14.AP.18.157; 14.AP.18.158; 14.AP.18.196; 14.AP.18.223; 14.AP.18.240; 14.AP.18.244; 14.AP.18.243; 14.AP.18.247; 14.AP.26.157; 14.AP.26.158; 14.AP.26.196; 14.AP.26.223; 14.AP.26.240; 14.AP.26.244; 14.AP.26.243; 14.AP.26.247; 14.AP.27.157; 14.AP.27.158; 14.AP.27.196; 14.AP.27.223;
14.AP.27.240; 14.AP.27.244; 14.AP.27.243; 14.AP.27.247; 14.AP.29.157; 14.AP.29.158; 14.AP.29.196; 14.AP.29.223; 14.AP.29.240; 14.AP.29.244; 14.AP.29.243; 14.AP.29.247; 14.AP.54.157; 14.AP.54.158; 14.AP.54.196; 14.AP.54.223; 14.AP.54.240; 14.AP.54.244; 14.AP.54.243; 14.AP.54.247; 14.AP.55.157; 14.AP.55.158; 14.AP.55.196; 14.AP.55.223; 14.AP.55.240; 14.AP.55.244; 14.AP.55.243; 14.AP.55.247; 14.AP.56.157; 14.AP.56.158; 14.AP.56.196; 14.AP.56.223; 14.AP.56.240; 14.AP.56.244; 14.AP.56.243; 14.AP.56.247; 14.AP.157.157; 14.AP.157.158; 14.AP.157.196; 14. AP. 157.223; 14.AP. 157.240; 14.AP. 157.244; 14.AP. 157.243; 14.AP. 157.247; 14.AP.196.157; 14.AP.196.158; 14. AP. 196.196; 14.AP. 196.223; 14.AP. 196.240: 14. AP. 196.244: 14.AP. 196.243; 14.AP. 196.247; 14.AP.223.157; 14.AP.223.158; 14.AP.223.196; 14.AP.223.223; 14.AP.223.240; 14.AP.223.244; 14.AP.223.243; 14.AP.223.247; 14.AP.240.157; 14.AP.240.158; 14.AP.240.196; 14.AP.240.223; 14.AP.240.240; 14.AP.240.244; 14.AP.240.243; 14.AP.240.247; 14.AP.244.157; 14.AP.244.158; 14.AP.244.196; 14.AP.244.223; 14.AP.244.240; 14.AP.244.244; 14.AP.244.243; 14.AP.244.247; 14.AP.247.157; 14.AP.247.158; 14.AP.247.196; 14.AP.247.223; 14.AP.247.240; 14.AP.247.244; 14.AP.247.243; 14.AP.247.247;
Prodrugs of 14.AZ
14.AZ.4.157; 14.AZ.4.158; 14.AZ.4.196; 14.AZ.4.223; 14.AZ.4.240; 14.AZ.4.244; 14.AZ.4.243; 14.AZ.4.247; 14.AZ.5.157; 14.AZ.5.158; 14.AZ.5.196; 14.AZ.5.223; 14.AZ.5.240; 14.AZ.5.244; 14.AZ.5.243; 14.AZ.5.247; 14.AZ.7.157; 14.AZ.7.158; 14.AZ.7.196; 14.AZ.7.223; 14.AZ.7.240; 14.AZ.7.244; 14.AZ.7.243; 14.AZ.7.247; 14.AZ.15.157; 14.AZ.15.158; 14.AZ.15.196; 14.AZ.15.223; 14.AZ.15.240; 14.AZ.15.244; 14. AZ. 15.243; 14.AZ. 15.247; 14.AZ.16.157; 14.AZ.16.158; 14.AZ.16.196; 14.AZ. 16.223; 14.AZ.16.240; 14.AZ.16.244; 14.AZ.16.243; 14.AZ.16.247; 14.AZ.18.157; 14.AZ.18.158; 14.AZ.18.196; 14.AZ.18.223; 14.AZ.18.240; 14.AZ.18.244; 14.AZ.18.243; 14.AZ.18.247; 14.AZ.26.157; 14.AZ.26.158; 14.AZ.26.196; 14.AZ.26.223; 14.AZ.26.240; 14.AZ.26.244; 14.AZ.26.243; 14.AZ.26.247; 14.AZ.27.157; 14.AZ.27.158; 14.AZ.27.196; 14.AZ.27.223; 14.AZ.27.240; 14.AZ.27.244; 14.AZ.27.243; 14.AZ.27.247; 14.AZ.29.157; 14.AZ.29.158; 14.AZ.29.196; 14.AZ.29.223; 14.AZ.29.240; 14.AZ.29.244; 14.AZ.29.243; 14.AZ.29.247; 14.AZ.54.157; 14.AZ.54.158; 14.AZ.54.196; 14.AZ.54.223; 14.AZ.54.240; 14.AZ.54.244; 14.AZ.54.243; 14.AZ.54.247; 14.AZ.55.157; 14.AZ.55.158; 14.AZ.55.196; 14.AZ.55.223; 14.AZ.55.240; 14.AZ.55.244; 14.AZ.55.243; 14.AZ.55.247; 14.AZ.56.157; 14.AZ.56.158; 14.AZ.56.196; 14.AZ.56.223; 14.AZ.56.240; 14.AZ.56.244; 14.AZ.56.243; 14.AZ.56.247; 14.AZ.157.157; 14.AZ.157.158; 14.AZ.157.196; 14.AZ. 157.223; 14.AZ. 157.240; 14.AZ. 157.244; 14. AZ. 157.243; 14.AZ. 157.247; 14. AZ. 196.157; 14.AZ.196.158; 14. AZ. 196.196; 14. AZ. 196.223; 14. AZ. 196.240; 14. AZ. 196.244; 14. AZ. 196.243; 14. AZ. 196.247; 14.AZ.223.157; 14.AZ.223.158; 14.AZ.223.196; 14.AZ.223.223; 14.AZ.223.240; 14.AZ.223.244; 14.AZ.223.243; 14.AZ.223.247; 14.AZ.240.157; 14.AZ.240.158; 14. AZ.240.196; 14.AZ.240.223; 14.AZ.240.240; 14.AZ.240.244; 14.AZ.240.243; 14.AZ.240.247; 14.AZ.244.157; 14.AZ.244.158; 14.AZ.244.196; 14.AZ.244.223; 14.AZ.244.240; 14.AZ.244.244; 14.AZ.244.243; 14.AZ.244.247; 14.AZ.247.157; 14.AZ.247.158; 14.AZ.247.196; 14.AZ.247.223; 14.AZ.247.240; 14.AZ.247.244; 14.AZ.247.243; 14.AZ.247.247;
Prodrugs of 14.BF
14.BF.4.157; 14.BF.4.158; 14.BF.4.196; 14.BF.4.223; 14.BF.4.240: 14.BF.4.244; 14.BF.4.243; 14.BF.4.247; 14.BF.5.157; 14.BF.5.158; 14.BF.5.196; 14.BF.5.223;
14.BF.5.240; 14.BF.5.244; 14.BF.5.243; 14.BF.5.247; 14.BF.7.157; 14.BF.7.158; 14.BF.7.196; 14.BF.7.223; 14.BF.7.240; 14.BF.7.244; 14.BF.7.243; 14.BF.7.247; 14.BF.15.157; 14.BF.15.158; 14.BF.15.196; 14.BF.15.223; 14.BF.15.240; 14.BF.15.244; 14.BF.15.243; 14.BF.15.247; 14.BF.16.157; 14.BF.16.158; 14.BF.16.196; 14.BF.16.223; 14.BF.16.240; 14.BF.16.244; 14.BF.16.243; 14.BF.16.247; 14.BF.18.157; 14.BF.18.158; 14.BF.18.196; 14.BF.18.223; 14.BF.18.240; 14.BF.18.244; 14.BF.18.243; 14.BF.18.247; 14.BF.26.157; 14.BF.26.158; 14.BF.26.196; 14.BF.26.223; 14.BF.26.240; 14.BF.26.244; 14.BF.26.243; 14.BF.26.247; 14.BF.27.157; 14.BF.27.158; 14.BF.27.196; 14.BF.27.223; U.RF.27.240; 14.BF.27.244; 14.BF.27.243; 14.BF.27.247; 14.BF.29.157; 14.BF.29.158; 14.BF.29.196; 14.BF.29.223; 14.BF.29.240; 14.BF.29.244; 14.BF.29.243; 14.BF.29.247; 14.BF.54.157; 14.BF.54.158; 14.BF.54.196; 14.BF.54.223; 14.BF.54.240; 14.BF.54.244; 14.BF.54.243; 14.BF.54.247; 14.BF.55.157; 14.BF.55.158; 14.BF.55.196; 14.BF.55.223; 14.BF.55.240; 14.BF.55.244; 14.BF.55.243; 14.BF.55.247; 14.BF.56.157; 14.BF.56.158; 14.BF.56.196; 14.BF.56.223; 14.BF.56.240; 14.BF.56.244; 14.BF.56.243; 14.BF.56.247; 14.BF. 157.157; 14.BF.157.158; 14.BF.157.196; 14.BF. 157.223; 14.BF. 157.240; 14.BF. 157.244; 14.BF.157.243; 14.BF. 157.247; 14.BF.196.157; 14.BF.196.158; 14.BF.196.196; 14.BF. 196.223; 14.BF. 196.240; 14.BF. 196.244; 14.BF. 196.243; 14.BF. 196.247; 14.BF.223.157; 14.BF.223.158; 14.BF.223.196; 14.BF.223.223; 14.BF.223.240; 14.BF.223.244; 14.BF.223.243; 14.BF.223.247; 14.BF.240.157; 14.BF.240.158; 14.BF.240.196; 14.BF.240.223; 14.BF.240.240; 14.BF.240.244; 14.BF.240.243; 14.BF.240.247; 14.BF.244.157; 14.BF.244.158; 14.BF.244.196; 14.BF.244.223; 14.BF.244.240; 14.BF.244.244; 14.BF.244.243; 14.BF.244.247; 14.BF.247.157; 14.BF.247.158; 14.BF.247.196; 14.BF.247.223; 14.BF.247.240; 14.BF.247.244; 14.BF.247.243; 14.BF.247.247;
Prodrugs of 14.CI
14.CL4.157; 14.CI.4.158; 14.CI.4.196; 14.CI.4.223; 14.CI.4.240; 14.CI.4.244; 14.CI.4.243; 14.CI.4.247; 14.CI.5.157; 14.CI.5.158; 14.CI.5.196; 14.CI.5.223; 14.CI.5.240; 14.CI.5.244; 14.CI.5.243; 14.CI.5.247; 14.CI.7.157; 14.CI.7.158; 14.CL7.196; 14.CI.7.223; 14.CI.7.240; 14.CI.7.244; 14.CI.7.243; 14.CI.7.247; 14. CI. 15.157; 14.CI.15.158; 14.CI.15.196; 14.CI.15.223; 14.CI.15.240; 14.CI.15.244; 14.CI.15.243; 14.CI.15.247; 14.CI.16.157; 14.CI.16.158; 14.CI.16.196; 14.CI. 16.223; 14.CI. 16.240; 14.CI. 16.244; 14.CI.16.243; 14.CI.16.247; 14.CI.18.157; 14.CI.18.158; 14.CL18.196; 14.CI.18.223; 14.CI.18.240; 14.CI.18.244; 14.CI.18.243; 14.CI.18.247; 14.CL26.157; 14.CL26.158; 14.CI.26.196; 14.CI.26.223; 14.CI.26.240; 14.CI.26.244; 14.CI.26.243; 14.CI.26.247; 14.CI.27.157; 14.CI.27.158; 14.CI.27.196; 14.CI.27.223; 14.CI.27.240; 14.CI.27.244; 14.CI.27.243; 14.CI.27.247; 14.CI.29.157; 14.CI.29.158; 14.CI.29.196; 14.CI.29.223; 14.CI.29.240; 14.CI.29.244; 14.CI.29.243; 14.CI.29.247; 14.CI.54.157; 14.CI.54.158; 14.CI.54.196; 14.CI.54.223; 14.CI.54.240; 14.CI.54.244; 14.CI.54.243; 14.CI.54.247; 14.CI.55.157; 14.CI.55.158; 14.CI.55.196; 14.CI.55.223; 14.CI.55.240; 14.CI.55.244; 14.CL55.243; 14.CI.55.247; 14.CI.56.157; 14.CI.56.158; 14.CI.56.196; 14.CI.56.223; 14.CI.56.240; 14.CI.56.244; 14.CI.56.243; 14.CI.56.247; 14.CI.157.157; 14.CI.157.158; 14.CI.157.196; 14.CI. 157.223; 14.CI. 157.240; 14.CI. 157.244; 14.CI. 157.243; 14.CI.157.247; 14.CI.196.157; 14.CI.196.158; 14.CI.196.196; 14.CI. 196.223; 14.CI. 196.240; 14.CI. 196.244; 14.CI. 196.243; 14.CI. 196.247; 14.CI.223.157; 14.CI.223.158; 14.CI.223.196; 14.CI.223.223; 14.CI.223.240; 14.CI.223.244; 14.CI.223.243; 14.CI.223.247; 14.CI.240.157; 14.CI.240.158; 14.CI.240.196; 14.CI.240.223; 14.CI.240.240; 14.CI.240.244; 14.CI.240.243; 14.CI.240.247; 14.CI.244.157; 14.CI.244.158; 14.CI.244.196; 14.CI.244.223; 14.CI.244.240; 14.CI.244.244;
14.CI.244.243; 14.CI.244.247; 14.CI.247.157; 14.CI.247.158; 14.CI.247.196; 14.CI.247.223; 14.CI.247.240; 14.CI.247.244; 14.CI.247.243; 14.CI.247.247;
Prodrugs of 14.CO
14.CO.4.157; 14.CO.4.158; 14.CO.4.196; 14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.C0.4.243; 14.CO.4.247; 14.CO.5.157; 14.CO.5.158; 14.CO.5.196; 14.CO.5.223; 14.CO.5.240; 14.CO.5.244; 14.CO.5.243; 14.CO.5.247; 14.CO.7.157; 14.CO.7.158; 14.CO.7.196; 14.CO.7.223; 14.CO.7.240; 14.CO.7.244; 14.CO.7.243; 14.CO.7.247; 14.CO.15.157; 14.CO.15.158; 14.CO.15.196; 14.CO.15.223; 14.CO.15.240; '14.CO.15.744; 14.CO.15.243; 14.CO.15.247; 14.CO.16.157; 14.CO.16.158; 14.CO.16.196; 14.CO.16.223; 14.CO. 16.240; 14.CO. 16.244; 14.CO. 16.243; 14.CO. 16.247; 14.CO.18.157; 14.CO.18.158; 14.C0.18.196; 14.CO.18.223; 14.CO.18.240; 14.CO.18.244; 14.CO.18.243; 14.CO.18.247; 14.C0.26.157; 14.CO.26.158; 14.CO.26.196; 14.CO.26.223; 14.CO.26.240; 14.CO.26.244; 14.CO.26.243; 14.CO.26.247; 14.CO.27.157; 14.CO.27.158; 14.CO.27.196; 14.CO.27.223; 14.CO.27.240; 14.CO.27.244; 14.CO.27.243; 14.CO.27.247; 14.CO.29.157; 14.CO.29.158; 14.C0.29.196; 14.CO.29.223; 14.CO.29.240; 14.CO.29.244; 14.CO.29.243; 14.CO.29.247; 14.CO.54.157; 14.CO.54.158; 14.CO.54.196; 14.CO.54.223; 14.CO.54.240; 14.CO.54.244; 14.CO.54.243; 14.CO.54.247; 14.CO.55.157; 14.CO.55.158; 14.CO.55.196; 14.CO.55.223; 14.CO.55.240; 14.CO.55.244; 14.CO.55.243; 14.CO.55.247; 14.CO.56.157; 14.CO.56.158; 14.CO.56.196; 14.CO.56.223; 14.CO.56.240; 14.CO.56.244; 14.CO.56.243; 14.CO.56.247; 14.C0.157.157; 14.CO.157.158; 14.CO.157.196; 14.CO. 157.223; 14.CO. 157.240; 14.CO. 157.244; 14.CO. 157.243; 14.CO. 157.247; 14.CO.196.157; 14.CO.196.158; 14.CO.196.196; 14.CO. 196.223; 14.CO. 196.240; 14.CO. 196.244; 14.CO. 196.243; 14.CO. 196.247; 14.CO.223.157; 14.CO.223.158; 14.CO.223.196; 14.CO.223.223; 14.CO.223.240; 14.CO.223.244; 14.CO.223.243; 14.CO.223.247; 14.CO.240.157; 14.CO.240.158; 14.CO.240.196; 14.CO.240.223; 14.CO.240.240; 14.CO.240.244; 14.CO.240.243; 14.CO.240.247; 14.CO.244.157; 14.CO.244.158; 14.CO.244.196; 14.CO.244.223; 14.CO.244.240; 14.CO.244.244; 14.CO.244.243; 14.CO.244.247; 14.C0.4.157; 14.CO.4.158; 14.CO.4.196; 14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.C0.4.243; 14.CO.4.247;
Recursive Substituents
Selected substituents within the compounds of the invention are present to a recursive degree. In this context, "recursive substituent" means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number of compounds may be present in any given embodiment. For example, Rx contains a Ry substituent. Ry can be R2, which in turn can be R3. If R3 is selected lo be R °, then a second instance of Rx can be selected. One of ordinary skill in the art of medicinal chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
By way of example and not limitation, W3, Ry and R3 are all recursive substituents in certain embodiments. Typically, each of these may independently occur 20, 19, 18,17,16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5,4, 3, 2,1, or 0, times in a given embodiment. More typically, each of these may independently occur 12 or fewer times in a given embodiment. More typically yet, W3 will occur 0 to 8 times, Ry will occur 0 to 6 times and R3 will occur 0 to 10 times in a given embodiment. Even more typically, W3 will occur 0 to 6 times, Ry will occur 0 to 4 times and R3 will occur 0 to 8 times in a given embodiment.
Recursive substituents are an intended aspect of the invention. One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in an embodiment of the invention, the total number will be determined as set forth above.
Protecting Groups
In the context of the present invention, embodiments of protecting groups include prodrug moieties and chemical protecting groups.
Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group "PRT" will be dependent upon the chemistry of the reaction to be protected against (e.g.,
acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PRT groups do not need to be, and generally are not, the same if the compound is substituted with multiple PRT. In general, PRT will be used to protect functional groups such as carboxyl, hydroxyl or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free, deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.
Various functional groups of the compounds of the invention may be protection. For example, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or other functions) are embodiments of "ether- or ester-forming groups". Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.
A very large number of hydroxyl protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) ("Greene"). See also Kocienski, Philip J.; "Protecting Groups" (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its entiretyherein. In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below. Such groups include by way of example and not limitation, esters, amides, hydrazides, and the like.
Ether- and Ester-forming protecting groups
Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3) sulphur ester-forming groups, such as sulphonate, sulfate, and sulfmate.
The phosphonate moieties of the compounds of the invention may or may not be prodrug moieties, i.e. they may or may not be susceptible to hydrolytic or enzymatic cleavage or modification. Certain phosphonate moieties are stable under most or nearly all metabolic conditions. For example, a dialkylphosphonate, where the alkyl groups are two or more carbons, may have appreciable stability in vivo due to a slow rate of hydrolysis.
Within the context of phosphonate prodrug moieties, a large number of structurally-diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997) and are included within the scope of the present invention. An exemplary embodiment of a phosphonate ester-forming group is the phenyl carbocycle in substructure AS having the formula:

wherein ml is 1, 2, 3, 4, 5, 6, 7 or 8, and the phenyl carbocycle is substituted with 0 to 3 R2 groups. Also, in this embodiment, where YI is O, a lactate ester is formed. Alternatively, where YI is N(Ro), N(OR2) or N(N(R2>2, then phosphonamidate esters result.
RI may be H or Q-Cn alkyl. The corollary exemplary substructure A is included in the invention with Y , R and R substituents.
In its ester-forming role, a protecting group typically is bound to any acidic group such as, by way of example and not limitation, a -CO2H or -C(S)OH group, thereby resulting in -CO2RX where Rx is defined herein. Also, Rx for example includes the enumerated ester groups of WO 95/07920.
Examples of protecting groups include:
C3~Ci2 heterocycle (described above) or aryl. These aromatic groups optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl,
Cs-Ci2 heterocycle or aryl substituted with halo, R1, Rl-O-Ci-Ci2 alkylene, Ci-Ci2 alkoxy, CN, NO2, OH, carboxy, carboxyester, thiol, thioester, C\-C\2 haloalkyl (1-6 halogen atoms), C2-Ci2 alkenyl or C2-Ci2 alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (Ci-Ci2 alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3-and 4-O-acetylphenyl, 2-, 3- and 4-dimethylarninophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalophenyl (including 2,4-difluorophenyl and 3,5-difluorophenyl), 2-, 3- and 4-haloalkylphenyl (1 to 5 halogen atoms, Ci-Ci2 alkyl including 4-trifluoromethylphenyl), 2-, 3- and 4-cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1 to 5 halogen atoms, Ci-Ci2 alkyl including 4-trifluoromethylbenzyl and 2-, 3- and 4-trichloromethylphenyl and 2-, 3- and 4-trichlorornethylphenyl), 4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl, benzyl, alkylsalicylphenyl (Ci-C4 alkyl, including 2-, 3- and 4-ethylsalicylphenyl), 2-,3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (-CioHe-OH) and aryloxy ethyl [Ce-Cg aryl (including phenoxy ethyl)], 2,2-dihydroxybiphenyl, 2-, 3- and4-N,N-dialkylaminophenol, -

trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl (€1.4 alkyl); O "
;C4-Cg esters of 2-carboxyphenyl; and Ci-€4 alkylene-Cs-Ce aryl (including benzyl, -CH2-pyrrolyl, -CH2-thienyl, -CHo-imidazolyl, -CH2-oxazolyl, -CH2-isoxazolyl, -CH2-thiazolyl, -CH2-isothiazolyl, -CH2-pyrazolyl, -CH2-pyridinyl and -CH2-pyrimidinyl) substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, Ci-Ci2 alkoxy (including methoxy and ethoxy), cyano, nitro, OH, Ci-Q2 haloalkyl (1 to 6 halogen atoms; including -CH2CC13), Ci-Ci2 alkyl (including methyl and ethyl), C2-Ci2 alkenyl or C?-Ci2 alkynyl; alkoxy ethyl
alkyl including -CH2-CH2-O-CH3 (methoxy ethyl)]; alkyl substituted by any of the groups set forth above for aryl, in particular OH or by 1 to 3 halo atoms (including -CH3; -CH(CH3)2, -C(CH3)3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -(CH2)4CH3, -

(CH2)5CH3,CH2CH2F, -CH2CH2C1, -CH2CF3) and-CH2CC!3); propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester, -CH2-C(O)-N(Rl)2, -CH2-S(0)(Rl), -CH2-S(0)2(R1), -CH2-CH(OC(O)CH2R1)-CH2(OC(O)CH2R1), cholesteryl, enolpyruvate (HOOC-C(=CH2)-), glycerol;
a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9 monosaccharide residues);
triglycerides such as a-D-p-diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated Ce-26. C6-18 or Ce-io fatty acids such as linoleic, lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic and the like fatty acids) linked to acyl of the parental compounds herein through a glyceryl oxygen of the triglyceride;
phospholipids linked to the carboxyl group through the phosphate of the phospholipid;
phthalidyl (shown in Fig. 1 of Clayton et aL, Antimicrob. Agents Chemo. (1974) 5(6):670-671;
cyclic carbonates such as (5-Rd-2-oxo-l,3-dioxolen-4-yl) methyl esters (Sakamoto et
aL, Chem. Phann. Bull. (1984) 32(6)2241-2248) where Rd is RI, R4 or aryl; and
The hydroxyl groups of the compounds of this invention optionally are substituted with one of groups III, IV or V disclosed in WO 94/21604, or with isopropyl.
As further embodiments, Table A lists examples of protecting group ester moieties that for example can be bonded via oxygen to -C(O)O- and -P(O)(O-)2 groups. Several amidates also are shown, which are bound directly to -C(O)- or -P(O)2- Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like) and N ,N-dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CsCO3, N,N-
dimethylaniline and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone). When the compound to be protected is a phosphonate, the esters of structures 5-7, 11, 12, 21, and 23-26 are synthesized by reaction of the alcohol or alkoxide salt (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate).
-CH(Rl or W5)((CO)OR38) (linked to oxygen of the acidic group) wherein R37 and R38 are alkyl, aryl, or alkylaryl groups (see U.S. Patent No. 4,968,788). Frequently R37 and R38 are bulky groups such as branched alkyl, ortho-substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms. An example is the pivaloyloxymethyl group. These are of particular use with prodrugs for oral administration. Examples of such useful protecting groups are alkylacyloxymethyl esters and their derivatives, including -

CH(CH2CH2OCH3)OC(0)C(CH3)3, -CH2OC(O)C10Hi5, -CH2OC(O)C(CH3)3, -CH(CH20CH3)OC(O)C(CH3)3, -CH(CH(CH3)2)OC(O)C(CH3)3, -CH2OC(O)CH2CH(CH3)2) -CH2OC(O)C6Hii, -CH2OC(0)C6H5, -CH2OC(0)CioHi5, -CH2OC(O)CH2CH3, -CH2OC(O)CH(CH3)2, -CH2OC(O)C(CH3)3 and -CH2OC(O)CH2C6H5.
For prodrug purposes, the ester typically chosen is one heretofore used for antibiotic drugs, in particular the cyclic carbonates, double esters, or the phthalidyl, aryl or alkyl esters.
In some embodiments the protected acidic group is an ester of the acidic group and is the residue of a hydroxyl-containing functionality. In other embodiments, an amino compound is used to protect the acid functionality. The residues of suitable hydroxyl or ammo-containing functionalities are set forth above or are found in WO 95/07920. Of particular interest are the residues of amino acids, amino acid esters, polypeptides, or aryl alcohols. Typical amino acid, polypeptide and carboxyl-esterified amino acid residues are described on pages 11-18 and related text of WO 95/07920 as groups LI or L2. WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.
Typical esters for protecting acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication. Typical ester groups are defined at least on WO 95/07920 pages 89-93 (under R31 or R3^), the table on page 105, and pages 21-23 (as R). Of particular interest are esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and/or alkylestercarboxy-substituted aryl or alkylaryl,
especially phenyl, ortho-ethoxyphenyl, or C\-C^ alkylestercarboxyphenyl (salicylate Q-Ci2 alkylesters).
The protected acidic groups, particularly when using the esters or amides of WO 95/07920, are useful as pro-drugs for oral administration. However, it is not essential that the acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route. When the compounds of the invention having protected groups, in particular amino acid amidates or substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydrolytic cleavage in vivo to yield the free acid.
One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and ester may be used.
Typical hydroxy protecting groups described in Greene (pages 14-118) include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates. For example:
• Ethers (methyl, r-butyl, allyl);
• Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, r-Butylthiomethyl,
(Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl,p-Methoxybenzyloxymethyl,
(4-Methoxyphenoxy)methyl, Guaiacolmethyl, f-Butoxymethyl, 4-Pentenyloxymethyl,
Siloxymethyl, 2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2-
chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-
Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-
Methoxytetrahydropyranyl, 4-Methoxytetrahydrothiopyranyl, 4-
MethoxytetrahydropthiopyranylS.iS-Dioxido, l-[(2-Chloro-4-methyl)phenyl]-4-
methoxypiperidin-4-yl, l,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-Octahydro-7,8)8-trimethyl-4,7-methanobenzofuran-2-yl));
• Substituted Ethyl Ethers (1-EthoxyethyI, l-(2-Chloroethoxy)ethyl, 1-Methyl-1-
methoxyethyl, 1-Methyl-1-benzyloxyethyl, l-Methyl-l-benzyloxy-2-fluoroethyl, 2,2,2-
Trichloroethyl, 2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl,
• p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl);
• Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-
Nitrobenzyl, /?-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl, p-Phenylbenzyl, 2- and
4-Picolyl, 3-Methyl-2-picolyl W-Oxido, Diphenylmethyl, ^^'-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl, a-Naphthyldiphenylmethyl, /?-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl, 4-(4'-Bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-Tris(levulinoyloxyphenyl)methyl, 4,4',4"-Tris(benzoyloxyphenyl)methyl, 3-(Imidazol-l-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl, l,l-Bis(4-methoxyphenyl)-r-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl, l,3-Benzodithiolan-2-yl, Benzisothiazolyl 5,5-Dioxido);
• Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl, Dimethylisopropylsilyl,
Diethylisopropylsilyl, Dimethylthexylsilyl, f-Butyldimethylsilyl, f-Butyldiphenylsilyl,
Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl, t-
Butylmethoxyphenylsilyl);
• Esters (Formate, Benzoylformate, Acetate, Choroacetate, Dichloroacetate,
Trichloroacetate, Trifluoroacetate, Methoxyacetate, Triphenylrriethoxyacetate,
Phenoxyacetate, p-Chlorophenoxyacetate, p-poly-Phenylacetate, 3-Phenylpropionate, 4-
Oxopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate,
Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate
(Mesitoate));
• Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-
(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl,
Vinyl, Allyl, p-Nitrophenyl, Benzyl, /7-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-
Nitrobenzyl, p-Nitrobenzyl, 5-Benzyl Thiocarbonate, 4-Ethoxy-l-naphthyl, Methyl
Dithiocarbonate);
• Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate, 4-Nitro-4-
methylpentanoate, o-(Dibromomethyl)benzoate, 2-Formylbenzenesulfonate, 2-
(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate, 2-
(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters (2,6-Dichloro-4-
methylphenoxyacetate, 2,6-Dichloro-4-(l,1,3,3 tetramethylbutyl)phenoxyacetate, 2,4-
Bis(l, l-dimethylpropyl)phenoxyacetate, Chlorodiphenylacetate, Isobutyrate,
Monosuccinate, (£)-2-Methyl-2-butenoate (Tigloate), o-(Methoxycarbonyl)benzoate, p-
poly-Benzoate, a-Naphthoate, Nitrate, Alkyl MA'i^'^'-Tetramethylphosphorodiamidate,
N-Phenylcarbamate, Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and Sulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate, Tosylate).
Typical 1,2-diol protecting groups (thus, generally where two OH groups are taken together with the protecting functionality) are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-f-Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene, a-Methoxybenzylidene, l-(Ar,AT-Dimethylamino)ethylidene Derivative, a -(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene); Silyl Derivatives (Di-t-butylsilylene Group, l,3-(l,l,3,3-Tetraisopropyldisiloxanylidene), and Tetra-f-butoxydisiloxane-l,3-diylidene), Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate and Phenyl Boronate.
More typically, 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals.
herein R.9 is Ci-Cs alkyl. Amino protectuig groups
Another set of protecting groups include any of the typical amino protecting groups described by Greene at pages 315-385. They include:
Carbamates: (methyl and ethyl, 9-fluorenylmethyl, 9(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-r-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methyl, 4-methoxyphenacyl);
Substituted Ethyl: (2,2,2-trichoroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-l-methylethyl, l,l-dimethyl-2-haloethyl, l,l-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, l-methyl-l-(4-biphenylyl)ethyl, l-(3,5-di-f-butylphenyl)-l-methylethyl, 2-(2'- and 4'-pyiidyl)ethyl, 2-(N,A^dicyclohexylcarboxamido)ethyl, f-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl);
Groups With Assisted Cleavage: (2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(l,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, l,l-dimethyl-2-cyanoethyl, ra-choro-p-acyloxybenzyl, /7-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonyhTiethyl); Groups Capable of Photolytic Cleavage: (m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives (phenothiazinyl-(lO)-carbonyl, AP-p-toluenesulfonylaminocarbonyl, N'-phenylaminothiocarbonyl);
Miscellaneous Carbamates: (f-amyl, 5-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,A^-dimethylcarboxamido)benzyl, 1> l-dimethyl-3-(A/,A/'-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl) methyl, 2-furanylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl, p-(p'-Methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-l-cyclopropylmethyl, l-methyl-l-(3,5-dimethoxyphenyl)ethyl, l-methyl-l-(p-phenylazophenyl)ethyl, 1-methyl-l-phenylethyl, 1-methyl-l-(4-pyridyl)ethyl, phenyl,p-(phenylazo)benzyl, 2,4,6-tri-^-butylphenyl, 4-(trimethylammonium)benzyl, 2,4,6-trunethylbenzyl);
Amides: (N-formyl, N-acetyl, A^-choroacetyl, A^-trichoroacetyl, A^-trifluoroacetyl, N-phenylacetyl, A^-3-phenylpropionyl, A^-picoUnoyl, A^-3-pyridylcarboxamide, N-
benzoylphenylalanyl, W-benzoyl, //-/>-phenylbenzoyl);
Amides With Assisted Cleavage: (W-o-nitrophenylacetyl, //-o-nitrophenoxyacetyl, N-
acetoacetyl, (A^'-dithiobenzyloxycarbonylamino)acetyl, //-3-(p-hydroxyphenyl)propionyl,
A^-3-(o-nitrophenyl)propionyl, A^-2-methyl-2-(o-nitrophenoxy)propionyl, W-2-methyl-2-
(o-phenylazophenoxy)propionyl, //-4-chlorobutyryl, A^-3-methyl-3-nitrobutyryl, N-o-
nitrocinnamoyl, //-acetylmethionine, //-o-nitrobenzoyl, //-0-(benzoyloxymeuiyl)benzoyl,
4,5-diphenyl-3-oxazolin-2-one);
Cyclic Imide Derivatives: (N-phthalimide, //-dithiasuccinoyl, A^-2,3-diphenylmaleoyl, N-
2,5-dimethylpyrrolyl, //-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted
l,3-dimethyl-l,3,5-triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3-5-
triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridonyl);
A^-Alkyl and A^-Aryl Amines: (//-methyl, W-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, ^V-
3-acetoxypropyl, A/-(l-isopropyl-4-nitro-2-oxo-3-pyrrolk-3-yl), Quaternary Ammonium
Salts, A^-benzyl, A^-di(4-methoxyphenyl)methyl, //-5-dibenzosuberyl, JV-triphenylmethyl,
A^-(4-methoxyphenyl)diphenylmethyl, A^-9-phenylfluorenyl, N-2,7-dichloro-9-
fluorenyknethylene, //-ferrocenylmethyl, A/-2-picolylamine AT-oxide);
Imine Derivatives: (7V-l,l-dimethylthiomethylene, N-benzylidene, N-p-
methoxybenylidene, AT-diphenylmethylene, JV-[(2-pyridyl)mesityl]methylene, AT,(A^1)A/'-
dimethylaminomethylene, Af,W-isopropylidene, AT-p-nitrobenzylidene, 7V-salicylidene, N-
5-chlorosalicylidene, AT-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-
cyclohexylidene);
Enamine Derivatives: (?/-(5,5-dimethyl-3-oxo-l-cyclohexenyl));
A^-Metal Derivatives (^V-borane derivatives, AT-diphenylborinic acid derivatives, JV-
[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, //-copper or //-zinc chelate);
N-N Derivatives: (Af-nitro, A'-nitroso, A'-oxide);
N-P Derivatives: (//-diphenylphosphinyl, AT-dimethylthiophosphinyl, N-
diphenylthiophosphinyl, A'-dialkyl phosphoryl, A^-dibenzyl phosphoryl, W-diphenyl
phosphoryl);
N-Si Derivatives, N-S Derivatives, and N-Sulfenyl Derivatives: (A^-benzenesulfenyl, N-o-
nitrobenzenesulfenyl, //-2,4-dinitrobenzenesulfenyl, A^-pentachlorobenzenesulfenyl, A^-2-
nitro-4-methoxybenzenesulfenyl, //-triphenylmethylsulfenyl, N-3 -nitropyridinesulfenyl);
and //-sulfonyl Derivatives (//-p-toluenesulfonyl, A/^-benzenesulfonyl, Af-2,3,6-trimethyl-
4-methoxybenzenesulfonyl, Afr-2,4,6-trimethoxybenzenesulfonyl, Ar-2,6-dimethyl-4-methoxybenzenesulfonyl, //-pentamethylbenzenesulfonyl, yV-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl, Af-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, A/^-2,6-dimethoxy-4-methylbenzenesulfonyl, A/-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, W-p-trimethylsilyethanesulfonyl, AA 9-anthracenesulfonyl,A^-4-(4',8'-dknethoxynaphthyhnethyl)benzenesukcbnyl,A^-benzylsulfonyl, AT-trifluoromethylsulfonyl, A^-phenacylsulfonyl).
Protected amino groups include carbamates, amides and amidines, e.g. -NHC(O)OR1, -NHC(O)R1 or -N=CR1N(R1)2. Another protecting group, also useful as a
prodrug for amino or -NH(R5), is:
"OSee for example Alexander, J. et al (1996) /. Med. Chem. 39:480-486.
Amino acid and polypeptide protecting group and conjugates
An amino acid or polypeptide protecting group of a compound of the invention has the structure R15NHCH(R16)C(O)-, where R15 is H, an amino acid or polypeptide residue, or R5, and R16 is defined below.
R16 is lower alkyl or lower alkyl (Ci-Ce) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, Ce-Cy aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R16 also is taken together with the amino acid a-N to form a proline residue (R16 = -CH2)3-). However, R16 is generally the side group of a naturally-occurring amino acid such as H, -CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CHCH3-CH2-CH3, -CH2-C6H5, -CH2CH2-S-CH3, -CH2OH, -CH(OH)-CH3, -CH2-SH, -CH2-C6H4OH, -CH2-CO-NH2, -CH2-CH2-CO-NH2, -CH2-COOH, -CH2-CH2-COOH, -(CH2)4-NH2 and -(CH2)3-NH-C(NH2)-NH2. R16 also includes l-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.
Another set of protecting groups include the residue of an amino-containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHSO2R,
NHC(O)R, -N(R)2, NH2 or -NH(R)(H), whereby for example a carboxylic acid is reacted, i.e. coupled, with the amine to form an amide, as in C(O)NR2. A phosphonic acid may be reacted with the amine to form a phosphonamidate, as in -P(O)(OR)(NR2)-
Amino acids have the structure R17C(O)CH(R16)NH-, where R17 is -OH, -OR, an amino acid or a polypeptide residue. Amino acids are low molecular weight compounds, on the order of less than about 1000 MW and which contain at least one amino or imino group and at least one carboxyl group. Generally the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man. Suitable amino acids typically are alpha amino acids, i.e. compounds characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom. Of particular interest are hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parental drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent.
Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally-occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutarhic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline. Additionally, unnatural amino acids, for example, valanine, phenylglycine and homoarginine are also included. Commonly encountered amino acids that are not gene-encoded may also be used in the present invention. All of the amino acids used in the present invention may be either the D- or L- optical isomer. In addition, other peptidomimetics are also useful in the present invention. For a general review, see Spatola, A. F., in Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983).
When protecting groups are single amino acid residues or polypeptides they optionally are substituted at R3 of substituents A1, A2 or A3 in Formula I, or substituted at Ra of substituents Ai, AZ or Aj in Formula II. These conjugates are generally produced by forming an amide bond between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example). Alternatively, conjugates are formed between R3
(Formula I) or R3 (Formula II) and an amino group of an amino acid or polypeptide. Generally, only one of any site in the scaffold drug-like compound is amidated with an amino acid as described herein, although it is within the scope of this invention to introduce amino acids at more than one permitted site. Usually, a carboxyl group of R3 is amidated with an amino acid. In general, the a-amino or a-carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the scaffold, parental functionalities, Carboxyl or amino groups in the amino acid side chains generally may be used to form the amide bonds with the parental compound or these groups may need to be protected during synthesis of the conjugates as described further below.
With respect to the carboxyl-containing side chains of amino acids or polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g. by R1, esterified with R5 or amidated. Similarly, the amino side chains R16 optionally will be blocked with R1 or substituted with R5.
Such ester or amide bonds with side chain amino or carboxyl groups, like the esters or amides with the parental molecule, optionally are hydrolyzable in vivo or in vitro under acidic (pH 10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments. The esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl groups. The free acid or base of the parental compound, for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures.
When an amino acid residue contains one or more chiral centers, any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof may be used. In general, if the intermediates are to be hydro lyzed non-enzymatically (as would be the case where the amides are used as chemical intermediates for the free acids or free amines), D isomers are useful. On the other hand, L isomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.
Examples of suitable amino acids whose residues are represented by Rx or Ry include the following:
Glycine;
Aminopolycarboxylic acids, e.g., aspartic acid, p-hydroxyaspartic acid, glutamic acid, P -hydroxyglutamic acid, p-methylaspartic acid, p-methylglutamic acid, p, p-dimethylaspartic acid, y-hydroxyglutamic acid, p, y-dihydroxyglutamic acid, p -phenylglutamic acid, y-methyleneglutamic acid, 3-arninoadipic acid, 2-aminopimelic acid, 2-amino suberic acid and 2-aminosebacic acid;
Amino acid amides such as glutamine and asparagine;
Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine, P -aminoalanine, y -aminobutyrine, ornithine, citruline, homoarginine, homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;
Other basic amino acid residues such as histidine;
Diaminodicarboxylic acids such as a, a'-diaminosuccinic acid, a, a'-diaminoglutaric acid, a, a'-diaminoadipic acid, a, a'-diaminopimelic acid, a, a'-diamino- p-hydroxypimelic acid, a, a'-diaminosuberic acid, a, a'-diaminoazelaic acid, and a, a'-diaminosebacic acid;
Imino acids such as proline, hydroxyproUne, allohydroxyproline, y-methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2-carboxylic acid;
A mono- or di-alkyl (typically Ci-Cg branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, a-methylserine, a-amino-a-methyl-y-hydroxyvaleric acid, a-amino- a-methyl-8-hydroxyvaleric acid, a-amino-a-methyl-e-hydroxycaproic acid, isovaline, a-methylglutamic acid, a-aminoisobutyric acid, a-aminodiethylacetic acid, a-aminodiisopropylacetic acid, a-aminodi-n-propylacetic acid, p-phenylserinyl;
Aliphatic a-arnino-p-hydroxy acids such as serine, p-hydroxyleucine, P-hydroxynorleucine, p -hydroxynorvaUne, and a-amino-p-hydroxystearic acid;
a-Amino, a-, y-, 5- or e-hydroxy acids such as homoserine, 8 -hydroxynorvaUne, y-hydroxynorvaline and e-hydroxynorleucine residues; canavine and canaline; y -hydroxyornithine;
2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acid;
a-Amino-p-thiols such as penicillamine, p-thiolnorvaline or p-thiolbutyrine;
Other sulfur containing amino acid residues including cysteine; homocystine, P-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine;
Phenylalanine, tryptophan and ring-substituted a-amino acids such as the phenyl- or cyclohexylamino acids a-aminophenylacetic acid, a-aminocyclohexylacetic acid and a-amino-p-cyclohexylpropionic acid; phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dichloro, o-, m- or/i-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5-nitro- and p-nitro-phenylalanine); furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and tryptophan analogues and derivatives including kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan;
a-Amino substituted amino acids including sarcosine (N-methylglycine), N-benzylglycine, N-rnethylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline; and
a-Hydroxy and substituted a -hydroxy amino acids including serine, threonine, allothreonine, phosphoserine and phospho threonine.
Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond. Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
The polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not immunogenic in the animal to which it is administered) or against the epitopes on the remainder of the compound of this invention.
Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound. The conjugates of parental compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make
the polypeptide more immunogenic for facilitating raising antibodies against it. Accordingly, the polypeptide or protein may be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat. The polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzymatic recognition structures, e.g. a particular sequence of residues recognized by a peptidolytic enzyme.
Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases, which digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences. Such enzymes and their substrate requirements in general are well known. For example, a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its a-amino group to the phosphorus or carbon atoms of the compounds herein. In certain embodiments, a phosphonate group substituted with an amino acid or peptide will be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosphonoamidate bond.
Suitable dipeptidyl groups (designated by their single letter code) are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, El, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, 1C, IE, IQ, IG, IH, II, EL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KG, KE, KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN,
TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY andW.
Tripeptide residues are also useful as protecting groups. When a phosphonate is to be protected, the sequence -X4-pro-X5- (where X4 is any amino acid residue and X is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X4 with a free carboxyl, which in turn is expected to autocatalytically cleave the phosphonoamidate bond. The carboxy group of X5 optionally is esterified with benzyl.
Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types. Dipeptides and tripeptides lacking an a-amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J.P.F., (1992) Pharm Res. 9:969-978. Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds. Di- or tripeptides having one or more amino acids in the D configuration may be compatible with peptide transport. Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N. In addition, di- or tripeptides alternatively are selected on the basis of thek relative resistance to hydrolysis by proteases found in the lumen of the intestine. For example, tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A, di- or tripeptides lacking amino acid residues on the N-terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp) are poor substrates for endopeptidase, and peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates for carboxypeptidase P. Similar considerations can also be applied to the selection of peptides that are either relatively resistant or relatively susceptible to hydrolysis by cytosolic, renal, hepatic, serum or other peptidases. Such poorly cleaved polypeptide amidates are immunogens or are useful for bonding to proteins in order to prepare irnmunogens.
Phosphonate analogs of known experimental or approved Protease Inhibitor Drugs
The known experimental or approved protease inhibitor drugs which can be derivatized in accord with the present invention must contain at least one functional group capable of Unking, i.e. bonding to the phosphorus atom in the phosphonate moiety. The phosphonate derivatives of Formulas I-VIE may cleave in vivo in stages after they have reached the desired site of action, i.e. inside a cell. One mechanism of action inside a cell may entail a first cleavage, e.g. by esterase, to provide a negatively-charged "locked-in" intermediate. Cleavage of a terminal ester grouping in Formulas I-VIE thus affords an unstable intermediate which releases a negatively charged "locked in" intermediate.
After passage inside a cell, intracellular enzymatic cleavage or modification of the phosphonate prodrug compound may result in an intracellular accumulation of the cleaved or modified compound by a "trapping" mechanism. The cleaved or modified compound may then be "locked-in" the cell, i.e. accumulate in the cell by a significant change in charge, polarity, or other physical property change which decreases the rate at which the cleaved or modified compound can exit the cell, relative to the rate at which it entered as the phosphonate prodrug. Other mechanisms by which a therapeutic effect is achieved may be operative as well. Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphatases.
In selected instances in which the drug is of the nucleoside type, such as is the case of zidovudine and numerous other antiretroviral agents, it is known that the drug is activated in vivo by phosphorylation. Such activation may occur in the present system by enzymatic conversion of the "locked-in" intermediate with phosphokinase to the active phosphonate diphosphate and/or by phosphorylation of the drug itself after its release from the "locked-in" intermediate as described above. In either case, the original nucleoside-type drug will be converted, via the derivatives of this invention, to the active phosphorylated species.
From the foregoing, it will be apparent that many structurally different known approved and experimental HIV protease inhibitor drugs can be derivatized in accord with the present invention. Numerous such drugs are specifically mentioned herein. However, it should be understood that the discussion of drug families and their specific members for derivatization according to this invention is not intended to be exhaustive, but merely illustrative.
As another example, when the selected drug contains multiple reactive hydroxyl functions, a mixture of intermediates and final products may again be obtained. In the unusual case in which all hydroxy groups are approximately equally reactive, there is not expected to be a single, predominant product, as each mono-substituted product will be obtained in approximate by equal amounts, while a lesser amount of multiply-substituted product will also result. Generally speaking, however, one of the hydroxyl groups will be more susceptible to substitution than the other(s), e.g. a primary hydroxyl will be more reactive than a secondary hydroxyl, an unhindered hydroxyl will be more reactive than a hindered one. Consequently, the major product will be a mono-substituted one in which the most reactive hydroxyl has been derivatized while other mono-substituted and multiply-substituted products may be obtained as minor products.
Formula I compounds having a 3-hydroxy-5-amino-pentamide core include Indinavir-like phosphonate protease inhibitors (ILPPI). Compounds of the invention include phosphonate analogs of other known PI compounds with a 3-hydroxy-5-amino-pentamide core which have been identified as CGP-49689, CGP-53437, CGP-57813 (Novartis); L-689502, L-693549, L-748496, L-754394, MK-944a, Iddb63, Iddb88 (Merck); Lasinavir (Bristol-Myers Squibb); U-81749 (PNU/Pfizer); SB-203386, SKF-108922 (SmithKline Beecham).

O Formula n compounds having a 2-hydroxy-l, 3-amino-propylamide or 2-hydroxy-
1,3-amino-propylaminosulfone core include Amprenavir-like phosphonate protease inhibitors (AMLPPI). Compounds of the invention include phosphonate analogs of other known PI compounds with a 2-hydroxy-3-amido-propylamide or 2-hydroxy-3-amido-propylaminosulfone core which have been identified as Droxinavir, Telinavir, IddbSl (Searle); Ph4556 (WO 95/29922; Ph5145 (WO 96/31527; DPC-681, DPC-684 (DuPont); VB-11328 (Vertex); TMC-114 (Tibotech/Johnson & Johnson). Formula II compounds also include phosphonate analogs of fosamprenavir where the 2-hydroxy is phosphorylated, i.e. having a or 2-phosphate-l,3-amino-propylaminosulfone core (US Patent No. 6,436,989).
The embodiments of the invention also include the following phosphonate analogs of
Formula n, represented as Formulas Ila-Ig:
described as "(I)" in: WO 94/05639 (published 17 March 1994) at page 4, line 15, to page 6, line 27, page 15, line 21, to page 17, line 33, and Claim 1; US Patent No. 5,585,397 (issued 17 December 1996) at coL 2, line 45, to col. 3, line 53, and col. 8, line 1, to col. 9, line 12; US Patent No. 5,783, 701 (issued 21 July 1998) at col. 2, line 43, to col. 3, line 64, col. 8, line 13, to col. 9, line 33, and Claim 1; US Patent No. 5,856,353 (issued 5 January 1999) at col. 2, line 45, to col. 3, line 65, col. 8, line 14, to col. 9, line 37, and Claim 1; US Patent No. 5,977,137 (issued 2 November 1999) at col. 2, line 43, to col. 3, line 65, col. 8, line 15, to col. 9, line 38, and Claim 1; and US Patent No. 6,004,957 (issued 21 December 1999) at col. 2, line 47, to col. 4, line 3, col. 8, line 18, to col. 9, line 41, and Claim 1 therein.
described as "(I)" in: WO 96/33184 (published 24 October 1996) at page 4, line 19, to page 6, line 5, page 17, line 11, to page 19, line 31, and Claim 1; and US Patent No. 5,723,490 (issued 3 March 1998) at col. 2, line 49, to col. 3, line 39, col. 8, line 66, to col. 10, line 36, and Claim 1.
described as "(I)" in: WO 96/33187 (published 24 October 1996) at page 4, line 23, to page 6, line 18, page 18, line 8, to page 21, line 18, and Claims 1 and 6; US Patent No. 5,691,372 (issued 25 November 1997) at col. 2, line 43, to col. 3, line 47, col. 9, line 21, to col. 11, line 5, and Claims 1 and 5; and US Patent No. 5,990,155 (issued 23 November 1999) at col. 2, line 46, to col. 3, line 55, col. 9, line 25, to col. 11, line 13, and Claims 1 and 3.


described as "(I)" in: WO 99/33793 (published 8 July 1999) at page 4, line 1, to page 7, line
OQ nao-p. 17 lin/» 1 tn n-acr^ 9fl lin*» ^T anH r"laim 1
29, page 17, line 1, to page 20, line 33, and Claim 1.
described as "(I)" in: WO 99/33815 (published 8 July 1999) at page 4, line 1, to page 7, line 19, page 12, line 18, to page 16, line 7, and Claim 1; and WO 99/65870 (published 23 December 1999) at page 4, line 7, to page 8, line 4, page 12, line 7, to page 16, line 4, and Claim 1.

described as "(I)" in: WO 00/47551 (published 17 August 2000) at page 4, line 10, to page 8, line 29, page 13, line 14, to page 17, line 32, and Claim 1.
described as "(I)" in: WO 00/76961 (published 21 December 2000) at page 5, line 1, to page 10, line 24, page 14, line 28, to page 20, line 21, and Claim 1.

(Figure Remove) described as "(I)" in: WO 99/33792 (published 8 July 1999) at page 4, line 5, to page 7, line 35, page 17, line 10, to page 21, line 6, and Claim 1; WO 95/24385 (published 14 September 1995) at page 4, line 24, to page 7, line 14, page 16, line 20, to page 19, line 8, and Claims 1 and 29; and US Patent No. 6,127,372 (issued 3 October 2000) at col. 2, line 58, to col. 4, line 28, col. 8, line 66, to col. 10, line 37, and Claim 1.
Formula m compounds having a 2-hydroxy-3-amino-propylamide core include KNI-like phosphonate protease inhibitors (KNILPPI). Compounds of the invention include phosphonate analogs of other known PI compounds with a 2-hydroxy-3-amido-propylamide or 2-hydroxy-3-amido-propylaminosulfone core which have been identified as KNI-764 (JE-2147, AG1776); KNI-102, KNI-227, KNI-241, KNI-272, KNI-413, KNI-549, KNI-577, KNI-727, JE-2178 (Japan Energy); Ph3939 (EP 587311); R-87366, Iddbl34 (Sankyo); VLE-776 (Scripps Institute).
Formula IV compounds having a 2-hydroxy-4-amino-butylamine core include Ritonavir-like phosphonate protease inhibitors (RLPPI) and Lopinavir-like phosphonate protease inhibitors (LLPPI). Compounds of the invention include phosphonate analogs of other known PI compounds with a 2-hydroxy-4-amino-butylamine core which have been identified as A-76928, A-80735, A-80987 (Abbott Laboratories).
Formula V compounds having an acylated 1,3-diaminopropane core include Saquinavir-like phosphonate protease inhibitors (SLPPI) and Nelfinavir-like phosphonate protease inhibitors (NLPPI). Compounds of the invention include phosphonate analogs of other known PI compounds with an acylated 1,3-diaminopropane core which have been identified as Ro-33-2910, Ro-33-4649 (Hofman La Roche); BMS-182193, BMS-186318, BMS-187071 (Bristol-Myers Squibb); JG-365 (Univ. of Wisconsin); L-704325, L-738872, L-739594, L-743770 (Merck & Co.); LB-71206 (LG Chemical Ltd.); LY-296242, LY-314163, LY-316683, LY-326620 (Eli Lilly Co.), Palinavir (BioMega/Bl); Ph5640, Ph6090 (WO
97/21100).
Formula VI compounds having a 2-hydroxy-3-diaza-propylamide core include Atazanavir-like phosphonate protease inhibitors (ATLPPI). Compounds of the invention include phosphonate analogs of other known PI compounds with a 2-hydroxy-3-diaza-propylamide core which have been identified as CGP-56603, CGP-53820, CGP-70726 (Novartis), ABT-538 (Abbott Laboratories), and DG-35 (National Cancer Institute).
Formula VH compounds having sulfonamide 5,6-dihydro-4-hydroxy-2-pyrone core include Tipranavir-like phosphonate protease inhibitors (TLPPI).
Formula VDI compounds have a six or seven-membered ring, cyclic carbonyl, sulfone, or sulfonyl core, where Y1 is oxygen, sulfur, or substituted nitrogen and ivI2 is 1 01 2. The invention includes Cyclic carbonyl-like phosphonate protease inhibitor compounds (CCLPPI), e.g. Formula Vffla-d.

Cyclic carbonyl protease inhibitors without a phosphonate group are described in US Patent Nos. RE37781; 6,503,898; 5,880,295; 5,811,422; 5,610,294; 5,559,252; and 5,506,355, as well as patent applications and granted patents which are equivalents of, or related by priority claims thereto. CCLPPI compounds also include phosphonate analogs of:
(Figure Remove)described as "(I)" in WO 94/19329 (published 1 September 1994) at page 4, line 23, to page 21, line 16 and Claim 1. Also contemplated are patent applications and granted patents which are equivalents of or related by priority claims to WO 94/19329.
Stereoisomers
The compounds of the invention, exemplified by Formula I and n, may have chiral centers, e.g. chiral carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or aJl asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. The racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
The compounds of the invention can also exist as tautomeric isomers in certain cases. All though only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the iinvention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
Salts and Hydrates
The compositions of this invention optionally comprise salts of the compounds herein,
especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+> Ca+2 and Mg+2. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. Monovalent salts are preferred if a water soluble salt is desired.
Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt may be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
In addition, salts may be formed from acid addition of certain organic and inorganic
acids, e.g., HC1, HBr, H2SO4, HsPCH or organic sulfonic acids, to basic centers, typically amines, or to acidic groups. Finally, it is to be understood that the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids. Any of the amino acids described above are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
Methods of Inhibition of HTV Protease
Another aspect of the invention relates to methods of inhibiting the activity of HIV protease comprising the step of treating a sample suspected of containing HIV with a composition of the invention.
Compositions of the invention may act as inhibitors of HIV protease, as intermediates for such inhibitors or have other utilities as described below. The inhibitors will bind to locations on the surface or in a cavity of HIV protease having a geometry unique to HIV protease. Compositions binding HIV protease may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, the substantially irreversibly binding compositions are useful as probes for the detection of HTV protease. Accordingly, the invention relates to methods of detecting HTV protease in a sample suspected of containing HIV protease comprising the steps of: treating a sample suspected of containing HIV protease with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label. Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. The compounds herein are labeled in conventional fashion using functional groups such as hydroxyl, carboxyl, sulfhydryl or amino.
Within the context of the invention, samples suspected of containing HIV protease include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospina!
fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of containing an organism which produces HIV protease, frequently a pathogenic organism such as HIV. Samples can be contained in any medium including water and organic solventXwater mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
The treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the sample. The addition step comprises any method of administration as described above.
If desired, the activity of HTV protease after application of the composition can be observed by any method including direct and indirect methods of detecting HIV protease activity. Quantitative, qualitative, and semiquantitative methods of determining HTV protease activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
Organisms that contain HIV protease include the HIV virus. The compounds of this invention are useful in the treatment or prophylaxis of HIV infections in animals or in man.
However, in screening compounds capable of inhibiting human immunodeficiency viruses, it should be kept in mind that the results of enzyme assays may not correlate with cell culture assays. Thus, a cell based assay should be the primary screening tool.
Screens for HTV protease Inhibitors.
Compositions of the invention are screened for inhibitory activity against HIV protease by any of the conventional techniques for evaluating enzyme activity. Within the context of the invention, typically compositions are first screened for inhibition of HIV protease in vitro and compositions showing inhibitory activity are then screened for activity
in vivo. Compositions having in vitro Ki (inhibitory constants) of less then about 5 X 10"^
M, typically less than about 1 X 10"7 M and preferably less than about 5 X 10'8 M are preferred for in vivo use.
Useful in vitro screens have been described in detail and will not be elaborated here. However, the examples describe suitable in vitro assays.
Pharmaceutical Formulations
The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
For infections of the eye or other external tissues e.g. mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.
If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, Le. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
Pharmaceutical formulations according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a
longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a
mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 |ig of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such
formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about 1.5% w/w.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of HIV infections as described below.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
Compounds of the invention are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") hi which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about .01 to about 5 mg/kg body weight per day. More typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
Routes of Administration
One or more compounds of the invention (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the
condition of the recipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
Combination Therapy
Compositions of the invention are also used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. For example, when treating viral infections the compositions of the invention may be combined with other antivirals such as other protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors or HIV integrase inhibitors.
It is possible to combine any compound of the invention with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to an HIV infected patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. Second and third active ingredients in the combination may have anti-HTV activity. Exemplary active ingredients to be administered in combination with compounds of the invention are protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and HIV integrase inhibitors. The combination therapy may provide "synergy" and "synergistic", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic anti-viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.
Metabolites of the Compounds of the Invention
Also falling within the scope of this invention are the in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. 14C or 3H) compound of the invention, administering it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no HIV protease inhibitory activity of their own.
Recipes and methods for determining stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37°C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. The phosphonate prodrugs of the invention typically will be stable in the digestive system but may be substantially hydro lyzed to the parental drug in the digestive lumen, liver or other metabolic organ, or within cells in general.
Exemplary Methods of Making the Compounds of the Invention.
The invention provides many methods of making the compositions of the invention. The compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art, such as those elaborated in "Compendium of
Organic Synthetic Methods" (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and
Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., "Advanced Organic Chemistry, Third Edition", (John Wiley & Sons, New York, 1985), "Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes", Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing).
Dialkyl phosphonates may be prepared according to the methods of: Quast et al (1974) Synthesis 490; Stowell et al (1990) Tetrahedron Lett. 3261; US Patent No. 5,663,159.
In general, synthesis of phosphonate esters is achieved by coupling a nucleophile amine or alcohol with the corresponding activated phosphonate electrophilic precursor. For example, chlorophosphonate addition on to 5'-hydroxy of nucleoside is a well known method for preparation of nucleoside phosphate monoesters. The activated precursor can be prepared by several well known methods. Chlorophosphonates useful for synthesis of the prodrugs are prepared from the substituted- 1,3-propanediol (Wissner, et al, (1992) J. Med Chem. 35:1650). Chlorophosphonates are made by oxidation of the corresponding chlorophospholanes (Anderson, et al, (1984) /. Org. Chem. 49:1304) which are obtained by reaction of the substituted diol with phosphorus trichloride. Alternatively, the chlorophosphonate agent is made by treating substituted- 1,3-diols with phosphorusoxychloride (Patois, et al, (1990) J. Chem. Soc. Perkin Trans. I, 1577). Chlorophosphonate species may also be generated in situ from corresponding cyclic phosphites (Silverburg, et al., (1996) Tetrahedron Lett., 37:771-774), which in turn can be either made from chlorophospholane or phosphoramidate intermediate. Phosphoroflouridate intermediate prepared either from pyrophosphate or phosphoric acid may also act as precursor in preparation of cyclic prodrugs (Watanabe et al., (1988) Tetrahedron Lett., 29:5763-66). Caution: fluorophosphonate compounds may be highly toxic!
Phosphonate prodrugs of the present invention may also be prepared from the precursor free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1; Campbell,
(1992) J. Org. Chem., 52:6331), and other acid coupling reagents including, but not limited
to, carbodiimides (Alexander, et al, (1994) Collect. Czech. Chem. Commun. 59:1853; Casara,
et al, (1992) Bioorg. Med. Chem. Lett., 2:145; Ohashi, et al, (1988) Tetrahedron Lett.,
29:1189), andbenzotriazolyloxytris-(dimethylamino)phosphonium salts (Campagne, et al,
(1993) Tetrahedron Lett., 34:6743).
Aryl halides undergo Ni+2 catalyzed reaction with phosphite derivatives to give aryl phosphonate containing compounds (Balthazar, et al (1980) /. Org. Chem. 45:5425). Phosphonates may also be prepared from the chlorophosphonate in the presence of a palladium catalyst using aromatic inflates (Petrakis, et al, (1987) J. Am, Chem. Soc. 109:2831; Lu, et al, (1987) Synthesis, 726). In another method, aryl phosphonate esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin (1981) Tetrahedron Lett. 22:3375; Casteel, et al, (1991) Synthesis, 691). N-Alkoxy aryl salts with alkali metal derivatives of cyclic alkyl phosphonate provide general synthesis for heteroaryl-2-phosphonate linkers (Redmore (1970) /. Org. Chem. 35:4114). These above mentioned methods can also be extended to compounds where the W5 group is a heterocycle. Cyclic-1,3-propanyl prodrugs of phosphonates are also synthesized from phosphonic diacids and substituted propane-1,3-diols using a coupling reagent such as 1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine). Other carbodiimide based coupling agents like 1,3-disopropylcarbodiimide or water soluble reagent, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) can also be utilized for the synthesis of cyclic phosphonate prodrugs.
The carbamoyl group may be formed by reaction of a hydroxy group according to the methods known in the art, including the teachings of Ellis, US 2002/0103378 Al and Hajima, US Patent No. 6,018,049.
Schemes and Examples
A number of exemplary methods for the preparation of the compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods.
General aspects of these exemplary methods are described below and in the Examples. Each of the products of the following processes is optionally separated, isolated, and/or purified prior to its use in subsequent processes.
Generally, the reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically the temperatures will be -100°C to 200°C, solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partition between a
water/organic layer system (extraction) and separating the layer containing the product.
Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20°C), although for metal hydride reductions frequently the temperature is reduced to 0°C to -100°C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0°C to -100°C) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
The terms "treated", "treating", "treatment", and the like, mean contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities. This means that "treating compound one with compound two" is synonymous with "allowing compound one to react with compound two", "contacting compound one with compound two", "reacting compound one with compound two", and other expressions common in the art of organic synthesis for reasonably indicating that compound one was "treated", "reacted", "allowed to react", etc., with compound two.
"Treating" indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures (-100°C to 250°C, typically -78°C to 150°C, more typically -78°C to 100°C, still more typically 0°C to 100°C), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions and apparatus for "treating" in a given process. In particular, one of ordinary skill in the art of organic synthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
Modifications of each of the exemplary schemes above and in the examples (hereafter
"exemplary schemes") leads to various analogs of the specific exemplary materials produce. The above cited citations describing suitable methods of organic synthesis are applicable to such modifications.
In each of the exemplary schemes it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (8MB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LDQ, or the like.
Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point, and molecular weight hi distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media m multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation.
A single stereoisomer, e.g. an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds," (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) /. Chromatogr., 113:(3) 283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2)
formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-p-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds. John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g. (-) menthyl chloroformate in the presence of base, or Mosher ester, oc-rnethoxy-a-(trifluoromethyl)phenyl acetate (Jacob JH. (1982) J. Org. Chem, 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
All literature and patent citations above are hereby expressly incorporated by reference at the locations of their citation. Specifically cited sections or pages of the above cited works are incorporated by reference with specificity. The invention has been described
in detail sufficient to allow one of ordinary skill in the art to make and use the subject matter of the following Embodiments. It is apparent that certain modifications of the methods and compositions of the following Embodiments can be made within the scope and spirit of the invention.
Examples General Section
The following Examples refer to the Schemes.
Some Examples have been performed multiple times. In repeated Examples, reaction conditions such as time, temperature, concentration and the like, and yields were within normal experimental ranges. In repeated Examples where significant modifications were made, these have been noted where the results varied significantly from those described. In Examples where different starting materials were used, these are noted. When the repeated Examples refer to a "corresponding" analog of a compound, such as a "corresponding ethyl ester", this intends that an otherwise present group, hi this case typically a methyl ester, is taken to be the same group modified as indicated.
In a number of the following schemes, the term "etc" appears as a substituent on chemical structures and as a term within the schemes. When used in the charts, the term is defined for each chart. When the term "etc" appears in a scheme and is not a substituent on a chemical structure, it means "and the like".
Saquinavir-like phosphonate protease inhibitors (SLPPD Preparation of the intermediate phosphonate esters.
The structures of the intermediate phosphonate esters 1 to 6, and the structures for the component groups R1, R4 and R7 of this invention are shown in Chart 1. The structures of the R2NHCH(R3)CONHR4 and R5XCH2 components are shown in Charts 2 and 2a, and the structures of the R6COOH components are shown in Charts 3a, 3b and 3c. Specific stereoisomers of some of the structures are shown in Charts 1, 2 and 3; however, all stereoisomers are utilized in the syntheses of the compounds 1 to 6. Subsequent chemical modifications to the compounds 1 to 6, as described herein, permit the synthesis of the final compounds of this invention.
The intermediate compounds 1 to 6 incorporate a phosphonate moiety (R'O^PCO) connected to the nucleus by means of a variable linking group, designated as "link" in the attached structures. Charts 4 and 5 illustrate examples of the Unking groups present in the structures 1 - 5, and in which "etc" refers to the scaffold, e.g., saquinavir.
(Figure Remove)Schemes 1-69 illustrate the syntheses of the intermediate phosphonate compounds of this invention, 1- 4, and of the intermediate compounds necessary for their synthesis. The 5 preparation of the phosphonate esters 5 and 6, in which the phosphonate moiety is
incorporated into the groups R6COOH and R2 NHCH(R3)CONHR4, are also described below.
Protection of reactive substituents.
10 Depending on the reaction conditions employed, it may be necessary to protect certain
reactive substituents from unwanted reactions by protection before the sequence described, and to deprotect the substituents afterwards, according to the knowledge of one skilled in the
art. Protection and deprotection of functional groups are described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990. Reactive substituents which may be protected are shown in the accompanying schemes as, for example, [OH], [SH].
Preparation of the phosphonate intermediates 1.
Scheme 1 illustrates one method for the preparation of the phosphonate esters 1.6 in which X is a direct bond. In this procedure, an amine R2NHCH(R3)CONHR41.2 is reacted with an epoxide 1.1 to afford the aminoalcohol 1.3. The preparation of the epoxide 1.1 is described below, (Scheme 2) The preparation of aminoalcohols by reaction between an amine and an epoxide is described, for example, in Advanced Organic Chemistry, by J. March, McGraw Hill, 1968, p 334. In a typical procedure, equimolar amounts of the reactants are combined in a polar solvent such as an alcohol or dimethylformamide and the like, at from ambient to about 100°, for from 1 to 24 hours, to afford the product 1.3. The carbobenzyloxy protecting group is then removed. The removal of carbobenzyloxy protecting groups is described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p 335. The reaction can be effected by means of catalytic hydrogenation in the presence of hydrogen or a hydrogen donor, by reaction with a Lewis acid such as aluminum chloride or boron tribromide, or by basic hydrolysis, for example employing barium hydroxide in an aqueous organic solvent mixture. Preferably, the protected amine 1.3 is converted into the free amine 1.4 by means of hydrogenation over 10% palladium on carbon catalyst in ethanol, as described in US Patent 5196438. The amine product 1.4 is then reacted with a carboxylic acid 1.5 to afford the amide 1.6. The coupling reaction of amines 1.4 and a carboxylic acid 1.5 can be effected under a variety of conditions, for example as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 972ff. The carboxylic acid can be activated by conversion to an imidazolide, mixed anhydride or active ester such as, for example, the ester with hydroxybenztriazole or N-hydroxysuccinimide. Alternatively, the reactants can be combined in the presence of a carbodiimide, such as, for example, dicyclohexylcarbodiimide or diisopropylcarbodiimide, to afford the amide product 1.6. Preferably, equimolar amounts of the amine and the carboxylic acid are reacted in tetrahydrofuran at ca. -10°, in the presence of dicyclohexylcarbodiimide, as described in
U.S. Patent 5,196,438, to afford the amide 1.6. The carboxylic acid 1.5 employed in the above reaction is obtained by means of the reaction between the substituted quinoline-2-carboxylic acid 1.7, in which the substituent A is either the group link-P(O)(OR )2 or a precursor group thereto, such as [OH], [SH], Br, as described below, and an aminoacid 1.8. The reaction is performed under similar conditions to those described above for the preparation of the amide 1.6. Preferably, the quinoline carboxylic acid 1.7 is reacted with N-hydroxy succinimide and a carbodiimide to afford the hydroxysuccinimide ester, which is then reacted with the aminoacid 1.8 in dimethylformamide at ambient temperature for 2-4 days, as described in U.S. Patent 5,196,438, to afford the amide product 1.5. The preparation of the substituted quinoline carboxylic acids 1.7 is described below, Schemes 24-27.
Scheme 2 illustrates the preparation of the epoxides 1.1 used above in Scheme 1. The preparation of the epoxide 1.1 in which RIO is H is described in J. Med. Chem., 1997, 40, 3979. Analogs in which RIO is one of the substituents defined in Chart 2 are prepared as shown in Scheme 2. A substituted phenylalanine 2.1 is first converted into the benzyloxycarbonyl derivative 2.2. The preparation of benzyloxycarbonyl amines is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 335. The aminoacid 2.1 is reacted with benzyl chloroformate or dibenzyl carbonate in the presence of a suitable base such as sodium carbonate or triethylamine, to afford the protected amine product 2.2. The conversion of the carboxylic acid 2.2 into the epoxide 1.1 for example using the sequence of reactions which is described in J. Med. Chem., 1994, 37, 1758, is then effected. The carboxylic acid is first converted into an activated derivative such as the acid chloride 2.3, in which X is Cl, for example by treatment with oxalyl chloride, or into a mixed carbonate, for example by treatment with isobutyl chloroformate, and the activated derivative thus obtained is reacted with ethereal diazomethane, to afford the diazoketone 2.4. The reaction is performed by the addition of a solution of the activated carboxylic acid derivative to an ethereal solution of three or more molar equivalents of diazomethane at 0°C. The diazoketone is converted into the chloroketone 2.5 by reaction with anhydrous hydrogen chloride, in a suitable solvent such as diethyl ether, as described in J. Med. Chem., 1997, 40, 3979. The latter compound is then reduced, for example by the use of an equimolar amount of sodium borohydride in an ethereal solvent such as tetrahydrofuran at 0°C, to produce a mixture of chlorohydrins from which the desired 2S, 3S diastereomer 2.6 is
separated by chromatography. The chlorohydrin 2.6 is then converted into the epoxide 1.1 by treatment with a base such as an alkali metal hydroxide in an alcoholic solvent, for example as described in J. Med. Chem., 1997, 40, 3979. Preferably, the compound 2.6 is reacted with ethanolic potassium hydroxide at ambient temperature to afford the epoxide 1.1.
Scheme 3 illustrates the preparation of the amine reactant R2 NHCH(R3)CONHR4 (1.2) employed above (Scheme 1). In this procedure, the carboxylic acid R2NHCH(R3)COOH 3.1 is first converted into the N-protected analog 3.2, for example by reaction with benzyloxychloroformate and triethylamine in tetrahydrofuran. The carboxyl group is then activated, for example by conversion to the acid chloride or a mixed anhydride, or by reaction with isobutyl chloroformate, as described in Chimia, 50, 532, 1996 and in Synthesis, 1972, 453, and the activated derivative is then reacted with the amine R4NH2 to produce the amide 3.4. Deprotection, for example as described above, then affords the free amine 1.2.
Scheme 4 depicts an alternative method for the preparation of the compounds 1 in which X is a direct bond. In this procedure, a hydroxymethyl-substituted oxazolidinone 4.1 is converted into an activated derivative 4.2 which is then reacted with the amine R2NHCH(R3)CONHR4 (1.2) to afford the amide 4.3. The preparation of the hydroxymethyl-substituted oxazolidinone 4.1 is described below, (Scheme 5) The hydroxyl group can be converted into a bromo derivative, for example by reaction with triphenylphosphine and carbon tetrabromide, as described in J. Am. Chem. Soc., 92, 2139, 1970, or a methanesulfonyloxy derivative, by reaction with methanesulfonyl chloride and a base, or, preferably, into the 4-nitrobenzenesulfonyloxy derivative 4.2, by reaction in a solvent such as ethyl acetate or tetrahydrofuran, with 4-nitrobenzenesulfonyl chloride and a base such as triethylamine or N-methylmorpholine, as described in WO 9607642. The nosylate product 4.2 is then reacted with the amine component 1.2 to afford the displacement product 4.3. Equimolar amounts of the reactants are combined in an inert solvent such as dimethylformamide, acetonitrile or acetone, optionally in the presence of an organic or inorganic base such as triethylamine or sodium carbonate, at from about 0°C to 100°C to afford the amine product 4.3. Preferably, the reaction is performed in methyl isobutyl ketone at 80°C, in the presence of sodium carbonate, as described in WO 9607642. The oxazolidinone group present in the product 4.3 is then hydrolyzed to afford the hydroxyamine 4.4. The hydrolysis reaction is effected in the presence

of aqueous solution of a base such as an alkali metal hydroxide, optionally in the presence of an organic co-solvent. Preferably, the oxazolidinone compound 4.3 is reacted with aqueous ethanolic sodium hydroxide at reflux temperature, as described in WO 9607642, to afford the amine 4.4. This product is then reacted with the carboxylic acid or activated derivative thereof, 1.5, the preparation of which is described above, to afford the product 1.6. The amide-forming reaction is conducted under the same conditions as described above, (Scheme 1)
Scheme 5 depicts the preparation of the hydroxymethyl oxazolidinones 4.1, which are utilized in the preparation of the phosphonate esters 1, as described above in Scheme 4. In this procedure, phenylalanine, or a substituted derivative thereof, 2.1, in which Rl°is as defined in Chart 2, is converted into the phthalimido derivative 5.1. The conversion of amines into phthalimido derivatives is described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 358. The amine is reacted with phthalic anhydride, 2-carboethoxybenzoyl chloride or N-carboethoxyphthalimide, optionally in the presence of a base such as triethylamine or sodium carbonate, to afford the protected amine 5.1. Preferably, the aminoacid is reacted with phthalic anhydride in toluene at reflux, to yield the phthalimido product. The carboxylic acid is then transformed into an activated derivative such as the acid chloride 5.2, in which X is Cl. The conversion of a carboxylic acid into the corresponding acid chloride can be effected by treatment of the carboxylic acid with a reagent such as, for example, thionyl chloride or oxalyl chloride in an inert organic solvent such as dichloromethane, optionally in the presence of a catalytic amount of a tertiary amide such as dimethylformamide. Preferably, the carboxylic acid is transformed into the acid chloride by reaction with oxalyl chloride and a catalytic amount of dimethylformamide, in toluene solution at ambient temperature, as described in WO 9607642. The acid chloride 5.2, X = Cl, is then converted into the aldehyde 5.3 by means of a reduction reaction. This procedure is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 620. The transformation can be effected by means of catalytic hydrogenation, a procedure which is referred to as the Rosenmund reaction, or by chemical reduction employing, for example, sodium borohydride, lithium aluminum tri-tertiarybutoxy hydride or triethylsilane. Preferably, the acid chloride 5.2 X = Cl, is hydrogenated in toluene solution over a 5% palladium on carbon catalyst, in the presence of
butylene oxide, as described in WO 9607642, to afford the aldehyde 5.3. The aldehyde 5.3 is then transformed into the cyanohydrin derivative 5.4. The conversion of aldehydes into cyanohydrins is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 211. For example, the aldehyde 5.3 is converted into the cyanohydrin 5.4 by reaction with trimethylsilyl cyanide in an inert solvent such as dichloromethane, followed by treatment with an organic acid such as citric acid, as described in WO 9607642, or by alternative methods described therein. The cyanohydrin is then subjected to acidic hydrolysis, to effect conversion of the cyano group into the corresponding carboxy group, with concomitant hydrolysis of the phthalimido substituent to afford the aminoacid 5.5 The hydrolysis reactions are effected by the use of aqueous mineral acid. For example, the substrate 5.4 is reacted with aqueous hydrochloric acid at reflux, as described in WO 9607642, to afford the carboxylic acid product 5.5. The aminoacid is then converted into a carbamate, for example the ethyl carbamate 5.6. The conversion of amines into carbamates is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 317. The amine is reacted with a chloroformate, for example ethyl chloroformate, in the presence of a base such as potassium carbonate, to afford the carbamate 5.6. For example, the aminoacid 5.5 is reacted, in aqueous solution, with ethyl chloroformate and sufficient aqueous sodium hydroxide to maintain a neutral pH, as described in WO 9607642, to afford the carbamate 5.6. The latter compound is then transformed into the oxazolidinone 5.7, for example by treatment with aqueous sodium hydroxide at ambient temperature, as described in WP 9607642. The resultant carboxylic acid is transformed into the methyl ester 5.8 by means of a conventional esterification reaction. The conversion of carboxylic acids into esters is described for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 966. The conversion can be effected by means of an acid-catalyzed reaction between the carboxylic acid and an alcohol, or by means of a base-catalyzed reaction between the carboxylic acid and an alkyl halide, for example an alkyl bromide. For example, the carboxylic acid 5.7 is converted into the methyl ester 5.8 by treatment with methanol at reflux temperature, in the presence of a catalytic amount of sulfuric acid, as described in WO 9607642. The carbomethoxyl group present in the compound 5.8 is then reduced to yield the corresponding carbinol 4.1. The reduction of carboxylic esters to the carbinols is described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 550. The transformation can be effected by the use of reducing agents such as
borane-dimethylsulfide, lithium borohydride, diisobutyl aluminum hydride, lithium aluminum hydride and the like. For example, the ester 5.8 is reduced to the carbinol 4.1 by reaction with sodium borohydride in ethanol at ambient temperature, as described in WO 9607642.

(Figure Remove)
The procedures illustrated in Schemes 1 and 4 depict the preparation of the compounds 1.6 in which X is a direct bond, and in which the substituent A is either the group link-P(O)(ORl)2 or a precursor thereto, such as [OH], [SH] Br, as described below. Scheme 6 illustrates the conversion of compounds 1.6 in which A is a precursor to the group link-PCOXOR1^ into the compounds 1. Procedures for the conversion of the substituent A into the group link-P(O)(OR1)2 are illustrated below, (Schemes 24 - 69). In the procedures illustrated above, Schemes 1, 4 and in the procedures illustrated below (Schemes 24-69) for the preparation of the phosphonate esters 2-6, compounds in which the group A is a precursor to the group link-P(O)(OR1)2 may be converted into compounds in which A is link-P(O)(ORI)2 at any appropriate stage in the reaction sequence, or, as shown in Scheme 6, at the end of the sequence. The selection of an appropriate stage to effect the conversion of the group A into the group link-P(O)(ORl)2 is made after consideration of the nature of the reactions involved in the conversion, and the stability of the various components of the substrate to those conditions.-In this sequence, methanesulfonic acid 2-benzoyloxycarbonylamino-2-(2,2-dimethyl-[l,3]dioxolan-4-yl)-ethyl ester, 7.1, prepared as described in J. Org. Chem, 2000, 65, 1623, is reacted with a thiol R4SH 7.2, as defined above, to afford the thioether 7.3. The reaction is conducted in a suitable solvent such as, for example, pyridine, DMF and the like, in the presence of an inorganic or organic base, at from 0°C to 80°C, for from 1-12 hours, to afford the thioether 7.3. Preferably the mesylate 7.1 is reacted with an equimolar amount of the thiol R4SH, in a mixture of a water-immiscible organic solvent such as toluene, and water, in the presence of a phase-transfer catalyst such as, for example, tetrabutyl ammonium bromide, and an inorganic base such as sodium hydroxide, at about 50°C, to give the product 7.3. The 1,3-dioxolane protecting group present in the compound 7.3 is then removed by acid catalyzed hydrolysis or by exchange with a reactive carbonyl compound to afford the diol 7.4. Methods for conversion of 1,3-dioxolanes to the corresponding diols are described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Second Edition 1990, p. 191. For example, the 1,3-dioxolane compound 7.3 is hydrolyzed by reaction with a catalytic amount of an acid in an aqueous organic solvent mixture. Preferably, the 1,3-dioxolane 7.3 is dissolved in aqueous methanol containing hydrochloric acid, and heated at ca, 50°C, to yield the product 7.4.
The primary hydroxyl group of the diol 7.4 is then selectively acylated by reaction with an electron-withdrawing acyl halide such as, for example, pentafluorobenzoyl chloride or mono-or di-nitrobenzoyl chlorides. The reaction is conducted in an inert solvent such as dichloromethane and the like, in the presence of an inorganic or organic base. Preferably, equimolar amounts of the diol 7.4 and 4-nitrobenzoyl chloride are reacted in a solvent such as ethyl acetate, in the presence of a tertiary organic base such as 2-picoline, at ambient temperature, to afford the hydroxy ester 7.5. The hydroxy ester is next reacted with a sulfonyl chloride such as methanesulfonyl chloride, 4-toluenesulfonyl chloride and the like, in the presence of a base, in an aprotic polar solvent at low temperature, to afford the corresponding sulfonyl ester 7.6. Preferably, equimolar amounts of the carbinol 7.5 and methanesulfonyl chloride are reacted together in ethyl acetate containing triethylamine, at about 10°C, to yield the mesylate 7.6. The compound 7.6 is then subjected to a hydrolysis-cyclization reaction to afford the oxirane 7.7. The mesylate or analogous leaving group present in 7.6 is displaced by hydroxide ion, and the carbinol thus produced, without isolation, spontaneously transforms into the oxirane 7.7 with elimination of 4-nitrobenz.oate. To effect
this transformation, the sulfonyl ester 7.6 is reacted with an alkali metal hydroxide or tetraalkylammonium hydroxide in an aqueous organic solvent. Preferably, the mesylate 7.6 is reacted with potassium hydroxide in aqueous dioxan at ambient temperature for about 1 hour, to afford the oxirane 7.7.
The oxirane compound 7.7 is then subjected to regiospecific ring-opening reaction by treatment with a secondary amine 1.2, to give the aminoalcohol 7.8. The amine and the oxirane are reacted in a protic organic solvent, optionally in the additional presence of water, at 0°C to 100°C, and in the presence of an inorganic base, for 1 to 12 hours, to give the product 7.8. Preferably, equimolar amounts of the reactants 7.7 and 1.2 are reacted in aqueous methanol at about 60°C in the presence of potassium carbonate, for about 6 hours, to afford the aminoalcohol 7.8. The carbobenzyloxy (cbz) protecting group in the product 7.8 is removed to afford the free amine 7.9. Methods for removal of cbz groups are described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Second Edition, p. 335. The methods include catalytic hydrogenation and acidic or basic hydrolysis.
For example, the cbz-protected amine 7.8 is reacted with an alkali metal or alkaline earth hydroxide in an aqueous organic or alcoholic solvent, to yield the free amine 7.9. Preferably, the cbz group is removed by the reaction of 7.8 with potassium hydroxide in an alcohol such as isopropanol at ca. 60°C to afford the amine 7.9. The amine 7.9 so obtained is next acylated with a carboxylic acid or activated derivative 1.5, using the conditions described above for the conversion of the amine 1.4 into the amide 1.6 (Scheme 1), to yield the final amide product 7.10.
The procedures illustrated in Scheme 7 depict the preparation of the compounds 1 in which X is S, and in which the substituent A is either the group link-P(O)(OR1)2 or a precursor thereto, such as [OH], [SH] Br , as described below. Scheme 8 illustrates the conversion of compounds 7.10 in which A is a precursor to the group Unk-P(O)(OR1)2 into the compounds 1. Procedures for the conversion of the substituent A into the group Unk-P(O)(OR1)2 are illustrated below, (Schemes 24 - 69).
The reactions illustrated in Schemes 1-7 illustrate the preparation of the compounds 1 in which A is either the group link-P(O)(OR1)2 or a precursor thereto, such as, for example, optionally protected OH, SH, NH , as described below. Scheme 8 depicts the conversion of the
compounds 1 in which A is OH, SH, NH , as described below, into the compounds 1 in which A is the group hjik-P(O)(ORI)2. Procedures for the conversion of the group A into the group link-P(O) )(OR!)2 are described below, (Schemes 24-69).
In this and succeeding examples, the nature of the phosphonate ester group can be varied, either before or after incorporation into the scaffold, by means of chemical transformations. The transformations, and the methods by which they are accomplished, are described below, (Scheme 54)
Preparation of the phosphonate intermediates 2.
Scheme 9 depicts the one method for the preparation of the compounds 2 in which X is a direct bond, and in which the substituent A is either the group link-PfOXOR1^ or a precursor thereto, such as [OH], [SH] Br, as described below. In this procedure, the hydroxymethyl oxazolidinone 9.1, the preparation of which is described below, is converted into an activated derivative, for example the 4-nitrobenzenesulfonate 9.2. The conditions for this transformation are the same as those described above (Scheme 4) for the conversion of the carbinol 4.1 into the nosylate 4.2. The activated ester 9.2 is then reacted with the amine 1.2, under the same conditions as described above for the preparation of the amine 4.3 to afford the oxazolidinone amine 9.3. The oxazolidinone group is then hydrolyzed by treatment with aqueous alcoholic base, to produce the primary amine 4.4. For example, the oxazolidinone 9.3 is reacted with aqueous ethanolic sodium hydroxide at reflux temperature, as described in WO 9607642, to afford the amine product 9.4. The latter compound is then coupled with the carboxylic acid 9.6, to afford the amide 9.5; The conditions for the coupling reaction are the same as those described above for the preparation of the amide 1.6. The phosphonate esters 2-6 which incorporate the group R6 CO derived formally from the carboxylic acids depicted in Chart 2c contain a carbamate group. Various methods for the preparation of carbamates are described below, (Scheme 55)
Scheme 10 illustrates an alternative method for the preparation of the compounds 2 in which X is a direct bond, and in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor thereto, such as [OH], [SH] Br, as described below. In this procedure, the oxirane 10.1, the preparation of which is described below, is reacted with the amine 1.2 to afford the
aminoalcohol 10.2. The reaction is conducted under the same conditions as are described above for the preparation of the aminoalcohol 1.3. (Scheme 1) The benzyloxycarbonyl protecting group is then removed from the product 10.2 to afford the free amine 10.3. The conditions for the debenzylation reaction are the same as those described above for the debenzylation of the compound 1.3. The amine 10.3 is then coupled with the carboxylic acid 9.6 to produce the amide 9.5, employing the same conditions as are described above (Scheme 9).
The procedures illustrated in Schemes 9 and 10 depict the preparation of the compounds 9.5 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor thereto, such as [OH], [SH] Br, as described below. Scheme 11 illustrates the conversion of compounds 9.5 in which A is a precursor to the group link-P(O)(OR1)2 into the compounds 2. Procedures for the conversion of the substituent A into the group link-PtOXOR1^ are illustrated below, (Schemes 24 -69).
Schemes 12 and 13 depict the preparation of compounds 2 in which X is sulfur. As shown in Scheme 12, a substituted thiophenol 12.2, in which the substituent A is either the group link-P(O)(ORl)2 or a precursor thereto, such as [OH], [SH] Br, as described below, is reacted with methanesulfonic acid 2-benzyloxycarbonylamino-2-(2,2-dimethyl-[ 1,3]dioxolan-4-yl)-ethyl ester 12.1, the preparation of which is described in J. Org. Chem, 2000, 65, 1623, to afford the displacement product 12.3. The conditions for the reaction are the same as described above for the preparation of the thioether 7.3. Methods for the preparation of the substituted thiophenol 12.2 are described below, Schemes 35 - 44. The thioether product 12.3 is then transformed, using the series of reactions described above, Scheme 7, for the conversion of the thioether 7.3 into the amine 7.9. The conditions employed for this series of reactions are the same as those described above, (Scheme 7). The amine 12.4 is then reacted with the carboxylic acid or activated derivative thereof, 9.6 to afford the amide 12.5. The conditions for the reaction are he same as those described above for the preparation of the amide 9.5.
The procedures illustrated in Scheme 12 depict the preparation of the compounds 12.5 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor thereto, such as [OH], [SH] Br, as described below. Scheme 13 illustrates the conversion of compounds 12.5
in which A is a precursor to the group link-P(O)(OR')2 into the compounds 2. Procedures for the conversion of the substituent A into the group link-P(O)(OR
Preparation of the phosphonate intermediates 3.
Schemes 14-16 depict the preparation of the phosphonate esters 3 in which X is a direct bond. As shown in Scheme 14, the oxirane 1.1, the preparation of which is described above, is 10 reacted with the amine 14.1 in which the substituent A is either the group link-P(O)(OR')2 or a. precursor thereto, such as [OH], [SH] Br, as described below, to yield the hydroxyamine 14.2. The conditions for the reaction are the same as described above for the preparation of the amine 1.3. Methods for the preparation of the amine 14.1 are described below, Schemes 45 -
48. The hydroxyamine product 14.2 is then deprotected to afford the free amine 14.3. The conditions for the debenzylation reaction are the same as those described above for the preparation of the amine 1.4. (Scheme 1). The amine 14.3 is then coupled with the carboxylic acid or activated derivative thereof, 9.6, to afford the amide 14.4, using the conditions described above for the preparation of the amide 12.5.
Scheme 15 illustrates an alternative method for the preparation of the phosphonate esters 14.4. In this reaction sequence, the 4-nitrobenzenesulfonate 4.2, the preparation of which is described above, (Scheme 4), is reacted with the amine 14.1, in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor thereto, such as [OH], [SH] Br, as described below, to yield the amine 15.1. The reaction is conducted under the same conditions as described above for the preparation of the amide 4.3. The oxazolidine moiety present in the product is then removed, using the procedure described above for the conversion of the oxazolidine 4.3 into the hydroxyamine 4.4, to afford the hydroxyamine 15.2. The latter compound is then coupled, as described above, with the carboxylic acid or activated derivative thereof, 9.6, to afford the amide 14.4.
The procedures illustrated in Schemes 14 and 15 depict the preparation of the compounds 14.4 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor thereto, such as [OH], [SH] Br, as described below. Scheme 16 illustrates the conversion of compounds 14.4 in which A is a precursor to the group link-P(O)(OR1)2 into the compounds 3, Procedures for the conversion of the substituent A into the group link-P(O)(ORl)2 are illustrated below, (Schemes 24 - 69).
Schemes 17 and 18 illustrates the preparation of the phosphonate esters 3 in which X is sulfur. As shown in Scheme 17, the oxirane 7.7, the preparation of which is described above, (Scheme 7) is reacted with the amine 14.1. The conditions for the ring-opening reaction are the same as those described above for the preparation of the arninoalcohol 7.8, (Scheme 7). The benzyloxycarbonyl protecting group is then removed to produce the free amine 17.2. The conditions for the deprotection reaction are the same as those described above for the conversion of the protected amine 7.8 to the amine 7.9 (Scheme 7) The amine product 17.2 is
then coupled with the carboxylic acid or activated derivative thereof, 9.6, using the same conditions as described above, to afford the amide 17.3.
The procedures illustrated in Scheme 17 depict the preparation of the compound 17.3 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor thereto, such as [OH], [SH] Br, as described below. Scheme 18 illustrates the conversion of compounds 17.3 in which A is a precursor to the group link-P(O)(OR1)2 into the compounds 3. Procedures for the conversion of the substituent A into the group link-P(O)(OR1)2 are illustrated below, (Schemes 24 - 69).5 Preparation of the phosphonate intermediates 4.
Scheme 19 illustrates one method for the preparation of the phosphonate esters 4 in which X is a direct bond. In this reaction sequence, the oxirane 1.1, the preparation of which is described above (Scheme 2) is reacted with the decahydroisoquinoline amine 19.1, in which
10 the substituent A is either the group link-P(O)(OR1)2 or a precursor thereto, such as [OH], [SH] Br, as described below, to afford the aminoalcohol product 19.2. The conditions for the ring-opening reaction are the same as those described above for the preparation of the aminoalcohol 1.3. The preparation of the decahydroisoquinoline derivatives 19.1 is described below, (Schemes 48a - 52). The cbz protecting group is then removed to yield the free amine
15 19.3, using the same conditions as described above for the preparation of the amine 1.4,
(Scheme 1). The amine 19.3 is then coupled with the carboxylic acid or activated derivative thereof, 9.6, using the same conditions as described above, to afford the amide 19.4.
Scheme 20 illustrates an alternative method for the preparation of the phosphonate intermediates 19.4. In this procedure, the 4-nitrobenzenesulfonyl ester 4.2, the preparation of which is described above, (Scheme 4) is reacted with the decahydroisoquinoline derivative 20.1, in which the substituent A is either the group Unk-P(O)(ORI)2 or a precursor thereto, such as [OH], [SH] Br, as described below. The reaction conditions for the displacement reaction are the same as those described above for the preparation of the amine 4.3, (Scheme 4). The oxazolidinone moiety present in the product 20.2 is then hydrolyzed, using the procedures described above (Scheme 4) to afford the free amine 20.3. This compound is then coupled with the carboxylic acid or activated derivative thereof,.9.6, using the same conditions as are described above, to afford the amide product 19.4.
The procedures illustrated in Schemes 19 and 20 depict the preparation of the compounds 19.4 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor thereto, such as [OH], [SH] Br, as described below. Scheme 21 illustrates the conversion of compounds 19.4 in which A is a precursor to the group link-P(O)(OR1)2 into the compounds 4. Procedures for the conversion of the substituent A into the group link-P(O)(OR1)2 are illustrated below, (Schemes 24 - 69).
Schemes 22 and 23 depict the preparation of the phosphonate esters 4 in which X is sulfur. As shown in Scheme 22, the oxirane 7.7, prepared as described above (Scheme 7) is reacted with the decahydroisoquinoline derivative 19.1, in which the substituent A is either the group link-P(O)(OR')2 or a precursor thereto, such as [OH], [SH] Br, as described below. The reaction is conducted under the same conditions as described above for the preparation of the amine 7.8, (Scheme 7), to produce the hydroxyamine 22.1. The cbz protecting group present in the product 22.1 is then removed, using the same procedures as described above (Scheme 7) to afford the free amine 22.2. This material is then coupled with the carboxylic acid or activated derivative thereof, 9.6 to yield the amide 22.3. The coupling reaction is preformed under the same conditions as previously described.
The procedures illustrated in Scheme 22 depict the preparation of the compounds 22.3 in which the substituent A is either the group link-PCOXOR1^ or a precursor thereto, such as [OH], [SH] Br, as described below. Scheme 23 illustrates the conversion of compounds 22.3 in which A is a precursor to the group Unk-P(O)(ORI)2 into the compounds 4. Procedures for the conversion of the substituent A into the group Mnk-P(O)(OR1)2 are illustrated below, (Schemes 24 - 69).
Preparation of quinoline 2-carboxylic acids 1.7 incorporating phosphonate moieties or precursors thereto.
The reaction sequence depicted in Scheme 1 requires the use of a quinoline-2-carboxylic acid reactant 1.7 in which the substituent A is either the group link-PCOXOR1^ or a precursor thereto, such as [OH], [SH] Br.
A number of suitably substituted quinoline-2-carboxylic acids are available commercially or are described in the chemical literature. For example, the preparations of 6-hydroxy, 6-amino and 6-bromoquinoline-2-carboxylic acids are described respectively in DE 3004370, J. Het. Chem., 1989, 26, 929 and J. Labelled Comp. Radiopharra, 1998,41, 1103, and the preparation of 7-aminoquinoline-2-carboxylic acid is described in J. Am. Chem. Soc., 1987, 109, 620. Suitably substituted quinoline-2-carboxylic acids can also be prepared by procedures known to those skilled in the art. The synthesis of variously substituted quinolines is described, for example, in Chemistry of Heterocyclic Compounds, Vol. 32, G. Jones, ed., Wiley, 1977, p. 93ff. Quinoline-2-carboxylic acids can be prepared by means of the Friedlander reaction, which is described in Chemistry of Heterocyclic Compounds, Vol. 4, R. C. Elderfield, ed., Wiley, 1952, p. 204.
Scheme 24 illustrates the preparation of quinoline-2-carboxylic acids by means of the Friedlander reaction, and further transformations of the products obtained. In this reaction sequence, a substituted 2-aminobenzaldehyde 24.1 is reacted with an alkyl pyruvate ester 24.2, in the presence of an organic or inorganic base, to afford the substituted quinoline-2-carboxylic ester 24.3. Hydrolysis of the ester, for example by the use of aqueous base, then afford the corresponding carboxylic acid 24.4. The carboxylic acid product 24.4 in which X is NHa can be further transformed into the corresponding compounds 24.6 in which Z is OH, SH or Br. The latter transformations are effected by means of a diazotization reaction. The conversion of aromatic amines into the corresponding phenols and bromides by means of a diazotization reaction is described respectively in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, pages 167 and 94; the conversion of amines into the corresponding thiols is described in Sulfur Lett., 2000, 24, 123. The amine is first converted into the diazonium salt by reaction with nitrous acid. The diazonium salt, preferably the diazonium
tetrafluoborate, is then heated in aqueous solution, for example as described in Organic Functional Group Preparations, by S.R.Sandler and W. Karo, Academic Press, 1968, p. 83, to afford the corresponding phenol 24.6, X = OH. Alternatively, the diazonium salt is reacted in aqueous solution with cuprous bromide and lithium bromide, as described in Organic Functional Group Preparations, by S.R.Sandler and W. Karo, Academic Press, 1968, p. 138, to yield the corresponding bromo compound, 24.6, Y = Br. Alternatively, the diazonium tetrafluoborate is reacted in acetonitrile solution with a sulfhydryl ion exchange resin, as described in Sulfur Lett., 200, 24, 123, to afford the thiol 24.6, Y = SH. Optionally, the diazotization reactions described above can be performed on the carboxylic esters 24.3 instead of the carboxylic acids 24.5.
For example, 2,4-diaminobenzaldehyde 24.7 (Apin Chemicals) is reacted with one molar equivalent of methyl pyruvate 24.2 in methanol, in the presence if a base such as piperidine, to afford methyl-7-aminoquinoline-2-carboxylate 24.8. Basic hydrolysis of the product, employing one molar equivalent of lithium hydroxide in aqueous methanol, then yields the carboxylic acid 24.9. The amino-substituted carboxylic acid is then converted into the diazonium tetrafluoborate 24.10 by reaction with sodium nitrite and tetrafluoboric acid. The diazonium salt is heated in aqueous solution to afford the 7-hydroxyquinoline-2-carboxylic acid, 24.11, Z = OH. Alternatively, the diazonium tetrafluoborate is heated in aqueous organic solution with one molar equivalent of cuprous bromide and lithium bromide, to afford 7-bromoquinoline-2-carboxylic acid 24.11, X = Br. Alternatively, the diazonium tetrafluoborate 24.10 is reacted in acetonitrile solution with the sulfhydryl form of an ion exchange resin, as described in Sulfur Lett., 2000, 24,123, to prepare 7-mercaptoquinoline-2-carboxylic acid 24.11, Z = SH.
Using the above procedures, but employing, in place of 2,4-diaminobenzaldehyde 24.7, different aminobenzaldehydes 24.1, the corresponding amino, hydroxy, bromo or mercapto-substituted quinoline-2-carboxylic acids 24.6 are obtained. The variously substituted quinoline carboxylic acids and esters can then be transformed, as described below, (Schemes 25 - 27) into phosphonate-containing derivatives.
Scheme 25 depicts the preparation of quinoline-2-carboxylic acids incorporating a phosphonate moiety attached to the quinoline ring by means of an oxygen or a sulfur atom. In this procedure, an amino-substituted quinoline-2-carboxylate ester 25.1 is transformed, via a
diazotization procedure as described above (Scheme 24) into the corresponding phenol or thiol 25.2. The latter compound is then reacted with a dialkyl hydroxymethylphosphonate 25.3, under the conditions of the Mitsonobu reaction, to afford the phosphonate ester 25.4. The preparation of aromatic ethers by means of the Mitsonobu reaction is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 448, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 153-4. The phenol or thiophenol and the alcohol component are reacted together in an aprotic solvent such as, for example, tetrahydrofuran, in the presence of a dialkyl azodicarboxylate and a triarylphosphine, to afford the thioether products 25.5. Basic hydrolysis of the ester group, for example employing one molar equivalent of lithium hydroxide in aqueous methanol, then yields the carboxylic acid 25.6. For example, methyl 6-amino-2-quinoline carboxylate 25.7, prepared as described in J. Het. Chem., 1989, 26, 929, is converted, by means of the diazotization procedure described above, into methyl 6-mercaptoquinoline-2-carboxylate 25.8. This material is reacted with a dialkyl hydroxymethylphosphonate 25.9 (Aldrich) in the presence of diethyl azodicarboxylate and triphenylphosphine in tetrahydrofuran solution, to afford the thioether 25.10. Basic hydrolysis then afford the carboxylic acid 25.11.
Using the above procedures, but employing, in place of methyl 6-amino-2-quinoline carboxylate 25.7, different aminoquinoline carboxylic esters 25.1J and/or different dialkyl hydroxymethylphosphonates 25.9 the corresponding phosphnoate ester products 25.3 are obtained.
Scheme 26 illustrates the preparation of quinoline-2-carboxylic acids incorporating phosphonate esters attached to the quinoline ring by means of a saturated or unsaturated carbon chain. In this reaction sequence, a bromo-substituted quinoline carboxylic ester 26.1 is coupled, by means of a palladium-catalyzed Heck reaction, with a dialkyl alkenylphosphonate 26.2. The coupling of aryl halides with olefins by means of the Heck reaction is described, for example, in Advanced Organic Chemistry, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 503ff. The aryl bromide and the olefin are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or palladium(II) catalyst such as palladium(II) acetate, and optionally in the presence of a base such as triethylamine or potassium carbonate.
Thus, Heck coupling of the bromo compound 26.1 and the olefin 26.2 affords the olefinic ester 26.3. Hydrolysis, for example by reaction with lithium hydroxide in aqueous methanol, or by treatment with porcine liver esterase, then yields the carboxylic acid 26.4. Optionally, the unsaturated carboxylic acid 26.4 can be reduced to afford the saturated analog 26.5. The reduction reaction can be effected chemically, for example by the use of diimide or diborane, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 5. For example, methyl 7-bromoquinoline-2-carboxylate, 26.6, prepared as described in J. Labelled Comp. Radiopharm, 1998, 41, 1103, is reacted in dimethylformamide at 60°C with a dialkyl vinylphosphonate 26.7 (Aldrich) in the presence of 2 mol% of tetrakis(triphenylphosphine)palladium and triethylamine, to afford the coupled product 26.8. The product is then reacted with lithium hydroxide in aqueous tetrahydrofuran to produce the carboxylic acid 26.9. The latter compound is reacted with diimide, prepared by basic hydrolysis of diethyl azodicarboxylate, as described in Angew. Chem. Int. Ed., 4, 271, 1965, to yield the saturated product 26.10.
Using the above procedures, but employing, in place of methyl 6-bromo-2-quinolinecarboxylate 26.6, different bromoquinoline carboxylic esters 26.1, and/or different dialkyl alkenylphosphonates 26.2, the corresponding phosphonate ester products 26.4 and 26.5 are obtained.
Scheme 27 depicts the preparation of quinoline-2-carboxylic acids 27.5 in which the phosphonate group is attached by means of a nitrogen atom and an alkylene chain. In this reaction sequence, a methyl aminoquinoline-2-carboxylate 27.1 is reacted with a phosphonate aldehyde 27.2 under reductive amination conditions, to afford the aminoalkyl product 27.3. The preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p 421, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 269. In this procedure, the amine component and the aldehyde or ketone component are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride, optionally in the presence of a Lewis acid, such as titanium tetraisopropoxide, as described in J. Org. Chem., 55, 2552,1990. The ester product 27.4 is then hydrolyzed to yield the free carboxylic acid 27.5.
For example, methyl 7-aminoquinoline-2-carboxylate 27.6, prepared as described in J. Amer. Chem. Soc., 1987, 109, 620, is reacted with a dialkyl formylmethylphosphonate 27.7 (Aurora) in methanol solution in the presence of sodium borohydride, to afford the alkylated product 27.8. The ester is then hydrolyzed, as described above, to yield the carboxylic acid 27.9. Using the above procedures, but employing, in place of the formylmethyl phosphonate 27.2, different formylalkyl phosphonates, and/or different aminoquinolines 27.1, the corresponding products 27.5 are obtained.Preparation of phenylalanine derivatives 9.1 and 10.1 incorporating phosphonate moieties or precursors thereto.
Scheme 28 illustrates the preparation of the hydroxymethyl oxazolidine derivative 9.1, in which the substituent A is either the group Hnk-P(O)(OR1)2 or a precursor thereto, such as [OH], [SH] Br. In this reaction sequence, the substituted phenylalanine 28.1, in which A is as defined above, is transformed, via the intermediates 28.2-28.9, into the hydroxymethyl product 9.1. The reaction conditions for each step in the sequence are the same as those described above for the corresponding step shown in Scheme 5. The conversion of the substituent A into the group Unk-P(O)(OR')2 may be effected at any convenient step in the reaction sequence, or after the reactant 9.1 has been incorporated into the intermediates 9.5 (Scheme 9). Specific examples of the preparation of the hydroxymethyl oxazolidinone reactant 9.1 are shown below, (Schemes 30-31).
Scheme 29 illustrates the preparation of the oxirane intermediate 10.1, in which the substituent A is either the group link-P(O)(ORl)2 or a precursor thereto, such as [OH], [SH] Br. In this reaction sequence, the substituted phenylalanine 29.1, in which A is as defined above, is transformed, via the intermediates 29.2-29.6, into the oxirane 10.1. The reaction conditions for each step in the sequence are the same as those described above for the corresponding step shown in Scheme 2. The conversion of the substituent A into the group link-PCOXOR1)^ may be effected at any convenient step in the reaction sequence, or after the reactant 10.1 has been incorporated into the intermediates 9.5 (Scheme 10). Specific examples of the preparation of the oxiranes reactant 10.1 are shown below, (Schemes 32-34).
Scheme 30 depicts the preparation of hydroxymethyloxazolidinones 30.9 in which the phosphonate ester moiety is attached directly to the phenyl ring. In this procedure, a bromo-substituted phenylalanine 30.1 is converted, using the series of reactions illustrated in Scheme 28, into the bromophenyloxazolidinone 30.2. The bromophenyl compound is then coupled, in the presence of a palladium (0) catalyst, with a dialkyl phosphite 30.3, to afford the phosphonate product 30.4. The reaction between aryl bromide and dialkyl phosphites to yield aryl phosphonates is described in Synthesis, 56, 1981, and in J. Med. Chem., 1992, 35, 1371.
The reaction is conducted in an inert solvent such as toluene or xylene, at about 100°C, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium and a tertiary organic base such as triethylamine. The carbomethoxy substituent in the resultant phosphonate ester 30.4 is then reduced with sodium borohydride to the corresponding hydroxymethyl derivative 30.5, using the procedure described above (Scheme 28) For example, 3-bromophenylalanine 30.6, prepared as described in Pept. Res., 1990, 3, 176, is converted, using the sequence of reactions shown in Scheme 28, into 4-(3-bromo-benzyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester 30.7. This compound is then coupled with a dialkyl phosphite 30.3, in toluene solution at reflux, in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium(0) and triethylamine, to afford the phosphonate ester 30.8. The carbomethoxy substituent is then reduced with sodium borohydride, as described above, to afford the hydroxymethyl product 30.9.
Using the above procedures, but employing, in place of 3-bromophenylalanine 30.6 different bromophenylalanines 30.1 and/or different dialkyl phosphites 30.3, the corresponding products 30.5 are obtained.
Scheme 31 illustrates the preparation of phosphonate-containing hydroxymethyl oxazolidinones 31.9 and 31.12 in which the phosphonate group is attached by means of a heteroatom and a carbon chain. In this sequence of reactions, a hydroxy or thio-substituted phenylalanine 31.1 is converted into the benzyl ester 31.2 by means of a conventional acid catalyzed esterification reaction. The hydroxyl or mercapto group is then protected. The protection of phenyl hydroxyl and thiol groups are described, respectively, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 10, and p. 277. For example, hydroxyl and thiol substituents can be protected as trialkylsilyloxy groups. Trialkylsilyl groups are introduced by the reaction of the phenol or thiophenol with a chlorotrialkylsilane and a base such as imidazole, for example as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 10, p. 68-86. Alternatively, thiol substituents can be protected by conversion to tert-butyl or adamantyl thioethers, or 4-methoxybenzyl thioethers, prepared by the reaction between the thiol and 4-methoxybenzyl chloride in the presence of ammonium hydroxide, as described in Bull. Chera Soc. Jpn., 37, 433, 1974. The protected ester 31.3 is then reacted with phthalic anhydride, as described above (Scheme 28) to afford the phthalimide 31.4. The
benzyl ester is then removed, for example by catalytic hydrogenation or by treatment with aqueous base, to afford the carboxylic acid 31.5. This compound is transformed, by means of the series of reactions shown in Scheme 28, into the carbomethoxy oxazolidinone 31.6, using in each step the same conditions as are described above (Scheme 28). The protected OH or SH group is then deprotected. Deprotection of phenols and thiophenols is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. For example, trialkylsilyl ethers or thioethers can be deprotected by treatment with a tetraalkylammonium fluoride in an inert solvent such as tetrahydrofuran, as described in J. AmChem. Soc., 94, 6190, 1972. Tert-butyl or adamantyl thioethers can be converted into the corresponding thiols by treatment with mercuric trifluoroacetate in aqueous acetic acid at ambient temperatures, as described in Chem. Pharm. Bull., 26, 1576, 1978. The resultant phenol or thiol 31.7 is then reacted with a hydroxyalkyl phosphonate 31.20 under the conditions of the Mitsonobu reaction, as described above (Scheme 25), to afford the ether or thioether 31.8. The latter compound is then reduced with sodium borohydride, as described above (Scheme 28) to afford the hydroxymethyl analog 31.9.
Alternatively, the phenol or thiophenol 31.7 is reacted with a dialkyl bromoalkyl phosphonate 31.10 to afford the alkylation product 31.11. The alkylation reaction is preformed in a polar organic solvent such as dimethylformamide, acetonitrile and the like, optionally in the presence of potassium iodide, and in the presence of an inorganic base such as potassium or cesium carbonate, or an organic base such as diazabicyclononene or dimethylaminopyridine. The ether or thioether product is then reduced with sodium borohydride to afford the hydroxymethyl compound 31.12.
For example, 3-hydroxyphenylalanine 31.13 (Fluka) is converted in to the benzyl ester 31.14 by means of a conventional acid-catalyzed esterification reaction. The ester is then reacted with tert-butylchlorodhnethylsilane and imidazole in dimethylformamide, to afford the silyl ether 31.15. The protected ether is then reacted with phthalic anhydride, as described above (Scheme 28) to yield the phthalimido-protected compound 31.16. Basic hydrolysis, for example by reaction with lithium hydroxide in aqueous methanol, then affords the carboxylic acid 31.17. This compound is then transformed, by means of the series of reactions shown in Scheme 28, into the carbomethoxy-substituted oxazolidinone 31.18. The silyl protecting group is then removed by treatment with tetrabutylammonium fluoride in tetrahydrofuran at ambient temperature, to produce the phenol 31.19. The latter compound is reacted with a
dialkyl hydroxymethyl phosphonate 31.20 diethylazodicarboxylate and triphenylphosphine, by means of the Mitsonobu reaction, as described above (Scheme 25) to yield the phenolic ether 31.21. The carbomethoxy group is then reduced by reaction with sodium borohydride, as described above, to afford the carbinol 31.22.
Using the above procedures, but employing, in place of 3-hydroxyphenylalanine 31.13, different hydroxy or mercapto-substituted phenylalanines 31.1, and/or different dialkyl hydroxyalkyl phosphonates 31.20, the corresponding products 31.9 are obtained. As a further example of the methods illustrated in Scheme 31, 4-mercaptophenylalanine 31.23, prepared as described in J. Amer. Chem. Soc., 1997, 119, 7173, is converted into the benzyl ester 31.24 by means of a conventional acid-catalyzed esterification reaction. The mercapto group is then protected by conversion to the S-adamantyl group, by reaction with 1-adamantanol and trifluoroacetic acid at ambient temperature as described in Chem. Pharm. Bull., 26, 1576, 1978. The amjno group is then converted into the phthalimido group as described above, and the ester moiety is hydrolyzed with aqueous base to afford the carboxylic acid 31.27. The latter compound is then transformed, by means of the series of reactions shown in Scheme 28, into the carbomethoxy oxazolidinone 31.28. The adamantyl protecting group is then removed by treatment of the thioether 31.28 with mercuric acetate in trifluoroacetic acid at 0°C, as described in Chem. Pharm. Bull., 26, 1576, 1978, to produce the thiol 31.29. The thiol is then reacted with one molar equivalent of a dialkyl bromoethylphosphonate 31.30, (Aldrich) and cesium carbonate in dimethylformamide at 70°C, to afford the thioether product 31.31. The carbomethoxy group is then reduced with sodium borohydride, as described above, to prepare the carbinol 31.32. Using the above procedures, but employing, in place of 4-mercaptophenylalanine 31.23, different hydroxy or mercapto-substituted phenylalanines 31.10, and/or different dialkyl bromoalkyl phosphonates 31.10, the corresponding products 31.12 are obtained.
Scheme 32 illustrates the preparation of phenylalanine derivatives 32.3 in which the phosphonate group is attached directly to the phenyl ring. In this procedure, a bromo-substituted phenylalanine 32.1 is converted, by means of the series of reactions shown in Scheme 29 into the oxirane 32.2. This compound is then coupled with a dialkyl phosphite 30.3, in the presence of a palladium(0) catalyst and an organic base, to afford the phosphonate
oxirane 32.3. The coupling reaction is performed under the same conditions previously
described, (Scheme 30).
For example, 3-bromophenylalanine 32.4, prepared as described in Pept. Res., 1990, 3, 176, is
converted, as described above, into the oxirane 32.5. This compound is reacted, in toluene
solution at reflux temperature, with a dialkyl phosphonate 30.3, in the presence of
tetrakis(triphenylphosphine)palladiuin(0) and triethylamine to afford the phosphonate ester
32.6.
Using the above procedures, but employing, in place of 4-bromophenylalanine 32.4, different
bromo-substituted phenylalanines 32.1, and/or different dialkyl phosphites 30.3, the
corresponding products 32.3 are obtained.
Scheme 33 depicts the preparation of compounds 33.4 in which the phosphonate group is attached to the phenyl ring by means of a styrene moiety. In this reaction sequence, a vinyl-substituted phenylalanine 33.1 is converted, by means of the series of reactions shown in Scheme 29, into the oxirane 33.2. This compound is then coupled with a dialkyl bromophenylphosphonate 33.3, employing the conditions of the Heck reaction, as described above (Scheme 26) to afford the coupled product 33.4.
For example, 4-vinylphenylalanine 33.5, prepared as described in EP 206460, is converted, as described above, into the oxirane 33.6. This compound is then coupled with a dialkyl 4-bromophenylphosphonate 33.7, prepared as described in J. Chem. Soc. Perkin Trans., 1977, 2, 789, using tetrakis(triphenylphosphine)palladium(0) as catalyst, to yield the phosphonate ester 33.8.
Using the above procedures, but employing, in place of 4-vinylphenylalanine 33.5, different vinyl-substituted phenylalanines 33.1, and/or different dialkyl bromophenylphosphonates 33.3, the corresponding products 33.4 are obtained.
Scheme 34 depicts the preparation of phosphonate-substituted phenylalanine derivatives in which the phosphonate moiety is attached by means of an alkylene chain incorporating a heteroatom. In this procedure, a hydroxymethyl-substituted phenylalanine 34.1 is converted into the cbz protected methyl ester 34.2, using the procedures described above (Scheme 29). The product 34.2 is then converted into a halomethyl-substituted compound 34.3. For example, the carbinol 34.2 is treated with triphenylphosphine and carbon tetrabromide, as
described in J. Amer. Chem. Soc., 108, 1035, 1986 to afford the product 34.3 in which Z is Br. The bromo compound is then reacted with a dialkyl terminally hetero-substituted alkylphosphonate 34.4. The reaction is accomplished in the presence of a base, the nature of which depends on the nature of the substituent X. For example, if X is SH, NH2 or NHalkyl, an inorganic base such as cesium carbonate, or an organic base such as diazabicyclononene or dimethylaminopyridine, can be employed. If X is OH, a strong base such as lithium hexamethyldisilylazide or the like can be employed. The condensation reaction affords the phosphonate-substituted ester 34.5, which is hydrolyzed to afford the carboxylic acid 34.6. The latter compound is then, by means of the sequence of reactions shown in Scheme 29, is transformed into the epoxide 34.7.
For example, the protected 4-hydroxymethyl-substituted phenylalanine derivative 34.9, obtained from the 4-hydroxymethyl phenylalanine 34.8, the preparation of which is described in Syn. Comm., 1998, 28,4279, is converted into the bromo derivative 34.10, as described above. The product is then reacted with a dialkyl 2-aminoethyl phosphonate 34.11, the preparation of which is described in J. Org. Chem., 2000, 65, 676, in the presence of cesium carbonate in dimethylformarnide at ambient temperature, to afford the amine product 34.12. The latter compound is then converted, using the sequence of reactions shown in Scheme 29, into the epoxide 34.14.
Using the above procedures, but employing different carbinols 34.1 in place of the carbinol 34.8, and/or different phosphonates 34.4, the corresponding products 34.7 are obtained.
Preparation of thiophenols 12.2 incorporating phosphonate groups.
Scheme 35 illustrates the preparation of thiophenols in which a phosphonate moiety is attached directly to the aromatic ring. In this procedure, a halo-substituted thiophenol 35.1 is subjected to a suitable protection procedure. The protection of thiophenols is described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p 277ff. The protected compound 35.2 is then coupled, under the influence of a transition metal catalyst, with a dialkyl phosphite 30.3, to afford the product 35.3. The product is then deprotected to afford the free thiophenol 35.4. Suitable protecting groups for this procedure include alkyl groups such as triphenylmethyl and the like. Palladium (0) catalysts are employed, and the reaction is conducted in an inert solvent such as benzene, toluene and the like, as described in J. Med. Chem., 35,1371, 1992. Preferably, the 3-bromothiophenol 35.5 is protected by conversion to the 9-fluorenylmethyl derivative 35.6, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, pp. 284, and the product is reacted in toluene with a dialkyl phosphite in the presence of tetrakis(triphenylphosphine)palladium (0) and triethylamine, to yield the product 35.7. Deprotection, for example by treatment with aqueous ammonia in the presence of an organic co-solvent, as described in J. Chem. Soc. Chem. Comm. 1501, 1986, then gives the thiol 35.8.
Using the above procedures, but employing, in place of the bromo compound 35.5, different bromo compounds 35.2, and/or different phosphonates 30.3, there are obtained the corresponding thiols 35.4.
Scheme 36 illustrates an alternative method for obtaining thiophenols with a directly attached phosphonate group. In this procedure, a suitably protected halo-substituted thiophenol 36.2 is metallated, for example by reaction with magnesium or by transmetallation with an alkyllithium reagent, to afford the metallated derivative 36.3. The latter compound is reacted with a halodialkyl phosphate 36.4, followed by deprotection as described previously, to afford the product 36.5.
For example, 4-bromothiophenol 36.7 is converted into the S-triphenylmethyl (trityl) derivative 36.8, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, pp. 287. The product is converted into the lithium derivative 36.9
by reaction with butyllithium in an ethereal solvent at low temperature, and the resulting lithio compound is reacted with a dialkyl chlorodiethyl phosphite 36.10 to afford the phosphonate 36.11. Removal of the trityl group, for example by treatment with dilute hydrochloric acid in acetic acid, as described in J. Org. Chem., 31, 1118, 1966, then affords the thiol 36.12. Using the above procedures, but employing, in place of the bromo compound 36.7, different halo compounds 36.2, and/or different halo dialkyl phosphites 36.4, there are obtained the corresponding thiols 36.6.
Scheme 37 illustrates the preparation of phosphonate-substituted thiophenols in which the phosphonate group is attached by means of a one-carbon link. In this procedure, a suitably protected methyl-substituted thiopheuol 37.1 is subjected to free-radical bromination to afford a bromomethyl product 37.1a. This compound is reacted with a sodium dialkyl phosphite 37.2 or a trialkyl phosphite, to give the displacement or rearrangement product 37.3, which upon deprotection affords the thiophenols 37.4.
For example, 2-methylthiophenol 37.5 is protected by conversion to the benzoyl derivative 37.6, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, pp. 298. The product is reacted with N-bromosuccinimide in ethyl acetate to yield the bromomethyl product 37.7. This material is reacted with a sodium dialkyl phosphite 37.2, as described in J. Med. Chem., 35, 1371, 1992, to afford the product 37.8. Alternatively, the bromomethyl compound 37.7 can be converted into the phosphonate 37.8 by means of the Arbuzov reaction, for example as described in Handb. Organophosphorus Chem., 1992, 115. In this procedure, the bromomethyl compound 37.7 is heated with a trialkyl phosphate PCOR1^ at ca. 100°C to produce the phosphonate 37.8. Deprotection of 37.8, for example by treatment with aqueous ammonia, as described in J. Amer. Chem. Soc., 85, 1337, 1963, then affords the thiol 37.9.
Using the above procedures, but employing, in place of the bromomethyl compound 37.7, different bromomethyl compounds 37.2, there are obtained the corresponding thiols 37.4.
Scheme 38 illustrates the preparation of thiophenols bearing a phosphonate group linked to the phenyl nucleus by oxygen or sulfur. In this procedure, a suitably protected hydroxy or thio-substituted thiophenol 38.1 is reacted with a dialkyl hydroxyalkylphosphonate 38.2 under the conditions of the Mitsonobu reaction, for example as described in Org. React., 1992, 42,
335, to afford the coupled product 38.3. Deprotection then yields the O- or S-linked products 38.4.
For example, the substrate 3-hydroxythiophenol, 38.5, is converted into the monotrityl ether 38.6, by reaction with one equivalent of trityl chloride, as described above. This compound is reacted with diethyl azodicarboxylate, triphenyl phosphine and a dialkyl 1-hydroxymethyl phosphonate 38.7 in benzene, as described in Synthesis, 4, 327, 1998, to afford the ether compound 38.8. Removal of the trityl protecting group, as described above, then affords the thiophenol 38.9.
Using the above procedures, but employing, in place of the phenol 38.5, different phenols or thiophenols 38.1, and /or different phosphonates 38.2, there are obtained the corresponding thiols 38.4.
Scheme 39 illustrates the preparation of thiophenols 39.4 bearing a phosphonate group linked to the phenyl nucleus by oxygen, sulfur or nitrogen. In this procedure, a suitably protected O, S or N-substituted thiophenol 39.1 is reacted with an activated ester, for example the trifluoromethanesulfonate 39.2, of a dialkyl hydroxyalkyl phosphonate, to afford the coupled product 39.3. Deprotection then affords the thiol 39.4.
For example, 4-methylaminothiophenol 39.5, is reacted with one equivalent of acetyl chloride, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, pp. 298, to afford the product 39.6. This material is then reacted with, for example, a dialkyl trifluoromethanesulfbnylmethyl phosphonate 39.7, the preparation of which is described in Tet. Lett., 1986, 27, 1477, to afford the displacement product 39.8. Preferably, equimolar amounts of the phosphonate 39.7 and the amine 39.6 are reacted together in an aprotic solvent such as dichloromethane, in the presence of a base such as 2,6-lutidine, at ambient temperatures, to afford the phosphonate product 39.8. Deprotection, for example by treatment with dilute aqueous sodium hydroxide for two minutes, as described in J. Amer. Chera Soc., 85, 1337, 1963, then affords the thiophenol 39.9.
Using the above procedures, but employing, in place of the thioamine 39.5, different phenols, thiophenols or amines 39.1, and/or different phosphonates 39.2, there are obtained the corresponding products 39.4.
Scheme 40 illustrates the preparation of phosphonate esters linked to a thiophenol nucleus by means of a heteroatom and a multiple-carbon chain, employing a nucleophilic displacement
reaction on a dialkyl bromoalkyl phosphonate 40.2. In this procedure, a suitably protected
hydroxy, thio or amino substituted thiophenol 40.1 is reacted with a dialkyl bromoalkyl phosphonate 40.2 to afford the product 40.3. Deprotection then affords the free thiophenol 40.4.
For example, 3-hydroxythiophenol 40.5 is converted into the S-trityl compound 40.6, as described above. This compound is then reacted with, for example, a dialkyl 4-bromobutyl phosphonate 40.7, the synthesis of which is described in Synthesis, 1994, 9, 909. The reaction is conducted in a dipolar aprotic solvent, for example dimethylformamide, in the presence of a base such as potassium carbonate, and optionally in the presence of a catalytic amount of potassium iodide, at about 50°C to yield the ether product 40.8. Deprotection, as described above, then affords the thiol 40.9.
Using the above procedures, but employing, in place of the phenol 40.5, different phenols, thiophenols or amines 40.1, and/or different phosphonates 40.2, there are obtained the corresponding products 40.4.
Scheme 41 depicts the preparation of phosphonate esters linked to a thiophenol nucleus by means of unsaturated and saturated carbon chains. The carbon chain linkage is formed by means of a palladium catalyzed Heck reaction, in which an olefinic phosphonate 41.2 is coupled with an aromatic bromo compound 41.1. Deprotection, or hydrogenation of the double bond followed by deprotection, affords respectively the unsaturated phosphonate 41.4, or the saturated analog 41.6.
For example, 3-bromothiophenol is converted into the S-Fm derivative 41.7, as described
i above, and this compound is reacted with diethyl 1-butenyl phosphonate 41.8, the preparation
of which is described in J. Med. Chem,, 1996, 39, 949, in the presence of a palladium (II) catalyst, for example, bis(triphenylphosphine) palladium (IT) chloride, as described in J. Med. Chem, 1992, 35. 1371. The reaction is conducted in an aprotic dipolar solvent such as, for example, dimethylformamide, in the presence of triethylamine, at about 100°C to afford the coupled product 41.9. Deprotection, as described above, then affords the thiol 41.10. Optionally, the initially formed unsaturated phosphonate 41.9 can be subjected to catalytic hydrogenation, using, for example, palladium on carbon as catalyst, to yield the saturated product 41.11, which upon deprotection affords the thiol 41.12.
Using the above procedures, but employing, in place of the bromo compound 41.7, different bromo compounds 41.1, and/or different phosphonates 41.2, there are obtained the corresponding products 41.4 and 41.6
Scheme 42 illustrates the preparation of an aryl-linked phosphonate ester 42.4 by means of a palladium(0) or palladium(II) catalyzed coupling reaction between a bromobenzene and a phenylboronic acid, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 57. The sulfur-substituted phenylboronic acid 42.1 is obtained by means of a metallation-boronation sequence applied to a protected bromo-substituted thiophenol, for example as described in J. Org. Chem., 49, 5237, 1984. A coupling reaction then affords the diaryl product 42.3 which is deprotected to yield the thiol 42.4.
For example, protection of 4-bromothiophenol by reaction with tert-butylchlorodimethylsilane, in the presence of a base such as imidazole, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, p. 297, followed by metallation with butyllithium and boronation, as described in J. Organomet. Chem., 1999, 581, 82, affords the boronate 42.5. This material is reacted with diethyl 4-bromophenylphosphonate 42.6, the preparation of which is described in J. Chem. Soc., Perkin Trans., 1977, 2, 789, in the presence of tetrakis(triphenylphosphine) palladium (0) and an inorganic base such as sodium carbonate, to afford the coupled product 42.7. Deprotection, for example by the use of tetrabutylammonium fluoride in anhydrous tetrahydrofuran, then yields the thiol 42.8. Using the above procedures, but employing, in place of the boronate 42.5, different boronates 42.1, and/or different phosphonates 42.2, there are obtained the corresponding products 42.4.
Scheme 43 depicts the preparation of dialkyl phosphonates in which the phosphonate moiety is linked to the thiophenyl group by means of a chain which incorporates an aromatic or heteroaromatic ring. In this procedure, a suitably protected O, S or N-substituted thiophenol 43.1 is reacted with a dialkyl bromomethyl-substituted aryl or heteroarylphosphonate 43.2, prepared, for example, by means of an Arbuzov reaction between equimolar amounts of a bis(bromo-methyl) substituted aromatic compound and a trialkyl phosphite. The reaction product 43.3 is then deprotected to afford the thiol 43.4. For example, 1,4-dimercaptobenzene is converted into the monobenzoyl ester 43.5 by reaction with one molar equivalent of benzoyl chloride, in the presence of a base such as pyridine. The monoprotected thiol 43.5 is then reacted with, for example diethyl 4-(bromomethyl)phenylphosphonate, 43.6,
the preparation of which is described in Tetrahedron, 1998, 54, 9341. The reaction is conducted in a solvent such as dimethylformamide, in the presence of a base such as potassium carbonate, at about 50°C. The thioether product 43.7 thus obtained is deprotected, as described above, to afford the thiol 43.8.
Using the above procedures, but employing, in place of the thiophenol 43.5, different phenols, thiophenols or amines 43.1, and/or different phosphonates 43.2, there are obtained the corresponding products 43.4.
Scheme 44 illustrates the preparation of phosphonate-containing thiophenols in which the attached phosphonate chain forms a ring with the thiophenol moiety.
In this procedure, a suitably protected thiophenol 44.1, for example an indoline (in which X-Y is (CH2)2), an indole (X-Y is CH=CH) or a tetrahydroquinoline (X-Y is (CH2>3) is reacted with a dialkyl trifluoromethanesulfonyloxymethyl phosphonate 44.2, in the presence of an organic or inorganic base, in a polar aprotic solvent such as, for example, dimethylformamide, to afford the phosphonate ester 44.3. Deprotection, as described above, then affords the thiol 44.4. The preparation of thio-substituted indolines is described in EP 209751. Thio-substituted indoles, indolines and tetrahydroquinolines can also be obtained from the corresponding hydroxy-substituted compounds, for example by thermal rearrangement of the dimethylthiocarbamoyl esters, as described in J. Org. Chem., 31, 3980, 1966. The preparation of hydroxy-substituted indoles is described in Syn., 1994,10, 1018; preparation of hydroxy-substituted indolines is described in Tet. Lett., 1986, 27,4565, and the preparation of hydroxy-substituted tetrahydroquinolines is described in J. Het. Chem., 1991, 28, 1517, and in J. Med. Chem., 1979, 22, 599. Thio-substituted indoles, indolines and tetrahydroquinolines can also be obtained from the corresponding amino and bromo compounds, respectively by diazotization, as described in Sulfur Letters, 2000, 24, 123, or by reaction of the derived organolithium or magnesium derivative with sulfur, as described in Comprehensive Organic Functional Group Preparations, A. R. Katritzky et al, eds, Pergamon, 1995, Vol. 2, p 707. For example, 2,3-dihydro-lH-indole-5-thiol, 44.5, the preparation of which is described in EP 209751, is converted into the benzoyl ester 44.6, as described above, and the ester is then reacted with the triflate 44.7, using the conditions described above for the preparation of 39.8, (Scheme 39, to yield the phosphonate 44.8. Deprotection, for example by reaction with dilute aqueous ammonia, as described above, then affords the thiol 44.9.

Using the above procedures, but employing, in place of the thiol 44.5, different thiols 44.1, and/or different triflates 44.2, there are obtained the corresponding products 44.4.
Preparation of tert-butylamine derivatives incorporating phosphonate groups.
Scheme 45 describes the preparation of tert-butylamines in which the phosphonate moiety is
directly attached to the tert-butyl group. A suitably protected 2.2-dimethyl-2-aminoethyl
bromide 45.1 is reacted with a trialkyl phosphite 45.2, under the conditions of the Arbuzov
reaction, as described above, to afford the phosphonate 45.3, which is then deprotected as
described previously to give 45.4
For example, the cbz derivative of 2,2-dimethyl-2-aminoethyl bromide 45.6, is heated with a
trialkyl phosphite at ca 150°C to afford the product 45.7. Deprotection, as previously
described, then affords the free amine 45.8.
Using the above procedures, but employing different trisubstituted phosphites, there are
obtained the corresponding amines 45.4.
Scheme 46 illustrates the preparation of phosphonate esters attached to the tert butylamine by means of a heteroatom and a carbon chain. An optionally protected alcohol or thiol 46.1 is reacted with a bromoalkylphosphonate 46.2, to afford the displacement product 46.3. Deprotection, if needed, then yields the amine 46.4.
For example, the cbz derivative of 2-amino-2,2-dimethylethanol 46.5 is reacted with a dialkyl 4-bromobutyl phosphonate 46.6, prepared as described in Synthesis, 1994, 9, 909, in
dimethylformamide containing potassium carbonate and potassium iodide, at ca 60°C to afford the phosphonate 46.7 Deprotection then affords the free arnine 46.8. Using the above procedures, but employing different alcohols or thiols 46.1, and/or different bromoalkylphosphonates 46.2, there are obtained the corresponding products 46.4.
Scheme 47 describes the preparation of carbon-linked phosphonate tert butylamine derivatives, in which the carbon chain can be unsaturated or saturated. In the procedure, a terminal acetylenic derivative of tert-butylamine 47.1 is reacted, under basic conditions, with a dialkyl chlorophosphite 47.2, as described above in the preparation of 36.5, (Scheme 36). The coupled product 47.3 is deprotected to afford the arnine 47.4. Partial or complete catalytic hydrogenation of this compound affords the olefinic and saturated products 47.5 and 47.6 respectively.
For example, 2-amino-2-methylprop-l-yne 47.7, the preparation of which is described in WO 9320804, is converted into the N-phthalimido derivative 47.8, by reaction with phthalic anhydride, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, pp. 358. This compound is reacted with lithium diisopropylamide in tetrahydrofuran at -78°C. The resultant anion is then reacted with a dialkyl chlorophosphite 47.2 to afford the phosphonate 47.9. Deprotection, for example by treatment with hydrazine, as described in J. Org. Chera, 43, 2320, 1978, then affords the free arnine 47.10. Partial catalytic hydrogenation, for example using Lindlar catalyst, as described in Reagents for Organic Synthesis, by L. F. Fieser and M. Fieser, Volume 1, p 566, produces the olefinic phosphonate 47.11, and conventional catalytic hydrogenation, as described in Organic Functional Group Preparations, by S.R. Sandier and W. Karo, Academic Press, 1968, p3. for example using 5% palladium on carbon as catalyst, affords the saturated phosphonate 47.12. Using the above procedures, but employing different acetylenic amines 47.1, and/or different dialkyl halophosphites, there are obtained the corresponding products 47.4, 47.5 and 47.6.
Scheme 48 illustrates the preparation of a tert butylamine phosphonate in which the phosphonate moiety is attached by means of a cyclic arnine.
In this method, an aminoethyl-substituted cyclic arnine 48.1 is reacted with a limited amount of a bromoalkyl phosphonate 48.2, using, for example, the conditions described above for the preparation of 40.3, (Scheme 40) to afford the displacement product 48.3.
For example, 3-(l-amino-l-methyl)ethylpyrrolidine 48.4, the preparation of which is described in Chem. Pharm. Bull., 1994, 42, 1442, is reacted with a dialkyl 4-bromobutyl phosphonate 48.5, prepared as described in Synthesis, 1994, 9, 909, to afford the displacement product
48.6.
Using the above procedures, but employing different cyclic amines 48.1, and/or different bromoalkylphosphonates 48.2, there are obtained the corresponding products 48.3.
Preparation of decahydroquinolines with phosphonate moieties at the 6-position.
Scheme 48a illustrates methods for the synthesis of intermediates for the preparation of decahydroquinolines with phosphonate moieties at the 6-position. Two methods for the preparation of the intermediate 48a.4 are shown.
In the first route, 2-hydroxy-6-methylphenylalanine 48a.l, the preparation of which is described in J. Med. Chem., 1969,12, 1028, is converted into the protected derivative 48a.2. For example, the carboxylic acid is first transformed into the benzyl ester, and the product is reacted with acetic anhydride in the presence of an organic base such as, for example, pyridine, to afford the product 48a.2, in which R is benzyl. This compound is reacted with a brominating agent, for example N-bromosuccinimide, to effect benzylic bromination and yield the product 48a.3. The reaction is conducted in an aprotic solvent such as, for example, ethyl acetate or carbon tetrachloride, at reflux. The brominated compound 48a.3 is then treated with acid, for example dilute hydrochloric acid, to effect hydrolysis and cyclization to afford the tetrahydroisoquinoline 48a.4, in which R is benzyl.
Alternatively, the tetrahydroisoquinoline 48a.4 can be obtained from 2-hydroxyphenylalanine 48a.5, the preparation of which is described in Can. J. Bioch., 1971,49, 877. This compound is subjected to the conditions of the Pictet-Spengler reaction, for example as described in Chem. Rev., 1995, 95, 1797.
Typically, the substrate 48a.5 is reacted with aqueous formaldehyde, or an equivalent such as paraformaldehyde or dimethoxymethane, in the presence of hydrochloric acid, for example as described in J. Med. Chem., 1986, 29, 784, to afford the tetrahydroisoquinoline product 48a.4, in which R is H. Catalytic hydrogenation of the latter compound, using, for example, platinum as catalyst, as described in J. Amer. Chem. Soc., 69, 1250, 1947, or using rhodium on alumina as catalyst, as described in J. Med. Chem., 1995, 38, 4446, then gives the hydroxy-substituted decahydroisoquinoline 48a.6. The reduction can also be performed electrochemically, as described in Trans SAEST 1984, 19, 189.
For example, the tetrahydroisoquinoline 48a.4 is subjected to hydrogenation in an alcoholic solvent, in the presence of a dilute mineral acid such as hydrochloric acid, and 5% rhodium on alumina as catalyst. The hydrogenation pressure is ca. 750 psi, and the reaction is conducted at ca 50°C, to afford the decahydroisoquinoline 48a.6.
Protection of the carboxyl and NH groups present in 48a.6 for example by conversion of the carboxylic acid into the trichloroethyl ester, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, p. 240, and conversion of the NH into the N-cbz group, as described above, followed by oxidation, using, for example, pyridinium chlorochromate and the like, as described in Reagents for Organic Synthesis, by L. F. Fieser and M. Fieser, Volume 6, p. 498, affords the protected ketone 48a.9, in which R is trichloroethyl and RI is cbz. Reduction of the ketone, for example by the use of sodium borohydride, as described in J. Amer. Chem. Soc., 88, 2811, 1966, or lithium tri-tertiary butyl aluminum hydride, as described in J. Amer. Chem. Soc., 80, 5372, 1958, then affords the alcohol 48a.lO.
For example, the ketone is reduced by treatment with sodium borohydride in an alcoholic solvent such as isopropanol, at ambient temperature, to afford the alcohol 48a.lO. The alcohol 48a.6 can be converted into the thiol 48a.l3 and the amine 48a.l4, by means of displacement reactions with suitable nucleophiles, with inversion of stereochemistry. For example, the alcohol 48a.6 can be converted into an activated ester such as the trifluoromethanesulfonyl ester or the methanesulfonate ester 48a.7, by treatment with methanesulfonyl chloride and a base. The mesylate 48a.7 is then treated with a sulfur nucleophile, for example potassium thioacetate, as described in Tet. Lett., 1992, 4099, or sodium thiophosphate, as described in Acta Chem. Scand., 1960, 1980, to effect displacement of the mesylate, followed by mild basic hydrolysis, for example by treatment with aqueous ammonia, to afford the thiol 48a.l3.
For example, the mesylate 48a.7 is reacted with one molar equivalent of sodium thioacetate in a polar aprotic solvent such as, for example, dimethylformamide, at ambient temperature, to afford the thioacetate 48a.l2, in which R is COCH3. The product then treated with, a mild base such as, for example, aqueous ammonia, in the presence of an organic co-solvent such as ethanol, at ambient temperature, to afford the thiol 48a.l3. The mesylate 48a.7 can be treated with a nitrogen nucleophile, for example sodium phthalimide or sodium bis(trimethylsilyl)amide, as described in Comprehensive Organic Transformations, by R. C. Larock, p. 399, followed by deprotection as described previously, to afford the amine 48a.l4.
For example, the mesylate 48a.7 is reacted, as described in Angew. Chem. Int. Ed., 7, 919, 1968, with one molar equivalent of potassium phthalimide, in a dipolar aprotic solvent, such
as, for example, dimethylformamide, at ambient temperature, to afford the displacement product 48a.8, in which NRaRb is phthalimido. Removal of the phthalimido group, for example by treatment with an alcoholic solution of hydrazine at ambient temperature, as described in J. Org. Chem., 38, 3034, 1973, then yields the amine 48a.l4. The application of the procedures described above for the conversion of the p-carbinol 48a.6 to the a-thiol 48a.l3 and the a-amine 48a.l4 can also be applied to the a-carbinol 48a.lO, so as to afford the p-thiol and p-amine, 48a.ll.
Scheme 49 illustrates the preparation of compounds in which the phosphonate moiety is attached to the decahydroisoquinoline by means of a heteroatom and a carbon chain. In this procedure, an alcohol, thiol or amine 49.1 is reacted with a bromoalkyl phosphonate 49.2, under the conditions described above for the preparation of the phosphonate 40.3 (Scheme 40), to afford the displacement product 49.3. Removal of the ester group, followed by conversion of the acid to the R4NH amide and N-deprotection, as described below, (Scheme 53) then yields the amine 49.8.
For example, the compound 49.5, in which the carboxylic acid group is protected as the trichloroethyl ester, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, p. 240, and the amine is protected as the cbz group, is reacted with a dialkyl 3-bromopropylphosphonate, 49.6, the preparation of which is described in J. Amer. Chem. Soc., 2000, 122, 1554 to afford the displacement product 49.7. Deprotection of the ester group, followed by conversion of the acid to the R4NH amide and N-deprotection, as described below, (Scheme 53) then yields the amine 49.8.
Using the above procedures, but employing, in place of the a-thiol 49.5, the alcohols, thiols or amines 48a.6,48a.lO, 48a.ll, 48a.l3, 48a.l4, of either a- or p-orientation, there are obtained the corresponding products 49.4, in which the orientation of the side chain is the same as that of the O, N or S precursors.
Scheme 50 illustrates the preparation of phosphonates linked to the decahydroisoquinoline moiety by means of a nitrogen atom and a carbon chain. The compounds are prepared by means of a reductive amination procedure, for example as described in Comprehensive Organic Transformations, by R. C. Larock, p. 421.
In this procedure, the amines 48a.l4 or 48a.ll are reacted with a phosphonate aldehyde 50.1, in the presence of a reducing agent, to afford the alkylated amine 50.2. Deprotection of the ester group, followed by conversion of the acid to the R4NH amide and N-deprotection, as described below, (Scheme 53) then yields the amine 50.3. For example, the protected amino compound 48a.l4 is reacted with a dialkyl formylphosphonate 50.4, the preparation of which is described in U.S. Patent 3,784,590, in the presence of sodium cyanoborohydride, and a polar organic solvent such as ethanolic acetic acid, as described in Org. Prep. Proc. Int., 11, 201,1979, to give the amine phosphonate 50.5. Deprotection of the ester group, followed by conversion of the acid to the R NH amide and N-deprotection, as described below, (Scheme 53) then yields the amine 50.6. Using the above procedures, but employing, instead of the a-amine 48a.l4, the p isomer, 48a.ll and/or different aldehydes 50.1, there are obtained the corresponding products 50.3, in which the orientation of the side chain is the same as that of the amine precursor.
Scheme 51 depicts the preparation of a decahydroisoquinoline phosphonate in which the phosphonate moiety is linked by means of a sulfur atom and a carbon chain. In this procedure, a thiol phosphonate 51.2 is reacted with a mesylate 51.1, to effect displacement of the mesylate group with inversion of stereochemistry, to afford the thioether product 51.3. Deprotection of the ester group, followed by conversion of the acid to the tert. butyl amide and N-deprotection, as described below, (Scheme 53) then yields the amine 51.4. For example, the protected mesylate 51.5 is reacted with an equimolar amount of a dialkyl 2-mercaptoethyl phosphonate 51.6, the preparation of which is described in Aust. J. Chera, 43, 1123, 1990. The reaction is conducted in a polar organic solvent such as ethanol, in the presence of abase such as, for example, potassium carbonate, at ambient temperature, to afford the thio ether phosphonate 51.7. Deprotection of the ester group, followed by conversion of the acid to the tert. butyl amide and N-deprotection, as described below, (Scheme 53) then yields the amine 51.8
Using the above procedures, but employing, instead of the phosphonate 51.6, different phosphonates 51.2, there are obtained the corresponding products 51.4.
Scheme 52 illustrates the preparation of decahydroisoquinoline phosphonates 52.4 in which the phosphonate group is linked by means of an aromatic or heteroaromatic ring. The
compounds are prepared by means of a displacement reaction between hydroxy, thio or amino substituted substrates 52.1 and a bromomethyl substituted phosphonate 52.2. The reaction is performed in an aprotic solvent in the presence of a base of suitable strength, depending on the nature of the reactant 52.1. If X is S or NH, a weak organic or inorganic base such as triethylamine or potassium carbonate can be employed. If X is O, a strong base such as sodium hydride or lithium hexamethyldisilylazide is required. The displacement reaction affords the ether, thioether or amine compounds 52.3. Deprotection of the ester group, followed by conversion of the acid to the R4NH amide and N-deprotection, as described below, (Scheme 53) then yields the amine 52.4.
For example, the protected alcohol 52.5 is reacted at ambient temperature with a dialkyl 3-bromomethylphenylmethylphosphonate 52.6, the preparation of which is described above, (Scheme 43). The reaction is conducted in a dipolar aprotic solvent such as, for example, dioxan or dimethylfbrmamide. The solution of the carbinol is treated with one equivalent of a strong base, such as, for example, lithium hexamethyldisilylazide, and to the resultant mixture is added one molar equivalent of the bromomethyl phosphonate 52.6, to afford the product 52.7. Deprotection of the ester group, followed by conversion of the acid to the R4NH amide and N-deprotection, as described below, (Scheme 53) then yields the amine 52.8. Using the above procedures, but employing, instead of the p-carbinol 52.5, different carbinols, thiols or amines 52.1, of either a- or (J-orientation, and/or different phosphonates 52.2, in place of the phosphonate 52.6, there are obtained the corresponding products 52.4 in which the orientation of the side-chain is the same as that of the starting material 52.1.
Schemes 49-52 illustrate the preparation of decahydroisoquinoline esters incorporating a
phosphonate group linked to the decahydroisoquinoline nucleus.
Scheme 53 illustrates the conversion of the latter group of compounds 53.1 (in which the
group B is link-P(O)(OR1)2 or optionally protected precursor substituents thereto, such as, for
example, OH, SH, NH2) to the corresponding R4NH amides 53.5.
As shown in Scheme 53, the ester compounds 53.1 are deprotected to form the corresponding
carboxylic acids 53.2. The methods employed for the deprotection are chosen based on the
nature of the protecting group R, the nature of the N-protecting group R2, and the nature of
the substituent at the 6-position. For example, if R is trichloroethyl, the ester group is removed
by treatment with zinc in acetic acid, as described in J. Amer. Chem. Soc., 88, 852, 1966.
Conversion of the carboxylic acid 53.2 to the R4NH amide 53.4 is then accomplished by reaction of the carboxylic acid, or an activated derivative thereof, with the amine R4NH2 53.3 to afford the amide 53.4, using the conditions described above for the preparation of the amide 1.6. Deprotection of the NR2 group, as described above, then affords the free amine 53.5(Figure Remove)Interconversions of the phosphonates R-Hnk-PCOXOR1)!, R-link-P(O)(ORl)(OH) and R-Iink-P(O)(OH)2.
Schemes 1-69 described the preparations of phosphonate esters of the general structure R-link-P(O)(OR')2, in which the groups R1, the structures of which are defined in Chart 1, may be the same or different. The R1 groups attached to a phosphonate esters 1-6, or to precursors thereto, may be changed using established chemical transformations. The
interconversions reactions of phosphonates are illustrated in Scheme 54. The group R in Scheme 54 represents the substructure to which the substituent link-P(O)(OR')2 is attached, either in the compounds 1-6 or in precursors thereto. The R1 group may be changed, using the procedures described below, either in the precursor compounds, or in the esters 1-6. The methods employed for a given phosphonate transformation depend on the nature of the substituent R1. The preparation and hydrolysis of phosphonate esters is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 9ff.
The conversion of a phosphonate diester 54.1 into the corresponding phosphonate monoester 54.2 (Scheme 54, Reaction 1) can be accomplished by a number of methods. For example, the ester 54.1 in which R4s an aralkyl group such as benzyl, can be converted into the monoester compound 54.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine, as described in J. Org. Chem., 1995, 60, 2946. The reaction is performed in an inert hydrocarbon solvent such as toluene or xylene, at about 110°C. The conversion of the diester 54.1 in which R'is an aryl group such as phenyl, or an alkenyl group such as allyl, into the monoester 54.2 can be effected by treatment of the ester 54.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran. Phosphonate diesters 54.1 in which one of the groups R!is aralkyl, such as benzyl, and the other is alkyl, can be converted into the monoesters 54.2 in which R'is alkyl by hydrogenation, for example using a palladium on carbon catalyst. Phosphonate diesters in which both of the groups R'are alkenyl, such as allyl, can be converted into the monoester 54.2 in which R*is alkenyl, by treatment with chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) hi aqueous ethanol at reflux, optionally in the presence of diazabicyclooctane, for example by using the procedure described in J. Org. Chem., 38 3224 1973 for the cleavage of allyl carboxylates.
The conversion of a phosphonate diester 54.1 or a phosphonate monoester 54.2 into the corresponding phosphonic acid 54.3 (Scheme 54, Reactions 2 and 3) can effected by reaction of the diester or the monoester with trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm., 739, 1979. The reaction is conducted in an inert solvent such as, for example, dichloromethane, optionally in the presence of a silylating agent such as bis(trimethylsilyl)trifluoroacetamide, at ambient temperature. A phosphonate monoester 54.2 in which R is aralkyl such as benzyl, can be converted into the corresponding phosphonic acid
54.3 by hydrogenation over a palladium catalyst, or by treatment with hydrogen chloride in an ethereal solvent such as dioxan. A phosphonate monoester 54.2 in which R is alkenyl such as, for example, allyl, can be converted into the phosphonic acid 54.3 by reaction with Wilkinson's catalyst in an aqueous organic solvent, for example in 15% aqueous acetonitrile, or in aqueous ethanol, for example using the procedure described in Helv. Chim. Acta., 68, 618, 1985. Palladium catalyzed hydrogenolysis of phosphonate esters 54.1 in which R is benzyl is described in J. Org. Chem., 24, 434, 1959. Platinum-catalyzed hydrogenolysis of phosphonate esters 54.1 in which R!is phenyl is described in J. Amer. Chem. Soc., 78, 2336, 1956.
The conversion of a phosphonate monoester 54.2 into a phosphonate diester 54.1 (Scheme 54, Reaction 4) in which the newly introduced R1 group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl can be effected by a number of reactions in which the substrate 54.2 is reacted with a hydroxy compound R^H, in the presence of a coupling agent. Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in a basic organic solvent such as pyridine, or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma), in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine. Alternatively, the conversion of the phosphonate monoester 54.2 to the diester 54.1 can be effected by the use of the Mitsonobu reaction, as described above (Scheme 25). The substrate is reacted with the hydroxy compound R'OH, in the presence of diethyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine. Alternatively, the phosphonate monoester 54.2 can be transformed into the phosphonate diester 54.1, in which the introduced R1 group is alkenyl or aralkyl, by reaction of the monoester with the halide R!Br, in which R1 is as alkenyl or aralkyl. The alkylation reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base such as cesium carbonate. Alternatively, the phosphonate monoester can be transformed into the phosphonate diester in a two step procedure. In the first step, the phosphonate monoester 54.2 is transformed into the chloro analog RP(O)(OR!)C1 by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17, and the thus-obtained product RP(O)(OR1)C1 is
then reacted with the hydroxy compound R/OH, in the presence of a base such as triethylamine, to afford the phosphonate diester 54.1.
A phosphonic acid R-link-P(O)(OH)2 can be transformed into a phosphonate monoester RP(O)(OR')(OH) (Scheme 54, Reaction 5) by means of the methods described above of for the preparation of the phosphonate diester R-Unk-P(O)(OR1)2 54.1, except that only one molar proportion of the component R^H or R'Br is employed.
A phosphonic acid R-Unk-P(O)(OH)2 54.3 can be transformed into a phosphonate diester R-link-P(O)(OR1)2 54.1 (Scheme 54, Reaction 6) by a coupling reaction with the hydroxy compound R1OH, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine. The reaction is conducted in a basic solvent such as pyridine. Alternatively, phosphonic acids 54.3 can be transformed into phosphonic esters 54.1 in which R1 is aryl, by means of a coupling reaction employing, for example, dicyclohexylcarbodiimide in pyridine at ca 70°C. Alternatively, phosphonic acids 54.3 can be transformed into phosphonic esters 54.1 in which R1 is alkenyl, by means of an alkylation reaction. The phosphonic acid is reacted with the alkenyl bromide RLBr in a polar organic solvent such as acetonitrile solution at reflux temperature, the presence of a base such as cesium carbonate, to afford the phosphonic ester 54.1.
Preparation of the phosphonate esters 1-6 incorporating carbamate moieties.
The phosphonate esters 1-6 in which the R6CO group is formally derived from the carboxylic acid synthons C39 - C49 as shown in Chart 2c, contain a carbamate moiety. The preparation of carbamates is described in Comprehensive Organic Functional Group Transformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and in Organic Functional Group Preparations, by S. R. Sandier and W. Karo, Academic Press, 1986, p. 260ff.
Scheme 55 illustrates various methods by which the carbamate linkage can be synthesized. As shown in Scheme 55, in the general reaction generating carbamates, a carbinol 55.1 is convened into the activated derivative 55.2 in which Lv is a leaving group such as halo, imidazolyl, benztriazolyl and the like, as described below. The activated derivative 55.2 is then reacted with an amine 55.3, to afford the carbamate product 55.4. Examples 1 - 7 in Scheme 55 depict methods by which the general reaction can be effected. Examples 8-10 illustrate alternative methods for the preparation of carbamates.
Scheme 55, Example 1 illustrates the preparation of carbamates employing a chloroformyl derivative of the carbinol 55.5. In this procedure, the carbinol 55.5 is reacted with phosgene, in an inert solvent such as toluene, at about 0"C, as described in Org. Syn. Coll. Vol. 3, 167, 1965, or with an equivalent reagent such as trichloromethoxy chloroformate, as described in Org. Syn. Coll. Vol. 6, 715,1988, to afford the chloroformate 55.6. The latter compound is then reacted with the amine component 55.3, in the presence of an organic or inorganic base, to afford the carbamate 55.7. For example, the chloroformyl compound 55.6 is reacted with the amine 55.3 in a water-miscible solvent such as tetrahydrofaran, in the presence of aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the carbamate 55.7. Alternatively, the reaction is preformed in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine. Scheme 55, Example 2 depicts the reaction of the chloroformate compound 55.6 with imidazole, 55.7, to produce the imidazolide 55.8. The imidazolide product is then reacted with the amine 55.3 to yield the carbamate 55.7. The preparation of the imidazolide is performed in an aprotic solvent such as dichloromethane at 0°C, and the preparation of the carbamate is conducted in a similar solvent at ambient temperature, optionally in the presence of a base such as dimethylaminopyridine, as described in J. Med. Cbc^a., 19K9, H2, 337
Scheme 55 Example 3, depicts the reaction of the chloroformate 55.6 with an activated hydroxyl compound R"OH, to yield the mixed carbonate ester 55.10. The reaction is conducted in an inert organic solvent such as ether or dichloromethane, in the presence of a base such as dicyclohexylamine or triethylamine. The hydroxyl component R"OH is selected from the group of compounds 55.19 - 55.24 shown in Scheme 55, and similar compounds. For example, if the component R"OH is hydroxybenztriazole 55.19, N-hydroxysuccinimide 55.20, or pentachlorophenol, 55.21, the mixed carbonate 55.10 is obtained by the reaction of the chloroformate with the hydroxyl compound in an ethereal solvent in the presence of dicyclohexylamine, as described in Can. J. Chem., 1982, 60, 976. A similar reaction in which the component R"OH is pentafluorophenol 55.22 or 2-hydroxypyridine 55.23 can be performed in an ethereal solvent in the presence of triethylamine, as described in Syn., 1986, 303, and Chem. Ber. 118, 468, 1985.
Scheme 55 Example 4 illustrates the preparation of carbamates in which an alkyloxycarbonylimidazole 55.8 is employed. In ttiis procedure, a carbinol 55.5 is reacted with an equimolar amount of carbonyl diimidazole 55.11 to prepare the intermediate 55.8. The reaction is conducted in an aprotic organic solvent such as dichloromethane or tetrahydrofuran. The acyloxyimidazole 55.8 is then reacted with an equimolar amount of the amine R'NHk to afford the carbamate 55.7. The reaction is performed in an aprotic organic solvent such as dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the carbamate 55.7.
Scheme 55, Example 5 illustrates the preparation of carbamates by means of an intermediate alkoxycarbonylbenztriazole 55.13. In this procedure, a carbinol ROH is reacted at ambient temperature with an equimolar amount of benztriazole carbonyl chloride 55.12, to afford the alkoxycarbonyl product 55.13. The reaction is performed in an organic solvent such as benzene or toluene, in the presence of a tertiary organic amine such as triethylamine, as described in Syn., 1977, 704. This product is then reacted with the amine R'NKk to afford the carbamate 55.7. The reaction is conducted in toluene or ethanol, at from ambient temperature to about 80"C as described in Syn., 1977, 704.
Scheme 55, Example 6 illustrates the preparation of carbamates in which a carbonate (R"O)2CO, 55.14, is reacted with a carbinol 55.5 to afford the intermediate alkyloxycarbon}'! intermediate 55.15. The latter reagent is then reacted with the amine R'NH2 to afford the carbamate 55.7. The procedure in which the reagent 55.15 is derived from
hydroxybenztriazole 55.19 is described in Synthesis, 1993, 908; the procedure in which the reagent 55.15 is derived from N-hydroxysuccinimide 55.20 is described in Tet Lett., 1992, 2781; the procedure in which the reagent 55.15 is derived from 2-hydroxypyridine 55.23 is described in Tet. Lett., 1991, 4251; the procedure in which the reagent 55.15 is derived from 4-nitrophenol 55.24 is described in Syn. 1993, 103. The reaction between equimolar amounts of the carbinol ROH and the carbonate 55.14 is conducted in an inert organic solvent at ambient temperature.
Scheme 55, Example 7 illustrates the preparation of carbamates from alkoxycarbonyl azides 55.16. in this procedure, an alkyl chlorofbrmate 55.6 is reacted with an azide, for example sodium azide, to afford the alkoxycarbonyl azide 55.16. The latter compound is then reacted with an equimolar amount of the amine R'NH2 to afford the carbamate 55.7. The reaction is conducted at ambient temperature in a polar aprotic solvent such as dimethylsulfbxide, for example as described in Syn., 1982,404.
Scheme 55, Example 8 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and the chloroformyl derivative of an amine. In this procedure, which is described in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, the reactants are combined at ambient temperature in an aprotic solvent such as acetonitrile, in the presence of a base such as triethylamine, to afford the carbamate 55.7. Scheme 55, Example 9 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an isocyanate 55.18. In this procedure, which is described in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 645, the reactants are combined at ambient temperature in an aprotic solvent such as ether or dichloromethane and the like, to afford the carbamate 55.7.
Scheme 55, Example 10 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an amine R'NHa. In this procedure, which is described in Chem. Lett. 1972, 373, the reactants are combined at ambient temperature in an aprotic organic solvent such as tetrahydrofuran, in the presence of a tertiary base such as triethylamine, and selenium. Carbon monoxide is passed through the solution and the reaction proceeds to afford the carbamate 55.7.
Preparation of phosphonate intermediates 5 and 6 with phosphonate moieties incorporated into the group R fiCOOH and R2NHCH(R3)CONHR4.
The chemical transformations described in Schemes 1-55 illustrate the preparation of compounds 1-4 in which the phosphonate ester moiety is attached to the quinoline-2-carboxylate substructure, (Schemes 1-8), the phenylalanine or thiophenol moiety (Schemes 9-13), the tert-butylamine moiety (Schemes 14-18) and the decahydroisoquinoline moiety (Schemes 19 - 22).
The various chemical methods employed herein (Schemes 25 - 69)for the preparation of phosphonate groups can, with appropriate modifications known to those skilled in the art, be applied to the introduction of phosphonate ester groups into the compounds R6COOH, as defined in Charts 3a, 3b and 3c, and into the compounds R2NHCH(R3)CONHR4 as defined in Chart 2. For example, Schemes 56 - 61 illustrate the preparation of phosphonate-containing analogs of the phenoxyacetic acid C8 (Chart 3a), Schemes 62 - 65 illustrate the preparation of phosphonate-containing analogs of the carboxylic acid C4, Schemes 66 - 69 illustrate the preparation of phosphonate-containing analogs of the amine A12 (Chart 2), and Schemes 70-75 illustrate the preparation of phosphonate-containing analogs of the carboxylic acid C38. The resultant phosphonate-containing analogs R6aCOOH and R2aNHCH(R3a)CONHR4 can then, using the procedures described above, be employed in the preparation of the compounds 5 and 6. The procedures required for the introduction of the phosphonate-containing analogs R6aCOOH and R2aNHCH(R3a)CONHR4 are the same as those described above for the introduction of the R6CO and R2NHCH(R3)CONHR4 moieties.
Preparation of dimethylphenoxyacetic acids incorporating phosphonate moieties.
Scheme 56 illustrates two alternative methods by means of which 2,6-dimethylphenoxyacetic acids bearing phosphonate moieties may be prepared. The phosphonate group may be introduced into the 2,6-dimethylphenol moiety, followed by attachment of the acetic acid group, or the phosphonate group may be introduced into a preformed 2,6-dimethylphenoxyacetic acid intermediate. In the first sequence, a substituted 2,6-dimethylphenol 56.1, in which the substituent B is a precursor to the group Unk-P(O)(OR1)2, and in which the phenolic hydroxyl may or may not be protected, depending on the reactions to be performed, is converted into a phosphonate-containing compound 56.2. Methods for
the conversion of the substituent B into the group link-P(O)(OR1)2 are described in Schemes
25 - 69.
The protected phenolic hydroxyl group present in the phosphonate-containing product 56.2 is
then deprotected, using methods described below, to afford the phenol 56.3.
The phenolic product 56.3 is then transformed into the corresponding phenoxyacetic acid
56.4, in a two step procedure. In the first step, the phenol 56.3 is reacted with an ester of
bromoacetic acid 56.5, in which R is an alkyi group or a protecting group. Methods for the
protection of carboxylic acids are described in Protective Groups in Organic Synthesis, by
T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 224ff. The alkylation of
phenols to afford phenolic ethers is described, for example, in Comprehensive Organic
Transformations, by R. C. Larock, VCH, 1989, p. 446ff. Typically, the phenol and the
alkylating agent are reacted together in the presence of an organic or inorganic base, such as,
for example, diazabicyclononene, (DBN) or potassium carbonate, in a polar organic solvent
such as, for example, dimethylformamide or acetonitrile.
Preferably, equimolar amounts of the phenol 56.3 and ethyl bromoacetate are reacted together
in the presence of cesium carbonate, in dioxan at reflux temperature, for example as described
in U.S. Patent 5,914,332, to afford the ester 56.6.
The thus-obtained ester 56.6 is then hydrolyzed to afford the carboxylic acid 56.4. The
methods used for this reaction depend on the nature of the group R. If R is an alkyi group
such as methyl, hydrolysis can be effected by treatment of the ester with aqueous or aqueous
alcoholic base, or by use of an esterase enzyme such as porcine liver esterase. If R is a
protecting group, methods for hydrolysis are described in Protective Groups in Organic
Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 224ff.
Preferably, the ester product 56.6 which R is ethyl is hydrolyzed to the carboxylic acid 56.4 by
reaction with lithium hydroxide in aqueous methanol at ambient temperature, as described in
U.S. Patent 5,914,332.
Alternatively, an appropriately substituted 2,6-dimethylphenol 56.7, in which the substituent B
is a precursor to the group link-P(O)(ORI)2, is transformed into the corresponding
phenoxyacetic ester 56.8. The conditions employed for the alkylation reaction are similar to
those described above for the conversion of the phenol 56.3 into the ester 56.6.
The phenolic ester 56.8 is then converted, by transformation of the group B into the group
link-P(O)(OR')i followed by ester hydrolysis, into the carboxylic acid 56.4. The group B
which is present in the ester 56.4 may be transformed into the group link-P(O)(OR )a either before or after hydrolysis of the ester moiety into the carboxylic acid group, depending on the nature of the .chemical transformations required.
Schemes 56 - 61 illustrate the preparation of 2,6-dimethylphenoxyacetic acids incorporating phosphonate ester groups. The procedures shown can also be applied to the preparation of phenoxyacetic esters acids 56.8, with, if appropriate, modifications made according to the knowledge of one skilled in the art.
Scheme 57 illustrates the preparation of 2,6-dimethylphenoxyacetic acids incorporating a phosphonate ester which is attached to the phenolic group by means of a carbon chain incorporating a nitrogen atom. The compounds 57.4 are obtained by means of a reductive alkylation reaction between a 2,6-dimethylphenol aldehyde 57.1 and an aminoalkyl phosphonate ester 57.2. The preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 421. In this procedure, the amine component 57.2 and the aldehyde component 57.1 are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride or diisobutylaluminum hydride, to yield the amine product
57.3. The amination product 573 is then converted into the phenoxyacetic acid compound
57.4, using the alkylation and ester hydrolysis procedures described above, (Scheme 56)
For example, equimolar amounts of 4-hydroxy-3,5-dimethylbenzaldehyde 57.5 (Aldrich) and a dialkyl aminoethyl phosphonate 57.6, the preparation of which is described in J. Org. Chem., 2000, 65, 676, are reacted together in the presence of sodium cyanoborohydride and acetic acid, as described, for example, in J. Amer. Chem. Soc., 91, 3996, 1969, to afford the amine product 57.3. The product is then converted into the acetic acid 57.8, as described above. Using the above procedures, but employing, in place of the aldehyde 57.5, different aldehydes 57.1, and/or different aminoalkyl phosphonates 57.2, the corresponding products 57.4 are obtained.
In this and succeeding examples, the nature of the phosphonate ester group can be varied, either before or after incorporation into the scaffold, by means of chemical transformations. The transformations, and the methods by which they are accomplished, are described above (Scheme 54)
Scheme 58 depicts the preparation of 2,6-dimethylphenols incorporating a phosphonate group linked to the phenyl ring by means of a saturated or unsaturated alkylene chain. In this procedure, an optionally protected bromo-substituted 2,6-dimethylphenol 58.1 is coupled, by means of a palladium-catalyzed Heck reaction, with a dialkyl alkenyl phosphonate 58.2. The coupling of aryl bromides with olefins by means of the Heck reaction is described, for example, in Advanced Organic Chemistry, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 503. The aryl bromide and the olefin are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(0) or palladium (2) catalyst. Following the coupling reaction, the product 58.3 is converted, using the procedures described above, (Scheme 56) into the corresponding phenoxyacetic acid 58.4. Alternatively, the olefinic product 58.3 is reduced to afford the saturated 2,6-dimethylphenol derivative 58.5. Methods for the reduction of carbon-carbon double bonds are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 6. The methods include catalytic reduction, or chemical reduction employing, for example, diborane or diimide. Following the reduction reaction, the product 58.5 is converted, as described above, (Scheme 56) into the corresponding phenoxyacetic acid 58.6.
For example, 3-bromo-2,6-dimethylphenol 58.7, prepared as described in Can. J. Chem., 1983, 61, 1045, is converted into the tert-butyldimethylsilyl ether 58.8, by reaction with chloro-tert-butyldimethylsilane, and a base such as imidazole, as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990 p. 77. The product 58.8 is reacted with an equimolar amount of a dialkyl allyl phosphonate 58.9, for example diethyl allylphosphonate (Aldrich) in the presence of ca. 3 mol % of bis(triphenylphosphine) paUadium(II) chloride, in dimethylformamide at ca. 60°C, to produce the coupled product 58.10. The silyl group is removed, for example by the treatment of the ether 58.10 with a solution of tetrabutylammonium fluoride in tetrahydrofuran, as described in J. Am. Chem., Soc., 94, 6190, 1972, to afford the phenol 58.11. This compound is converted, employing the procedures described above, (Scheme 56) into the corresponding phenoxyacetic acid 58.12. Alternatively, the unsaturated compound 58.11 is reduced, for example by catalytic hydrogenation employing 5% palladium on carbon as catalyst, in an alcoholic solvent such as methanol, as described, for example, in Hydrogenation Methods, by R. N. Rylander, Academic Press, 1985, Ch. 2, to afford the saturated analog 58.13. This compound is

converted, employing the procedures described above, (Scheme 56) into the corresponding phenoxyacetic acid 58.14.
Using the above procedures, but employing, in place of 3-bromo-2,6-dimethylphenol 58.7, different bromophenols 58.1, and/or different dialkyl alkenyl phosphonates 58.2, the corresponding products 58.4 and 58.6 are obtained.
Scheme 59 illustrates the preparation of phosphonate-containing 2,6-dimethylphenoxyacetic acids 59.1 in which the phosphonate group is attached to the 2,6-dimethylphenoxy moiety by means of a carbocyclic ring. In this procedure, a bromo-substituted 2,6-dimethylphenol 59.2 is converted, using the procedures illustrated in Scheme 56, into the corresponding 2,6-dimethylphenoxyacetic ester 59.3. The latter compound is then reacted, by means of a palladium-catalyzed Heck reaction, with a cycloalkenone 59.4, in which n is 1 or 2. The coupling reaction is conducted under the same conditions as those described above for the preparation of 58.3 (Scheme 58). The product 59.5 is then reduced catalytically, as described above for the reduction of 58.3, (Scheme 58), to afford the substituted cycloalkanone 59.6. The ketone is then subjected to a reductive amination procedure, by reaction with a dialkyl 2-aminoethylphosphonate 59.7 and sodium triacetoxyborohydride, as described in J. Org. Chera, 61, 3849, 1996, to yield the amine phosphonate 59.8. The reductive amination reaction is conducted under the same conditions as those described above for the preparation of the amine 57.3 (Scheme 57). The resultant ester 59.8 is then hydrolyzed, as described above, to afford the phenoxyacetic acid 59.1.
For example, 4-bromo-2,6-dimethylphenol 59.9 (Aldrich) is converted, as described above, into the phenoxy ester 59.10. The latter compound is then coupled, in dimethylformamide solution at ca. 60°C, with cyclohexenone 59.11, in the presence of
tetrakis(triphenylphosphine)palladium(0) and triethylamine, to yield the cyclohexenone 59.12. The enone is then reduced to the saturated ketone 59.13, by means of catalytic hydrogenation employing 5% palladium on carbon as catalyst. The saturated ketone is then reacted with an equimolar amount of a dialkyl aminoethylphosphonate 59.14, prepared as described in J. Org. Chem., 2000, 65, 676, in the presence of sodium cyanoborohydride, to yield the amine 59.15. Hydrolysis, employing lithium hydroxide in aqueous methanol at ambient temperature, then yields the acetic acid 59.16.
Using the above procedures, but employing, in place of 4-bromo-2,6-dimethylphenol 59.9, different bromo-substituted 2,6-dimethylphenols 59.2, and/or different cycloalkenones 59.4, and/or different dialkyl arninoalkylphosphonates 59.7, the corresponding products 59.1 are obtained.
Scheme 60 illustrates the preparation of 2,6-dimethylphenoxyacetic acids incorporating a phosphonate group attached to the phenyl ring by means of a heteroatom and an alkylene chain. The compounds are obtained by means of alkylation reactions in which an optionally protected hydroxy, thio or amino-substituted 2,6-dimethylphenol 60.1 is reacted, in the presence of a base such as, for example, potassium carbonate, and optionally in the presence of a catalytic amount of an iodide such as potassium iodide, with a dialkyl bromoalkyl phosphonate 60.2. The reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile at from ambient temperature to about 80°C. The product of the alkylation reaction, 60.3 is then converted, as described above (Scheme 56) into the phenoxyacetic acid 60.4.
For example, 2,6-dimethyl-4-mercaptophenol 60.5, prepared as described in EP 482342, is reacted in dimethylformamide at ca. 60°C with an equimolar amount of a dialkyl bromobutyl phosphonate 60.6, the preparation of which is described in Synthesis, 1994, 9, 909, in the presence of ca. 5 molar equivalents of potassium carbonate, to afford the thioether product 60.7. This compound is converted, employing the procedures described above, (Scheme 56) into the corresponding phenoxyacetic acid 60.8.
Using the above procedures, but employing, in place of 2,6-dimethyl-4-mercaptophenol 60.5, different hydroxy, thio or aminophenols 60.1, and/or different dialkyl bromoalkyl phosphonates 60.2, the corresponding products 60.4 are obtained.
Scheme 61 illustrates the preparation of 2,6-dimethylphenoxyacetic acids incorporating a phosphonate ester group attached by means of an aromatic or heteroaromatic group. In this procedure, an optionally protected hydroxy, mercapto or amino-substituted 2.6-dimethylphenol 61.1 is reacted, under basic conditions, with a bis(halomethyl)aryl or heteroaryl compound 61.2. Equimolar amounts of the phenol and the halomethyl compound are reacted in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base such as potassium or cesium carbonate, or dimethylaminopyridine, to afford
the ether, thioether or amino product 61.3. The product 61.3 is then converted, using the procedures described above, (Scheme 56) into the phenoxyacetic ester 61.4. The latter compound is then subjected to an Arbuzov reaction by reaction with a trialkylphosphite 61.5 at ca. 100°C to afford the phosphonate ester 61.6. The preparation of phosphonates by means of the Arbuzov reaction is described, for example, in Handb. Organophosphorus Chem., 1992, 115. The resultant product 61.6 is then converted into the acetic acid 61.7 by hydrolysis of the ester moiety, using the procedures described above, (Scheme 56). For example, 4-hydroxy-2,6-dimethylphenol 61.8 (Aldrich) is reacted with one molar equivalent of 3,5-bis(chloromethyl)pyridine, the preparation of which is described in Eur. J. Inorg. Chem., 1998, 2, 163, to afford the ether 61.10. The reaction is conducted in acetonitrile at ambient temperature in the presence of five molar equivalents of potassium carbonate. The product 61.10 is then reacted with ethyl bromoacetate, using the procedures described above, (Scheme 56) to afford the phenoxyacetic ester 61.11. This product is heated at 100°C for 3 hours with three molar equivalents of triethyl phosphite 61.12, to afford the phosphonate ester 61.13. Hydrolysis of the acetic ester moiety, as described above, for example by reaction with lithium hydroxide in aqueous ethanol, then affords the phenoxyacetic acid 61.14.
Using the above procedures, but employing, in place of the bis(chloromethyl) pyridine 61.9, different bis(halomethyl) aromatic or heteroaromatic compounds 61.2, and/or different hydroxy, mercapto or amino-substituted 2,6-dimethylphenols 61.1 and/or different trialkyl phosphites 61.5, the corresponding products 61.7 are obtained.
(Figure Remove)Preparation of benzyl carbamate compounds incorporating phosphonate groups.
Scheme 62 depicts the preparation of phosphonate-containing analogs of the benzyl carbamate aminoacid derivative C4 in which the phosphonate moiety is either directly attached to the phenyl ring or attached by means of an alkylene chain. In this procedure, a dialkyl hydroxymethylphenyl alkylphosphonate 62.1 is converted into an activated derivative 62.2, in which Lv is a leaving group, as described above (Scheme 55). The product is then reacted with a suitably protected aminoacid 62.3, to afford the carbamate product 62.4. The reaction is conducted under the conditions described above for the preparation of carbaraates (Scheme 55). The protecting group on the carboxylic acid group in the product 62.4 is then removed to afford the free carboxylic acid 62.5. Methods for the protection and deprotection of carboxylic acids are described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 224ff. For example, as shown in Scheme 62, Example 1, a dialkyl 4-hydroxymethylphenyl phosphonate 62.6, prepared as described in US 5569664, is reacted with phosgene, or an equivalent thereof, as described above (Scheme 55), to afford the chloroformyl product 62.7. This compound is then reacted in an inert solvent such as dichloromethane or tetrahydrofuran, with the tert. butyl aminoacid ester 62.3, in the presence of a base such as triethylamine, to yield the carbamate product 62.8. The conversion of acids into tert. butyl esters is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 245ff. The ester can be prepared by the reaction of the carboxylic acid with isobutylene and an acid catalyst, or by conventional esterification procedures employing tert. butanol. The tert. butyl protecting group is then removed from the product 62.8, for example by reaction with trifluoroacetic acid at ambient temperature for about one hour, to afford the carboxylic acid 62.9.
As a further example, Scheme 62, Example 2 shows the conversion of a dialkyl 4-hydroxymethyl benzyl phosphonate 62.10, prepared as described in J. Am. Chem. Soc., 1996, 118, 5881, into the hydroxybenztriazole derivative 62.11. The reaction is performed as described above (Scheme 55). The activated derivative is then reacted with the aminoacid
derivative 62.3, as described above, to afford the carbamate 62.12. deprotection, as previously described, then affords the carboxylic acid 62.13.
Using the above procedures, but employing, in place of the phosphonates 62.6 and 62.10, different phosphonates 62.1, and/or different aminoacid derivatives 62.3, the corresponding products 62.5 are obtained.
Scheme 63 depicts the preparation of phosphonate-containing analogs of the benzyl carbamate aminoacid derivative C4 in which the phosphonate moiety is attached to the phenyl ring by means of a saturated or unsaturated alkylene chain. In this procedure, a bromo-substituted benzyl alcohol 63.1 is subjected to a palladium catalyzed Heck reaction, as described above, (Scheme 26) with a dialkyl alkenyl phosphonate 63.2, to afford the olefinic product 63.3. The product is then converted into the activated derivative 63.4, which is then reacted with aminoacid derivative 62.3, as described above, to afford, after deprotection of the carboxyl group, the carbamate product 63.5. Optionally, the olefinic coupling product can be reduced to the saturated analog 63.6. The reduction reaction can be effected chemically, for example by the use of diimide or diborane, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 5. The product 63.6 is then converted, as described above, into the carbamate derivative 63.8.
For example, 3-bromobenzyl alcohol 63.9 is coupled in acetonitrile solution, with a dialkyl allylphosphonate 63.10 (Aldrich), in the presence of palladium acetate, triethylamine and tri-o-tolylphosphine, as described in Synthesis, 1983, 556, to afford the product 63.11. This material is then reacted with carbonyl diimidazole, as described above, (Scheme 55) to afford the imidazolide 63.12. The product is then coupled with the aminoacid derivative 62.3, to afford after deprotection, the product 63.13. Alternatively, the unsaturated phosphonate 63.11 is reduced, for example by reaction with diborane in tetrahydrofuran at ambient temperature, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 5., to afford the saturated analog 63.14. The latter compound is then transformed, as described above, into the carbamate aminoacid derivative 63.15. Using the above procedures, but employing, in place of the 3-bromobenzyl alcohol 63.9, different bromobenzyl alcohols 63.1, and/or different alkenyl phosphonates 63.2, and/or different amino acid derivatives, the corresponding products 63.5 and 63.8 are obtained.
Scheme 64 depicts the preparation of phosphonate-containing analogs of the benzyl carbamate aminoacid derivative C4 in which the phosphonate moiety is attached to the phenyl ring by means of an amino-containing alkylene chain. In this procedure, a formyl-substituted benzyl alcohol 64.1 is converted, using the procedures described above is Schemes 55 and 63, into the aminoacid carbamate derivative 64.2. The product is then subjected to a reductive animation reaction with a dialkyl aminoalkyl phosphonate 64.3, to afford the phosphonate product 64.4. Reductive amination of carbonyl compounds is described above (Scheme 27). For example, 3-formyl benzyl alcohol 64.5 is converted into the carbamate derivative 64.6. The product is then reacted in ethanol solution at ambient temperature with a dialkyl aminoethyl phosphonate 64.7, the preparation of which is described in J. Org. Chem., 2000, 65, 676, in the presence of sodium cyanoborohydride, to yield the phosphonate product 64.8. Using the above procedures, but employing, in place of the 3-formylbenzyl alcohol 64.5, different formylbenzyl alcohols 64.1, and/or different aminoalkyl phosphonates 64.3, the corresponding products 64.4 are obtained.
Scheme 65 depicts the preparation of phosphonate-containing analogs of the benzyl carbamate aminoacid derivative C4 in which the phosphonate moiety is attached to the phenyl ring by means of an O, S or N-alkyl-containing alkylene chain. In this procedure, a chloromethyl-substituted benzyl alcohol 65.1 is reacted with a dialkyl hydroxy, mercapto or alkylaminoalkyl phosphonate 65.2. The alkylation reaction is conducted between equimolar amounts of the reactants in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of an inorganic or organic base, such as diisopropylethylamine, dimethylaminopyridine, potassium carbonate and the like. The alkylated product 65.3 is then converted, as previously described, into the carbamate aminoacid derivative 65.4.
For example, 4-chloromethylbenzyl alcohol 65.5, (Aldrich) is reacted at ca. 60°C in acetonitrile solution with a dialkyl hydroxypropyl phosphonate 65.6, the preparation of which is described in Zh. Obschei. Khim, 1974,44,1834, in the presence of dimethylaminopyridine, to afford the ether product 65.7. The product is then converted, as previously described, into the carbamate derivative 65.8.
Using the above procedures, but employing, in place of 4-(chloromethyl)benzyl alcohol 65.5, different chloromethyl benzyl alcohols 65.1, and/or different hydroxy, mercapto or alkylamino phosphonates 65.2, the corresponding products 65.4 are obtained.

Preparation of pyridinyloxymethyl piperidine derivatives incorporating phosphonate groups.
Scheme 66 illustrates the preparation of phosphonate-containing analogs of the amine A12 in which the phosphonate moiety is attached to the pyridine ring by means of a heteroatom and an alkylene chain. In this procedure, 2-bromo-4-hydroxymethylpyridine, the preparation of which is described in Chem. Pharm. Bull., 1990, 38, 2446, is subjected to a nucleophilic
displacement reaction with a dialkyl hydroxy, thio or aminoalkyl-substituted alkyl phosphonate 66.2. The preparation of pyridine ethers, thioethers and amines by means of displacement reactions of 2-bromopyridines by alcohols, thiols and amines is described, for example, in Heterocyclic Compounds, Volume 3, R. A. Abramovitch, ed., Wiley, 1975, p. 597, 191, and 41 respectively. Equimolar amounts of the reactants are combined in a polar solvent such as dimethylformamide at ca 100°C in the presence of a base such as potassium carbonate. The displacement product 66.3 is then converted into the activated derivative 66.4, in which Lv is a leaving group such as halo, methanesulfonyloxy, p-toluenesulfonyloxy and the like. The conversion of alcohols into chlorides and bromides is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 354ff and p. 356ff. For example, benzyl alcohols can be transformed into the chloro compounds, in which Ha is chloro, by reaction with triphenylphosphine and N-chlorosuccinimide, as described in J. Am. Chem. Soc., 106, 3286, 1984. Benzyl alcohols can be transformed into bromo compounds by reaction with carbon tetrabromide and triphenylphosphine, as described in J. Am. Chem. Soc., 92, 2139, 1970. Alcohols can be converted into sulfonate esters by treatment with the alkyl or aryl sulfonyl chloride and a base, in a solvent such as dichloromethane or pyridine. Preferably, the carbinol 66.3 is converted into the corresponding chloro compound, 66.4, in which Lv is Cl, as described above. The product is then reacted with the piperidinol derivative 66.5. The preparation of the compounds 66.5 is described in U.S. 5,614,533, and in J. Org. Chem., 1997, 62, 3440. The piperidinol derivative 66.5 is treated in dimethytformamide with a strong base such as sodium hydride, and the alkylating agent 66.4 is then added. The reaction proceeds to afford the ether product 66.6, and the BOC protecting group is then removed to yield the free amine compound 66.7. The removal of BOC protecting groups is described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 328. The deprotection can be effected by treatment of the BOC compound with anhydrous acids, for example, hydrogen chloride or trifluoroacetic acid, or by reaction with trimethylsilyl iodide or aluminum chloride. Preferably, the BOC group is removed by treatment of the substrate 66.6 with hydrochloric acid, as described in J. Org. Chem., 1997, 62, 3440.
For example, 2-bromo-4-hydroxymethylpyridine 66.1 the preparation of which is described in Chem. Pharm. Bull., 1990, 38, 2446, is reacted in dimethylformarnide solution at ca 80°C with an equimolar amount of a dialkyl mercaptoethyl phosphonate 66.8, prepared as described in
Zh. Obschei. Khim., 1973, 43, 2364, and potassium carbonate, to yield the tbioether product 66.9. The product is then reacted with one molar equivalent of methanesulfonyl chloride in pyridine at 0°C, to produce the mesylate compound 66.10. This material is reacted with the piperidinol reagent 66.5, using the conditions described above, to afford the ether 66.11. The BOC protecting group is then removed as previously described, to afford the amine product 66.12.
Using the above procedures, but employing, in place of the mercaptoethyl phosphonate 66.8, different hydroxy, mercapto or alkylamino phosphonates 66.2, the corresponding products 66.7 are obtained.
Scheme 67 illustrates the preparation of phosphonate-containing analogs of the amine A12 in which the phosphonate moiety is directly attached to the pyridine ring. In this procedure, a bromo-substituted 4-hydroxymethylpyridine 67.1 is coupled, in the presence of a palladium catalyst, with a dialkyl phosphite 67.2. The reaction between aryl bromides and dialkyl phosphites to yield aryl phosphonates is described in Synthesis, 56, 1981, and in J. Med. Chera, 1992, 35,1371. The reaction is conducted in an inert solvent such as toluene or xylene, at about 100°C, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium and a tertiary organic base such as triethylamine. The thus-obtained pyridylphosphonate 67.3 is then converted, as described above (Scheme 66) into an activated derivative 67.4, and the latter compound is transformed as described above into the amine 67.5.
For example, 3-bromo-4-hydroxymethylpyridine 67.5, prepared as described in Bioorg. Med. Chem. Lett., 1992, 2, 1619, is reacted with a dialkyl phosphite 67.2, as described above, to prepare the phosphonate 67.7. The product is then transformed into the chloro derivative by reaction with triphenylphosphine and N-chlorosuccinimide, and the product is converted, as described above (Scheme 66) into the amine 67.9.
Using the above procedures, but employing, in place of the 3-bromopyridine derivative 67.6, different bromopyridines 67.1, and/or different phosphites, the corresponding products 67.5 are obtained.
Scheme 68 illustrates the preparation of phosphonate-containing analogs of the amine A12 in which the phosphonate moiety is attached to the pyridine ring by means of an amine group and
an alkyl chain. In this procedure, an amino-substituted 4-hydroxymethylpyridine 68.1 is subjected to a reductive amination reaction with a dialkyl formylalkyl phosphonate 68.2. The preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 421, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 269. In this procedure, the amine component and the aldehyde or ketone component are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride, optionally in the presence of a Lewis acid, such as titanium tetraisopropoxide, as described in J. Org. Chem., 55, 2552, 1990. The amine product 68.3 is then converted, as described above, into the piperidine derivative 68.5.
For example, 2-amino-4-hydroymethylpyridine 68.6, prepared as described in Aust. J. Chem., 1993, 46, 9897, is reacted in ethanol solution with a dialkyl formylmethylphosphonate 68.7, prepared as described in Zh. Obschei. Khim., 1987, 57, 2793, in the presence of sodium cyanoborohydride, to yield the amine product 68.8. This material is then transformed into the chloro derivative 68.9 by reaction with hydrogen chloride in ether. The chloro product is then transformed, as described above, into the piperidine derivative 68.10. Using the above procedures, but employing, in place of the 2-aminopyridine derivative 68.6, different aminopyridines 68.1, and/or different formylalkyl phosphonates 68.2 the corresponding products 68.5 are obtained.
Scheme 69 illustrates the preparation of phosphonate-containing analogs of the amine A12 in which the phosphonate moiety is attached to the pyridine ring by means of a saturated or unsaturated alkyl chain. In this procedure, a bromo-substituted 4-hydroxymethylpyridine 69.1 is coupled, by means of a palladium-catalyzed Heck reaction, with a dialkyl alkenyl phosphonate 69.2. The coupling of aryl bromides and olefins is described above (Scheme 26). The product is then converted, as described above, into the piperidine derivative 69.5. Optionally, the latter compound can be reduced, for example as described above in Scheme 26, to afford the saturated analog 69.6.
For example, 3-bromo-4-hydroxymethylpyridine 69.7, prepared as described in Bioorg. Med. Chem. Lett., 1992, 2, 1619, is coupled with a dialkyl vinylphosphonate 69.8, prepared as described in Synthesis, 1983, 556, to yield the olefinic product 69.9. The product is reacted
with one molar equivalent of p-toluenesulfonyl chloride in pyridine at ambient temperature to afford the tosylate 69.10. The latter compound is then transformed, as previously described, into the piperidine derivative 69.11. Optionally, the latter compound is reduced, for example by reaction with diimide, to yield the saturated analog 69.12.
Using the above procedures, but employing, in place of the 3-bromopyridine derivative 69.7, different bromopyridines 69.1, and/or different alkenyl phosphonates 69.2 the con-esponding products 69.5 and 69.6 are obtained.
General applicability of methods for introduction of phosphonate substituents.
The procedures described herein for the introduction of phosphonate moieties are, with appropriate modifications, transferable to different chemical substrates. For example, the methods described above for the introduction of phosphonate groups into the quinoline-2-carboxylic moiety (Schemes 24-27), can, with appropriate modifications known to those skilled in the art, be applied to che introduction of phosphonate groups into the phenylalanine, thiophenol, tert-butylamine and decahydroisoquinoline moieties. Similarly, the methods described above for the introduction of phosphonate groups into the phenylalanine moiety (Schemes 28-34), the thiophenol moiety (Schemes 35-44) the tert-butylamine moiety (Schemes 45-48), decahydroisoquinoline moiety (Schemes 48a-52), dimethylphenoxyacetic acids (Schemes 56 - 61), benzyl carbamates (Schemes 62 - 65) and pyridines (Schemes 66 -69) can, with appropriate modifications known to those skilled in the art, be applied to the introduction of phosphonate groups into the quinoline-2-carboxylic acid component.
Preparation of (Pyridin-3-yloxy)-acetic acids incorporating phosphonate moieties.
Scheme 70 illustrates two alternative methods by means of which (pyridin-3-yloxy)-acetic acids bearing phosphonate moieties may be prepared. The phosphonate group may be introduced into the pyridyl moiety, followed by attachment of the acetic acid group, or the phosphonate group may be introduced into a preformed (Pyridin-3-yloxy)-acetic acid intermediate. In the first sequence, a substituted 3-hydroxypyridine 70.1, in which the substituent B is a precursor to the group link-PCOXOR1^, and in which the aryl hydroxyl may or may not be protected, depending on the reactions to be performed, is converted into a phosphonate-containing compound 70.2. Methods for the conversion of the substituent B into the group link-P(O)(OR1)2 are described in Schemes 25 - 75.
The protected aryl hydroxyl group present in the phosphonate-containing product 70.2 is then deprotected, using methods described below, to afford the phenol 70.3. The product 70.3 is then transformed into the corresponding (pyridin-3-yloxy) acetic acid 70.4, in a two step procedure. In the first step, the phenol 70.3 is reacted with an ester of bromoacetic acid 70.9, in which R is an alkyl group or a protecting group. Methods for the protection of carboxylic acids are described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 224ff. The alkylation of 317!
hydroxyl groups to afford aryl ethers is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 446ff. Typically, the aryl reagent and the alkylating agent are reacted together in the presence of an organic or inorganic base, such as, for example, diazabicyclononene, (DBN) or potassium carbonate, in a polar organic solvent such as, for example, dimethylformamide or acetonitrile.
Preferably, equimolar amounts of the phenol 70.3 and ethyl bromoacetate are reacted together in the presence of cesium carbonate, in dioxan at reflux temperature, for example as described in U.S. Patent 5,914,332, to afford the ester 70.4.
The thus-obtained ester 70.4 is then hydrolyzed to afford the carboxylic acid 70.5. The methods used for this reaction depend on the nature of the group R. If R is an alkyl group such as methyl, hydrolysis can be effected by treatment of the ester with aqueous or aqueous alcoholic base, or by use of an esterase enzyme such as porcine liver esterase. If R is a protecting group, methods for hydrolysis are described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 224ff. Preferably, the ester product 70.4 which R is ethyl is hydrolyzed to the carboxylic acid 70.5 by reaction with lithium hydroxide in aqueous methanol at ambient temperature, as described in U.S. Patent 5,914,332.
Alternatively, an appropriately substituted 3-hydroxypyridine 70.6, in which the substituent B is a precursor to the group unk-P(O)(OR')2, is transformed into the corresponding acetic acid ester 70.7. The conditions employed for the alkylation reaction are similar to those described above for the conversion of the phenol 70.3 into the ester 70.4.
The acetic acid ester 70.7 is then converted into the carboxylic acid 70.5 using the 2 step procedure shown above, involving transformation of the group B into the group link-P(0)(ORl)2 followed by ester hydrolysis of the acetic acid ester. The group B which is present in the ester 70.7 may be transformed into the group link-P(O)(ORI)2 either before or after hydrolysis of the ester moiety into the carboxylic acid group, depending on the nature of the chemical transformations required.
Schemes 70-75 illustrate the preparation of (Pyridin-3-yloxy)-acetic acids incorporating phosphonate ester groups. The procedures shown can also be applied to the preparation of acetic esters acids 70.7, with, if appropriate, modifications made according to the knowledge of one skilled in the art.
Scheme 71 depicts the preparation of (pyridin-3-yloxy) acetic acids incorporating a phosphonate group linked to the pyridyl ring by means of a saturated or unsaturated alkylene chain. In this procedure, an optionally protected halo-substituted 3-hydroxypyridine 71.1 is coupled, by means of a palladium-catalyzed Heck reaction, with a dialkyl alkenyl phosphonate 71.2. The coupling of aryl bromides with olefins by means of the Heck reaction is described, for example, in Advanced Organic Chemistry, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 503. The aryl halide and the olefin are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(0) or palladium (2) catalyst. Following the coupling reaction, the product 71.3 is converted, using the procedures described above, (Scheme 70) into the corresponding (pyridin-3-yloxy) acetic acid 71.4. Alternatively, the olefinic product 71.3 is reduced to afford the saturated derivative 71.5. Methods for the reduction of carbon-carbon double bonds are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 6. The methods include catalytic reduction, or chemical reduction employing, for example, diborane or diimide. Following the reduction reaction, the product 71.5 is converted, as described above, (Scheme 70) into the corresponding (pyridin-3-yloxy) acetic acid 71.6.
For example, 2-iodo-5-hydroxy pyridine 71.7, prepared as described in J. Org. Chem., 1990, 55, 18, p. 5287, is converted into the tert-butyldimethylsilyl ether 71.8, by reaction with chloro-tert-butyldimethylsilane, and a base such as imidazole, as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990 p. 77. The product 71.8 is reacted with an equimolar amount of a dialkyl allyl phosphonate 71.9, for example diethyl allylphosphonate (Aldrich) in the presence of ca. 3 mol % of bis(triphenylphosphine) palladium(II) chloride, in dimethylformamide at ca. 60°C, to produce the coupled product 71.10. Alternatively see J. Med. Chem. 1999,42,4, p. 669 for alternative conditions for this reaction. The silyl group is removed, for example by the treatment of the ether 71.10 with a solution of tetrabutylammonium fluoride in tetrahydrofuran, as described in J. Am. Chem., Soc., 94, 6190, 1972, to afford the phenol 71.11. This compound is converted, employing the procedures described above, (Scheme 70) into the corresponding (pyridin-3-yloxy) acetic acid 71.12. Alternatively, the unsaturated compound 71.11 is reduced, for example by catalytic hydrogenation employing 5% palladium on carbon as catalyst, in an alcoholic solvent such as methanol, as described, for example, in Hydrogenation Methods, by R. N. Rylander, Academic Press, 1985, Ch. 2, to afford the saturated analog 71.13. This
compound is converted, employing the procedures described above, (Scheme 70) into the
corresponding (pyridin-3-yloxy) acetic acid 71.14.
Using the above procedures, but employing, in place of 2-iodo-5-hydroxy pyridine 71.7,
different iodo or bromohydroxypyridines 71.1, and/or different dialkyl alkenyl phosphonates
71.2, the corresponding products 71.4 and 71.6 are obtained.
In this and succeeding examples, the nature of the phosphonate ester group can be varied,
either before or after incorporation into the scaffold, by means of chemical transformations.
The transformations, and the methods by which they are accomplished, are described above
(Scheme 54).
Scheme 72 illustrates the preparation of phosphonate-containing analogs of (pyridin-3-yloxy) acetic acids in which the phosphonate moiety is attached to the pyridine ring by means of a heteroatom and an alkyl chain. In this procedure, a suitably protected 2-halo-5-hydroxypyridine, (see Scheme 71) is subjected to a nucleophilic displacement reaction with a dialkyl hydroxy, thio or aminoalkyl-substituted alkyl phosphonate 72.2. The preparation of pyridine ethers, thioethers and amines by means of displacement reactions of 2-bromopyridines, by alcohols, thiols and amines is described, for example, in Heterocyclic Compounds, Volume 3, R. A. Abramovitch, ed., Wiley, 1975, p. 597, 191, and 41 respectively. Equimolar amounts of the reactants are combined in a polar solvent such as dimethylformamide at ca 100°C in the presence of a base such as potassium carbonate. The displacement product 72.3 is then converted into the hydroxyl derivative 72.4 and then into the (pyridin-3-yloxy) acetic acid phosphonate ester 72.5 using the procedures described above (Scheme 70).
For example, 2-iodo-5-hydroxypyridine 71.7 (Scheme 71) is treated with benzyl bromide in the presence of base such as potassium carbonate as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Third Edition 1999, p. 266 to give 72.6. The benzyl ether 72.6 is reacted in dimethylformamide solution at ca 80°C with an equimolar amount of a dialkyl mercaptoethyl phosphonate 72.7, prepared as described in Zh. Obschei. Khim., 1973, 43, 2364, and potassium carbonate, to yield the thioether product 72.8. The benzyl group is then removed by catalytic hydrogenation employing 5% palladium on carbon as catalyst, in an alcoholic solvent such as methanol, as described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Third Edition 1999 p.
266ff., to afford the hydroxyl compound 72.9. The product 72.9 is then converted into the (pyridin-3-yloxy) acetic acid phosphonate ester 72.10 using the procedures described above (Scheme 70).
Using the above procedures, but employing, in place of the mercaptoethyl phosphonate 72.7, different hydroxy, mercapto or alkylamino phosphonates 72.2, and/or in place of the pyridine
71.7 different halo pyridines 71.1, the corresponding products 72.5 are obtained.
Scheme 73 illustrates the preparation of phosphonate-containing analogs of (pyridin-3-yloxy) acetic acids in which the phosphonate moiety is directly attached to the pyridine ring. In this procedure, a suitably protected 2-bromo-5-hydroxypyridine 73.1 is coupled, in the presence of a palladium catalyst, with a dialkyl phosphite 73.2. The reaction between aryl bromides and dialkyl phosphites to yield aryl phosphonates is described in Synthesis, 70, 1981, and in J. Med. Chem., 1992, 35, 1371. The reaction is conducted in an inert solvent such as toluene or xylene, at about 100°C, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium and a tertiary organic base such as triethylamine. The thus-obtained pyridylphosphonate 73.3 is then converted, as described above (Scheme 72) into the (pyridin-3-yloxy) acetic acid phosphonate ester 73.5.
For example, 3-bromo-5-hydroxypyridine 73.6 (Synchem-OHG) is treated with benzyl bromide in the presence of base such as potassium carbonate as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Third Edition 1999, p. 266 to give 73.7. The product 73.7 is then treated with a dialkylphosphite 73.2 as described above to give the phosphonate 73.8. Employing the conditions described above (Scheme 72)
73.8 is converted in several steps to the (pyridin-3-yloxy) acetic acid phosphonate ester 73.10.
Using the above procedures, but employing, in place of the 3-bromopyridine derivative 73.6,
different bromopyridines 73.1, and/or different phosphites, the corresponding products 73.5
are obtained.
i
Scheme 74 illustrates the preparation of (pyridin-3-yloxy) acetic acids incorporating a phosphonate group attached to the pyridyl ring by means of a heteroatom and an alkylene chain. The compounds are obtained by means of alkylation reactions in which an hydroxy, thio or amino-substituted 3-hydroxy pyridine 74.1, protected at the 3-hydroxyl position is reacted, in the presence of a base such as, for example, potassium carbonate, and optionally in
the presence of a catalytic amount of an iodide such as potassium iodide, with a dialkyl bromoalkyl phosphonate 74.6. The reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile at from ambient temperature to about 80°C. The product of the alkylation reaction, 74.2 is then converted, as described above for converting 72.3 to 72.5 (Scheme 72) into the acid 74.5.
Alternatively, the protected pyridine 74.7 is converted to the acetic acid ester derivative 74.8 using the procedures described above in Scheme 70. The acetic acid ester 74.8, is then deprotected following the procedures described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Third Edition 1999, ch 3,6, and 7, and the product treated with a dialkyl bromoalkyl phosphonate 74.6 to give 74.4. The ester 74.4 is converted to the acid 74.5 using the procedures described above (Scheme 70).
For example, 3-benzyloxy, 5-hydroxy pyridine 74.10, prepared as described Bioorg and Med. Chem. Lett. 1998, p. 2797, is converted to the ester 74.11 by treatment with ethylbromoacetate as described above (Scheme 70). The benzyl group is removed, for example by catalytic hydrogenation employing 5% palladium on carbon as catalyst, in an alcoholic solvent such as methanol, as described, for example, in Hydrogenation Methods, by R. N. Rylander, Academic Press, 1985, Ch. 2, to afford the hydroxy pyridine 74.12. The product 74.12 is reacted in dimethylformamide at ca. 60°C with an equimolar amount of a dialkyl bromobutyl phosphonate 74.14, the preparation of which is described in Synthesis, 1994, 9, 909, in the presence of ca. 5 molar equivalents of potassium carbonate, to afford the phosphonate ether product 74.13. This compound is converted, employing the procedures described above, (Scheme 70) into the corresponding acid 74.15.
Using the above procedures, but employing, in place of the pyridine 74.10, different hydroxy, thio or aminophenols 74.1, and/or different dialkyl bromoalkyl phosphonates 74.6, the corresponding products 74.5 are obtained.
Scheme 75 illustrates the preparation of (Pyridin-3-yloxy)-acetic acids incorporating a phosphonate ester which is attached to the pyridyl group by means of a carbon chain incorporating a nitrogen atom. The compounds 75.4 are obtained by means of a reductive alkylation reaction between hydroxyl protected 3-hydroxypyridyl aldehyde 75.1 and an aminoalkyl phosphonate ester 75.2. The preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations,
by R. C. Larock, VCH, p. 421. In this procedure, the amine component 75.2 and the aldehj'de component 75.1 are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride or diisobutylaluminum hydride, to yield the amine product 75.3. The amination product 75.3 is then deprotected according to procedures described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Third Edition 1999, ch3, and subsequently converted into the (pyridin-3-yloxy) acetic acid compound 75.4, using the alkylation and ester hydrolysis procedures described above (Scheme 70).
For example, the ester 75.5 (TCI-US) is reacted with benzyl bromide in the presence of base such as potassium carbonate as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Third Edition 1999, p. 266 to give 75.6. The benzyl ether 75.6 is then converted to the aldehyde 75.7 by reaction with DEBAL (see Comprehensive Organic Transformations, by R. C. Larock, 2nd Edition, 1999, p. 1267. for examples). Equimolar amounts of aldehyde 75.7, and a dialkyl aminoethyl phosphonate 75.8, the preparation of which is described in J. Org. Chera, 2000, 65, 676, are reacted together in the presence of sodium cyanoborohydride and acetic acid, as described, for example, in J. Amer. Chem. Soc., 91, 3996,1969, to afford the amine product 75.9. The benzyl group is then removed by catalytic hydrogenation employing 5% palladium on carbon as catalyst, in an alcoholic solvent such as methanol, as described, for example, in Hydrogenation Methods, by R. N. Rylander, Academic Press, 1985, Ch. 2, to afford the hydroxyl compound 75.10. The product 75.10 is then converted into the acetic acid 75.11, as described above (Scheme 70). Using the above procedures, but employing, in place of the aldehyde 75.7, different aldehydes 75.1, and/or different aminoalkyl phosphonates 75.2, the corresponding products 75.4 are obtained.
Ritonavir-like phosphonate protease inhibitors (RLPPI) 5
Chemistry for Ritonavir analogs.
Preparation of the intermediate phosphonate esters.
The structures of the intermediate phosphonate esters 1 to 7, and the structures for the 10 component groups R1 of this invention are shown in Chart 1. The structures of the components R2COOH, R3COOH and R4 are shown in Charts 2a, 2b and 2c. Specific stereoisomers of some of the structures are shown in Charts 1 and 2; however, all stereoisomers are utilized in the syntheses of the compounds 1 to 7. Subsequent chemical modifications to the compounds 1 to 7, as described herein, permit the synthesis of the final 15 compounds of this invention.
The intermediate compounds 1 to 7 incorporate a phosphonate moiety connected to the nucleus by means of a variable linking group, designated as "link" in the attached structures. Charts 3 and 4 illustrate examples of the linking groups present in the structures 1 - 7, and in which "etc" refers to the scaffold, e.g., ritonavir.
Schemes 1 - 28 illustrate the syntheses of the intermediate phosphonate compounds of this invention, 1- 5, and of the intermediate compounds necessary for their synthesis. The preparation of the compounds 6 and 7, in which the phosphonate moiety is attached to the R2COOH or R3COOH group, is also described below.

(Figure Remove)Protection of reactive substituents.
Depending on the reaction conditions employed, it may be necessary to protect certain reactive substituents from unwanted reactions by protection before the sequence described, and to deprotect the substituents afterwards, according to the knowledge of one skilled in the art. Protection and deprotection of functional groups are described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990. Reactive substituents which may be protected are shown in the accompanying schemes as, for example, [OH], [SH].
Preparation of the phosphonate intermediates 1.
Two methods for the preparation of the phosphonate intermediate compounds 1, in which the phosphonate moiety is attached to the isopropyl group of the carboxylic acid reactant 1.5, are shown in Schemes 1 and 2. The selection of the route to be employed for a given compound is made after consideration of the substituents which are present, and their stability under the reaction conditions required.
As shown in Scheme 1, 5-amino-2-dibenzylamino-l,6-diphenyl-hexan-3-ol, 1.1, the preparation of which is described in Org. Process Res. Dev., 1994, 3, 94, is reacted with a carboxylic acid R2COOH 1.2, or an activated derivative thereof, to produce the amide 1.3. The preparation of amides from carboxylic acids and derivatives is described, for example, in Organic Functional Group Preparations, by S.R.Sandler and W. Karo, Academic Press, 1968, p. 274, and Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 972ff. The carboxylic acid is reacted with the amine in the presence of an activating agent, such as, for example, dicyclohexylcarbodumide or diisopropylcarbodiimide, optionally in the presence of hydroxybenztriazole, in a non-protic solvent such as, for example, pyridine, dimethylformamide or dichloromethane, to afford the amide.
Alternatively, the carboxylic acid may first be converted into an activated derivative such as the acid chloride, anhydride, imidazolide and the like, and then reacted with the amine, in the presence of an organic base such as, for example, pyridine, to afford the amide. The conversion of a carboxylic acid into the corresponding acid chloride can be effected by treatment of the carboxylic acid with a reagent such as, for example, thionyl chloride or oxalyl chloride in an inert organic solvent such as dichloromethane.
Preferably, the carboxylic acid 1.2 is converted into the acid chloride, and the latter compound is reacted with an equimolar amount of the amine 1.1, in an aprotic solvent such as, for example, tetrahydrofuran, at ambient temperature. The reaction is conducted in the presence of an organic base such as triethylarnine, so as to afford the amide 1.3. The N, N-dibenzylamino amide product 1.3 is then transformed into the free amine compound 1.4 by means of a debenzylation procedure. The deprotection of N-benzyl amines is described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p 365. The transformation can be effected under
reductive conditions, for example by the use of hydrogen or a hydrogen donor, in the presence of a palladium catalyst, or by treatment of the N-benzyl arnine with sodium in liquid ammonia, or under oxidative conditions, for example by treatment with 3-chloroperoxybenzoic acid and ferrous chloride.
Preferably, the N, N-dibenzyl compound 1.3 is converted into the amine 1.4 by means of hydrogen transfer catalytic hydrogenolysis, for example by treatment with methanolic ammonium formate and 5% palladium on carbon catalyst, at ca. 75°C for ca. 6 hours, for example as described in U.S. Patent 5,914,332.
The thus-obtained amine 1.4 is then transformed into the amide 1.6 by reaction with the carboxylic acid 1.5, or an activated derivative thereof, in which the substituent A is either the group link-P(O)(ORI)2 or a precursor thereto. Preparations of the carboxylic acids 1.5 are described below, Schemes 13 - 15. The amide-forming reaction is conducted under similar conditions to those described above for the preparation of the amide 1.3, Preferably, the carboxylic acid is converted into the acid chloride, and the acid chloride is reacted with the amine 1.4 in a solvent mixture composed of an organic solvent such as ethyl acetate, and water, in the presence of a base such as sodium bicarbonate, for example as described in Org. Process Res. Dev., 2000, 4, 264, to afford the amide product 1.6. Scheme 2 illustrates an alternative method for the preparation of the phosphonate-containing diamides 1. In this procedure, 2-phenyl-l-[4-phenyl-2-(l-vinyl-propenyl)-[l,3,2]oxazaborinan-6-yi]-ethylamine 2.1, the preparation of which is described in WO 9414436, is reacted with the carboxylic acid R2COOH 1.2, or an activated derivative thereof, to afford the amide product 2.2. The reaction is effected employing the same conditions as were described above for the preparation of the amide 1.3. Preferably, equimolar amounts of the acid chloride derived from the carboxylic acid 1.2 is reacted with the amine 2.1 in a polar aprotic solvent such as tetrahydrofuran or dimethylformamide, at from ambient temperature to about -60° C, in the presence of an organic or inorganic base, to produce the amide 2.2. The product is then reacted with the carboxylic acid 1.5, or an activated derivative thereof, to afford the amide 1.6. The amide-forming reaction is conducted under similar conditions to those described above for the preparation of the amide 1.3. Preferably, the acid 1.5 and the amine 2.2 are reacted in the presence of hydroxybenztriazole, and N-ethyl-N'-dimethylaminopropyl carbodiimide, in tetrahydrofuran at ambient temperature, as described in U.S. Patent 5,484,801, to yield the amide 1.6.
The reactions fflustrated to Schemes 1 and 2 Ulustrate the preparation of the compounds 1.6 B
which A is either the group link-P(O)(OR'), or a precursor thereto, such as. for example,
option* protected OH, SH, NH, as described below. Scheme 3 depicts the
the compounds 1.6 in which A is OH, SH, NH, as described below, into the compounds 1.
which A is the group nnlc-P(O)(OR'), Procedures for the conversion of the group A mto the
group link-P(0) )(OR')2 are described below, (Schemes 16-26).
In this and succeeding examples, the nature of the phosphonate ester group can be vaned,
either before or after incorporation into the scaffold, by means of chemical transformauons.
The transformations, and the methods by which they are accomplished, are descnbed below,
Preparation of the phosphonate intermediates 2.
Two methods for the preparation of the phosphonate intermediate compounds 2 are shown in Schemes 4 and 5. The selection of the route to be employed for a given compound is made after consideration of the substituents which are present, and their stability under the reaction conditions required,
As depicted in Scheme 4, the tribenzylated phenylalanine derivative 4.1, in which the substituent A is either the group Hnk-P(O)(OR1)2 or a precursor thereto, as described below, is reacted with the anion 4.2 derived from acetonitrile, to afford the ketonitrile 4.3. Preparations of the tribenzylated phenylalanine derivatives 4.1 are described below, Schemes 16-18. The anion of acetonitrile is prepared by the treatment of acetonitrile with a strong base, such as, for example, lithium hexamethyldisilylazide or sodium hydride, in an inert organic solvent such as tetrahydrofuran or dimethoxyethane, as described, for example, in U.S. Patent 5,491,253. The solution of the acetonitrile anion 4.2, in an aprotic solvent such as tetrahydrofuran, dimethoxyethane and the like, is then added to a solution of the ester 4.1 at low temperature, to afford the coupled product 4.3.
Preferably, a solution of ca. two molar equivalent of acetonitrile, prepared by the addition of ca. two molar equivalent of sodium amide to a solution of acetonitrile in tetrahydrofuran at -40°C, is added to a solution of one molar equivalent of the ester 4.1 in tetrahydrofuran at -40'C, as described in J. Org. Chem., 1994, 59,4040, to produce the ketonitrile 4.3. The above-described ketonitrile compound 4.3 is then reacted with an organometallic benzyl reagent 4.4, such as a benzyl Grignard reagent or benzyllithium, to afford the ketoenamine 4.5. The reaction is conducted in an inert aprotic organic solvent such as diethyl ether, tetrahydrofuran or the like, at from -80°C to ambient temperature. Preferably, the ketonitrile 4.3 is reacted with three molar equivalents of benzylmagnesium chloride in tetrahydrofuran at ambient temperature, to produce, after quenching by treatment with an organic carboxylic acid such as citric acid, as described in J. Org. Chem., 1994, 59, 4040, the ketoenamine 4.5.
The ketoenamine 4.5 is then reduced, in two stages, via the ketoamine 4.6, to produce the amino alcohol 4.7. The transformation of the ketoenamine 4.5 to the aminoalcohol4.7 can be
effected in one step, or in two steps, with or without isolation of the intermediate ketoamine 4.6, as described in U.S. Patent 5,491,253.
For example, the ketoenamine 4.5 is reduced with a boron-containing reducing agent such as sodium borohydride, sodium cyanoborohydride and the like, in the presence of an acid such as methanesulfonic acid, as described in J. Org. Ghent, 1994, 59, 4040, to afford the ketoamine 4.6. The reaction is performed in an ethereal solvent such as, for example, tetrahydrofuran or methyl tert-butyl ether. The latter compound is then reduced with sodium borohydride-trifluoroacetic acid, as described in U.S. Patent 5,491,253, to afford the aminoalcohol 4.7. Alternatively, the ketoenamine 4.5 can be reduced to the aminoalcohol 4.7 without isolation of the intermediate ketoamine 4.6. In this procedure, described in U.S. Patent 5,491,253, the ketoenamine 4.5 is reacted with sodium borohydride-methanesulfonic acid, in an ethereal solvent such as dimethoxyethane and the like. The reaction mixture is then treated with a quenching agent such as triethanolamine, and the procedure is continued by the addition of sodium borohydride and a solvent such as dimethyl formamide or dimethylacetamide or the like, to afford the aminoalcohol 4.7.
The aminoalcohol 4.7 is converted into the amide 4.9 by reaction with the acid R3COOH 4.8, or an activated derivative thereof, to produce the amide 4.9. This reaction is conducted under similar conditions to those described above for the preparation of the amides 1.3 and 1.6. The dibenzylated amide product 4.9 is deprotected to afford the free amine 4.10. The conditions for the debenzylation reaction are the same as those described above for the deprotection of the dibenzyl amine 1.3 to yield the amine 1.4, (Scheme 1). The amine 4.10 is then reacted with the carboxylic acid R2COOH 1.2, or an activated derivative thereof, to produce the amide 4.11. This reaction is conducted under similar conditions to those described above for the preparation of the amides 1.3 and 1.6.
Alternatively, the amide 4.11 can be prepared by means of the sequence of reactions illustrated in Scheme 5.
In this sequence, the tribenzylated amino acid derivative 4.1 is converted, by means of the reaction sequence shown in Scheme 4 into the dibenzylated amine 4.7. This compound is then converted into a protected derivative, for example the tert-butoxycarbonyl (BOG) derivative 5.1. Methods for the conversion of amines into the BOC derivative are described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990,
p. 327. For example, the amine can be reacted with di-tert-butoxycarbonylanhydride (BOC anhydride) and a base, or with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOG-ON), and the like.
Preferably, the amine is reacted with ca. 1.5 molar equivalents of BOC anhydride and excess potassium carbonate, in methyl tert-butyl ether, at ambient temperature, for example as described in U.S. Patent 5,914,3332, to yield the BOC-protected product 5.1. The N-benzyl protecting groups are then removed from the amide product 5.1 to afford the free amine 5.2. The conditions for this transformation are similar to those described above for the preparation of the amine 1.4, (Scheme 1).
Preferably, the N, N-dibenzyl compound 5.1 is converted into the amine 5.2 by means of hydrogen transfer catalytic hydrogenolysis, for example by treatment with methanolic ammonium formate and 5% palladium on carbon catalyst, at ca. 75"C for ca. 6 hours, for example as described in U.S. Patent 5,914,332.
The amine compound 5.2 is then reacted with the carboxylic acid R2COOH 1.2, or an activated derivative thereof, to produce the amide 5.3. This reaction is conducted under similar conditions to those described above for the preparation of the amides 1.3 and 1.6, to afford the amide product 5.3.
The latter compound is then converted into the amine 5.4 by removal of the BOC protecting group. The removal of BOC protecting groups is described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 328. The deprotection can be effected by treatment of the BOC compound with anhydrous acids, for example, hydrogen chloride or trifluoroacetic acid, or by reaction with trimethylsilyl iodide or aluminum chloride.
Preferably, the BOC group is removed by treatment of the substrate 5.3 with trifluoroacetic acid in dichloromethane at ambient temperature, for example as described in U.S. Patent 5,914,232, to afford the free amine product 5.4.
The free amine thus obtained is then reacted with the carboxylic acid R3COOH 4.8, or an activated derivative thereof, to produce the amide 4.11. This reaction is conducted under similar conditions to those described above for the preparation of the amides 1.3 and 1.6.
The reactions shown in Schemes 4 and 5 illustrate the preparation of the compounds 4.11 in which A is either the group link-P(O)(OR1)2 or a precursor thereto, such as, for example,
optionally protected OH, SH, NH, as described below. Scheme 6 depicts the conversion of the compounds 4.11 in which A is OH, SH, NH, as described below, into the compounds 2. Procedures for the conversion of the group A into the group link-P(O) XOR1)! are described below, (Schemes 16-26).(Figure Remove)Preparation of the phosphonate intermediates 3.
The phosphonate ester intermediate compounds 3 can be prepared by two alternative methods, illustrated in Schemes 7 and 8. The selection of the route to be employed for a given compound is made after consideration of the substituents which are present, and their stability under the reaction conditions required.
As shown in Scheme 7, 4-dibenzylamino-3-oxo-5-phenyl-pentanenitrile 7.1, the preparation of
which is described in J. Org. Chera, 1994, 59, 4040, is reacted with a substituted
benzylmagnesium halide reagent 7.2, in which the group B is a substituent, protected if
appropriate, which can be converted, during or after the sequence of reactions shown in
Scheme 7, into the moiety Unk-P(O)(OR1)2. Examples of the substituent B are Br, [OH],
[SH], [NH2] and the like; procedures for the transformation of these groups into the
phosphonate moiety are shown below in Schemes 16-26. The conditions for the reaction
between the benzylmagnesium halide and the ketonitrile are similar to those described above
for the preparation of the ketoenamine 4.5 (Scheme 4).
Preferably, the ketonitrile 7.1 is reacted with three molar equivalents of the substituted
benzylmagnesium chloride 7.2 in tetrahydrofuran at ambient temperature, to produce, after
quenching by treatment with an organic carboxylic acid such as citric acid, as described in J.
Org. Chem., 1994, 59,4040, the ketoenamine 7.3.
The thus-obtained ketoenamine 7.3 is then transformed, via the intermediate compounds 7.4,
7.5, 7.6, and 7.7 into the diacylated carbinol 7.8. The conditions for each step in the
conversion of the ketoenamine 7.3 to the diacylated carbinol 7.8 are the same as those
described above (Scheme 4) for the transformation of the ketoenamine 4.5 into the diacylated
carbinol 4.11.
The diacylated carbinol 7.8 is then converted into the phosphonate ester 3, using procedures
illustrated below in Schemes 16-26.
Alternatively, the phosphonate esters 3 can be obtained by means of the reactions illustrated in
Scheme 8. In this procedure, the amine 7.5, the preparation of which is described above,
(Scheme 7) is converted into the BOC derivative 8.1. The conditions for the introduction of
the BOG group are similar to those described above for the protection of the amine 5.1,
(Scheme 5).
Preferably, the amine is reacted with ca. 1.5 molar equivalents of BOC anhydride and excess
potassium carbonate, in methyl tert-butyl ether, at ambient temperature, for example as
described in U.S. Patent 5,914,332, to yield the BOC-protected product 8.1.
The BOC-protected amine 8.1 is then converted, via the intermediates 8.2, 8.3 and 8.4 into the
diacylated carbinol 8.5. The reaction conditions for this sequence of reactions are similar to
those described above for the transformation of the BOC-protected amine 5.1 into the
diacylated carbinol 5.4 (Scheme 5).
The diacylated carbinol 8.5 is then converted into the phosphonate ester 3, using procedures
illustrated below in Schemes 16-26.
Preparation of the phosphonate intermediates 4.
Scheme 9 illustrates the preparation of the intermediate phosphonate esters 9.2 in which the substituent A, which is the phosphonate ester moiety or a precursor group thereto, is attached to one of the urea nitrogen atoms in the carboxylic acid reactant 9.1. The preparation of the carboxylic acid reactant 9.1 is described below, Schemes 24-25. In this procedure, the amine 1.4, prepared as described in Scheme 1, is reacted with the carboxylic acid 9.1, to afford the amide 9.2. The reaction between the amine 1.4 and the carboxylic acid 9.1, or an activated derivative thereof, is conducted under the same general conditions as those described above for the preparation of the amide 1.6 (Scheme 1). Preferably, the reactants are combined in the
presence of hydroxybenztriazole and a carbodiimide, as described in U.S. Patent 5,484,801, to yield the amide product 9.2.
The procedure shown in Scheme 9 describes the preparation of the compounds 9.2 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor group thereto, such as [OH], [SH, [NH], as described below. Scheme 10 depicts the conversion of compounds 9.2 in which A is [OH], [SH, [NH], into the compounds 4, in which the group A has been transformed into the group Iink-P(O)(OR1)2. The methods for accomplishing this transformation are described below, Schemes 16-26.
Scheme 11 illustrates the preparation of the intermediate phosphonate esters 11.2 in which the
substituent A, which is the phosphonate ester moiety or a precursor group thereto, is attached to the valine moiety in the carboxylic acid reactant 11.1. The preparation of the carboxylic acid reactant 11.1 is described below, Scheme 26. The reaction between the amine 1.4 and the
carboxylic acid 11.1, or an activated derivative thereof, is conducted under the same general conditions as those described above for the preparation of the amide 1.3 (Scheme 1). Preferably, the reactants are combined in the presence of hydroxybenztriazole and a carbodiimide, as described in U.S. Patent 5,484,801, to yield the amide product 11.2. The procedure shown in Scheme 11 describes the preparation of the compounds 11.2 in which the substituent A is either the group link-P(O)(ORl)2 or a precursor group thereto, such as [OH], [SH, [NH] Ha, as described below,. Scheme 12 depicts the conversion of compounds 11.2 in which A is [OH], [SH, [NH] Br, into the compounds 5, in which the group A has been transformed into the group link-P(O)(OR1)2. The methods for accomplishing this transformation are described below, Schemes 16-26. (Figure Remove)
Preparation of carboxylic acids 1.5, with a phosphonate moiety attached to the isopropyl group.
Scheme 13 illustrates the preparation of carboxylic acid reactants 1.5, in which a substituent A, attached to the isopropyl group, is either the group link-P(O)(OR1)2 or a precursor group thereto, such as [OH], [SH, [NH] Br. During the series of reaction shown in Scheme 13, the group A may, at an appropriate stage, be converted into the group link-P(O)(OR1)2, according to the knowledge of one skilled in the art. Alternatively, the carboxylic acid 1.5, in which A is Unk-P(O)(OR1)2, may be incorporated into the diamide compounds 1.6, as described above, (Schemes 1 and 2) before effecting the transformation of the group A into the group link-PCOXOR1);,.
As shown in Scheme 13, a substituted derivative of isobutyramide 13.1 is converted into the corresponding thioamide 13.2. The conversion of amides into thioamides is described in Synthetic Organic Chemistry, by R. B. Wagner and H. D. Zook, Wiley, 1953, p. 827. The amide is reacted with a sulfur-containing reagent such as phosphorus pentasulfide or Lawessson's reagent, as described in Reagents for Organic Synthesis, by L. F. Fieser and M. Fieser, Wiley, VoL 13, p. 38, to yield the thioamide 13.2. Preferably, the amide 13.1 is reacted with phosphorus pentasulfide in ether solution, at ambient temperature, as described in U.S. Patent 5,484,801, to afford the amide 13.2. The latter compound is then reacted with 1,3-dichloroacetone 13.3 to produce the substituted thiazole 13.4. The preparation of thiazoles by the reaction between a thioamide and a chloroketone is described, for example, in Heterocyclic Chemistry, by T. A. Gilchrist, Longman, 1997, p. 321. Preferably, equimolar amounts of the reactants are combined in acetone solution at reflux temperature, in the presence of magnesium sulfate, as described in U.S. Patent 5,484,801, to produce the thiazole product 13.4. The chloromethyl thiazole 13.4 is then reacted with methylamine to afford the substituted methylamine 13.6. The preparation of amines by the reaction of amines with alkyl halides is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 397. Typically, the components are reacted together in a polar solvent such as an alkanol or dimethylformamide and the like. Preferably, the chloro compound 13.4 is reacted with excess aqueous methylamine at ambient temperature, as described in U.S. Patent 5,484,801, to afford the amine product 13.6. The amine is then converted into the urea
derivative 13.8 by reaction with an activated derivative of the valine carbamic acid 13.7, in which X is a leaving group such as alkanoyloxy or 4-nitrophenoxy. The preparation of ureas by the reaction between carbamic acid derivatives and amines is described in Chem. Rev., 57, 47, 1957. Suitable carbamic acid derivatives are prepared by the reaction between an amine and an alkyl or aryl chloroformate, for example as described in WO 9312326. Preferably, the reaction is performed using carbamic acid derivative 13.7, in which X is 4-nitrophenoxy, and the amine 13.8; the reaction is conducted at about 0°C in an inert solvent such as dichloromethane, in the presence of an organic base such as dimethylaminopyridine or N-methylmorpholine, as described in U.S. Patent 5,484,801, to yield the urea product 13.8. The ester group present in the urea product 13.8 is then hydrolyzed to afford the corresponding carboxylic acid 1.5. Hydrolysis methods for converting esters into carboxylic acids are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 981. The methods include the use of enzymes such as pig liver esterase, and chemical methods such as the use of alkali metal hydroxides in aqueous organic solvent mixtures. Preferably, the methyl ester is hydrolyzed by treatment with lithium hydroxide in aqueous dioxan, as described in U.S. Patent 5,848,801, to yield the carboxylic acid 1.5. Scheme 14 illustrates the preparation of the carboxylic acids 9.1 in which the group A, attached to the amine moiety, is either the group link-PfPXOR1^ or a precursor group thereto, such as [OH], [SH, [NH] Br. During the series of reaction shown in Scheme 14, the group A may, at an appropriate stage, be converted into the group link-P(O)(OR1)2, according to the knowledge of one skilled in the art. Alternatively, the carboxylic acid 9.1, in which A is link-P(O)(OR1)2, may be incorporated into the diamide compounds 9.2, as described above, (Scheme 9) before effecting the transformation of the group A into the group link-P(O)(OR')2. As shown in Scheme 14,4-chloromethyl-2-isopropyl-thiazole 14.1, prepared as described in WO 9414436, is reacted with an amine 14.2, in which A is as described above, to afford the amine 13.6. The conditions for the alkylation reaction are the same as those described above for the preparation of the amine 13.6. The product is then transformed, via the intermediate ester 14.4, into the carboxylic acid 9.1. The conditions for the reactions required to transform the amine 14.3 into the carboxylic acid 9.1 are the same as those described above (Scheme 13) for the analogous chemical steps.
Scheme 15 illustrates the preparation of the carboxylic acids 11.1 in which the group A, attached to the valine moiety, is either the group Iink-P(O)(OR1)2 or a precursor group thereto, such as [OH], [SH, [NH] Br. During the series of reaction shown in Scheme 15, the group A may, at an appropriate stage, be converted into the group link-P(O)(OR1)2, according to the knowledge of one skilled in the art. Alternatively, the carboxylic acid 11.1, in which A is link-P(O)(OR1)2 may be incorporated into the diamide compounds 11.2, as described above, (Scheme 11) before effecting the transformation of the group A into the group link-P(0)(OR')2.
As shown in Scheme IS, (2-isopropyl-thiazol-4-ylmethyl)-methyl-amine, 15.1, prepared as described in WO 9414436, is reacted with a substituted valine derivative 15.2, in which the group A is as defined above. Methods for the preparation of the valine derivatives 15.2 are described below, Scheme 26. The resultant ester 15.3 is then hydrolyzed, as described above, to afford the carboxylic acid 11.1
Preparation of phenylalanine derivatives 4.1 incorporating phosphonate moieties.
Scheme 16 illustrates the preparation of phenylalanine derivatives incorporating phosphonate moieties attached to the phenyl ring by means of a heteroatom and an alkylene chain. The compounds are obtained by means of alkylation or condensation reactions of hydroxy or mercapto-substituted phenylalanine derivatives 16.1.
In this procedure, a hydroxy or mercapto-substituted phenylalanine is converted into the benzyl ester 16.2. The conversion of carboxylic acids into esters is described for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 966. The conversion can be effected by means of an acid-catalyzed reaction between the carboxylic acid and benzyl alcohol, or by means of a base-catalyzed reaction between the carboxylic acid and a benzyl halide, for example benzyl chloride. The hydroxyl or mercapto substituent present in the benzyl ester 16.2 is then protected. Protection methods for phenols and thiols are described respectively, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 10, p 277. For example, suitable protecting groups for phenols and thiophenols include tert-butyldimethylsilyl or tert-butyldiphenylsilyl. Thiophenols may also be protected as S-adamantyl groups, as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 289. The protected hydroxy- or mercapto ester 16.3 is then reacted with a benzyl or substituted benzyl halide and a base, for example as described in U.S. Patent 5,491,253, to afford the N, N-dibenzyl product 16.4. For example, the amine 16.3 is reacted at ca. 90°C with two molar equivalents of benzyl chloride in aqueous ethanol containing potassium carbonate, to afford the tribenzylated product 16.4, as described in U.S. Patent 5,491,253. The protecting group present on the O or S substituent is then removed. Removal of O or S protecting groups is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 10, p. 277. For example, silyl protecting groups are removed by treatment with tetrabutylammonium fluoride and the like, in a solvent such as tetrahydrofuran at ambient temperature, as described in J. Am. Chem. Soc., 94, 6190, 1972. S-Adamantyl groups can be removed by treatment with mercuric trifluoroacetate in acetic acid, as described in Chem. Pharm. Bull., 26, 1576, 1978.

The resultant phenol or thiophenol 16.5 is then reacted under various conditions to provide protected phenylalanine derivatives 16.9,16.10 or 16.11, incorporating phosphonate moieties attached by means of a heteroatom and an alkylene chain.
In this step, the phenol or thiophenol 16.5 is reacted with a dialkyl bromoalkyl phosphonate 16.6 to afford the product 16.9. The alkylation reaction between 16.5 and 16.6 is effected in the presence of an organic or inorganic base, such as, for example, diazabicyclononene, cesium carbonate or potassium carbonate, The reaction is performed at from ambient temperature to ca. 80°C, in a polar organic solvent such as dimethylformamide or acetonitrile, to afford the ether or thioether product 16.9.
For example, as illustrated in Scheme 16, Example 1, a hydroxy-substituted phenylalanine derivative such as tyrosine, 16.12 is converted, as described above, into the benzyl ester 16.13. The latter compound is then reacted with one molar equivalent of chloro tert-butyldimethylsilane, in the presence of a base such as imidazole, as described in J. Am, Chem. Soc., 94, 6190, 1972, to afford the silyl ether 16.14. This compound is then converted, as described above, into the tribenzylated derivative 16.15. The silyl protecting group is removed by treatment of 16.15 with a tetrahydrofuran solution of tetrabutyl ammonium fluoride at ambient temperature, as described in J. Am. Chem. Soc., 94, 6190, 1972, to afford the phenol 16.16. The latter compound is then reacted in dimethylformamide at ca. 60°C, with one molar equivalent of a dialkyl 3-bromopropyl phosphonate 16.17 (Aldrich), in the presence of cesium carbonate, to afford the alkylated product 16.18.
Using the above procedures, but employing, in place of the hydroxy-substituted phenylalanine derivative 16.12, different hydroxy or thio-substituted phenylalanine derivatives 16.1, and/or different bromoalkyl phosphonates 16.6, the corresponding ether or thioether products 16.9 are obtained.
Alternatively, the hydroxy or mercapto-substituted tribenzylated phenylalanine derivative 16.5 is reacted with a dialkyl hydroxymethyl phosphonate 16.7 under the conditions of the Mitsonobu reaction, to afford the ether or thioether compounds 16.10. The preparation of aromatic ethers by means of the Mitsonobu reaction is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 448, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 153-4. The phenol or thiophenol and the alcohol component are reacted together in an
aprotic solvent such as, for example, tetrahydrofuran, in the presence of a dialkyl azodicarboxylate and a triarylphosphine, to afford the ether or thioether products 16.10. For example, as shown in Scheme 16, Example 2, 3-mercaptophenylalanine 16.19, prepared as described in WO 0036136, is converted, as described above, into the benzyl ester 16.20. The resultant ester is then reacted in tetrahydrofuran solution with one molar equivalent of 4-methoxybenzyl chloride in the presence of ammonium hydroxide, as described in Bull. Chera Soc. Jpn., 37, 433, 1974, to afford the 4-methoxybenzyl thioether 16.21. This compound is then converted, as described above for the preparation of the compound 16.4, into the tribenzyl derivative 16.22. The 4-methoxybenzyl group is then removed by the reaction of the thioether 16.22 with mercuric trifluoroacetate and anisole in trifluoroacetic acid, as described in J.Org. Chem., 52, 4420, 1987, to afford the thiol 16.23. The latter compound is reacted, under the conditions of the Mitsonobu reaction, with diethyl hydroxymethyl phosphonate 16.7, diethylazodicarboxylate and triphenylphosphine, for example as described in Synthesis, 4, 327, 1998, to yield the thioether product 16.24.
Using the above procedures, but employing, in place of the mercapto-substituted phenylalanine derivative 16.19, different hydroxy or mercapto-substituted phenylalanines 16.1, and/or different dialkylhydroxymethyl phosphonates 16.7, the corresponding products 16.10 are obtained.
Alternatively, the hydroxy or mercapto-substituted tribenzylated phenylalanine derivative 16.5 is reacted with an activated derivative of a dialkyl hydroxymethylphosphonate 16.8 in which Lv is a leaving group. The components are reacted together in a polar aprotic solvent such as, for example, dimethylformamide or dioxan, in the presence of an organic or inorganic base such as triethylamine or cesium carbonate, to afford the ether or thioether products 16.11. For example, as illustrated in Scheme 16, Example 3, 3-hydroxyphenylalanine 16.25 (Fluka) is converted, using the procedures described above, into the tribenzylated compound 16.26. The latter compound is reacted, in dimethylformamide at ca. 50°C, in the presence of potassium carbonate, with diethyl trifluoromethanesulfonyloxymethylphosphonate 16.27, prepared as described in Tet. Lett., 1986, 27, 1477, to afford the ether product 16.28. Using the above procedures, but employing, in place of the hydroxy-substituted phenylalanine derivative 16.25, different hydroxy or mercapto-substituted phenylalanines 16.1, and/or different dialkyl trMuoromethanesulfonyloxymethylphosphonates 16.8, the corresponding products 16.11 are obtained.
Scheme 17 illustrates the preparation of phenylalanine derivatives incorporating phosphonate moieties attached to the phenyl ring by means of an alkylene chain incorporating a nitrogen atom. The compounds are obtained by means of a reductive alkylation reaction between a formyl-substituted tribenzylated phenylalanine derivative 17.3 and a dialkyl aminoalkylphosphonate 17.4.
In this procedure, a hydroxymethyl-substituted phenylalanine 17.1 is converted into the tribenzylated derivative 17.2 by reaction with three equivalents of a benzyl halide, for example, benzyl chloride, in the presence of an organic or inorganic base such as diazabicyclononene or potassium carbonate. The reaction is conducted in a polar solvent optionally in the additional presence of water. For example, the aminoacid 17.1 is reacted with three equivalents of benzyl chloride in aqueous ethanol containing potassium carbonate, as described in U.S. Patent 5,491,253, to afford the product 17.2. The latter compound is then oxidized to afford the corresponding aldehyde 17.3. The conversion of alcohols to aldehydes is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 604ff. Typically, the alcohol is reacted with an oxidizing agent such as pyridinium chlorochromate, silver carbonate, or dimethyl sulfoxide/acetic anhydride, to afford the aldehyde product 17.3. For example, the carbinol 17.2 is reacted with phosgene, dimethyl sulfoxide and triethylamine, as described in J. Org. Chem., 43, 2480, 1978, to yield the aldehyde 17.3. This compound is reacted with a dialkyl aminoalkylphosphonate 17.4 in the presence of a suitable reducing agent to afford the amine product 17.5. The preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 421, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 269. In this procedure, the amine component and the aldehyde or ketone component are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride, optionally in the presence of a Lewis acid, such as titanium tetraisopropoxide, as described in J. Org. Chem., 55, 2552, 1990. For example, 3-(hydroxymethyl)-phenylalanine 17.6, prepared as described in Acta Chem. Scand. Ser. B, 1977, B31, 109, is converted, as described above, into the formylated derivative 17.7. This compound is then reacted with a dialkyl aminoethylphosphonate 17.8,
prepared as described in J. Org. Chem., 200, 65, 676, in the presence of sodium cyanoborohydride, to produce the aJkylated product 17.9.
Using the above procedures, but employing, in place of 3-(hydroxymethyl)-phenylalanine 17.6, different hydroxymethyl phenylalanines 17.1, and/or different aminoalkyl phosphonates 17.4, the corresponding products 17.5 are obtained.
Scheme 18 depicts the preparation of phenylalanine derivatives in which a phosphonate moiety is attached directly to the phenyl ring. In this procedure, a bromo-substituted phenylalanine 18.1 is converted, as described above, (Scheme 17) into the tribenzylated derivative 18.2. The product is then coupled, in the presence of a palladium(0) catalyst, with a dialkyl phosphite 18.3 to produce the phosphonate ester 18.4. The preparation of arylphosphonates by means of a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Med. Chem., 35, 1371, 1992.
For example, 3-bromophenylalanine 18.5, prepared as described in Pept. Res., 1990, 3, 176, is converted, as described above, (Scheme 17) into the tribenzylated compound 18.6. This compound is then reacted, in toluene solution at reflux, with diethyl phosphite 18.7, triethylamine and tetrakis(triphenylphosphine)palladium(0), as described in J. Med. Chem., 35, 1371, 1992, to afford the phosphonate product 18.8.
Using the above procedures, but employing, in place of 3-bromophenylalanine 18.5, different bromophenylalanines blS.l, and/or different dialkylphosphites 18.3, the corresponding products 18.4 are obtained.
(Figure Remove)Preparation of phosphonate esters with structure 3.
Scheme 19 illustrates the preparation of compounds 3 in which the phosphonate ester moiety is attached directly to the phenyl ring. In this procedure, the ketonitrile 7.1, prepared as described in J. Org. Chem., 1994, 59, 4080, is reacted with a bromobenzylmagnesium halide reagent 19.1. The resultant ketoenamine 19.2 is then converted into the diacylated bromophenyl carbinol 19.3. The conditions required for the conversion of the ketoenamine 19.2 into the carbinol 19.3 are similar to those described above (Scheme 4) for the conversion of the ketoenamine 4.5 into the carbinol 4.12. The product 19.3 is then reacted with a dialkyl phosphite 18.3, in the presence of a palladium (0) catalyst, to yield the phosphonate ester 19.4. The conditions for the coupling reaction are the same as those described above (Scheme 18) for the preparation of the phosphonate ester 18.4.
For example, the ketonitrile 7.1 is reacted, in tetrahydrofuran solution at -40°C, with three molar equivalents of 4-bromobenzylmagnesium bromide 19.5, the preparation of which is described in Tetrahedron, 2000, 56, 10067, to afford the ketoenamine 19.6. The latter compound is then converted into the bromophenyl carbinol 19.7, using the sequence of reactions described above (Scheme 4) for the conversion of the ketoenamine 4.5 into the carbinol 4.12. The resultant bromo compound 19.7 is then reacted with diethyl phosphite 18.3 and triethylamine, in toluene solution at reflux, in the presence of
tetrakis(triphenylphosphine)palladium(0), as described in J. Med. Chem., 35, 1371, 1992, to afford the phosphonate product 19.8.
Using the above procedures, but employing, in place of 4-bromobenzylmagnesium bromide 19.5, different bromobenzylmagnesium halides 19.1 and/or different dialkyl phosphites 18.3, there are obtained the corresponding phosphonate esters 19.4.
Scheme 20 illustrates the preparation of compounds 3 in which the phosphonate ester moiety is attached to the nucleus by means of a phenyl ring. In this procedure, a bromophenyl-substituted benzylmagnesium bromide 20.1, prepared from the corresponding bromomethyl compound by reaction with magnesium, is reacted with the ketonitrile 7.1. The conditions for this transformation are the same as those described above (Scheme 4). The product of the Grignard addition reaction is then transformed, using the sequence of reactions described
above, (Scheme 4) into the diacylated carbinol 20.2. The latter compound is then coupled, in the presence of a palladium(O) catalyst, with a dialkyl phosphite 18.3, to afford the phenylphosphonate 20.3. The procedure for the coupling reaction is the same as those described above for the preparation of the phosphonate 19.8.
For example, 4-(4-bromophenyl)benzyl bromide, prepared as described in DE 2262340, is reacted with magnesium to afford 4-(4-bromophenyl)benzylmagnesium bromine 20.4. This product is then reacted with the ketonitrile 7.1, as described above, to yield, after the sequence of reactions shown in Scheme 4, the diacylated carbinol 20.5. The latter compounds then reacted, as described above, (Scheme 18) with a dialkyl phosphite 18.3, to afford the phenylphosphonate 20.6.
Using the above procedures, but employing, in place of 4-(4-bromophenyl)benzyl bromide 20.4, different bromophenylbenzyl bromides 20.1, and/or different dialkyl phosphites 18.3, the corresponding products 20.3 are obtained.
Scheme 21 depicts the preparation of phosphonate esters 3 in which the phosphonate group is attached by means of a heteroatom and a methylene group. In this procedure, a hetero-substituted benzyl alcohol 21.1 is protected, affording the derivative 21.2. The protection of phenyl hydroxyl, thiol and amino groups are described, respectively, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 10, p. 277, 309. For example, hydroxyl and thiol substituents can be protected as trialkylsilyloxy groups. Trialkylsilyl groups are introduced by the reaction of the phenol or thiophenol with a chlorotrialkylsilane, for example as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 10, p. 68-86. Alternatively, thiol substituents can be protected by conversion to tert-butyl or adamantyl thioethers, as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 289. Amino groups can be protected, for example by dibenzylation. The conversion of amines into dibenzylamines, for example by treatment with benzyl bromide in a polar solvent such as acetonitrile or aqueous ethanol, in the presence of a base such as triethylamine or sodium carbonate, is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.O. M Wuts, Wiley, Second Edition 1990, p. 364. The resultant protected benzyl alcohol 21.1 is converted into a halo derivative 21.2, in which Ha is chloro or bromo. The conversion of alcohols into chlorides and bromides is described, for example, in
Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 354ff and p. 356ff. For example, benzyl alcohols 21.2 can be transformed into the chloro compounds 21.3, in which Ha is chloro, by reaction with triphenylphosphine and N-chlorosuccinimide, as described in J. Am. Chem. Soc., 106, 3286, 1984. Benzyl alcohols can be transformed into bromo compounds by reaction with carbon tetrabromide and triphenylphosphine, as described in J. Am. Chem. Soc., 92, 2139, 1970. The resultant protected benzyl halide 21.3 is then converted into the corresponding benzyimagnesium halide 21.4 by reaction with magnesium metal in an ethereal solvent, or by a Grignard exchange reaction treatment with an alkyl magnesium halide. The resultant substituted benzyimagnesium halide 21.4 is then converted, using the sequence of reactions described above (Scheme 4) for the preparation of the diacylated carbinol 4.11, into the carbinol 21.5 in which the substituent XH is suitably protected.
The protecting group is then removed to afford the phenol, thiophenol or amine 21.6. Deprotection of phenols, thiophenols and amines is described respectively in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990. For example, trialkylsilyl ethers or thioethers can be deprotected by treatment with a tetraalkylammonium fluoride in an inert solvent such as tetrahydrofuran, as described in J. Am Chem. Soc., 94, 6190, 1972. Tert-butyl or adamantyl thioethers can be converted into the corresponding thiols by treatment with mercuric trifluoroacetate in aqueous acetic acid at ambient temperatures, as described in Chem. Pharm. Bull., 26,1576, 1978. N,N-dibenzyl amines can be converted into the unprotected amines by catalytic reduction in the presence of a palladium catalyst, as described above (Scheme 1). The resultant phenol, thiophenol or amine 21.6 is then converted into the phosphonate ester 21.7 by reaction with an activated derivative of a dialkyl hydroxymethyl phosphonate 16.27, in which Lv is a leaving group. The reaction is conducted under the same conditions as described above for the conversion of 16.5 to 16.11 (Scheme 16).
For example, 3-hydroxybenzyl alcohol 21.8 (Aldrich) is reacted with chlorotriisopropylsilane and imidazole in dimethylformamide, as described in Tet. Lett., 2865, 1964, to afford the silyl ether 21.9. This compound is reacted with carbon tetrabromide and triphenylphosphine in dichloromethane, as described in J. Am. Chem. Soc., 109, 2738, 1987, to afford the brominated product 21.10. This material is reacted with magnesium in ether to afford the Grignard reagent 21.11, which is then subjected to the series of reaction shown in Scheme 4 to
afford the carbinol 21.12. The triisopropylsilyl protecting group is then removed by treatment of the ether 21.12 with tetrabutylammonium fluoride in tetrahydrofuran, as descnbed m J. Org. Chem 51 4941,1986. The resultant phenol 21.13 is then reacted with a dialkyl trifluoromlthanesulfonyloxymethylphosphonate 16.27, prepared as described in Tet. Lett., 1986, 27, 1477, in dimethylformamide solution at 60°C in the presence of cesium carbonate, to afford the phosphonate product 21.14.
Usin* the above procedures, but employing, in place of 3-hydroxybenzyl alcohol 21.8, different hydroxy, mercapto or amino-substituted benzyl alcohols 21.1, and/or different dudkyl trifluoromethanesulfonyloxymethyl phosphonates 16.27, the corresponding products 21.7 are obtained.
(Figure Remove)Preparation of phosphonate-containing carboxylic acids 1.5.
Scheme 22 illustrates methods for the preparation of carboxylic acids 1.5, in which A is Br, and methods for the conversion of the bromo substituent into various phosphonate-containing substituents.
In this procedure, 3-bromo-2-methylpropanamide 22.1 is substituted for the isobutyrarnide derivative 13.1 in the reaction sequence illustrated in Scheme 13, so as to afford 2-{3-[2-(2-bromo-1 -methyl-ethyl)-thiazol-4-ylmethyl]-3-methyl-ureido}-3-methyl-butyric acid methyl ester, 22.2. The conditions required for the various reactions are the same as those described above (Schemel3). The bromo-substituted ester 22.2 is then subjected to various transformations so as to introduce phosphonate-containing substituents. For example, the ester 22.2 is reacted with a trialkyl phosphate 22.3 in an Arbuzov reaction, to afford the phosphonate ester 22.4. The preparation of phosphonates by means of the Arbuzov reaction is described, for example, in Handb. Organophosphorus Chem., 1992, 115. The reaction is performed by heating the substrate at 100°C to 150°C with an excess of the trialkyl phosphite. The methyl ester group in the phosphonate product 22.4 is then hydroiyzed, using the procedures described above, (Scheme 13) to prepare the carboxylic acid 22.5. For example, as shown in Scheme 22, Example 1, the bromo compound 22.2 is heated at 120°C with a ten molar excess of tribenzyl phosphite 22.6 to afford the benzylphosphonate 22.7. Hydrolysis of the methyl ester, as described above, then yields 2-(3-{2-[2-(bis-benzyloxy-phosphoryl)-l-methyI-ethyl]-thiazol-4-ytaiethyl}-3-methyl-ureido)-3-methyl-butyric acid 22.8.
Alternatively, the bromoester 22.2 is oxidized to the corresponding aldehyde 22.9. Methods for the oxidation of bromo compounds to the corresponding aldehyde are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989 p. 599. The transformation can be effected by reaction of the aldehyde with dimethyl sulfoxide, optionally in the presence of a silver salt, as described in Chem. Rev., 67, 247,1967. Alternatively, the bromo compound is reacted with trimethylamine oxide, as described in Ber., 94, 1360, 1961, to prepare 3-methyl-2-{3-methyl-3-[2-(l-methyl-2-oxo-ethyl)-thiazol-4-ylmethyl]-ureido}-butyric-acid methyl ester 22.9. The aldehyde is then reacted with a dialkyl aminoalkyl phosphonate 22.10 in a reductive amination reaction to afford the
aminophosphonate 22.11. The conditions for the reductive amination reaction are the same as those described above for the preparation of the aminophosphonate 17.5, (Scheme 17). The methyl ester group present in the product 22.11 is then hydrolyzed, as described above, to yield the carboxylic acid 22.12.
For example, as shown in Scheme 22, Example 2, the bromo compound 22.2 is heated at SOT in dimethylsulfoxide solution, in the presence of one molar equivalent of silver tetrafluoborate and triethylamine, as described in J. Chem. Soc., Chem. Comm., 1338, 1970, to afford the aldehyde 22.9. Reductive amination of the product, in the presence of a dialkyl aminoethyl phosphonate 22.13, the preparation of which is described in J. Org. Chem., 2000, 65, 676 and sodium triacetoxy borohydride, then affords the amino phosphonate 22.14. Hydrolysis of the methyl ester, as described above, then afford the carboxylic acid 22.15. Alternatively, the bromo compound 22.2 is reacted with a dialkyl thioalkyl phosphonate 22.16 to effect displacement of the bromo substituent to afford the thioether 22.17. The preparation of thioethers by the reaction of bromo compounds with thiols is described, for example, in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 787. The reactants are combined in the presence of a suitable base, such as sodium hydroxide, dimethylaminopyridine, potassium carbonate and the like, in a polar organic solvent such as dimethylforrnarnide or ethanol, to afford the thioether 22.17. The product is then subjected to hydrolysis, as described above, to afford the carboxylic acid 22.18.
For example, as shown in Scheme 22, Example 3, the bromo compound 22.2 is reacted with a dialkyl thioethylphosphonate 22.19, the preparation of which is described in Aust. J. Chem., 43,1123, 1990, and dimethylaminopyridine, in dimethylformamide solution at ambient temperature, to yield the thioether 22.20. Hydrolysis of the methyl ester group, as described above, then afford the carboxylic acid 22.21.
Scheme 23 illustrates the preparation of carboxylic acids 23.7 in which the phosphonate moiety is attached to the isopropyl group by means of a phenyl ring and a heteroatom. In this procedure, the hydroxy or mercapto substituent on a phenylbutanamide 23.1 is protected. Methods for the protection of hydroxyl and thiol groups are described above (Scheme 21). The protected amide 23.2 is then subjected to the series of reactions illustrated in Scheme 13, so as to afford the O- or S-protected ester 23.3. The protecting group is then removed. Methods for the deprotection of phenols and thiophenols are described above (Scheme 16).
The resultant phenol or thiophenol 23.4 is then reacted with a dialkyl bromoalkyl phosphonate 23.5, to afford the ether or thioether compounds 23.6. Conditions for the alkylation of phenols and thiophenols are described above (Scheme 16). The ester groups present in the product 23.6 is then hydrolyzed, as described above, to afford the corresponding carboxylic acid 23.7.
For example, 3-(4-hydroxyphenyl)butyric acid 23.8, prepared as described in J. Med. Chem., 1992, 35, 548, is converted into the acid chloride by reaction with thionyl chloride. The acid chloride is then reacted with excess aqueous ethanolic ammonia to afford the amide 23.9. This compound is converted into the tert. butyldimethylsilyl derivative 23.10 by treatment with tert-butylchlorodimethylsilane and imidazole in dichloromethane. The resultant amide 23.10 is then subjected to the series of reactions shown in Scheme 13, so as to yield the ester 23.11. Desilylation, by treatment with tetrabutylammonium fluoride in tetrahydrofuran, then affords the phenol 23.12. This compound is reacted with a dialkyl bromoethyl phosphonate 23.13 (Aldrich) and potassium carbonate, in dimethylformamide at 80° C, to produce the ether 23.14. Hydrolysis of the ester group, by treatment with aqueous methanolic lithium hydroxide, then affords the carboxylic acid 23.15.
Using the above procedures, but employing, in place of the amide 23.9, different hydroxy- or thio-substituted amides 23.23.1, and/or different bromoalkylphosphonates 23.5, the corresponding products 23.7 are obtained.
Scheme 24 and 25 describes the preparation of carboxylic acids 9.1 in which the phosphonate moiety is attached to the amine component. In this procedure, the chloromethylthiazole 14.1, is reacted with a dialkyl aminoalkyl phosphonate 24.1 to produce the substituted amine 24.2. The preparation of amines by reacting amines with alkyl halides is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 397. Typically, the components are reacted together in a polar solvent such as an alkanol or dimethylformamide and the like, to yield the substituted amine 24.2. The latter compound is then converted into the carboxylic acid 24.3, by means of the series of reactions shown in Scheme 14. For example, the chloromethyl thiazole 14.1 is reacted at 50°C in acetonitrile solution containing potassium carbonate, with one molar equivalent of a dialkyl aminomethyl phosphonate 24.4, prepared as described in Bioorg. Chem., 2001, 29, 77, to afford the
substituted amine 24.5. The product is then converted, using the reactions shown in Scheme
14, into the carboxylic acid 24.6.
Using the above procedures, but employing, in place of the dialkyl aminoethyl phosphonate
24.4, different dialkyl aminoalkyl phosphonates 24.1, the corresponding products 24.3 are
obtained.
Scheme 25 illustrates the preparation of carboxylic acids 9.1 in which the phosphonate moiety is attached to the amine component by means of a saturated or unsaturated alkyl chain and a phenyl ring. In this procedure, the chloromethylthiazole 14.1 is reacted with allylamine 25.1, using the procedures described above (Scheme 24) to afford allyl-(2-isopropyl-thiazol-4-ylmethyl)-amine 25.2. The ester amine is then converted, by means of the series of reactions shown in Scheme 14, into 2-[3-allyl-3-(2-isopropyl-thiazol-4-ylmethyl)-ureido]-3-methyl-butyric acid methyl ester 25.3. This material is coupled with a dialkyl bromo-substituted phenylphosphonate 25.4, under the conditions of the palladium-catalyzed Heck reaction, to afford the coupled product 25.5. The coupling of aryl halides with olefins by means of the Heck reaction is described, for example, in Advanced Organic Chemistry, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 503ff. The aryl bromide and the olefin are coupled in a polar solvent such as dirnethylformamide or dioxan, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)pa]ladium(0) or palladium(II) catalyst such as palladium(H) acetate, and optionally in the presence of a base such as triethylamine or potassium carbonate. Hydrolysis of the methyl ester, as described above, then yields the carboxylic acid 25.6. Optionally, the double bond present in the product 25.6 is reduced to afford the dihydro analog 25.7. The double bond is reduced in the presence of a palladium catalyst, such as, for example, 5% palladium on carbon, in a solvent such as methanol or ethanol, to afford the product 25.7.
For example, the allyl-substituted urea 25.3 is reacted with a dialkyl 4-bromophenyl phosphonate 25.8, prepared as described in J. Chem. Soc., Perkin Trans., 1977, 2, 789 in the presence of tetrakis(triphenylphosphine)palladium (0) and triethylamine, to afford the phosphonate ester 25.9. Ester hydrolysis, as described above, then affords the carboxylic acid 25.10. Hydrogenation, as described above, then affords the saturated analog 25.11.
Using the above procedures, but employing, in place of the 4-bromophenyl phosphonate 25.8, different bromophenyl phosphonates 25.4, the corresponding products 25.6 and 25.7 are obtained.
Scheme 26 illustrates the preparation of carboxylic acids 11.1 in which the phosphonate moiety is attached to the valine substructure. In this procedure, 2-amino-4-bromo-3-methyl-butyric acid methyl ester 26.1, prepared as described in U.S. Patent 5,346,898, is reacted with a chloroformate, for example 4-nitrophenyl chloroformate, to prepare the activated derivative 26.2 in which X is a leaving group. For example, the aminoester 26.1 is reacted with 4-nitrophenylchloroformate in dichloromethane at 0°C, as described in U.S. 5,484,801, to afford the product 26.2 in which X is 4-nitrophenoxy. The latter compound is reacted with (2-isopropyl-thiazol-4-ylmethyl)-methyl-amine 26.3, prepared as described in U.S. 5,484,801, in the presence of a base such as triethylamine or dimethylaminopyridine, in an inert solvent such as dichloromethane or tetrahydrofuran, to afford 4-bromo-2-[3-(2-isopropyl-thiazol-4-ylmethyl)-3-methyl-ureido]-3-methyl-butvric acid methyl ester 26.4. The bromo compound 26.4 is then oxidized to afford the aldehyde 26.5. The oxidation of bromo compounds to afford the corresponding aldehydes is described above (Scheme 22). In a typical procedure, the bromo compound is heated at 80°C in dimethylsulfoxide solution, optionally in the presence of silver salt such as silver perchlorate or silver tetrafluoborate, as described in J. Am. Chem. Soc., 81, 4113, 1959, to afford 2-[3-(2-isopropyl-thiazol-4-ylmethyl)-3-methyl-ureido]-3-methyl-4-oxo-butyric acid methyl ester 26.5. The aldehyde is then subjected to a reductive amination procedure, in the presence of a dialkyl aminoalkyl phosphonate 26.6, to afford the amine product 26.7. The preparation of amines by means of reductive alkylation reactions is described above (Scheme 22). Equimolar amounts of the aldehyde 26.5 and the amine 26.6 are reacted in the presence of a boron-containing reducing agent such as, for example, sodium triacetoxyborohydride, to yield the amine 26.7. The methyl ester is then hydrolyzed, as described above, to yield the carboxylic acid 26.8.
For example, 2-[3-(2-isopropyl-thiazol-4-ylmethyl)-3-methyl-ureido]-3-methyl-4-oxo-butyric acid methyl ester 26.5 is reacted with a dialkyl aminoethylphosphonate 26.9 and sodium cyanoborohydride, to afford the amine product 26.10. The methyl ester is then hydrolyzed, as described above to yield the carboxylic acid 26.11.
Using the above procedures, but employing, in place of the dialkyl aminoethylphosphonate 26.9, different aminoalkyl phosphonates 26.6, the corresponding products 26.8 are obtained. Alternatively, the bromo-substituted methyl ester 26.4 is then reacted with a dialkyl mercaptoalkyl phosphonate 26.12 to afford the thioether 26.13. The preparation of thioethers by the reaction of bromo compounds with thiols is described, for example, in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 787. The reactants are combined in the presence of a suitable base, such as sodium hydroxide, dimethylamino pyridine, potassium or cesium carbonate and the like, in a polar organic solvent such as dimethylformamide or ethanol, to afford the thioether 26.13. The methyl ester is then hydrolyzed, as described above to yield the carboxylic acid 26.14.
For example, the bromo compound 26.4 is reacted with a dialkyl mercaptoethyl phosphonate 26.15, the preparation of which is described in Aust. J. Chem., 43,1123, 1990, in dimethylformamide solution, in the presence of cesium carbonate, to produce the thio ether product 26.16. The methyl ester is then hydrolyzed, as described above, to yield the carboxylic acid 26.17.
Using the above procedures, but employing, in place of the dialkyl mercaptoethyl phosphonate 26.15, different mercaptoalkyl phosphonates 26.12, the corresponding products 26.14 are obtained.
I II described the preparations of phosphonate esters of the general structure R-link-P(O)(OR')2, in which the groups R1, the structures of which are defined in Chart 1, may be the same or different. The R1 groups attached to a phosphonate esters 1-7, or to precursors thereto, may be changed using established chemical transformations. The interconversions reactions of phosphonates are illustrated in Scheme 27. The group R in Scheme 27 represents the substructure to which the substituent Unk-P(O)(OR1)2 is attached, either in the compounds 1-7 or in precursors thereto. The R1 group may be changed, using the procedures described below, either in the precursor compounds, or in the esters 1-7. The methods employed for a given phosphonate transformation depend on the nature of the substituent R1. The preparation and hydrolysis of phosphonate esters is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 9ff.
The conversion of a phosphonate diester 27.1 into the corresponding phosphonate monoester 27.2 (Scheme 27, Reaction 1) can be accomplished by a number of methods. For example, the ester 27.1 in which R'is an aralkyl group such as benzyl, can be converted into the monoester compound 27.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine, as described in J. Org. Chem., 1995, 60, 2946. The reaction is performed in an inert hydrocarbon solvent such as toluene or xylene, at about 110°C. The conversion of the diester 27.1 in which R*is an aryl group such as phenyl, or an alkenyl group such as allyl, into the monoester 27.2 can be effected by treatment of the ester 27.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran. Phosphonate diesters 27.1 in which one of the groups R'is aralkyl, such as benzyl, and the other is alkyl, can be converted into the monoesters 27.2 in which R*is alkyl by hydrogenation, for example using a palladium on carbon catalyst. Phosphonate diesters in which both of the groups R'are alkenyl, such as allyl, can be converted into the monoester 27.2 in which R'is alkenyl, by treatment with chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueous ethanol at reflux, optionally in the presence of diazabicyclooctane, for example by
using the procedure described in J. Org. Chem., 38 3224 1973 for the cleavage of allyl carboxylates.
The conversion of a phosphonate diester 27.1 or a phosphonate monoester 27.2 into the corresponding phosphonic acid 27.3 (Scheme 27, Reactions 2 and 3) can effected by reaction of the diester or the rnonoester with trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm., 739, 1979. The reaction is conducted in an inert solvent such as, for example, dichloromethane, optionally in the presence of a silylating agent such as bis(trimethylsilyl)trifluoroacetamide, at ambient temperature. A phosphonate monoester 27.2 in which R'is aralkyl such as benzyl, can be converted into the corresponding phosphonic acid 27.3 by hydrogenation over a palladium catalyst, or by treatment with hydrogen chloride in an ethereal solvent such as dioxan. A phosphonate monoester 27.2 in which R!is alkenyl such as, for example, allyl, can be converted into the phosphonic acid 27.3 by reaction with Wilkinson's catalyst in an aqueous organic solvent, for example in 15% aqueous acetonitrile, or in aqueous ethanol, for example using the procedure described in Helv. Chim. Acta., 68, 618, 1985. Palladium catalyzed hydrogenolysis of phosphonate esters 27.1 in which Rlis benzyl is described in J. Org. Chem., 24, 434, 1959. Platinum-catalyzed hydrogenolysis of phosphonate esters 27.1 in which R*is phenyl is described in J. Amer. Chem. Soc., 78, 2336, 1956.
The conversion of a phosphonate monoester 27.2 into a phosphonate diester 27,1 (Scheme 27, Reaction 4) in which the newly introduced R1 group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl can be effected by a number of reactions in which the substrate 27.2 is reacted with a hydroxy compound R^H, in the presence of a coupling agent. Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in a basic organic solvent such as pyridine, or (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma), in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine. Alternatively, the conversion of the phosphonate monoester 27.2 to the diester 27.1 can be effected by the use of the Mitsonobu reaction, as described above (Scheme 16). The substrate is reacted with the hydroxy compound R'OH, in the presence of
diethyl azodicarboxylate and a triarylphospbine such as triphenyl phosphine. Alternatively, the phosphonate monoester 27.2 can be transformed into the phosphonate diester 27.1, in which the introduced R1 group is alkenyl or aralkyl, by reaction of the monoester with the halide R'Br, in which R1 is as alkenyl or aralkyl. The alkylation reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base such as cesium carbonate. Alternatively, the phosphonate monoester can be transformed into the phosphonate diester in a two step procedure. In the first step, the phosphonate monoester 27.2 is transformed into the chloro analog RP(O)(OR1)C1 by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17, and the thus-obtained product RP(O)(OR1)C1 is then reacted with the hydroxy compound R'OH, in the presence of a base such as triethylamine, to afford the phosphonate diester 27.1.
A phosphonic acid R-link-P(O)(OH)2 can be transformed into a phosphonate monoester RPCOXOR'XOH) (Scheme 27, Reaction 5) by means of the methods described above of for the preparation of the phosphonate diester R-link-P(O)(OR1)2 27.1, except that only one molar proportion of the component R'OH or R*Br is employed.
A phosphonic acid R-link-P(O)(OH)2 27.3 can be transformed into a phosphonate diester R-Iink-P(O)(OR1)2 27.1 (Scheme 27, Reaction 6) by a coupling reaction with the hydroxy compound R^H, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine. The reaction is conducted in a basic solvent such as pyridine. Alternatively, phosphonic acids 27.3 can be transformed into phosphonic esters 27.1 in which R1 is aryl, by means of a coupling reaction employing, for example, dicyclohexylcarbodiimide in pyridine at ca 70°C. Alternatively, phosphonic acids 27.3 can be transformed into phosphonic esters 27.1 in which R1 is alkenyl, by means of an alkylation reaction. The phosphonic acid is reacted with the alkenyl bromide R!Br in a polar organic solvent such as acetonitrile solution at reflux temperature, the presence of a base such as cesium carbonate, to afford the phosphonic ester 27.1.
Scheme 26
General applicability of methods for introduction of phosphonate substituents.
The procedures described above for the conversion of various functional groups into phosphonate moieties are of general application. For example, the methods described above for the introduction of phosphonate groups into the phenylalanine moiety, can, with appropriate modifications known to those skilled in the art, be applied to the introduction of phosphonate groups into the thiazole compounds 1.5, 9.1 and 11.1, and for the preparation of the phosphonate esters 3. Similarly, the methods described above for the introduction of phosphonate groups into the thiazole compounds 1.5, 9.1 and 11.1 can, with appropriate modifications known to those skilled in the art, be applied to the introduction of phosphonate groups into the phenylalanine intermediates 4.1 and for the preparation of the compounds 3.
Phosphonate esters 1-7 incorporating carbamate moieties.
The phosphonate esters 1-7 in which the R2CO or R3CO groups are formally derived from the carboxylic acid synthons 14-16,19, 21, 22, 25, 34, 51 or 52 as shown in Charts 2a, 2b, and 2c, contain a carbamate moiety. The preparation of carbamates is described in Comprehensive Organic Functional Group Transformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and in Organic Functional Group Preparations, by S. R. Sandier and W. Karo, Academic Press, 1986, p. 260ff.
Scheme 28 illustrates various methods by which the carbamate linkage can be synthesized. As shown in Scheme 28, in the general reaction generating carbamates, a carbinol 28.1 is converted into the activated derivative 28.2 in which Lv is a leaving group such as halo, imidazolyl, benztriazolyl and the like, as described below. The activated derivative 28.2 is then reacted with an amine 28.3, to afford the carbamate product 28.4. Examples 1 - 7 in Scheme 28 depict methods by which the general reaction can be effected. Examples 8-10 illustrate alternative methods for the preparation of carbamates.
Scheme 28, Example 1 illustrates the preparation of carbamates employing a chloroformyl derivative of the carbinol 28.5. In this procedure, the carbinol 28.5 is reacted with phosgene, in an inert solvent such as toluene, at about 0°C, as described in Org. Syn. Coll. Vol. 3, 167, 1965, or with an equivalent reagent such as trichloromethoxy chloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, to afford the chloroformate 28.6. The latter compound is
then reacted with the amine component 28.3, in the presence of an organic or inorganic base, to afford the carbamate 28.7. cFor example, the chloroformyl compound 28.6 is reacted with the amine 28.3 in a water-miscible solvent such as tetrahydrofuran, in the presence of aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the carbamate 28.7. cAlternatively, the reaction is preformed in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine. Scheme 28, Example 2 depicts the reaction of the chloroformate compound 28.6 with imidazole, 28.7, to produce the imidazolide 28.8. The imidazolide product is then reacted with the amine 28.3 to yield the carbamate 28.7. The preparation of the imidazolide is performed in an aprotic solvent such as dichloromethane at 0°C, and the preparation of the carbamate is conducted in a similar solvent at ambient temperature, optionally in the presence of a base such as dimethylaminopyridine, as described in J. Med. Chem., 1989, 32, 357. Scheme 28 Example 3, depicts the reaction of the chloroformate 28.6 with an activated hydroxyl compound R"OH, to yield the mixed carbonate ester 28.10. The reaction is conducted in an inert organic solvent such as ether or dichloromethane, in the presence of a base such as dicyclohexylamine or triethylamine. The hydroxyl component R"OH is selected from the group of compounds 28.19 - 28.24 shown in Scheme 28, and similar compounds. For example, if the component R"OH is hydroxybenztriazole 28.19, N-hydroxysuccinimide 28.20, or pentachlorophenol, 28.21, the mixed carbonate 28.10 is obtained by the reaction of the chloroformate with the hydroxyl compound in an ethereal solvent in the presence of dicyclohexylamine, as described in Can. J. Chem., 1982, 60, 976. A similar reaction in which the component R"OH is pentafluorophenol 28.22 or 2-hydroxypyridine 28.23 can be performed in an ethereal solvent in the presence of triethylamine, as described in Syn., 1986, 303, and Chem. Ber. 118, 468, 1985.
Scheme 28 Example 4 illustrates the preparation of carbamates in which an alkyloxycarbonylimidazole 28.8 is employed. In this procedure, a carbinol 28.5 is reacted with an equimolar amount of carbonyl diimidazole 28.11 to prepare the intermediate 28.8. The reaction is conducted in an aprotic organic solvent such as dichloromethane or tetrahydrofuran. The acyloxyimidazole 28.8 is then reacted with an equimolar amount of the amine R'NH2 to afford the carbamate 28.7. The reaction is performed in an aprotic organic solvent such as dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the carbamate 28.7.
Scheme 28, Example 5 illustrates the preparation of carbamates by means of an intermediate alkoxycarbonylbenztriazole 28.13. In this procedure, a carbinol ROH is reacted at ambient temperature with an equimolar amount of benztriazole carbonyl chloride 28.12, to afford the alkoxycarbonyl product 28.13. The reaction is performed in an organic solvent such as benzene or toluene, in the presence of a tertiary organic amine such as triethylamine, as described in Syn., 1977, 704. This product is then reacted with the amine R'NH2 to afford the carbamate 28.7. The reaction is conducted in toluene or ethanol, at from ambient temperature to about 80°C as described in Syn., 1977, 704.
Scheme 28, Example 6 illustrates the preparation of carbamates in which a carbonate (R"O)2CO, 28.14, is reacted with a carbinol 28.5 to afford the intermediate alkyloxycarbonyl intermediate 28.15. The latter reagent is then reacted with the amine R'NHz to afford the carbamate 28.7. The procedure in which the reagent 28.15 is derived from hydroxybenztriazole 28.19 is described in Synthesis, 1993, 908; the procedure in which the reagent 28.15 is derived from N-hydroxysuccinimide 28.20 is described in Tet. Lett., 1992, 2781; the procedure in which the reagent 28.15 is derived from 2-hydroxypyridine 28.23 is described in Tet. Lett., 1991, 4251; the procedure in which the reagent 28.15 is derived from 4-nitrophenol 28.24 is described in Syn. 1993, 103. The reaction between equimolar amounts of the carbinol ROH and the carbonate 28.14 is conducted in an inert organic solvent at ambient temperature.
Scheme 28, Example 7 illustrates the preparation of carbamates from alkoxycarbonyl azides 28.16. in this procedure, an alkyl chloroformate 28.6 is reacted with an azide, for example sodium azide, to afford the alkoxycarbonyl azide 28.16. The latter compound is then reacted with an equimolar amount of the amine R'NHi to afford the carbamate 28.7. The reaction is conducted at ambient temperature in a polar aprotic solvent such as dimethylsulfoxide, for example as described in Syn., 1982, 404.
Scheme 28, Example 8 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and the chloroformyl derivative of an amine. In this procedure, which is described in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, the reactants are combined at ambient temperature in an aprotic solvent such as acetonitrile, in the presence of a base such as triethylamine, to afford the carbamate 28.7. Scheme 28, Example 9 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an isocyanate 28.18. In this procedure, which is described in
Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 645, the reactants are combined at ambient temperature in an aptotic solvent such as ether or dichloromethane and the like, to afford the carbamate 28.7.
Scheme 28, Example 10 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an amine RNHj. In this procedure, which is described in Chem. Lett. 1972, 373, the reactants are combined at ambient temperature in an aprotic organic solvent such as tetrahydrofuran, in the presence of a tertiary base such as triethylamine, and selenium. Carbon monoxide is passed through the solution and the reaction proceeds to afford the carbamate 28.7.
Preparation of phosphonate intermediates 6 and 7 with phosphonate moieties incorporated into the group R2COOH and R3COOH.
The chemical transformations described in Schemes 1-28 illustrate the preparation of compounds 1-5 in which the phosphonate ester moiety is attached to the thiazole substructure, (Schemes 1-3, 9-10, and 11-12), the phenylalanine moiety (Schemes 4-6), and the benzyl moiety (Schemes 7-8).
The various chemical methods employed for the preparation of phosphonate groups can, with appropriate modifications known to those skilled in the art, be applied to the introduction of phosphonate ester groups into the compounds R2COOH and R3COOH, as defined in Charts 2a, 2b and 2c. The resultant phosphonate-containing analogs, designated as R^COOH and R3aCOOH can then, using the procedures described above, be employed in the preparation of the compounds 6 and 7. The procedures required for the introduction of the phosphonate-containing analogs R2aCOOH and R3aCOOH are the same as those described above (Schemes 4, 5, and 28) for the introduction of the R2CO and R3CO moieties.
Indinavir-like phosphonate protease inhibitors (ILPPD Preparation of the intermediate phosphonate esters 1-24.
The structures of the intermediate phosphonate esters 1 to 22 and the structures of the component groups R1, R4, R8, R9', R11, X and X' of this invention are shown in Charts 1-3. The structures of the R2R3NH components are shown in Chart 4; the structures of the amines components R7NHCH(R6)CONHR4 are shown as the structures Al - A16 in Chart 4. The structures of the R5XCH2 groups are shown in Chart 5, and those of the R10CO components are illustrated in Chart 6. The structures of the R7NHCH(R6)COOH components are shown in Chart 10.
Specific stereoisomers of some of the structures are shown in Charts 1 -10; however, all stereoisomers are utilized in the syntheses of the compounds 1 to 24. Subsequent chemical modifications to the compounds 1 to 24, as described herein, permit the synthesis of the final compounds of this invention.
The intermediate compounds 1 to 24 incorporate a phosphonate moiety (R1O)2P(O) connected to the nucleus by means of a variable linking group, designated as "link" in the attached structures. Charts 7, 8 and 9 illustrate examples of the Unking groups present in the structures 1-24.
Schemes 1 - 207 illustrate the syntheses of the intermediate phosphonate compounds of this invention, 1 - 22, and of the intermediate compounds necessary for their synthesis. The preparation of the phosphonate esters 23 and 24, in which a phosphonate moiety is incorporated into one of the groups R2, R3, R5, R10 or R11 is also described below. In compounds 2, 6, 23 and 24 where two groups are the same Chart 4 it is noted that these groups may be independent or identical.
(Figure Remove)Protection of reactive substituents.
Depending on the reaction conditions employed, it may be necessary to protect certain reactive substituents from unwanted reactions by protection before the sequence described, and to deprotect the substituents afterwards, according to the knowledge of one skilled in the art. Protection and deprotection of functional groups are described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990. Reactive substituents which may be protected are shown in the accompanying schemes as, for example, [OH], [SH].
Preparation of the phosphonate ester intermediates 1 in which X is a direct bond.
The intermediate phosphonate esters 1, in which the group A is attached to the aminoindanol
moiety, are prepared as shown in Schemes 1 and 2.
In this procedure, the propionic acid 1.1, or an activated derivative thereof, is reacted with an
aminoindanol derivative 1.2, in which the substituent A is either the group link-P(O)(OR1)2 or
a precursor such as [OH], [SH], [NH], Br, to afford the amide 1.3. The preparation of the
aminoindanol derivatives 1.2 is described in Schemes 133 -137.
The preparation of amides from carboxylic acids and derivatives is described, for example, in
Organic Functional Group Preparations, by S.R.Sandler and W. Karo, Academic Press, 1968,
p. 274. The carboxylic acid is reacted with the amine in the presence of an activating agent,
such as, for example, dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in the
presence of, for example, hydroxybenztriazole, in a non-protic solvent such as, for example,
pyridine, DMF or dichloromethane, to afford the amide.
Alternatively, the carboxylic acid may first be converted into an activated derivative such as
the acid chloride or anhydride, and then reacted with the amine, in the presence of an organic
base such as, for example, pyridine, to afford the amide.
The conversion of a carboxylic acid into the corresponding acid chloride is effected by
treatment of the carboxylic acid with a reagent such as, for example, thionyl chloride or oxalyl
chloride in an inert organic solvent such as dichloromethane.
Preferably, the carboxylic acid 1.1 is reacted with an equimolar amount of the amine 1.2 in the presence of dicyclohexylcarbodiimide and hydroxybenztriazole, in an aprotic solvent such as, for example, tetrahydrofuran, at about ambient temperature, so as to afford the amide product 1.3. The amide is then reacted with 2-(S)glycidyl tosylate 1.4, or an equivalent thereof, such as, for example, 2-(S) glycidyl p-nitrobenzenesulfonate, as described in Tet Lett., 35, 673, 1994. To effect the reaction, the amide 1.3 is first converted into the a-anion, by treatment with a strong base, such as, for example, sodium hydride, potassium tert. butoxide and the like. The anion is then reacted with the epoxide 1.4, or an equivalent, as described above, in an inert solvent such as, for example, dimethylformamide, dioxan and the like. The reaction is conducted at a temperature of from 0°C to -100°C to yield the alkylated product 1.5. Preferably, equimolar amounts of the amide 1.3 and the epoxide 1.4 are dissolved in tetrahydrofuran at about -50°C, and a slight excess of lithium hexamethyldisilylazide is added, as described in WO 9612492 and Tet. Lett., 35, 673, 1994. The temperature is raised to about -25"C to effect stereo selective alkylation and conversion to the epoxide 1.5. The thus-obtained epoxide 1.5 is then subjected to a regiospecific ring-opening reaction with the amine 1.6 to yield the hydroxyamine 1.7. The preparation of hydroxyamines by the reaction between an amine and an epoxide is described, for example, in Organic Functional Group Preparations, by S. R. Sandier and W. Karo, Academic Press, 1968, p. 357. The amine and the epoxide are reacted together in a polar organic solvent such as, for example, dimethylformamide or an alcohol, to effect the ring-opening reaction. Preferably, equimolar amounts of the amine 1.6 and the epoxide 1.5 are heated in isopropanol at reflux for about 24 hours, to prepare the hydroxyamine product 1.7, for example as described in WO 9628439 and Tet. Lett., 35, 673, 1994.
The hydroxyamine product 1.7 is then deprotected to remove the acetonide group and produce the compound 1.8 in which A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Acetonide protecting groups are removed by treatment with an acid, for example acetic acid or dilute hydrochloric acid, optionally in the presence of water and a water-miscible organic solvent such as, for example, tetrahydrofuran or an alcohol. Preferably, the acetonide protecting group is removed by treatment of the acetonide 1.7 with 6N hydrochloric acid in isopropanol at ambient temperature, as described in WO 9612492, to afford the indanol 1.8.
The reactions shown in Scheme 1 illustrate the preparation of the compounds 1.8 in which A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 2 depicts the conversion of the compounds 1.8 in which A is [OH], [SH], [NH], Br, into the compounds 1 in which A is the group link-PCOXOR1^. In this procedure, the compounds 1.7 are converted, using the procedures described below, Schemes 133 -197, into the compounds 2.1. Deprotection, by removal of the acetonide protecting group, as described above, then affords the intermediate phosphonate esters 1 in which X is a direct bond.
In the preceding and following schemes, the conversion of various substituents into the group link-P(O)(OR1)2 can be effected at any convenient stage of the synthetic sequence, or in the final step. The selection of an appropriate step for the introduction of the phosphonate substituent is made after consideration of the chemical procedures required, and the stability of the substrates to those procedures. It may be necessary to protect reactive groups, for example hydroxyl, during the introduction of the group link-P(O)(ORl)2. In the preceding and succeeding examples, the nature of the phosphonate ester group can be varied, either before or after incorporation into the scaffold, by means of chemical transformations. The transformations, and the methods by which they are accomplished, are described below (Scheme 199).
Preparation of the phosphonate ester intermediates 1 in which X is sulfur.
Schemes 3 and 4 illustrate the preparation of the phosphonate esters 1 in which X is sulfur. As shown in Scheme 3, methyl 2-allyl-3-hydroxypropionate 3.1, prepared as described in Tet. Lett., 1973, 2429, is converted into the benzyl ether 3.2. The conversion of alcohols into
benzyl ethers is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 47. The reaction is effected by treatment of the carbinol with a benzyl halide, in the presence of a base such as potassium hydroxide, silver oxide, sodium hydride and the like, in an organic or aqueous organic solvent, optionally in the presence of a phase transfer catalyst. Preferably, the carbinol 3.1 is reacted with benzyl bromide and silver oxide in dimethylformamide at ambient temperature for 48 hours, to afford the product 3.2. The benzyl ether is then subjected to an epoxidation reaction to produce the epoxide 3.3. The conversion of olefins into epoxides is described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 456. The reaction is performed by the use of a peracid such as peracetic acid, m-chloroperbenzoic acid or monoperphthalic acid, optionally in the presence of a base such as potassium carbonate or sodium bicarbonate, or by the use of tert. butyl hydroperoxide, optionally in the presence of a chiral auxiliary such as diethyl tartrate. Preferably, equimolar amounts of the olefin and m-chloroperbenzoic acid are reacted in dichloromethane in the presence of sodium bicarbonate, as described in Tet. Lett., 849, 1965, to afford the epoxide 3.3. This compound is then reacted with the amine 1.6 to yield the hydroxyamine 3.4. The reaction is performed as described above for the preparation of the hydroxyamine 1.7. The hydroxyl substituent is then protected by conversion to the silyl ether 3.5, in which OTBD is tert. butyldimethylsilyloxy. The preparation of silyl ethers is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 77. The reaction is effected by treatment of the carbinol with tert. butylchlorodimethylsilane and a base such as imidazole, dimethylaminopyridine or 2,6-lutidine, in an organic solvent such as dichloromethane or dimethylformamide. Preferably, equimolar amounts of the carbinol, tert. butylchlorodimethylsilane and imidazole are reacted in dimethylformamide at ambient temperature to give the silyl ether 3.5, The benzyl ether is then removed to afford the carbinol 3.6. The removal of benzyl protecting groups is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 49. The conversion is effected by means of catalytic hydrogenation over a palladium catalyst, with hydrogen or a hydrogen transfer agent, or by electrolytic reduction, by treatment with trimethylsilyl iodide, or by the use of a Lewis acid such as boron trifluoride or stannic chloride, or by oxidation with ferric chloride or ruthenium dioxide. Preferably, the benzyl ether is removed by reaction of the substrate with 5% palladium on carbon catalyst and ammonium formate in refluxing methanol, as described in Synthesis, 76, 1985. The resultant
carbinol 3.6 is then converted into the mesylate ester 3.7 by reaction with one molar equivalent of methanesulfonyl chloride or anhydride, in an organic solvent such as dichloromethane, and in the presence of a base such as dimethylaminopyridine or diisopropylethylamine. The product 3.7 is then reacted with the tniol R5SH, to prepare the thioether 3.9. The preparation of thioethers by alkylation of thiols is described in Synthetic Organic Chemistry, by R. B. Wagner, H. D. Zook, Wiley, 1953, p. 787. The reaction is effected by treatment of the thiol with a base such as sodium hydroxide, potassium carbonate or diazabicyclononene, in a solvent such as ethanol or dioxan, in the presence of the mesylate 3.7, to afford the product
3.9. The methyl ester moiety present in the latter compound is then hydrolyzed to give the
carboxylic acid 3.10. The transformation is effected hydrolyticaUy, for example by the use of
an alkali metal hydroxide in an aqueous organic solvent, or enzymicaUy, for example by the
use of porcine liver esterase, as described in J. Am. Chem. Soc., 104, 7294, 1982. Preferably,
the ester group is hydrolyzed by treatment of the ester 3.9 with one molar equivalent of
lithium hydroxide in aqueous methanol at ambient temperature, to give the carboxylic acid
3.10. The latter compound is then reacted, as described above, with the aminoindanol
acetonide 1.3 to give the amide 3.11. Removal of the acetonide group, as described above,
with concomitant desilylation, then affords the hydroxyamide 3.12.
The reactions shown in Scheme 3 illustrate the preparation of the compounds 3.12 in which A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 4 depicts the conversion of the compounds 3.11 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 1 in which X is sulfur. In this procedure, the compounds 3.11 are converted, using the procedures described below, Schemes 133 -197, into the compounds 4.1. Deprotection, by removal of the acetonide protecting group, as described above, then affords the intermediate phosphonate esters 1 in which X is sulfur.
Preparation of the phosphonate ester intermediates 2 in which X is a direct bond.
Schemes 5 and 6 illustrate the preparation of the phosphonate esters 2 in which X is a direct bond. As shown in Scheme 5, the substituted phenyl propionic ester 5.1, in which the substituent A is either the group link-P(O)(OR')2 or a precursor such as [OH], [SH], [NH], Br, is reacted with the glycidyl tosylate 1.4 to afford the alkylated product 5.2. The preparation of the phenylpropionic esters 5.1 is described below, (Schemes 138 -143). The reaction is performed as described above for the preparation of the oxirane 1.5. The product 5.2 is then reacted with the amine R2R3NH (1.6) to yield the hydroxyamine 5.3. The reaction is performed as described above for the preparation of the hydroxyamine 1.7. The secondary hydroxy group is then protected, for example by conversion to the tert. butyldimethyl silyl ether 5.4, using the conditions described above for the preparation of the silyl ether 3.5. The methyl ester is then hydrolyzed to produce the carboxylic acid 5.5, using the conditions described above for the hydrolysis of the methyl ester 3.9. The carboxylic acid is then coupled with the amine 1.6 to give the amide 5.6. The reaction is effected under the conditions described above for the preparation of the amide 1.3. The product is desilylated, for example by treatment with 1M tetrabutyl ammonium fluoride in tetrahydrofuran, as described in J. Am. Chera Soc., 94, 6190, 1972, to give the carbinol 5.7.
The reactions shown in Scheme 5 illustrate the preparation of the compounds 5.7 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br, as described herein. Scheme 6 depicts the conversion of the compounds 5.7 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 2 in which X is a direct bond. In this procedure, the compounds 5.7 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 2.
Preparation of the phosphonate ester intermediates 2 in which X is sulfur.
Schemes 7 and 8 illustrate the preparation of the phosphonate esters 2 in which X is sulfiir. As shown in Scheme 7, the mesylate 3.7 is reacted with the thiophenol 7.1, in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br, to afford the thioether 7.2. The reaction is performed under the same conditions as described above for the preparation of the thioether 3.9. The preparation of the thiophenols 7.2 is described in Schemes 144 -153. The product 7.2 is then transformed, using the sequence of reactions described above for the conversion of the ester 5.4 into the aminoamide 5.7, into the aminoamide 7.3.
The reactions shown in Scheme 7 illustrate the preparation of the compounds 7.3 in which the substituent A is either the group link-P(O)(OR')2 or a precursor such as [OH], [SH], [NH], Br. Scheme 8 depicts the conversion of the compounds 7.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 2 in which X is sulfur. In this procedure, the compounds 7.3 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 2.
Preparation of the phosphonate ester intermediates 3 in which X is a direct bond.
Schemes 9 and 10 illustrate the preparation of the phosphonate esters 3 in which X is a direct bond. As shown in Scheme 9, the methyl ester 9.1 is reacted, as described above, (Scheme 1) with the epoxide 1.4 to afford the alkylated ester 9.2. The product is then reacted with the amine 9.3, in which the substituent A is either the group link-P(O)(OR1)a or a precursor, to yield the hydroxyamine 9.4. The preparation of the tert. butylamine derivatives 9.3 is described below, (Schemes 154 -158). The hydroxyamine is then transformed, using the sequence of reactions described above for the conversion of the aminoester 5.3 into the aminoamide 5.7, into the aminoamide 9.5.
The reactions shown in Scheme 9 illustrate the preparation of the compounds 9.5 in which the substituent A is either the group link-P(O)(OR')2 or a precursor such as [OH], [SH], [NH], Br. Scheme 10 depicts the conversion of the compounds 9.5 in which A is [OH], [SH], [NH],
Br, into the phosphonate esters 3 in which X is a direct bond. In this procedure, the compounds 9.5 are converted, using the procedures described below, Schemes 133 -197, into the compounds 3.
Preparation of the phosphonate ester intermediates 3 in which X is sulfur.
Schemes 11 and 12 illustrate the preparation of the phosphonate esters 3 in which X is sulfur. As shown in Scheme 11, the benzyl-protected oxirane 3.3 is reacted, as described above, with the substituted tert. butylamine 9.3 to afford the hydroxyamine 11.1. The product is then converted, using the sequence of reactions shown in Scheme 5 for the conversion of the hydroxyamine 5.3 into the aminoamide 5.7, into .the aminoamide 11.2.
The reactions shown in Scheme 11 illustrate the preparation of the compounds 11.2 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 12 depicts the conversion of the compounds 11.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 3 in which X is sulfur. In this procedure, the compounds 11.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 3.

(Figure Remove)Preparation of the phosphonate ester intermediates 4 in which X is a direct bond.
Schemes 13 and 14 illustrate the preparation of the phosphonate esters 4 in which X is a direct bond. As shown in Scheme 13, the oxirane 9.2 is reacted, as described in Scheme 1, with the pyridyl piperazine derivative 13.1 to produce the hydroxyamine 13.2. The preparation of the pyridyl piperazine derivatives 13.1 is described in Schemes 159 -164. The product is then transformed, as described previously, (Scheme 5) into the amide 13.3.
The reactions shown in Scheme 13 illustrate the preparation of the compounds 13.3 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH], [SH], [NH], Br. Scheme 12 depicts the conversion of the compounds 13.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 4 in which X is a direct bond. In this procedure, the compounds 13.3 are converted, using the procedures described below, Schemes 133 -197, into the compounds 4.
Preparation of the phosphonate ester intermediates 4 in which X is sulfur.
Schemes 15 and 16 illustrate the preparation of the phosphonate esters 4 in which X is sulfur. As shown in Scheme 15, the benzyl-protected oxirane 3.3 is reacted, as described above, with the pyridyl piperazine derivative 13.1 to afford the hydroxyamine 15.1. The product is then converted, as described above (Scheme 5) into the aminoamide 15.2.
The reactions shown in Scheme 15 illustrate the preparation of the compounds 15.2 in which the substituent A is either the group link-P(0)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 16 depicts the conversion of the compounds 15.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 4 in which X is sulfur. In this procedure, the compounds 15.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 4.
Preparation of the phosphonate ester intermediates 5 in which X is a direct bond.
Schemes 17 and 18 illustrate the preparation of the phosphonate esters 5 in which X is a direct bond. As shown in Scheme 17, the oxirane 9.2 is reacted, as described in Scheme 1, with the decahydroisoquinoline derivative 17.1 to produce the hydroxyamine 17.2. The preparation of the decahydroisoquinoline derivatives 17.1 is described in Schemes 192 -197. The product is then transformed, as described previously, (Scheme 3) into the amide 17.3.
The reactions shown in Scheme 17 illustrate the preparation of the compounds 17.3 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 18 depicts the conversion of the compounds 17.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 5 in which X is a direct bond. In this procedure, the compounds 17.3 are converted, using the procedures described below, Schemes 133 -197, into the compounds 5.
Preparation of the phosphonate ester intermediates 5 in which X is sulfur.
Schemes 19 and 20 illustrate the preparation of the phosphonate esters 5 in which X is sulfur. As shown in Scheme 19, the benzyl-protected oxirane 3.3 is reacted, as described above, with the decahydroisoquinoline derivative 17.1 to afford the hydroxyamine 19.1. The product is then converted, as described above (Scheme 5) into the aminoamide 19.2.
The reactions shown in Scheme 19 illustrate the preparation of the compounds 19.2 in which the substituent A is either the group link-P(O)(ORI)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 20 depicts the conversion of the compounds 19.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 5 in which X is sulfur. In this procedure, the compounds 19.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 5.
Preparation of the phosphonate ester intermediates 6 in which X is a direct bond.
Schemes 21 and 22 illustrate the preparation of the phosphonate esters 6 in which X is a direct bond. As shown hi Scheme 21, the glycidyl tosylate 1.4 is reacted, as described in Scheme 5, with the anion of the dimethoxyphenyl propionic ester 21.1 to afford the alkylated product 21.2. The preparation of the dimethoxyphenyl propionic ester derivatives 21.1 is described in Scheme 186. The product is then transformed, as described previously, (Scheme 5) into the amide 21.3.
The reactions shown in Scheme 21 illustrate the preparation of the compounds 21.3 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 22 depicts the conversion of the compounds 21.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 6 in which X is a direct bond. In this procedure, the compounds 21.3 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 6.
Preparation of the phosphonate ester intermediates 6 in which X is sulfur.
Schemes 23 and 24 illustrate the preparation of the phosphonate esters 6 in which X is sulfur. As shown in Scheme 23, the mesylate 3.7 is reacted, as described in Scheme 3, with the dimethoxyphenyl mercaptan 23.1 to yield the thioether 23.2. The preparation of the substituted thiols 23.1 is described below in Schemes 170 -173. The product is then converted, as described above (Scheme 5) into the aminoamide 23.3.
The reactions shown in Scheme 23 illustrate the preparation of the compounds 23.3 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 24 depicts the conversion of the compounds 23.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 6 in which X is sulfur, hi this procedure, the compounds 23.3 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 6.
Preparation of the phosphonate ester intermediates 7 in which X is a direct bond.
Schemes 25 and 26 illustrate the preparation of the phosphonate esters 7 in which X is a direct bond. As shown in Scheme 25, the oxirane 9.2 is reacted, as described above (Scheme 1) with the amine 1.6 to afford the hydroxyamine 25.1. The product is then converted into the silyl ether 25.2, using the procedures described in Scheme 3. The methyl ester is then hydrolyzed to give the carboxylic acid 25.3, and this compound is then coupled with the tert. butylamine derivative 25.4, using the procedures described in Scheme 1, to yield the amide 25.5. The preparation of the tert. butylamine derivatives 25.4 is described in Schemes 154 -157. Desilylation then produces the hydroxyamide 25.6.
The reactions shown in Scheme 25 illustrate the preparation of the compounds 25.6 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH], [SH], [NH], Br. Scheme 26 depicts the conversion of the compounds 25.6 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 7 in which X is a direct bond. In this procedure, the compounds 25.6 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 7.
Preparation of the phosphonate ester intermediates 7 in which X is sulfur.
Schemes 27 and 28 illustrate the preparation of the phosphonate esters 7 in which X is sulfur. As shown in Scheme 27, the carboxylic acid 3.10 is coupled, as described in Scheme 3, with the tert. butylamine derivative 25.4 to yield the amide product 27.1. The product is then desilylated, as described above, to afford the amide 27.2.
The reactions shown in Scheme 27 illustrate the preparation of the compounds 27.2 in which the substituent A is either the group link-PCOXOR1)! or a precursor such as [OH], [SH], [NH], Br. Scheme 28 depicts the conversion of the compounds 27.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 7 in which X is sulfur. In this procedure, the compounds 27.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 7.
Preparation of the phosphonate ester intermediates 8 in which X is a direct bond.
Schemes 29 and 30 illustrate the preparation of the phosphonate esters 8 in which X is a direct bond. As shown in Scheme 29, the silylated carboxylic acid 25.3 is coupled, as described above, (Scheme 1) with the amine 29.1 to afford the amide 29.2 which upon desilylation produces the hydroxyamide 29.3. The preparation of the ethanolamine derivatives 29.1 is described in Schemes 174 -178.
The reactions shown in Scheme 29 illustrate the preparation of the compounds 29.3 in which the substituent A is either the group link-PCOXOR1)^ or a precursor such as [OH], [SH], [NH], Br. Scheme 30 depicts the conversion of the compounds 29.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 8 in which X is a direct bond. In this procedure, the compounds 29.3 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 8.
Preparation of the phosphonate ester intermediates 8 in which X is sulfur.
Schemes 31 and 32 illustrate the preparation of the phosphonate esters 8 in which X is sulfur. As shown in Scheme 31, the carboxylic acid 3.10 is coupled, as described previously, with the ethanolamine derivative 29.1 to yield the amide; the product is then desilylated, as described above, to afford the hydroxyamide 31.1.
The reactions shown in Scheme 31 illustrate the preparation of the compounds 31.1 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH], [SH], [NH], Br. Scheme 32 depicts the conversion of the compounds 31.1 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 8 in which X is sulfur. In this procedure, the compounds 31.1 are converted, using the procedures described below, Schemes 133 -197, into the compounds 8.
Preparation of the phosphonate ester intermediates 9 in which X is a direct bond.
Schemes 33 and 34 illustrate the preparation of the phosphonate esters 9 in which X is a direct bond. As shown in Scheme 33, the silylated carboxylic acid 25.3 is coupled, as described above, (Scheme 1) with the chroman amine 33.1 to afford the corresponding amide, which upon desilylation produces the hydroxyamide 33.2. The preparation of the chroman amines 33.1 is described in Schemes 179 - 181a.
The reactions shown in Scheme 33 illustrate the preparation of the compounds 33.2 in which the substituent A is either the group link-P(O)(ORl)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 34 depicts the conversion of the compounds 33.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 9 in which X is a direct bond. In this procedure, the compounds 33.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 9.
Preparation of the phosphonate ester intermediates 9 in which X is sulfur.
Schemes 35 and 36 illustrate the preparation of the phosphonate esters 9 in which X is sulfur. As shown in Scheme 35, the carboxylic acid 3.10 is coupled, as described previously, with the chroman amine 33.1 to yield the amide; the product is then desilylated, as described above, to afford the amide 35.1.
The reactions shown in Scheme 35 illustrate the preparation of the compounds 35.1 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 36 depicts the conversion of the compounds 35.1 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 9 in which X is sulfur. In this procedure, the compounds 35.1 are converted, using the procedures described below, Schemes 133 -197, into the compounds 9.
Preparation of the phosphonate ester intermediates 10 in which X is a direct bond.
Schemes 37 and 38 illustrate the preparation of the phosphonate esters 10 in which X is a direct bond. As shown in Scheme 37, the silylated carboxylic acid 25.3 is coupled, as described above, (Scheme 1) with the phenylalanine derivative 37.1 to afford the corresponding amide, which upon desilylation produces the hydroxyamide 37.2. The preparation of the phenylalanine derivatives 37.1 is described in Schemes 182 - 185.
The reactions shown in Scheme 37 illustrate the preparation of the compounds 37.2 in which the substituent A is either the group link-P(O)(OR')2 or a precursor such as [OH], [SH], [NH], Br. Scheme 38 depicts the conversion of the compounds 37.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 10 in which X is a direct bond. In this procedure, the compounds 37.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 10.
Preparation of the phosphonate ester intermediates 10 in which X is sulfur.
Schemes 39 and 40 illustrate the preparation of the phosphonate esters 10 in which X is sulfur. As shown in Scheme 39, the carboxylic acid 3.10 is coupled, as described previously, with the phenylalanine derivative 37.1 to yield the corresponding amide; the product is then desilylated, as described above, to afford the amide 39.1.
The reactions shown in Scheme 39 illustrate the preparation of the compounds 39.1 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 40 depicts the conversion of the compounds 39.1 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 10 in which X is sulfur. In this procedure, the compounds 39.1 are converted, using the procedures described below, Schemes 133 -197, into the compounds 10.
Preparation of the phosphonate ester intermediates 11 in which X is a direct bond.
Schemes 41 and 42 illustrate the preparation of the phosphonate esters 11 in which X is a direct bond. As shown in Scheme 41, the silylated carboxylic acid 25.3 is coupled, as described above, (Scheme 1) with the decahydroisoquinoline carboxamide 41.1, prepared as described in Scheme 158, to afford the corresponding amide, which upon desilylation produces the hydroxyamide 41.2.
The reactions shown in Scheme 41 illustrate the preparation of the compounds 41.2 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 42 depicts the conversion of the compounds 41.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 11 in which X is a direct bond. In this procedure, the compounds 41.2 are converted, using the procedures described below, Schemes 133 -197, into the compound
Preparation of the phosphonate ester intermediates 11 in which X is sulfur.
Schemes 43 and 44 illustrate the preparation of the phosphonate esters 11 in which X is sulfur. As shown in Scheme 43, the carboxylic acid 3.10 is coupled, as described previously, with the decahydroisoquinoline carboxamide 41.1 to yield the corresponding amide; the product is then desilylated, as described above, to afford the amide 43.1.
The reactions shown in Scheme 43 illustrate the preparation of the compounds 43.1 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 44 depicts the conversion of the compounds 43.1 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 11 in which X is sulfur. In this procedure, the compounds 43.1 are converted, using the procedures described below, Schemes 133 -197, into the compounds 11.Preparation of the phosphonate ester intermediates 12 in which X is a direct bond.
Schemes 45 and 46 illustrate the preparation of the phosphonate esters 12 in which X is a 5 direct bond. As shown in Scheme 45, the silylated carboxylic acid 25.3 is coupled, as described above, (Scheme 1) with the decahydroisoquinoline derivative 45.1 to afford the
corresponding amide, which upon desilylation produces the hydroxyamide 45.2. The preparation of the decahydroisoquinoline derivatives 45.1 is described in Schemes 192 -197.
The reactions shown in Scheme 45 illustrate the preparation of the compounds 45.2 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 46 depicts the conversion of the compounds 45.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 12 in which X is a direct bond. In this procedure, the compounds 45.2 are converted, using the procedures described below. Schemes 133 -197, into the compounds 12.
Preparation of the phosphonate ester intermediates 12 in which X is sulfur.
Schemes 47 and 48 illustrate the preparation of the phosphonate esters 12 in which X is sulfur. As shown in Scheme 47, the carboxylic acid 3.10 is coupled, as described previously, with the decahydroisoquinoline derivative 45.1 to yield the corresponding amide; the product is then desilylated, as described above, to afford the amide 47.1.
The reactions shown in Scheme 47 illustrate the preparation of the compounds 47.1 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 48 depicts the conversion of the compounds 47.1 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 12 in which X is sulfur. In this procedure, the compounds 47.1 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 12.
Preparation of the phosphonate ester intermediates 13 in which X and X1 are direct bonds.
Schemes 49 and 50 illustrate the preparation of the phosphonate esters 12 in which X and X' are direct bonds. As shown in Scheme 49, a BOC-protected aminoacid 49.1 is converted into the corresponding aldehyde 49.2. A number of methods are known for the conversion of carboxylic acids and derivatives into the corresponding aldehydes, for example as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 619-627. The
conversion is effected by direct reduction of the carboxylic acid, for example employing diisobutyl aluminum hydride, as described in J. Gen. Chem. USSR., 34, 1021, 1964, or alkyl borane reagents, for example as described in J. Org. Chem., 37, 2942, 1972. Alternatively, the carboxylic acid is converted into an amide, such as the N-methoxy N-methyl amide, and the latter compound is reduced with lithium aluminum hydride, for example as described in J. Med. Chem., 1994, 37, 2918, to afford the aldehyde. Alternatively, the carboxylic acid is reduced to the corresponding carbinol which is then oxidized to the aldehyde. The reduction of carboxylic acids to carbinols is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 548ff. The reduction reaction is performed by the use of reducing agents such as borane, as described in J. Am. Chem. Soc., 92, 1637, 1970, or by lithium aluminum hydride, as described in Org. Reac., 6, 649, 1951. The resultant carbinol is then converted into the aldehyde by means of an oxidation reaction. The oxidation of a carbinol to the corresponding aldehyde is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 604ff. The conversion is effected by the use of oxidizing agents such as pyridinium chlorochromate, as described in J.Org. Chem., 50, 262, 1985, or silver carbonate, as described in Compt. Rend. Ser. C., 267, 900, 1968, or dimethyl sulfoxide/acetic anhydride, as described in J. Am. Chem. Soc., 87, 4214, 1965. Preferably, the procedure described in EP 708085 is employed. The carboxylic acid 49.1 is first reacted with equimolar amounts of isobutyl chloroformate and triethylamine in tetrahydrofuran, to afford a mixed anhydride which is then reduced by treatment with sodium borohydride in aqueous tetrahydrofuran at ambient temperature to afford the carbinol 49.2. The carbinol is then oxidized to the aldehyde 49.3 by reaction with oxalyl chloride and dimethylsulfoxide in dichloromethane at -60°C, as described in EP708085. To transform the aldehyde into the hydroxyester 49.5, ethyl 3-iodopropionate 49.4 is reacted first with a zinc-copper couple, prepared as described in Org. Syn. Coll. Vol. 5, 855, 1973, and the product is then reacted with trichlorotitanium isopropoxide, as described in EP 708085. The resultant reagent is then treated with the aldehyde 49.3 in dichloromethane at -20°C to yield the hydroxyester 49.5. The hydroxyester is then cyclized to the lactone 49.6 by treatment with acetic acid in toluene at 100°C, as described in EP 708085. A number of alternative preparations of the lactone 49.6 are known, for example as described in J. Org. Chem., 1985, 50, 4615, J. Org. Chem., 1995, 60, 7927 and J. Org. Chem., 1991, 56, 6500. The lactone 49.6 is then reacted with a substituted benzyl iodide 49.7 to afford the alkylated product 49.8.
The preparation of the benzyl halides 49.7 is described below, (Schemes 165 -169). The alkylation reaction is performed in an aprotic organic solvent such as dimethylformamide or tetrahydrofuran, in the presence of a strong base such as sodium hydride or lithium hexamethyl disilylazide. Preferably, the lactone is first reacted with lithium bis(trimethylsilyl)amide in a mixture of tetrahydrofuran and 1,3-dimethyltetrahydropyrimidinone, and then ethyl 3-iodopropioinate is added, as described in EP 708085, to prepare the alkylated lactone 49.8. The lactone is then converted into the corresponding hydroxyacid 49.9 by alkaline hydrolysis, for example by treatment with lithium hydroxide in aqueous dimethoxyethane, as described in EP 708085. The hydroxyacid is then converted into the tert. butyldimethylsilyl ether 49.10, by reaction with excess chloro tert. butyldimethylsilane and imidazole in dimethylformainide, followed by alkaline hydrolysis, employing potassium carbonate in aqueous methanolic tetrahydrofuran, as described in EP 708085, to yield the silyl ether 49.10. The carboxylic acid is then coupled, as described above (Scheme 5) with the amine R2R3NH to afford the amide product 49.11. The BOC protecting group is then removed to give the free amine 49.12. The removal of BOC protecting groups is described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 328. The deprotection can be effected by treatment of the BOC compound with anhydrous acids, for example, hydrogen chloride or trifluoroacetic acid, or by reaction with trimethylsilyl iodide or aluminum chloride. Preferably, the BOC protecting group is removed by treatment of the substrate with 3M hydrogen chloride in ethyl acetate, as described in J. Org. Chera, 43, 2285, 1978, a procedure which also removes the silyl protecting group to afford the hydroxy amine 49.12. The latter compound is then coupled with the carboxylic acid R10COOH, or a functional equivalent thereof, to give the amide or carbamate product 49.13. The preparation of amides by the reaction between amines and amides is described above (Scheme 1). Compounds in which the group R10 is alkoxy are carbamates; the preparation of carbamates is described below (Scheme 198)
The reactions shown in Scheme 49 illustrate the preparation of the compounds 49.13 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 50 depicts the conversion of the compounds 49.13 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 13 in which X and X' are direct bonds. In this procedure, the compounds 49.13 are converted, using the procedures described below, Schemes 133 -197, into the compounds 13.
Preparation of the phosphonate ester intermediates 13 in which X is a direct bond and X' is sulfur.
Schemes 51 and 52 illustrate the preparation of the phosphonate esters 13 in which X is a direct bond and X' is sulfur. In this procedure, BOC serine methyl ester mesylate, 51.1, the preparation of which is described in Synlett., 1997, 169, is reacted with the thiol 51.2, employing the conditions described in Scheme 3, to prepare the thioether 51.3. The methyl ester group is then transformed into the corresponding aldehyde 51.4. The reduction of esters to aldehydes is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 621. The conversion is effected by treatment with diisobutyl aluminum hydride, sodium aluminum hydride, lithium tri-tertiary butoxy aluminum hydride and the like. Preferably, the ester 51.3 is reduced to the aldehyde 51.4 by reaction with the stoichiometric amount of diisobutyl aluminum hydride in toluene at -80°C, as described in Syn., 617, 1975. The aldehyde is then transformed into the diamide 51.5, using the sequence of reactions and reaction conditions described above (Scheme 49) for the conversion of the aldehyde 49.3 into the diamide 49.13.
The reactions shown in Scheme 51 illustrate the preparation of the compounds 51.5 in which the substituent A is either the group link-P(O)(OR!)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 52 depicts the conversion of the compounds 51.5 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 13 in which X is a direct bond and X1 is sulfur. In this procedure, the compounds 51.5 are converted, using the procedures described below, Schemes 133 -197, into the compounds 13.
Preparation of the phosphonate ester intermediates 13 in which X and X' are sulfur.
Schemes 53, 54 and 55 illustrate the preparation of the phosphonate esters 13 in which X and X' are sulfur. As shown in Scheme 53, the aldehyde 51.4 is reacted with the dianion of N-methylmethacrylamide 53.1 to form the hydroxyamide 53.2. The dianion is generated by treatment of N-rnethylmethacrylarnide with two equivalents of an alkyllithium, for example n-butyllithium, in an organic solvent such as tetrahydrofuran or dimethoxyethane, as described in J. Org. Chem., 1986, 51, 3921. The dianion is then reacted with the aldehyde in the presence
of chlorotitanium triisopropoxide, to afford the olefinic amide 53.2. The product is cyclized to produce the methylene lactone 53.3 by heating in an inert solvent such as xylene, at reflux temperature, as described in J. Org. Chem., 1986, 51, 3921. The methylene lactone is then reacted with the thiol 53.4 to yield the thioether 53.5. The preparation of the thiols 53.4 is described below, (Schemes 170 - 173). The addition of thiols to methylene lactones analogous to the compound 53.3 is described in J. Org. Chem., 1986, 51, 3921. Equimolar amounts of the reactants are combined in an alcoholic solvent such as methanol at about 60°C, in the presence of a tertiary base such as triethylamine, to give the addition product 53.5. The latter compound is then subjected to basic hydrolysis, for example by reaction with lithium hydroxide, as described above, (Scheme 49) to produce the hydroxyacid 53.6. The product is silylated, as described in Scheme 49, to give the silylated carbinol 53.7, and the product is then converted, as described in Scheme 49, into the diamide 53.8.
Scheme 54 illustrates an alternative method for the preparation of the diamides 53.8. In this procedure, the anion of the lactone 54.1, obtained as an intermediate in the conversion of the aldehyde 51.4 into the diamide 51.5, (Scheme 51) is reacted with formaldehyde or a functional equivalent thereof, to afford the hydroxymethyl compound 54.2. The generation of the anion of lactones analogous to 54.1, and alkylation thereof, is described above in Scheme 49. Preferably, the anion is prepared by reaction of the lactone, in a solvent mixture composed of tetrahydrofuran and 1,3-dimethyltetrahydropyrimidinone, with lithium bis(trimethylsilyl)amide, as described in EP 708085, and formaldehyde, generated by pyrolysis of paraformaldehyde, is then introduced in an inert gas stream. The hydroxymethyl product is then converted into the corresponding mesylate 54.3, by reaction with methanesulfonyl chloride in dichloromethane containing a tertiary base such as triethylamine or dimethylaminopyridine, and the mesylate is then reacted with the thiol reagent 53.4, using the procedure described above for the preparation of the thioether 51.3, to yield the thioether 53.5. The product is then transformed, as described above, into the diamide 53.8.
The reactions shown in Schemes 53 and 54 illustrate the preparation of the compounds 53.8 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 55 depicts the conversion of the compounds 53.8 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 13 in which X and X' are sulfur. In this
procedure, the compounds 53.8 are converted, using the procedures described below, Schemes 133 -197, into the compounds 13.
Scheme 45


Preparation of the phosphonate ester intermediates 13 in which X is sulfur and X' is a direct bond.
Schemes 56 and 57 illustrate the preparation of the phosphonate esters 13 in which X is sulfur and X' is a direct bond. In this procedure, the BOC-protected aldehyde 49.3 is converted, as described in Scheme 53, into the methylene lactone 56.1. The lactone is then reacted with the thiol 53.4 and a base, as described in Scheme 53, to yield the thioether 56.2. The thioether is then transformed, as described in Scheme 53, into the diamide 56.3.
The reactions shown in Scheme 56 illustrate the preparation of the compounds 56.3 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 57 depicts the conversion of the compounds 56.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 13 in which X is sulfur and X1 is a direct bond. In this procedure, the compounds 56.3 are converted, using the procedures described below, Schemes 133 -197, into the compounds 13.
Preparation of the phosphonate ester intermediates 14 in which X and X' are direct bonds.
Schemes 58 and 59 illustrate the preparation of the phosphonate esters 14 in which X and X1 are direct bonds. In this procedure, the lactone 49.6 is reacted, as described in Scheme 49, with a substituted benzyl iodide 58.1, to produce the alkylated compound 58.2. The preparation of the benzyl iodides 58.1 is described in Schemes 187 -191. The product is then transformed, as described in Scheme 49, into the diamide 58.3.
The reactions shown in Scheme 58 illustrate the preparation of the compounds 58.3 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 59 depicts the conversion of the compounds 58.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 14 in which X and X' are direct bonds. In this procedure, the compounds 58.3 are converted, using the procedures described below, Schemes 133 -197, into the compounds 14.
Preparation of the phosphonate ester intermediates 14 in which X is a direct bond and X' is sulfur.
Schemes 60 and 61 illustrate the preparation of the phosphonate esters 14 in which X is a direct bond and X' is sulfur. In this procedure, the lactone 54.1 is reacted, as described in Scheme 49, with a substituted benzyl iodide 58.1, to produce the alkylated compound 60.1. The product is then transformed, as described in Scheme 49, into the diamide 60.2.
The reactions shown in Scheme 60 illustrate the preparation of the compounds 60.2 in which the substituent A is either the group link-P(O)(ORl)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 61 depicts the conversion of the compounds 60.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 14 in which X is a direct bond and X' is sulfur. In this procedure, the compounds 60.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 14.
Preparation of the phosphonate ester intermediates 14 in which X and X' are sulfur.
Schemes 62, 63 and 64 illustrate the preparation of the phosphonate esters 14 in which X and X' are sulfur. As shown in Scheme 62, the methylene lactone 53.3 is reacted, as described in Scheme 53, with a substituted thiophenol 62.1 to produce the addition product 62.2. The preparation of the substituted thiophenols 62.1 is described below, (Schemes 144 -153). The product is then transformed, as described in Scheme 53, into the diamide 62.3.
Scheme 63 illustrates an alternative method for the preparation of the diamide 62.3. In this procedure, the mesylate 54.3 is reacted, as described in Scheme 54, with the thiol 62.1 to afford the alkylation product 63.1. The product is then transformed, as described in Scheme 53, into the diamide 62.3.
The reactions shown in Schemes 62 and 63 illustrate the preparation of the compounds 62.3 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 64 depicts the conversion of the compounds 62.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 14 in which X and X' are sulfur. In this procedure, the compounds 62.3 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 14.
Preparation of the phosphonate ester intermediates 14 in which X is sulfur and X1 is a direct bond.
Schemes 65 and 66 illustrate the preparation of the phosphonate esters 14 in which X is sulfur and X' is a direct bond. In this procedure, the methylene lactone 56.1 is reacted, as described in Scheme 53, with a substituted thiophenol 62.1, to produce the thloether 65.1. The product is then transformed, as described in Scheme 53, into the diamide 65.2.
The reactions shown in Scheme 65 illustrate the preparation of the compounds 65.2 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 66 depicts the conversion of the compounds 65.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 14 in which X is sulfur and X' is a direct bond. In this procedure, the compounds 65.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 14.
Preparation of the phosphonate ester intermediates 15 in which X and X' are direct bonds.
Schemes 67 and 68 illustrate the preparation of the phosphonate esters 15 in which X and X' are direct bonds. In this procedure, the BOC-protected phenylalanine derivative 67.1 is converted into the corresponding aldehyde 67.2, using the procedures described above (Scheme 49). The preparation of the phenylalanine derivatives 67.1 is described below, (Schemes 182 -184 ). The aldehyde is then converted, using the procedures described in Scheme 49, into the lactone 67.3. The latter compound is then alkylated, as described in Scheme 49, with the reagent R5CH2I, (67.4), to afford the alkylated product 67.5. This compound is then converted, as described in Scheme 49, into the diamide 67.6.
The reactions shown in Scheme 67 illustrate the preparation of the compounds 67.6 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 68 depicts the conversion of the compounds 67.6 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 15 in which X and X' are direct bonds. In this
procedure, the compounds 67.6 are converted, using the procedures described below, Schemes 133 -197, into the compounds 15.


Preparation of the phosphonate ester intermediates 15 in which X is a direct bond and X' is sulfur.
Schemes 69 and 70 illustrate the preparation of the phosphonate esters 15 in which X is a direct bond and X' is sulfur. In this procedure, the mesylate 51.1 is reacted, as described in Scheme 51, with the thiophenol derivative 69.1. The preparation of the thiophenol derivatives 69.1 is described below, Schemes 144 - 153. The product is then converted, as described in Scheme 51, into the corresponding aldehyde 69.3, and the latter compound is then transformed, as described in Scheme 49, into the lactone 69.4. The lactone is then alkylated, as described in Scheme 49, with the reagent R5CH2I, (67.4), to afford the alkylated product 69.5. This compound is then converted, as described in Scheme 49, into the diamide 69.6.
The reactions shown in Scheme 69 illustrate the preparation of the compounds 69.6 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH], [SH], [NH], Br. Scheme 70 depicts the conversion of the compounds 69.6 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 15 in which X is a direct bond and X' is sulfur. In this procedure, the compounds 69.6 are converted, using the procedures described below, Schemes 133 -197, into the compounds 15.
Preparation of the phosphonate ester intermediates 15 in which X and X' are sulfur.
Schemes 71, 72 and 73 illustrate the preparation of the phosphonate esters 15 in which X and X1 are sulfur. As shown in Scheme 71, the aldehyde 69.3 is converted, as described in Scheme 53, into the methylene lactone 71.1. The lactone is then reacted, as described in Scheme 53, with the thiol reagent 71.2 to yield the thioether product 71.3. The product is then transformed, as described in Scheme 53, into the diamide 71.4.
Scheme 72 illustrates an alternative method for the preparation of the diamide 71.4. In this procedure, the lactone 69.4 is reacted, as described in Scheme 54, with formaldehyde or a formaldehyde equivalent, to afford the hydroxymethyl product 72.1. The product is then transformed, by mesylation followed by reaction of the mesylate with the thiol reagent 71.2, using the procedures described in Scheme 53, into the thioether 71.3.The latter compound is then converted, as described in Scheme 53, into the diamide 71.4.
The reactions shown in Schemes 71 and 72 illustrate the preparation of the compounds 71.4 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 73 depicts the conversion of the compounds 71.4 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 15 in which X and X' are sulfur. In this procedure, the compounds 71.4 are converted, using the procedures described below, Schemes 133 -197, into the compounds 15.
Preparation of the phosphonate ester intermediates 15 in which X is sulfur and X' is a direct bond.
Schemes 74 and 75 illustrate the preparation of the phosphonate esters 15 in which X is sulfur and X' is a direct bond. In this procedure, the aldehyde 67.2 is converted, as described in Scheme 53, into the methylene lactone 74.1. The lactone is then reacted, as described in Scheme 53, with the thiol 71.2 to afford the thioether 74.2. This compound is then converted, as described in Scheme 53, into the diamide 74.3.
The reactions shown in Schemes 74 illustrate the preparation of the compounds 74.3 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 75 depicts the conversion of the compounds 74.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 15 in which X is sulfur and X' is a direct bond. In this procedure, the compounds 74.3 are converted, using the procedures described below, Schemes 133 -197, into the compounds 15.
Preparation of the phosphonate ester intermediates 16 in which X and X' are direct bonds.
Schemes 76 and 77 illustrate the preparation of the phosphonate esters 16 in which X and X' are direct bonds. In this procedure, the lactone 49.6 is reacted, as described in Scheme 49, with the iodo compound 67.4 to yield the alkylated lactone 76.1. The lactone is then converted, as described in Scheme 49, into the carboxylic acid 76.2. The carboxylic acid is then coupled, as described in Scheme 1, with the aminoindanol derivative 1.2 to afford the amide 76.3. The latter compound is then converted, as described in Scheme 49, into the diamide 76.4.
The reactions shown in Scheme 76 illustrate the preparation of the compounds 76.4 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 77 depicts the conversion of the compounds 76.4 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 16 in which X and X' are direct bonds. In this procedure, the compounds 76.4 are converted, using the procedures described below, Schemes 133 -197, into the compounds 16.
Preparation of the phosphonate ester intermediates 16 in which X is a direct bond and X1 is sulfur.
Schemes 78 and 79 illustrate the preparation of the phosphonate esters 16 in which X is a direct bond and X1 is sulfur. In this procedure, the lactone 54.1 is reacted, as described in Scheme 49, with the iodo compound 67.4, to produce the alkylated compound 78.1. This material is then transformed, as described in Scheme 49, into the carboxylic acid 78.2, which is then transformed, as described in Scheme 76, into the diamide 78.3.
The reactions shown in Scheme 78 illustrate the preparation of the compounds 78.3 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH], [SH], [NH], Br. Scheme 79 depicts the conversion of the compounds 78.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 16 in which X is a direct bond and X' is sulfur. In this procedure, the compounds 78.3 are converted, using the procedures described below, Schemes 133 -197, into the compounds 16.
Preparation of the phosphonate ester intermediates 16 in which X and X' are sulfur.
Schemes 80, 81 and 82 illustrate the preparation of the phosphonate esters 15 in which X and X' are sulfur. As shown in Scheme 80, the methylene lactone 53.3 is reacted with the thiol 71.2 to produce the thioether 80.1. The compound is then transformed, as described in Scheme 49, into the silyl-protected carboxylic acid 80.2. This material is then converted, as described in Scheme 76, into the diamide 80.3.
Scheme 81 illustrates an alternative method for the preparation of the compounds 80.2. In this . procedure, the mesylate 54.3 is reacted, as described in Scheme 54, with the thiol 71.2, to
prepare the thioether 80.1. The product is then transformed, as described in Scheme 54, into the diamide 80.3.
The reactions shown in Schemes 80 and 81 illustrate the preparation of the compounds 80.3 in which the substituent A is either the group nnk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 82 depicts the conversion of the compounds 80.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 16 in which X and X' are sulfur. In this procedure, the compounds 80.3 are converted, using the procedures described below, Schemes 133 -197, into the compounds 16.
Preparation of the phosphonate ester intermediates 16 in which X is sulfur and X' is a direct bond.
Schemes 83 and 84 illustrate the preparation of the phosphonate esters 16 in which X is sulfur and X1 is a direct bond. In this procedure, the methylene lactone 53.3 is reacted, as described in Scheme 53, with the thiol 71.2 to yield the thioether 83.1. The product is then converted, as described in Scheme 76, into the diamide 83.2.
The reactions shown in Scheme 83 illustrate the preparation of the compounds 83.2 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH], [SH], [NH], Br. Scheme 84 depicts the conversion of the compounds 83.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 16 in which X is sulfur and X' is a direct bond. In this procedure, the compounds 83.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 16.
Preparation of the phosphonate ester intermediates 17 in which X and X1 are direct bonds.
Schemes 85 and 86 illustrate the preparation of the phosphonate esters 17 in which X and X' are direct bonds. In this procedure, the carboxylic acid 76.2 is coupled, as described in Scheme 1, with the aminochroman derivative 33.1 to afford the amide 85.1. The product is then converted, as described in Scheme 49, into the diamide 85.2.
The reactions shown in Scheme 85 illustrate the preparation of the compounds 85.2 in which the substituent A is either the group Hnk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 86-depicts the conversion of the compounds 85.2 in which A is [OH], [SH],
[NH], Br, into the phosphonate esters 17 in which X and X' are direct bonds. In this procedure, the compounds 85.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 17.
Preparation of the phosphonate ester intermediates 17 in which X is a direct bond and X' is sulfur.
Schemes 87 and 88 illustrate the preparation of the phosphonate esters 17 in which X is a direct bond and X' is sulfur. In this procedure, the carboxylic acid 78.2 is coupled with the amine 33.1 to afford the amide 87.1. The product is then converted, as described in Scheme 49, into the diamide 87.2.
The reactions shown in Scheme 87 illustrate the preparation of the compounds 87.2 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 88 depicts the conversion of the compounds 87.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 17 in which X is a direct bond and X' is sulfur. In this procedure, the compounds 87.2 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 17.
Preparation of the phosphonate ester intermediates 17 in which X and X1 are sulfur.
Schemes 89 and 90 illustrate the preparation of the phosphonate esters 17 in which X and X' are sulfur. As shown in Scheme 89, the carboxylic acid 80.2 is coupled, as described in Scheme 1, with the chroman amine 33.1 to give the amide 89.1. The product is then transformed, as described in Scheme 49, into the diamide 89.2.
The reactions shown in Scheme 89 illustrate the preparation of the compounds 89.2 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 90 depicts the conversion of the compounds 89.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 17 in which X and X' are sulrur. In this procedure, the compounds 89.2 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 17.
Preparation of the phosphonate ester intermediates 17 in which X is sulfur and X1 is a direct bond.
Schemes 91 and 92 illustrate the preparation of the phosphonate esters 17 in which X is sulfur and X' is a direct bond. In this procedure, the carboxylic acid 91.1, which is an intermediate compound in the conversion of the lactone 83.1 into the diamide 83.2, (Scheme 83), is coupled, as described in Scheme 1, with the chrornan araine 33.1 to afford the amide 91.2. The product is then converted, as described in Scheme 49, into the diamide 91.3.
The reactions shown in Scheme 91 illustrate the preparation of the compounds 91.3 in which the substituent A is either the group link-P(O)(OR')2 or a precursor such as [OH], [SH], [NH], Br. Scheme 92 depicts the conversion of the compounds 91.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 17 in which X is sulfur and X' is a direct bond. In this procedure, the compounds 91.3 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 17.
Preparation of the phosphonate ester intermediates 18 in which X and X' are direct bonds.
Schemes 93 and 94 illustrate the preparation of the phosphonate esters 18 in which X and X' are direct bonds. In this procedure, the carboxylic acid 76.2 is coupled, as described in Scheme 1, with the ethanolamine derivative 29.1 to afford the amide 93.1. The product is then converted, as described in Scheme 49, into the diamide 93.2.
The reactions shown in Scheme 93 illustrate the preparation of the compounds 93.2 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH], [SH], [NH], Br. Scheme 94 depicts the conversion of the compounds 93.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 18 in which X and X' are direct bonds. In this procedure, the compounds 93.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 18.

Preparation of the phosphonate ester intermediates 18 in which X and X' are sulfur.
Schemes 97 and 98 illustrate the preparation of the phosphonate esters 18 in which X and X' are sulfur. As shown in Scheme 97, the carboxylic acid 80.2 is coupled, as described in Scheme 1, with the ethanolamine derivative 29.1 to give the amide 97.1. The product is then transformed, as described in Scheme 49, into the diamide 97.2.
The reactions shown in Scheme 97 illustrate the preparation of the compounds 97.2 in which the substituent A is either the group Unk-F(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 98 depicts the conversion of the compounds 97.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 18 in which X and X' are sulfur. In this procedure, the compounds 97.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 18.
Preparation of the phosphonate ester intermediates 18 in which X is sulfur and X' is a direct bond.
Schemes 99 and 100 illustrate the preparation of the phosphonate esters 18 in which X is sulfur and X' is a direct bond. In this procedure, the carboxylic acid 91.1 is coupled, as described in Scheme 1, with the ethanolamine derivative 29.1 to afford the amide 99.1. The product is then converted, as described in Scheme 49, into the diamide 99.2.
The reactions shown in Scheme 99 illustrate the preparation of the compounds 99.2 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 100 depicts the conversion of the compounds 99.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 18 in which X is sulfur and X' is a direct bond. In this procedure, the compounds 99.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 18.
Preparation of the phosphonate ester intermediates 19 in which X and X' are direct bonds.
Schemes 101 and 102 illustrate the preparation of the phosphonate esters 19 in which X and X' are direct bonds. In this procedure, the carboxylic acid 76.2 is coupled, as described in
Scheme 1, with the phenylalanine derivative 37.1 to afford the amide 101.1. The product is then converted, as described in Scheme 49, into the diamide 101.2.
The reactions shown in Scheme 101 illustrate the preparation of the compounds 101.2 in which the substituent A is either the group Unk-P(O)(OR')2 or a precursor such as [OH], [SH], [NH], Br. Scheme 102 depicts the conversion of the compounds 101.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 19 in which X and X' are direct bonds. In this procedure, the compounds 101.2 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 19.
Preparation of the phosphonate ester intermediates 19 in which X is a direct bond and X1 is sulfur.
Schemes 103 and 104 illustrate the preparation of the phosphonate esters 19 in which X is a direct bond and X' is sulfur. In this procedure, the carboxylic acid 78.2 is coupled, as described in Scheme 1, with the amine 37.1 to afford the amide 103.1. The product is then converted, as described in Scheme 49, into the diamide 103.2.
The reactions shown in Scheme 103 illustrate the preparation of the compounds 103.2 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH], [SH], [NH], Br. Scheme 104 depicts the conversion of the compounds 103.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 19 in which X is a direct bond and X' is sulfur. In this procedure, the compounds 103.2 are converted, using the procedures described below, Schemes 133 - 197, into the compounds 19.
Preparation of the phosphonate ester intermediates 19 in which X and X' are sulfur.
Schemes 105 and 106 illustrate the preparation of the phosphonate esters 19 in which X and X' are sulfur. As shown in Scheme 105, the carboxylic acid 80.2 is coupled, as described in Scheme 1, with the phenylalanine derivative 37.1 to give the amide 105.1. The product is then transformed, as described in Scheme 49, into the diamide 105.2.
The reactions shown in Scheme 105 illustrate the preparation of the compounds 105.2 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH],
[SH], [NH], Br. Scheme 106 depicts the conversion of the compounds 105.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 19 in which X and X' are sulfur. In this procedure, the compounds 105.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 19.

(Figure Remove)Preparation of the phosphonate ester intermediates 19 in which X is sulfur and X* is a direct bond.
5 Schemes 107 and 108 illustrate the preparation of the phosphonate esters 19 in which X is sulfur and X' is a direct bond. In this procedure, the carboxylic acid 91.1 is coupled, as described in Scheme 1, with the phenylalanine derivative 37.1 to afford the amide 107.1. The product is then converted, as described in Scheme 49, into the diamide 107.2.
The reactions shown in Scheme 107 illustrate the preparation of the compounds 107.2 in 10 which the substituent A is either the group link-P(O)(OR')2 or a precursor such as [OH], [SH], [NH], Br. Scheme 108 depicts the conversion of the compounds 107.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 19 in which X is sulfur and X' is a direct
bond. In this procedure, the compounds 107.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 19.
Preparation of the phosphonate ester intermediates 20 in which X and X' are direct bonds.
Schemes 109 and 110 illustrate the preparation of the phosphonate esters 20 in which X and X1 are direct bonds. In this procedure, the carboxylic acid 76.2 is coupled, as described in Scheme 1, with the tert. butylamine derivative 41.1 to afford the amide 109.1. The product is then converted, as described in Scheme 49, into the diamide 109.2.
The reactions shown in Scheme 109 illustrate the preparation of the compounds 109.2 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 110 depicts the conversion of the compounds 109.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 20 in which X and X' are direct bonds. In this procedure, the compounds 109.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 20.
Preparation of the phosphonate ester intermediates 20 in which X is a direct bond and X* is sulfur.
Schemes 111 and 112 illustrate the preparation of the phosphonate esters 20 in which X is a direct bond and X' is sulfur. In this procedure, the carboxylic acid 78.2 is coupled, as described in Scheme 1, with the amine 41.1 to afford the amide 111.1. The product is then converted, as described in Scheme 49, into the diamide 111.2.
The reactions shown in Scheme 111 illustrate the preparation of the compounds 111.2 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 112 depicts the conversion of the compounds 111.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 20 in which X is a direct bond and X' is sulfur. In this procedure, the compounds 111.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 20.
Preparation of the phosphonate ester intermediates 20 in which X and X' are sulfur.
Schemes 113 and 114 illustrate the preparation of the phosphonate esters 20 in which X and X' are sulfur. As shown in Scheme 113, the carboxylic acid 80.2 is coupled, as described in Scheme 1, with the tert. butylamine derivative 41.1 to give the amide 113.1. The product is then transformed, as described in Scheme 49, into the diamide 113.2.
The reactions shown in Scheme 113 illustrate the preparation of the compounds 113.2 in which the substituent A is either the group Unk-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 114 depicts the conversion of the compounds 113.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 20 in which X and X' are sulfur. In this procedure, the compounds 113.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 20.
Preparation of the phosphonate ester intermediates 20 in which X is sulfur and X' is a direct bond.
Schemes 115 and 116 illustrate the preparation of the phosphonate esters 20 in which X is sulfur and X1 is a direct bond. In this procedure, the carboxylic acid 91.1 is coupled, as described in Scheme 1, with the tert. butylamine derivative 41.1 to afford the amide 115.1. The product is then converted, as described in Scheme 49, into the diamide 115.2.
The reactions shown in Scheme 115 illustrate the preparation of the compounds 115.2 in which the substituent A is either the group link-P(O)(OR')2 or a precursor such as [OH], [SH], [NH], Br. Scheme 116 depicts the conversion of the compounds 115.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 20 in which X is sulfur and X' is a direct bond. In this procedure, the compounds 115.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 20.
Preparation of the phosphonate ester intermediates 21 in which X and X' are direct bonds.
Schemes 117 and 118 illustrate the preparation of the phosphonate esters 21 in which X and X' are direct bonds. In this procedure, the carboxylic acid 76.2 is coupled, as described in Scheme 1, with the decahydroisoquinoline derivative 45.1 to afford the amide 117.1. The product is then converted, as described in Scheme 49, into the diamide 117.2.
The reactions shown in Scheme 117 illustrate the preparation of the compounds 117.2 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 118 depicts the conversion of the compounds 117.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 21 in which X and X' are direct bonds. In this procedure, the compounds 117.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 21.
Preparation of the phosphonate ester intermediates 21 in which X is a direct bond and X' is sulfur.
Schemes 119 and 120 illustrate the preparation of the phosphonate esters 21 in which X is a direct bond and X1 is sulfur. In this procedure, the carboxylic acid 78.2 is coupled, as described in Scheme 1, with the amine 45.1 to afford the amide 119.1. The product is then converted, as described in Scheme 49, into the diamide 119.2.
The reactions shown in Scheme 119 illustrate the preparation of the compounds 119.2 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH], [SH], [NH], Br. Scheme 120 depicts the conversion of the compounds 119.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 21 in which X is a direct bond and X' is sulfur. In this procedure, the compounds 119.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 21.
Preparation of the phosphonate ester intermediates 21 in which X and X' are sulfur.
5 Schemes 121 and 122 illustrate the preparation of the phosphonate esters 21 in which X and X' are sulfur. As shown in Scheme 121, the carboxylic acid 80.2 is coupled with the amine
45.1 to give the amide 121.1. The product is then transformed, as described in Scheme 49, into the diamide 121.2.
The reactions shown in Scheme 121 illustrate the preparation of the compounds 121.2 in which the substituent A is either the group link-PCOXOR1);, or a precursor such as [OH], [SH], [NH], Br. Scheme 122 depicts the conversion of the compounds 121.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 21 in which X and X' are sulfur. In this procedure, the compounds 121.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 21.
Preparation of the phosphonate ester intermediates 21 in which X is sulfur and X' is a direct bond.
Schemes 123 and 124 illustrate the preparation of the phosphonate esters 21 in which X is sulfur and X' is a direct bond. In this procedure, the carboxylic acid 91.1 is coupled, as described in Scheme 1, with the amine 45.1 to afford the amide 123.1. The product is then converted, as described in Scheme 49, into the diamide 123.2.
The reactions shown in Schemes 123 illustrate the preparation of the compounds 123.2 in which the substituent A is either the group link-P(O)(OR')2 or a precursor such as [OH], [SH], [NH], Br. Scheme 124 depicts the conversion of the compounds 123.2 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 21 in which X is sulfur and X' is a direct bond. In this procedure, the compounds 123.2 are converted, using the procedures described below, Schemes 133 -197, into the compounds 21.
Preparation of the phosphonate ester intermediates 22 in which X and X' are direct bonds.
Schemes 125 and 126 illustrate the preparation of the phosphonate esters 22 in which X and X' are direct bonds. In this procedure, the carboxylic acid 76.2 is coupled, as described in Scheme 5 with the amine 1.6, to afford the amide 125.1. The BOG protecting group is then removed, as described in Scheme 49, to yield the amine 125.2. The latter compound is then
coupled with the carboxylic acid 125.3 to produce the amide 125.4. The preparation of the carboxylic acid reactant 125.3 is described in Scheme 191.
The reactions shown in Scheme 125 illustrate the preparation of the compounds 125.4 in which the substituent A is either the group link-PCOXOR1^ or a precursor such as [OH], [SH], [NH], Br. Scheme 126 depicts the conversion of the compounds 125.4 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 22 in which X and X' are direct bends. In this procedure, the compounds 125.4 are converted, using the procedures described below, Schemes 133 -197, into the compounds 22
Preparation of the phosphonate ester intermediates 22 in which X is a direct bond and X' is sulfur.
Schemes 127 and 128 illustrate the preparation of the phosphonate esters 22 in which X is a direct bond and X' is sulfur. In this procedure, the carboxylic acid 78.2 is coupled, as described in Scheme 5 with the amine 1.6, to afford the amide 127.1. The BOC protecting group is then removed, as described in Scheme 49, to yield the amine 127.2. The latter compound is then coupled, as described in Scheme 1, with the carboxylic acid 125.3 to produce the amide 127.3.
The reactions shown in Scheme 127 illustrate the preparation of the compounds 127.3 in which the substituent A is either the group link-P(O)(ORI)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 128 depicts the conversion of the compounds 127.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 22, in which X is a direct bond and X' is sulfur. In this procedure, the compounds 127.3 are converted, using the procedures described below, Schemes 133 -197, into the compounds 22.
Preparation of the phosphonate ester intermediates 22 in which X and X1 are sulfur.
Schemes 129 and 130 illustrate the preparation of the phosphonate esters 22 in which X and X' are sulfur. As shown in Scheme 129, the carboxylic acid 80.2 is coupled, as described in Scheme 5, with the amine 1.6, to afford the amide 129.1. The BOC protecting group is then ,
removed, as described in Scheme 49, to yield the amine 129.2. The latter compound is then coupled, as described in Scheme 1, with the carboxylic acid 125.3 to produce the amide 129.3.
The reactions shown in Scheme 129 illustrate the preparation of the compounds 129.3 in which the substituent A is either the group link-PCOXOR1)^ or a precursor such as [OH], [SH], [NH], Br. Scheme 130 depicts the conversion of the compounds 129.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 22, in which X and X' are sulfur. In this procedure, the compounds 129.3 are converted, using the procedures described below, Schemes 133 -197, into the compounds 22.
Preparation of the phosphonate ester intermediates 22 in which X is sulfur and X' is a direct bond.
Schemes 131 and 132 illustrate the preparation of the phosphonate esters 22 in which X is sulfur and X1 is a direct bond. In this procedure, the carboxylic acid 91.1 is coupled, as described in Scheme 5, with the amine 1.6, to afford the amide 131.1. The BOC protecting group is then removed, as described in Scheme 49, to yield the amine 131.2. The latter compound is then coupled, as described in Scheme 1, with the carboxylic acid 125.3 to produce the amide 131.3.
The reactions shown in Scheme 131 illustrate the preparation of the compounds 131.3 in which the substituent A is either the group link-P(O)(OR1)2 or a precursor such as [OH], [SH], [NH], Br. Scheme 132 depicts the conversion of the compounds 131.3 in which A is [OH], [SH], [NH], Br, into the phosphonate esters 22 in which X is sulfur and X' is a direct bond. In this procedure, the compounds 131.3 are converted, using the procedures described below, Schemes 133 -197, into the compounds 22.
Preparation of aminoindanol derivatives 1.2 incorporating phosphonate moieties.
Scheme 133 illustrates the preparation of variously substituted derivatives of 3-amino-indan-
1,2-diol, the preparation of which is described in J. Med. Chem., 1991, 34, 1228. The
alcohols, thiols, amines and bromo compounds shown in Scheme 133 can then be transformed
into phosphonate-containing reactants 1.2, as described below, (Schemes 134 -137). The
reactants 1.2 are employed in the preparation of the phosphonate esters 1 and 16.
In order to effect changes to the 1-substituent, the starting material 133.1 is transformed into
the protected compound 133.2. For example, the aminoalcohol 133.1 is treated with 2-
methoxypropene in the presence of an acid catalyst, such as p-toluenesulfonic acid, in a
solvent such as tetrahydrofuran, as described in WO9628439, to afford the acetonide-
protected product 133.2.
The amino group present in 133.2 is protected to afford the intermediate 133.3, in which R12 is
a protecting group, stable to the subsequent reactions. For example, R12 can be
carbobenzyloxy (cbz), tert-butoxycarbonyl (BOC) and the like, as described in Protective
Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990,
p. 309.
The free hydroxyl group present in the N-protected acetonide 133.3 is then converted into a
suitable leaving group, such as, for example, trifluoromethylsulfonyloxy, p-toluenesulfonyloxy
or, preferably, methanesulfonyloxy. This transformation is effected by treatment of 133.3 with
a slight molar excess of the corresponding acid chloride or anhydride, in the presence of an
organic base.
For example, treatment of 133.3 with methanesulfonyl chloride and pyridine in
dichloromethane at ambient temperature affords the mesylate 133.4.
The a-mesylate group in the product 133.4 is then subjected to displacement reactions with
nitrogen, sulfur or oxygen nucleophiles, to effect introduction of the various heteroatoms with
inversion of stereochemistry.
For example, the mesylate 133.4 is reacted with a nitrogen nucleophile such as potassium
phthalimide or sodium bis(trimethylsilyl)amide, as described in Comprehensive Organic
Transformations, by R. C. Larock, VCH, p. 399, to afford the amine 133.9.
Preferably, the mesylate 133.4 is reacted, as described in Angew. Chem. Int. Ed., 7, 919,
1968, with one molar equivalent of potassium phthalimide, in a dipolar aprotic solvent, such
as, for example, dimethylformamide, at ambient temperature, to afford the displacement
product 133.5, in which NRaRb is phthalimido. Removal of the phthalimido group, for
example by treatment with an alcoholic solution of hydrazine at ambient temperature, as
described in J. Org. Chem., 38, 3034, 1973, then yields the p-amine 133.9.
The mesylate 133.4 is treated with a sulfur nucleophile, for example potassium thioacetate, as
described in Tet. Lett., 1992, 4099, or sodium thiophosphate, as described in Acta Chem.
Scand., 1960, 1980, to effect displacement of the mesylate group, followed by mild basic
hydrolysis, for example by treatment with aqueous sodium bicarbonate or aqueous ammonia,
to afford the p-thiol 133.12.
Preferably, the mesylate 133.4 is reacted with one molar equivalent of potassium thioacetate in
a polar aprotic solvent such as, for example, dimethylformamide, at ambient temperature, to
afford the thioacetate 133.8. The product then treated with a mild base such as, for example,
aqueous ammonia, in the presence of an organic co-solvent such as ethanol, at ambient
temperature, to afford the P-thiol 133.12.
The mesylate 133.4 is transformed into the p-carbinol 133.7, by treatment with an oxygen
nucleophile. Conversion of sulfonate esters and related compounds to the corresponding
carbinols is described, for example, in Comprehensive Organic Transformations, by R. C.
Larock, VCH, p. 481. For example, the mesylate can be reacted with potassium superoxide,
in the presence of a crown ether such as 18-crown-6, as described in Tet. Lett., 3183, 1975, to
afford the p-carbinol 133.7.
The carbinol 133.3 is also transformed into the p-bromo compound 133.6. Methods for the
conversion of carbinols to bromo compounds are described, for example, in Comprehensive
Organic Transformations, by R. C. Larock, VCH, p. 356.
For example, the a-carbinol 133.3 is reacted with hexabromoethane and triphenylphosphine, in
an aprotic solvent such as ethyl acetate, as described in Syn., 139,1983, to afford the p-bromo
compound 133.6.
Using the above described procedures for the conversion of the a-carbinol 133.3 into the P-
oriented amine 133.9, thiol 133.12 and bromo compound 133.6, the p-carbinol 133.7 is
transformed into the a-oriented amine or thiol 133.11 or the bromo compound 133.10.
Schemes 134 -137 illustrate the preparation of aminoindanol derivatives incorporating the group link-PCOXOR1)!, derived from the intermediates whose syntheses are described above (Scheme 133).
Scheme 134 depicts the preparation of phosphonate esters linked to the aminoindanol nucleus by means of a carbon chain and a heteroatom O, S or N. In this procedure, the hetero-substituted indanol 134.1 is reacted with a bromoalkylphosphonate 134.2, in the presence of a suitable base. The base required for this transformation depends on the nature of the heteroatom X. For example, if X is N or S, an excess of an inorganic base such as, for example, potassium carbonate, in the presence of an organic solvent such as dimethylformamide, is suitable. The reaction proceeds at from ambient temperature to about 80°C to afford the displacement products 134.3. If X is O, an equimolar amount of a strong base, such as, for example, lithium hexamethyldisilylazide and the like, is employed, in the presence of a solvent such as tetrahydrofuran. Deprotection, by removal of the group R12, then affords the amine 134.4.
For example, the p-thiol 133.12 is reacted with an equimolar amount of dialkyl 4-bromobutyl phosphonate 134.5, the preparation of which is described in Synthesis, 1999, 9, 909, in dimethylformamide containing excess potassium carbonate, at ca 60°C to afford the thioether phosphonate product 134.6. Deprotection then affords the amine 134.7. Using the above procedures, but employing, in place of the thiol 133.12, different carbinols, thiols or amines 134.1, and/or different bromoalkylphosphonates 134.2, the corresponding products 134.4 are obtained.
Scheme 135 illustrates the preparation of aminoindanol derivatives in which the phosphonate ester group is attached by means of a nitrogen atom and a carbon chain. In this method, the aminoindanol 135.1 is reacted with a forrnyl-substituted phosphonate ester, utilizing a reductive amination procedure. The preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 421. In this procedure, the amine component 135.1 and the aldehyde component 135.2 are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride or diisobutylaluminum hydride, to yield the amine product 135.3. Deprotection, by removal of the R12 group, then affords the amine 135.4.
For example, equimolar amounts of the amine 133.11 and a dialkylformylphosphonate 135.5, prepared as described in US 3784590, are reacted together in the presence of sodium cyanoborohydride and acetic acid, as described, for example, in J. Am. Chem. Soc., 91, 3996, 1969, to afford the product 135.6 which is then deprotected to produce the amine 135.7. Using the above procedures, but employing, in place of the a-amine 133.11, the p-amine 133.9, and/or different formyl-substituted phosphonates 135.2, the corresponding products 135.4 are obtained.
Scheme 136 depicts the preparation of aminoindanol phosphonates in which the phosphonate moiety is attached to the nucleus by means of a heteroatom and one carbon. In this procedure, a carbinol, thiol or amine 136.1 is reacted with a dialkyl trifluoromethylsulfonyloxy phosphonate 136.2, in the presence of a suitable base, to afford the alkylation product 136.3. Deprotection of the product 136.3 then yields the amine 136.4. The base required for this reaction between 136.1 and 136.2 depends on the nature of the heteroatom X. For example, if X is N or S, an excess of inorganic base such as, for example, potassium carbonate, cesium carbonate or the like, in the presence of an organic solvent such as dimethylformamide, is suitable. The reaction proceeds at from ambient temperature to about 80° to afford the displacement products 136.3. If X is O, an equimolar amount of a strong base, such as, for example, lithium hexamethyldisilylazide, sodium hydride or the like, is employed, in the presence of a solvent such as tetrahydrofuran.
For example, the a-carbinol 133.3 is reacted with one equivalent of lithium hexamethyl disilylazide in tetrahydrofuran, followed by addition of an equimolar amount of a dialkyl trifluoromethylsulfonyloxymethyl phosphonate 136.5, the preparation of which is described in Tet. Lett., 1986, 27, 1497, to afford the ether product 136.6. Deprotection, by removal of the R12 group, then affords the amine 136.7.
Using the above procedures, but employing, in place of the a-carbinol 133.3, different carbinols, thiols or amines 136.1, and /or different dialkyl trifluoromethylsulfonyloxymethyl phosphonates 136.2, the corresponding products 136.4 are obtained.
Scheme 137 illustrates the preparation of aminoindanol phosphonate esters in which the phosphonate group is attached directly to the aminoindanol nucleus.
In this procedure, the bromoindanol derivative 137.1 is reacted with a sodium dialkyl phosphite, in a suitable aprotic polar solvent such as dimethyl formamide or N-methylpyrrolidinone. Displacement of the bromo substituent occurs to yield the phosphonate 137.3. Deprotection, by removal of the R12 group, then affords the amine 137.4. For example, equimolar amounts of the a-bromo compound 133.10 and the dialkyl sodium phosphite 137.2, are dissolved in dimethylformamide and the mixture is heated at ca. 60°C, as described in J. Med. Chem., 35, 1371, 1992, to afford the p-phosphonate 137.5. Alternatively, the phosphonate compound 137.5 is obtained by means of an Arbuzov reaction between the bromo compound 133.10 and a trialkyl phosphite PCOR1^. In this procedure, as described in Handb. Organophosphorus Chem., 1992, 115, the reactants are heated together at ca. 100°C to afford the product 137.5. Deprotection of the latter compound affords the amine 137.6.
Using the above procedures, but employing, in place of the a-bromo compound 133.10, the P-bromo compound 133.6, and/or different phosphites 137.2, the corresponding phosphonates 137.4 are obtained.
Preparation of phenylpropionic acid intermediates 5.1 incorporating phosphonate moieties.
Phenylpropionic acid derivatives incorporating the substituent link-P(O)(OR1)2 are prepared by the reactions illustrated in Schemes 139-143, using as starting materials variously substituted phenylpropionic acids. The phenylpropionic acid derivatives 5.1 are employed in the preparation of the phosphonate esters 2 in which X is a direct bond. A number of the substituted phenylpropionic acids required for the reactions shown in Schemes 139-143 are commercially available; in addition, the syntheses of variously substituted phenylpropionic acids have been reported. For those substituted phenylpropionic acids which are not commercially available, and whose syntheses have not been reported, a number of well-established synthetic routes are available. Representative methods for the synthesis of substituted phenylpropionic acids from commercially available starting materials are shown in Scheme 138.
For example, variously substituted benzaldehydes 138.1 are subjected to a Wittig reaction with carboethoxymethylenetriphenylphosphorane 138.2, as described in Ylid Chemistry, by A. W.
Johnson, Academic Press, 1966, p. 132, to afford the corresponding cinnamate esters 138.3. Equimolar amounts of the reactants 138.1 and 138.2 are heated in an inert solvent such as dioxan or dimethylformamide, at ca 50°C, to afford the product 138.3. Reduction of the double bond in the product 138.3 then afford the saturated ester 138.6, (X =H) which upon hydrolysis yields the phenylpropionic acid intermediate 138.10.
Methods for the reduction of carbon-carbon double bonds are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 6. Typical of the available reduction methods are catalytic hydrogenation, for example using palladium catalysts, as described in Hydrogenation Methods, by P. N. Rylander, Academic Press, New York, 1985, hydroboration-protonolysis, as described in J. Am. Chem. Soc., 81, 4108, 1959, or diimide reduction, as described in J. Org. Chem., 52, 4665, 1987. The choice of a particular reduction method is made by one skilled in the ait, depending on the nature of the substituent groups attached to the cinnamic acid ester 138.3.
Alternatively, the cinnamic esters 138.3 are obtained by means of a palladium-catalyzed Heck reaction between an appropriately substituted bromobenzene 138.5 and ethyl acrylate 138.4. In this procedure, a substituted bromobenzene 138.5 is reacted with ethyl acrylate in the presence of a palladium (II) catalyst, as described in J. Med. Chem., 35, 1371, 1992, to afford the cinnamate ester 138.3. Equimolar amounts of the reactants 138.4 and 138.5 are dissolved in a polar aprotic solvent such as dimethylformamide or tetrahydrofuran, at a temperature of about 60°C, in the presence or ca. 3 mol % of, for example, bis(triphenylphosphine)palladium (II) chloride and triethylamine, to afford the product 138.3.
Alternatively, the substituted phenylpropionic acid intermediates are obtained from the correspondingly substituted methylbenzenes 138.7. In this procedure, the methylbenzene 138.7 is subjected to free-radical bromination, for example by reaction with an equimolar amount of N-bromosuccinimide, as described in Chem. Rev., 63, 21, 1963, to afford the bromomethyl derivative 138.8. The latter compound is then reacted with a salt of an ester of malonic acid, for example the sodium salt of diethyl malonate 138.9, as described in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 489, to afford the displacement product 138.6, (X = COOEt). The latter compound is subjected to hydrolysis and decarboxylation, for example by treatment with aqueous alkali or dilute aqueous acid, to afford the phenylpropionic acid 138.10.
Scheme 139 illustrates the preparation of phosphonate-containing phenylpropionic acids in which the phosphonate moiety is attached to the phenyl ring by means of an aromatic group. In this procedure, the carboxyl group of a bromo-substituted phenylpropionic acid 139.1 is protected. Methods for the protection of carboxylic acids are described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 224. The product 139.2 is then subjected to halogen-methyl exchange, for example by reaction with an alkyllithium, to afford the product 139.3 in which M is Li. The latter compound is subjected to palladium (II) or palladium (0) catalyzed coupling, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 57. Compound 139.3 is first converted into the boronic acid 139.4, by reaction with a trialkyl borate, and the boronic acid product is coupled with a dialkyl bromophenylphosphonate 139.5 to yield the product 139.6. Deprotection then affords the intermediate phosphonate-substituted phenylpropionic acid 139.7.
For example, 4-bromophenylpropionic acid 139.8, prepared as described in U.S. 4,032,533, is converted into the acid chloride, by treatment with thionyl chloride, oxalyl chloride and the like. The acid chloride is then reacted with 3-methyl-3-oxetanemethanol 139.9 (Aldrich), in the presence of a tertiary organic base such as pyridine, in a solvent such as dichloromethane, to afford the ester 139.10. This product is then rearranged by treatment with boron trifluoride etherate in dichloromethane, at about -15°C as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 268, to yield the orthoester 139.11, known as an OBO ester. The ktter product is then reacted with one molar equivalent of n-butyllithium, in a solvent such as ether, at about -80°C, to afford the lithio derivative, which is reacted with a trialkyl borate, as described in J. Organomet. Chem., 1999, 581, 82, to yield the boronate 139.12. This material is coupled, in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium(0), and an inorganic base such as sodium carbonate, with a dialkyl 4-bromophenylphosphonate 139.13, prepared as described in J. Chem. Soc., Perkin Trans., 1977, 2, 789, to give the coupled product 139.14. Deprotection, for example by treatment with aqueous pyridine p-toluenesulfonate, as described in Can. J. Chem., 61, 712, 1983, then affords the carboxylic acid 139.15.
Using the above procedures, but employing, in place of the 4-bromophenylpropionic acid 139.8, different bromophenylpropionic acids 139.1, and/or different dialkyl bromophenyl phosphonates 139.5, the corresponding products 139.7 are obtained.
Scheme 140 depicts the preparation of phenylpropionic acids in which a phosphonate ester is attached to the phenyl ring by means of a heteroatom. In this procedure, a suitably protected hydroxy, thio or amino-substituted phenyl propionic acid 140.1 is reacted with a derivative of a hydroxymethyl dialkylphosphonate 140.2, in which Lv is a leaving group such as methanesulfonyloxy and the like. The reaction is conducted in a polar aprotic solvent, in the presence of an organic or inorganic base, to afford the displacement product 140.3. Deprotection then affords the carboxylic acid 140.4.
For example, trichloroethyl 3-hydroxyphenylpropionic acid 140.5, prepared by reaction of 3-hydroxyphenylpropionic acid (Fluka) with trichloroethanol and dicyclohexylcarbodiimide, as described in J. Am. Chem. Soc., 88, 852, 1966, is reacted with a dialkyl trifluoromethanesulfonyloxymethyl phosphonate 140.6, prepared as described in Tet. Lett., 1986, 27, 1477, to afford the ether product 140.7. Equimolar amounts of the reactants are combined in a polar solvent such as dimethylformamide, in the presence of a base such as potassium carbonate, at about 50°C, to afford the product 140.7. Removal of the trichloroethyl ester group, for example by treatment with zinc in acetic acid at 0°C, as described in J. Am. Chem. Soc., 88, 852, 1966, then yields the carboxylic acid 140.8. Using the above procedures, but employing, in place of the phenol 140.5, different phenols, thiols or amines 140.1, and/or different phosphonates 140.2, the corresponding products 140.4 are obtained.
i Scheme 141 illustrates the preparation of phenylpropionic acids in which a phosphonate
moiety is attached by means of a chain incorporating a heteroatom. In this procedure, a carboxyl protected halomethyl substituted phenylpropionic acid 141.1 is reacted with a dialkyl hydroxy, thio or amino-substituted alkylphosphonate 141.2. The reaction is performed in the presence of a base, in a polar aprotic solvent such as dioxan or N-methylpyrrolidinone. The base employed in the reaction depends on the nature of the reactant 141.2. For example, if X is O, a strong base such as, for example, lithium hexamethyldisilylazide or potassium tert. butoxide is employed. If X is S, NH or N-alkyl, an inorganic base such as cesium carbonate and the like is employed.
For example, 4-bromomethyl phenylpropionic acid, prepared as described in U.S. 4,032,533, is converted into the methoxymethyl ester 141.5, by reaction with methoxymethyl chloride and
triethylamine in dimethylformamide, as described in J. Chem. Soc, 2127, 1965. Equimolar amounts of the ester 141.5 and a dialkyl 2-aminoethyl phosphonate 141.6, prepared as described in J. Org. Chem., 2000, 65, 676, are reacted in dimethylformamide at ca 80°C, in the presence of potassium carbonate, to afford the displacement product 141.7. Deprotection, for example by treatment with trimethylsilyl bromide and a trace of methanol, as described in Aldrichimica Acta, 11, 23, 1978, then yields the carboxylic acid 141.8. Using the above procedures, but employing, in place of the amine 141.6, different amines, alcohols or thiols 141.2 and/or different halomethyl-substituted phenylpropionic acids 141.1, the corresponding products 141.4 are obtained.
Scheme 142 illustrates the preparation of phosphonate esters attached to the phenyl ring by means of an oxygen or sulfur link, by means of a Mitsonobu reaction. In this procedure, a protected hydroxy- or thio-substituted phenylpropionic acid 142.1 is reacted with a dialkyl hydroxyalkyl phosphonate 142.2. The condensation reaction between 142.1 and 142.2 is effected in the presence of a triaryl phospnine and diethyl azodicarboxylate, as described in Org. React., 1992,42, 335. The product 142.3 is then deprotected to afford the carboxylic acid 142.4.
For example, 3-mercaptophenylpropionic acid (Apin Chemicals) is converted into the tert. butyl ester 142.5, by treatment with carbonyl diimidazole, tert. butanol and diazabicycloundecene, as described in Synthesis, 833, 1982. The ester is reacted with a dialkyl hydroxymethylphosphonate 142.6, prepared as described in Synthesis, 4, 327, 1998, in the presence of triphenyl phosphine, triethylamine and diethyl azodicarboxylate, to afford the thioether 142.7. The tert. butyl group is removed by treatment with formic acid at ambient temperature, as described in J. Org. Chera, 42, 3972, 1977, to yield the carboxylic acid 142.8. Using the above procedures, but employing, in place of the thiol 142.5, different phenols or thiols 142.1 and/or different hydroxyalkyl phosphonates 142.2, the corresponding products 142.4 are obtained.
Scheme 143 depicts the preparation of phenylpropionic acids linked to a phosphonate ester by means of an aromatic or heteroaromatic ring. The products 143.3 are obtained by means of an alkylation reaction in which a bromomethyl aryl or heteroaryl phosphonate 143.1 is reacted with a carboxyl-protected hydroxy, thio or amino-substituted phenylpropionic acid 140.1. The
reaction is conducted in the presence of a base, the nature of which is determined by the substituent X in the reactant 140.1. For example, if X is O, a strong base such as lithium hexamethyldisilylazide or sodium hydride is employed. If X is S or N, an organic or inorganic base, such as diisopropylethylamine or cesium carbonate is employed. The alkylated product 143.2 is then deprotected to afford the carboxylic acid 143.3. For example, 3-(4-aminophenyl)propionic acid (Aldrich) is reacted with tert. butyl chlorodimethylsilane and imidazole in dimethylformamide, as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 262, to afford the silyl ester 143.4. This compound is reacted with a an equimolar amount of a dialkyl 4-bromomethylbenzylphosphonate 143.5, prepared as described in Tet. Lett., 1998, 54, 9341, in the presence of cesium carbonate in dimethylformamide at ambient temperature, to afford the product 143.6. The silyl ester is removed by treatment with tetrabutylammonium fluoride in tetrahydrofuran at ambient temperature, as described in J. Am. Chem. Soc., 94, 6190, 1972, to give the carboxylic acid 143.7.
Using the above procedures, but employing, in place of the amino compound 143.4, different phenols, mercaptans or amines 140.1, and/or different halomethyl phosphonates 143.1, the corresponding products 143.3 are obtained.

Preparation of the phosphonate-containing thiophenol derivatives 7.1.
Schemes 144 -153 describe the preparation of phosphonate-containing thiophenol derivatives 7.1 which are employed in the preparation of the phosphonate ester intermediates 2,14 and 19 in which X is sulfur, and of the intermediate 15 in which X' is sulfur.
Scheme 144 depicts the preparation of thiophenol derivatives in which the phosphonate moiety is attached directly to the phenyl ring. In this procedure, a halo-substituted thiophenol 144.1 is protected to afford the product 144.2. The protection and deprotection of thiophenols is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 277. For example, thiol substituents are protected as trialkylsilyloxy groups. Trialkylsilyl groups are introduced by the reaction of the thiophenol with a chlorotrialkylsilane and a base such as imidazole. Alternatively, thiol substituents are protected by conversion to tert-butyl or adamantyl thioethers, or 4-methoxybenzyl thioethers, prepared by the reaction between the thiol and 4-methoxybenzyl chloride in the presence of ammonium hydroxide, as described in Bull. Chem. Soc. Jpn., 37, 433, 1974. The product is then coupled, in the presence of a palladium catalyst, with a dialkyl phosphite 144.3, to afford the phosphonate ester 144.4. The preparation of arylphosphonates by the coupling of aryl halides with dialkyl phosphites is described in J. Med. Chem., 35, 1371, 1992. The thiol protecting group is then removed, as described above, to afford the thiol 144.5. For example, 3-bromothiophenol 144.6 is converted into the 9-fluorenylmethyl (Fm) derivative 144.7 by reaction with 9-fluorenylmethyl chloride and diisopropylethylamine in dimethylfbrmamide, as described in Int. J. Pept. Protein Res., 20,434, 1982. The product is then reacted with a dialkyl phosphite 144.3 to afford the phosphonate ester 144.8! The preparation of arylphosphonates by means of a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Med. Chem., 35, 1371, 1992. The compound 144.7 is reacted, in toluene solution at reflux, with a dialkyl phosphite 144.3, triethylamine and tetrakis(triphenylphosphine)palladium(0), as described in J. Med. Chem., 35, 1371, 1992, to afford the phosphonate product 144.8. The Fm protecting group is then removed by treatment of the product with piperidine in dimethylformamide at ambient temperature, as described in J. Chem. Soc., Chem. Comm., 1501, 1986, to give the thiol 144.9.
Using the above procedures, but employing, in place of 3-bromothiophenol 144.6, different thiophenols 144.1, and/or different dialkyl phosphites 144.3, the corresponding products 144.5 are obtained.
Scheme 145 illustrates an alternative method for obtaining thiophenols with a directly attached phosphonate group. In this procedure, a suitably protected halo-substituted thiophenol 145.2 is metallated, for example by reaction with magnesium or by transmetallation with an alkyllithium reagent, to afford the metallated derivative 145.3. The latter compound is reacted with a halodialkyl phosphite 145.4 to afford the product 145.5; deprotection then affords the thiophenol 145.6
For example, 4-bromothiophenol 145.7 is converted into the S-triphenylmethyl (trityl) derivative 145.8, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, p. 287. The product is converted into the lithium derivative 145.9 by reaction with butyllithium in an ethereal solvent at low temperature, and the resulting lithio compound is reacted with a dialkyl chlorophosphite 145.10 to afford the phosphonate 145.11. Removal of the trityl group, for example by treatment with dilute hydrochloric acid in acetic acid, as described in J. Org. Chem., 31, 1118, 1966, then affords the thiol 145.12. Using the above procedures, but employing, in place of the bromo compound 145.7, different halo compounds 145.1, and/or different halo dialkyl phosphites 145.4, there are obtained the corresponding thiols 145.6.
Scheme 146 illustrates the preparation of phosphonate-substituted thiophenols in which the phosphonate group is attached by means of a one-carbon link. In this procedure, a suitably protected methyl-substituted thiophenol 146.1 is subjected to free-radical bromination to afford a bromomethyl product 146.2. This compound is reacted with a sodium dialkyl phosphite 146.3 or a trialkyl phosphite, to give the displacement or rearrangement product 146.4, which upon deprotection affords the thiophenol 146.5.
For example, 2-methylthiophenol 146.5 is protected by conversion to the benzoyl derivative 146.7, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, p. 298. The product is reacted with N-bromosuccinimide in ethyl acetate to yield the bromomethyl product 146.8. This material is reacted with a sodium dialkyl phosphite 146.3, as described in J. Med. Chem., 35, 1371, 1992, to afford the product 146.9.
Alternatively, the bromomethyl compound 146.8 is converted into the phosphonate 146.9 by means of the Arbuzov reaction, for example as described in Handb. Organophosphorus Chem., 1992, 115. In this procedure, the bromomethyl compound 146.8 is heated with a trialkyl phosphate PCOR1^ at ca. 100°C to produce the phosphonate 146.9. Deprotection of the phosphonate 146.9, for example by treatment with aqueous ammonia, as described in J. Am. Chem. Soc., 85, 1337, 1963, then affords the thiol 146.10.
Using the above procedures, but employing, in place of the bromomethyl compound 146.8, different bromomethyl compounds 146.2, there are obtained the corresponding thiols 146.5.
Scheme 147 illustrates the preparation of thiophenols bearing a phosphonate group linked to the phenyl nucleus by oxygen or sulfur, hi this procedure, a suitably protected hydroxy or thio-substituted thiophenol 147.1 is reacted with a dialkyl hydroxyalkylphosphonate 147.2 under the conditions of the Mitsonobu reaction, for example as described in Org. React., 1992,42, 335, to afford the coupled product 147.3., Deprotection then yields the O- or S- -linked products 147.4.
For example, 3-hydroxythiophenol, 147.5, is converted into the monotrityl ether 147.6, by reaction with one equivalent of trityl chloride, as described above. This compound is reacted with diethyl azodicarboxylate, triphenyl phosphine and a dialkyl 1-hydroxymethyl phosphonate 147.7 in benzene, as described in Synthesis, 4, 327,1998, to afford the ether compound 147.8. Removal of the trityl protecting group, as described above, then affords the thiophenol 147.9. Using the above procedures, but employing, in place of the phenol 147.5, different phenols or thiophenols 147.1, there are obtained the corresponding thiols 147.4.
Scheme 148 illustrates the preparation of thiophenols 148.4 bearing a phosphonate group linked to the phenyl nucleus by oxygen, sulfur or nitrogen. In this procedure, a suitably protected O, S or N-substituted thiophenol 148.1 is reacted with an activated ester, for example the trifluoromethanesulfonate 148.2, of a dialkyl hydroxyalkyl phosphonate, to afford the coupled product 148.3. Deprotection then affords the thiol 148.4. For example, 4-methylaminothiophenol 148.5 is reacted in dichloromethane solution with one equivalent of acetyl chloride and a base such as pyridine, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, p. 298, to afford the S-acetyl product 148.6. This material is then reacted with a dialkyl
trifluoromethanesulfonyloxymethyl phosphonate 148.7, the preparation of which is described in Tet. Lett., 1986, 27, 1477, to afford the displacement product 148.8. Preferably, equimolar amounts of the phosphonate 148.7 and the amine 148.6 are reacted together in an aprotic solvent such as dichloromethane, in the presence of a base such as 2,6-lutidine, at ambient temperatures, to afford the phosphonate product 148.8. Deprotection, for example by treatment with dilute aqueous sodium hydroxide for two minutes, as described in J. Am. Chem. Soc., 85, 1337, 1963, then affords the thiophenol 148.9.
Using the above procedures, but employing, in place of the thioamine 148.5, different phenols, thiophenols or amines 148.1, and/or different phosphonates 148.2, there are obtained the corresponding products 148.4.
Scheme 149 illustrates the preparation of phosphonate esters linked to a thiophenol nucleus by means of a heteroatom and a multiple-carbon chain, employing a nucleophilic displacement reaction on a dialkyl bromoalkyl phosphonate 149.2. In this procedure, a suitably protected hydroxy, thio or amino substituted thiophenol 149.1 is reacted with a dialkyl bromoalkyl phosphonate 149.2 to afford the product 149.3. Deprotection then affords the free thiophenol 149.4.
For example, 3-hydroxythiophenol 149.5 is converted into the S-trityl compound 149.6, as described above. This compound is then reacted with a dialkyl 4-bromobutyl phosphonate 149.7, the synthesis of which is described in Synthesis, 1994, 9, 909. The reaction is conducted in a dipolar aprotic solvent, for example dimethylformarnide, in the presence of a base such as potassium carbonate, and optionally in the presence of a catalytic amount of potassium iodide, at about 50°C to yield the ether product 149.8. Deprotection, as described above, then affords the thiol 149.9.
Using the above procedures, but employing, in place of the phenol 149.5, different phenols, thiophenols or amines 149.1, and/or different phosphonates 149.2, there are obtained the corresponding products 149.4.
Scheme 150 depicts the preparation of phosphonate esters Linked to a thiophenol nucleus by means of unsaturated and saturated carbon chains. The carbon chain linkage is formed by means of a palladium catalyzed Heck reaction, in which an olefinic phosphonate 150.2 is coupled with an aromatic bromo compound 150.1. The coupling of aryl halides with olefins
by means of the Heck reaction is described, for example, in Advanced Organic Chemistry, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 503ffand in Ace. Chem. Res., 12, 146, 1979. The aryl bromide and the olefin are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or a palladium(II) catalyst such as palladium(H) acetate, and optionally in the presence of a base such as triethylamine or potassium carbonate, to afford the coupled product 150.3. Deprotection, or hydrogenation of the double bond followed by deprotection, affords respectively the unsaturated phosphonate 150.4, or the saturated analog 150.6.
For example, 3-bromothiophenol is converted into the S-Fm derivative 150.7, as described above, and this compound is reacted with a dialkyl 1-butenyl phosphonate 150.8, the preparation of which is described in J. Med. Chem., 1996, 39, 949, in the presence of a palladium (IT) catalyst, for example, bis(triphenylphosphine) palladium (II) chloride, as described in J. Med. Chem, 1992, 35, 1371. The reaction is conducted in an aprotic dipolar solvent such as, for example, dimethylformamide, in the presence of triethylamine, at about 100°C to afford the coupled product 150.9. Deprotection, as described above, then affords the thiol 150.10. Optionally, the initially formed unsaturated phosphonate 150.9 is subjected to catalytic or chemical reduction, for example using diimide, as described in Scheme 138, to yield the saturated product 150.11, which upon deprotection affords the thiol 150.12. Using the above procedures, but employing, in place of the bromo compound 150.7, different bromo compounds 150.1, and/or different phosphonates 150.2, there are obtained the corresponding products 150.4 and 150.6
Scheme 151 illustrates the preparation of an aryl-linked phosphonate ester 151.4 by means of a palladium(0) or palladium(II) catalyzed coupling reaction between a bromobenzene and a phenylboronic acid, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 57. The sulfur-substituted phenylboronic acid 151.1 is obtained by means of a metallation-boronation sequence applied to a protected bromo-substituted thiophenol, for example as described in J. Org. Chem., 49, 5237, 1984. A coupling reaction then affords the diaryl product 151.3 which is deprotected to yield the thiol 151.4.
For example, protection of 4-bromothiophenol by reaction with tert-butylchlorodimethylsilane, in the presence of a base such as imidazole, as described in Protective Groups in Organic
Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, p. 297, followed by metallation with butyllithium and boronation, as described in J. Organomet. Chem., 1999, 581, 82, affords the boronate 151.5. This material is reacted with a dialkyl 4-bromophenylphosphonate 151.6, the preparation of which is described in J. Chem. Soc., Perkin Trans., 1977, 2, 789, in the presence of tetrakis(triphenylphosphine) palladium (0) and an inorganic base such as sodium carbonate, to afford the coupled product 151.7. Deprotection, for example by the use of tetrabutylammonium fluoride in anhydrous tetrahydrofuran, then yields the thiol 151.8. Using the above procedures, but employing, in place of the boronate 151.5, different boronates 151.1, and/or different phosphonates 151.2, there are obtained the corresponding products 151.4.
Scheme 152 depicts the preparation of dialkyl phosphonates in which the phosphonate moiety is linked to the thiophenyl group by means of a chain which incorporates an aromatic or heteroaromatic ring. In this procedure, a suitably protected O, S or N-substituted thiophenol 152.1 is reacted with a dialkyl bromomethyl-substituted aryl or heteroarylphosphonate 152.2, prepared, for example, by means of an Arbuzov reaction between equimolar amounts of a bis(bromo-methyl) substituted aromatic compound and a trialkyl phosphite. The reaction product 152.3 is then deprotected to afford the thiol 152.4.
For example, 1,4-dimercaptobenzene is converted into the monobenzoyl ester 152.5 by reaction with one molar equivalent of benzoyl chloride, in the presence of a base such as pyridine. The monoprotected thiol 152.5 is then reacted with a dialkyl 4-(bromomethyl)phenylphosphonate, 152.6, the preparation of which is described in Tetrahedron, 1998, 54, 9341. The reaction is conducted in a solvent such as dimethylformarnide, in the presence of a base such as potassium carbonate, at about 50°C. The thioether product 152.7 thus obtained is deprotected, as described above, to afford the thiol 152.8.
Using the above procedures, but employing, in place of the thiophenol 152.5, different phenols, thiophenols or amines 152.1, and/or different phosphonates 152.2, there are obtained the corresponding products 152.4.
Scheme 153 illustrates the preparation of phosphonate-containing thiophenols in which the attached phosphonate chain forms a ring with the thiophenol moiety.
In this procedure, a suitably protected thiophenol 153.1, for example an indoline (in which X-Y is (CH2)2), an indole (X-Y is CH=CH) or a tetrahydroquinoline (X-Y is (CH2)3) is reacted with a dialkyl trifluoromethanesulfonyloxymethyl phosphonate 153.2, in the presence of an organic or inorganic base, in a polar aprotic solvent such as, for example, dimethylformamide, to afford the phosphonate ester 153.3. Deprotection, as described above, then affords the thiol 153.4. The preparation of thio-substituted indolines is described in EP 209751. Thio-substituted indoles, indolines and tetrahydroquinolines are also obtained from the corresponding hydroxy-substituted compounds, for example by thermal rearrangement of the dimethylthiocarbamoyl esters, as described in J. Org. Chem., 31, 3980, 1966. The preparation of hydroxy-substituted indoles is described in Syn., 1994, 10, 1018; preparation of hydroxy-substituted indolines is described in Tet. Lett., 1986, 27, 4565, and the preparation of hydroxy-substituted tetrahydroquinolines is described in J. Het. Chem., 1991, 28, 1517, and in J. Med. Chem., 1979, 22, 599. Thio-substituted indoles, indolines and tetrahydroquinolines are also obtained from the corresponding amino and bromo compounds, respectively by diazotization, as described in Sulfur Letters, 2000, 24, 123, or by reaction of the derived organolithium or magnesium derivative with sulfur, as described in Comprehensive Organic Functional Group Preparations, A. R. Katritzky et al, eds, Pergamon, 1995, Vol. 2, p. 707. For example, 2,3-dihydro-lH-indole-5-thiol, 153.5, the preparation of which is described in EP 209751, is converted into the benzoyl ester 153.6, as described above, and the ester is then reacted with the trifluoromethanesulfonate 153.7, using the conditions described above for the preparation of the phosphonate 148.8, (Scheme 148), to yield the phosphonate 153.8. Deprotection, for example by reaction with dilute aqueous ammonia, as described above, then affords the thiol 153.9.
Using the above procedures, but employing, in place of the thiol 153.5, different thiols 153.1, and/or different triflates 153.2, there are obtained the corresponding products 153.4.

.OR1
(Figure Remove)Schemes 154 - 158 illustrate the preparation of the tert. butylamine derivatives 9.3 and 25.4 in which the substituent A is either the group link P(O)(ORl)2 or a precursor, such as [OH], [SH], Br, which are employed in the preparation of the intermediate phosphonate esters 3, 7, 11 and 20.
Scheme 154 describes the preparation of tert-butylamines in which the phosphonate moiety is directly attached to the tert-butyl group. A suitably protected 2.2-dimethyl-2-aminoethyl bromide 154.1 is reacted with a trialkyl phosphite 154.2, under the conditions of the Arbuzov reaction, as described in Scheme 137, to afford the phosphonate 154.3, which is then deprotected to give the amine 154.4.
For example, the cbz derivative of 2.2-dimethyl-2-aminoethyl bromide 154.6, is heated with a trialkyl phosphite at ca 150°C to afford the product 154.7. Deprotection then affords the free amine 154.8. The removal of carbobenzyloxy substituents to afford the corresponding amines is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 335. The conversion is effected by the use of catalytic hydrogenation, in the presence of hydrogen or a hydrogen donor and a palladium catalyst. Alternatively, the cbz group is removed by treatment of the substrate with triethylsilane,
triethylamine and a catalytic amount of palladium (II) chloride, as described in Chem. Ber., 94, 821, 1961, or by the use of trimethylsilyl iodide in acetonitrile at ambient temperature, as described in J. Chem. Soc., Perkin Trans. I, 1277, 1988. The cbz group is also removed by treatment with Lewis acid such as boron tribromide, as described in J. Org. Chem., 39, 1247, 1974, or aluminum chloride, as described in Tet. Lett., 2793, 1979.
Using the above procedures, but employing different trialkyl phosphites, there are obtained the corresponding amines 154.4.
Scheme 155 illustrates the preparation of phosphonate esters attached to the tert butylamine by means of a heteroatom and a carbon chain. A protected alcohol or thiol 155.1 is reacted with a dialkyl bromoalkylphosphonate 155.2, to afford the displacement product 155.3. Deprotection, if needed, then yields the amine 155.4.
For example, the cbz derivative of 2-amino-2,2-dimethylethanol 155.5 is reacted with a dialkyl 4-bromobutyl phosphonate 155.6, prepared as described in Synthesis, 1994, 9, 909, in dimethylformamide containing potassium carbonate and a catalytic amount of potassium iodide, at ca 60° to afford the phosphonate 155.7 Deprotection, by hydrogenation over a palladium catalyst, then affords the free amine 155.8.
Using the above procedures, but employing different alcohols or thiols 155.1, and/or different bromoalkylphosphonates 155.2, there are obtained the corresponding ether and thioether products 155.4.
Scheme 156 describes the preparation of carbon-linked tert. butylamine phosphonate
derivatives, in which the carbon chain is unsaturated or saturated.
In the procedure, a terminal ace'tylenic derivative of tert-butylamine 156.1 is reacted, under
basic conditions, with a dialkyl chlorophosphite 156.2, to afford the acetylenic phosphonate
156.3. The coupled product 156.3 is deprotected to afford the amine 156.4. Partial or
complete catalytic hydrogenation of this compound affords the olefinic and saturated products
156.5 and 156.6 respectively.
For example, 2-amino-2-methylprop-l-yne 156.7, the preparation of which is described in WO
9320804, is converted into the N-phthalimido derivative 156.8, by reaction with phthalic
anhydride, as described in Protective Groups in Organic Synthesis, by T. W. Greene and
P.G.M. Wuts, Wiley, 1991, pp. 358. This compound is reacted with lithium diisopropylamide
in tetrahydrofuran at -78°C. The resultant anion is then reacted with a dialkyl chlorophosphite 156.2 to afford the phosphonate 156.9. Deprotection, for example by treatment with hydrazine, as described in J. Org. Chem., 43, 2320, 1978, then affords the free amine 156.10. Partial catalytic hydrogenation, for example using Lindlar catalyst, as described in Reagents for Organic Synthesis, by L. F. Fieser and M. Fieser, Volume 1, p. 566, produces the olefinic phosphonate 156.11, and conventional catalytic hydrogenation, as described in Organic Functional Group Preparations, by S.R. Sandier and W. Karo, Academic Press, 1968, p. 3. for example using 5% palladium on carbon as catalyst, affords the saturated phosphonate 156.12. Using the above procedures, but employing different acetylenic amines 156.1, and/or different dialkyl halophosphites, there are obtained the corresponding products 156.4,156.5 and 156.6.
Scheme 157 illustrates the preparation of a tert butylamine phosphonate in which the
phosphonate moiety is attached by means of a cyclic amine.
In this method, an aminopropyl-substituted cyclic amine 157.1 is reacted with a limited
amount of a bromoalkyl phosphonate 157.2, using, for example, the conditions described
above (Scheme 149) to afford the displacement product 157.3.
For example, 3-(l-amino-l-methyl)ethylpyrrolidine 157.4, the preparation of which is
described in Chem. Pharm. Bull., 1994, 42, 1442, is reacted with one molar equivalent of a
dialkyl 4-bromobutyl phosphonate 157.5, prepared as described in Synthesis, 1994, 9, 909, to
afford the displacement product 157.6.
Using the above procedures, but employing, in place of 3-(l-amino-l-methyl)ethylpyrrolidine
157.4, different cyclic amines 157.1, and/or different bromoalkylphosphonates 157.2, there are
obtained the corresponding products 157.3.
Scheme 158 illustrates the preparation of the amides 9.3 which are employed in the preparation of the phosphonate esters 3. In this procedure, the carboxylic acids 158.1, the structures of which are illustrated in Chart 10, compounds Cl - C16, are converted into the BOC-protected derivatives 155.8. Methods for the conversion of amines into the BOC derivative are described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 327. For example, the amine is reacted with di-tert-butoxycarbonylanhydride (BOC anhydride) and a base, or with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON), and the like. The carboxylic acid
158.2 is then coupled, as described in Scheme 1, with the tert. butylamine derivatives 25.4, or precursors thereto, the preparation of which is described in Schemes 154 -157, to afford the amide 158.3. The BOC group is then removed to yield the amine 9.3. The removal of BOC protecting groups is described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 328. The deprotection is effected by treatment of the BOC compound with anhydrous acids, for example, hydrogen chloride or trifluoroacetic acid, or by reaction with trimethylsilyl iodide or aluminum chloride.
Preparation of pyridine intermediates 13.1 incorporating phosphonate substituents.
Schemes 159 -163, described the preparation of chloromethyl or formyl pyridine derivatives incorporating phosphonate moieties. Scheme 164 illustrates the conversion of the above compounds into the piperazine derivatives 13.1 which are employed in the preparation of the phosphonate esters 4.
Scheme 159 illustrates the preparation of chloromethyl-substituted pyridines in which a phosphonate moiety is directly attached to the pyridine ring.
In this procedure, a halo-substituted methylpyridine 159.1 is reacted with a dialkyl phosphite 159.2, to afford the phosphonate product 159.3. The coupling reaction is conducted in the presence of a palladium (0) catalyst, for example as described in J. Med. Chem., 35, 1371, 1992. The product 159.3 is then converted into the chloromethyl derivative 159.4 by means of a chlorination reaction. The chlorination of benzylic methyl groups is described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 313. A variety of free-radical chlorinating agents are employed.
For example, 3-bromo-5-methylpyridine, 159.5 (ChemPacific) is reacted with an equimolar amount of a dialkyl sodium phosphite, 13.2 in the presence of
tetrakis(triphenylphosphine)palladium(0) and triethylamine, in toluene at reflux, to yield the phosphonate 159.6. The latter compound is then chlorinated, for example by the use of one molar equivalent of phenyliodoniumdichloride, as described in J. Org. Chem., 29, 3692, 1964, to prepare the chloromethyl compound 159.7.
Using the above procedures, but employing, in place of the bromomethyl pyridine 159.5, different halomethyl pyridines 159.1, and/or different dialkyl phosphites 159.2 the
corresponding products 159.4 are obtained.
Scheme 160 depicts the preparation of chloromethyl pyridines incorporating a phosphonate group attached to the pyridine ring by means of a carbon link. In this procedure, a bis(chloromethyl)pyridine 160.1 is reacted with a sodium dialkyl phosphite 146.3, employing, for example, procedures described in J. Med. Chem., 35, 1371, 1992, to afford the displacement product 160.2.
For example, 3,5-bis(chloromethyl)pyridine 160.3, the preparation of which is described in Eur. J. Inorg. Chem., 1998, 2, 163, is reacted with one molar equivalent of a dialkyl sodium phosphite 146.3 in tetrahydrofuran, at ambient temperature, to afford the product 160.4. Using the above procedures, but employing, in place of the bis(chloromethyl) compound 160.3, different bis(chloromethyl) pyridines 160.1, and/or different dialkyl sodium phosphites 146.3 the corresponding products 160.2 are obtained.
Scheme 161 illustrates the preparation of pyridine aldehydes incorporating a phosphonate group linked to the pyridine nucleus by means of a saturated or unsaturated carbon chain. In this procedure, a suitably protected halo-substituted pyridine carboxaldehyde 161,1 is coupled, by means of a palladium-catalyzed Heck reaction, as described in Scheme 150, with a dialkyl alkenyl phosphonate 161.2. Methods for the protection of aldehydes are described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, p. 175. The protected aldehyde 161.1 is reacted with an olefinic phosphonate 161.2, in the presence of a palladium (0) catalyst, to afford the coupled product 161.3. Deprotection of the aldehyde group then affords the product 161.6. Alternatively, the unsaturated compound 161.3 is reduced to afford the saturated analog 161.5, which upon deprotection yields the saturated analog 161.7. Methods for the reduction of carbon-carbon double bonds are described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 6. The methods include catalytic reduction, and chemical reduction, the latter for example employing diborane or diimide.
For example, 5-bromopyridine-3-carboxaldehyde 161.8 (ChemPacific) is converted into the dimethyl acetal, by reaction with methanolic ammonium chloride, as described in J. Org. Chem., 26,1156, 1961. The acetal 161.9 is then reacted with a dialkyl butenyl phosphonate 161.10, the preparation of which is described in J. Med. Chem., 1996, 39, 949, in the presence of bis(triphenylphosphine) palladium(lT) chloride, as described in J. Med. Chem., 1992, 35, 1371, to afford the coupled product 161.11. Deprotection, for example by treatment with formic acid in pentane, as described in Synthesis, 651, 1983. yields the free aldehyde 161.13.
The product is reduced, for example by reaction with diimide, as described in J. Org. Chem., 30, 3965, 1965, to afford the saturated product 161.12.
Using the above procedures, but employing, in place of the aldehyde 161.8, different aldehydes 161.1, and/or different phosphonates 161.2, the corresponding products 161.6 and 161.7 are obtained.
Scheme 162 illustrates the preparation of pyridine aldehydes incorporating a phosphonate group linked to the pyridine by a heteroatom and a carbon chain. In this procedure, a 2- or 4-halo-substiruted pyridine aldehyde 162.1 is reacted with a dialkyl hydroxy- or thio-alkylphosphonate 162.2. The preparation of alkoxypyridines by the reaction of alkoxides with halopyridines is described, for example, in J. Am. Chem. Soc., 82, 4414,1960. The preparation of pyridine thioethers by reaction of halopyridines with thiols is described, for example, in Chemistry of Heterocyclic Compounds, Pyridine and its derivatives, E. Klingsberg, Ed, part 4, p. 358. The alcohols and thiols are transformed into metal salts, for example sodium or potassium salts, and then reacted with the halopyridine substrates at elevated temperatures, optionally in the presence of copper powder catalyst, to afford the ether or thioether products 162.3.
For example, a tetrahydrofuran solution of 2-bromo-pyridine-5-aldehyde 162.4, prepared as described in Tet. Lett., 2001,42, 4841, is heated at reflux with an equimolar amount of a dialkyl 2-mercaptoethylphophonate 162.5, the preparation of which is described in Aust. J. Chem., 43, 1123,1990, in the presence of sodium carbonate, to afford the thioether product 162.6.
Using the above procedures, but employing, in place of the haloaldehyde 162.4, different haloaldehydes 162.1, and/or different hydroxy or thio-alkyl phosphonates 162.2, the corresponding products 162.3 are obtained.
Scheme 163 depicts the preparation of pyridine aldehydes 163.3 in which the phosphonate group is attached to the pyridine nucleus by means of a chain incorporating a nitrogen atom. In this procedure, a pyridine dicarboxaldehyde 163.1 is reacted with a dialkyl aminoalkyl phosphonate 163.2, in the presence of a reducing agent, so as to effect a reductive amination reaction, yielding the product 163.3. The preparation of amines by means of reductive amination of aldehydes is described, for example, in Advanced Organic Chemistry, F. A.
Carey, R. J. Sundberg, Plenum, 2001, part B, p. 269. The reactants are combined in an inert solvent such as an alcohol or ether, and treated with a reducing agent such as, for example, sodium cyanoborohydride or sodium triacetoxy borohydride, so as to yield the amine product 163.3.
For example, equimolar amounts of pyridine 3,5-dicarboxaldehyde 163.4, prepared as described in Tet. Lett., 1994, 35, 6191, and a dialkyl 2-aminoethyl phosphonate 163.5 prepared as described in J. Org. Chera, 2000, 65, 676, are reacted with sodium cyanoborohydride in isopropanol containing acetic acid, at ambient temperature, so as to produce the amine product 163.6
Using the above procedures, but employing, in place of the dicarboxaldehyde 163.4, different dicarboxaldehydes 163.1, and/or different aminoalkyl phosphonates 163.2, the corresponding products 163.3 are obtained.
Scheme 164 illustrates the incorporation of the formyl or chloromethyl pyridines, the syntheses of which are described above, into the piperazine reagent 13.1. Compounds 164.2 in which Z is chloromethyl are reacted with the mono-protected piperazine derivatives 164.1, the preparation of which are described in WO 9711698, to afford the alkylated product 164.3. The preparation of amines by means of alkylation reactions is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 397. Equimolar amounts of the reactants 164.1 and the halomethyl pyridine compound 164.2, are combined in a organic solvent such as an alcohol or dimethylformamide, in the presence of a base such as triethylamine or potassium carbonate, to give the alkylated products 164.3. The alkylation of a piperazine derivative by a 3-chloromethylpyridine is described in WO9628439. Alternatively, the amine 164.1 is reacted with the aldehyde 164.2 to afford the product 164.3 in a reductive alkylation reaction. The preparation of amines by means of reductive amination procedures is described in Scheme 163. In this procedure, the amine component and the aldehyde component are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride or diisobutylaluminum hydride, optionally in the presence of a Lewis acid, such as titanium tetraisopropoxide, as described in J. Org. Chem., 55, 2552, 1990. The reductive alkylation reaction between 3-pyridinecarboxaldehyde and a substituted piperazine is described in WO9628439. Deprotection of the product 164.3 then yields the free amine 13.1.



Preparation of dimethoxybenzyl halides 49.7 incorporating phosphonate groups.
Schemes 165 - 169 illustrate the preparation of dimethoxybenzyl halides 49.7 incorporating phosphonate groups, which are employed in the synthesis of the phosphonate esters 6 and 13.
Scheme 165 depicts the preparation of dimethoxybenzyl alcohols in which the phosphonate group is attached either directly to the phenyl ring or by a saturated or unsaturated alkylene
chain. In this procedure, a bromo-substituted dimethoxy benzyl alcohol is coupled, in the presence of a palladium catalyst, with a dialkyl alkenyl phosphonate 165.2, to afford the coupled product 165.3. The reaction is conducted under the conditions described in Scheme 150. The product 165.3 is then reduced, for example by treatment with diimide, as described in Scheme 150, to yield the saturated analog 165.4. Alternatively, the bromo compound 165.1 is coupled, hi the presence of a palladium catalyst, as described in Scheme 144, with a dialkyl phosphite 165.5, to afford the phosphonate 165.6.
For example, 4-bromo-3,5-dimethoxybenzyl alcohol 165.7, the preparation of which is described in J. Med. Chem., 1977, 20, 299, is coupled with a dialkyl allyl phosphonate 165.8 (Aldrich) in the presence of bis(triphenylphosphine) palladium (II) chloride, as described in J. Med. Chem, 1992, 35, 1371. The reaction is conducted in an aprotic dipolar solvent such as, for example, dimethylformamide, in the presence of triethylamine, at about 100°Cto afford the coupled product 165.9. The product is reduced, for example by treatment with diimide, as described in J. Org. Chem,, 52, 4665, 1987, to yield the saturated compound 165.10. Using the above procedures, but employing, in place of the dimethoxy bromobenzyl alcohol 165.7, different benzyl alcohols 165.1, and/or different alkenyl phosphonates 165.2, the corresponding products 165.3 and 165.4 are obtained.
As a further example, 3-bromo-4,5-dimethoxybenzyl alcohol 165.11, the preparation of which is described in J. Org. Chem., 1978,43, 1580, is coupled, in toluene solution at reflux, with a dialkyl phosphite 165.5, triethylamine and tetrakis(triphenylphosphine)palladium(0), as described in J. Med. Chem., 35, 1371, 1992, to yield the phenyl phosphonate 165.12. Using the above procedures, but employing, in place of the dimethoxy bromobenzyl alcohol 165.11, different benzyl alcohols 165.1, and/or different dialkyl phosphites 165.5, the corresponding products 165.6 are obtained.
Scheme 166 illustrates the preparation of dimethoxybenzyl alcohols incorporating phosphonate groups attached by means of an amide group. In this procedure, a carboxy-substituted dimethoxybenzyl alcohol 166.1 is coupled, as described in Scheme 1, with a dialkyl aminoalkyl phosphonate 166.2 to prepare the amide 166.3.
For example, 2,6-dimethoxy-4-(hydroxymethyl)benzoic acid 166.4, the preparation of which is described in Chem. Pharm. Bull., 1990, 38, 2118, is coupled in dimethylformamide solution, in
the presence of dicyclohexylcarbodiimide, with a dialkyl aminoethyl phosphonate 166.5, the preparation of which is described in J. Org. Chem., 2000, 65, 676, to afford the amide 166.6. Using the above procedures, but employing, in place of the dimethoxybenzoic acid 166.4, different benzoic acids 166.1, and/or different aminoalkyl phosphites 166.2, the corresponding products 166.3 are obtained.
Scheme 167 illustrates the preparation of dimethoxybenzyl alcohols incorporating
phosphonate groups attached by means of an aminoalkyl or an amide group. In this
procedure, an amino-substituted dimethoxybenzyl alcohol 167.1 is reacted, under reductive
amination conditions, as described in Scheme 163, with a dialkyl formylalkylphosphonate
167.2 to yield the aminoalkyl product 167.3. Alternatively, the amino-substituted
dimethoxybenzyl alcohol 167.1 is coupled, as described in Scheme 1, with a dialkyl
carboxyalkyl phosphonate 167.4, to produce the amide 167.5.
For example, 3-amino-4,5-dimethoxybenzyl alcohol 167.6, the preparation of which is
described in Bull Chem. Soc. Jpn., 1972, 45, 3455, is reacted, in the presence of sodium
triacetoxyborohydride, with a dialkyl formylmethyl phosphonate 167.7, as described in
Scheme 135, to afford the aminoethyl phosphonate 167.8.
Using the above procedures, but employing, in place of the amine 167.6, different amines
167.1, and/or different formylalkyl phosphites 167.2, the corresponding products 167.3 are
obtained.
As a further example, 4-amino-3,5-dimethoxybenzyl alcohol 167.9, the preparation of which is
described in Bull. Chem. Soc. Jpn., 1972,45, 3455, is coupled, in the presence of dicyclohexyl
carbodiimide, with a dialkyl phosphonoacetic acid 167.10, (Aldrich) to afford the amide
167.11.
Using the above procedures, but employing, in place of the amine 167.6, different amines
167.1, and/or different carboxyalkyl phosphonates 167.4, the corresponding products 167.5
are obtained.
Scheme 168 illustrates the preparation of dimethoxybenzyl alcohols incorporating phosphonate groups attached by means of an alkoxy group. In this procedure, a dimethoxyhydroxy benzyl alcohol 168.1 is reacted with a dialkyl alkylphosphonate 168.2 with a terminal leaving group to afford the alkoxy product 168.3. The alkylation reaction is
effected in a polar organic solvent such as dimethylformamide in the presence of a base such as
dimethylaminopyridine or cesium carbonate.
For example, 4-hydroxy-3,5-dimethoxybenzyl alcohol 168.4, the preparation of which is
described in J. Med. Chem. 1999, 43, 3657, is reacted in dimethylformamide at 80°C with an
equimolar amount of a dialkyl bromopropyl phosphonate 168.5, prepared as described in J.
Am. Chem. Soc., 2000, 122, 1554, and cesium carbonate, to give the alkylated product 168.6.
Using the above procedures, but employing, in place of the phenol 168.4, different phenols
168.1, and/or different alkyl phosphonates 168.2, the corresponding products 168.3 are
obtained.
As a further example, 4,5-dimethoxy-3-hydroxybenzyl alcohol 168.7, prepared as described in
J. Org. Chem., 1989, 54, 4105, is reacted, as described above, with a dialkyl
trifluoromethanesulfonyloxymethyl phosphonate 168.8, prepared as described in Tet. Lett.,
1986, 27, 1477, to produce the alkylated product 168.9.
Using the above procedures, but employing, in place of the phenol 168.7, different phenols
168.1, and/or different alkyl phosphonates 168.2, the corresponding products 168.3 are
obtained.
Scheme 169 illustrates the conversion of the benzyl alcohols 169.1, in which the substituent A is the group link-P(O)(OR1)2, or a precursor, prepared as described above, into the corresponding halides 169.2. The conversion of alcohols into chlorides, bromides and iodides is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 354ff, p. 356ff and p. 358ff. For example, benzyl alcohols are transformed into the chloro compounds, in which Ha is chloro, by reaction with triphenylphosphine and N-chlorosuccinimide, as described in J. Am. Chem. Soc., 106, 3286, 1984. Benzyl alcohols are transformed into bromo compounds by reaction with carbon tetrabromide and triphenylphosphine, as described in J. Am. Chem. Soc., 92, 2139,1970. Benzyl alcohols are transformed into iodides by reaction with sodium iodide and boron trifluoride etherate, as described in Tet. Lett., 28,4969, 1987, or by reaction with diphosphorus tetraiodide, as described in Tet. Lett., 1801, 1979. Benzylic chlorides or bromides are transformed into the corresponding iodides by reaction with sodium iodide in acetone or methanol, for example as described in EP 708085.
Preparation of dimethoxythiophenols 23.1 incorporating phosphonate groups.
Schemes 170 -173 illustrate the preparation of the dimethoxythiophenols 23.1 incorporating phosphonate groups, which are used in the synthesis of the phosphonate esters 6 and 13.
Scheme 170 illustrates the preparation of dimethoxythiophenol derivatives incorporating a phosphonate group attached by means of an amide group. In this procedure, a dimethoxyamino-substituted benzoic acid 170.1 is converted into the corresponding thiol
170.2. The conversion of amines into the corresponding thiols is described in Sulfur Lett.,
2000, 24, 123. The amine is first converted into the diazonium salt by reaction with nitrous
acid. The diazonium salt, preferably the diazonium tetrafluoborate, is reacted in acetonitrile
solution with a sulfhydryl ion exchange resin, as described in Sulfur Lett., 2000, 24, 123, to
afford the thiol 170.2. The product is then coupled, as described above, with a dialkyl
aminoalkyl phosphonate 170.3, to yield the amide 170.4.
For example, 5-amino-2,3-dimethoxybenzoic acid 170.5, the preparation of which is described in JP 02028185, is converted, as described above, into 2,3-dimethoxy-5-mercaptobenzoic acid 170.6. The product is then coupled, as described in Scheme 1, in the presence of dicyclohexyl carbodiimide, with a dialkyl aminopropyl phosphonate 170.7, (Acros) to afford the amide 170.8.
Using the above procedures, but employing, in place of the amine 170.5, different amines 170.1, and/or different aminoalkyl phosphonates 170.3, the corresponding products 170.4 are obtained.
Scheme 171 illustrates the preparation of dimethoxythiophenol derivatives incorporating a phosphonate group attached by means of a saturated or unsaturated alkylene chain. In this procedure, a bromodimethoxyaniline 171.1 is converted, as described in Scheme 170, into the corresponding thiophenol 171.2. The thiol group is then protected to give the derivative
171.3. The protection and deprotection of thiol groups is described in Protective Groups in
Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 277.
For example, thiol substituents are protected as trialkylsilyloxy groups. Trialkylsilyl groups
are introduced by the reaction of the thiophenol with a chlorotrialkylsilane and a base such as
imidazole. Alternatively, thiol substituents are protected by conversion to tert-butyl or
adamantyl thioethers, or 4-methoxybenzyl thioethers, prepared by the reaction between the thiol and 4-methoxybenzyl chloride in the presence of ammonium hydroxide, as described in Bull. Chem. Soc. Jpn., 37, 433, 1974. The product 171.3 is then coupled, in the presence of a palladium catalyst, as described in Scheme 165, with a dialkyl alkenyl phosphonate 171.4, to give the alkenyl product 171.5. Deprotection then yields the thiol 171.6. Reduction of the double bond, for example by reaction with diimide, as described in J. Org. Chem., 52, 4665, 1987, affords the saturated product 171.7.
For example, 4-bromo-3,5-dimethoxyaniline 171.8, prepared as described in WO9936393, is converted, by diazotization, into 4-bromo-3,5-dimethoxythiophenol 171.9. The product is then transformed into the S-benzoyl derivative 171.10, by reaction with benzoyl chloride in pyridine, and the product is coupled, as described in Scheme 165, with a dialkyl butenyl phosphonate 171.11, the preparation of which is described in J. Med. Chem., 1996, 39, 949, to yield the phosphonate 171.12. Deprotection, for example by treatment with aqueous ammonia at ambient temperature, as described in J. Am. Chem. Soc., 85, 1337, 1963, then afford the thiol 171.13. The double bond is reduced with diimide to give the saturated analog 171.14.
Using the above procedures, but employing, in place of the amine 171.8, different amines 171.1, and/or different alkenyl phosphonates 171.4, the corresponding products 171.6 and 171.7 are obtained.
Scheme 172 illustrates the preparation of dimethoxythiophenol derivatives incorporating a phosphonate group directly attached to the phenyl ring. In this procedure, a protected bromodimethoxythiophenol 172.1, prepared, for example, from the corresponding aniline, as described above, is coupled, in the presence of a palladium catalyst, as described in Scheme 165, with a dialkyl phosphite 172.2. The product is then deprotected to afford the phosphonate ester 172.4.
For example, 3-bromo-4,5-dimethoxyaniline 172.5, prepared as described in DE 2355394, is converted, as described above in Schemes 165 and 171, into S-benzoyl 3-bromo-4,5-dimethoxythiophenol 172.6. This compound is then coupled, in toluene solution at reflux, with a dialkyl phosphite 172.2, triethylamine and tetrakis(triphenylphosphine)palladium(0), as described in J. Med. Chem., 35, 1371, 1992, to yield the phenyl phosphonate 172.7. Deprotection, as described in Scheme 171, then affords the thiol 172.8.
Using the above procedures, but employing, in place of the protected thiol 172.6, different thiol 172.1, the corresponding products 172.4 are obtained.
Scheme 173 illustrates the preparation of dimethoxythiophenol derivatives incorporating a phosphonate group attached to the phenyl ring by means of an alkoxy group. In this procedure, a dimethoxy aminophenol 173.1 is converted, via the diazo compound, into the corresponding thiophenol 173.2. The thiol group is then protected, and the product 173.3 is alkylated, as described in Scheme 168, with a dialkyl bromoalkyl phosphonate 173.4. Deprotection of the product 173.5 then affords the thiophenol 173.6. For example, 5-amino-2,3-dimethoxyphenol 173.7, prepared as described in WO 9841512, is converted by diazotization, as described above, into the thiophenol 173.8, and the product is protected by reaction with one molar equivalent of benzoyl chloride in pyridine, to yield the S-benzoyl product 173.9. The latter compound is then reacted, in dimethytformamide solution at 80°C, with a dialkyl bromoethyl phosphonate 173.10 (Aldrich) and cesium carbonate, to produce the ethoxyphosphonate 173.11. Deprotection, as described in Scheme 171, then yields the thiol 173.12.
Using the above procedures, but employing, in place of the thiol 173.8, different thiol 173.2, and/or different bromoalkyl phosphonates 173.4, the corresponding products 173.6 are obtained.

(Figure Remove)Preparation of ethanolamine derivatives 29.1 incorporating phosphonate groups.
Schemes 174 -178 illustrate the preparation of the ethanolamine derivatives 29.1 which are employed in the preparation of the phosphonate esters 18 and 8.
Scheme 174 illustrates the preparation of ethanolamine derivatives in which the phosphonate group is attached by means of an alkyl chain. In this procedure, ethanolamine 174.1 is protected to give the derivative 174.2. The product is then reacted with a dialkyl alkyl phosphonate 174.3 in which the alkyl group incorporates a leaving group Lv. The alkylation
reaction is performed in a polar organic solvent such as acetonitrile or dimethylformamide, in the presence of a strong base such as sodium hydride or lithium hexamethyldisilazide, to afford the ether product 174.4. The protecting group is then removed to yield the amine 174.5. The protection and deprotection of amines is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 309. The amino compound 174.5 is then coupled, as described in Scheme 1, with the aminoacid 174.6, to give the amide 174.7.
For example, equimolar amounts of phthalimide and ethanolamine are reacted in toluene at 70°C, as described in J. Org. Chem., 43, 2320, 1978, to prepare the phthalimido derivative 174.8, in which Phth is phthalimido. The product is then reacted, in tetrahydrofuran, with sodium hydride and an equimolar amount of a dialkyl trifluoromethylsulfonyloxymethyl phosphonate 174.9, the preparation of which is described in Tet. Lett., 1986, 27, 1497, to afford the ether product 174.10. The phthalimido group is then removed by treatment of the product 174.10 with ethanolic hydrazine at ambient temperature, as described in J. Org. Chem., 43, 2320, 1978, to yield the amine 174.11. The product is then coupled, in the presence of dicyclohexylcarbodiimide, with the aminoacid 174.6, to yield the amide 174.12. Using the above procedures, but employing, in place of the methylphosphonate 174.9, different alkylphosphonates 174.3, the corresponding products 174.7 are obtained.
Scheme 175 illustrates the preparation of ethanolamine derivatives in which the phosphonate group is attached by means of an alkylene chain incorporating a nitrogen. In this procedure, ethanolamine 174.1 and the aminoacid 174.6 are coupled, as described in Scheme 1, to form the amide 175.1. The product is then alkylated with a bromoalkyl aldehyde 175.2 to yield the ether 175.3. The alkylation reaction is performed in a polar organic solvent such as acetonitrile or dioxan, in the presence of a strong base such, as potassium tert. butoxide or sodium hydride, at about 60°C. The aldehyde product is then reacted, under reductive amination conditions, as described in Scheme 135, with a dialkyl aminoalkyl phosphonate 175.4, to produce the amine product 175.5.
For example, the amide 175.1 is reacted, as described above, with bromoacetaldehyde 175.6, to afford the ether 175.7. The product is then reacted in ethanol with a dialkyl aminoethyl phosphonate 175.8, (Aurora)and sodium triacetoxyborohydride, to yield the amine 175.9.
Using the above procedures, but employing, in place of the bromoacetaldehyde 175.6, different bromoalkyl aldehydes 175.2, and/or different aminoalkyl phosphonates 175.4, the corresponding products 175.5 are obtained.
Scheme 176 illustrates the preparation of ethanolamine derivatives in which the phosphonate group is attached by means of a phenyl ring. In this procedure, bromoethylamine 176.1 and the aminoacid 174.6 are coupled, as described in Scheme 1, to afford the amide 176.2. The product is then reacted with the dialkyl hydroxyalkyl-substituted phenylphosphonate 176.3 to prepare the ether 176.4. The alkylation reaction is performed in a polar organic solvent such as dimethyl sulfoxide or dioxan, in the presence of a base such as lithium bis(trimethylsilyl)amide, sodium hydride or lithium piperidide. For example, the amide 176.2 is reacted in dimethylformamide with a dialkyl 4-(2-hydroxyethyl)phenyl phosphonate 176.5, prepared as described in J. Am. Chem. Soc., 1996, 118, 5881, and sodium hydride, to furnish the ether product 176.6.
Using the above procedures, but employing, in place of the hydroxyethyl phenylphosphonate 176.5, different phosphonates 176.3, the corresponding products 176.4 are obtained.
Scheme 177 illustrates the preparation of ethanolamine derivatives in which the phosphonate group is attached by means of an alkylene chain. In this procedure, the aminoacid 174.6 is coupled with a bromoalkoxy-substituted ethylamine 177.1 to give the amide 177.2. The product is then subjected to an Arbuzov reaction with a trialkyl phosphite PCOR1^. In this procedure, described in Handb. Organophosphorus Chem., 1992, 115, the reactants are heated together at ca. 100°C to afford the product 177.4.
For example, the aminoacid 174.6 is coupled, as described in Scheme 1, in acetonitrile solution containing dicyclohexylcarbodiimide, with 2-bromoethoxyethylamine 177.5, prepared as described in Vop. Khim. Tekh., 1974, 34, 6, to produce the amide 177.6. The product is then heated at 120°C with excess trialkyl phosphite 177.3, to afford the phosphonate 177.7. Using the above procedures, but employing, in place of the bromoethoxyethylamine 177.5, different bromoalkyl ethylamines 177.1, the corresponding products 177.4 are obtained.
Scheme 178 depicts the preparation of the amines 29.1. The BOC-protected ethanolamine derivatives 178.1, in which the group A is either the substituent link-P(O)(OR1)2, or a
precursor thereto, prepared as described in Schemes 174 -177, are deprotected to afford the amines 29.1. The removal of BOC protecting groups is described, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 328. The deprotection is effected by treatment of the BOC compound with anhydrous acids, for example, hydrogen chloride in ethyl acetate, or trifluoroacetic acid, or by reaction with trimethylsilyl iodide or aluminum chloride.
Preparation of the chroman phosphonate esters 33.1.
Schemes 179 - 181a illustrate the preparation of the chroman phosphonate esters 33.1 which are employed in the preparation of the phosphonate esters 17 and 9.
Scheme 179 depicts the preparation of (2-methyl-3a,9b-dihydro-4H-chromeno[4,3-d]oxazol-4-yl)-methanol, 179.6, 2-methyl-3a,9b-dihydro-4H-chromeno[4,3-d]oxazole-4-carbaldehyde, 179.7, and 2-methyl-3a,9b-dihydro-4H-chromeno[4,3-d]oxazole-4-carboxyUc acid, 179.8, which are used in the preparation of the phosphonates 33.1. In this procedure, (2H-chromen-2-yl)-methanol 179.1, prepared as described in J. Chem. Soc., (D), 344, 1973, is converted, as described above, (Scheme l)into the tert. butyldimethylsilyl ether 179.2. The product is then reacted, as described in J. Het. Chem., 1975, 12, 1179, with silver cyanate and iodine in ether, so as to afford the addition product 179.3. This compound is then heated on methanol to yield the carbamate derivative 179.4. The latter compound is heated in xylene at reflux, as described in J. Het. Chem., 1975, 12, 1179, to produce the oxazoline derivative 179.5. The silyl group is then removed by reaction with tetrabutylammonium fluoride in tetrahydrofuran to yield the carbinol 179.6. The carbinol is oxidized to produce the aldehyde 179.7. The conversion of alcohols to aldehydes is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 604ff. The alcohol is reacted with an oxidizing agent such as pyridinium chlorochromate, silver carbonate, dimethyl sulfoxide/acetic anhydride or dimethyl sulfoxide-dicyclohexyl carbodiimide. The reaction is conducted in an inert aprotic solvent such as dichloromethane or toluene. The aldehyde 179.7 is oxidized to the carboxylic acid 179.8. The oxidation of aldehydes to carboxylic acids is described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 838ff. The conversion is effected by treatment with oxidizing agents such as potassium permanganate,
ruthenium tetroxide, chromium trioxide in acetic acid, or, preferably, by the use of silver oxide, as described in J. Am. Chem. Soc., 73, 2590, 1951.
Scheme 180 illustrates the preparation of chroman derivatives in which the phosphonate group is attached by means of an aminoalkyl chain. In this procedure, the aldehyde 179.7 is reacted, under reductive amination conditions, as described in Scheme 175, with a dialkyl aminoaJkyl phosphonate 180.1, to give the amine 180.2. The oxazoline group is then hydrolyzed, for example by reaction with aqueous potassium hydroxide, as described in J. Het. Chem., 1975, 12,1179, to yield the hydroxyamine 180.3.
For example, the aldehyde 179.7 is reacted in ethanol with a dialkyl aminomethyl phosphonate 180.4, (Interchim) and sodium triacetoxyborohydride, to produce the amine 180.5. The oxazoline is then hydrolyzed, as described above, to afford the hydroxyamine 180.6. Using the above procedures, but employing, in place of the aminomethyl phosphonate 180.4, different phosphonates 180.1, the corresponding products 180.3 are obtained.
Scheme 181 illustrates the preparation of chroman derivatives in which the phosphonate group
is attached by means of an amide group. In this procedure, the carboxylic acid 179.8 is
coupled, as described in Scheme 1, with a dialkyl aminoalkyl phosphonate 180.1, to produce
the amide 181.1. Hydrolysis of the oxazoline group, as described above, then yields the
hydroxyamine 181.2.
For example, the carboxylic acid 179.8 is coupled with a dialkyl aminopropyl phosphonate
181.3, (Acros) to afford the amide 181.4, which is then hydrolyzed to give the hydroxyamine
181.5.
Using the above procedures, but employing, in place of the aminopropyl phosphonate 181.3,
different phosphonates 180.1, the corresponding products 181.2 are obtained.
Scheme 181a illustrates the preparation of chroman derivatives in which the phosphonate group is attached by means of a thioalkyl group. In this procedure, the carbinol 179.6 is converted into the bromo derivative ISla.l. The conversion of alcohols into bromides is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 356ff. For example, the alcohol is reacted with triphenyl phosphine and carbon tetrabromide, trimethylsilyl bromide, thionyl bromide and the like. The bromo compound is
then reacted with a dialkyl thioalkyl phosphonate 181a.2 to effect displacement of the bromide
and formation of the thioether 181a.3. The reaction is performed in a polar organic solvent
such as ethanol in the presence of a base such as potassium carbonate. Removal of the
isoxazoline group then produces the hydroxyamine 181a.4.
For example, the bromo compound 181a.l is reacted in ethanol with a dialkyl thioethyl
phosphonate ISla.S, prepared as described in Zh. Obschei. Khim., 1973,43, 2364, and
potassium carbonate, to yield the thioether product 181a.6. Hydrolysis, as described above,
then affords the hydroxyamine 181a.7.
Using the above procedures, but employing, in place of the thioethyl phosphonate 181a.5,
different phosphonates 181a.2, the corresponding products 181a.4 are obtained.
Schemes 182 -185 illustrate the preparation of phosphonate-containing phenylalanine derivatives 37.1 which are employed in the preparation of the intermediate phosphonate esters 10 and 19.
Scheme 182 illustrates the preparation of phenylalanine derivatives incorporating phosphonate moieties attached to the phenyl ring by means of a heteroatom and an alkylene chain. The compounds are obtained by means of alkylation or condensation reactions of hydroxy or mercapto-substituted phenylalanine derivatives 182.1.
In this procedure, a hydroxy or mercapto-substituted phenylalanine is converted into the benzyl ester 182.2. The conversion of carboxylic acids into esters is described for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 966. The conversion is effected by means of an acid-catalyzed reaction between the carboxylic acid and benzyl alcohol, or by means of a base-catalyzed reaction between the carboxylic acid and a benzyl halide, for example benzyl chloride. The hydroxyl or mercapto substituent present in the benzyl ester 182.2 is then protected. Protection methods for phenols and thiols are described respectively, for example, in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 10, p. 277. For example, suitable protecting groups for phenols and thiophenols include tert-butyldimethylsilyl or tert-butyldiphenylsilyl. Thiophenols are also protected as S-adamantyl groups, as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 289. The protected hydroxy- or mercapto ester 182.3 is then converted into the BOC derivative 182.4. The protecting group present on the O or S substituent is then removed. Removal of O or S protecting groups is described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Second Edition 1990, p. 10, p. 277. For example, silyl protecting groups are removed by treatment with tetrabutylammonium fluoride, in a solvent such as tetrahydrofuran at ambient temperature, as described in J. Am. Chem. Soc., 94, 6190, 1972. S-Adamantyl groups are removed by treatment with mercuric trifluoroacetate in acetic acid, as described in Chem. Pharm. Bull., 26, 1576, 1978. The resultant phenol or thiophenol 182.5 is then reacted under various conditions to provide protected phenylalanine derivatives 182.9,182.10 or 182.11, incorporating phosphonate moieties attached by means of a heteroatom and an alkylene chain.
In this step, the phenol or thiophenol 182.5 is reacted with a dialkyl bromoalkyl phosphonate 182.6 to afford the ether or thioether product 182.9. The alkylation reaction is effected in the presence of an organic or inorganic base, such as, for example, diazabicyclononene, cesium carbonate or potassium carbonate. The reaction is performed at from ambient temperature to ca. 80°C, in a polar organic solvent such as dimethylformamide or acetonitrile, to afford the ether or thioether product 182.9. Deprotection of the benzyl ester group, for example by means of catalytic hydrogenation over a palladium catalyst, then yields the carboxylic acid 182.12. The benzyl esters 182.10 and 182.11, the preparation of which is described above, are similarly deprotected to produce the corresponding carboxylic acids. For example, as illustrated in Scheme 182, Example 1, a hydroxy-substituted phenylalanine derivative such as tyrosine, 182.13 is converted, as described above, into the benzyl ester 182.14. The latter compound is then reacted with one molar equivalent of chloro tert-butyldimethylsilane, in the presence of a base such as imidazole, as described in J. Am. Chem. Soc., 94, 6190, 1972, to afford the silyl ether 182.15. This compound is then converted, as described above, into the BOC derivative 182.16. The silyl protecting group is removed by treatment of the silyl ether 182.16 with a tetrahydrofuran solution of tetrabutylammonium fluoride at ambient temperature, as described in J. Am. Chem. Soc., 94, 6190, 1972, to afford the phenol 182.17. The latter compound is then reacted in dimethylformamide at ca. 60°C, with one molar equivalent of a dialkyl 3-bromopropyl phosphonate 182.18 (Aldrich), in the presence of cesium carbonate, to afford the alkylated product 182.19. Debenzylation then produces the carboxylic acid 182.20.
Using the above procedures, but employing, in place of the hydroxy-substituted phenylalanine derivative 182.13, different hydroxy or thio-substituted phenylalanine derivatives 182.1, and/or different bromoalkyl phosphonates 182.6, the corresponding ether or thioether products 182.12 are obtained.
Alternatively, the hydroxy or mercapto-substituted phenylalanine derivative 182.5 is reacted with a dialkyl hydroxymethyl phosphonate 182.7 under the conditions of the Mitsonobu reaction, to afford the ether or thioether compounds 182.10. The preparation of aromatic ethers and thioethers by means of the Mitsonobu reaction is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 448, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 153-4. The phenol or thiophenol and the alcohol component are reacted together in an aprotic
solvent such as, for example, tetrahydrofuran, in the presence of a dialkyl azodicarboxylate and a triarylphosphine, to afford the ether or thioether products 182.10. For example, as shown in Scheme 182, Example 2, 3-mercaptophenylalanine 182.21, prepared as described in WO 0036136, is converted, as described above, into the benzyl ester 182.22. The resultant ester is then reacted in tetrahydrofuran solution with one molar equivalent of 4-methoxybenzyl chloride in the presence of ammonium hydroxide, as described in Bull. Chem. Soc. Jpn., 37, 433, 1974, to afford the 4-methoxybenzyl thioether 182.23. This compound is then converted into the BOC-protected derivative 182.24. The 4-methoxybenzyl group is then removed by the reaction of the thioether 182.24 with mercuric trifluoroacetate and anisole in trifluoroacetic acid, as described in J.Org. Chem., 52, 4420, 1987, to afford the thiol 182.25. The latter compound is reacted, under the conditions of the Mitsonobu reaction, with a dialkyl hydroxymethyl phosphonate 182.7, diethylazodicarboxylate and triphenylphosphine, for example as described in Synthesis, 4, 327, 1998, to yield the thioether product 182.26. The benzyl ester protecting group is then removed to afford the carboxylic acid 182.27. Using the above procedures, but employing, in place of the mercapto-substituted phenylalanine derivative 182.21, different hydroxy or mercapto-substituted phenylalanines 182.1, and/or different dialkyl hydroxymethyl phosphonates 182.7, the corresponding products 182.10 are obtained.
Alternatively, the hydroxy or mercapto-substituted protected phenylalanine derivative 182.5 is reacted with an activated derivative of a dialkyl hydroxymethylphosphonate 182.8 in which Lv is a leaving group. The components are reacted together in a polar aprotic solvent such as, for example, dimethylformamide or dioxan, in the presence of an organic or inorganic base such as triethylamine or cesium carbonate, to afford the ether or thioether products 182.11. For example, as illustrated in Scheme 182, Example 3, 3-hydroxyphenylalanine 182.28 (Fluka) is converted, using the procedures described above, into the protected compound 182.29. The latter compound is reacted, in dimethylformamide at ca. 50°C, in the presence of potassium carbonate, with diethyl trifluoromethanesulfonyloxymethylphosphonate 182.30, prepared as described in Tet. Lett., 1986, 27, 1477, to afford the ether product 182.31. Debenzylation then produces the carboxylic acid 182.32.
Using the above procedures, but employing, in place of the hydroxy-substituted phenylalanine derivative 182.28, different hydroxy or mercapto-substituted phenylalanines 182.1, and/or
different dialkyl trifluoromethanesulfonyloxymethylphosphonates 182.8, the corresponding products 182.11 are obtained.
Scheme 183 illustrates the preparation of phenylalanine derivatives incorporating phosphonate moieties attached to the phenyl ring by means of an alkylene chain incorporating a nitrogen atom. The compounds are obtained by means of a reductive alkylation reaction between a formyl-substituted protected phenylalanine derivative 183.3 and a dialkyl aminoalkylphosphonate 183.4.
In this procedure, a hydroxymethyl-substituted phenylalanine 183.1 is converted, as described above, into the BOC protected benzyl ester 183.2. The latter compound is then oxidized to afford the corresponding aldehyde 183.3. The conversion of alcohols to aldehydes is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 604ff. Typically, the alcohol is reacted with an oxidizing agent such as pyridinium chlorochromate, silver carbonate, or dimethyl sulfoxide/acetic anhydride, to afford the aldehyde product 183.3. For example, the carbinol 183.2 is reacted with phosgene, dimethyl sulfoxide and triethylamine, as described in J. Org. Ghent, 43, 2480,1978, to yield the aldehyde 183.3. This compound is reacted with a dialkyl aminoalkylphosphonate 183.4 in the presence of a suitable reducing agent to afford the amine product 183.5. The preparation of amines by means of reductive amination procedures is described, for example, in Comprehensive Organic Transformations, by R. C. Larock, VCH, p. 421, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p. 269. In this procedure, the amine component and the aldehyde or ketone component are reacted together in the presence of a reducing agent such as, for example, borane, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminum hydride, optionally in the presence of a Lewis acid, such as titanium tetraisopropoxide, as described in J. Org. Chem., 55, 2552, 1990. The benzyl protecting group is then removed to prepare the carboxylic acid 183.6. For example, 3-(hydroxymethyl)-phenylalanine 183.7, prepared as described in Acta Chem. Scand. Ser. B, 1977, B31, 109, is converted, as described above, into the formylated derivative 183.8. This compound is then reacted with a dialkyl aminoethylphosphonate 183.9, prepared as described in J. Org. Chem., 200, 65, 676, in the presence of sodium cyanoborohydride, to produce the alkylated product 183.10, which is then deprotected to give the carboxylic acid 183.11.
Using the above procedures, but employing, in place of 3-(hydroxymethyl)-phenylalanine 183.7, different hydroxymethyl phenylalanines 183.1, and/or different aminoalkyl phosphonates 183.4, the corresponding products 183.6 are obtained.
Scheme 184 depicts the preparation of phenylalanine derivatives in which a phosphonate moiety is attached directly to the phenyl ring. In this procedure, a bromo-substituted phenylalanine 184.1 is converted, as described above, (Scheme 182) into the protected derivative 184.2. The product is then coupled, in the presence of a palladium(0) catalyst, with a dialkyl phosphite 184.3 to produce the phosphonate ester 184.4. The preparation of arylphcsphonates by means of a coupling reaction between aryl bromides and dialkyl phosphites is described in J. Med. Chem., 35, 1371,1992. The product is then deprotected to afford the carboxylic acid 184.5.
For example, 3-bromophenylalanine 184.6, prepared as described in Pept. Res., 1990, 3, 176, is converted, as described above, (Scheme 182) into the protected compound 184.7. This compound is then reacted, in toluene solution at reflux, with diethyl phosphite 184.8, triethylamine and tetrakis(triphenylphosphine)palladium(0), as described in J. Med. Chem., 35, 1371,1992, to afford the phosphonate product 184.9. Debenzylation then yields the carboxylic acid 184.10.
Using the above procedures, but employing, in place of 3-bromophenylalanine 184.6, different bromophenylalanines 184.1, and/or different dialkylphosphites 184.3, the corresponding products 184.5 are obtained.
Scheme 185 depicts the preparation of the aminoacid derivative 37.1 which is employed in the preparation of the phosphonate esters 10 and 19. In this procedure, the BOC-protected phenylalanine derivatives 185.1, in which the substituent A is the group link-P(O)(OR1)2 or a precursor group, the preparation of which is described in Schemes 182 - 184, is converted into the esters or amides 185.2 in which R9 is morpholino or alkoxy. The transformation is accomplished by coupling the acid, as described in Scheme 1, with morpholine or an alkanol in the presence of a carbodiimide. The product 185.2 is then deprotected to afford the free amine 185.3, for example as described in Scheme 3. The amine 185.3 is then coupled, as described in Scheme 1, with the aminoacid 174.6, to give the amide 185.4. The BOC group is then removed, as described in Scheme 49, to produce the amine 37.1.
Preparation of the dimethoxyphenylpropionic esters 21.1 incorporating phosphonate groups.
Scheme 186 illustrates the preparation of the dimethoxyphenylpropionic acid derivatives 21.1 which are employed in the preparation of the phosphonate esters 6. In this procedure, the dimethoxybenzyl alcohol derivative 186.1, in which the substituent A is the group link-P(O)(OR')2 or a precursor group, the preparation of which is described in Schemes 165 - 168, is converted into the corresponding aldehyde 186.2. The oxidation is effected as described in Scheme 175. The aldehyde is then subjected to a Wittig reaction with methyl triphenylphosphoranylideneacetate 138.2, as described in Scheme 138, to generate the cinnamic ester derivative 186.3. The double bond is then reduced, as described in Scheme 138, to afford the phenylpropionic ester 21.1. Alternatively, the dimethoxybenzyl bromide derivative 186.4, the preparation of which is described in Scheme 169, is reacted, as described in Scheme 138, with dimethyl malonate 186.5 to yield the malonic ester derivative 186.6, which is then transformed, as described in Scheme 138, into the ester 21.1.
Preparation of the phosphonate-containing benzyl iodides 58.1 and benzylcarbamates 125.3.
Schemes 187 -191 illustrate methods for the preparation of the benzyl iodide derivatives 58.1 which are employed in the synthesis of the phosphonate esters 14, and of the benzyl carbamates 125.3 which are employed in the preparation of the phosphonate esters 22.
Scheme 187 illustrates the preparation of benzaldehyde phosphonates 187.3 in which the phosphonate group is attached by means of an alkylene chain incorporation a nitrogen atom. In this procedure, a benzene dialdehyde 187.1 is reacted with one molar equivalent of a dialkyl aminoalkyl phosphonate 187.2, under reductive amination conditions, as describe above in Scheme 135, to yield the phosphonate product 187.3.
For example, benzene-1,3-dialdehyde 187.4 is reacted with a dialkyl aminopropyl phosphonate 187.5, (Acros) and sodium triacetoxyborohydride, to afford the product 187.6.
Using the above procedures, but employing, in place of benzene-1,3-dicarboxaldehyde 187.4, different benzene dialdehydes 187.1, and/or different phosphonates 187.2, the corresponding products 187.3 are obtained.
Scheme 188 illustrates the preparation of benzaldehyde phosphonates either directly attached to the benzene ring or attached by means of a saturated or unsaturated carbon chain. In this procedure, a bromobenzaldehyde 188.1 is coupled, under palladium catalysis as described in Scheme 150, with a dialkyl alkenylphosphonate 188.2, to afford the alkenyl phosphonate 188.3. Optionally, the product is reduced, as described in Scheme 150, to afford the saturated phosphonate ester 188.4. Alternatively, the bromobenzaldehyde is coupled, as described in Scheme 144, with a dialkyl phosphite 188.5 to afford the formylphenylphosphonate 188.6. For example, as shown in Example 1, 3-bromobenzaldehyde 188.7 is coupled with a dialkyl propenylphosphonate 188.8 (Aldrich) to afford the propenyl product 188.9. Optionally, the product is reduced, as described in Scheme 150, to yield the propyl phosphonate 188.10. Using the above procedures, but employing, in place of 3-bromobenzaldehyde 188.7, different bromobenzaldehydes 188.1, and/or different alkenyl phosphonates 188.2, the corresponding products 188.3 and 188.4 are obtained.
Alternatively, as shown in Example 2, 4-bromobenzaldehyde 188.11 is coupled, as described in Scheme 144, with a dialkyl phosphite 188.5 to afford the 4-formylphenyl phosphonate product 188.12.
Using the above procedures, but employing, in place of 4-bromobenzaldehyde 188.11, different bromobenzaldehydes 188.1, the corresponding products 188.6 are obtained.
Scheme 189 illustrates the preparation of formylphenyl phosphonates in which the phosphonate moiety is attached by means of alkylene chains incorporating two heteroatoms O, S or N. In this procedure, a formyl phenoxy, phenylthio or phenylamino alkanol, alkanethiol or alkylamine 189.1 is reacted with a an equimolar amount of a dialkyl haloalkyl phosphonate 189.2, to afford the phenoxy, phenylthio or phenylamino phosphonate product 189.3. The alkylation reaction is effected in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base. The base employed depends on the nature of the nucleophile 189.1. In cases in which Y is O, a strong base such as sodium hydride or lithium
hexamethyldisilazide is employed. In cases in which Y is S or N, a base such as cesium
carbonate or dimethylaminopyridine is employed.
For example,. 2-(4-formylphenylthio)ethanol 189.4, prepared as described in Macromolecules,
1991, 24, 1710, is reacted in acetonitrile at 60°C with one molar equivalent of a dialkyl
iodomethyl phosphonate 189.5, (Lancaster) to give the ether product 189.6.
Using the above procedures, but employing, in place of the carbinol 189.4, different carbinols,
thiols or amines 189.1, and/or different haloalkyl phosphonates 189.2, the corresponding
products 189.3 are obtained.
Scheme 190 illustrates the preparation of formylphenyl phosphonates in which the phosphonate group is linked to the benzene ring by means of an aromatic or heteroaromatic ring. In this procedure, a formylbenzeneboronic acid 190.1 is coupled, in the presence of a palladium catalyst, with one molar equivalent of a dibromoarene, 190.2, in which the group Ar is an aromatic or heteroaromatic group. The coupling of aryl boronates with aryl bromides to afford diaryl compounds is described in Palladium Reagents and Catalysts, by J. Tsuji, Wiley 1995, p. 218. The components are reacted in a polar solvent such as dimethylformamide in the presence of a palladium(0) catalyst and sodium bicarbonate. The product 190.3 is then coupled, as described above (Scheme 144) with a dialkyl phosphite 190.4 to afford the phosphonate 190.5.
For example, 4-formylbenzeneboronic acid 190.6 is coupled with 2,5-dibromothiophene 190.7 to yield the phenylthiophene product 190.8. This compound is then coupled with the dialkyl phosphite 190.4 to afford the thienyl phosphonate 190.9.
Using the above procedures, but employing, in place of dibromothiophene 190.7, different dibromoarenes 190.2, and/or different formylphenyl boronates 190.1, the corresponding products 190.5 are obtained.
Scheme 191 illustrates the preparation of the benzyl carbamates 125.3 and the benzyl iodides 58.1, which are employed respectively in the preparation of the phosphonate esters 22 and 4. In this procedure, the substituted benzaldehydes 191.1, prepared as shown in Schemes 187 -190, are converted into the corresponding benzyl alcohols 191.2. The reduction of aldehydes to afford alcohols is described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 527ff. The transformation is effected by the use of reducing agents such as
sodium borohydride, lithium aluminum tri-tertiarybutoxy hydride, diisobutyl aluminum hydride and the like. The resultant benzyl alcohol is then reacted with the aminoester 191.3 to afford the carbamate 191.4. The reaction is performed under the conditions described below, Scheme 198. For example, the benzyl alcohol is reacted with carbonyldiimidazole to produce an intermediate benzyloxycarbonyl imidazole, and the intermediate is reacted with the aminoester 191.3 to afford the carbamate 191.4. The methyl ester is then hydrolyzed, as described in Scheme 3, to yield the carboxylic acid 125.3. Alternatively, the benzyl alcohol 191.2 is converted, using the procedures of Scheme 169, into the iodide 58.1. (Figure Remove)
5 Preparation of phosphonate-substituted decahydroquinolines 17.1.
Schemes 192 - 97 illustrate the preparation of decahydroisoquinoline derivatives 17.1 in which the substituent A is either the group link P(O)(OR1)2 or a precursor, such as [OH], [SH], Br.
The compounds are employed in the preparation of the intermediate phosphonate esters 5, 12 and 21.
Scheme 192 illustrates methods for the synthesis of intermediates for the preparation of decahydroquinolines with phosphonate moieties at the 6-position. Two methods for the preparation of the benzenoid intermediate 192.4 are shown.
In the first route, 2-hydroxy-6-methylphenylalanine 192.1, the preparation of which is described in J. Med. Chem., 1969, 12, 1028, is converted into the protected derivative 192.2. For example, the carboxylic acid is first transformed into the benzyl ester, and the product is reacted with acetic anhydride in the presence of an organic base such as, for example, pyridine, to afford the product 192.2, in which R is benzyl. This compound is reacted with a brominating agent, for example N-bromosuccinimide, to effect benzylic bromination and yield the product 192.3. The reaction is conducted in an aprotic solvent such as, for example, ethyl acetate or carbon tetrachloride, at reflux. The brominated compound 192.3 is then treated with acid, for example dilute hydrochloric acid, to effect hydrolysis and cyclization to afford the tetrahydroisoquinoline 192.4, in which R is benzyl.
Alternatively, the tetrahydroisoquinoline 192.4 is obtained from 2-hydroxyphenylalanine 192.5, the preparation of which is described in Can. J. Bioch., 1971, 49, 877. This compound is subjected to the conditions of the Pictet-Spengler reaction, for example as described in Chem. Rev., 1995, 95, 1797.
Typically, the substrate 192.5 is reacted with aqueous formaldehyde, or an equivalent such as parafonnaldehyde or dimethoxymethane, in the presence of hydrochloric acid, for example as described in J. Med. Chem., 1986, 29, 784, to afford the tetrahydroisoquinoline product 192.4, in which R is H. Catalytic hydrogenation of the latter compound, using, for example, a platinum catalyst, as described in J. Am. Chem. Soc., 69, 1250, 1947, or using rhodium on alumina as catalyst, as described in J. Med. Chem., 1995, 38,4446, then gives the hydroxy-substituted decahydroisoquinoline 192.6. The reduction is also performed electrochemically, as described in Trans SAEST 1984, 19,189.
For example, the tetrahydroisoquinoline 192.4 is subjected to hydrogenation in an alcoholic solvent, in the presence of a dilute mineral acid such as hydrochloric acid, and 5% rhodium on alumina as catalyst. The hydrogenation pressure is ca. 750 psi, and the reaction is conducted at ca 50°C, to afford the decahydroisoquinoline 192.6.
Protection of the carboxyl and NH groups present in 192.6, for example by conversion of the carboxylic acid into the trichloroethyl ester, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, p. 240, and conversion of the NH into the N-cbz group, as described above, followed by oxidation, using, for example, pyridinium chlorochromate and the like, as described in Reagents for Organic Synthesis, by L. F. Fieser and M. Fieser, Volume 6, p. 498, affords the protected ketone 192.9, in which R is trichloroethyl and R1 is cbz. Reduction of the ketone, for example by the use of sodium borohydride, as described in J. Am. Chem. Soc., 88, 2811, 1966, or lithium tri-tertiary butoxy aluminum hydride, as described in J. Am. Chem. Soc., 80, 5372, 1958, then affords the alcohol 192.10.
For example, the ketone is reduced by treatment with sodium borohydride in an alcoholic solvent such as isopropanol, at ambient temperature, to afford the alcohol 192.10. The alcohol 192.6 is converted into the thiol 192.13 and the amine 192.14, by means of displacement reactions with suitable nucleophiles, with inversion of stereochemistry. For example, the alcohol 192.6 is converted into an activated ester such as the trMuoromethanesulfonyloxy ester or the methanesulfonate ester 192.7, by treatment with methanesulfonyl chloride and a base. The mesylate 192.7 is then treated with a sulfur nucleophile, for example potassium thioacetate, as described in Tet. Lett., 1992,4099, or sodium thiophosphate, as described in Acta Chem. Scand., 1960, 1980, to effect displacement of the mesylate, followed by mild basic hydrolysis, for example by treatment with aqueous ammonia, to afford the thiol 192.13.
For example, the mesylate 192.7 is reacted with one molar equivalent of sodium thioacetate in a polar aprotic solvent such as, for example, dimethylformamide, at ambient temperature, to afford the thioacetate 192.12, in which R is COCH3. The product then treated with a mild base such as, for example, aqueous ammonia, in the presence of an organic co-solvent such as ethanol, at ambient temperature, to afford the thiol 192.13.
The mesylate 192.7 is treated with a nitrogen nucleophile, for example sodium phthalimide or sodium bis(trimethylsilyl)amide, as described in Comprehensive Organic Transformations, by R. C. Larock, p. 399, followed by deprotection as described previously, to afford the amine 192.14.
For example, the mesylate 192.7 is reacted, as described in Angew. Chem Int. Ed., 7, 919, 1968, with one molar equivalent of potassium phthalimide, in a dipolar aprotic solvent, such
as, for example, dimethylformamide, at ambient temperature, to afford the displacement product 192.8, in which NRaRb is phthalimido. Removal of the phthalimido group, for example by treatment with an alcoholic solution of hydrazine at ambient temperature, as described in J. Org. Chem., 38, 3034, 1973, then yields the amine 192.14. The application of the procedures described above for the conversion of the p-carbinol 192.6 to the a-thiol 192.13 and the a-amine 192.14 can also be applied to the a-carbinol 192.10, so as to afford the p-thiol and p-amine, 192.11.
Scheme 193 illustrates the preparation of compounds in which the phosphonate moiety is attached to the decahydroisoquinoline by means of a heteroatom and a carbon chain. In this procedure, an alcohol, thiol or amine 193.1 is reacted with a bromoalkyl phosphonate 193.2, under the conditions described above for the preparation of the phosphonate 155.4 (Scheme 155), to afford the displacement product 193.3. Removal of the ester group, followed by conversion of the acid to the R4NH amide and N-deprotection, as described below, (Scheme 197) then yields the amine 193.4.
For example, the thiol 193.5, in which the carboxylic acid group is protected as the trichloroethyl ester, as described in Protective Groups in Organic Synthesis, by T. W. Greene and P.G.M. Wuts, Wiley, 1991, p. 240, and the amine is protected as the cbz group, is reacted with a dialkyl 3-bromopropylphosphonate, 193.6, the preparation of which is described in J. Am. Chem. Soc., 2000, 122, 1554 to afford the displacement product 193.7. Deprotection of the ester group, followed by conversion of the acid to the R4NH amide and N-deprotection, as described below, (Scheme 197) then yields the amine 193.8.
Using the above procedures, but employing, in place of the a-thiol 193.5, the alcohols, thiols or amines 192.6,192.10,192.11,192.13,192.14, of either a- or p-orientation, there are obtained the corresponding products 193.4, in which the orientation of the side chain is the same as that of the O, N or S precursors.
(Figure Remove)Scheme 194 illustrates the preparation of phosphonates linked to the decahydroisoquinoline moiety by means of a nitrogen atom and a carbon chain. The compounds are prepared by means of a reductive amination procedure, for example as described in Comprehensive Organic Transformations, by R. C. Larock, p. 421.
In this procedure, the amines 192.14 or 192.11 are reacted with a phosphonate aldehyde 194.1, in the presence of a reducing agent, to afford the alkylated amine 194.2. Deprotection of the ester group, followed by conversion of the acid to the R4NH amide and N-deprotection, as described below, (Scheme 197) then yields the amine 194.3. For example, the protected amino compound 192.14 is reacted with a dialkyl formylphosphonate 194.4, the preparation of which is described in U.S. Patent 3,784,590, in the presence of sodium cyanoborohydride, and a polar organic solvent such as ethanolic acetic acid, as described in Org. Prep. Proc. Int., 11, 201, 1979, to give the amine phosphonate 194.5. Deprotection of the ester group, followed by conversion of the acid to the R NH amide and N-deprotection, as described in Scheme 197, then yields the amine 194.6. Using the above procedures, but employing, instead of the a-amine 192.14, the (3 isomer, 192.11 and/or different aldehydes 194.1, there are obtained the corresponding products 194.3, in which the orientation of the side chain is the same as that of the amine precursor.
Scheme 195 depicts the preparation of a decahydroisoquinoline phosphonate in which the
phosphonate moiety is linked by means of a sulfur atom and a carbon chain.
In this procedure, a dialkyl mercaptoalkyl phosphonate 195.2 is reacted with a mesylate 195.1,
to effect displacement of the mesylate group with inversion of stereochemistry, to afford the
thioether product 195.3. Deprotection of the ester group, followed by conversion of the acid
to the R4NH amide and N-deprotection, as described in Scheme 197, then yields the amine
195.4.
For example, the protected mesylate 195.5 is reacted with an equimolar amount of a dialkyl 2-
mercaptoethyl phosphonate 195.6, the preparation of which is described in Aust. J. Chem., 43,
1123, 1990. The reaction is conducted in a polar organic solvent such as ethanol, in the
presence of a base such as, for example, potassium carbonate, at ambient temperature, to
afford the thioether phosphonate 195.7. Deprotection of the ester group, followed by
conversion of the acid to the R4NH amide and N-deprotection, as described in Scheme 197,
then yields the amine 195.8
Using the above procedures, but employing, instead of the phosphonate 195.6, different
phosphonates 195.2, there are obtained the corresponding products 195.4.
Scheme 196 illustrates the preparation of decahydroisoquinoline phosphonates 196.4 in which the phosphonate group is linked by means of an aromatic or heteroaromatic ring. The compounds are prepared by means of a displacement reaction between hydroxy, thio or amino substituted substrates 196.1 and a bromomethyl-substituted arylphosphonate 196.2. The reaction is performed in an aprotic solvent in the presence of a base of suitable strength, depending on the nature of the reactant 196.1. If X is S or NH, a weak organic or inorganic base such as triethylamine or potassium carbonate is employed. If X is O, a strong base such as sodium hydride or lithium hexamethyldisilylazide is employed. The displacement reaction affords the ether, thioether or amine compounds 196.3. Deprotection of the ester group, followed by conversion of the acid to the R4NH amide and N-deprotection, as described in Scheme 197, then yields the amine 196.4.
For example, the alcohol 196.5 is reacted at ambient temperature with a dialkyl 3-bromomethyl benzylphosphonate 196.6, the preparation of which is described above, (Scheme 143). The reaction is conducted in a dipolar aprotic solvent such as, for example, dioxan or dimethytformamide. The solution of the carbinol is treated with one equivalent of a strong base, such as, for example, lithium hexamethyldisilylazide, and to the resultant mixture is added one molar equivalent of the bromomethyl phosphonate 196.6, to afford the product 196.7. Deprotection of the ester group, followed by conversion of the acid to the R4NH amide and N-deprotection, as described in Scheme 197, then yields the amine 196.8. Using the above procedures, but employing, instead of the p-carbinol 196.5, different carbinols, thiols or amines 196.1, of either a- or p-orientation, and/or different phosphonates 196.2, in place of the phosphonate 196.6, there are obtained the corresponding products 196.4 in which the orientation of the side-chain is the same as that of the starting material 196.1.
Schemes 193 -196 illustrate the preparation of decahydroisoquinoline esters incorporating a
phosphonate group linked to the decahydroisoquinoline nucleus.
Scheme 197 illustrates the conversion of the latter group of compounds 197.1 (in which the
group A is Unk-P(O)(OR1>2 or optionally protected precursor substituents, such as, for
example, OH, SH, or NH2 to the corresponding R4NH amides 17.1.
As shown in Scheme 197, the ester compounds 197.1 are deprotected to form the
corresponding carboxylic acids 197.2. The methods employed for the deprotection are chosen
based on the nature of the protecting group R, the nature of the N-protecting group R2, and
the nature of the substituent at the 6-position. For example, if R is trichloroethyl, the ester group is removed by treatment with zinc in acetic acid, as described in J. Am. Chem. Soc., 88, 852, 1966. Conversion of the carboxylic acid 197.2 to the R4NH amide 197.4 is then accomplished by reaction, as described in Scheme 1, of the carboxylic acid, or an activated derivative thereof, with the amine R4NH2 (197.3) to afford the amide 197.4. Deprotection of the NR2 group, as described above, then affords the free amine 17.1.
Preparation of carbamates.
The phosphonate esters 13 - 20 in which the R10 is alkoxy, and the phosphonate esters 22 contain a carbamate linkage. The preparation of carbamates is described in Comprehensive Organic Functional Group Transformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and in Organic Functional Group Preparations, by S. R. Sandier and W. Karo, Academic Press, 1986, p. 260ff.
Scheme 198 illustrates various methods by which the carbamate linkage is synthesized. As shown in Scheme 198, in the general reaction generating carbamates, a carbinol 198.1, is converted into the activated derivative 198.2 in which Lv is a leaving group such as halo, imidazolyl, benztriazolyl and the like, as described below. The activated derivative 198.2 is then reacted with an amine 198.3, to afford the carbamate product 198.4. Examples 1 - 7 in Scheme 198 depict methods by which the general reaction is effected. Examples 8-10 illustrate alternative methods for the preparation of carbamates.
Scheme 198, Example 1 illustrates the preparation of carbamates employing a chloroformyl derivative of the carbinol 198.1. In this procedure, the carbinol is reacted with phosgene, in an inert solvent such as toluene, at about 0°C, as described in Org. Syn. Coll. Vol. 3, 167, 1965, or with an equivalent reagent such as trichloromethoxy chloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, to afford the chloroformate 198.6. The latter compound is then reacted with the amine component 198.3, in the presence of an organic or inorganic base, to afford the carbamate 198.7. For example, the chloroformyl compound 198.6 is reacted with the amine 198.3 in a water-miscible solvent such as tetrahydrofuran, in the presence of aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 3,167, 1965, to yield the carbamate 198.7. Alternatively, the reaction is performed in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.
Scheme 198, Example 2 depicts the reaction of the chloroformate compound 198.6 with imidazole to produce the imidazolide 198.8. The imidazolide product is then reacted with the amine 198.3 to yield the carbamate 198.7. The preparation of the imidazolide is performed in an aprotic solvent such as dichloromethane at 0°C, and the preparation of the carbamate is conducted in a similar solvent at ambient temperature, optionally in the presence of a base such as dimethylaminopyridine, as described in J. Med. Chem., 1989, 32, 357. Scheme 198 Example 3, depicts the reaction of the chloroformate 198.6 with an activated hydroxyl compound R"OH, to yield the mixed carbonate ester 198.10. The reaction is conducted in an inert organic solvent such as ether or dichloromethane, hi the presence of a base such as dicyclohexylamine or triethylamine. The hydroxyl component R"OH is selected from the group of compounds 198.19 - 198.24 shown in Scheme 198, and similar compounds. For example, if the component R"OH is hydroxybenztriazole 198.19, N-hydroxysuccinimide 198.20, or pentachlorophenol, 198.21, the mixed carbonate 198.10 is obtained by the reaction of the chloroformate with the hydroxyl compound in an ethereal solvent in the presence of dicyclohexylamine, as described in Can. J. Chem., 1982, 60, 976. A similar reaction in which the component R"OH is pentafluorophenol 198.22 or 2-hydroxypyridine 198.23 is performed in an ethereal solvent in the presence of triethylamine, as described in Syn., 1986, 303, and Chem. Ber. 118,468, 1985.
Scheme 198 Example 4 illustrates the preparation of carbamates in which an alkyloxycarbonylimidazole 198.8 is employed. In this procedure, a carbinol 198.5 is reacted with an equimolar amount of carbonyl diimidazole 198.11 to prepare the intermediate 198.8. The reaction is conducted in an aprotic organic solvent such as dichloromethane or tetrahydrofuran. The acyloxyimidazole 198.8 is then reacted with an equimolar amount of the amine R'NH2 to afford the carbamate 198.7. The reaction is performed in an aprotic organic solvent such as dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the carbamate 198.7.
Scheme 198, Example 5 illustrates the preparation of carbamates by means of an intermediate alkoxycarbonylbenztriazole 198.13. In this procedure, a carbinol ROH is reacted at ambient temperature with an equimolar amount of benztriazole carbonyl chloride 198.12, to afford the alkoxycarbonyl product 198.13. The reaction is performed in an organic solvent such as benzene or toluene, in the presence of a tertiary organic amine such as triethylamine, as described in Syn., 1977, 704. The product is then reacted with the amine R'NH2 to afford the
carbamate 198.7. The reaction is conducted in toluene or ethanol, at from ambient temperature to about 80°C as described in Syn., 1977, 704.
Scheme 198, Example 6 illustrates the preparation of carbamates in which a carbonate (R"O)2CO, 198.14, is reacted with a carbinol 198.5 to afford the intermediate alkyloxycarbonyl intermediate 198.15. The latter reagent is then reacted with the amine R'NH2 to afford the carbamate 198.7. The procedure in which the reagent 198.15 is derived from hydroxybenztriazole 198.19 is described in Synthesis, 1993, 908; the procedure in which the reagent 198.15 is derived from N-hydroxysuccinimide 198.20 is described in Tet. Lett., 1992,2781; the procedure in which the reagent 198.15 is derived from 2-hydroxypyridine 198.23 is described in Tet. Lett., 1991, 4251; the procedure in which the reagent 198.15 is derived from 4-nitrophenol 198.24 is described in Syn. 1993,199. The reaction between equimolar amounts of the carbinol ROH and the carbonate 198.14 is conducted in an inert organic solvent at ambient temperature.
Scheme 198, Example 7 illustrates the preparation of carbamates from alkoxycarbonyl azides 198.16. In this procedure, an alkyl chloroformate 198.6 is reacted with an azide, for example sodium azide, to afford the alkoxycarbonyl azide 198.16. The latter compound is then reacted with an equimolar amount of the amine R'NH2 to afford the carbamate 198.7. The reaction is conducted at ambient temperature in a polar aprotic solvent such as dimethylsulfoxide, for example as described in Syn., 1982,404.
Scheme 198, Example 8 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and the chloroformyl derivative of an amine 198.17. In this procedure, which is described in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, the reactants are combined at ambient temperature in an aprotic solvent such as acetonitrile, in the presence of a base such as triethylamine, to afford the carbamate 198.7.
Scheme 198, Example 9 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an isocyanate 198.18. In this procedure, which is described in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 645, the reactants are combined at ambient temperature in an aprotic solvent such as ether or dichloromethane and the like, to afford the carbamate 198.7.
Scheme 198, Example 10 illustrates the preparation of carbamates by means of the reaction between a carbinol ROH and an amine R'NH2. In this procedure, which is described in Chem.
Lett. 1972, 373, the reactants are combined at ambient temperature in an aprotic organic solvent such as tetrahydrofuran, in the presence of a tertiary base such as triethylamine, and selenium Carbon monoxide is passed through the solution and the reaction proceeds to afford the carbamate 198.7.
the procedures described below, either in the precursor compounds, or in the esters 1 - 24. The methods employed for a given phosphonate transformation depend on the nature of the substituent R1. The preparation and hydrolysis of phosphonate esters is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 9ff.
The conversion of a phosphonate diester 199.1 into the corresponding phosphonate monoester 199.2 (Scheme 199, Reaction 1) is accomplished by a number of methods. For example, the ester 199.1 in which R1 is an aralkyl group such as benzyl, is converted into the monoester compound 199.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine, as described in J. Org. Chem., 1995, 60, 2946. The reaction is performed in an inert hydrocarbon solvent such as toluene or xylene, at about 110°C. The conversion of the diester 199.1 in which R1 is an aryl group such as phenyl, or an alkenyl group such as allyl, into the monoester 199.2 is effected by treatment of the ester 199.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran. Phosphonate diesters 199.1 in which one of the groups R1 is aralkyl, such as benzyl, and the other is alkyl, are converted into the monoesters 199.2 in which R1 is alkyl by hydrogenation, for example using a palladium on carbon catalyst. Phosphonate diesters in which both of the groups R1 are alkenyl, such as allyl, are converted into the monoester 199.2 in which R1 is alkenyl, by treatment with chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueous ethanol at reflux, optionally in the presence of diazabicyclooctane, for example by using the procedure described in J. Org. Chem., 38, 3224, 1973 for the cleavage of allyl carboxylates.
The conversion of a phosphonate diester 199.1 or a phosphonate monoester 199.2 into the corresponding phosphonic acid 199.3 (Scheme 199, Reactions 2 and 3) is effected by reaction of the diester or the monoester with trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm., 739, 1979. The reaction is conducted in an inert solvent such as, for example, dichloromethane, optionally in the presence of a silylating agent such as bis(trimethylsilyl)trifluoroacetamide, at ambient temperature. A phosphonate monoester 199.2 in which R1 is aralkyl such as benzyl, is converted into the corresponding phosphonic acid 199.3 by hydrogenation over a palladium catalyst, or by treatment with hydrogen chloride in an ethereal solvent such as dioxan. A phosphonate monoester 199.2 in which R1 is alkenyl such as, for example, allyl, is converted into the phosphonic acid 199.3 by reaction with Wilkinson's catalyst in an aqueous organic solvent, for example in 15% aqueous acetonitrile, or in aqueous ethanol, for example using the procedure described in Helv. Chim. Acta., 68, 618, 1985. Palladium catalyzed hydrogenolysis of phosphonate esters 199.1 in which R1 is benzyl is described in J. Org. Chem, 24, 434, 1959. Platinum-catalyzed hydrogenolysis of phosphonate esters 199.1 in which R1 is phenyl is described in J. Am. Chem Soc., 78, 2336, 1956.
The conversion of a phosphonate monoester 199.2 into a phosphonate diester 199.1 (Scheme 199, Reaction 4) in which the newly introduced R1 group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl is effected by a number of reactions in which the substrate 199.2 is reacted with a hydroxy compound R'OH, in the presence of a coupling agent. Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in a basic organic solvent such as pyridine, or (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PYBOP, Sigma), in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine. Alternatively, the conversion of the phosphonate monoester 199.2 to the diester 199.1 is effected by the use of the Mitsonobu reaction, as described above (Scheme 142). The substrate is reacted with the hydroxy compound R'OH, in the presence of diethyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine. Alternatively, the phosphonate monoester 199.2 is transformed into the phosphonate diester 199.1, in which the
introduced R1 group is alkenyl or aralkyl, by reaction of the monoester with the halide R'Br, in which R1 is as alkenyl or aralkyl. The alkylation reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base such as cesium carbonate. Alternatively, the phosphonate monoester is transformed into the phosphonate diester in a two step procedure. In the first step, the phosphonate monoester 199.2 is transformed into the chloro analog RP(O)(OR')C1 by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17, and the thus-obtained product RPCOXOR^Cl is then reacted with the hydroxy compound R'OH, in the presence of a base such as triethylamine, to afford the phosphonate diester 199.1.
A phosphonic acid R-link-P(O)(OH)2 is transformed into a phosphonate monoester RPCOXOR^OH) (Scheme 199, Reaction 5) by means of the methods described above of for the preparation of the phosphonate diester R-link-P(O)(OR1)2199.1, except that only one molar proportion of the component R!OH or RlBr is employed.
A phosphonic acid R-link-P(O)(OH)2199.3 is transformed into a phosphonate diester R-link-P(O)(ORl)2 199.1 (Scheme 199, Reaction 6) by a coupling reaction with the hydroxy compound R^H, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine. The reaction is conducted in a basic solvent such as pyridine. Alternatively, phosphonic acids 199.3 are transformed into phosphonic esters 199.1 in which R1 is aryl, by means of a coupling reaction employing, for example, dicyclohexylcarbodiimide in pyridine at ca 70°C. Alternatively, phosphonic acids 199.3 are transformed into phosphonic esters 199.1 in which R1 is alkenyl, by means of an alkylation reaction. The phosphonic acid is reacted with the alkenyl bromide R'Br in a polar organic solvent such as acetonitrile solution at reflux temperature, the presence of a base such as cesium carbonate, to afford the phosphonic ester 199.1.

General applicability of methods for introduction of phosphonate substituents.
The procedures described for the introduction of phosphonate moieties (Schemes 133 - 192) are, with appropriate modifications known to one skilled in the art, transferable to different chemical substrates. Thus, the methods described above for the introduction of phosphonate groups into indanols (Schemes 133 - 137 ) are applicable to the introduction of phosphonate moieties into phenylpropionic acids, thiophenols, tert. butylamines, pyridines, benzyl halides, ethanolamines, aminochromans, phenylalanines and benzyl alcohols, and the methods described for the introduction of phosphonate moieties into the above-named substrates (Schemes 138 - 192) are applicable to the introduction of phosphonate moieties into indanol substrates.
Preparation of phosphonate intermediates 23 and 24 with phosphonate moieties incorporated into the R2, R3, Rs, R10 or R" groups.
The chemical transformations described in Schemes 1 • 192 illustrate the preparation of compounds 1 - 22 in which the phosphonate ester moiety is attached to the indanol moiety, (Schemes 1 - 4, 76 - 84), the phenyl group (Schemes 5 - 8, 21 - 24, 37 - 40, 49 - 52, 58 -61, 67 - 68, 74, 75,101 - 108,125 - 132) the tert. butylamine group, (Schemes 9 -12, 25 -28, 41 - 44, 109 - 116), the pyridine group (Schemes 13 - 16), the decahydroisoquinoline group (Schemes 17 - 20, 45 - 48,117 -124), the ethanolamine group (Schemes 29- 32, 93 -100), the aminochroman group (Schemes 33 - 36, 85 - 92), and the thiophenyl group
(Schemes 53 - 57, 62 - 66, 69 - 73). The various chemical methods employed for the introduction of phosphonate ester groups into the above-named moieties can, with appropriate modifications known to those skilled in the art, be applied to the introduction of a phosphonate ester group into the compounds R2R3NH, R5SH, R5CH2I, R10CO, RUSH, and RUCH2CH(NH2)COOH. The resultant phosphonate-containing analogs, designated as R2aR3aNH, R5aSH, R5aCH2I, R10aCO, R1IaSH, and RllaCH2CH(NH2)COOH are then, using the procedures described above, employed in the preparation of the compounds 23 and 24. The procedures required for the utilization of the phosphonate-containing analogs are the same as those described above for the utilization of the compounds R2R3NH, R5SH, R5CH2I, R10CO, RUSH, and RUCH2CH(NH2)COOH.
For example, Schemes 200-204 and Schemes 205-207 depict the introduction of the group link-P(O)(OR1)2 or a precursor thereto, such as, [OH], [NH2], [SH] onto the R2R3NH amines AlOa and AlOb in Chart 4, to give amines 200.5 and 205.10 respectively. These amine products are then utilized in the generation of compounds 23 where R2R3NH is now R2lR3aNH in Chart 3 following the same procedures outlined in Schemes 13 and 15 but replacing the amine 13.1 with 200.5 or 205.10 respectively.
Preparation of piperazine furan compounds 200.5 with phosphonate attachments
Schemes 200 - 204 depict the preparation of the piperazine furan aryl phosphonate compounds 200.5 that are employed in the preparation of the phosphonate esters 23 where R2R3NH is now R2aR3aNH as described above.
Scheme 200 depicts the preparation of piperazine biaryl phosphonates in which the terminal aryl ring bears the phosphonate moiety through a linking group. Methods for the preparation of the reagents 200.2 are shown in Schemes 201-204. Furan 200.1 prepared as described in WO02/096359, is treated with the aryl bromide 200.2 in the presence of palladium catalyst by the method of Gronowitz et al. (J. Heterocyclic Chemistry, 1995, 35, p. 771) to give 200.3. The product 200.3 is then subjected to the sequence of reactions and conditions described in WO02/096359 to prepare the piperazine 200.5. The preparation of reagent 200.6 where R4 = CH2CF3 is also described in WO02/096359. Alternatively, deprotection of amines 164.1 by treatment with trifluoroacetic acid at room temperature as described in Int. J. Pept. Protein Res., 12, 258, 1978, followed by treatment with alloc chloro formate and a base such as
pyridine, as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Third Edition 1999 p. 526-527 yields 200.6 where R4 is as defined in Chart 1.
Scheme 201 depicts the preparation of phosphonates 200.2 in which the phosphonate moiety is attached to the phenyl ring by means of a heteroatom and an alkyl chain. Many halogenated aromatic compounds are commercially available or can be generated from readily available aromatic compounds through aromatic substitution. Methods for chlorinating or brominating an aryl ring can be found in Comprehensive Organic Transformations, by R. C. Larock, 2nd Edition, 1999 p619. The phenol, thiol or amine 201.1 is reacted with a derivative of a hydroxymethyl dialkylphosphonate 140.2, in which Lv is a leaving group such as methanesulfonyloxy and the like. The reaction is conducted in a polar aprotic solvent, in the presence of an organic or inorganic base, to afford the displacement product 201.2. For example, the phenols 201.5 (Aldrich) or 201.9 (Apollo-Chem) are reacted with a dialkyl trifluoromethanesulfonyloxymethyl phosphonate 140.6, prepared as described in Tet. Lett., 1986, 27, 1477, to afford the ether products. Equimolar amounts of the reactants are combined in a polar solvent such as dimethylformamide, in the presence of a base such as potassium carbonate, at about 50°C, to afford the products 201.6 and 201.10 respectively. Alternatively treatment of amine 201.11 (Apollo) or 201.7 (Aldrich) with the dialkyl trifluoromethylsulfonyloxymethyl phosphonate 140.6 in the presence of a base as described above affords 201.12 and 201.8 respectively.
Using the above procedures, but employing, in place of the phenols and amines, different phenols, thiols or amines 201.1, and /or different dialkyl trifluoromethyl-sulfonyloxymethyl phosphonates 140.2, the corresponding products 201.2 are obtained.
Scheme 202 illustrates the preparation of compounds in which the phosphonate group is attached by means of an aminoalkyl chain. In this procedure, the aldehyde 202.1 is reacted, under reductive amination conditions, as described in Scheme 135, with a dialkyl aminoalkyl phosphonate 202.2, to give the amine 202.3.
For example, the aldehyde 202.4 (Aldrich) is reacted in ethanol with a dialkyl aminoethyl phosphonate 166.5, the preparation of which is described in J. Org. Chem., 2000, 65, 676, and sodium triacetoxyborohydride, to produce the amine 202.5.
Using the above procedures, but employing, in place of the aldehyde, 202.4 different aldehydes 202.1 and different phosphonates 202.2, the corresponding products 202.3 are obtained.
Scheme 203 illustrates the preparation of aryl halides incorporating phosphonate groups attached by means of an amide group. In this procedure, a carboxy-substituted aryl halide
203.1 is coupled, as described in Scheme 1, with a dialkyl aminoalkyl phosphonate 202.2 to
prepare the amide 203.2.
R>r«xeaHpl»,5-chlDro-4-broniobenzoic acid 203.4, the preparation of which is described in Bioorg. Med. Chem. Lett. 2001, 11, 10, p. 1257, is coupled in dimethylformamide solution, in the presence of dicyclohexylcarbodiimide, with a dialkyl aminoethyl phosphonate 166.5, the preparation of which is described in J. Org. Chem., 2000, 65, 676, to afford the amide 203.5. Using the above procedures, but employing, in place of the benzoic acid 203.4, different benzoic acids 203.1, and/or different aminoalkyl phosphonates 202.2, the corresponding products 203.2 are obtained.
Scheme 204 illustrates the preparation of phosphonate-substituted aryl halides in which the phosphonate group is attached by means of a one-carbon link. In this procedure, a benzoic acid 203.1 is first methylated to give methyl ester 204.1 and then reduced with a reducing agent, as described in J. Org Chem 1987, 52, p. 5419 to give alcohol 204.2. The alcohol
204.2 is then reacted with hexabromoethane in the presence of triphenyl phosphine as
described in Syn. 1983, p. 139 to give the bromide 204.3. The bromide 204.3 is reacted with
a sodium dialkyl phosphite 204.5 or a trialkyl phosphite, to give the product 204.4
For example, acid 204.6 (Lancaster) is converted to the methyl ester 204.7 by refluxing in methanol and concentrated sulfuric acid and then reduced with lithium aluminum hydride in THF to give 204.8 as described above. The product 204.8 is reacted with hexabromoethane in the presence of triphenyl phosphine as described in Syn. 1983, p. 139 to give the bromide 204.9. This material is reacted with a sodium dialkyl phosphite 204.5, as described in J. Med. Chem., 35, 1371, 1992, to afford the product 204.10. Alternatively, the bromomethyl compound 204.9 is converted into the phosphonate 204.10 by means of the Arbuzov reaction, for example as described in Handb. Organophosphorus Chem., 1992, 115. In this procedure,
the bromomethyl compound 204.9 is heated with a trialkyl phosphate P(OR')3 at ca. 100°C to produce the phosphonate 204.10.
Using the above procedures, but employing, in place of the acid 204.6, different acids 203.1, and different phosphites 204.5 there are obtained the corresponding aryl halides 204.4.
The phosphonate-containing bromobenzene derivatives prepared as described in Schemes 201 - 204 are then transformed, as described in Scheme 200, into the phenylfuran piperazine derivatives 200.5.
Preparation of piperazine ozaxole compounds 205.10 bearing phosphonate attachments

Schemes 205 - 207 depict the preparation of the piperazine oxazole phosphonate compounds 205.10 that are employed in the preparation of the phosphonate esters 23 where R2R3NH is now R2aR3aNH as described above.
Scheme 205 depicts the preparation of piperazine oxazole phosphonates 205.10 in which the terminal aryl ring bears the phosphonate moiety. The acid 205.1 is converted to the Weinreb amide, for example ,as described in J. Med. Chem., 1994, 37, 2918, and then reacted with a methyl Grignard reagent e.g. MeMgBr. Examples of this procedure are reviewed in Org prep Proc Intl 1993, 25, 15. Ketone 205.3 is then brominated using conditions described in Comprehensive Organic Transformations, by R. C. Larock, 2nd Edition, 1999, p. 710-711. For example, treatment of 205.3 with bromine in acetic acid yields 205.4. Conversion of the bromomethyl compound 205.4 into the piperazine derivative 205.10, via the intermediates 205.5 - 205.9, is effected by means of the reactions and procedures described in WO02/096359 for related compounds in which R4 is CH2CF3 and A is H.
Scheme 206 illustrates the preparation of benzoic acid phosphonates in which the phosphonate moiety is attached by means of alkylene chains and a heteroatom O, S or N. In this procedure, a benzoic acid 206.1 is protected with a suitable protecting group (see Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Third Edition 1999 ch5 and then reacted with a an equimolar amount of a dialkyl phosphonate 206.3, in which Ha is a leaving group e.g. halogen, to afford the alkyl phosphonate product 206.4. The alkylation reaction is effected hi a polar organic solvent such as dimethylfonnamide or acetonitrile, in the presence of a base. The base employed depends on the nature of the nucleophile 206.2. In cases in which Y is O, a strong base such as sodium hydride or lithium hexamethyldisilazide is employed. In cases in which Y is S or N, a base such as cesium carbonate or dimethylaminopyridine is employed. Following this reaction the product 206.4 is hydrolyzed by treatment with base to give the acid 206.5
For example, benzoic acid 206.6, (Aldrich) is reacted with diazomethane in ether at 0°C to give the methyl ester 206.7 or simply refluxed in acidic methanol. The ester in acetonitrile at 60°C is treated with one molar equivalent of a dialkyl iodomethyl phosphonate 206.8, (Lancaster) to give the ether product 206.9. This product 206.9 is then hydrolyzed by treatment with lithium hydroxide in aqueous THF to give the acid 206.10. Using the above procedures, but employing, in place of the benzoic acid 206.6, different acids 206.1, and/or different haloalkyl phosphonates 206.3, the corresponding products 206.5 are obtained.
Scheme 207 depicts the preparation of phosphonate esters linked to a benzoic acid nucleus by means of unsaturated and saturated carbon chains. The carbon chain linkage is formed by means of a palladium catalyzed Heck reaction, in which an olefinic phosphonate 207.3 is coupled with an aromatic bromo compound 207.2. The coupling of aryl halides with olefins by means of the Heck reaction is described, for example, in Advanced Organic Chemistry, by F. A. Carey and R. J. Sundberg, Plenum, 2001, p. 503ffand in Ace. Chem. Res., 12, 146, 1979. The aryl bromide and the olefin are coupled in a polar solvent such as dimethylformamide or dioxan, in the presence of a palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium(0) or a palladium(II) catalyst such as palladium(II) acetate, and optionally in the presence of a base such as triethylamine or potassium carbonate, to afford the coupled product 207.4. Deprotection, or hydrogenation of the double bond
followed by deprotection, affords respectively the unsaturated phosphonate acid 207.5, or the saturated analog 207.6 respectively.
For example, 4-bromo-3-fluorobenzoic acid 207.7 (Apollo) is converted to the tert butyl ester 207.8 by treatment with t-butanol and DCC in the presence of dimethylaminopyridine. The ester 207.8 is then reacted with a dialkyl 1-propenyl phosphonate 150.8, the preparation of which is described in J. Med. Chem., 1996, 39, 949, in the presence of a palladium (II) catalyst, for example, bis(triphenylphosphine) palladium (II) chloride, as described in J. Med. Chem, 1992, 35, 1371. The reaction is conducted in an aprotic dipolar solvent such as, for example, dirnethylformamide, in the presence of triethylamine, at about 100°C to afford the coupled product 207.10. Deprotection as described in Protective Groups in Organic Synthesis, by T.W. Greene and P.G.M Wuts, Wiley, Third Edition 1999 p. 406-408, then affords the acid 207.11. Optionally, the acid 207.11 is subjected to catalytic or chemical reduction, for example using diimide, as described in Scheme 138, to yield the saturated product 207.12.
Using the above procedures, but employing, in place of the acid compound 207.7, different acid compounds 207.1, and/or different phosphonates 207.3, there are obtained the corresponding products 207.5 and 207.6.
The phosphonate-containing benzoic acids, prepared as described in Schemes 206 and 207, are then transformed, using the procedures shown in Scheme 205, into the phenyloxazole piperazine derivatives 205.10.
(Figure Remove)Nelfinavir-like phosphonate protease inhibitors - (NLPPI)
Preparation of the intermediate phosphonate esters.
The intermediate phosphonate esters 1 to 4a of this invention are shown in Chart 1.
Subsequent chemical modifications, as described herein, permit the synthesis of the final
compounds of this invention.
The structures of the amine components R2NHCH(R3)CONHBuc 6-20e are shown in Chart 2.
Although specific stereoisomers of some of the amines are shown, all stereoisomers of the
amine components are utilized. Chart 2 also illustrates that, in addition to the tert. butyl
amines 5, the corresponding 2,2,2-triflvororoethyl and 2-methylbenzyl amides are utilized in
the synthesis of the phosphonate intermediate compounds of this invention.
Chart 3 depicts the structures of the R4 components 21-26. Charts 4a-4c illustrate the
structures of the carboxylic acid components R5COOH, C1-C49.
The intermediate compounds 1 to 4a incorporate a phosphonate moiety connected to the
a nucleus by means of a variable linking group, designated as "link" in the attached structures.
Charts 5 and 5a illustrate examples of the linking groups 38-59 present in the structures l-4a,
and in which "etc" refers to the scaffold, e.g., nelfinavir.
Schemes 1-50 illustrate the syntheses of the intermediate phosphonate compounds of this
invention, l-4a, and of the intermediate compounds necessary for their synthesis.Chart 1. Structures of phosphonate ester intermediate compounds
Protection of reactive substituents.
5
Depending on the reaction conditions employed, it may be necessary to protect certain reactive substituents from unwanted reactions by protection before the sequence described, and to deprotect the substituents afterwards, according to the knowledge of one skilled in the art. Protection and deprotection of functional groups are described, for example, in Protective 10 Groups in Organic Synthesis, by T.W. Greene and P.O. M Wuts, Second Edition 1990.
Reactive substituents which may be protected are shown in the accompanying schemes as, for example, [OH], [SH].
Preparation of the phosphonate intermediates 1, in which X=S.
The syntheses of the phosphonates 1 in which X=S, and in which the group link-P(O)(OR )2 is attached to the benzoic acid moiety, are shown in Schemes 1- 3.
Scheme 1 illustrates the preparation of the phosphonate intermediate compounds 1, or precursors thereto. 4-Amino-tetrahydro-furan-3-ol 60, the preparation of which is described in Tet. Lett., 2000, 41, 7017, is reacted with the carboxylic acid 61, or an activated derivative thereof, the preparations of which are described below, to form the amide 62. The preparation of amides by reaction of carboxylic acids and derivatives is described, for example, in Organic Functional Group Preparations, by S.R. Sandier and W. Karo, Academic Press, 1968, p 274. The carboxylic acid is reacted with the amine in the presence of an activating agent, such as, for example, dicyclohexylcarbodiimide, optionally in the presence of, for example, hydroxybenztriazole, in a non-protic solvent such as, for example, pyridine, DMF or dichloromethane, to afford the amide.
Alternatively, the carboxylic acid may first be converted into an activated derivative such as the acid chloride or anhydride, and then reacted with the amine, in the presence of an organic base such as, for example, pyridine, to afford the amide.
Preferably, the carboxylic acid is first converted into the acid chloride by reaction with, for example, thionyl chloride, oxalyl chloride and the like. The acid chloride 61, in which X is Cl, is then reacted with an equimolar amount of the amine 60, in the presence of a weak inorganic base such as sodium bicarbonate, in an aprotic solvent such as dichloromethane, at ambient temperature, to afford the amide 62.
The hydroxyl group on the tetrahydrofuran moiety so obtained is converted into a leaving group such as p-toluenesulfonyl or the like, by reaction with a sulfqnyl chloride in an aprotic solvent such as pyridine or dichloromethane.
Preferably, the hydroxy amide 62 is reacted with an equimolar amount of methanesulfonyl chloride in pyridine, at ambient temperature, to afford the methanesulfonyl ester 63. The product 63, bearing a suitable sulfonyl ester leaving group, is then subjected to acid-catalyzed rearrangement to afford the isoxazoline 64. The rearrangement reaction is conducted in the presence of an acylating agent such as a carboxylic anhydride, in the presence of a strong acid catalyst.
Preferably, the mesylate 63 is dissolved in an acylating agent such as acetic anhydride at about
0°, in the presence of about 5 mole % of a strong acid such as sulfuric acid, to afford the
isoxazoline mesylate 64.
The leaving group, for example a mesylate group, is next subjected to a displacement reaction
with an amine.
The compound 64 is reacted with an amine 5, as defined in Chart 2, in a protic solvent such as
an alcohol, in the presence of an organic or inorganic base, to yield the displacement product
65.
Preferably, the mesylate compound 64 is reacted with an equimolar amount of the amine 5, in
the presence of an excess of an inorganic base such as potassium carbonate, at ambient
temperature, to afford the product 65.
The isoxazoline compound 65 is then reacted with a thiol R4SH 66, in which R4 is phenyl, 4-
fluorophenyl or 2-naphthyl, as shown in Chart 3, to afford the thioether 1. The reaction is
conducted in a polar solvent such as DMF, pyridine or an alcohol, in the presence of a weak
organic or inorganic base, to afford the product 1.
Preferably, the isoxazoline 65 is reacted, in methanol, with an equimolar amount of the thiol
R4SH 66, in the presence of an excess of a base such as potassium bicarbonate, at ambient
temperature, to afford the thioether 1.
Alternatively, the compounds 1 can be obtained by means of the reactions shown in Scheme 2.
In this sequence, methanesulfonic acid 2-benzoyloxycarbonylamino-2-(2,2-dimethyl-
[l,3]dioxolan-4-yl)-ethyl ester, 67, prepared as described in J. Org. Chem, 2000, 65, 1623, is
reacted with a thiol R4SH 66, as denned above, to afford the thioether 68.
The reaction is conducted in a suitable solvent such as, for example, pyridine, DMF and the
like, in the presence of an inorganic or organic base, at from 0° to 80°, for from 1-12 hours, to
afford 68.
Preferably the mesylate 67 is reacted with an equimolar amount of the thiol R4SH 66, in a
mixture of a water-immiscible organic solvent such as toluene, and water, in the presence of a
phase-transfer catalyst such as, for example, tetrabutyl ammonium bromide, and an inorganic
base such as sodium hydroxide, at about 50°, to give the product 68.
The 1,3-dioxolane protecting group present in the compound 68 is removed by acid catalyzed
hydrolysis or by exchange with a reactive carbonyl compound to afford the diol 69. Methods
for conversion of 1,3-dioxolanes to the corresponding diols are described in Protective Groups
in Organic Synthesis, by T.W. Greene and P.O. M Wuts, Second Edition 1990, p. 191.
For example, the 1,3-dioxolane compound 68 is hydrolyzed by reaction with a catalytic
amount of an acid in an aqueous organic solvent mixture.
Preferably, the 1,3-dioxolane 68 is dissolved in aqueous methanol containing hydrochloric
acid, and heated at ca. 50°, to yield the product 69.
The primary hydroxyl group of the diol 69 is then selectively acylated by reaction with an
electron-withdrawing acyl halide such as, for example, pentafluorobenzoyl chloride or mono-
or di-nitrobenzoyl chlorides. The reaction is conducted in an inert solvent such as
dichloromethane and the like, in the presence of an inorganic or organic base.
Preferably, equirnolar amounts of the diol 69 and 4-nitrobenzoyl chloride are reacted in a
solvent such as ethyl acetate, in the presence of a tertiary organic base such as 2-picoline, at
ambient temperature, to afford the ester 70.
The hydroxy ester 70 is next reacted with a sulfonyl chloride such as methanesulfonyl chloride,
4-toluenesulfonyl chloride and the like, in the presence of a base, in an aprotic polar solvent at
low temperature, to afford the corresponding sulfonyl ester 71.
Preferably, equimolar amounts of the carbinol 70 and methanesulfonyl chloride are reacted
together in ethyl acetate containing triethylamine, at about 10°C, to yield the mesylate 71.
The compound 71 is then subjected to a hydrolysis-cyclization reaction to afford the oxirane
72.
The mesylate or analogous leaving group present in 71 is displaced by hydroxide ion, and the
carbinol thus produced, without isolation, spontaneously transforms into the oxirane 72 with
elimination of 4-nitrobenzoate. To effect this transformation, the sulfonyl ester 71 is reacted
with an alkali metal hydroxide or tetraalkylammonium hydroxide in an aqueous organic
solvent.
Preferably, the mesylate 71 is reacted with potassium hydroxide in aqueous dioxan at ambient
temperature for about 1 hour, to afford the oxirane 72.
The oxirane compound 72 is then subjected to regiospecific ring-opening reaction by
treatment with an amine 5, to give the aminoalcohol 73.
The amine and the oxirane are reacted in a protic organic solvent, optionally in the additional
presence of water, at 0° to 100°, and in the presence of an inorganic base, for 1 to 12 hours, to
give the product 73.
Preferably, equimolar amounts of the reactants 5 and 72 are reacted in aqueous methanol at
about 60° in the presence of potassium carbonate, for about 6 hours, to afford 73.
The carbobenzyloxy (cbz) protecting group in the product 73 is removed to afford the free
amine 74. Methods for removal of cbz groups are described, for example, in Protective
Groups in Organic Synthesis, by T.W. Greene and P.G. M. Wuts, Second Edition, p. 335.
The methods include catalytic hydrogenation and acidic or basic hydrolysis.
For example, the cbz-protected amine 73 is reacted with an alkali metal or alkaline earth
hydroxide in an aqueous organic or alcoholic solvent, to yield the free amine 74.
Preferably, the cbz group is removed by the reaction of 73 with potassium hydroxide in an
alcohol such as isopropanol at ca. 60° to afford the amine 74.
The amine 74 so obtained is next acylated with a carboxylic acid or activated derivative 61,
using the conditions described above for the conversion of 60 to 62, to yield the final amide
product 75.
The reactions shown in the above-described Schemes 1 and 2 depict the preparation of
intermediates 1 in which A is either link-P(O)(ORI)2 or precursor groups to Unk-P(O)(OR1)2
such as OH, SH, NH, as described herein.
Scheme 3 shows the conversion of the compounds 75 in which A is OH, SH, NH, to the
compounds 1 in which A is link-P(O)(OR1)2.
Methods for these transformations are described below, Schemes 20-48, in the descriptions of
the preparations of the phosphonate-containing reactants.
Preparation of the phosphonate intermediates 2, in which X = S.
The synthesis of the phosphonate compounds 2 in which the link-PCOXOR1^ group is attached to the phenylthio moiety, is shown in Scheme 4.
In this sequence, 4-arnino-tetrahydro-furan-3-ol, 60, the preparation of which is described in
Tet. Lett., 2000, 41, 7017, is reacted with a carboxylic acid or activated derivative thereof,
R5COX, 76, using the conditions described above for the preparation of the amide 62, Scheme
1, to afford the amide 77. The compounds 77, and analogous acylation products described
below, in which the carboxylic acid R5COOH is one of the carbonic acid derivatives C36-C49,
as defined in Chart 4c, are carbamates. Methods for the preparation of carbamates are
described below, (Scheme 50).
The amide product 77 is then transformed, using the sequence of reactions shown in
Scheme 4, into the isoxazoline compound 80. The conditions for this sequence of
transformations are the same as those described for the preparation of the isoxazoline 65 in
Scheme 1.
The isoxazoline compound 80 is then reacted with a thiol compound 66, in which the
substituent A is either the group link-P(O)(OR1)2, or a precursor thereto, such as OH, SH,
NH, as described herein, to afford the thioether 81.
The conditions for this reaction are the same as those described above for the preparation of
the thioether 1, (Scheme 1).
Alternatively, the thioether 81 can be prepared by the sequence of reactions shown in Scheme
5. In this sequence, the previously described 1,3-dioxolane mesylate compound 67 is reacted
with a thiol compound 66 in which the substituent A is either the group link-P(0)(OR1)2, or a
precursor thereto, such as OH, SH, NH, as described herein, to afford the thioether 82. The
conditions for this reaction are the same as those described above for the preparation of the
thiether 68, (Scheme 2).
The thus-obtained thioether 82 is then transformed, using the sequence of reactions shown in
Scheme 2 into the compound 81.
The reactions shown in the above-described Schemes 4 and 5 depict the preparation of
intermediates 81 in which A is either link-P(O)(OR')2 or precursor groups to link-PtOXOR1^
such as OH, SH, NH, as described herein.
Scheme 6 shows the conversion of the compounds 81 in which A is OH, SH, NH, into the
compounds 2 in which A is link-P(O)(OR1)2.
Methods for these transformations are shown in Schemes 20-48 and are discussed in the descriptions of the preparations of the phosphonate-containing reactants.
The phosphonate intermediates 3 in which X = S, and in which the link-P(O)(OR1)2 group is 5 attached to the tert. butyl moiety, are prepared as shown in Schemes 7 and 8.
(Figure Remove)As shown in Scheme 7, the isoxazolines 79, the preparation of which are described above, are
reacted with the amines 83, using the conditions described above for the conversion of 64 to
65, (Scheme 1) to afford the product 84.
This compound is then converted, using the methods described above, (Scheme 1) into the
compound 85, in which B is either link-P(O)(OR1)2 or precursor groups to link-P(O)(OR1)2
such as OH, SH, NH, as described herein.
Alternatively, the compounds 85 can be prepared by the reactions shown in Scheme 8.
In this method, the oxirane 72, the preparation of which is described above, (Scheme 2) is
reacted with the amine 83, using the reaction conditions described above for the conversion of
72 to 73 (Scheme 2), to afford the hydroxyamine 86. This compound is then converted, using
the procedures described above, into the compound 85, in which B is either link-P(O)(OR1)2
or precursor groups to link-P(O)(OR1)2 such as OH, SH, NH, as described herein.
The reactions shown in the above-described Schemes 7 and 8 depict the preparation of
intermediates 85 in which A is either link-PtOXOR1^ or precursor groups to link-PCOXOR1^
such as OH, SH, NH, as described herein.
Scheme 9 shows the conversion of the compounds 85 in which A is OH, SH, NH, into the
compounds 3 in which A is link-P(O)(ORI)2.
Methods for these transformations are described below in Schemes 20 to 48 in which the
preparations of the phosphonate-containing reactants are depicted.
Preparation of the phosphonate intermediates 4 in which X = S.
The preparations of the phosphonate intermediates 4, in which the link-P(O)(ORl)2 group is
attached to the decahydroisoquinoline moiety, are shown in Schemes 10 to 12.
As shown in Scheme 10, the isoxazoline mesylate 79, the preparation of which is described
above, (Scheme 4) is reacted with the amine 88, the preparation of which is described below.
The reaction is preformed using the procedures described above for the preparation of 65
(Scheme 1).
The reaction product 89 is then transformed, using the procedures described above,
(Scheme 1) into the compound 90, in which B is either link-P(O)(OR1)2 or precursor groups
to link-P(O)(ORl)2 such as OH, SH, NH, as described herein.
Alternatively, the compound 90 can be prepared by the reactions shown in Scheme 11.
In this reaction scheme, the oxirane 72, the preparation of which is described above,
(Scheme 2) is reacted with the amine 88, using the conditions described above for the
preparation of 73 (Scheme 2) to afford the hydroxyamine 91. This compound is then
converted, using the reaction schemes and conditions described above for the preparation of 1,
(Scheme 2) into the compound 90, in which B is either Unk-P(O)(OR1)2 or precursor groups
to link-PCOXOR1^ such as OH, SH, NH, as described herein.
The reactions shown in the above-described Schemes 10 and 11 depict the preparation of
intermediates 90 in which B is either link-P(0)(OR1)2 or precursor groups to link-P(O)(OR1)2
such as OH, SH, NH, as described herein.
Scheme 12 shows the conversion of the compounds 90 in which B is OH, SH, NH, to the
compounds 4 in which A is Unk-P(O)(OR1)2.
Methods for these transformations are described below in Schemes 20-48 in which the
preparations of the phosphonate-containing reactants are depicted.
Preparation of the phosphonate intermediates 1, in which X is a direct bond
As shown in Scheme 13, the oxirane 92, in which X is H, the preparation of which is described
in J. Med. Chem,, 1997, 40, 1995, and in Bioorg. Med. Chem. Lett., 5, 2885, 1995, is reacted
with the amine 5. The compounds are reacted together using the conditions described above
for the preparation of 73, (Scheme 2) to afford the hydroxyamine 93, This compound is then
transformed, using the procedures described above for the preparation of 1, (Scheme 2) into
the compound 94, in which A is either link-P(O)(OR1)2 or precursor groups to link-
PCOXOR'fc such as OH, SH, NH, as described herein.
Scheme 14 shows the conversion of the compounds 94 in which A is OH, SH, NH, to the
compounds 1 in which A is unk-P(O)(OR1)2.
Methods for these transformations are described below in Schemes 20-43 in which the
preparations of the phosphonate-containing reactants are depicted.
Preparation of the phosphonate intermediates 2, in which X is a direct bond.
The preparation of the compounds 2, in which X is a direct bond, and the group link-P(O)(OR1)2 is