Title of Invention

"NOVEL HETEROCYCLIC COMPOUNDS AS HSP90-INHIBITORS"

Abstract Novel heterocyclic compounds are described and demonstrated to have utility as Heat Shock Protein 90 (HSP90) inhibiting agent. Method of synthesis and use of such compounds are also described.
Full Text NOVEL HETEROCYCLIC COMPOUNDS AS HSP90-INHIB1TORS
FIELD OF THE INVENTION
The invention relates in general to heterocyclics and related compounds and their broad-spectrum utility, e.g., in inhibiting heat shock protein 90 (HSP90) to thereby treat or prevent HSP90-mediated diseases.
BACKGROUND
HSP90s are ubiquitous chaperone proteins that are involved in folding, activation and assembly of a wide range of proteins, including key proteins involved in signal transduction, cell cycle control and transcriptional regulation. Researchers have reported that HSP90 chaperone proteins are associated with important signaling proteins, such as steroid hormone receptors and protein kinases, including, e.g., Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 ( Buchner J. TIBS 1999,24,136-141; Stepanova, L. et al. Genes Dev. 1996, JO, 1491-502; Dai, K. et al. J. Biol. Chenu 1996,271, 22030-4). Studies further indicate that certain co-chaperones, e.g., HSP70, p60/Hop/Stil, Hip, Bagl, HSP40/Hdj2/Hsj 1, immunophilins, p23, and p50, may assist HSP90 in its function (see, e.g., Caplan, A. Trends in Cell Biol 1999, 9,262-68).
Ansamycin antibiotics, e.g., herbimycin A (HA), geldanamycin (GM), and 17-allylaminogeldanamycin (17-AAG) are thought to exert their anticancerous effects, by tight binding of the N-terminus pocket of HSP90, thereby destabilizing substrates that normally interact with HSP90 (Stebbins, C. et al. Cell 1991, 89,239-250). This pocket is highly conserved and has weak homology to the ATP-binding site of DNA gyrase (Stebbins, C. et a!., supra-, Grenert, J.P. et al. J. Biol. Chem. 1997,272,23843-50). Further, ATP and ADP have both been shown to bind this pocket with low affinity and to have weak ATPase activity (Proromou, C. et al. Cell 1997,90,65-75; Panaretou, B. et a). EMBO J. 1998, 17,4829-36). In vitro and in vivo studies have demonstrated that occupancy of this N-terminal pocket by ansamycins and other HSP90 inhibitors alters HSP90 function and inhibits protein folding. At high concentrations, ansamycins andother HSP90 inhibitors have been shown to prevent binding of protein substrates to HSP90 (Scheibel, T.H. et al. Proc. Natl. Acad, Sci. USA 1999, 96,1297-302; Schulte, T. W. et al. J. Biol Own. 1995, 270, 24585-8; Whitehorse, L., et al, Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328). Ansamycins have also been demonstrated to inhibit the ATP-dependent release of chaperone-associated protein substrates (Schneider, C.L. et al. Proc. Natl. Acad. Sci„USA 1996, 93,14536-41; Sepp-Lorenzino et al../. Biol. Chem. 1995,270, 16580-16587). In either event, the substrates are degraded by a ubiquitin-dependent process in the proteasome (Schneider, C. L., supra; Sepp-Lorenzino, L., et al. J. Biol Chem. 1995,270, 16580-16587; Whitesell, L et al. Proc. Natl. Acad. Sci. USA
1994, 91, 8324-8328).
HSP90 substrate destabilization occurs in tumor and non-transformed cells alike and has been shown to be especially effective on a subset of signaling regulators, e.g., Raf (Schulte, T. W. et al. Biochem. Biophys. Res. Commun. 1997,239,655-9; Schulte, T. W., et al. J. Biol Chem. 1995, 270, 24585-8), nuclear steroid receptors (Segnitz, B.; U. Gehring J. Biol Chem. 1997,272,18694-18701; Smith, D. F. et al. Mot. Celt. Biol
1995, 15, 6804-12), v-Src (Whitesell, L„ et al. Proc. Natl Acad Sci. USA 1994, 91,
8324-8328) and certain transmembrane tyrosine kinases (Sepp-Lorenzino, L. et al. J.
Biot.Chem. 1995,270,16580-16587) such as EGF receptor (EGFR) and HER2/Neu
(Hartmann, F., et al. Int. J. Cancer 1997, 70,221-9; Miller, P. et al. Cancer Res. 1994,
54, 2724-2730; Mimnaugh, E. G., et al. J. Biol. Cltem. 1996,271,22796-801; Schnur, R.
et al. J. Med. Chem. 1995, 38, 3806-3812), CDK4, and mutant p53. Erlichman et al.
Proc. AACR 2001, 42, abstract 4474. The ansamycin-induced loss of these proteins
leads to the selective disruption of certain regulatory pathways and results in growth
arrest at specific phases of the cell cycle (Muise-Heimcricks, R. C. et al. J. Biol. Chem.
1998, 273, 29864-72), and apoptosis, and/or differentiation of cells so treated
(Vasilevskaya, A. et al. Cancer Res., 1999,59, 3935-40). Ansamycins thus hold great
promise for the treatment and/or prevention of many types of cancers and proliferative
disorders, and also hold promise as traditional antibiotics. However, their relative
insolubility makes them difficult to formulate and administer, and they are not easily
synthesized and currently must, at least in part, be generated through fermentation.
Further, the dose limiting toxicity of ansamyins is hepatic.
In addition to anti-cancer and antitumorgenic activity, HSP90 inhibitors have also been implicated in a wide variety of other utilities, including use as anti-inflammation agents, anti-infectious disease agents, agents for treating autoimmunity, agents for treating stroke, ischemia, multiple sclerosis, cardiac disorders, central nervous system related disorders and agents useful in promoting nerve regeneration (See, eg,, Rosen et al. WO 02/09696 (PC1YUS0 L/23640); Degranco et al. WO 99/51223 (PCT/US99/07242); Gold, U.S. Patent 6,210,974 Bl; DeFranco et al., US Patent . 6,174,875. Overlapping somewhat with the above, there are reports in the literature that fibrogenetic disorders including but not limited to scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis, and pulmonary fibrosis also may be treatable with HSP90 inhibitors. Strehlow, WO 02/02123 {PCT/US01/20578). Still further HSP90 modulation, modulators and uses thereof are reported in Application Nos. PCT/US03/04283, PCT/US02/35938, PCT/US02/16287, PCT7US02/06518, PCT/US98/09805,PCT/US00/09512, PCT7US01/09512, PCT/US01/23640, PCT/US01/46303, PCT/US01/46304, PCT/US02/06518,PCT/US02/29715,PCT/US02/35069,PCT/US02/35938, PCT/US02/39993, 60/293,246, 60/371,668, 60/335,391, 60/128,593, 60/337,919, 60/340,762, 60/359,484 and 60/331,893.
Recently, purine derivatives showing HSP90 inhibitory activity have been reported, e.g., in PCT/US02/35069 and PCT/US02/36075. Purine moieties are well accepted bioisosteres for a variety of ATP-dependent molecular targets, see, JP 10025294; US Patent 4,748,177; US Patent 4,772,606; US Patent 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083; European Patent 0178178; Eur. J. Med. Chem. 1994, 29(1), 3-9; and J. Met. Chem, 1990,27(5), 1409. However, compounds having the desired potency, selectivity and pharmaceutical properties required for effective HSP90 inhibition in vivo have not been reported. Therefore, a need remains for additional novel and potent HSP90 inhibitors that meet the demanding biological and pharmaceutical criteria required to proceed towards human clinical trials.
SUMMARY OF THE INVENTION
The present invention is directed towards heterocyclic compounds, particularly heterocyclic compounds and related analogs that show broad utility, e.g., by inhibiting HSP9G and treating and preventing diseases that are HSP9G-dependent.
In one aspect, the invention comprises the heterocyclic compounds and related analogs as specified below in Formulae A, I, IA-E, II, IIA-D, III, IIIA-B, and IV and IVA and heterocyclic compounds that are produced by a process of the invention. Also included in the scope of the present invention are stereoisomeric forms, including the individual enantiomers and diastereomers, racemic mixtures, and diastereomeric mixtures, as well as polymorphs, solvates, esters, tautomers, pharmaceutically acceptable salts and prodrugs of these compounds. Stereoisomers of the compounds of the present invention may be isolated by standard resolution techniques such as, for example, fractional crystallization and chiral column chromatography.
In one aspect, the invention provides compounds of Formula A, or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, which show utility for inhibiting HSP90 and/or treating and preventing diseases that are HSP90-dependent.
(Formula Removed)
Various genuses and subgenuses of compounds of Formula A that are within the scope of the invention are illustrated in FIGURE I. Particularly, the invention provides compounds of Formula 1-1V.
(Formula Removed)
In another aspect, the invention provides compounds, or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, which show utility for inhibiting HSP90 and/or treating and preventing diseases that arc HSP90-dependent, that are prepared by the process comprising:
reacting a compound of Formula Y and a compound of Formula Z, wherein:
Y is represented by any of the following formulae:

(Formula Removed)
Z is L'-R4R5
In another aspect, the present invention is directed to pharmaceutical compositions comprising the compounds of the invention, in particular, the compounds of Formulae A, I, II, III and IV and related analogs, and compounds formed by the process of the invention, and their polymorphs, solvates, esters, tautomers, diastereomer, enantiomers, pharmaceutically acceptable salts and prodrugs thereof, and one or more
pharmaceutical excipients, for use in treatment or prevention of diseases that are HSP90-dependent.
In another aspect, the invention features a method of treating an individual having an HSP90-mediated disorder by administering to the individual a pharmaceutical composition that comprises a pharmaceutically effective amount of a compound of Formulae A, I, II, III or IV, or a. polymorph, solvate, ester, tautomer, diastereomer, enantiomer, enantiomets pharmaceutically acceptable salt or prodrug thereof.
In one embodiment, the invention provides a method for treating an individual having a disorder selected from the group of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorders, neurological disorders, fibrogenetic disorders, proliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and malignant diseases.
In yet another embodiment, the invention provides a method for treating an individual having a fibrogenetic disorder, such as, for example, scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.
In another embodiment, the invention provides a combination therapy comprising the administration of a pharmaceutically effective amount of a compound of Formulae A, I, II, III or IV and related analogs, or a polymorph, solvate, ester, rautomer, diastereomer, enantiomer, pharmaceutically acceptable salt and prodrug thereof, according to any of the preceding aspects or embodiments, and at least one therapeutic agent selected from the group of cytotoxic agents, anti-angiogenesis agents and antineoplastic agents. The antineoplastic agent may be selected from the group of alkylating agents, anti­metabolites, epidophyllotoxins antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.
Any of the above described aspects and embodiments of the invention can be combined where practical.
he individual compounds, methods and compositions prescribed do not preclude the utilization of other, unspecified steps and agents, and those of ordinary skill in the art will appreciate that additional steps and compounds may also be combined usefully within the spirit of various aspects and embodiments of the invention.
Advantages of the invention depend on the specific aspect and embodiment and may include one or more of: ease of synthesis and/or formulation, solubility, and IC50 relative to previously existing compounds in the same or different classes of HSP90 inhibitors.
BRIEF DESCRIPTION OF THE FIGURES
FIGURE 1 shows various illustrative genuses and subgenuses of Formula A.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
I. Definitions
A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or a pharmaceutically active metabolite or residue thereof. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient {e.g., by allowing orally administered compound to be more readily absorbed into blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system).
A "pharmaceutically acceptable salt" may be prepared for any compound of the invention having a functionality capable of forming a salt, for example, an acid or base functionality. Pharmaceutically acceptable salts may be derived from organic or inorganic acids and bases. Compounds of the invention that contain one or more basic functional groups, e.g., amino or alkylamino, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable organic and inorganic acids. These
salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gtucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate,, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecampate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation cf salts useful as intermediates in obtaining the compounds of the invention and their phannaceutically acceptable acid addition salts. See, e.g., Berge et al. "Pharmaceutical Salts", J. Pharm. Set 1977, 66:l-19.
Compounds of the present invention that contain one or more acidic functional groups are capable of forming pharmaceutically acceptable salts with phannaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Illustrative examples of some of the bases that can be used include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, djethylamine, ethylcnediamine, ethanolamine, diethanolamine, piperazine and the like. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein- Water or
oil-soluble or dispersible products may be obtained by such quaternization. See, for example, Berge et al., supra,
Pharmaceutically acceptable prodrugs of the compounds of this invention include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates, phosphate esters, metal salts and sulfonate esters,
Suitable positions for derivatization of the compounds of the invention to create "prodrugs" include but are not limited, 2-amino substitution. Those of ordinary skill in the art have the knowledge and means to accomplish this without undue experimentation. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see, e.g.,
a) Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396;
a) Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and
a) Bundgaard, H., Advanced Drug Delivery Reviewt 1992,8, 1-38. Each of which is incorporated herein by reference,
The term "prodrugs" as employed herein includes, but is not limited to, the following groups and combinations of these groups;
Amine prodrugs:: (Formula Removed)

Hydroxy prodrugs:
Acyloxyalkyl esters;
Alkoxycarbonyloxyalkyl esters;
Alkyl esters;
Aryl esters; and
Disulfide containing esters. The term "alkyl," alone or in combination, refers to an optionally substitutes straight-chain, or optionally substituted branched-chain saturated hydrocarbon radical having from one to about thirty carbons, more preferably one to twelve carbons. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like. The term "cycloalkyl" embraces cyclic alkyl radicals which include monocyclic, bicyclic, tricyclic, and higher multicyclic alkyl radicals wherein each cyclic moiety has from three to about eight carbon atoms. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, A "lower alkyl" is a shorter alkyl, e.g,, one containing from one to about six carbon atoms.
The term "alkenyl," alone or in combination, refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from two to about thirty carbon atoms, more preferably two to about eighteen carbons. Examples of alkenyl radicals include ethenyl, propenyl, butenyl, 1,3-butadienyl and the like. The term "cytcoalkenyt" refers to cyclic alkenyl radicals which include monocyclic, bicyclic, tricyclic, and higher multicyclic alkenyl radicals wherein each cyclic moiety has from three to about eight carbon atoms, A "lower alkenyl" refers to an alkenyl having from two to about six carbons,
The term "alkynyl," alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon radical liaving one or more carbon-carbon triple-bonds and having from two to about thirty carbon atoms, more preferably from two to about tweove carbon atoms, from two to about six carbon atoms as well as those having from two to about four carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. The term "cycloalkynyl" refers to cyclic alkynyl radicals which include monocyclic, bicyclic,

ricyclic, and higher multicyclic alkynyl radicals wherein each cyclic moiety has from three to about eight carbon atoms, A "lower alkynyl" refers to an alkynyl having from two to about six carbons.
The terms "heteroalkyl, heteroalkenyl and heteroalkynyl" include optionally substituted alkyl, alkenyl and alkynyl structures, as described above, and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g„ oxygen, nitrogen, sulfur, phosphorous or combinations thereof.
The term "carbon chain" embraces any alkyl, alkenyl, alkynyl, or heteroalkyl, heteroalkenyl, or heteroalkynyl group, which are linear, cyclic, or any combination thereof. If the chain is part of a linker and that linker comprises one or more rings as part of the core backbone, for purposes of calculating chain length, the "chain" only includes those carbon atoms that compose the bottom or top of a given ring and not both, and where the top and bottom of the ring(s) are not equivalent in length, the shorter distance shall be used in determining the chain length. If the chain contains heteroatoms as part of the backbone, those atoms are not calculated as part of the carbon chain length.
The term "membered ring" can embrace any cyclic structure, including aromatic, heteroaromatic, alicyclic, heterocyclic and polycyclic fused ring systems as described below. The term "membered" is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, pyridine, pyran, and pyrimidine are six-membered rings and pyrrole, tetrahydrofuran, and thiophene are five-membered rings.
The term "aryl," alone or in combination, refers to an optionally substituted aromatic hydrocarbon radical of six to about twenty ring atoms, and includes mono-aromatic rings and fused aromatic ring, A fused aromatic ring radical contains from two to four fused rings where the ring of attachment is an aromatic ring, and the other individual rings within the fused ring may be aromatic, heteroaromatic, alicyclic or heterocyclic. Further, the term aryl includes mono-aromatic ring and fused aromatic rings containing from six to about twelve carbon atoms, as well as those containing from six to about ten carbon atoms. Examples of aryl groups include, without limitation, phenyl, naphthyl, antluyl, chrysenyl, and benzopyrenyl ring systems. The term "lower aryl" refers to an aryl having six to about ten skeletal ring carbons, e.g., phenyl and naphthyl ring systems.
The term "heteroaiyr refers to optionally substituted aromatic radicals containing from about five to about twenty skeletal ring atoms and where one or more of the ring atoms is a heteroatom such as, for example, oxygen, nitrogen, sulfur, selenium and phosphorus. The term heteroaryl includes optionally substituted mono-heteroaryl radicals and fused heteroaryl radicals having at least one heteroatom (e.g., quinoline, benzothiazole). A fused heteroaryl radical may contain from two to four fused rings and where the ring of attachment is a heteroaromatic ring, the other individual rings within the fused ring system may be aromatic, heteroaromatic, alicyclic or heterocyclic. The term heteroaryl also includes mono-heteroaryls or fused heteroaryls having from five to about twelve skeletal ring atoms, as well as those having from five to about ten skeletal ring atoms. Examples of heteroaryls include, without limitation, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl, indolyl, quinolinyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazoly], pyrazolyl, oxazolyl, tsoxazolyl, benzothiozole, benzimidazole, benzoxazoles, benzothiadtazole, benzoxadiazole, benzotriazote, quinolmes, isoquinolines, indoles, purinyl, indolizinyl, thienyl and the like and their oxides. The term 'lower heteroaryl" refers to a heteroaryl having five to about ten skeletal ring atoms, e.g., pyridyl, thienyl, pyrimidyl, pyrazinyl, pyrrolyl, or furanyl.
The term "alicyclic" alone or in combination, refers to an optionally substituted saturated or unsaturated nonaromatic hydrocarbon ring system containing from three to about twenty ring atoms. The term alicyclic includes mono-alicyclic and fused alicyclic radicals. A fused alicyclic may contain from two to four fused rings where the ring of attachment is an alicyclic ring, and the other individual rings within the fused-alicyclic radical may be aromatic, heteroaromatic, alicyclic and heterocyclic. The term alicyclic also includes mono-alicyclic and fused alicyclic radicals containing from three to about twelve carbon atoms, as well as those containing from three to about ten carbon atoms. Examples of alicyclics include, without limitation, cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclodecyl, cyclododecyl, cyclopentadienyl, indanyl, and cyclooctatetraenyl ring systems. The term "lower alicyclic" refers to an alicyclic having three to about ten skeletal ring carbons, e.g., cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, decalinyl, and cyclohexyl.
The term "heterocyclic" refers to optionally substituted saturated or unsaturated nonaromatic ring radicals containing from five to about twenty ring atoms where one or
more of the ring atoms are hcteroatoms such as, for example, oxygen, nitrogen, sulfur, and phosphorus. The term alicyclic includes mono-heterocyclic and fused heterocyclic ring radicals. A fused heterocyclic radical may contain ftom two to four fused rings where the attaching ring is a hderocyclic, and the other individual rings within the fused heterocyclic radical may be aromatic, heteroaromaric, alicyclic or heterocyclic. The term heterocyclic also includes mono-heterocrclic and fused alicyclic radicals having from five to about twelve skeletal ring atoms, as well as those having from five to abouften skeletal ring atoms. Example of heterocyclics include without limitation, tetrahydrofuranyl, benzodiazepinyl, tetrahydroindazoleyl, dihyroquinolinyl, and the like. The terra "lower heterocyclic" refers to a heterocyclic ring system having five to about ten skeletal ring atoms, e.g., dihydropyranyl, pyrrolidinyl, indoly), piperidinyl, piperaziny], and the like.
The term "alkylaryl," or "araalkyl," alone or in combination, refers to an aryl radical as defined above in which one H atom is replaced by an alkyl radical as defined above, such as, for example, tolyl, xylyl and the like.
The term "arylalkyl," alone or in combination, refers to an alkyl radical as defined above in which one H atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like.
The term "heteroarylalkyl" refers to an alkyl radical as defined above in which one H atom is replaced by a heteroaryl radical as defined above, each of which may be optionally substituted.
The term "alkoxy," alone or in combination, refers to an alkyl ether radical, alkyl-0-, wherein the term alkyl is defined as above. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term "aryloxy," alone or in combination, refers to an aryl ether radical wherein the term aryl is defined as above. Examples of aryloxy radicals include phenoxy, benzyloxy and the like.
The term "alkylthio," alone or in combination, refers to an alkyl thio radical, alkyl-S-, wherein the term alkyl is as defined above.
The term "aryltlito," alone or in combination, refers to an aryl thio radical, aryl-S-wherein the term aryl is as defined above.
The term "heteroarylthio" refers to the group heteroaryl-S-, wherein the term heteroaryl is as defined above.
The term "acyl" refers to a radical -C(O)R where R includes alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocylic, arylalkyl or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroryl, alicylic, heterocylic, arylalkyl or heteroaryl alkyl groups may be optionally substituted.
The term "acyloxy" refers to the ester group -OC(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl, or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroarylalkyi may be optionally substituted.
The term "carboxy esters" refers to -C(O)OR where R is alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
The term "carboxamido" refers to
(Formula Removed)
where each of R and R' are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl, aryl, heteroaryl, alicyclic, heterocyclic, or arylalkyl groups may be optionally substituted.
The term "oxo" refers to =O.
The term "halogen" includes F, CI, Br and I.
The terms "haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.
The terms "perhaloalkyl, perhaloalkyloxy and perhaloacyl" refer to alkyl, alkyloxy and acyl radicals as described above, that all the H atoms are substituted with fluorines, chlorines, bromines or iodines, or combinations thereof.
The terms "cycloalkyl, arylalkyl, aryl, heteroaryl, alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl, and heteroalkyl" include optionally substituted cycloalkyl, arylalkyl, aryl, heteroaryl, alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl and heteroalkyl groups.
The terms "alkylamino', refers to the group -NHR where R is independently selected from alkyl.
TIio terms "dialkylamino", refers to the group -NRR' where R and R' are alkyls.
The term "sulfide" refers to a sulfur atom covalently linked to two atoms; the formal oxidation state of said sulfur is (II). The term "thioether" may be used interchangebly with the term "sulfide."
The term "sulfoxide" refers to a sulfur atom covalently linked to three atoms, at least one of which is an oxygen atom; the formal oxidation state of said sulfur atom is (IV).
The term "sulfone" refers to a sulfur atom covalently linked to four atoms, at least two of which are oxygen atoms; the formal oxidation state of said sulfur atom is (VI).
The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in whic-h it does not. For example, "aryl optionally mono- or di-substituted with an alkyl** means that the alkyl may but need not be present, or either one alkyl or two may be present, and the description includes situations where the aryl is substituted with one or two alkyls and situations where the aryl is not substituted with an alkyl.
"Optionally substituted" groups may be substituted or unsubstituted. The substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or designated subsets thereof: lower alkyl, tower alkenyl, lower alkynyl, lower aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl, heteroarylalkyl, lower alkoxy, lower aryloxy, amino, alkylamino, dialkylamino, diarylalkylamino, alkylthio, arylthio, heteroarylthio, oxo, oxa, carbonyl (-C(O)), carboxyesters (-C(O)OR), carboxamido (-C(O)NH2), carboxy, acyloxy, -H, halo, -CN, -NO2, -N3, -SH, -OH, -C(O)CH3, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, rndazole, esters, amides, phosphonates, phosphonic acid, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas, thioamides, fhioalkyls. An optionally substituted group may be unsubstituted (e.g., -CH2CH2), fully substituted
(e.g., -CF2CF3). monosubstiluled {e.g.t -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstututed (e.g., •CH2CF3).
The term "pyridine- 1-oxy" also means "pyridine-N-oxy."
Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover all isomers per se, as well as mixtures of cis and trans isomere, mixtures of diastereomers and racemic mixtures of enantiomers" (optical isomers) as well. Further, it is possible using well known techniques to separate the various forms, and some embodiments of the invention may feature purified or enriched species of a given enantiomer or diasteriomer.
A "pharmacological composition" refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as pharmaceutically acceptable carriers and/or excipients. The purpose of a pharmacological composition is to facilitate administration of a compound to an organism.
The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, .0 another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) atginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic
compatible substances employed in pharmaceutical formulations. A physiologically acceptable carrier should not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
An "excipient" refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound. Examples of excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
A "pharmaceuiically effective amount" means an amount which is capable of providing a therapeutic and/or prophylactic effect. The specific dose of compound administered according to this invention to obtain therapeutic and/or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the specific compound administered, the route of administration, the condition being treated, and the individual being treated. A typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 50-100 mg/lcg of body weight of an active compound of the invention, Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such as clearance rate, half-life and maximum tolerated dose (MTD) have yet to be determined but one of ordinary skill in the art can determine these using standard procedures.
In some method embodiments, the preferred therapeutic effect is the inhibition, to some extent, of the growth of cells characteristic of a proliferative disorder, e.g., breast cancer, A therapeutic effect will also normally, but need not, relieve to some extent one or more of the symptoms other than cell growth or size of cell mass. A therapeutic effect may include, for example, one or more of 1) a reduction in the number of cells; 2) a reduction in cell size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cell infiltration into peripheral organs, e.g.t in (he instance of cancer metastasis; 3) inhibition (ie,, slowing to some extent, preferably stopping) of tumor metastasis; 4) inhibition, to some extent, of cell growth; and/or 5) relieving to some extent one or more of the symptoms associated with the disorder,
As used herein, the term ICjo refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response. In some method embodiments of the invention, the
"IC50" value of a compound of the invention can be greater for normal cells than for cells exhibiting a proliferative disorder, e.g., breast cancer cells. The value depends on the assay used.
By a "standard" is meant a positive or negative control. A negative control in the context of HER2 expression levels is, e.g,, a sample possessing an amount of HER2 protein that correlates with a normal cell. A negative control may also include a sample that contains no HER2 protein. By contrast, a positive control does contain HER2" protein, preferably of an amount that correlates with overexpression as found in proliferative disorders, e.g., breast cancers. The controls may be from cell or tissue samples, or else contain purified ligand (or absent ligand), immobilized or otherwise. In some embodiments, one or more of the controls may be in the form of. diagnostic "dipstick,"
By "selectively targeting" is meant affecting one type of cell to a greater extent than another, e.g., in the case of cells with high as opposed to relatively low or normal HER2 levels.
II. Compounds of the Invention
Compounds of the invention and their polymorphs, solvates, esters, tautomers, diastereomers, enantiomers, pharmaceutically acceptable salts or prodrugs show utility for inhibiting HSP90 and treating and preventing diseases that are HSP90-dependent.
One embodiment of the compounds of the invention is of Formula A:
(Formula Removed)
or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically 25 acceptable salt or prodrug thereof, wherein:
X1 and X1 are the same or different and each is nitrogen or -CR6;
X1 is nitrogen or -CRJ wherein R3 is hydrogen, OH, a keto tautomer, -OR8, -CN,
halogen, lower alkyl, or -C(O)R9;
X4 is nitrogen or a group CR6 when X3 is nitrogen, and X4 is -CR6R7 when X3 is -
CR3
R1 is halogen, -OR8, -SR8, or lower alkyl;
R2 is -NR8R10;
R4 is -(CH2)n- wherein n - 0-3, -C(O), -C(S), -SOr, or -SO2N-; and
RJ is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, each of which is optionally bi-or tricyclic, and optionally substituted with H, halogen, lower alkyl, lower alkenyl, tower alkynyl, lower aryl, lower alicyclic, araalkyl, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -N3, -SR8, -OR8, -CN, -CO2R9, -NO2) or NR8R'°;
with the provisos that:
the compound is not one found or described in one or more of JP 10025294; US Patent 4,748,177; US Patent 4,748,177; US Patent 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083; Eur. J. Med. Chem., 1994,29(1), 3-9; and J. Met. Chem. 1990,27(5), 1409;
-R^5 is not a ribose or derivative thereof, or a sugar or derivative thereof;
-R R is not a phosphonate or phosphonic acid, or a group substituted witha phosphonate or phosphonic acid; and
when R4 is (CH2)n where n= 0 or 1, then R4 and R5 are not connected with 'O', e.g., -CHrO-CH2- or -CH2-CH2 -0-CHr.
In one embodiment of the compound, tautomer, pharmaceuticaUy acceptable salt thereof, or prodrug thereof of Formula A, X1 and Xi are the same or different and each is nitrogen or -CRS; R1 is halogen, -OR8, -SRe, or lower alkyl; R1 is -NR8R10; R3 is hydrogen, -OH or keto tautomer, -OR8, halogen, -CN, lower alkyl, or ~C(O)R9; R4 is -(CH2)n- wherein n = 0-3, -C(O), -C(S), -SO2-, or -SO2N-; and Rs is alkyl, aromatic, heteroaromatic, alicyclic, heiurocydic, each of which is optionally bi-or tricyclic, and optionally substituted with H, halogen, lower alkyl, -SR8, -OR8, -CN, -COiR\ -NO; or -NRBR10; R8 is hydrogen, lower alkyl- lower aryl or -(CO)R9; R9
is lower alkyl, lower aryl, lower heteroaryl, -NR8R10 or OR1'; R" is lower alkyl or lower aryl; and R10 is hydrogen or lower alkyl.
In one embodiment, the compound, tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof of Formula A, Rl is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl and C1-4 alkyl; and R2 is -NH2; R3 is hydrogen.
In another embodiment, R4 is -(CH2)n-f where n = 0-3.
In another embodiment, R1 is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl or C1-4 alkyl; optionally, R2 is NH2.
In another embodiment, R4 is -CH2-.
In another embodiment, R4 is -(CH2)n. wherein n = 0-3, R1 is selected from halogen, hydroxyl, lower alkoxy, lower thioalkyl, and C1-4 alkyl, and R2 is optionally NHi.
In another embodiment, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R is optionally NHj, R4 is -(CH2)-, and R5 is phenyl, benzyl, or pyridyl, all optionally substituted with H, halogen, lower alkyl, -SR8, -OR8 (or cyclic ethers such as methylenedioxy), -CN, -CO2R9, -NO2, or-NRBR10; R8 is hydrogen, lower alkyl, lower aryl or -(CO)R9; R is lower alkyl, lower aryl, lower heteroaryl, -NR8R10 or -OR11; R11 is lower alky] or lower aryl; and R10 is hydrogen or lower alkyl,
In another embodiment R1 is halogen, R2 is -NH2, R4 is -CH2-, R6 is H or halogen, and R5 is phenyl optionally substituted with H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio,perhaloalkyl, perhaloalkyloxy, -CN, -NO:, -NH2 or-CO2R".
In anomer embodiment, Rl is halogen, R2 is -NH2, R4 is -CH2-, R6 is H, and R5 is 2-haIo-3, 5-dimethoxyphenyl optionally substituted with H, halogen, O.4 alkyl, C1-4 alkoxy, C1-4 alkylthio, perhaloalkyl, perhaloalkyloxy, -CN, -NO2, -NH2, or -CO2R11 at the para (4-) position.
In another embodiment, R1 is chloro, R2 is -NH2, R4 is -CH2-, R6 is H and R5 is 2-ch!oro-3, 4,5-trimethoxyphenyl.
In anomer embodiment, R1 is chloro, R2 is -NH2, R4 is -CH2-, R6 is H and RJ is 2-bromo-3, 4,5-trimethoxyphenyl. In other embodiments, R5 is selected from 2-iodo-3,4,5-trimethoxyphenyl, 2-fluoro-3,4,5-trimethoxyphenyl, or 2-bromo-3,4,5-trimethoxyphenyl.
Any of the foregoing embodiments can be combined where feasible and appropriate.
In one aspect, the invention provides compounds of Formula I:
(Formula Removed)or tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein: X1 and X2 are the same or different and each is nitrogen or -CR6; R1 is halogen, -OR8, -SR8 or lower alkyl; R2 is -NR8R10;
R3 is hydrogen, OH or a keto tautomer, -OR8, halogen, -CN, lower alkyl or -C(O)R9;
R4 is -(CH2)n- where n = 0-3, -C R6 is hydrogen, halogen, lower alkyl, -SR8, -OR8, -NR8R10, -N3) or -C(O)R9;
R5 is alkyl, aromatic, heteroaromatic, alicyclic, heterocyclic, all optionally bi- or
tricyclic, and all optionally substituted with H, halogen, lower alkyl, -SRg,
-OR8, -CN,
-CO2R9, -NO2, or -NR8R10; Rg is hydrogen, lower alkyl, lower aryl, or -(CO)Rs; R9 is lower alkyl, lower aryl, lower heteroaryl, -NR58R10 or -OR11; R10 is hydrogen or lower alkyl; and R11 is lower alkyl or lower aryl.
In one embodiment of the compounds of Formula I, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen, hydroxy], lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2is NH2.
In another embodiment of the compounds of Formula 1, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R4 is-(CH;)n-, wherein n - 0-3.
n another embodiment of the compounds of Formula I, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2; R4 is-(CH2)n-, wherein n - 0-3.
In another embodiment of the compounds of Formula I, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen; R2 is NH2; and R4 is -CHr.
In another aspect, the invention provides compounds of Formula IA:
(Formula Removed)
or tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein:
X1 and X2 are the same or different and each is nitrogen or a group -CR ;
R1 is halogen, -OR8, -SR8, or lower alkyl;
R1 is -NR8R10;
R4 is -(CH2) where n = 0-3, -C(O), -C(S), -SO2- or -SO2N-;
Rs is alkyl, aromatic, heteroaromatic, alicyclic, heterocyclic, all optionally bi- or
tricyclic, and all optionally substituted with H, halogen, lower alkyl, -SR8,
-OR8, -CN,
-C02R',-N02,or-NR8R10; R6 is hydrogen, halogen, lower alkyl. -SR8, -OR8, -NRRR10, -N3, -CN, -C(O)R9, or
taken together with R7 is carbonyl (C=O); R7 is independently selected from hydrogen, lower alkyl or taken together with
R6 is
-C(O); R8 is hydrogen, lower alkyl, lower aryl, or -(CO)R9; R9 is lower alkyl, lower aryl, lower heteroaryl, -NR8R10 or -OR11; R10 is hydrogen or lower alkyl, and R11 is lower alkyl or lower aryl.
In one embodiment of the compounds of Formula 1A, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2,
In another embodiment of the compounds of Formula IA, or a tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof, R4 is-(CH2)n-) where n = 0-3.
In another embodiment of the compounds of Formula IA, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, Ri is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2; R4 is-(CH2)n-, and wherein n ~ 0-3.
In another embodiment of the compounds of Formula IA, or a tautomer, pharmaceutically acceptable salt thereof, Rj is halogen; R2 is NH2, R4 is -CH2-.
In one embodiment, the invention provides compounds of Formula IB:
(Formula Removed)
or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R° is selected ftom hydrogen, halogen, lower alkyl, -SR8, -OR8, -CN, and -NHR8, R1 is halogen, -OR11, -SR11 or lower alkyl; R2 is -NHR8;
R3 is selected from the group consisting of hydrogen, halogen, -SR8, -OR8, -CN, -C(O)R9,
-C(O)OH, -NO2, -NR8R10, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic and heterocyclic, all optionally substituted, wherein:
the aryl, heteroaryl, alicyclic and heterocyclic groups arc optionally mono-, bi- or tri-cyclic,
R.8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N, and the optional substituents on RJ are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, -SR8, -OR8, -CN, -C(O)OH,
-C(O)R9, -NOj, -NR8R10, lower aryl, heteroaryl, alicyclic, lewer heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally fonn a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, Sand N; R° or R3 is -OH or -SH, the compound may exist as the corresponding (thio)keto
tautomer or a mixture of keto-enol tautomers; R4 is -CHR12-, -C(O)-, -C(S), -S(O)- or -SO2-; RJ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, the alicyclic group is substituted with 3 to 5 substituents, the heterocyclic group is substituted with 3 to 5 substituents, and the substituents are selected from the group consisting of halogen, lower alky], lower alkenyl, lower alkynyl, -SR8, -OR8, -CN, -C(O)OH, -C(O)R9, -NO:, -NR8R,01 lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,
carbamates, ureas, thioureas and thioamides, wherein R8and Ri0 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of 0, S and N; Ra is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower
heteroaryl, or -C(O)R9; R9 is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, -NRl0R10,or -OR1', wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N; R10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryj or lower
heteroaryl; Ru is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl or lower
aryl; and R1 is hydrogen or lower alkyl.
In one embodiment of the compounds of Formula IB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, each of the aryl, heteroaryl, alicyolic or heterocyclic group is monocyclic or bicyclic.
In another embodiment of the compounds of Formula IB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R° is hydrogen, halogen, -SH, -OH, or-CN; R1 is halogen; and R2 is -NHRg, where Rs is hydrogen or -C(O)R9
In another embodiment of the compounds of Formula IB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R2 is -NHR8, where RB is hydrogen or -C(O)R9; R3 is hydrogen, halogen, OR8, SR8, NR8R10, lower alkyl, lower alkenyl, or lower alkynyl, lower peThaloalkyl, lower aryl, or lower heteroaryl.
In another embodiment of the compounds of Formula IB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R° is hydrogen, halogen or -CN; R2 is -NHR\ where Rs is hydrogen or -C(O)R9; and R4 is -CH2-.
In another embodiment of the compounds of Formula IB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R° is hydrogen, halogen, -SH, -OH or -CN; R1 is halogen; R2 is -NH2, R3 is hydrogen, halogen, -OR8, -SR8,
-NReR10, lower alkyl, lower alkenyl, lower alkynyl, perhaloalkyl, lower aryl, or lower heteroaryl, wherein Rs is hydrogen, lower alkyl, lower aryl, or -C (O)R9; R4 is -CHi-; and Rs is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents,
In another embodiment of the compounds of Formula IB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R' is chloro or bromo, R2 is -NH2, and Rs is a phenyl having at least three substituents.
In another embodiment of the compounds of Formula IB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, Rl is chloro or bromo, R2 is -NH2 and R5 is a pyridyl having at least two substituents.
In another embodiment of the compounds of Formula IB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R2 is -NH2, and Rs is 1-oxy-pyridyl (N-oxy-pyridyl) having at least two substituents.
Another embodiment of the invention is compounds of Formula IC:
(Formula Removed)or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R° is hydrogen, halogen, lower alkyl, -SR8, -OR8, -CN or -NHR8;
Rl is halogen, -OR11, -SR" or lower alkyl;
R2 is -NH2;R4 is -CHR12-, -C(O)-, -C(S)-, -S(O)- or -SO2-;
R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:
the aryl group is substituted with 3 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, the alicyclic group is substituted with 3 to 5 substituents, the heterocyclic group is substituted with 3 to 5 substituents, and the substituents on Rs are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, -SR8, -OR8, -CN, -C(O)OH, -C(O)R9, -NO2, -NR8RI(), lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylaraino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein when Rs and Rm taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N; R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower
heteroaryl, or -C(O)R9; R9 is H, lower alkyl, lower aryl, lower heteroaryl, -NRI0R10, or -OR1', wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1 -3 of the ring atoms are heteroatoms selected from the group of O, S and N; R10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower
alkynyl; Rl' is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl or lower
aryl; R12 is hydrogen or lower alkyl; and
R and R when taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3-7 ring atoms and optionally
1-3 of the ring atoms are heteroatoms selected from the group of O, S and N.
In one embodiment of the compounds of Formula IC, or apolymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen or lower alkyl; R4 is -CHR11-; Rs is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
In another embodiment of the compounds of Formula IC, or a polymorphs solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R° is hydrogen or -NHR8, R1 is halogen, -OR1', -SR11 or lower alkyl; R10 is hydrogen or lower alkyl.
In another embodiment of the compounds of Formula IC, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R° is hydrogen; R1 is halogen; R4 is -CH2-; Rs is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents; and R10 is hydrogen..
In another embodiment of the compounds of Formula IC, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R1 is chloro or bromo, Rs is phenyl, pyridyl or 1-oxy-pyridyl (N-oxy-pyridyl) each of R5has at least two substituents.
Another embodiment of the invention is compounds represented by Formula ID:

(Formula Removed)
or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:wherein:
R1 is halogen, -OR1 \ -SRn or lower alkyl;
R2 is -NH2;
R3 is selected from the group consisting of hydrogen, halogen, -SR8, -OR8, -CN, -C(O)R9,
-C(O)OH, -NO2, -NR8R10, lower atkyl, lower alkenyl, lower alkynyl, lower pcrhaloalkyl, aryl, heteroaryl, alicyclic, heterocyclic, all optionally substituted, wherein: the atyl, heteroaryl, alicyclic and heterocyclic groups are optionally
mono-, bi- or tri-cyclic, R8 and R10 taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N, and the optional substituents on R3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, -SR8, -OR8, -CN, -C(O)OH,
-C(O)R9, -NO2, -NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arytalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, SandN; R4 is -CHR12-, -C(O)-, -C(S)-, -S(O)- or -SO2-; R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, the alicyclic group is substituted with 3 to 5 substituents, the heterocyclic group is substituted with 3 to 5 substituents, and the substituents on R5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, tower alkynyl, -SR8, -OR8, -CN, -C(O)OH, -C(O)R9, -NOi, -NR8R10, lower aryl, heteroaryl,
alicyctic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10 taken together optionally fonn a ring of 3-7 ring atoms and.. optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N; R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower
heteroaryl, or -C(O)R9; R9 is H, lower alkyl, lower aryl, lower heteroaryl, -NRloR10 or -OR11, wherein when R1(>and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoras selected from the group of O, S and N; R is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower
alkynyl, R is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl; Ru is hydrogen or lower alkyl; and
R3 and R10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoras selected from the group of O, S and N. In one embodiment of the compounds of Formula ID, or a polymorph, solvate, ester, tautomer, enantiomers, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R3 is hydrogen, halogen, -OR8, -SR8, -NR8R8, lower alkyl, lower alkenyl, or lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl, wherein R8 is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower heteroaryl, or -C (O)R9; R4 is -CH2-; RJ is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents, and R10 is hydrogen or lower alkyl.
In another embodiment of the compounds of Formula ID, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R4 is
-CH2-; RJ is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents; and R10 is hydrogen.
In another embodiment of the compounds of Formula ID, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R3 is hydrogen; R4 is -CH2-; R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents; and R!0 is hydrogen,
In another embodiment of the compounds of Formula ID, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R1 is chloro or bromo, R5 is phenyl, pyridyl or 1-oxy-pyridyl (N-oxy-pyridyl), each of which has at least two substituents.
Another embodiment of the invention is a compounds represented by Formula IE:
(Formula Removed)
or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is halogen, -OR1', -SR11 or lower alkyl; R2 is -NH2;
R3 is selected from the group consisting of hydrogen, halogen, -SR8, -ORs, -CN, -C(O)R9,
-C(O)OH, -NO:, -NRBR10, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic, heterocyclic, all optionally substituted, wherein:
the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic,
Rs and R10 taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N, and the optional substituents on R3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, -SR8, -OR8, -CN, -C(O)OHt
-C(O)R9, -NO:, -NR8R!0, lower aryl, heteroaryl, alicyclic, tower heterocyclic, arylalkyl, heteroarylalkyl, ammo, alkylamino, diallcylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, suites, sulphonamides, carbamates, ureas, thioureas and thtoamides, wherein R and Rl taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of 0, S and N; R4 is -CHR12-, -C(O)-, -C(S)-, -S(O)- or -SO2-; Rs is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, the alicyclic group is substituted with 3 to 5 substituents, the heterocyclic group is substituted with 3 to 5 substituents, and the substituents on R5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, -SRS, -OR8, -CN, -C(O)OH, -C(O)R9,
-NO2 and -NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R8 and R10
taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, Sand N; R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower
heteroaryl, or -C(O)R9; R9 is H, lower alkyl, lower aryl, lower heteroaryl, -NR10R10, or -OR11, wherein
R10 and R10 taken together optionally form a ring of 3-7 ring atom»and
optionally 1-3 of the ring atoms are heteroatoms selected from the group
of O, S and N; R1 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower
alkynyl, R1 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl; R12 is hydrogen or lower alkyl; and R3 and R10 taken together optionally form an exocyclic double bond which is
optionally substituted, or optionally form a ring of 3-7 ring atoms and
optionally 1 -3 of the ring atoms are heteroatoms selected from the group
of O, S and N.
In one embodiment of the compounds of Formula IE, or a polymorph, solvate, ester, tautomei, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R4 is
-CH;-; R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
In another embodiment of the compounds of Formula IE, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R5 is phenyl, pyridyl or 1-oxy-pyridyl (N-oxy-pyridyl), each of which has at least two substituents.
It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.
Illustrative species of the compounds of Formula IB are described in TABLE I. Prodrugs which can be employed with the compound of the invention include, but are not limited to, those listed in the Definition section above.
B. Compounds of Formula II
In one aspect, the invention provides compounds of Formula II:
(Formula Removed)or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
X1 and X2 are the same or different and each is nitrogen or -CR6;
Ri is halogen, -OR8, -SR8,, or lower alkyl;
R2 is -NR8R10;
R4 is -(CH2)n- wherein = 0-3, -C(O), -C(S), -SO2-, or -SO2N-;
Re is hydrogen, halogen, lower alkyl, -SR8,, -OR8, -NR8R10, -N3, -ON, or -C(O)R9;
Rs is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, all optionally bi- or tri­cyclic, and all optionally substituted with H, halogen, lower alkyl, -SR8, -ORg, -CN, - CO2R0, -NO2, or -NR8R10;
R8 is hydrogen, lower alkyl, lower aryl, or -(CO)R9;
R9 is lower alkyl, lower aryl, lower heteroaryl,-NR8Rio or-OR11;
R10 is hydrogen or lower alkyl,
R11 is lower alkyl or lower aryl.
In one embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, Ri is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R4 is-(CH2)n- where n = 0-3.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2; R4 is-CH2), wherein n = 0-3.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt thereof, R| is halogen; R2 is NH2, R4 is -CH2-
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R4 is -(CH2)-; R5 is phenyl, benzyl, or pyridyl, and is independently optionally substituted with H, halogen, lower alkyl, -SR8, -OR8 (or cyclic ethers such as methylenedioxy), -CN, -CO2R9, -NO2, or - NR8R10; Rs is hydrogen, lower alkyl, lower aryl or -(CO)R9; R9 is lower alkyl, lower aryl, lower heteroaryl, -NR8R10 or -OR1'; R1' is lower alkyl or lower aryl; and Rt0 is hydrogen or lower alkyl.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceuticaHy acceptable salt, or prodrug thereof, R1 is halogen, R2 is -NH2, R4 is -CHj-, R6 is H or halogen, Rs is phenyl optionally substituted with H, halogen, C1-4 alkyl, C21-4 alkoxy, C1-4alkylthio, perhaloalkyl, perhaloalkyloxy,-CN,-NO2,-NH2or-CO2R'.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen, R2 is -NH2> R4 is -CH2-, R6 is H, wherein Rs is
2-halo-3,5dimethoxyphenyI optionally substituted with H, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, perhaloalkyl, perhaloalkyloxy, -CN, -NO2, -NH2, or -CO2R1' at the para (4-) position,
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is chloro, R2 is -NH2, R4 is -CHj-, R6 is H and R5 is 2-chloro-3,4,5-trimethoxyphenyl.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is chloro, R2 is -NH2, R4 is -CHr, R6 is H and R3 is 2-bromo-3,4,5-trimethoxyphenyl.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is chloro, R2 is -NH2 R4 is -CH2-, R6 is H and Rs is 2-iodo-3,4,5-trimethoxyphenyl.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, Ri is chloro, R1 is -NH2, R4 is -CH2-
, Rs is H and RJ is 2-fluoro-3,4,5-trimethoxyphenyl.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is bromo, R2 is -NHj, R4 is -CH2-, R6 is H, and R5 is 2-bromo-3,4,5-trimethoxyphenyl.
In another embodiment of the compounds of Formula 17, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R| is bromo, R2 is -NH2, R4 is -CH2-, Rfi is H, and R1 is 2-iodo-3,4,5-trimelhoxyphenyl,
In another embodiment of the compounds of Formula II, or tautomer, , pharmaceutically acceptable salt, or prodrug thereof, R1 is bromo, R2 is -NH2, R4 is -CH2-, R6 is H and R! is 2-iodo-3,4,5-rrimethoxyphenyl.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, Rl is bromo, R2 is -NH2. R4 is -CH2-, R6 is H and R5 is 2-fluoro-3,4,5-trimethoxyphenyl.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, Rl is chloro, R2 is -NH2, R4 is -CH2-, R6 is halo and R5 is 2-chIoro-3,4,5-trimethoxyphenyl,
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is chloro, R2 is NH2, R4 is -CH2-, Rs is halo, and Rs is 2-bromo-3,4,5-trimethoxyphenyl.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is bromo, R2 is -NH2, R4 is -CH2-, R6 is halo and RJ is 2-chloro-3,4,5-trimethoxyphenyl.
In another embodiment of the compounds of Formula II, or tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is bromo, R2 is -NH2, R4 is -CH2-, R is halo and R5 is 2-bromo-3,4,5-trimethoxyphenyI.
In one embodiment, the invention provides compounds of Formula IIA:

or a polymorph, solvate, ester, tautomer, (Formula Removed)harmaceutically acceptable salt or prodrug thereof, wherein:
Ri is halogen, -ORs, -SR8, or lower alkyl;
R2 is -NR8Rio;
R4 is -(CH2V where n » 0-3, -C(O), -C(S), -SO2- or -SO2N-;
R6 is hydrogen, halogen, lower alkyl, -SR8,, -OR8, -NR8R10, -N3> -CN or C(O)R9;
Rs is alkyl, aromatic, heteroaromatic, alicyclic, heterocyclic, all optionally bi- or
tricyclic, and all optionally substituted with H, halogen, lower alkyl, -SR8,,
-ORB, -CN,
-CO2R9, -NO2, or-NR8R10; R8 is hydrogen, lower alkyl, lower aryl, or -{CO)R9; R9 is lower alkyl, lower aryl, lower heteroaryl, -NRjRio or OR11; R10 is hydrogen or lower alkyl; and R11 is lower alkyl or lower aryl.
In one embodiment of the compounds of Formula IIA, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2.
In another embodiment of the compounds of Formula IIA, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R4 is-(CH2)n-, where n = 0-3.
In another embodiment of the compounds of Formula IIA, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R| is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2; R4 is (CHj)n-, wherein n= 0-3.
In another embodiment of the compounds of Formula IIA, or a tautomer, pharmaceutically acceptable salt thereof, R1 is halogen; R2 is NH2, R4 is -CH2-.
In one embodiment, the invention provides compounds of Formula IIB:
(Formula Removed)wherein:
R1 is halogen, -ORg, -SRj or lower alkyl;
R2 is -NR8R10;
R4 is -(CH2)n-, where n - 0-3, -C(O), -C(S), -SOr or -SO2N-;
R6 is hydrogen, halogen, lower alkyl, -SR8,, -OR8, -NR8R10, -N3, -CN or -C(O)R9;
R5 is alkyl, aryl, heteroaromatic, alicyclic, heterocyclic, all optionally bi- or
tricyclic, and all optionally substituted with H, halogen, lower alkyl, -SR8,
-OR8, -CN, - CO2R9,
-NO2, or-NR8Ri0; R8 is hydrogen, lower alkyl, lower aryl, or -(CO)R9; R9 is lower alkyl, lower aryl, lower heteroaryl, -NR8R10 or -OR11; R10 is hydrogen or lower alkyl, R11 is lower alkyl or lower aryl.
In one embodiment of the compounds of Formula IIB, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is -NH2.
In another embodiment of the compounds of Formula IIB, or tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof, R4 is-{CHj)n-> where n = 0-3.
In another embodiment of the compounds of Formula IIB, or a tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2; R4 is-(CH2)n-, wherein n - 0-3.
In another embodiment of the compounds of Formula IIB, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, Ri is halogen; R2 is -NH2; and R4 is -CHz-.
In one embodiment, the invention provides compounds of Formula 1IC:
(Formula Removed)
or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is halogen or lower alkyl;
R2is-NR8R10;
R4is-CHR12s
R3 is hydrogen, halogen, or -CN;
Rs is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring, the alicyclic group is substituted with 3 to 5 substituents, the heterocyclic group is substituted with 3 to 5 substituents, and the subsituents are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, axyloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -N3, -SR8, -OR8, -CN, -C(O)R9, -NO2, -NR8R10, phosphonate and phosphonic acid;
R8 is hydrogen, lower alkyl, lower aryl, or -C(O)R9;
R9 is lower alkyl, lower aryl, lower heteroaryl, -NR10RI0or -OR";
R)0 is independently hydrogen or lower alkyl;
R1l is lower alkyl, lower aryl or lower heteroaryl;
R12 is hydrogen or lower alkyl; provided that
when Rs is aryl, R5 is not an organo-metallic cyclopentadiene;
when R5 is phenyl, the substituents are not 3,5 di-halo;
when Rs is alicyclic, the ring system does not contain any tetra-substituted sp
ring carbons; when R5 is heterocyclic, the ring system does not contain any tetra-substituted sp1
ring carbons or the ring system is not a tetra-substituted pyrrolidine.
In another embodiment, the invention provides compounds of Formula IID, which are compounds of Formula IIC where R4 is --CH2-,
(Formula Removed)or a polymorph, solvate, ester, tautomer, enantiomer, diastereomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is halogen or lower alkyl;
R2 is -NR8R10;
R3 is hydrogen, halogen, or -CN;
Rs is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substinients, the two substituents must form part of an optionally substituted fused ring, the alicyclic group is substituted with 3 to 5 substituents, the heterocyclic group is substituted with 3 to 5 substituents, and the subsihients are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -N3,
SR8, -OR8, -CN, -C(O)R9, -N02, -NR8R10, phosphonate and phosphonic acid;
R8 is hydrogen, lower alkyl, lower aryl, or -C(O)R9;
R9 is lower alkyl, lower aryl, lower heteroaryl, -NRl0R10 or -OR11;R10 is independently hydrogen or lower alkyl;
R1' is lower alkyl, lower aryl or lower heteroaryl; provided that
when R5 is aryl, R5 is not an organo-metallic cyclopentadiene;
when R5 is phenyl, the substituents are not 3,5 di-halo;
when Rs is al cyclic, the ring system does not contain any tetra-substituted sp3 ring carbons;
when R5 is heterocyclic, the ring system does not contain any tetra-substituted sp3 ring carbons or the ring system is not a tetra-substituted pyrrolidine,
In one embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen or methyl; and R2 is -NHR8, where R8 is hydrogen or -C(O)R9.
In another enibodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, Rl is halogen.
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R2 is -NH2 and R3 is hydrogen.
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R2 is -NH2; R3 is hydrogen; R5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl groups is monocyclic or bicyclic, the aryl group is substituted with 4 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring.
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R2 is -NH2, and R5 is a phenyl having 3 to 5 substituents.
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R2 is -NH2, and RJ is a pyridyl having 3 to S substituents,In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R is chloro or bromo, R2 is -Nth, and Rs is an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, pfiarmaceutically acceptable salt or prodrug thereof, each of the aryl, heteroaryl, alicyclic or heterocyclic group is monocyclic or bicyclic,
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen or methyl; and R2 is -NHRS, where RB is hydrogen or -C(O)R9.
In another emlx>dirnent of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R1 is halogen.
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R2 is -NH2 and R3 is hydrogen,
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R2 is -NH2; R3 is hydrogen; Rs is aryl or heteroaryl, wherein each of the aryl and heteroaryl groups is monocyclic or bicyclic, the aryl group is substituted with 4 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring.
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R1 is -NH2, and R5 is a phenyl having 3 to 5 substituents,
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, Rl is chloro or bromo, R2 is -NH2, and Rs is a pyridyl having 3 to 5 substituents.
In another embodiment of the compounds of Formula IID, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof,
wherein R1 is chloro or bromo, R2 is -NH.2, and R* is an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.
It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.
In another embodiment, the invention provides compounds, or polymorphs, solvates, esters, tautomers, pharmaceutically acceptable salts or prodrugs thereof, prepared by the process comprising:
reacting a compound of formula Y and a compound of formula Z, wherein:
Y is represented by any one of the following formulae:
(Formula Removed)and
Z is Ll-R*-Rs; wherein:
V is halogen, NR8Rl0,trifIate, tosylate, or mesylate; R4 is -CHR12-,
R is aryl, heteroaryl, alicyclic, or heterocyclic, wherein: the aryl group is substituted with 3 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents,
wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring, the alicyclic group is substituted with 3 to 5 substituents, the heterocyclic group is substituted with 3 to 5 substituents, and the subsituents are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -N3, -SR8, -OR8, -CN, -C(O)R9, -NO2, -NR8R10, phosphonate and phosphonic acid; R8 is hydrogen, lower alkyl, lower aryl, or -C(O)R9;
R9 is lower alkyl, lower aryl, lower heteroaryl, -NRI0R10 or -OR11; Rm is independently hydrogen or lower alkyl; R1' is lower alkyl, lower aryl or lower heteroaryl; R12 is independently hydrogen or lower alkyl; R21 is halogen, lower alkyl or -OH; R22 is -NR8R10;
R23 is hydrogen, halogen, or -CN; R24 is-NH2,-NO2 or-NO; R25 is halogen or -OH; R26 is -C(O)NH2 or C(O)OEt; and R27 is -NH2, -OH or halogen; provided that:
when R5 is aryl, RJ is not an organo-metallic cyclopentadiene; when Rs is phenyl, the substituents are not 3, 5 di-halo; when R5 is alicyclic, the ring system does not contain any tetra-substituted sp3 ring carbons; or
when R5 is heterocyclic, the ring system does not contain any tetra-substituted spJ ring carbons or the ring system is not a tetra-substituted pyrrolidine. In one embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R is aryl, heteroaryl, alicyclic, or heterocyclic, optionally mono- or bicyclic.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R4 is -CH2-.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceuticany acceptable salt or prodrug thereof, L1 is -CI, -Br or NH2; Rs is aryl or heteroaryl, wherein the aryl group is substituted with 4 to 5 substituents.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, V is a substituted purine.
In another embodiment of the compounds prepared by the process of the . invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, the reaction is performed in a solvent comprising a member selected from the group of DMT, THF and DMSO.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, the reaction is performed in a solvent that comprises DMF.
Compounds for use in the method of treatment are inhibitors of HSP90 of the following Formula EC, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof,
(Formula Removed)wherein:
R1 is halogen, -OR11, -SRn, -NHR8, hydrogen, or lower alkyl;
R2is-NR*R10;
R3 is hydrogen, halogen, -N3, or -CN;
R4 is -(CHR12) „- where n = 0,1 or 2, -C(O)-, -C(S)-, or -S(O)-;
R5 is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, all optionally substituted with halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -Nj, -SR8, -OR8, -CN, -C(O)R9, -NO2, or -NR8R10;
R8 is hydrogen, lower alkyl, lower aryl, or -C(O)R9;
R' is lower alkyl, lower aryl, lower heteroaryl, -NRI0R10, or -OR1';
R10 is independently hydrogen or lower alkyl;
R1 is lower alkyl, lower aryl or lower heteroaryl;
R is hydrogen or lower alkyl; provided that:
-R*R5 is not a ribose or derivative thereof, or a sugar or derivative thereof;
-R4RS is not a phosphonate or phosphonic acid, or substituted with phosphonate or phosphonic acid; and
when R4 is -(CH2)n where n=l or 2, then R4 and R5 are not connected through an ether linkage.
In one embodiment of the compounds of Formula IIC for the method of the invention, R3 is hydrogen, halogen, or -CN; R5 is aryl, heteroaryl, alicyclic, or heterocyclic, all optionally substituted with halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -N3, -SR8, -OR8, -CN, -C(O)R9, -NO2, -NR R10, phosphonate, or phosphonic acid.
In another embodiment of the compounds of Formula IIC for the method of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen or methyl and R2 is -NHR8, where R8 is hydrogen or -C(O)R'
In another embodiment of the compounds of Formula IIC for the method of the invention, R2 is -NH2 and R3 is hydrogen.
In another embodiment of the compounds of Formula IIC for the method of the invention, R4 is -CH2..
In another embodiment of the compounds of Formula IIC for the method of the invention, wherein Rl is halogen; R2 is -NHj; R3 is hydrogen; R4 is -CH2-; R5 is aryl and heteroaryl, the aryl and heteroaryl groups are monocyclic or bicyclic, the aryl group is substituted with 4 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with two substituents, the two substituents must form part of an optionally substituted fused ring.
In another embodiment of the compounds of Formula IIC for the method of the invention, R1 is chloro or bromo, R2 is -NH2, and Rs is a phenyl having 3 to 5 substituents.
In another embodiment of the compounds of Formula IIC for the method of the invention, R1 is chloro or bromo, R2 is -NH2, and R5 is a pyridyl having 3 to 5 substituents.
In another embodiment of the compounds of Formula IIC for the method of the invention, R1 is chloro or bromo, R2 is -NH2, and R5 is an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.
It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.
Compounds of the invention that are based on the following Formula IIC have illustrative species as described in TABLE n. Suitable prodrugs which can be employed by the compounds include, but are not limited to, those listed in the Definition section.
C. COMPOUNDS OF FORMULA III
In another aspect, the invention provides compounds of Formula HI:
(Formula Removed)or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein
X1 and X2 are the same or different and each is nitrogen or CR6;
R1 is halogen, -OR8, -SR8 or lower alky];
R2 is -NR8RI0;
R3 is hydrogen, -OH or keto tautomer, -ORg, halogen, -CN, lower alkyl or -C(O)R9;
R4 is -(CH2)„- where n - 0-3, -C(O), -C(S), -S03- or -SO2N-;
R5 is alkyl, aryl, heteroaryl, alicyclic, heterocyclic, all optionally bi- or tricyclic, and all optionally substituted with H, halogen, lower alkyl, -SR8, -OR8, -CN, -COjR,, -NO2 or -NRsR,0;
R8 is hydrogen, lower alkyl, lower aryl or -(CO)R9;
R9 is lower alkyl, lower aryl, lower heteroaryl, -NR8R10 or OR11;
R11 is lower alkyl or lower aryl; and
R10 is hydrogen or lower alkyl.
In one embodiment of the compounds of Formula III, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R2 is NH2.
In another embodiment of the compounds of Formula III, or a tautomer, 5 pharmaceutically acceptable salt, or prodrug thereof, R4 is-(CH2)n-, where n - 0-6,
In another embodiment of the compounds of Formula III, or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, Ri is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4alkyl; and R2 is NH2; and R4 is-(CH2)n-, wherein n = 0-3.
In another embodiment of the compounds of Formula III, or a tautomer, 10 phannaceutically acceptable salt thereof, R1 is halogen; R2 is NH2, and R4 is -CH2-.
One embodiment of the compounds based on Formula III are compounds of Formula IIIA:
(Formula Removed)or a polymorph, solvate, ester, tautomer, diasteremer, enantiomer, pharmaceutically
acceptable salt or prodrug thereof, wherein:
Rl is halogen, -OR1', -SR1' or lower alkyl;
R2 is -NHR8;
R3 is selected from the group consisting of hydrogen, halogen, -SR8, -OR8, -CN,
-C(O)R9, -CO2H, -NO2, -NR8R10, lower alkyl, lower alkenyl, lower alkynyl,
lower perhaloalkyl, aryl, heteroaryl, alicyclic and heterocyclic, all optionally
substituted, wherein:
the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic;
R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-2 of the ring atoms are heteroatoms selected from the group of O, S and N, and the optional substituents on R3 are selected from the group consisting of halogen, lower atkyl, lower alkenyl, lower alkynyl, -SRS, -OR8, -CN, -C(O)R9, -C(O)OH, -N02 and -NR8Rl°, lower aryl, lower heteroaryl, lower alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, arbamates, ureas, thioureas, and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R4 is -CHR'12 -C(O), -C(S), -S(O)-, or-SO2;
RJ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents on R5 are selected from the group consisting of halogen,
lower alkyl, lower alkenyl, lower alkynyl, -SR8, -OR8, -CN, -C(O)OH,
-C(O)R9, -NO: and -NR8R10, lower aryl, heteroaryl, alicyclic, lower
heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino,
diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl,
guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates,
phosphates, phosphoramides, sulfonates, sulfones, sulfates,
sulphonamides, carbamates, ureas, thioureas, and thioamides, wherein R8
and R10 taken together optionally form a ring of 3-7 ring atoms and
optionally 1-3 of the ring atoms are heteroatoms selected from the group
of O, Sand N;
R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or -C(O)R9;
R9 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, -NRl0R10 or -OR1', R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
R11 is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl; and
R12 is hydrogen or lower alkyl.
In one embodiment of the compounds of Formula 1TIA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen or lower alkyl; R: is -NHR8, where R8 is hydrogen or -C(O)R9; R5 is aryl or heteroaryl, each of said aryl and heteroaryl groups is monocyclic or bicyclic.
In another embodiment of the compounds of Formula IHA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is -NH2 R3 is selected from hydrogen, halogen, -SR8, -OR8, -CN, -NR8R10, lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower ary], lower heteroaryl, lower alicyclic, lower heterocyclic, R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl, and R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N; and Rs is aryl or heteroaryl, each of said aryl and heteroaryl groups is monocyclic or bicyclic.
In another embodiment of the compounds of Formula IHA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen or lower alky!; R1 is -NH2; R4 is -(CH:)-; Rs is aryl, heteroaryl, alicyclic or heterocyclic, each of said aryl, heteroaryl alicyclic or heterocyclic groups is monocyclic or bicyclic.
In another embodiment of the compounds of Formula IIIA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R2 is -NH2; R3 is hydrogen, halogen, -SR8, -OR8, lower alkyl, lower aryl,
lower heteroaryl, or -NR8R10, R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N; R4 is -CH2-; Rs is aryl or heteroaryl, wherein each of said aryl and heteroaryl groups is monocyclic or bicyclic.
In another embodiment of the compounds of Formula IIIA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, and Rs is a phenyl having 3 to 5 substituents.
In another embodiment of the compounds of Formula IIIA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, Rl is chloro or bromo, and R5 is a pyridyl having 3 to 5 substituents.
In another embodiment of the compounds of Formula UlA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R' is chloro or bromo, and Rs is an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.
It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.
Other embodiments of compounds based on Formula IK are compounds of Formula IIIB:
(Formula Removed)or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is halogen, -OR11, -SRn or lower alkyl;
R2 is -NHR8;
R4 is -CHR12-, -C(O), -C(S), -S(O)-, or-SO:-;
R5 is aryj, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents, the alicyclic group is substituted with 3 to 5 substituents, the heterocyclic group is substituted with 3 to 5 substituents, and the substituents on R5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, -SR.8, -OR8, -CN, -C(O)OH, -C(O)R9, -NO: and -NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylatkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, ruranyl, indole, indazole, phosphorates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas, and hioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteioatoms selected from the group ofO, S and N;
R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or -C(O)R9;
R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower
heteroaryl, -NR'V0or -OR11, R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of 0, S and N;
R10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
Rl' is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl; and
R12 is hydrogen or lower alkyl; and
R!i is hydrogen, lower alkyl, lower alkenyl or lower alknyl.
In one embodiment of the compounds of Formula IIIB, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R2 is -NHR8, where R8 is hydrogen or -C(O)R9; R1 is aryl, heteroaryl, alicyclic, or heterocyclic, all optionally mono-, bi- or tri-cyclic; and R* is lower alkyl, lower alkenyl, lower alkynl, lower aryl or lower heteroaryl.
In another embodiment of the compounds of Formula IIIB, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, Rl is halogen or lower alkyl; R2 is -NHR8, where R8 is hydrogen or -CCOJR51; R4 is -CH2-, R5 is aryl, heteroaryl, alicyclic, or heterocyclic, all optionally mono-, bi- or tri-cyclic.
In another embodiment of the compounds of Formula IIIB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R1 is chloro or bromo, R2 is -NH2, Rs is a phenyl having 3 to 5 substituents.
In another embodiment of the compounds of Formula HIB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R1 is chloro or bromo, R1 is -NH2, Rs is a pyridyl having 3 to 5 substituents.
In another embodiment of the compounds of Formula MB, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R1 is chloro or bromo, R2 is -NH2, Rs is an 1 -oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.
It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate,
Other embodiments of the compounds of the invention based on Formula m are the compounds, or polymorphs, solvates, esters, tautomers, pharmaceutically acceptable salts or prodrugs thereof, prepared by the process comprising;
reacting a compound of Formula Y and a compound of Formula Z, wherein;
Y is represented by any one of the following formulae:
(Formula Removed)Z is L'-R^-R5; wherein:
L1 is halogen, -NR8R10p Inflate, tosylate, or mesylate;
R4 is -(CHR11)-, -C(O), -C(S), -S(OK or -S02-;
R5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and the substituents on R5 are selected from the group consisting of
halogen, lower alkyl, lower alkenyl, lower alkynyl, -SR8 , -OR8 , -CN, -C(O)OH, -C(O)R9, -N02 and -NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas, and thioamides, wherein Rs and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R* is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or -C(O)R9;
R9 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aiyl, lower heteroaryl, -NRt0R11 or -OR11,R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
R1' is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
R12 is hydrogen or lower alkyl;
R21 is halogen, -OR8, -SR! or lower alkyl;
R21 is-NR8R10;
R23 is hydrogen, -OH or its keto tautomer, -OR8, halogen, -CN, lower aikyl, lower aryl or -C(O)R9;
R24 is -CHO, -NH2, -N02 or -NO;
R2i is halogen or -OH;
R26 is -C(O)NH2 or C(O)OEt; and
R27 is -NH2) -OH or halogen.
Iii one embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, RJ is aryl, heteroaryl, alicyclic, or heterocyclic, optionally mono- orbicyclic.
In another embodiment of the compounds of the invention which are prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, L1 is -CI, -Br or -NH2; R4 is -CH2-; and R5 is aryl or heteroaryl.
In another embodiment of the compounds of the invention which are prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, Y is a pyrazolopyrimidine,
In another embodiment of the compounds of the invention which are prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, said reaction is performed in a solvent comprising a member selected from the group of DMF, THF and DMSO.
In another embodiment of the compounds of the invention which are prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, the said reaction is performed in a solvent that comprises DMF.
It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.
Illustrative species of the compounds of the invention that are based on Formula IIIA, where R1 = -NH2 are described in TABLE III. Prodrugs which can. be employed by those compounds include, but are not limited to, those listed in the Definition section.
D. Compounds of Formula IV
In another aspect, the invention provides compounds of Formula IV:
(Formula Removed)or a polymorph, solvate, ester, tautomer, diasteremer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
X1 and X2 are the same or different and each is nilrogen or CR6;
R1 is halogen, -OR8, -SR8,, or lower atkyl;
R3 is -NR8R10;
R4, is -CH2n,- where n = 0-3, -C(O), -C(S), -SO2-, or -SO2N-;
Rs is alkyl, aryl, heteioaiyl, alicyclic, or heterocyclic, all optionally bi-or
tricyclic, and all optionally substituted with H, halogen, lower alkyl, -SR8, -ORa, -CN,
-CO1R9, -NO:, or -NR8Rm; Rs is hydrogen, lower alkyl, lower aryl or -(CO)Rs; R9 is lower alkyl, lower aryl, lower heteroaryl, -NR8R10 or -OR11; R11 is lower
alkyl or lower aryl; and R10 is hydrogen or lower alkyl.
In one embodiment of the compounds of Formula IV, a tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R is -NH2.
In one embodiment of the compounds of Formula IV, a tautomer, pharmaceutical^ acceptable salt thereof; or prodrug thereof, R1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R1 is -NH2; R4 is -CH2- -C(O), -C(S), SQr. .
In one embodiment of the compounds of Formula IV, a tautomer, pharmaceutical^ acceptable salt thereof, or prodrug thereof, R1 is halogen or C1-4 alkyl; and R: is NH2, R4 is -CH2,-.
In one embodiment of the compounds of Formula IV, a tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof, R.1 is halogen, hydroxyl, lower alkoxy, lower thioalkyl, or C1-4 alkyl; and R1 is NH2, R4 is -(CH2)n, 'where n = 0-
3.
In one embodiment of the compounds of Formula IV, a tautomer, pharmaceutically acceptable salt, or prodrug thereof, R4 is -C(O) or -CH2-; R1 is halogen, lower alkoxy or C1-4 alkyl; and Rz is NH2.
In another embodiment of compounds based on Formula IV are compounds of Formula IIVA:
(Formula Removed)or a polymorph, solvate, ester, tautomer, enantiomer, diastereomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is halogen,-OR11, -SR11 or lower alkyl; R1 is -NHR8;
R4 is -CHR13-, -C(O)-, -C(S), -S(O)- or -SO2-; R is aryl, heteroaryl, alicyclic, or heterocyclic, wherein: the aryl group is substituted with 3 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, the alicyclic group is substituted with 3 to 5 substituents, the heterocyclic group is substituted with 3 to 5 substituents, and the substituents are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, -SR8, -OR8, -CN, -C(O)OH, -C(O)R9, -NO2 and -NR8R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhatoalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas, and thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and
optionally 1 -3 of the ring atoms are heteroatoms selected from the group ofO, S and N; RB is hydrogen, lower allcyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or -C(O)R9; R9 is H, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower heteroaryl,
-NRl0R'0, or -OR11, wherein R10 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N; R1C is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower
alkynyl, R1' is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl or lower
aryl; and R4 is -CHR12:-, -C(O)-, -C(S)-, ~S(O)- or -SO2-; and Ru is hydrogen or lower alkyl; provided that when R3 is alicyclic, the ring system does not contain any tetra-substituted sp3 ring carbons.
In one embodiment of the compounds of Formula IVA, or a polymorph, solvate, ester, tautomer, enanttomer, diastereomer, pharmaceutically acceptable salt or prodrug thereof, each of the aryl, heteroaryl, alicyclic or heterocyclic group is monocyclic or bicyclic,
In another embodiment of the compounds of Formula IVA, or a polymorph, solvate, ester, tautomer, enantiomer, diastereomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; and R2 is -NHRS, where R8 is hydrogen or -C(O)Rs, In another embodiment of the compounds of Formula IVA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, Rl is chloro or bromo, R2 is -NHR8, where R8 is hydrogen or -C(O)R9; and R4 is lower alkyl.
In another embodiment of the compounds of Formula IVA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, K2 is -NHR8, where R8 is hydrogen or -C(O)R9; and R4 is -CH2-.
In another embodiment of the compounds of Formula IVA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is halogen; R2 is-NH2, R4 is-CH2-; and Rs is aryl or lieteroaryl, wherein each of the aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
In another embodiment of the compounds of Formula IVA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R2 is -NH2, and R5 is a phenyl having at least three substituent.
In another embodiment of the compounds of Formula IVA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R1 is chloro or bromo, R2 is -NH2 and R5 is a pyridyl having at least two substituent,
In another embodiment of the compounds of Formula IVA, or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, R! is chloro or bromo, R2 is -NH2, and Rs is 1-oxy-pyridyl (N-oxy-pyridyl) having at least two substituent.
It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.
In another embodiment, the invention provides compounds, or polymorphs, solvates, esters, tautomers, pharmaceutically acceptable salts or prodrugs thereof, prepared by the process comprising:
reacting a compound of formula Y and a compound of formula Z, wherein:
Y is a represented by any one of the following formulae:
(Formula Removed)
Z is L1R4-R5; wherein:
Ll is halogen, -NR!RI0,triflate, tosylate, or mesylate;
R4 is -CHR13-, -C(O)-, -C(S) -S(O)- or -SOr;
R is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and the substituents are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, -SR8, -OR8, -CN, -C(O)OH, -C(O)R9, -N03 and -NR!R10, lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphorates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas, thioamides, wherein R8 and R10 taken together optionally form a ring of 3-7 ring atoms and optionally 1 -3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R3 is hydrogen, lower alkyl, lower alkcnyl, or lower alkynyl, lower aryl,
lower heteroaryl, or -C(O)R9;
R9 is H, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower
heteroaryl, -NR10'R10, or -OR11, wherein Rl0 and R10 taken together
optionally form a ring of 3-7 ring atoms and optionally 1 -3 of the ring
atoms are heteroatoms selected from the group of O, S and N;
R10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl,
or lower alkynyl,
R11 is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl or
lower aryl;
R!2 is hydrogen or lower alkyl;
R21 is halogen, -OR8, -SR8 or lower alkyl;
R22 is -NR8R10;
R24is-NH2,-NO2or-NO;
R" is halogen or -OH;
R26 is -C(O)NH2 or C(O)OEt; and
R21 is -NH2, -OH or halogen; provided that when R5 is alicyclic, the ring system does not contain any tetra-substituted sp ring carbons.
In one embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, L1 is -CI, -Br or -NH2; R5 is aryl or heteroaryl.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R4 is -CH2-.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, R5 is aryl, heteroaryl, alicyclic, or heterocyclic, optionally mono- or bicyclic.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, Li is -CI, -Br or -NH2; R4 is -CH2-; and Rs is aryl or heteroaryl.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, Y is a triazolopyrimidine.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, Y is a triazole.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, Y is a pyrimidine.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, the reaction is performed in a solvent comprising a member selected from the group of DMF, THF and DMSO.
In another embodiment of the compounds prepared by the process of the invention, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, the reaction is performed in a solvent Wat comprises DMF.
It should be understood that any of the foregoing embodiments can be combined where feasible and appropriate.
Illustrative species of the compounds of the invention that are based on Formula IVA are described in TABLE 4. Prodrugs which can be employed by these compounds include, but are not limited to, those listed in the Definition section.
TABLE I: Exemplary Compounds based on Formula IA
(Table Removed)
Compounds of interest in Table 1 are: 2,3,17,18,27,28,62,63,77,78,92,93,129, 130, 238, 239, 242,243, 245, 246, 247,248, 249, 250, 251,252,253, 267, 268, 287, 288, 291, 292, 293,294,295, 296, 297, 298, 312, 313, 332, 333, 334, 335, 336, 337, 338, 339, 351, 352, 365, 366, 384, 385, 398, 399, 400, 401, 402, 403,404,405,417, 418,431,432, 433, 434, 435, 436, 437,438,450, 451, 464, 465, 483, 484, 497, 498, 530, 531, 549, 550, 562, 563, 574, 575, 577, 578, 589, 590, 592, 593, 604, 605, 607, 608, 619, 620, 755, 756,
759, 760, 76J, 762, 763, 764, 765, 766, 780, 781, 800, 801, 804, 805, 806, 807, 808, 809, 810, 811, 825, 826, 845, 846, 863, 864, 865, 866, 875, and 876 (with those selected being 17, 18, 27, 28, 62, 63, 77, 78,242,243, 245,246, 247,248,249, 250, 251,252, 253, 267, 268,287,288,291, 292,293,294, 295,296, 312, 313,431, 432, 755, 756, 759,
759, 761, 762, 763, 764, 800, and 801.)
TABLE 2. Exemplary compounds of the Invention of formula IIC
(Table Removed)
Compounds of interest in Table 2 are: 2, 3,11, 44, 82, 83, 242, 243, 245,248, 249, 254, 255, 260,266,272, 273,278, 279, 284,286, 287, 308, 309, 343, 348, 349, 354,366, 367, 372, 373, 671 and 697 (with those selected being 2, 242, 243, 248, 254, 260, 266,272, 278, 284, 286,287, 308, 343, 348, 349, 354, 372,373, 671 and 697.)
TABLE 3: EXEMPLARY COMPOUNDS OF FORMULA II1A, R1 is * NH3

(Table Removed)
Compounds of interest in Table 4 are: compounds 2, 3, 13, 82,83, 162, 163,168,169, 174,175,180,181,186,187,192,193,198,199,204,205,210,211,228,229,230,231, 232, 233,234, 235, 236, 237,250, 251, 262, 263,268, 269, 274,275, 280,281, 286, 287, 292, 293,298, 299, 304, 305, 310, 311,316, 317,328, 329, 338,372,373,380 and 381 (with those selected being 162, 163,168,169,174,175,180,181,186,187, 192,193, 198, 199, 204,205, 228, 229, 262,263,268,269,274,275, 280,281, 286, 287,292, 293, 316, 317, 328, and 329.)
III. Synthesis ol the Compounds of the Inveptloo
Synthesis of compounds of the present invention may be accomplished by various methods known in the art, including those described in, for example, Montgomery, J. Med. Pharm. Chern,, 1962,5, 15-24; Sircar, U.S. Patent 4,772,606, 1988; Sircar, U.S. Patent 4,748,177, 1988; Hans, U.S. Patent 5,110,818,1992; Gillespie, PCT publication No. WO 02/055521; Matsuda,JP 10025294 A2,1998; Hans, U.S. Patent 5,110,818, 1992 and U.S. Publication No. US 2003/0078413. The synthesis of the several embodiments of the invention is illustrated. The process is applicable to other subgenus.
A. Synthesis of Compounds of Formula I and Related Analogs
The compounds of Formula I and related analogs of the present invention may be synthesized by various methods known in the art. Illustratively, the strategy for the sysnthesis of pyrrolopyrimidines is outlined in Scheme 1 and consists of three parts: (1) constructing the bicyclic system, starting from either a pyridine, a pyrimtdine, a pyrrole,
'> or an acyclic precursor
(2) appending the R5-R4- group, and (3) further elaborating the ring systems.
Importantly, one skilled in the art will recognize that the sequence of events is not necessarily (l)-(2)-(3), and that these events may be interchanged, provided there be no incompatibility between the reagents and the functional groups specific to the point in
1 case.

Scheme 1(Scheme Removed)
Also, the starting materials or the intermediates of Formula 1, 4, 5, and I can exist in tautomeric forms as shown in Fig. 1, and both forms are indiscriminately used in this patent.
Figure 1(Figure Removed)
1. Assembly of the pvrolo[2,3-d[pyrimidine
1.1. Assembly of the pyrolo[2,3-d]pyrimidine starting from a pyrimidine
The compounds of Formula 4 can be prepared from pyrimidines as outlined in
Scheme 2. For instance:
STARTING FROM A PYRIMIDINE METHODS TO PREPARE THE S-MEMBERED RING OF COMPOUND (4)
(Scheme Removed)Method 1.1.1
The compounds of Formula 4 can be made by intramolecular cyclization of an aldehyde or ketone, possibly protected, as in Formula 6. (See, J. Davoll, J. Chem. Soc. 1960,131; J. A. Montgomery, J, Chem. Soc. 1967, 665; G. Cristalli, J. Med. Chem. 1988,31, 390; T. Miwa, J. Org. Chem. 1993,58,1696; D.M. Williams, J. Chem. Soc, PerHn Trans 1,1997, 1171).
Method 1.1.2
The compounds of Formula 4, wherein RJ is H, R6 is CI, and R7 is NH2 can be prepared by treating compounds of Formula 7 wherein R is a halogen or a leaving group with ammonia. Similarly, compounds of Formula I wherein RJ is H, R1 is CI, R2 is NH2 can be prepared by treating the compound of Formula 7 wherein R is a halogen or leaving group with RS-R4-NH2 in butanol at reflux in presence of a base such as K2CO3, CS2CO3 t-PrNEt2. (A.B. Reitz J. Med Chem. 1994,37,3561). Compounds of Formula 7 can in turn be prepared as taught by G.W. Craig J. Prakt. Chem. 2000, 342, 504 and M. Semonsky Coll. Czech. Chem, Commtm. 1980, 45, 3583),
Method 1.1.3
The compounds of Formula 4 can be obtained by treatment of a a-haloketone of Formula 3 wherein X is a halogen with ammonia or an synthetic equivalent thereof.
Method 1.1.4
The compounds of Formula 4 wherein R° is methyl can be obtained by a tandem Pd-mediated intramolecular cyclization/double-bond migration of alkenes of Formula 9 (S. E. Watson, Synth. Commun. 1998,28,3885).
Method 1.1,5
The compounds of Formula 4 wherein R3 is H can be obtained by Pd-mediated intramolecular cyclization of alkynes of Formula 10, wherein Z in as electron-withdrawing group such as, e.g., tosyl-, or EtCOO;-.
Method 1,1.6
The compounds of Formula 4 wherein R3 is AcO- can be obtained by intramolecular Friedel-Crafts acylation of precursors of Formula 11 (E. D. Edstrom, J. Org. Chem. 1993, 58, 403).
Method 1.1.7
The compound of Formula 4, wherein R° is H, R6 is OH, and R7 is NH2, Can be prepared by treating-the compound of Formula 12 with an a-haloaldehydes of the formula R3-CHX-CHO. See, DM. Williams, /. Chem. Soc, PerHn Trans 1,1997, 1171; C. J. Bamett, Org. Proa. Res. Devop. 1999, 3, 184; A, Gangjee, J, Med. Chem. 2001,44, 1993.
Method 1.1.8
The compounds of Formula 4, wherein R6 is OH and R7 is NH2 can be obtained
by treating the compound of Formula 13 with an aldehyde of the formula R3-CHO. See,
A. Gangjee, J. Med Chem. 2003,46, 591; E. C. Taylor, Heierocycles 1996, 43, 323.
1.2: Assembly of the pyrolo[2,3-d]pyrimidine starting from a pyrrole
The compounds of Formula 4 can also be made from pyrroles of Formula 2. There is a variety of methods by which the 6-membered ring can be formed (e.g. R. J. Bontems, J. Med. Chem, 1990, 33,2174 and references therein). For instance:
(Scheme Removed)Scheme 3
Compounds of Formula 2 wherein R13 is -CN and R14 is R-NH-CR7=N- can be cyclized and rearranged to give compounds of Formula 4 where R6 is R-NH-. See, E. C. Taylor, J. Am. Chem. Soc. 1965,87,1995.Compounds of Formula 2 wherein R1J is -CN and R14 is -NH2 can lx treated with thiourea, guanidine, or chloroformamidine to give compounds of Formula 4 in which R is -NH2 and R7 is -NH2. See, H, Kosaku, Heterocycles, 2001, 55,2279; A. Gangjee, US Patent 5,939,420 (1999).
Compounds of Formula 2 wherein R13 is -CN and R14 is -NH2 can be treated formamidine acetate to give compounds of Formula 4 wherein R6 is -NH2 and R7 is H(J. A. Montgomery, J. Chem. Soc. 1967, 665). The same transformation can be accomplished by treatment with DMF-DMA or an orthoester such as (EtO)3CH, followed by treatment with ammonia. See, E. C. Taylor, J. Am. Chem. Soc, 1965, 87, 1995.
Compounds of Formula 2 wherein R13 is -CN and R14 is -NH2 can be treated with formic acid to give compounds of Formula 4 wherein R* is -OH and R7 is H (K. A. M. El-Bayouki, J. Chem. Res. Miniprint, 199S, 1901).
Compounds of Formula 2 wherein R13 is - CO2NH2 and R14 is -NH2 can be treated under Vilsmeyer-Haack conditions (DMF/POCI3) to give compounds of Formula 4 wherein R6 is OH or CI and R7 is H. See, K. A. M. El-Bayouki, J. Chem. Res. Miniprint, 1995, 1901.
Compounds of Formula 2 wherein R13 is -CONH2 and R14 is -NH2 can be treated
with CS2 or EUDCS2K to give compounds of Formula 4 in which R6 is -OH and R7 is -
SH. See, S. M. Bennett, J. Med. Chem. 1990,33,2162.
1.3. Assembly of the pyrolo[2,3-d]pyrimidine starting from an acyclic precursor
The compounds of Formula 14 can be prepared from an acyclic precursor a outlined in Scheme 4 (T. Miwa, J. Med. Chem. 1991, 34,555).
(Scheme Removed)Scheme 4
2. Incorporation of the -R4-R5 fragment
2.1. Alkylation of compounds of Formula 4
Compounds of Foiraula 4 can be alkylated in the presence of a base such as K2CO3, NaH, Cs2CO3, DBU etc. with/without the presence of a catalyst such as Nal, KI, (Bu)3NI etc., and in a polar solvent such as DMF, THF, DMSO etc. using electrophiles such as L]-R4-R5 where L1 is a leaving group. See Scheme 5. Leaving groups include but are not limited to, eg., halogen, triflate, tosylate, mesylate, triphenylphosphonium (generated under Mitsunobu conditions, e.g. PPh3/DEAD) etc. See Kasibhatla, PCT publication number WO 03/037860.
(Scheme RemovedScheme 5
2.2. Preparation of electrophiles Ll-R4-RJ whereinL1 is a leaving
group
2.2.1. Synthesis of benzyl type electrophile
(Scheme Removed)The electrophiles can be prepared from the substituted benzene derivatives using various methods reported in the literature, see Jerry March, Advanced Organic Chemistry, 4th edition; Larock, Comprehensive Organic Transformations, 1989,VCH, New York. For example the compounds wherein L1 is Br can be prepared by reduction of the corresponding benzoic acid or benzaldehyde, followed by balogenation. These benzyl derivatives can also be prepared by benzylic oxidation or benzylic halogenation.
Further modification of the benzyl ring can be done before or after the pyrolo[2,3-djpyrimidine alkylation step.
2.2.2. Synthesis of pyridyl methyl type electrophile
(Scheme Removed)
These compounds can be prepared from many methods reported in the literature.
Morisawa , J, Med Chem. 1974,17, 1083; Klaus, W., J. Med. Chem. 1992, 35,
438; Abramovitch, R.A.; Smith, E. M. "Pyridine-1 -oxide in Pyridine and its
Derivatives," in The Chemistry of Heterocyclic Compounds', Weissberger, A., Taylor, E.
C, Eds.; John Wiley, New York, 1974, Pt 2, pp 1-261; Jeromin, G. E., Chem. Ber. 1987,
120, 649. Blanz, E. J., J. Med. Chem. 1970,13,1124; Smith, Kline and French, EP
Application EP 0184322,1986; Abblard, J., Bull. Soc. Chim. Fr. 1972,2466; Fisher, B.
E., The Structure of Isomaltol. J. Org. Chem. 1964,29, 776. De Cat, A., Bull. Soc. Chim.
Belg. 1965, 74, 270; Looker, J. H.t J. Org. Chem. 1979, 44, 3407. Ackerman, J. F. PhD.
Dissertation, University of Notre Dame, June, 1949. These methods can be applied to
the synthesis of quinoline, and isoquinolines type compounds.
2.3. Incorporation of the -R4-Rs fragment by nucleophilic substitution.
In some cases, the -R -RJ group can be appended before the bicyclic pyrrolo[2,3-djpyrimidine bicyclic ring is constructed, and this is further detailed below (paragraph 4, schemes 8 and 9). In these cases the -R4-R group can be appended by an aromatic nuclophilic substitution using NH2-R4-R5, The compound NH2-R4-R5 is obtained by treating L'-R4R5 with ammonia at temperatures of 20-160 °C in a pressure vessel. The corresponding amines where L1 is -NH2 can be prepared by a variety of methods, for instance from compounds where L1 is leaving group such as chloride, bromide, losylate, mesylate etc. using ammonia, or with sodium azide followed by hydrogenation.
3, Further Elaboration of the ring systems
3.1. Functional group interconversions of R°
Compounds of Formula IA, wherein R° is H can be oxidized to compounds of Formula I wherein R° is -OH with pyridinium tribromide or polymer supported pyridinium tribromide in tert-butanol/acetic acid mixture followed by zinc reduction. See, C. Liang, US Patent 6,610,688 (2000); L, Sun, Bioorg. Med. Chem Lett., 2002,12, 2153.
Compounds of Formula I, wherein R° is H can be treated under Mannich conditions (HCHO + HNRR') to give compounds Formula IA wherein R° is -CH-NRR'. See F. Seela, Synthesis, 1997,1067.
Compounds of Formula IA, wherein R° is H can be lithiated and treated with electrophiles (e.g., I2, ArCHO) to provide compounds of Formula IA wherein R° is, e.g. -I or -CH(OH)Ar. See, E. Bisagni, Tetrahedron, 1983, 39, 1777; T, Sakamoto, Tetrahedron Lett. 1994,35,2919; T. Sakamoto, J. Chem. Soc, PerUn Trans 1,1996, 459.
3.2. Functional group interconversions of R]
Compounds of Formula IA, wherein R1 is OH, can be converted to halides using standard conditions POCb, POBr3 etc. with/without a base such as Et3N, N.N-dimethylaniline, (i-Pr)iNBt etc. and with/without a catalyst such as BnEtaN+Cl ~, in polar solvents such as CH3CN, CH2CI2 etc. Related methods include, but are not limited to, SOClj/DMF (M. J. Robins, Can. J. Chem. 1973,12, 3161), PPh3/CCLt (L. De Napoli, J. Chem. Soc. Perkin Trans 1,1994, 923), HMPT/CCL, or HMPT/NBS (E. A. Veliz, Tetrahedron Lett, 2000, 41,1695) or PPh3/I2 (X. Lin, Org. Letters, 2000,2, 3497).
Compounds of Formula IA, wherein R1 is -NH2, can be converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction (CI, Br, I) by means of a nitrosylating agent (NaNO2H+, NOBF4, RONO) and a halogen donor (BF4, CuX2, SbX3 where X is halogen).
Compounds of Formula IA, wherein R1 is alkyl can be prepared from compounds of Formula 4 where R1 is halogen and Irialkyl aluminum or dialkyl zinc (A. Holy, J. Med. Chem. 1999, 42, 2064).
ompounds of Formula IA, wherein R1 is a halide can be converted to compounds wherein R1 is -NH2, -OH, -SH, -OR8, -SR8 with standard reagents, e.g., NH3, NaOH, thiourea, RB0", R8S\ with or without a catalyst (eg. Pd, Ni, Cu, Uwis acid, it) (e.g., B. G. Ugarkar,y, Med. Chem. 2000, 43, 2883-2893 and 2894-2905).
Compounds of Formula IA, wherein Rl is halogen or another leaving group can be treated with ammonia to provide compounds of Formula IA wherein R1 is -NH2 (F. Seela, Liebtgs. Ann. Chem. 1985, 315).
3.3, Functional group interconversions of R2
Compounds of Formula IA, wherein R2 is -NH2 can be temporarily protected, e.g. as an amide (Ac20, PivCl), a carbamate (tBoc)20) or amidine (DMF-DMA).
Compounds of Formula IA, wherein R: is -NH2 can be converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction (CI, Br, I) by means of a nhtosylating agent (NaNOz/H*. NOBF4, RONO) and a halogen donor (BF4*, CuX2, SbX3).
Compounds of Formula IA, wherein R2 is a halide can be converted to compounds wherein R2 is -NH2, -OH, -SH, -OR8, -SRB with standard reagents, e.g. NHj, NaOH, thiourea, R80", R8S", with or without a catalyst (e.g. Pd, Ni, Cu, Lewis acid, it).
Compounds of Formula IA, wherein R2 is -SH can be converted to halides (Br2). They can also be oxidized (e.g., H2O2) and treated with ammonia to give a -NH2 group (S.M. Bennett,/ Med. Chem. 1990,55,2162).
Compounds of Formula IA, wherein R1 is a sulfide, e.g., MeS-, can be converted to a sulfone, e.g. MeS02~, and displaced with a nucleophile, e.g, NH3 or NH2-NH2, Na-, CN-.
3.4. Functional group interconversions of R3
Compounds of Formula IA, wherein R3 is H, can be halogenated (J, F. Gerster, J. Chem, Soc. 1969,207) and further functionalized by Pd-catalyzed reactions ((a) Sonogashira coupling: E. C. Taylor et al, Tetrahedron, 1992,48, 8089; (b) carboxylation: J. W. Pawlik, J. Heterocycl. Chem. 1992,29, 1357; (c) Suzuki coupling: T. Y. I Wu, Org. Lett., 2003, 5,3587) or by addition of nucleophiles (e.g. hydrazine, B. M. Lynch, Can. J. Chem. 1988, 66, 420).
Compounds of Formula IA wherein R3 is -CHO can be sujected to a Bayer-Villiger oxidation to provide compounds of Formula IA wherein R3 is -O-CHO. The latter can be hydrolyzed to R3 is -OH. (A.S, Bourlot, E, Desarbre, J.Y, M£rour Synthesis 1994, 411)
Compounds of Formula IA, wherein R3 is H can be treated under Mannich condition (HCHO + HNRR') to give compounds Formula IA wherein R3 is -CH-NRR' (F. Seela, Synthesis, 1997,1067)
Compounds of Formula IA, wherein R3 is -CH2-NB112 can be obtained by Mannich reaction and further treated with an aniline of Formula NH2-Ar to give compounds of Formula IA wherein R3 is -CKj-NH-Ar (D. C, Miller, J. Med, Chem. 2002, 45, 90).
Compounds of Formula IA, wherein R3 is Br can be metallated with BuLi, and treated with an electrophile such as Mel to give a compound of Formula IA, wherein R3 is methyl. Compounds of Formula IA, wherein Rl is -CI and R3 is -Br can undergo selective metallation at R3 (J. S. Pudlo, J. Med.Chem. 1990,33, 1984).
Compounds of Formula IA, wherein R° is -OH and R3 is H can be be monalkylated or bis-alkylated to give compounds of Formula ID, wherein R1 is an alkyl group. The alkylation can be effected in the presence of a base such as KHMDS, LHMDS, LDA etc. with/without the presence of a catalyst such as Nal, KI, (Bu^NI etc., and in a polar solvent such as THF, DMSO etc. using electrophiles such as L'-R3 where L1 is a leaving group. Leaving groups include but are not limited to, e.g., halogen, triflate, tosylate or mesylate.(Scheme Removed)
Scheme 6
Compounds of Formula IA, wherein R° is H and R3 is H can be oxidized to compounds of Formula 16/IE, with an oxidizing reagent such as ruthenium tetroxide in a binary solvent such as acetonitrile/water. (G. W. Gribble Org. Prep. Proced. Int. 2001, 33(6), 6\5).
Compounds of Formula IA, wherein R° is -OH and R3 is H can be oxidized to compounds of Formula IC, wherein R3 is an oxo group with an oxidizing reagent such as selenium dioxide or oxygen in presence of a cobalt (IH) catalyst. (Se02 oxidation: Romeo Helv. Chim.Acta. 1955,55,463, 465. Oxygen oxidation: A. Inada Heterocycles 1982,19, 2139).
3.5. Further elaboration of R5
Rs, especially when it is aryl or heteroaryl, can be further modified as needed, for example by halogenarion, nitration, palladium coupling of halogen, Friedel-Crafts alkylation/acylation, etc. or these modifications can also be done before alkylation, see Jerry March, Advanced Organic Chemistry. The heteroaromatic rings can also be oxidized to their
(Scheme Removed)
\ corresponding N-oxides using various oxidizing agents such as H2Oi, O3, MCPBA etc. in polar solvents such as CH2C12, CHCI3, CF3COOH etc. See Jerry March, Advanced Organic Chemistry, 4th edition, Chapter 19. Examples of modifications are suggested in Scheme 7.
Scheme 7
4. Permutations of the order of events
As mentioned above, the events (1) assembly of the bicyclic system (2) appendage of the R3-R4- moiety, and (3) further elaboration of the ring systems do not necessarily have to be made in the sequence (I)-(2)-(3), and it may be beneficial to proceed in a different sequence.
Method 4.1.
Scheme 8 shows a synthesis in which the order of events is not (l)-(2)-(3), but is (2)-(l)-(3). First RJ is appended via an aromatic nucleophilic substitution, then the bicyclic system is constructed, and finally it is elaborated.
(Scheme Removed)Scheme 8
Method 4.1.1
The compound of Formula 18, wherein R1 is CI and R2 is NH2, can be prepared by treating the compound of Formula 17 with R5-R4-NH2 in butanol at reflux in presence of a base such as K2C03, Cs2C03 or iPrNEt2. (A.B. Reitz J. Med. Chem. 1994,37,3561).
Method 4.1.2
The compound of Formula 19, wherein R1 is CI and R2 is NHi, can be prepared by refluxing the compound of Formula 18 in chloroform or dichloroethane in presence of an halogenattng reagent such as bromine, N-bromosuccinimide, iodine or N-iodosuccinimide and an acid such as acetic acid or p-toroenesulfonic acid. (A.P. Phillips J. Am. Chem. Soc. 1952, 74, 3922).
Method 4.1.3
The compound of Formula 20, wherein Rl is CI and R2 is NH2, can be prepared by coupling the compound of Formula 19 with trimethylsilylacetylene under Sonogashira conditions followed by hydroboration using dichlorohexytborane and oxidation using hydrogen peroxide in presence of sodium hydroxide, (Sonogashira coupling: E. C. Taylor Tetrahedron , 1992,48, 8089, Hydroboration/oxidation: G. Zweifel J. Am. Chem. Soc. 1976, 98, 3184).
Method 4.1.4
The compound of Formula 21, wherein Rl is CI and R2 is NH2, can be prepared by heating the compound of Formula 20 in a polar aprotic solvent such as THF, DME or dioxane in presence of oxalyl chloride, rhionyl chloride, mesyl chloride or alkyl chloroformate and a base such as iPrNEfc or pyridine. It can also be prepared by treating the compound of Formula 20 with coupling reagents such DCC/HOBt, DCC/DMAP or EDCI/HOBt. (R.C. Larock Comprehensive Organic Transformations Second Edition, pi 870).
Method 4.2
Again, as mentioned above, the events (1) assembly of the bicyclic system (2) appendage of the R5-R+- moiety, and (3) further elaboration of the ring systems do not necessarily have to be made in the sequence (l)-(2)-(3), and it may be beneficial to proceed in a different sequence. For illustrative purposes, Scheme 9 shows a putative synthesis in which the order of events is not (l)-(2)-{3), but is (2)-(l)-{3). First RJ is appended via an aromatic nucleophilic substitution, then the bicyclic system is constructed, and finally it is elaborated.
(Scheme Removed)Scheme 9
Method 4.3
For illustrative purposes, Scheme 10 shows a putative synthesis in which the order of events is not (l)-{2)-(3), but is (l)-(3)- (Scheme Removed)Scheme 10
Also, if R is for instance a pyridine, it can be converted to a N-oxide either before or after alkylation.
B. Synthesis of Compounds of Formula II (Imidazolopyridines and Aminopurines) and Related Analogs
The compounds of Formula II may be synthesized by various methods known in the art, A general strategy for the synthesis of aminopurines (Formulae IIC & IID) is outlined in Scheme 11. Other members of compounds of Formula II may also be synthesized following this route. It should be understood that other methods can also be
used.
(Scheme Removed)
Scheme 11The starting materials or the intermediates of the Formula 2, or/and 4 can exist in tautomeric forms as shown in Fig 4, Both forms are indiscriminately described in the specifications.
Fig 4 (Figure Removed)
1. Method 1: From purines:
The compounds of Formula IIC (see, Scheme 12) can be synthesized from the commercially available starting heterocycle, for example compounds of Formula 2 where R6 is -CI, -Br or -OH, R7 is -NH2 and R8 is -H are commercially available from Aldrich, AlfaAesar, etc, Accordingly, Formula 2 can be alkylated in the presence of a base such as K2CO3, NaH, CS2CO3, DBU etc. with/without the presence of halide such as Nal, KI, (Bu)3NI etc., and in a polar solvent such as DMF, THF, DMSO etc. using electrophiles such as Ll-R4-Rs where -L1 is a leaving group. Leaving groups include but are not

(Scheme Removed)
Scheme 12 limited to, e.g., halogen, triflate, tosylate , mesylate etc. See Kasibhatla, PCT publication number WO 03/037860. Compounds of Formula I, wherein Rl is -OH can be converted to halides using standard conditions POCI3, POBr3 etc, with/without the presence of base such as Et3N, N,N-diethylaniline, (i-pr)2NEt etc. in polar solvents such as CH3CN, CH2CI2 etc.
The compounds of Formula IIC, wherein R1 is -OR11, -SRl1, or -NHR8 where R11' is alkyl, R8 is hydrogen, lower alkyl, lower aryl, or -C(O)R', where R9 is lower alkyl, lower aryl, lower heteroaryl, -NR10R10, or -OR1', where R10 is independently hydrogen or lower alkyl, can be prepared from compounds of Formula IIC wherein R1 is halogen reacting with HOR', HSR1' or NH2R8 in presence of a base such as K2CO3 or NaH and a polar solvent such as DMF or THF. Compounds of Formula IIC where R8 is -C(O)R9 can be prepared when R1 is hydroxyl by simple acylation.
Compounds of Formula IIC where R1 is alkyl can be prepared from compounds of Formula n where R1 is halogen and trialkyl aluminum or dialkyl zinc. (See Holy, J. Med. Chem. 1999, 42,2064).
R especially when it is aryl or heteroaryl, can be further modified as needed, for example by halogenab'on, nitration, palladium coupling of halogen, Friedel-Crafts alkylation/acylation, etc. or these modifications can also be done before alkylation, see Jerry March, Advanced Organic Chemistry. The heteroaromatic rings can also be oxidized to their corresponding N-oxides using various oxidizing agents such as H2O2, 03, MCPBA etc. in polar solvents such as CH2CI2, CHCl3, CF3COOH etc. See Jerry March, Advanced Organic Chemistry, 4th edition, Chapter 19.
Compounds of Formula IIC where R3 is halogen, can be prepared from Formulae 1 or 2 using halogenating agents such as Br2, NBS, NCS, NIS etc. in polar solvents such as DMF, water, or suitable buffer solution. See Herdewijn, / Med. Chem. 1995,38, 3838. Alternatively, compounds of Formula 2 where Re is iodo can also be made using procedures known in the literature, e.g., Burger, J. Org. Chem. 2000, 65, 7825. These can be further modified as needed; for example, where R3 is -Nj, or -CN by reacting with an azide such as NaNj, LiN3 etc. or cynide such as KCN or NaCN in polar solvents such as DMF, DMSO etc. See Halbfmger, / Med. Cliem. 1999,42,1625; Jacobson, J. Med. Chem. 1999, 42, 5325. 2. Method 2: From Pyrimidines
Compounds of Formula IIC can also be prepared from the substituted pyrimidines of Formula 5 (see, Scheme 13). Accordingly, reaction of commercially available compounds of Formula 5, where R16 is hydrogen or -NO2, {see J. Chem.Soc.
1962, 4186, for the preparation of R16 = -NO2 compound) with NH2-R4R5 in solvents
such as EtOH, BuOH etc, in presence
(Scheme Removed)Scheme 13
of organic bases such as EtjN, (i-pr)2NEt etc. followed by nitrosation (when R ' = -H) using nitrous acid, then reduction with sodium dithionite or Zn/HCOOH etc. of Formula 6 (R16 = -NO or -NO2) to yield compounds of Formula 6 where RJ6 is -NH2. Condensation of Formula 6, where R16 is -NH2 using standard conditions such as triethylorthoformate, formic acid, cyanogenbromide etc. as described in./ Chem. Soc.
1963, 4186; Sircar, U.S. Patent 4,748,177, 1988; and Dang, WO 98/39344, followed by
reaction with POCl3 to give compounds of Formula II, Scheme 13. These compounds of
Formula IIC can be further modified as necessary.
Similarly, compounds of Formula IIC can also be synthesized from Formula 7,2-amino-4, 6-dichloro pyrimidine (see Scheme 14). Reaction of Formula 7 with NH2-R4-R5 in solvents such as EtOH, BuOH etc, in presence of organic bases such as EtjN, (ipr>2Net, etc, followed by reaction with diazonium salt prepared from 4-chloroaniline
(Scheme Removed)Scheme 14
and NaNO2 in aq. HC1 to give compound Formula 8, where R16 is azo-(4-chlorobenzene). Reduction of the azo compound with zinc in acetic acid to give compounds of Formula 8, where Rts is -NH2. (See, Meier, U.S. Patent 5,204,353 (1993)). Condensation of these compounds using standard conditions such as triethylorthoformate, formic acid, cyanogenbromide etc. as described in, J. Chem, Soc. 1963,4186; Sircar, U.S. Patent 4,748,177,1988, and Dang, WO 98/39344, followed by reaction with POCl3 to give compounds of Formula IIC, Schenie 14. These compounds of Formula IIC can be further modified as necessary.
Likewise, compounds of Formula 8 where R16 is NH2 can be made from the commercially available 2,5-diamino-4,6-dihydroxy pyrimidine as described in Daluge, U.S. Patent 5,917,042 (1999), See Scheme 15.
(Scheme Removed)
Scheme 15
3. Method 3: From imidazoles
Compounds of Formula IIC can also be prepared from the substituted imidazoles as shown in Scheme 6. Accordingly, compounds of Formula 4, wherein R14 is NHj, R13 is C(O)NH: and R(i is H, can be alkylated in the presence of a base such as KOH, NaOH, K2CO3, NaH, Cs2CO3, DBU etc. with/without the presence of halide such as Nal, KI, (Bu)3NI etc., and in a polar solvent such as DMF, THF, DMSO etc. using electrophiles such as L'-R4-R5 where L1 is a leaving group. Leaving groups include but are not limited to, e.g., halogen, triflate, tosylate, mesylate etc. to give compounds of Formula 10. The ring closure can be achieved using many methods reported in the literature, Alhede, J. Org. Chem., 1991,2139 and references cited therein to give guanines of Formula II, wherein R1 is OH. These compounds can be converted to the
(Scheme Removed)Scheme 16
compounds of Formula II, wherein R1 is CI using POCl3 as described earlier. Advantageously, these steps can be reversed as shown in Scheme 16 via Formula 11. Alternately, we can also construct these 2-aminopyrimidine rings from Formula 4, wherein RH is -OH or halide, R13 is -C(O)OEt and R15 is -H by reacting with guanidine hydrochloride as described in Chowdhury, J. Med, Chem. 1999, 42,4300,Preparation of electrophiles L-R4-R5 wherein L1 is a leaving group and nucleophiles
NH?-R4-RS.
Synthesis of benzyl type electrophile:
Benzyl type etectophites (Fig, 2 supra) can be prepared as described above in Section IU.A.2.2.1 using various methods reported in the literature, see Jerry March, Advanced Organic Chemistry, 4th edition; Larock, Comprehensive Organic Transformatiotts, 1989,VCH, New York. For example the L1 is -Br can be prepared by reduction followed by halogenation of the benzoic acid or aldehyde derivatives. These benzyl derivatives can also be prepared by benzylic oxidation or benzylic halogenation. Further modification of the benzyl ring can be done before or after the corresponding amines where L1 is -Nth can be prepared from the compounds where L1 is leaving group such as chloride, bromide, tosylate, mesylate etc, using ammonia. Synthesis of pyridyl methyl type electrophile:
Pyridyl methyl type electophiles can be prepared from many methods reported in the literature including those identified in Section ni.A.2.2,2.
Further modification of the pyridyl ring can be done after the purine alkylation see Scheme 16,
(Scheme Removed)D. Synthesis of Compounds of Formula ID (Pyrazolopyrimidines and Related
Analogs)
The compounds the present invention may be synthesized by various methods known in the art, including those described in, for example, Gillespie, PCT publication No. WO 02/055082; Dempcy, US publication No, US 2003/0078413 Al. For the synthesis of compounds of Formulae HI, ETTA and IIIB, a general strategy is outlined in Scheme 17 and consists of three parts: (1) constructing the bicyclie system, starting from either a pyridine or a pyrazole, (2) appending the -R4-R! group, and (3) further elaborating the ring systems.
Importantly, one skilled in the art will recognize that the sequence of events is not necessarily (l)-(2)-(3), and that these events may be interchanged, provided there be no incompatibility between the reagents and the functional groups specific to the point in case.
(Scheme Removed)Scheme 17
Also, the starting materials and the intermediates of the Formula 1,2,3, or 4 can exist in tautomeric forms as shown in Fig 5, and both forms are indiscriminately used in this patent.
Fig 5
1, Assembly of the pyrazolo [3,4-d]pyrimidine
1.1 Assembly of the pyrazo1o[3,4-d]pyrimidine starting from a pyrimidine
Scheme 18 (Scheme Removed)
The compounds of Formula 3 can be prepared from pyrrolidines as outlined in Scheme 18, Forinstance;
Method 1,1.1
The compound of Formula 3, wherein R6 is -CI, R7 is -NH2, and R3 is -H, is readily prepared by treating 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde (Formula 1) with hydrazine, see, F. Seela, Heterocycles 1985, 23, 2521; F. Seela, Helv. Chim. Acta 1986, 69,1602; and R. O. Dempcy, WO 03/022859.
Method 1,1.2
The compounds of Formula 3, wherein R6 is CI, R7 is NH2 and R3 is alkyl, aryl, or heteroaryl have not been previously reported. They can be made by converting a compound of Formula 1 to a compound of Formula 5 in two steps; i) Nucleophilic addition to the carbonyl group; and ii) Oxidation of the resulting alcohol. In a subsequent step, the compound of Formula 5 is converted to me compound of Formula 3 by reaction with hydrazine, or an equivalent thereof,
Method 1.1.3
The compounds of Formula 3 wherein R3 is NH2 can be obtained by treatment of a nitrile of Formula 6 with hydrazine (See A. M. El-Reedy, Phosph, Sulf, Silic, 1989,42, 231).
The compounds of Formula 3 wherein R3 is OH can be obtained by treatment of a nitrile of Formula 6 with hydrazine followed by hydrolysis (See Ciba, Patent UK 884,151(1961)).
Method 1.1.4
The compounds of Formula 3 wherein R3 is OH can be obtained by treatment of an acid, ester, or activated ester (or equivalent thereof) of Formula 7 with hydrazine
(Ciba, Patent UK 884,151 (1961)).
1.2. Assembly of the pyrazolo[3,4-d]pyrimidine starting from a pyrazole
The compounds of Formula 3 can also be made from pyrazoles of Formula 2 (Scheme 19). There are a variety of methods by which the 6-membered ring can be formed (e.g. R, J. Bontems, J. Med. Chem, 1990, 33,2174 and references therein). For
instance:
(Scheme Removed)Scheme 19
Compounds of Formula 2 wherein R13 is -CONH2 and R14 is NH2 can be treated with Ph-CO-NCS to give compounds of Formula 3 in which R6 is OH and R7 is NH2 (F. Babin,/ Heterocycl. Chem. 1983,20,1169.)
Compounds of Formula 2 wherein R13 is -CN and R14 is NH2 can be treated with thiourea or guanidine to give compounds of Formula 3 in which R6 is NH2 and R7 is NH2 (H. Kosaku, Heterocycies, 2001, 55,2279).
Compounds of Formula 2 wherein R13 is -CONH2 and R14 is NH2 can be treated with CS2 or EtOCS2K to give compounds of Formula 3 in which R6 is OH and R7 is SH (S. M. Bennett, J. Med. Chem. 1990,33,2162).
2. Incorporation of the -R4-R4 fragment
2.1. Alkylation of compounds of Formula 3
Compounds of Formula 3 can be alkylated in the presence of a base such as K2CO3, NaH, Cs2CO3, DBU etc. with/without the presence of a catalyst such as Nal, KI, (Bu)3NI etc., and in a polar solvent such as DMF, THF, DMSO etc. using electrophiles such as L'-R4-R5 where L1 is a leaving group (See Scheme 20). Leaving groups include but are not limited to, e.g.t halogen, Inflate, tosylate , mesylate, triphenylphosphonium (generated under Mitsunobu conditions, e.g. PPhj/DEAD) etc. (See Kasibhatla, WO 03/037860.)
(Scheme Removed)Scheme 20
2.2. Preparation of electrophiles L1-R4-R5 wherein L| is a leaving group and of nucleophiles NH2-R4-RS.
2.2.1. Synthesis of benzyl type electrophile:
Benzyl type electrophile, (Fig, 2, supra). The corresponding amines where L1 is NH2 can be prepared by a variety of methods, for instance from compounds where L is leaving group such as chloride, bromide, tosylate, mesylate, etc. using ammonia, or with sodium azide followed by hydrogenation,
2.2.2. Synthesis of pyridyl methyl type electrophile:
Pyridyl methyl type electrophiles (Fig. 3 supra) can be prepared from many methods reported in the literature, including those identified in Section III.A.2.2.2.
3. Further Elaboration of the ring systems
3.1. Functional group interconversions of R1
Compounds of Formula IIIA, wherein Rl is -OH, can be converted to halides using standard conditions POCI3, POBr3 etc, with/without the presence of base such as Et3N, N,N-dimethyla.niline, (i-Pr)2NEt etc. and with/without a catalyst such as BnEt3N+CI", in polar solvents such as CH3CN, CH2CI2 etc. Related methods include, but are not limited to, SOCI2/DMF (M. J. Robins , Can. J. Chem. 1973,12, 3161), PPh3/CCl4 (L. De Napoli, J. Chem. Soc. Perkin Trans 1, 1994, 923), HMPT/CCl4 or HMPT/NBS (E. A. Veliz, Tetrahedron Lett, 2000, 41, 1695) or PPh3/I2 (X. Lin, Org. Letters, 2000,2, 3497).Compounds of Formula IHA, wherein R1 is -NH2, can be converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction (CI, Br, I) by means of a nitrosylating agent (e.g. NaNO2/H+, NOBF4, RONO) and a halogen donor (e.g. BF4", CuX2, SbX3) where X is a halogen.
Compounds of Formula IITA, wherein R1 is alkyl can be prepared from compounds of Formula 3 where R1 is halogen and trialkyl aluminum or dialkyl zinc (A. Holy, J. Med. Chem. 1999, 42,2064).
Compounds of Formula IIIA, wherein R1 is a halide can be converted to compounds wherein R1 is -NH;, -OH, -SH, -OR, -SR with standard reagents, e,g. NH3, NaOH, thiourea, RO", RS", with or without a catalyst (e.g, Pd, Ni, Cu, Lewis acid, it), wherein R is lower alkyl.
3.2. Functional group interconversions of R2
Compounds of Formula IHA, wherein R2 is-NHj can be temporarily protected, e.g. as an amide (AC2O, PivCl, (tBoc)2O) or a formamidine (DMF-DMA).
Compounds of Formula IHA, wherein R2 is -NH2 can be converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction (CI, Br, I) by means of a nitrosylating agent (e.g. NaNO2/H+. NOBF4, RONO) and a halogen donor (e.g. BF4-, CuX2, SbX3) where X is a halogen.
Compounds of Formula HIA, wherein R2 is a halide can be converted to compounds wherein R2 is -NH2, -OH, -SH, -OR8, -SR8 with standard reagents, e.g. NHj, NaOH, thiourea, RsO\ R8S", with or without a catalyst (e,g. Pd, Ni, Cu, Lewis acid, H*).
Compounds of Formula I, wherein R2 is -SH can be converted to halides (BT2). They can also be oxidized (e.g. H2O2) and treated with ammonia to give a -NH2 group (S. M. Bennett, J. Med. Chem. 1990, 33, 2162).
Compounds of Formula IIIA, wherein R2 is a sulfide, e.g. MeS-, can be converted to a sulfone, eg. MeSO2~, and displaced with a micleophile, e.g. NH3 or NH2-NH2, N3-, CN-.
3.3. Functional group interconversions of R3:
Compounds of Formula IIIA, wherein R3 is H, can be converted to compounds of Formula IIIA wherein R3 is a halogen (e.g. NCS, NBS, N1S, Br2, ICI, I2/KOH) (See F. Seela et at, Helv. Chim. Acta 1999, 82,105).Compounds of Formula JJIA, wherein R3 is a halogen, can be functionalized by Pd-calayzed reactions ((a) Sonogashira coupling: E. C. Taylor et alt Tetrahedron , 1992, 48, 8089. (b)carboxylation: J. W. Pawlik, J. HeterocycL Chem, 1992,29, 1357 (c) Suzuki coupling: T. Y. I Wu, Org. Lett., 2003,5, 3587) or by addition of nucleophiles (e.g. hydrazine, B. M. Lynch, Can. J. Chem. 1988, 66, 420)
Compounds of Formula I, wherein R3 is a halide, can be converted to compounds wherein R3 is -NH2» -OH, -SH, -OR8, -SR8 with standard reagents, e.g. NH3, NaOH, thiourea, R80", R8S\ with or without a catalyst (e,g. Pd, Ni, Cu, Lewis acid, H*)
Compounds of Formula ICA, wherein R3 is MeO can be deraethylated to provide compounds of Formula IIIA, wherein R3 is OH (J. D. Anderson, J. HeterocycL Chem,, 1990 27,439).
3,4. Further elaboration of R5:
Rs especially when it is aryl or heteroaryl, can be further modified as needed, for example by halogenation, nitration, palladium coupling of halogen, Friedel-Crafts alkylation/acylarion, etc, or these modifications can also be done before alkylation, see Jerry March, Advanced Organic Chemistry. The heteroaromatic rings can also be oxidized to their corresponding N-oxides using various oxidizing agents such as H2O2, O3, MCPBA etc. in polar solvents such as CH2C12, CHCI3, CF3COOH etc. See Jerry March, Advanced Organic Chemistryt 4th edition, Chapter 19. Examples of modifications are suggested in Scheme 21.

(Scheme Removed)Scheme 21
4. Permutations of the order of events
As mentioned above, the events (1) assemby of the bicyclic system (2) appendage of the RJ-R4- moiety, and (3) further elaboration of the ring systems do not necessarily have to be made in the sequence of (l)-(2)-(3), and it may be beneficial to proceed in a different sequence.
For illustrative purposes, Scheme 6 shows a putative synthesis in which the order of events is not (l)-(2)-(3), but is (1)-(3)-(2).
First the bicyclic system is prepared, then it is elaborated, and finally Rs is appended via an alkylation.

(Scheme Removed)Scheme 22
For illustrative purposes, Scheme 23 shows a putative synthesis in which the order of events is not (l)-{2)-(3), but is (2)-(l)-(3). First the Rs group is appended to a pyrimidine via an aromatic nucleophilic substitution, then the bicyclic ring system is constructed, and finally a series of functional group interconversions yields the compound of Formula IIIA.
(Scheme Removed) Scheme 23
Also, if R5 is, for instance, a pyridine, it can be converted to a N-oxide either before or after alkylation.
E. Synthesis of Compounds of Formula IV (Triazolopyrimidines and Related Analogs)
The compounds of Formula IV and IVA (see Scheme 24) of the present invention may be synthesized by various methods known in the art, including those described in, for example, Parkanyi, J. Heterocyc, Chem,, 1990,27(5), 1409-13; Beauchamp, U.S. Patent 4,714,701,1987; Meier, U.S. Patent 5,204,353,1993. Gillespie, WO 02/055083; Peterson, J, Med, Chem.t 1990, 33(4), 1214-19. The general synthetic strategy is outlined in Scheme 1 and consists of three parts: (I) constructing the bicyclic system, stalling from either a pyrimidine or a 1,2,3-triazole, (2) appending the R5-R4- group, and (3) further elaborating the ring systems.
Importantly, one skilled in the art will recognize that the sequence of events is not necessarily (l)-(2)-(3), and that these events may be interchanged, provided there be no incompatibility between tfie reagents and the functional groups specific to the point in case.
(Scheme Removed)Scheme 24
The starting material and/or the intermediates of, e.g., Formulae 1,2 or/and 4 can exist in tautomeric forms, and both forms are indiscriminately described in the
specifications.
1. Synthesis of Compounds of Formula IV From Pyrrolidines
1.1 Method 1
Compounds of Formula IVA can be prepared from the commercially available substituted pyrimidines compounds of Formula 1 where R9 is -OH or halogen, R10 is amino or protected amino or any group that can be converted to amino, such as SMe, R1' is H or -NO:, R12 is -CI, (see Scheme 25) by treating with an excess halogenating agent such as POCl3, oxalyl chloride, or PC15, and a formulating agent such as DMF to give compounds of Formula IVA. where R9 is halogen, and R'2 is halogen, followed by halogen displacement with an nucleophile, such as NH2-R4-R5, in solvents such as EtOH, tBuOH etc. in presence of organic bases such as EtjN, (i-pr)2NEt etc. to yield a
compound of Formula 2. Formula 2, where R1' is -NO2 may then be reduced with zinc and formic acid or sodium dithionite to give compounds of Formula 2 where R11 is -NH2, sec Dcmpcy, U.S. Publication No. 2003/0078413 Al. Compounds of Formula IVA can then be prepared by diazotization with an alkali metal nitrite such as NaNCb in inorganic acids such as HCI, followed by hi situ cyclization. See Beauchamp, U.S. Patent 4,714,701; Meier, U.S. Patent 5,204,353. These compounds of Formula IVA canjbe further modified as necessary.
(Scheme Removed)Scheme 25
Formula 2, where R1 is H, can be treated with diazonium salts such as 4-chloroaniline diazonium salt prepared from 4-chloroaniline and NaN02 inorganic acids such as HCI to give pyrimidine 5-azo- analog, that can be reduced with zinc dust in EtOH/AcOH (1:1) solution to give compounds of Formula 2, where Rn is -NH2, see Meier, U.S. Patent 5,204,353.
1.2 Method 2
(Scheme Removed) Scheme 26
Also compounds of Formula IVA can be prepared from the commercially available substituted diamino pyrimidines compounds of Formula 1 where R9 is -OH 01 halogen, R is amino or protected amino or any group that can be converted to amino, such as SMe, Rn & R11 are -NH2, (see Scheme 26) following the diazotization method
described earlier in Method 1 to give compounds of Formula 4. Formula 4 can be alkylated in the presence of a base such as K1CO3, NaH, Cs2CO3, DBU etc. with/without the presence of halide such as Nal, KI, (Bu)3NI etc., and in a polar solvent such as DMF, TIIF, DMSO etc. using electrophiles such as L'-R4-Rs where L1 is a leaving group. Leaving groups include but are not limited to, e.g., halogen, triflate, tosylate, mesylate etc. See Kasibhatla, PCT WO 03/037860, Compound of Formula I can also be prepared from compounds of Formula D using Mitsunobu alkylation conditions using L'-R4-RJ where L1 is hydroxy!. See Kozai, Chem. Pharm. Bull, 1999,47(4), 574-575).
2. Synthesis of Compounds of Formula IV From Triazole
Compounds of Formula IVA can also be prepared from the substituted triazole as shown in Scheme 27. Accordingly, compounds of Formula 3, wherein R14 is -NH2, R13 is -C(O)NH2 and Rls is H (commercially available), can be alkylated in the presence of a base such as KOH, NaOH, K2CO3, NaH, CS2CO3, DBU etc. with/without the presence of halide such as Nal, KI, (BuJ)3NI etc., and in a polar solvent such as DMF, THF, DMSO etc. using electrophiles such as L'-R4-Rs where Ll is a leaving group. Leaving groups include but are not limited to, e.g., halogen, triflate, tosylate, mesylate etc. to give compounds of Formula 6. The ring closure can be achieved using many methods reported in the literature, Alhede, J. Org. Chem., 1991,2139 and references cited (herein to give compounds of Formula I, wherein Rl is -OH. These compounds can be converted to the compounds of Formula I, wherein R1 is -CI using POCl3 as described earlier. Alternately, we can also construct from Formula 3, wherein RH is -OH or halide, Rl is -C(O)OEt by reacting with guanidine hydrochloride as described in Chowdhury, J. Med. Chem. 1999, 42, 4300. (Scheme Removed) Scheme 27
3. Preparation of electrophiles L1-R4-R5 wherein L1 is a leaving group and
5 nucleophiles NH2-R4-R5
Benzyl type electophiles (Fig. 2 supra) can be prepared as described above in Section III.A.2.2.1 Synthesis of pvridvl methyl type electrophile:
Pyridine methyl type electrophile (Fig. 3 supra) can be prepared from many methods reported in the literature including those identified in Section III.A.2.2.2.
The compound R4-R5-NH2 is obtained by treating R4-R5 -L1 with ammonia at temperatures of 20-160 °C in a pressure vessel, wherein L1 is leaving group such as chloride, bromide, tosylate, mesylate etc. using ammonia, or with sodium azide followed by hydrogenation,
4. Further elaboration of the ring systems.
These modifications can be done at any stage depending upon the incompatibility of the functional groups present.
4.1 Functional group tnterconverslons of R1
Compounds of Formula IVA, wherein R1 is -OH, can be converted to halides using standard conditions POCI3, POBrj etc. with/without a base such as Et3N, N,N-dimethylanihne, (i-Pr)2NEt etc. and with/without a catalyst such as BnEi3N+Cl" , in polar solvents such as CH3CN, CH2Cl2 etc. Related methods include, but are not limited
to, SOCI2/DMF (M. J. Robins, Can. J. Chem. 1973,12, 3161), PP^/CCLt (L. De Napoli J. Chem. Soc. Perkin Trans 1, 1994, 923), HMPT/CCU or HMPT/NBS (E. A, Veliz, Tetrahedron Lett. 2000,41,1695) orPPhj/I2 (X. Lin, Org. Letters, 2000,2,3497),
Compounds of Formula IVA, wherein R1 is -NH2, can be converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction (CI, Br, I) by means of a nitrosylating agent (NaN(VH\ NOBF4f RONO) and a halogen donor (BF/, CuX3, SbX3).
Compounds of Formula IVA, wherein R1 is alkyl can be prepared from compounds of Formula 4 where R1 is halogen and trialkyl aluminum or dialkyl zinc (A. Holy, J. Med. Chem. 1999, 42, 2064).
Compounds of Formula IVA, wherein R1 is a halide can be converted to compounds wherein Rl is -NH2, -OH, -SH, -OR , -SR with standard reagents, e.g. NH3, NaOH, thiourea, R80", R8S", with or without a catalyst (e.g. Pd, Ni, Cu, Lewis acid, H+) (e.g. B. G. Ugarkar, / Med. Chem. 2000, 43, 2883-2893 and 2894-2905).
Compounds of Formula IVA, wherein R1 is halogen or another leaving group can be treated with ammonia to provide compounds of Formula IVA wherein R1 is NH2 (F. Seela.,Liebigs.Ann.Chem. 1985, 315) 4.2. Functional group Interconversjons of R2
Compounds of Formula IVA, wherein R2 is -NH2 can he temporarily protected, e.g. as an amide (AC2O, PivCl), a carbamate (tBoc)2O) or amidine (DMF-DMA).
Compounds of Formula IVA, wherein R2 is -NH2 can be converted to halides by a Balz-Schiemann (F) or Sandmeyer reaction (CI, Br, I) by means of a nitrosylating agent (NaNO2/H4", NOBF4, RONO) and a halogen donor (BF4', CuX2, SbX3 where Xis a halogen).
Compounds of Formula IVA, wherein R2 is a halide can be converted to compounds wherein R2 is -NH2, -OH, -SH, -OR8, -SR8 with standard reagents, e.g. NH3, NaOH, thiourea, R80", R8S", with or without a catalyst (e.g. Pd, Ni, Cu, Lewis acid, H4).
Compounds of Formula IVA, wherein R2 is -SH can be converted to halides (Bt2). They can also be oxidized (e.g, H2O2) and treated with ammonia to give a NH2 group (S. M. Bennett, J. Med. Chem. 1990, 33, 2162).
Compounds of Formula IVA, wherein R2 is a sulfide, e,g. MeS-, can be converted to a sulfone, e.g„ MeS02~, and displaced with a nucleophile, e.g. NH3 or NH2-NH2, N3~, CN".4.3 Further elaboration of It5
R5, especially when it is aryl or heteroaryl, can be further modified as needed, for example by halogenation, nitration, palladium coupling of halogen, Friedel-Crafts alkylation/acylation, etc. or these modifications can also be done before alkylation, see Jerry March, Advanced Organic Chemistry. The heteroaromatic rings can also be oxidized to their corresponding N-oxides using various oxidizing agents such as H2O2, Oj, MCPBA etc. in polar solvents such as CH2Cl2, CHCl3, CF3COOH etc. See Jerry March, Advanced Organic Chemistry, 4th edition, Chapter 19. Examples of modifications are suggested in Scheme 28.
Also, if R5 is for instance a pyridine, it can be converted to a N-oxide either before or after alkylation.

(Scheme Removed)Scheme 28 IV. Pharmaceutical Compositions, Posaging, and Modes of
ADMINISTRATION
The present invention is directed to the clinical use of the heterocyclics, in particular, the pyrazolopyrimidines and their related analogs of Formulae A, I-IV, and their polymorphs, solvates, esters, tautomers, diastereomers, enantiomers, pharmaceutical^ acceptable salts and prodrugs thereof, for use in treatment or prevention of diseases that are HSP90-dependent For example, a disorder such as inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorder, neurological disorders, fibrogenetic disorders, proliferative disorders, tumors,
leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and malignant disease. The fibrogenetic disorders include but are not limited to scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.
The present invention features pharmaceutical compositions comprising the compound of Formulae A, I-IV, or a polymorph, solvate, ester, tautomer, enantiomer, diastereomer, pharmaceutically acceptable salt thereof, or prodrug thereof, of any of the preceding aspect and embodiments and one or more pharmaceutical excipients,
Those of ordinary skill in the art are familiar with formulation and administration techniques that can be employed with the compounds and methods of the invention, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, (current edition), Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA.
The compounds utilized in the methods of the instant invention may be administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practices. The compounds can be administered orally or parenterally, including the intraventous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
For example, the therapeutic or pharmaceutical compositions of the invention can be administered locally to the area in need of treatment. This may be achieved by, for example, but not limited to, local infusion during surgery, topical application, e.g., cream, ointment, injection, catheter, or implant, said implant made, e.g., out of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. The administration can also be by direct injection at the site (or former site) of a tumor or neoplastic or pre-neoplastic tissue.
Still further, the compounds or compositions of the invention can be delivered in a vesicle, e.g., a liposome (see, for example, Langer, Science 1990,249,1527-1533; Treat et at,, Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Bernstein and Fidler, Ed., Liss, N.Y., pp. 353-365,1989).
The compounds and pharmaceutical compositions used in the methods of the present invention can also be delivered in a controlled release system. In one
embodiment, a purnp may be used (see, Sefton, 1987, CRC Crit Ref. Biomed. Eng, 14:201; Buchwald et al. Surgery, 1980, 88, 507; Saudek et al. N. Engl J. Med. 1989, 321, (574). Additionally, a controlled release system can be placed in proximity of the therapeutic target. (See, Goodson, Medical Applications of Controlled Release, 1984,2, 115-138).
The pharmaceutical compositions used in the methods of the instant invention can also contain the active ingredient in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. 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 selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as macrocrystalline cellulose, sodium crosscarmellose, com starch, or alginic acid; binding agents, for example starch, gelatin, potyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be un-coated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, or cellulose acetate butyrate may be employed as appropriate.
Formulations for oral use may also be presented as bard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydimypropylmefhyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hcxitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachisd oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example 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 butylated hydroxyanisol or alpha-tocopherol.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
The compounds and pharmaceutical compositions used in the methods of the instant invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or u mineral oil, for example
liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
The injectable solutions or microentulsions may be introduced into a patient's blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using fliose 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, for example as a solution in 1,3-butane diol. In addition, sterile, fixed oils are conventionally 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 find use in the preparation of injectables.
The compounds of the present invention used in the methods of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the inhibitors with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing a compound or composition of the invention can be used. As used herein, topical application can include mouth washes and gargles.
The compounds used in die methods of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in me form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The methods, compounds and compositions of the instant invention may also be used in conjunction with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents. Further, the instant methods and compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
The methods of the present invention may also be useful with other agents that inhibit angiogenesis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to VEGF receptor inhibitors, including ribozymes and antisense targeted to VEGF receptors, angiostatin and endostatin.
Examples of antineoplastic agents that can be used in combination with the compounds and methods of the present invention include, in general, and as appropriate,
alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomeiase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors. Exemplary classes of antineoplastic include the anthracyelines, vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones, discodermolides, pteridines, diynenes and podophyllotoxins. Particularly useful members of those classes include, for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like. Other useful antineoplastic agents include estramustine, carboplatin, cyclophosphamide, bleomycin, gemchibine, ifosamide, melphalan, hexamemyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
When a compound or composition of the invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms,
In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer, for example, breast cancer. Administration typically occurs in an amount of between about 0.01 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), more preferably at least about 0.1 mg/kg of body weight per day. A particular therapeutic dosage can include, e,g., from about 0.01 mg to about 1000 mg of compound, and preferably includes, e.g., from about 1 mg to about 1000 mg. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0,1 mg to 1000 mg, preferably from about 1 mg to 300 mg, more preferably 10 mg to 200 mg, according to the particular application. The amount administered will vary depending on the particular ICjo value of the compound used and the judgment of the attending clinician
taking into consideration factors such as health, weight, and age. In combinational applications in which the compound is not the sole active ingredient, it may be possible to administer lesser amounts of compound and still have therapeutic or prophylactic effect.
Preferably, the pharmaceutical preparation is in unit dosage form, tn such form, the preparation is subdivided into unit doses containing appropriate quantities ofjhe active component, e.g., an effective amount to achieve the desired purpose,
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The amount and frequency of administration of the compounds and compositions of the present invention used in the methods of the present invention, and if applicable other chemotherapeutic agents and/or radiation therapy, will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the disease being treated.
The chemotherapeuttc agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those . skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance 25 with the knowledge of the skilled clinician, the therapeutic protocols (e.g,, dosage
amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents {i.e., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
Also, in general, the compounds of the invention need not be administered in the 30 same pharmaceutical composition as a chemotherapeutic agent, and may, because of
different physical and chemical characteristics, be administered by a different route. For example, the compoundsycomposirions may be administered orally to generate and
maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
The particular choice of compound (and where appropriate, chemotherapeutic agent and/or radiation) will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol,
The compounds/compositions of the invention (and where appropriate chemotherapeutic agent and/or radiation) may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the compound/composition,
In combinational applications and uses, the compound/composition and the chemotherapeutic agent and/or radiation need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the compound/composition, and the chemotherapeutic agent and/or radiation, may not be important. Thus, the compounds/compositions of the invention may be administered first followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first followed by the administration of the compounds/compositions of the invention. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient. For example, the chemotherapeutic agent and/or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of the compounds/compositions of the invention followed, where
determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.
Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a compound/composition for treatment according to the individual patient's needs, as the treatment proceeds.
The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more Befinite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
v. Assays for determining HSP90 Binding anpDownstream effect
A variety of in vitro and in vivo assays are available to test the effect of the compounds of the invention on HSP90. HSP90 competitive binding assays and functional assays can be performed as known in me art substituting in the compounds of the invention. Chiosisetal. Chemistry & Biology 2001, Downstream effects can also be evaluated based on the known effect of HSP90 inhibition on function and stability of various steroid receptors and signaling proteins including, e.g., Rafl and HER2. Compounds of the present invention induce dose-dependent degradation of these molecules, which can be measured using standard techniques. Inhibition of HSP90 also results in up-regulation of HSP90 and related chaperone proteins that can similarly be measured. Antiproliferative activity on various
cancer cell lines can also be measured, as can morphological and functional differentiation related to HSP9Q inhibition.
Many different types of methods are known in the art for determining protein concentrations and measuring or predicting the level of proteins within cells and in fluid samples. Indirect techniques include nucleic acid hybridization and amplification using, e.g., polymerase chain reaction (PCR). These techniques are known to the person of skill and are discussed, e.g., in Sambrook, Fritsch & Maniatis Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1989; Ausubel, etal. Current Protocols in Molecular Biology, John Wiley & Sons, NY, 1994, and, as specifically applied to die quantification, detection, and relative activity of HER2/Neu in patient samples, e.g„ in U.S. Patents 4,699,877,4,918,162,4,968,603, and 5,846,749. A brief discussion of two generic techniques that can be used follows.
The determination of whether cells overexpress or contain elevated levels of HER2 can be determined using well known antibody techniques such as immunoblotting, radioimmunoassays, western blotting, immunopiecipitation, enzyme-linked irnmunosorbant assays (ELISA), and derivative techniques that make use of antibodies directed against HER2. As an example, HER2 expression in breast cancer cells can be determined with the use of an tmmunohistocheniical assay, such as the Dako Hercep™ test (Dako Corp., Carpinteria, CA). The Hercep™ test is an antibody staining assay designed to detect HER2 overexpression in tumor tissue specimens. This particular assay grades HER2 expression into four levels: 0,1,2, and 3, with level 3 representing the highest level of HER2 expression. Accurate quantitation can be enhanced by employing an Automated Cellular Imaging System (ACIS) as described, e.g., by Press, M. et al. Modern Pathology 2000,13,225A.
Antibodies, polyclonal or monoclonal, can be purchased from a variety of commercial suppliers, or may be manufactured using well-known methods, e.g., as described in Harlow et al. Antibodies; A Laboratory Manual, 2nd ed; Cold Spring Harbor Laboratory, Cold Spring Harbor, N. Y., 1988.
HER2 overexpression can also be determined at the nucleic acid level since there is a reported high correlation between overexpression of the HER2 protein and amplification of the gene that codes for it. One way to test this is by using RT-PCR. The genomic and cDNA sequences for HER2 are known. Specific DNA primers can be
generated using standard, well-known techniques, and can then be used to amplify template already present in the cell. An example of this is described in Kurokawa, H. et at. Cancer Res, 2000, 60, 5887-5894. PCR can be standardized such that quantitative differences are observed as between normal and abnormal cells, e.g., cancerous and noncancerous cells. Well known methods employing, e,g., densitometry, can be used to quantitate and/or compare nucleic acid levels amplified using PCR.
Similarly, fluorescent in situ hybridization (FISH) assays and other assays can be used, e,g., Northern and/or Southern blotting. These rely on nucleic acid hybridization between the BER2 gene or mKNA and a corresponding nucleic acid probe that can be designed in the same or a similar way as for PCR primers, above. See, e,g„ Mitchell MS, and Press M.F. OncoL, SuppL 1999,12,108-116. For FISH, this nucleic acid probe can be conjugated to a fluorescent molecule, e.g., fluorescein and/or rhodamine, that preferably does not interfere with hybridization, and which fluorescence can later be measured following hybridization. See, e.g.t Kurokawa, H et al, Cancer Res. 2000, 60, 5887-5894 (describing a specific nucleic acid probe having sequence 5'-FAM-NucleicAcid-TAMRA-p-3' sequence). ACIS-based approaches as described above can be employed to make the assay more quantitative (de la Torre-Bueno, J., et al. Modern Pathology 2000,13, 221 A).
Immuno and nucleic acid detection can also be directed against proteins other than HSP90 and HER2, which proteins are nevertheless affected in response to HSP90 inhibition.
The following examples are offered by way of illustration only and are not intended to be limiting of the full scope and spirit of the invention.
EXAMPLES
1. PREPARATION OF PYRROLOPYRIMIDINES AND RELATED ANALOGS
(Compounds of Formula 1)
A. Materials and Methods
The chemical reagents used to create the novel products of the invention below are alt available commercially, e.g., from Aldrich Chemical Co., Milwaukee, WI, USA. Otherwise their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein.
The final compounds were usually purified by preparative TLC (silica gel 60 A, Whatman Partisil PK6F) or flash chromatography (silica gel 60 A, EMD Chemicals) using EtOAc/hexane or MeOH/CH2Cl2 as eluents. Rf s were measured using silica gel TLC plates (silica gel 60 A, EMD Chemicals). Analytical HPLC chromatograms were obtained using a C18 column (Agilent Zorbax 300SB-C18; 5 microns; 4.6 mm x 150 mm). A gradient was applied between solvent A (0.1% TFA in H2O) and solvent B (0.5% TFA in CH3CN) increasing the proportion of A linearly from 5% (t=0) to 100% (t=7.00 min), with a constant flow rare of 1 mL/min. The samples were diluted to typically 0.1-1 mg/mL in MeOH or CH3CN and the injection volumes were typically 10 µL. The column was not heated, and UV detection was effected at 254 nm. 1H-NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer.
The chemical names were generated using the Beilstein Autonom 2,1 software.
B. General Procedures
1. General procedures to prepare and manipulate the pyrrolo[2,3-d]pyrimidine
ring
General procedure 1.1: Preparation of pyrrolo[2,3-d]pyrimidines (R0=OH)
(Scheme Removed)A suspension of 4-diamino-6-hydroxypyrimidine (6 mmol), AcONa (12 mmol)
and α-haloaldehyde (6 mmol) in CH3CN (20 mL) and H2O (20 mL) was stirred at 22-40
°C overnight whereupon the starting materials gradually dissolved and the desired
pyrrolo[2,3-d]pyrirmdine precipitated. The precipitate was collected by filtration and
washed (water, acetontrile, ether) and air-dried ((a) C. Jf. Bamett, Org. Proc. Res.
De\>elop. 1999, 3, 184. (b)F. Seela, liebigs Arm. Chan. 1987, IS).
General Procedure 1.2: Preparation of pyrroIo[2,3-d]pyrimidines (R° = OH)
(Scheme Removed)
A suspension of (2-amino-4,6-dicliloro-pyrimidin-5-yl)-acetic acid ethyl ester, RS-R4-NH; and EtN(i-Pr)2 in BuOH was heated at reflux for 24h whereupon the solvent was removed under reduce pressure. The residue was then dissolved in CH2CT2 and washed with sat. NaHCO3 solution and dried with Na2SO4. The crude material was purified by preparative TLC or flash chromatography (EtOAc/hexane or MeOH/CH2Cl2) to give the pure pyrrolo[3,4-d]pyrimidin-6"-one.
Genera] procedure 1.3; Alkylation of pyrrolo [2,3-d]pyrimidines at
N-7
(Scheme Removed)
A suspension of the 4-chloio-7H-pyrolo[2,3Hi]pyrirnidin-2-ykrnine (1 ihmol), benzyl halide (1 mmol) and K2CO3 or Cs2CO3 (1-5 mmol) in dry DMF (5 mL) was heated to 40 °C for 3 to 10 h. Work-up (EtOAc) and purification by preparative TLC or flash chromatography (EtOAc/hexane or MeOH/CH2Cl2) yielded the pure N-7 alkylated
product.
General procedure 1.4: Aminomethylation of pyrrolof2,3-djpyrimidines at C-5
(Scheme Removed) 9
A solution of 2-amino-7H-pyrrolo{2>3-d]pyrimidin-4-ol, formaldehyde (2-5
equiv.) and HNR9R9 (2-5 equiv.) in 80% aq. acetic acid was heated in a sealed tube to 60
"C overnight, concentrated, extracted in MeOHiCH2Cl2 (1:10), washed with sat.
NaHC03 and concentrated. See H. Akiraoto, J. Chem. Soc. Perkin Trans J. 1998,1637.
General procedure 1.5: Alkylationofpyrrolo[2,3-d]pyrunidin-6-one at C-5
(Scheme Removed)
To a solution of pyrroIo[2,3-d]pyrimidin-6-one in THF at -78°C was added a base such as LDA, LHMDS or KHMDS and after 30 mtn, the alkyl halide was further added to give monoalkylated and bisalkylated pyirolo[2,3-d]pyriniidhv6-ones which were purified by preparative TLC or flash chromatography (EtOAc/hexane or MeOH/CH2Cl2).
General procedure 1.6: Oxidation of pynolo[2,3-d}pyrimidines at C-5
(Scheme Removed)
A solution of 2-amino-4-chloro-pyirolo[3,4-d]pyrimidin-6-one and SeO2 in dioxane was heated at reflux until completion (1 h) whereupon the solvent was removed under reduce pressure. The crude was purified by preparative TLC or flash chromatography (EtOAc/hexane or MeOH/CH2Cl2) to give (he pure 4-chloro-5-hydroxy-2-imino-2,7-dmydro-pyirolo[2,3-d]pyrimidin-6-one.
2. General procedures to manipulate the pyridine ring
General procedure 2.1: Preparation of pyridine N-oxides
A solution of the pyridine derivative (1 mmol) in dichloromethane or chloroform
(5 mL) was cooled by means of an ice-bath, treated with m-CPBA (1.1 to 3 mmol) in
three portions, and allowed to warm to r.t. The mixture was extracted with
dichloromethane and washed with aqueous NaOH, followed by water. Drying (Na2SO4)
and concentration afforded the pyridine N-oxide.
General procedure 2.2: Preparation of 2-(acetoxymethyl)-pyridines
A solution of the 2-methylpyridine N-oxide (1.0 mmol) in acetic anhydride (5
mL) was heated to reflux for 0.5 h. Work-up (EtOAc), drying (MgSO4), evaporation and
purification by preparative TLC or flash chromatography afforded the 2-{acetoxymethyl)
pyridine.
General procedure 2.3: Preparation of 2-(hydroxymethyl)-pyridines
A suspension of 2-acetoxymethyl-pyridine derivative and solid K2CO3 in methanol was heated to 50 °C for 5-30 min. Evaporation, work-up (EtOAc), and drying (MgS04) afforded the 2-(hydroxymethyl)-pyridine.General procedure 2.4: Preparation of 2-(bromomethyl)-pyridines
A solution of 2-(hydroxymethyl)-pyridine (1-0 mmol) and fcriphenyl phosphine (1.2 mmol) in dichloromethane or chloroform (5 mL) was cooled to 0°C. A solution of CBr4 (1.5 mmol) in dichloromethane or chloroform was added dopwise, and the resulting mixture was stirred at 0 °C for 0.5-1 h. Work-up followed and purification by flash chromatography afforded the 2-(bromomethyl)-pyridine.
General procedure 2,5: Preparation of 2-(aminomethyl)-pyridines
The 2-(chloromethyl)-pyridine derivative in a solution of ammonia in MeOH was heated at 100°C overnight whereupon it was concentrated under reduce pressure and purified by flash chromatography (MeOH/CH2Cl2) to afford the 2-(aminomethyi)-pyridine derivative.
General procedure 2.6: Preparation of 2-chloropyridines
A suspension of 2-(hydroxymethyl)-pyridine (10 g) in POCl3 (30 mL) was stirred at 110"C for 1.5 h. The resulting viscous oil was cooled to r.t. and poured onto ice water (500 g). The pH was adjusted to 10 with solid KOH. Work-up (CHC13), drying (MgSO4) and evaporation gave the 2-chloropyridine, which was used without purification.
General procedure 2.7: Preparation of pyridinium salts.
A solution of the pyridine was heated in MeOH until it dissolved. A methanolic solution of acid (1.0 equiv of e.g. HC1, MsOH) was added, and the solvent was evaporated to give the pyridinium salt.
3. General procedure to manipulate benzene rings
General procedure 3.1: Halogenation of benzene rings.
Variant 1: A solution of the aromatic compound in MeOH/THF/acetate buffer (IN in each AcOH and AcONa) was treated with Br2 (1.3-equiv) at r.t for 5 min. The excess bromine and solvent were removed on a rotary evaporator. Work-up (CHCI3) and flash chromatography afforded the desired bromobenzeue.
Variant 2: A solution of the aromatic compound (7 mmol) and n-halosuccinimide (NCS, NBS, or NIS, 1.06 equiv) in acetic acid (40 mL) was heated to 40-40 °C for 0.3-1h. Evaporation, work-up (EtOAc) and flash chromatography afforded the desired halogenated benzene,
C. Preparation of Intermediates Example 1. 2-Chloro-l-cbloromethyl-3,4,5-trimethoxy-benzcne
(Scheme Removed)
The title compound was obtained by chlorination of 5-chloromethyI-lJ2,3-trimethoxy-benzene with NCS according to the general procedure 3.1.
1H-NMR (CDCl3): δ 6,82 (s, 1H), 4.70 Example 2. 2-Chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine

Step 1; 2-Chloromethyl-4-methoxy-3,5-dimethylpyridine-l-oxide
The title compound was obtained by oxidation of 2-chloromethyl-4-methoxy-3J5-dimethyl-pyridine according to the general procedure 2.1. HPLC Rt: 4.46 min. 'H-NMR (Scheme Removed)(CDC13): 5 8.05 (s, 1H), 4.93 (s, 2H), 3.77 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H).
Step 2: 2-Chloro-6-chloromemyl-4-memoxy-3,5-dirnethylpyridine
The title compound was obtained by treating 2-chloromethyl-4-methoxy-3,5-dimethylpyridine-1 -oxide wilh POCI3 according to the general procedure 2.6. HPLC Rt: 6.757 min. 1H-NMR (CDCI3): δ 4.64 (s, 2H), 3.79 (s, 3H), 2.35 (s, 3H), 2.33 (st 3H).
Example 3. 4-Cbloro-2-chloromethyl-3,5-dimethyl-pyridJne
(Scheme Removed)
The title compound was obtained by treating 2-chloromethyl-3,5-dirnethyl-pyridin-4-ol (Tarbit, et at. WO 99/10326) with POCb in the same manner as in flie general procedure 2,6 (74% yield). HPLC Rt 5.54 rain. 1H-NMR (CDCl3): δ.24 (s, 1H), 4.7J (s, 2H), 2.48 (s, 3H), 2.36 (s, 3H).
Example 4. 4-Bromo-2-bromomethyl-3,5-dimetliyl-pyrldine
4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine was prepared by any of the following three methods:
Method 1
(Scheme Removed)
Step 1: 2,3,5-Collidine-N-oxide
2,3,5-Collidme-N-oxide was obtained by oxidation of 2,3,5-collidine according to the general procedure 2.1 in 70% yield. HPLC Rt: 3.96 min. 1H-NMR (CDCl3): δ 8,03 (s, lH),6.90(s, 1H), 2.47 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H). m/z(%) 138.2 (M+l, 100%). Rf (20% MeOH/EtOAc): 0.35.
Step 2: 4-Bromo-2,3>5-collidine-N-oxide
2,3,5-collidine-N-oxide (1.3 g, 10 mmol) and K2CO3 (2.9 g, 20 mmol) were suspended in 10 mL of CCI4. Bromine (1 mL, 20 mmol) was added dropwise, and the reaction mixture was heated to reflux for 2 h. Work-up (EtOAc) and flash chromatography (10% MeOH/EtOAc) afforded the title compound us a solid (1.05 g, 51% yield). HPLC Rt: 5.24 min. 1H-NMR (CDCl3): δ 8.06 (s, 'H), 2.56 {s, 3H), 2,43 (s,
3H), 2.31 (s, 3H). m/z (%) 216.2 (M+l, 100%), 218.2 (M+3,100%). Rf (20% MeOH/EtOAc): 0.45.
Step 3: Acetic acid 4-bromo-3,5-oUmethyl-pyridhv2-yl methyl ester
4-Broino-2,3,5-collidine-N-oxide (0.25g, 11 mmol) was dissolved in acetic anhydride (5 mL) and the solution was heated to reflux for 30 min, Work-up and flash . chromatography (50% Hexane/EtOAc) afforded the title compound (0.27 g, 96% yield). Rf (50% Hexane/EtOAc): 0.70. HPLC Rt: 4.76 min. 1H-NMR (CDC13): δ 8.26 (s, 1H), 5.27 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H).
Step 4: 4-Bromo-3,5-dimethyl-pyridin-2-yl methanol
A suspension of acetic acid 4-bromo-3,5-dimethyl-pyrLdin~2-yt methyl ester (0.26 g, 1.0 mmol) and K2CO3 (excess) in MeOH (5 mL) was heated to 50 °C for 15 min. Work-up (CHCb), evaporation, and filtration through a silica gel pad (eluent-100% EtOAc) gave the title compound as a white solid (0.19 g, 88% yield). Rf (50% Hexane/EtOAc): 0.5. HPLC Rt: 3.80 min, 1H-NMR (CDCI3): δ 8.23 (s, 1H), 4.70 (s, 2H), 2.46 Step 5: 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine
The title compound was obtained from 4-bromo-3,5-dimethyl-pyridin-2-yl methanol according to the general procedure 2.4. HPLC Rt: 6.32 min. 1H-NMR (CDCI3): δ 8.22 (s, 1H), 4.63 (s, 2H), 2,52 (s, 3H), 2.40 (s, 3H).
Method 2:
(Scheme Removed)
Step J: 2-chloromethyl-3,5-dimethyl-pyridin-4-ol
The title compound was obtained by heating 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride in toluene as described in the patent by Tarbit, et at.
WO 99/10326.
Step 2: 4-bromo-2-ch]oromethyl-3,5-dimethyl pyridine
A mixture of 2-chloromethyl-3,5-dimethyl-pyridin-4-ol (8,2 g, 47.8 mmol) and POBr3 (60g, 209 mmol) was stirred at 130 ttC for 3 h. The resulting viscous oil was cooled to r.t. and poured onto ice water. The pH was adjusted to 10 with solid KOH. Work-up (CHCl3), drying (MgSO4) and evaporation afforded the title compound as a purple solid (8.7 g, 78% yield) which was used without purification. HPLC Rt: 6.03 min. 1H-NMR (CDCI3): 8.20 (s, 1H), 4.62 (s, 2H), 2.50 (s, 3H), 2.38 (6, 3H).
Method 3:

Step 1; 4-br(Scheme Removed)omo-2-chloromethyl-3,5-dimethyI pyridine
A suspension of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (3.24 g, 14,6 mmol) in PBi3 (8.0 mL, 85.1 mmol, 5.8 equiv.) was heated to 80 °C under nitrogen. A catalytic amount of DMF (0,50 mL, 6.4 mmol, 0.44 equiv.) was added, whereupon the suspension rapidly turned into an orange solution. After 40 min., the reaction was still incomplete as judged by HPLC. The temperature was raised to 110 °C and the reaction was prolonged for 30 min, at which point it was complete. The mixture was poured over ice, made basic with cone. aq. NH4OH and extracted into EtOAc. Washing with water, drying (brine, MgSO4) and concentration gave the title compound as a pink solid (1.51 g, 44%) containing 10% of an impurity by lH-NMR. The crude was used without further purification. 1H-NMR (CDC13) δ 8.19 (s, 1H), 4.59 (s, 2H), 2.48 (s, 3H), 2.37 {s, 3H).
D. Preparation of Final Compounds
Example 5. 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H- . pyrrolo [2,3-d]pyrlmidin-2-y]amine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-7H-pyrro1op,3-d]pyrimidin-2-y]amine (F. Seela, Liebigs Ann. Chem. 1987, I5) with 2-ch1oromethyl-4-mfcthoxy-3,5-dimethyl-pyridme hydrochloride according to the general procclure 1.3. HPLC Rt: 4.709 min, 1H-NMR (CDCI3): δ 8.23 (s, IH), 6.90 (m, IH), 6.38 (m 1H), 5.35 (s, 2H), 4.99 (s, 2H), 3.75 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H).
Example 6. 7-(2-Bromo-3,4,S-trimethoxy-benzyl)-4-chloro-7H-pyrroIo[2,3-dIpyrimidin-2-ylamlne
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2J3-d]pyrimidin-2-ylamine with 2-bromo-l-chloromemyl-3,4,5-trimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.937 min. 1H-NMR (DMSO-d6): δ 7.11 (m IH), 6.73(s, 2H), 6.42 (s, 1H), 6.37 (m IH), 5.23 (s, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 3.61 (s, 3H).
Example 7. 4-Chloro-7-(2-todo-3,4,5-trimethoxy-benzy1)-7H-pyrrolo(2>3-
d]pyrimidin-2-ylamine

The title compound was obtained by alkylation of 4-chloro-7H-pynoIo{2,3-dJpyrimidin-2-ylamine with l-chIoromettiyl-2-iodo-3,4,5-trimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 7.069 min. 1H-NMR (DMSO-d6): δ 7.08 (m 1H), 6.74 (a, 2H), 6.38 (m 1H), 6.3(Scheme Removed)6 (s, 1H), 5.19 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.60 (s,
3H).
Example 8. 4-Chloro-7-(4-methoxy-3,5-dimethyl-l-oxy-pyridin -2-ylmethyl)-7H-pyrroIo[2,3-d]pyrimidin-2-yIamine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamme with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine 1-oxide according to the general procedure 1.3. HPLC Rt: 5.079 min. 1H-NMR (DMSO-d6): δ 8.18 (s, 1H), 7.29 (m, 1H), 6.68(s, 2H), 6.24 (m, 1H), 5.38 (s, 2H), 3,70 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H), ESI-MS 334.2 (M+l). Example 9. 4-Chloro-7-(3,4,5-trimethoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-
ylamine
(Scheme Removed)

The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylarmne with 5-chloromethyl-l,2,3-trimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.036 min. 1H-NMR (CDC13): δ 6.82 (m, 1H), 6.41(s, 2H), 6.40 (m, 1H), 5,36 (s, 2H), 5.16 (s, 2H), 3.81 (s, 3H), 3.78 (s, 6H).
Example 10, 4-Chloro-7-(6-chloro-4-methoxy-3,5-diraethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d)pyrlmidin-2-ylamine
(Scheme Removed)The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 2-chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6.880 min. 1H-NMR PMSO-d6): δ 7.06 (m, 1H), 6.63(s, 2H), 6.32 (m, 1H), 5.29 (s, 2H), 3.74 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H).
Example 11. 4-ChIoro-7-(4-chloro-3,5-dimethyl-pyridin-2-y1methyl)-7H-pyrrolo(2,3-d] pyrimidin-2-yIamine
(Scheme Removed)The title compound was obtained by alkylation of 4-chloro-7-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-chloro-2-chloromethyl-3t5-dimethyI-pyridine according to the general procedure 1.3. HPLC Rt: 5.878 min. lH-NMR (CDC13): δ 8.27 (s, 1H), 6.89 (m, 1H), 6.40 (m, 111), 5.40 (s, 2H), 4,94 (s, 2H), 2.39 (st 3H), 2.37 (s, 3H).
Example 12. 4-Chloro-7-(2-chloro-4,5-dimethoxy-beazyl)-7H-pyrrolo[2,3-dIpyrimidin-2-ylamine
(Scheme Removed)The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-djpyrimidin-2-ylamine with l-broinomcthyl-2-chloro-4,S-dimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.635 min. 1H-NMR (CDCl3): δ 6.91 (m, 1H), 6.90 (s, 1H), 6.71 (s, 1H), 6.42 (m, 1H), 5.30 (s, 2H), 4.97 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H).
Example 13. 7-{4-Bromo-3,5-dimethyl-pyrldin-2-ylmethyl)-4-chLoro-7H-pyrrolo [2,3~d]pyrimldin-2-ylamine
(Scheme Removed)The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yIamine with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6,072 min. 1H-NMR (DMSO-d6): δ 8.15 (s, 1H), 7,10 (m, 1H), 6.60(8, 1H), 6.30 (in, 1H), 5.40(s, 2H), 2.46 (s, 3H), 2.30 (s, 3H).
Example 14. 4-Ch1oro-7-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pynmidin-2-ylamine
(Scheme Removed)The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according to the general procedure 1.3. HPLC Rt: 5.610 min. 1H-NMR (DMSO-d6): δ 8.36 (s, 1H), 7.26 (m, 1H), 6.69(s, 1H), 6.21 (m, 1H), 5.43(s, 2H), 2.60 (s, 3H), 2.27 (s,
3H).
Example 15. 7-(4-Bromo-3,5-dimethyl-l-oxy-pyridin-2-ylmethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrtmidin-2-ylainine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according to the general procedure 1.3. HPLC Rt: 5.734 min. 1H-NMR (DMSO-d6): δ 8.33 (s, 1H), 7.24 (m, 1H), 6.69 (s, 1H), 6.25 (m, 1H), 5.47(s, 2H), 2.65 (s, 3H), 2.29 (s, 3H).Example 16. 4-Chloro-7-(3,5-dimethoxy-2-nitro-benzyl)-7H-pyrrolo[2,3-
d] pyrimidln-2-ylamJne

The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with l-bromomethy1-4,5-dimethoxy-2-nitro-beiizene according to the general procedure 1.3. HPLC Rt: 6.345 rain. 1H-NMR (DMSO-d6): δ 7.73 (s, 1H), 7.16 (m, 1H), 6.72 (s, 2H), 6.41(Scheme Removed) (s, 1H), 6.40 (m, 1H), 5.58(s, 2H), 3.92 (s, 3H), 3.62 (s,
3H).
Example 17, 4-Chloro-7-(3,4-dlchloro-benzyl)-7H-pyrrolo[2,3-d)pyrimidin-2-ylamlne
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-7H-pyiroIo[2,3-d]pyrimidin-2-ylamine with 4-bromomethyl-1,2-dichloro-benzene according to the general procedure 1.3. HPLC Rt: 7.148 min. 1H-NMR (DMSO-d6): δ 7.60 (m, 1H), 7.59 (m, 1H), 7.25(q, 1H), 7.12(m, 1H), 6.71 (s, 2H), 6.37 (q, 1H), 5.26(s, 2H).
Example 18. 4-Chloro-7-(3,5-dimethoxy-benzyl)-7H-pyrrolo[2>3-d]pyrimidin-2-
ylamine
(Scheme Removed)
The title compound was obtained by allocation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 1 -chloromethyl-3,5-dimethoxy-benzene according to the general procedure 1.3. HPLC Rt 6.423 min. 1H-NMR (DMSO-d6): 8 7.21(ra, 1H), 6.69 (s, 2H), 6.40 (m, 3H), 6.34 (m, 1H), 5.34 (s, 2H), 3.6S (s, 6H).
Example 19. 4-Chloro-7-(2,S-dimethoxy-benzyl)-7H-pyrrolo[2^-dlpyriiiiidIa-2-
ylamine
(Scheme Removed)The title compound was obtained by alkylation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 2-chloromethyl-l,4-dimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6,537 min. 1H-NMR (DMSO-d6): 8 7.13 (m, 1H), 6.85 (d, 1H), 6.82 (m, 1H), 6.68 (s, 2H), 6.35 (m, 1H), 6.22 (d, 1H), 3.78 (s, 3H), 3.60 (s, 3H).
Example 20. 4-Bromo-7- (Scheme Removed)
The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (obtained as described in F. Seela, Liebigs Ann. Chem. 1987, IS for 4-chloro-7H-pyrro1o[2,3-d]pyrimidin-2-ylamine, but substituting POCl3 with POBr3) with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridme 1-oxide according to the general procedure 1.3. HPLC Rt: 5.158 min. 1H-NMR(DMSO-d6): δ 8.18 (s, 1H), 7.29 (m, 1H), 6.69 (s, 2H), 6.15 (m, 1H), 5.37(s, 2H), 3.70 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H).Example 21. 4-Bromo-7-(4-chloro-3,5-dimethy]-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrlmidin-2-ylamine
(Scheme Removed)The title compound was obtained by alkylation of 4-broino-7H-pyrrolo[2,3-djpyrimidin~2-ylamine with 4-chloro-2-chloromethyI-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 5,803 min. 1H-NMR (DMSO-d6): δ 8.20 (s, 1H), 7.04 (m, 1H), 6.61 (s, 2H), 6.21 (m, 1H), 5.38(8,2H), 2.42 (s, 3H), 2.28 (s, 3H).
Example 22. 4-Bromo-7- (Scheme Removed)
The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-chloro-2-chloromethyl-3,5-dimeihyl-pyridiiie 1-oxide according to the general procedure 1.3. HPLC Rt; 5.688 min. 1H-NMR (DMSO-d6); δ 8.35 (s, 1H), 7.25 (m, 1H), 6.70 (s, 2H), 6.15 (m, 1H), 5.43 (s, 2H), 2.60 (s, 3H), 2.27 (s,
3H).
Example 23. 4-Bromo-7-(4-bromo-3,5-dimethyI-pyrldln-2-y]methyl)-7H-pyrrolo{2,3-d]pyrlmtdin-2-ylamlne
(Scheme Removed)
The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-ylarame with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 5.996 min. 1H-NMR (DMSO-d6): δ 8.15 (s, 1H), 7.05 (m, III), 6.61 (s, 2H), 6.21 (m, 1H), 5.43 (s, 2H), 2.46 (s, 3H), 2.30 (s, 3H).
Example 24. 4-Bromo-7-(4-bronio-3,5-dimethyl-1-oxy-pyridin-2-ylmethyI)-7H-pyrrolo[2,3-d]pyrimidln-2-ylamine
(Scheme Removed)
The title compound was obtained by alkylation of 4-bromo-7H-pyirolo[2,3-d]pyrimidin-2-ylamine with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according to the general procedure 1.3. HPLC Rt: 5.798 rain. lH-NMR (DMSO-d6): δ 8.33 (s, 1H), 7.24 (m, 1H), 6.71 (s, 2H), 6.15 (m, 1H), 5.46 (s, 2H), 2.64 (s, 3H), 2.29 (s,
3H).
Example 25. 4-Bromo-7-(4-methoxy-3,5-dlmethyl-pyridin-2-yImethyl)-7H-pyrrolo [2,3-d]pyrimidin-2-ylamtne
(Scheme Removed)
The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2)3-d]pyrimidin-2-ylamine with 2-chloromethyl-4-metiioxy-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 4.847 min. 1H-NMR (DMSO-d6): δ 8.07 (s, 1H), 7.03 (m, 1H), 6.60 (s, 2H), 6.20 (m, IH), 5.29 (s, 2H), 3.72 (s, 3H), 2.24 3~dIpyrimidin-2-ylamine
(Scheme Removed)
The title compound was obtained by alkylation of 4-bromo-7H-pyrrolo[2,3-d]pyrimidm-2-ylamine with l-cloromethyl-3,5-dimethoxy-benzene according to the general procedure 1.3. HPLC Rt: 6.490 min. 1H-NMR (CDCl3): δ 7.20 (m, 1H), 6.70 (s, 2H), 6.40 (s, 1H), 6.34 (s, 2H), 6.23 (m, 1H), 5.16 (s, 2H), 3.69 (s, 6H).
Example 27, 4-Chloro-7-(3-methoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chIoro-7H-pyrrolo[2,3-dJpyrimidin-2-ylamine with l-chloromethyl-3-methoxy-benzene according to the general procedure 1.3. HPLC Rt: 7.177 min. lH-NMR (DMSO-d6): δ 7.26-7.18 (m, 2H), 6.82-6,80 (m, 1H), 6.67 (s, 1H), 6.70-6.67 (m, 3H), 6.32-6.30 (m, 1H), 5.20 {s, 2H), 3.68 (s, 3H).
Example 28. 4-Chloro-7-(4-methoxy-benzyl)-7H-pyrroIo[2,3-d]pyrimidin-2-ylamine
(Scheme Removed)
Example 31. N-(4-Chloro-5-iodo-7-{4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [23-d] pyrimidin-2-yl]-2,2-dimethyl-propionamide
(Scheme Removed)
The title compound was obtained by alkylation of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionarmde (A. Gangjee, J. Med. Chem, 2003,46, 591) with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6.627 min. 1H-NMR (DMSO-d6): δ 10.15 (s, 1H), 8.05(8,1H), 7.73 (s, 1H), 5.46 (s, 2H), 3.74 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.21 (s, 9H).
Example 32. N-[7-(4-Bromo-3,5-dimethyl-l-oxy-pyridin-2-ylmethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
(Scheme Removed)
The title compound was obtained by alkylation of N-(4-chloro-7H-pyirolo[2,3-d]pyrimidin~2-yl)-2,2-dimethyl-propionamide with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1 -oxide according to the general procedure 1.3. HPLC Rt: 6.806 min. 1H-NMR (DMSO-d6): δ 10.13 (s, 1H), 8.30(s, 1H), 7.74 (m, 1H), 6.52 (m, 1 H), 5.62 («, 2H), 2.73 (s, 3H), 2.28 (s, 3H), 1.23 (s, 9H).
Example 31. N-(4-Chloro-5-iodo-7-{4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [2,3-d] pyrimidin-2-yll-2,2-dimethyl-propionamidc
(Scheme Removed)
The title compound was obtained by alkylation of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionarmde (A. Gangjee, J. Med. Chem, 2003,46, 591) with 2-chloromethyl-4-methoxy-3J5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6.627 min. 1H-NMR (DMSO-d6): δ 10.15 (s, 1H), 8.05(8,1H), 7.73 (s, 1H), 5.46 (s, 2H), 3.74 (s, 3H), 2.33 (s, 3H), 2.16 (s, 3H), 1.21 (s, 9H).
Example 32. N-[7-(4-Bromo-3,5-dimethyl-l-oxy-pyridin-2-ylmethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
(Scheme Removed)
The title compound was obtained by alkylation of N-(4-chloro-7H-pyirolo[2,3-d]pyrimidin~2-yl)-2,2-dimethyl-propionamide with 4-bromo-2-chlorometiiyl-3,5-dimethyl-pyridine 1 -oxide according to the general procedure 1.3. HPLC Rt: 6.806 min. 1H-NMR (DMSO-d6): δ 10.13 (s, 1H), 8.30(s, 1H), 7.74 (m, 1H), 6.52 (m, 1 H), 5.62 («, 2H), 2.73 (s, 3H), 2.28 (s, 3H), 1.23 (s, 9H).
Example 33. N-[4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
(Scheme Removed)
The title compound was obtained by alkylation of N-(4-chloro-7H-pyrrolo[2,3-d]pyriraidin-2-yl)-2,2-dimethyl-propionamide with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 6.087 min. 'H-NMR (CDC13); δ 8.18 Example 34. N-[4-Chloro-7-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrro[o[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide
(Scheme Removed)
The title compound was obtained by alkylation of N-(4-chloio-7H-pynolopJ3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine 1-oxide according to the general procedure 1.3. HPLC Rt: 6.115 rain, 1H-NMR (CDCI3): δ 8.12 (s, 1H), 8.02(s, lH)t 7.93 (m, 1H), 6.49 (m, 1 H), 5.71 (s, 2H), 3.76 (s, 3H), 2.70 (s, 3H), 2.22 (s, 3H), 1.36 (s, 9H).
Example 35. N-[4-Chloro-7-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-5-iodo-7H-pyrroIo[2,3-d]pyrimidin-2-yl]-2,2-dimerhyl-propionamide
(Scheme Removed)The title compound was obtained by alkylation of N-(4-chIoro-7H-pyrrolo(2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionarnide with 4-chloro-2-chloromethyl-3,5-dimethyi-pyridine according to the general procedure 1.3. HPLC Rt: 6.761 min. H-NMR (CDC13): δ 8.23 (s, 1H), 8.1t(s, 1H), 7.15 (m, 1H), 6.50 (m, 1 H), 5.71 (s, 2H), 2.43 (s, 3H), 2.33 (s, 3H), 1,35 (s, 9H),
Example 36. N-[4-Chloro-7-(4-chloro-3,S-dimethyl-pyridln-2-ylmethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimldin-2-yl]-2,2-dimethyl-proplonamide
(Scheme Removed)
The title compound was obtained by alkylation of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyriraidin-2-yl)-2,2-dimethyl-propionamide with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt; 7.508 min. 'H-NMR (CDC13): δ 8.17 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 5.77 (s, 2H), 2.81 (s, 3H), 2.33 (s, 3H),I.37(s,9H).
Example 37. N-(4-Chloro-7-(4-chloro-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-djpyrlmidin-2-yl]-2,2-dimethyl-propionamide
(Scheme Removed)
The title compound was obtained by alkylation of N-(4-ch]oro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionaniidewith4-chloro-2-cri]orornethyl-3,5-dimethyl-pyridine 1 -oxide according to the general procedure 1.3. HPLC Rt: 6,688 min. lH-NMR (CDC13): δ 8.15 (s, 1H), 8.09 (s, 1H), 7.87 (m, 1H), 6.47 (m, 1H), 5.77 (s, 2H), 2.84 (s, 3H), 2.31 (s, 3H), 1.37 (s, 9H).
Example 38. N-[4-Chloro-7-('4-cj;pr0-3,5,-dimethyl-1-oxy-pyridin-2-ylmethyl)-5-iodo-7H-pyrrolo(2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propioamide
(Scheme Removed)
The title compound was obtained by alkylation of N-(4-chIoro-5-iodo-7H-pyrroIo[2,3-d]pyrimidii)-2-yI)-2,2-dimethyl-propionaniide with 4-chloro-2-chloromethyI-3,5-dimeihyl-pyridine 1-oxide according to the general procedure 1.3. HPLCRt: 7.619 min. 1H-NMR (CDC13): 5 8.25 (s, 1H), 8.13 (s, 1H), 7.33 (s, 1H), 5.55 (s, 2H), 2.47 (s, 3H), 2.36 (s,3H), 1.36 (s,9H).
Example 39. 4-Ch]oro-5-[(dibenzylamino)-methyl]-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo(2,3-d]pyrimidin-2-ylamine
(Scheme Removed)Step 1. Octanoic acid {4-chloro-5-[(dibenzy]amino)-methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl} -amide
A solution of octanoic acid {5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide (1.0 g, 2mtnol;./. Chem. Soc. Perktn Trans. I
1998,1637), BnNEt3Cl (1.4 g, 4 mmol), PhNMe2 (0.5 mL) and POCl3 (1.73 mL, 12 mmol) in CH3CN (9.2 mL) was heated to 100 °C for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (50 mL x 3), and evaporated, to give the title compound (0.80 g, 76%). HPLC Rt: 6.868 min. 1H-NMR (DMSO-d6): δ 12.19 (s, 1H), 10.49 (s, 1H), 1.45-7.21 (m, 11H), 3.80 (s, 2H), 3.59 Step 2. 4-Chloro-5-[(dibenzylamino)-methyl]-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrrimidin-2-ylamine
A suspension of octanoic acid {4-chloro-5-[(dibenzylamino)-methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide (150 mg, 0.30 mmol), 2-chIoromethyl-4-raethoxy-3,5-dimethyl-pyridine (56 mg, 0.30 mmol) and K2CO3 (84 mg, 0,60 mmol) in dry DMF (1 mL) was heated to 45 "C for overnight After work-up (EtOAc) and evaporation, the residue was taken up in methanolic 4N HC1 (1 mL), stirred at room temperature for 1 h, and neutralized to pH 7 with 2N NaOH. Extraction with EtOAc ( 10 mL x 3), evaporation and purification by preparative TLC (MeOH/CH2Cl2 10:1) gave the title compound ( 70.5 mg, 45%). HPLC Rt: 5.362 min. 1H-NMR (DMSO-d6): δ 8.05 (s, 1H), 7.30-7.22 (m, 10H), 6.99(s, 1H), 6.57s, 2H), 5.27 (s 2H), 3.70 (s, 2H), 3.65 (s, 3H), 3.54 (s, 4H), 2.17 (s,3H), 2.15 (s,3H),
Example 40. 4-Chloro-7-(4-methoxy-3,5~dimethyl-pyridin-2-ylmethyl)-5-phenylaminometbyl-7H-pyrrolo[2,3-d]pyrimidln-2-ylamine
(Scheme Removed)Step I. Octanoic acid (4-chloro-5-phenylaminomethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide
A solution of octanoic acid {5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide (2,42 g, 3 mmol) and aniline (10 mL) was heated to 90 °C in a selaed tube overnight, concentrated, filtered, and washed with MeOH (2 mL x3) to give the title compound (1.1 g, 57% ), HPLC Rt: 6.327 min. 1H-NMR (DMSO-d6): δ 11.77 (s, 1H), 11.47 (s, 1H), 11.37 (s, 1H), 7.05 (m, 2H), 6.85 (s, 1H), 6.62 (m, 2H), 6.52 (m, 1H), 5.58 (t, 1H), 4.31 (d, 2H), 2.43 (t, 2H), 1.58 (m, 2H), 1.27 (m,8H),0.86(t(3H).
(Scheme Removed)Step 2. 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5-phenylamJnomethyl-7H-pyrro]o[2,3-d]pyrimidin-2-ylamine
A solution of octanoic acid (4-chloro-5-phenyIaminomethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide (270 mg, 0.68 mmol), BnNEtjCl (0.48 g, 1.36 mmol), PhNMe2 ( 0.17 mL) and POCl3 (0.59 mL, 4.08 mmol) in CH3CN (3 mL) was heated to 100 °C for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (20 mL x3), evaporated, to give 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine as a crude oil (282 mg) which was used without purification. A suspension of this crude (282 mg, 0,68 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (140 mg, 0,68 mmol) and CS2CO3 (266 mg, 0.68 mmol) in dry DMF (1 mL) was heated to 45 °C overnight, After work-up (EtOAc) and evaporation, the residue was taken up in methanolic 4N HC1 (1 mL), stirred at room temperature for 1 h, and neutralized to pH 7 wim 2N NaOH, Extraction with EtOAc (10 mL x3), evaporation and purification by preparative TLC (MeOH/CH2Cl2 10:1) gave the title compound (4.8 mg, 1.6%). HPLC Rt: 4.785 min. 1H-NMR (CDCl3): δ.12 (s, 1H), 7.18(m, 2H), 6.75(m, 2H), 6.60 (s, 1H), 5.26[s, 2H), 4.93 (s, 2H), 4.74 (s, 2H), 3.70 (s, 3H), 3,00 (s, 3H), 2.23 (s, 3H), 2.16 (s, 3H).
Example 41. 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5-[(methyl-phenyl-amino)-methyl]-7H-pyrroloI2,3-d)pyrimidin-2-ylamine

Step 1: Octanoic acid(4-chloro-5-[(methyl-phenyl-amino)-methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide
The title compound was obtained by treating octanoic acid {5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrroIo[2,3-d]pyrimidin-2-yl}-amide {2.42 g, 3 mmol) and N-methylaniIine(10mL)asinstep 1 of the previous example. HPLCRt: 6.325 min. 1H-NMR (DMSO-d6): δ 11.73 (s, 1H), 11.47 (s, 1H), 11.35 (s, 1H), 7.13 (m, 2H)f 6.78 (s, 2H), 6.60 (m, 2H), 4.64(s, 2H), 2.98 Step 2: 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmemyl)-5-{(methyl-phenyl-amino)-methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
The title compound was obtained by alkylation of octanoic acid {4-chtoro-5-[(methyl-phenyl-amino)-memyl]-7H-pyrrolo[2J3-d]pyrimidin-2-yl}-aniide with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine and deprotection with 4N HC1 as in step 2 of the previous example. HPLC Rt 4.844 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 7.16 (m, 211), 6.87 (s, 1H), 6.70-6.64 (m, 2H), 5.28 (s, 2H), 5.13 (s, 2H), 4.46 (s, 2H), 4.15 ( br s, 1H), 3.73 (s, 3H), 2.25 (s, 3H), 2.18 (a, 3H).
Example 42. 4-Chloro-7-(4-methoxy,5-dlmethyl-pyridin-2-ylmethyl)-6-pyrrolidin-l-ylmethyl-7H-pyrrolo[2,3-dIpyrimldin-2-ylamine
(Scheme Removed)Step 1. Octanoic acid (4-chloro-6-pyrroHdin-l-ylmethyl-7H-pyrrolo[2,3-
d]pyrimidin-2-yl)-amide
A solution of octanoic acid (4-oxo-6-pyrrolidin-l-ylmethyI-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-aniide (0.36 g 1 mmol; J. Ckem. Soc, Perkin Trans. J 1998, 1637), BnNEt3Cl (0.70 g, 2 mmol), PhNMe2 (0.25 mL) and POCl3 (0.86 mL, 6 mmol) in CH3CN (5 mL) was heated to 100 °C for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (50 mL x3), and evaporated to give octanoic acid (4-chloro-6-pyrrolidin-l-yImethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide as a crude (0.33 g) which was used without purification. HPLC Rt: 6.737 min. 1H-NMR (CDCl3): δ 11.60 (br s, 1H), 10.20 (br s, 1H), 6.38 (s, 1H), 3.86 (s, 2H), 2.90 (m, 2H), 2.70 9s, 4H), 1.86 (s, 4H), 1.78 (t, 2H), 1.32-1.29 (m,8H), 0.90 (t,3H).
Step 2. 4-Chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-6-pyrrolidin-l-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
A suspension of the crude octanoic acid (4-chloro-6-pyrrolidin-l-yImethyl-7H-pyrrolo[2(3-d]pyrimidin-2-yl)-amide (330 mg, 0,87 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (162 mg, 0.87 mmol) and K2CO3 (121 mg, 0.87 mmol) in dry DMF (1 mL) was heated to 45 °C for overnight After work-up (EtOAc) and evaporation, the residue was taken up in 6N methanolic HC1 (1 mL), stirred at room temperature for 1 h, and neutralized to pH 7 with 2N NaOH. Extraction with EtOAc (10 mL x3), evaporation and purification by preparative TLC (MeOH/CH2Cl2 10:1) yielded 4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-6-pyrrolidin-l-ylmethyl-7H-
pyrrolo[2,3-d]pyrimidin-2-yIamine (4.1 rug, yield 1.0 %), HPLC Rt: 6.092 min. 'H-NMR (CDCl3): δ 809 (s, 1H), 6.31(s, 1H), 5.55(s, 2H), 4.85(8,2H), 3.77 (s, 3H), 3.52(brs, 2H), 2.43 (m, 4H), L76-1.71(m, 4H).
Example 43. 4-Chloro-5-lsopropyl-7-(4-methoxy-3,5-dimethyl-pyridln-2-ylmethyl)-7H-pyrrolo [2,3-d] pyrimidin-2-ylamtne
(Scheme Removed)
Stepl. 3-Bromo-4-methyl-pentanal
A mixture of 4-methyI-pentanal (8.60 g, 0.10 mol), 5,5-dibromobarbituric acid (DBBA, 17.15 g, 0.06 mol), 40% HBr (2 mL) and HOAc (1 mL) in CH2Ci2 (180 mL) was stirred at 25 °C for 5 h. after filtration, the filtrate was washed with IN Na2SO3, Na2CO3, and brine, dried with Na2SO4, and evaporated to give 3-bromo-4-methyl-pentanal (8.76 g, 53%). 1H-NMR (CDCl3): δ 9.40 (s, 1H), 4.40 (t, 1H), 2.10 (m, 1H), 1.06 (s,3H), 1.05 (s,3H).
Step2. 2-Amino-5-isopropyl-3,7-dihydro-pyttolo[2,3-d]pyrimidin-4-one
A suspension of 4-diamrao-6-hydroxypyrimidiiie (6,68 g, 50 mmol), AcONa (8.3 g 100 mmol) and 3-bromo-4-methyl-pentanal (8.76 g, 50 mmol) in CH3CN (100 mL) and H20 (100 mL) was stirred at 25 °C overnight whereupon the starting materials gradually dissolved and the desired pyirolo[2,3-d]pyrimidine precipitated. The precipitate was collected by filtration and washed with MeOH to give 2-amino-5-isopropyl-3,7-dmydro-pyrrolo[2,3-d]pyrimidin-4-orie (3.80 g, 40%). HPLC Rt: 4.408 min. 1H-NMR (DMSO-d6): δ 10,58 (s, 1H), 10.10 (s, 1H), 6.30 (s, 1H), 5.97 (s, 2H), 3.03 (7, 1H), 1.20 (s, 3H), 1.19 (s, 3H).
Step 3. 4-Chloro-5-isopropyl-7H-pyrrolo[2>3-d]pyrimidin-2-ylamine
A mixture of 2-amino-5-isopropyl-3,7-dmydro-pyrrolo[2,3-d]pyrimidin-4-one and acetic anhydride (20 mL) was heated to reflux for 3 h and evaporated. The residue was treated with BnNEt3Cl (8.99 g, 40 mmol), PhNMe2 ( 4.9 mL) and POCl3 (17 mL, 120 mmol) in CH3CN (100 mL) at 100 °C for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (80 mL x 3), and evaporated to give an oil which was digested with methanolic 4N HC1 (50 mL) at 50 °C for 2 h. After cooling, and neutralization to pH 7 with 2N NaOH, the solid was collected by filtration and dried to give 4-chloro-5-isopropy1-7H-pyrrolo[2,3-d]pyrimidin-2-ylamhie (1.88 g, 45%). HPLC Rt: 5.796 min. 1H-NMR (DMSO-d6): δ II. 170 (s, 1H), 6.82 (s, 1H), 6.42 (s, 2H), 3.24 (7, 1H), 1.25 (s, 3H), 1.23 (s, 3H).
Step 4. 4-Chloro-5-isopropyl-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
A suspension of 4-chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (105 mg, 0.5 mmol), 2-chloromethyl-4-mettioxy-3,5-dimethyl-pyridine (93 mg, 0.5 mmol) and K1CO3 (85 mg, 0.6 mmol) in dry DMF (1 mL) was heated to 45 °C overnight, Work-up (EtOAc), evaporation, and purification by preparative TLC ( MeOH/CH2Cl2 10:1) gave 4-chloro-5-isopropyl-7-(4-methoxy-3,5-dimethyl-pyridiri-2-yhnethyl)-7H-pyrro3o[2,3-dJpyrimidin-2-ylamine (36 mg). HPLC Rt: 5.867 min, 1H-NMR (DMSO-ds): δ 8.07 (s, 1H), 6.74(s, 1H), 6,5I(s, 2H), 5.22 (s, 2H), 3.70 ps, 3H), 3.23 (7,1H), 2.21 (s,3H),2.15(s,3H).Example 44. 4-chloro-7-(4-chloro-3-methyl-pyridin-2-ylmethyl)-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidln-2-ylamlne
(Scheme Removed)The title compound was obtained by alkylatton of 4-chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine with 4-chloro-2-chloromethyl-3,5-dimefliyl-pyridine according to the general procedure 1.3. HPLC Rt: 6,997 min. 1H-NMR (CDCl3): δ 8.27 (s, 1H), 6,61 (s, 1H), 5.33 (s, 2H)t 5.09 (s, 2H), 3.35 (7,1H), 2.35 (s, 6H), 1.25 (a, 3H),
1.23 (s,3H).
Example 45. 4-Chloro-7-(4-chloro-3-methyl-1-oxy-pyridin-2-ylmethyl)-5-isopropyI-7H-pyrrolo[2,3-d]pyrimidln-2-ylamine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-5-isopropyl-7H-pyrtolo[2,3-d]pyrimidin-2-ylamine with 2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according to the genera! procedure 1.3. HPLC Rt: 6,753 min. 1H-NMR (DMSO-d6): δ 8.37 (s, 1H), 7.03 (s, 1H), 6.63 (s, 2H), 5.40 (s, 2H), 3,20 (7, 1H), 2.59 (s, 3H), 2.27 (s} 3H), 1.20(8,311), 1.19 (s,3H).Example 46. 4-Chloro-5-(2-isobutylamino-ethyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethy])-7H-pyrrolo[2,3-(l]pyrimidin-2-ylamine
(Scheme Removed)Step 1, 4-(tert-ButyI-diphenyl-silanyloxy)-butan-l~ol
A mixture of/BuPh2SiCl (25 mL, 98 mmol), 1,4-butanediol (25 mL, 281 mmol), iPrNEti (50 mL, 303 mmol) and CH2CI2 (50 mL) was stirred at rt for 14 h, concentrated, diluted with diethyl ether, washed with water (3 x) and brine. Drying (Na2SO4) and concentration afforded the title compound as a clear oil (29.8 g, 93%) which was used without further purification. Rf(EtOAc:hexane 1:4)0.3. 1H-NMR (CDCl3): δ7.71 (dd, 4H), 7.43 (m, 6H), 3.74 (t, 2H), 3.70 (q, 2H), 2.10 (br. t, 1H), 1.69 (m,4H), 1.08 (s, 9H).
Step 2. 4-(tert-Butyl-diphenyl-sitanyloxy)-butyraldehyde
A solution of 4-(tert-butyl-diphenyI-silanyloxy)-butan-l-ol (29.8 g, 91 mmol) in CH1CI1 (70 mL) was added to a slurry of PCC (21.5 g, 100 mmol), celite (50 g) and CH2CI2 (300 mL). The mixture was stirred for 2 h at rt, and the celite was removed by filtration and washed with CHjCfc (300 mL). Concentration and chromatography (EtOAc/hexane 1:4) afforded the title compound as a clear oil (22.2 g, 75%). Rf
(EtOAc:hexane 1:4) 0.7. 1H-NMR (CDCl3): δ 9.82 ft, IH), 7.68 (dd, 4H), 7.41 (m, 6H), 3.71 ft 2H), 2.57 (t, 2H), 1.91 (q, 2H), 1.07 (s, 9H),
Step 3. 2-Bromo-4-(tert-butyl-diphenyl-silanyloxy)-butyraldehyde
A mixture of 4-(tert-butyl-diphenyl-silanyloxy)-butyra1dehyde (22,2 g, 68 mmol), 5,5-dibromobarbituric acid (12.1 g, 43 mmol) and CH2CI2 (80 mL) was treated with 70% aq HBr(l mL, 14 mmol) and stirred at rt for 1 h. The by-product (barbituric acid) was removed by filtration and washed with CH2CI2 (100 mL). The combined organic layers were washed (lNNa2S2O3, 5% NaHC03, half-sat. brine) and dried (Na2SO4). Concentration gave the title compound as a clear oil (25.3 g, 92%) which was used without further purification. Rf (EtO Ac:hexane 1:4) 0.7. 1H-NMR (CDCl3): δ 9.55 (d, 1H), 7.68 (dd, 4H), 7.41 (m, 6H), 4.60 (ddd, 1H), 3.84 (m, 2H), 2.35 (m, 1H), 2.10 (ra, IH), 1.07 (s,9H).
Step 4. 2-Amino-5-[2-(tert-butyt-diphenyl-silanyloxy)-emyl]-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one
The title compound was obtained by treating 2-bromo-4-{tert-butyl-diphenyl-silanyIoxy)-butyraidehyde (25, 3 g, 62 mmol) with 2,4-diarmno-6-hydroxypyrimidine (10.2 g, 124 mmol) according to the general procedure 1.1 (23,4 g, 87%). HPLC Rt: 6.981 min. 1H-NMR (CDC13): δ 10.67 (s, IH), 10.14 (s, IH), 7.55 (m, 4H), 7.38 (m, 6H), 6.37 (s, IH), 5.98 (s, 2H), 3.86 (t, 2H), 2.86 (t, 2H),0.95 (s, 9H).
Step 5. N-{7-AcetyI-5-[2-(tert-butyI-diphenyl-silanyloxy)-ethyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-acetamide
A solution of 2-amino-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyi)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (22.7 g, 52 mmol) in AcjO (200 mL) was heated to 110 °C for 2.5 h, concentrated,diluted with toluene (300 mL) and concentrated again to afford the title compound to afford the title compound as a crude brown oil (27 g) which was used without further purification. An aliquot was purified by chromatography for characterization. HPLC Rt: 8.349 min. 1H-NMR (CDCI3): δ 11.77 (s, IH), 8.81 (s, 1H), 7.61 (dd, 4H), 7,30 (m, 7H), 6.37 (s, IH), 4.00 (t, 2H), 3.02 (t, 2H), 2.70 (s, 3H), 2.23 (s, 3H), 1.04 (s,9H).Step 6. N-{7-Acetyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-acetamide
A solution of crude N-{7-acetyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-4-oxo-4,7-dihydro-SH-pyrrolo[2,3-d]prrimidin-2-yl}-acetamide (26.4 g, 51 mmol), BnNEt3Cl (23.2 g, 102 mmol), PhNMe2 (19.6 mL, 153 mmol) and POCI3 (9.3 mL, 77 mmol) in CH3CN (100 mL) was heated to 80 °C for 1.5 h. The mixture was diluted with EtOAc (800 mL), washed (sat NaHCOj, brine) and concentrated to afford the title compound as an oil (46 g) which was used without further purification. An aliquot was purified by chromatography for characterization. HPLC Rt: 8.562 min. 1H-NMR (CDCl3): δ 8.05 (s, 1H), 7.68 (s, 1H), 7.57 (dd, 4H), 7.40 (m, 6H), 3.99 (t, 2H), 3.06 (t, 2H), 2.98 (s, 3H), 2.52 (s, 3H), 1.04 (s, 9H).
Step 7. N-{5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-acetamide
A solution of crude N-{7-acetyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidm-2-yl}-acetamide (46 g) in MeOH (ISO mL) was treated with K2CO3 (8.0 g, 58 mmol) at rt for 15 min. Filtration, concentration, and chromatography (EtOAc/hexane 1:1) afforded the title compound as an oil contaminated with residual PhNMe2 from step 6. The oil was diluted with EtOAc (40 mL) and treated with hexane (40 mL) to obtained the desired product as a pale yellow precipitate (4.2 g, 16% over 3 steps). HPLC Rt: 8.558 min. 1H-NMR (CDC13): δ 11.75 (br, s, 1H), 11.35 (br. s, 1H), 7.60 (dd, 4H), 7.37 (m, 6H), 3.97 (t, 2H), 3.10 (t, 2H), 2.57 (s,3H), 1.06 (s, 9H).
Step 8. N-[5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmetiiyl)-7H-pyrrolo[2,3-d]pyrimidin-
2-yl]-acetamide
A mixture of N-{5-[2-(tert-butyl-diphenyl-silanyloxy)-ethylj-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-acetamide (344 mg, 0.70 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyI-pyridme hydrochloride (175 mg, 0.77 mmol), K2CO3 (516 mg, 3.7 mmol) and DMF (3.0 mL) was stirred at rt overnight. Work-up (EtOAc/water; brine) afforded the title compound as an off-white solid which was used without further purification (516 mg, "115%"). HPLC Rt: 8.419 min. 1H-NMR(CDCl3): S 8.20 (s, 1H),
7.95 (s, 1H), 7.55 (dd. 4H), 7.32 (m, 6H), 7.04 (s, IH), 5.37 (s, 211), 3.91 (t, 2H), 3.73 (s, 3H), 3.06 (t, 2H), 2.57 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 0.97 (s, 9H).
Step 9. 5-[2-(tert-Butyl-diphenyI-silanyloxy)-ethyI]-4-chloro-7-{4-methoxy-3,5-imethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-
2-ylamine
A solution of N-[5-[2-(tert-Butyl-dipheny]-silanyIoxy)-ethyl]-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-acetamide (511 mg) in THF (3 mL) and MeOH (3 mL) was treated with NaOH 2M (3 mL) at 45 °C for 1.5 h. Work-up and chromatography (EtOAc/hexane 1:1) afforded the title compound as a white powder (290 mg, 69% over 2 steps). HPLC Rt: 8,198 min. lH-NMR (CDCl3): δ 8.20 (s, IH), 7.57 (dd, 4H), 7.40 (m, 2H), 7.32 (m, 4H), 6.69 (s, IH), 5.26 (s, 2H), 4,90 (s, 2H), 3.98 (t, 2H), 3.66 (s, 3H), 3.00 (t, 2H), 2,24 (s, 3H), 2.18 (s, 3H), 0.96 (s, 9H).
Step 10. 2-[2-Amino-4-chloro-7-(4-niethoxy-3,5-Qimethyl-pyridin-2-ylmethy1)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethanol
A solution of 5-[2-(tert-buryl-diphenyl-silanyloxy)-emyl]-4-chloro-7-(4-meihoxy-3,5-dimethyl-pyridin-2-yImethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (246 mg, 0.41 mmol) in THF (5 mL) was treated with TBAF (IN in THF, 0.5 mL, 0.50 mmol) at rt for 1 h. Work-up (EtOAc/water, brine) gave the crude product as an oil, which was diluted with diethyl ether (15 mL) whereupon the desired product precipitated out of solution as a white powder (110 mg, 74%). HPLC Rt: 4.474 min. 1H-NMR (CDCl3): δ 8.21 (s, IH), 6.78 (s, IH), 5.30 (s, 2H), 4.93 (s, 2H), 3.87 (t, 2H), 3.76(s, 3H), 3.03 (t, 2H), 2.26 (s, 3H),2.23(s,3H).
Step 11. Methanesulfonic acid 2-[2-amino-4-ch1oro-7-(4-me£hoxy-3,5-,dimethyl-pyridin-2-ylmethyl)-7H-pyrroIo[2,3-d]pyrimidin-5-yl]-ethyl
ester
A solution of 2-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-ethanol (11,6 mg, 0.031 mmol) and EtjN (30 ul, 0.22 mmol) in THF (2 mL) was treated with MsCl (t 1 uL, 0.14 mmol) at rt for 15 min to give a solution of the title compound which was used without further purification. to a separate experiment, the material was purified by preparative TLC (EtOAc 100%).HPLC Rt: 4.765 min. 1H-NMR (CDCl3): δ 8.22 (s, 1H), 6.80 (s, 1H), 5.31 (a, 2H), 4.93 (s, 2H)> 4.42 (t, 2H), 3.77 (s, 3H), 2.98 (t, 2H), 2.85 (s, 3H), 2.23 (s, 3H), 2.07 (s, 311).
Step 12. 4-Chloro-5-(2-isobutylamino-ethyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-y]methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine
The solution of methanesulfonic acid 2-[2-amino-4-chloio-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyriniidin-5-yl]-ethyl ester in THF obtained from step 11 was diluted with i-BuNIfc (4 mL) and heated to 50 °C for 15 h. Concentration, work-up(EtOAc/NaHCOs sat.; brine) and preparative TLC (MeOH:Et3N:CH2Cl2 7:3:100) gave the title compound as a colorless oil (6 mg, 50 %). HPLC Rt: 4,263 min. 1H-NMR (CDCl3): δ 8.20 (s, 1H), 6.79 (s, 1H), 5.29 (s, 2H), 4.97 (s, 2H), 3.76 (s, 3H), 3.04 (t, 2H), 2,96 (t, 2H), 2.53 (d, 2H), 2.26 (s, 3H), 2.22 (a, 3H), 1.85 (OCL.1H), 0.90 (d,6H).
Example 47. 2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo [2,3-d] pyrimldln-6-one
(Scheme Removed)The title compound was obtained by condensation between (2-amino-4,6-dichloro-pyrimidin-5-yl)-acetic acid ethyl ester and C-(4-methoxy-3,5-dimethyl-pyridin-2-yl)-memylamine according to the general procedure 1.2, HPLC Rt: 4.893 min.'H-NMR (CDC13): δ 8.07 (s, 1H), 5.03 (s, 2H), 4.92 (s, 2H), 3.77 (s, 3H), 357 (s, 2H), 2.31 (s, 3H), 2.20 (a, 3H).
Example 48. 2-Amino-4-chloro-7-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
(Scheme Removed)The title compound was obtained by alkylation of 4-chloro-pyrroIo[2,3-d]pyrimidin-6-one with 2-chlororaethyl-4-chloro-3>5-dimethyl-pyridine according to the general procedure 1.3. HPLC Rt: 5.367 min-1H-NMR (CDC13): δ 8,09 (s, 1H), 5.02 (st 2H), 4.96 (s, 2H), 3.57 (s, 2H), 2.45 (s, 3H), 2.29 (s, 3H).
Example 49. 2-AmiD0-4-chloro-7-(3,5-dimethyl-4-methoxy-l-oxy-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3~d]pyrimidin-6-one
(Scheme Removed)The title compound was obtained by oxidation of 2-amino-4-chloro-7-(4-methoxy-3,5-dimemyl-pyridin--2-yImethyl)-5J7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with m-CPBA according to the general procedure 2.1. HPLC Rt: 4.763 mill. 1H-NMR (DMSO-d6): δ 8.01 (s, 1H), 7.01 (s, 2H), 4.93 (3, 2H), 3.73 (s, 3H), 3.46 (s, 2H), 2.40 (s, 3H),2.19(s,3H).
Example 50. 2-Amino-4-chloro-7-(4-chloro-3,S-dimethyl-l-oxy-pyridin-2-ylmethyI)-5,7-dihydro-pyrrolo[2,3-d]pyrimidiii-6-one
(Scheme Removed)
The title compound was obtained by oxidation of 2-amino-4-chloro-7-(4-chloro-3,5-dimethyl-pyridin-2-yImethyl)-5J-dibydra-pyrrolo[2,3si]pyrimidin-6-onewithm-CPBA according to the general procedure 2.1. HPLC Rt: 4.90 min.1H-NMR (CDCI3/CD3OD): δ 7.96 (s, 1H), 5.12 (s, 2H), 3.38 (s, 2H), 2.47 (s, 3H), 2.27 (s, 3H).
Example 51. 2-Amino-4-chIoro-7-(3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one
(Scheme Removed)The title compound was obtained by condensation between (2-Amino-4,6-
dichloro-pyrimidin-5-y])-acetic acid ethyl ester and 3,4,5-Trimethoxy-benzylamine according to the general procedure 1.2. HPLC Rt: 6.391 min.1H-NMR (CDCl3): δ 6.70 (s, 2H), 5.14 (s, 2H), 4.77 (s, 2H), 3.84 (s, 6H), 3,81 (s, 3H), 3.47 (s, 2H).
Example 52. 2-Amino-4-chloro-7-(2-bromo-3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrroIo{2>3-d]pyrimidin-6-one
(Scheme Removed)
The title compound was obtained by treating 2-amino-4-chloro-7-(3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo[2f3-d]pyrimidin-6-one with bromine in acetic acid according to the general procedure 3.1. HPLC Rt: 7.150 min.1H-NMR (CDCI3): δ 6.49 (s, 1H), 5.14 (s, 2H), 4.94 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.75 (s, 3H), 3.55 (s, 2H).
Example 53. 2-Amino-4-chloro-7-(4-mcthoxy-3,5-dlmethyl-pyridin-2-ylmethyl)-5-methyl-5,7-dinydro-pyrrolo(2,3-d]pyrimidiin-6-one
(Scheme Removed)The title compound was obtained by alkylation of 2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with iodomethane according to the general procedure 1,5. HPLC Rt: 4.091 min.1H-NMR (CDCl3): δ 8.01 (s, 1H), 5.15 (s, 2H), 4.93 (d, 1H), 4.87 {d, 1H), 3.76 (s, 3H), 3.51 (s, 1H), 2.29 (s, 3H), 2.20 (a, 3H), 1.78 (s, 3H).
Example 54. 2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,5-dlmethyl-5,7~dihy dro-pyrrolo [2,3-d] pyr imidln-6-one
(Scheme Removed)The title compound was obtained by alkylation of 2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with iodomethane according to the general procedure 1.5, HPLC Rt: 5.002 min 1H-NMR (CDCl3): δ 8.02 (s, 1H), 5.02 (s, 2H), 4.90 (s, 2H), 3,75 (s, 3H), 2,29 (s, 3H), 2.18 (s, 3H>f 1.53 (S.6H).
Example 55. 2-Amino-4-chloro-7-(2-bromo-3,4,5-trimethoxy-benzyl)-5,5-dimethyl-
5,7-dihydro-pyrrolo [2,3-d] pyrimidin-6-one
(Scheme Removed)The title compound was obtained by alkylation of 2-amino-4-chloro-7-(3,4,5-trimetboxy-benzyl)-5,7-dihydio-pynolo[2,3-d]pyrimidin-6-with iodomefhane according to the general procedure 1.5. HPLC Rt: 6.944 mm1H-NMR (CDCl3): δ 6.34 (s, 1H), 5.09 (s, 2H), 4.93 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.71 (s, 3H), 1.52 (s, 6H).
Example 56. 4-Chloro-5-hydroxy-2-imino-7-(4-methoxy-3,5-dimethyl-pyridln-2-ylmethyl)-2,7-d(hydro-pyrroIo[2,3-d]pyrimfdfn-6-one
(Scheme Removed)The title compound was obtained by oxidation of 2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridm-2-ymiethyl)-5,4-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with selenium dioxide according to the general procedure 1.6. HPLC Rt: 4.294 imVH-NMR (CDCI3): δ 8.04 (s, 1H), 5.93 (s, 1H), 5.76 (s, 1H), 4.97 (s, 2H), 3.765 (s, 3H), 2.29
(s, 3H), 2.20 (s, 3H).
Example 57. 4-Chloro-5-hydroxy-2-imino-7-(3,4,5-trimethoxy-benzyl)-2,7-dihydro-pyrrolo [2,3-d]py rimidin-6-one
(Scheme Removed)The title compound was obtained by oxidation of 2-amino-4-chloro-7-(3,4,5-trimethoxy-benzyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one with selenium dioxide according to the general procedure 1.6. HPLC Rt: 6.156 min.1H-NMR (CDCh): δ 6.68 (s, 2H), 6.12 (s, 1H), 5.93 (s, 1H), 4.84 (s, 2H), 3.86 (s, 6H), 3.83 (s, 3H).
Example 58. 4-Chloro-5-hydroxy-2-imino-7-(2-bromo-3,4,5-trimethoxy-benzyl)-2,7-dihydro-pyrrolo[2,3-dlpyrimidln-6-one
(Scheme Removed)
The title compound was obtained by oxidation of 4-chloro-5-hydroxy-2-imino-7-(2-bromo,4,5-trimethoxy-benzyl)-2,7-dinydio-pyrrolo[2,3-d]pyrimidin-6-one according to the general procedure 1.6. HPLC Rt: 6.230 min,1H-NMR (CDC13): δ 6.57 (s, 1H), 6.14 (s, 1H), 5.91 (s, 1H), 5.01 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.78.(s, 3H).
BIOLOGY EXAMPLES
Example A. rHSP90 Competitive Binding Assay
Five microgram of purified rHSP90 protein (Slressgen, BC, Canada, #SPP-770) in phosphated buffered saline (PBS) was coaled on 96 well plates by incubating overnight at 4°C. Unbound protein was removed and the coated wells were washed
wice with 200 µl PBS, DMSO controls (considered as untreated samples) or test compounds were then added at 100-30-10-3-1-0.3 µM dilutions (in PBS), the plates mixed for 30 seconds on the plate shaker, and then incubated for 60 min. at 37 °C. The wells were washed twice with 200 µL PBS, and 10 µM biotinylated-geldanamycin (biotin-GM) was added and incubated for 60 min. at 37 °C, The wells were washed again twice with 200 µL PBS, before the addition of 20 µg/mL streptavidin-phycoerythrin (streptavidin-PE) (Molecular Probes, Eugene, OR) and incubation for 60 min. at 37°C. The wells were washed again twice with 200 µL PBS. Relative fluorescence units (RFU) was measured using a SpectraMax Gemini XS Spectrofluorometer (Molecular Devices, Sunnyvale, CA) with an excitation at 485 nm and emission at 580 nm; data was acquired using SOFTmax®PRO software (Molecular Devices Corporation, Sunnyvale, CA). The background was defined as the RFU generated from wells that were not coated with HSP90 but were treated with the biotin-GM and streptavidin-PE. The background measurements were substrated from each sample treated with biotin-GM and streptavidin-PE measurements before other computation. Percent inhibition of binding for each sample was calculated from the background subtracted values as follows;
% binding inhibition = [RFU untreated - RFU treated]/RFU untreated] x 100.
Example B. Cell Lysate Binding Assay
MCF7 breast carcinoma cell lysates were prepared by douncing in lysing buffer (20 mM HEPES, pH 7.3, 1 mM EDTA, 5 mM MgCl2, 100 mM KC1), and then incubated with or without test compound for 30 mins at 4 "C, followed by incubation with biotin-GM linked to BioMag™ streptavidin magnetic beads (Qiagen) for 1 hr at 4 °C. The tubes were placed on a magnetic rack, and the unbound supernatant removed. The magnetic beads were washed three times in lysis buffer and boiled for 5 mins at 95 °C in SDS-PAGE sample buffer. Samples were analyzed on SDS protein gels, and Western blots done for rHSP90. Bands in the Western Blots were quantitated using the Bio-rad Fluor-S Multilmager, and the % inhibition of binding of rHSP90 to the biotin-GM was calculated.
The lysate binding ability of selected compounds of the invention based on the above assay is summarized in Table 5. The IC50 reported is the concentration of test
compound needed to achieve 50% inhibition of the biotin-GM binding to rHSP90 in the MCF7 cell lysates.
Example C. HER2 Degradation Assay
MCF7 breast carcinoma cells (ATCC) were grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) and 10 mM-HEPES, and plated in 24 well plates (50% confluent). Twenty-four hrs later (cells are 65-70% confluent), test compounds were added and incubated overnight for 16 h, For the less potent compounds, the amounts added were 100 µM, 30 µM, l0 µM and 1 µM, and for more potent compounds, the amounts added were 1 µM, 0,3 µM, 0.1 µM, 0.03 µM, 0.01 uM and 0.003 uM, The wells were washed with 1 mL phosphate buffered saline (PBS), and 200 µL trypsin was added to each well. After trypsmization was complete, 50 uL of FBS was added to each well. Then 200 uL cells was transferred to 96 well plates. The cells were pipetted up and down to obtain a single cell suspension. The plates were centrifuged at 2,500 rpm for 1 min using a Sorvall Legend RT™ tabletop centrifuge (Kendro Laboratory Products, Asheville, NC). The cells were then washed once in PBS containing 0.2% BSA and 0.2% sodium azide (BA buffer). Phycoerythrin (PE) conjugated anti HER2/Neu antibody (Becton Dickinson, #340552), or PE conjugated anti-keyhole limpet hemacyanin [KLH] (Becton Dickinson, #340761) control antibody was added at a dilution of 1:20 and 1:40 respectively (final concentration was 1 µg/mL) and the cells were pipeted up and down to form a single cell suspension, and incubated for 15 mins. The cells were washed twice with 200 uL BA buffer, and resuspended in 200 µL BA buffer, and transferred to FACSCAN tubes with an additional 250 µL BA buffer. Samples were analyzed using a FACSCalibur™ flow cytometer (Becton Dickinson, San Jose, CA) equipped with Argon-ion laser that emits 15 mW of 488 nm light for excitation of the PE fluorochrome. 10,000 events were collected per sample. A fluorescence histogram was generated and the mean fluorescence intensity (MF1) of each sample was determined using Cellquest software. The background was defined as the MFI generated from cells incubated with control IgG-PE, and was subtracted from each sample stained with the HER2/Neu antibody. Cells incubated with DMSO was always done as untreated controls since the compounds were resuspended in DMSO. Percent degradation of HER2 was calculated as follows:
% HER2 degraded - [(MF1 untreated cells - MF1 treated cells)/MFl untreated cell] x 100
The HER2 degradation ability of selected compounds of the invention based on this assay is summarized in Table 5. IC50 is defined as the concentration at which there was 50% degradation of the HER2/Neu protein.
Example D: MTS Assay
MTS assays measures the cytotoxicity of geldanamycin derivatives. MTS (3-(4,5-dimethylthiazoI-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium is a tetrazolvum dye that is converted to a formazan product by dehydrogenase enzymes of metabolically active cells (Corey, A. et al, "Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays m culture," Cancer Commun. 1991, 3, 207-212). Cells were seeded in 96 well plates at 2000 cells/well and allowed to adhere overnight in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum. The final culture volume was 100 ul Viable cell number was determined by using the Celltiter 96 AQueous Non-radioactive Cell Proliferation Assay (Promega, Madison WI). The MTS /PMS (phenazine methosulfate) solution was mixed at a ratio of 20:1, and 20 µL was added per well to 100 µl of culture medium. Aiter 2-4 hours, the formation of the formazan product was measured at 490 run absorbance using a multiwetl plate spectrophotometer. Background was determined by measuring the Abs 490 nm of cell culture medium and MTS-PMS in the absence of cells and was subtracted from all values. Percent viable cells was calculated as follows:
% viable cells - (Abs at 490 nm treated cells / Abs at 490 nm untreated cells) x 100
The effect of selected compounds of the invention on MCF7 breast carcinoma cells according to the MTS assay is summarized in Table 5, IC50 was defined as the concentration of the compound which gave rise to 50% viable cell number.
TABLE 5. Biological Activities of Pyrrolopyrimidines (Formula I)


(Table Removed)
ND, not determined.
II, Preparation of Aminopurines and related Analogs (Compounds of Formulam
A. Materials and Methods
The chemical reagents used to create the novel products of the invention below are all available commercially, e.g., from Aldrich Chemical Co,, Milwaukee, WI, USA. Otherwise their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein.
The final compounds were usually purified by preparative TLC (silica gel 60 A, Whatman Partisil PK6F) or flash chromatography (silica gel 60 A, EMD Chemicals) using EtOAc/hexane or MeOH/CH2Cl2 as eluents. Rf s were measured using silica gel TLC plates (silica gel 60 A, EMD Chemicals), Analytical HPLC chromatograms were obtained using a CIS column (Agilent Zorbax 300SB-C18; 5 microns; 4.6 mm x 150 mm). A gradient was applied between solvent A (0.1% TFA in H20) and solvent B (0.5% TFA in CH3CN) increasing the proportion of A linearly from 5% (r=0) to 100% (t=7.00 min), with a constant flow rate of 1 mL/min. The samples were diluted to typically 0.1-1 mg/mL in MeOH or CH3CN and the injection volumes were typically 10 µL. The column was not heated, and UV detection was effected at 254 nm, 1H-NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer.
The chemical names were generated using the Beilstein Autonom 2.1 software.
B. General procedure
1. General procedures to manipulate the purine ring
General procedure 1,1: Alkylation of purines atN-9
A suspension of the purine (3 mmol), (hetero)aryl-CH2-halide (3 mmol, if needed it can be added in batches) and K2CO3 (3.3 mmol) in dry DMF (15 mL) was heated to 40-60 °C for 3 to 10 h. Work-up (EtOAc) and purification by prepartive TLC or flash chromatography (EtOAc/hexane or MeOH/CH2Cl2) yielded the pure N-9 alkylated
product.General procedure 1.2: Halogenation of purines at C-8
A solution of purine in MeOH/THF/acctate buffer (1N in each AcOH and AcONa) was treated with Bri (1.3-equiv. 1M in CHCh) at room termperture (r.f) for 16 h. Evaporation, work-up (EtOAc), drying (MgSO4) and flash chromatography afforded the desired 8-bromopurine.
General procedure 1.3: Nucleophilic substitution of purines at C~6
For details, see J. Med. Chem. 1999, 42,2064-2086.
A) Sulfanyl derivatives: A suspension of 6-chloropurine and sodium or potassium thiolate in THF was heated to reflux for 6-24 hours. Work-up (EtOAc) and flash chromatography afforded the desired 6-sulfanylpurine.
A) Alkoxy derivatives: A suspension of 6-chloropurine and alkoxide in the appropriate alcohol was heated to reflux for 1-16 hours before quenching with water. Evaporation, work-up (EtOAc), and flash chromatography afforded the desired 6-alkoxypurine,
A) Amino derivatives: A solution of 6-chloropurine and alkylamine in MeOH was heated in a sealed tube to 100 °C for 16 hours. Evaporation, work-up (EtOAc), and flash chromatography afforded the desired 6-alkoxypurine.
General procedure 1.4: Methylation of purines at C-6
A suspension of 6-chloropurine (0.2 mmol) and tetrakis(triphenylphosphino)-palladium (0.02 mmol) in dry THF (3 mL) was treated with trimethylaluniinum (2M in toluene, 0.45 mmol) under nitrogen. The resulting solution was heated to reflux for 3 h, cooled to r.t, diluted with toluene (5 mL), and quenched with methanol (0,5 mL) followed by ammonium chloride (1 mmol). The mixture was heated to reflux for 2 h and filtered while hot through a Celite plug. Evaporation and purification by prep TLC afforded the 6-methyIpurine. See/ Med. Chem. 1999, 42,2064-2086.
General procedure 1.5: Reductive dehalogenation of 6-halopurine
The 6-halo purine derivative was dissolved in acetic acid and a catalytic amount of 5 % Pd/C was added, and the mixture stirred under H2 atmosphere (1 psi) at r.t for 1 h., evaporation, and purification afforded the dehalogenated derivatives,General procedure 1.6: Acetylation of 2-amino-purines
The 2-amino purine derivative was dissolved in acetic anhydride, treated with a catalytic amount of concentrated sulfuric acid at r.t. for 1 hour. Work-up (EtOAc), evaporation, and purification afforded the 2-acetamido-pyridine.
2. General procedures to manipulate the pyridine ring
General procedure 2.1: Preparation of pyridine N-oxides~
A solution of the pyridine derivative (1.0 mmol) in dichloromethane or chloroform (5 mL) was cooled by means of an ice-bath, treated with m-CPBA (1.1 to 3 mmol) in three portions, and allowed to warm to r.t The mixture was extracted with dichloromethane and washed with aqueous NaOH, followed by water. Drying (Na2SO4) and concentration afforded the pyridine N-oxide.
General procedure 2.2: Preparation of 2-(acetoxymethyl)pyridines
A solution of the 2-methyl pyridine N-oxide (1.0 mmol) in acetic anhydride (5 mmol) was heated to reflux for 0.5 h. Work-up (EtOAc), drying (MgSOij), evaporation and purification by preparative TLC or flash chromatography afforded the 2-
(acetoxymethyl) pyridine.
General procedure 2.3: Preparation of 2-(hydroxymethyl)pyridines
A suspension of 2-acetoxymethyl-pyridine derivative and solid K2CO3 in methanol was heated to 50 °C for 5-30 min. Evaporation, work-up (EtOAc), and drying (MgS04) afforded the 2-(hydroxymethyI)pyridine.
General procedure 2.4: Preparation of 2-(chloromethyl)pyridines
A suspension of 2-hydroxymethyl-pyridine (10 g) in POCI3 (30 mL) was stirred at 110 °C for 1.5 h. The resulting viscous oil was cooled to r.t. and poured onto ice water (500 g). The pH was adjusted to 10 with solid KOH. Work-up (CHCl3), drying (MgSO4) and evaporation gave the 2-(chloromethyl)pyridine, usually as a purple oil or solid, which was used without purification.
General procedure 2.5: Preparation of 2-(brornornethyl)pyridines
A solution of 2-(hydroxymethyl)pyridine (1.0 mmol) and triphenyl phosphinc (1.2 mmol) in dichloromethane or chloroform (5 mL) was cooled to 0 °C. A solution of
CBr4 (1.5 mmol) in dichloromethane or chloroform was added dopwise, and the resulting mixture was stirred at 0 °C for 0,5-1 h. Work up followed and purification by flash chromatography afforded the 2-(bromomethyI)pyridine.
General procedure 2,6: O-alkylation of 3- or 4-hydroxypyridines
A mixture of hydroxypyridine, alkyl halide (1.1 equiv.), base (K2CO1, KOH or NaH 1.2-2 equiv.) and solvent (THF or DMF) was stirred at 23-80 °C for 5-30 min. Work-up (EtOAc), drying (Na2SO4) and evaporation gave the crude 4-{alkoxy)pyridme, which was purified by preparative TLC or flash chromatography. General procedure 2.7: Preparation of salts.
Method 1: The free base (40 mmo!) was heated in MeOH (1:6, 300 mL) until it dissolved. A solution of H3PO4 in MeOH (40 mmol) was added dropwise at r.t. The mixture was stirred for 10 min., and the solvent was evaporated to give the pyridinium phosphate as a glassy white solid. The following solvents could also be used: THF, EtOH, or i-PrOH.
Method 2: The free base (50 mmol) was heated in i-PrOH (6 L) until it dissolved. The solution was allowed to cool to r.t. and a solution of HC1 in i-PiOH (75 mmol) was added slowly dropwise. The hydrochloride crystallized out of solution within a few minutes, and was collected by filtration, washed (acetone) and dried. The sulfate and mesylate salts were also prepared in this manner.
The hydrochloride salts can also be made Toy adding CH3COCI to the alcoholic solution of the pyridine or free base derivative.
Method 3; To a suspension of free base (5 mmol) in MeOH (50 mL) was added a solution of methane sulfonic acid in MeOH (75 mmol) was added slowly dropwise. The mixture became clear within a few minutes, upon addition of i-PrOH (50-100 ml) the salt precipitated out and was collected by filtration, washed with i-PrOH, ether and dried.
These methods can be applied to prepare all other salts.
3. General procedure fo manipulate benzene rings
General procedure 3.1: Halogenation of benzene rings.
Variant 1: A solution of the aromatic compound in MeOH/THF/acetate buffer (IN in each AcOH and AcONa) was treated with Bra (1.3 equiv) at r.t, for 5 min. The
xcess bromine and solvent were removed on 8 rotary evaporator. Work-up (CHCb) and flash chromatography afforded the desired bromobenzene,
Variant 2: A solution of the aromatic compound (7 mmol) and N-halosuccinimide (NCS, NBS, or N1S, 1.06 equiv) in acetic acid (40 mL) was heated to 40-90 °C for 0.3-1 h. Evaporation, work-up (EtOAc) and flash chromatography afforded the desired halogenated benzene,
General procedure 3.2: Preparation of benzylic alcohols
Benzoic actd derivatives were reduced to the corresponding benzylic alcohols according to the procedure given by Bhaskar et al. / Org. Chem. 1991,56, 5964-5965.
4. Specific Examples
Example 59. N-9 and N-7 alkylatioii of purines,
A suspension of purine {28.4 mmoles), benzyl halide (28.7 mmoles) in dry DMF (80 mis) was treated with K2C03 (31.2 mmoles) at 70 °C for Mrs. Extraction with EtOAc and chromatography EtOAc/Hexanes (1:1) yielded pure N9 and N-7 alkylated products. All HPLC was performed per the following parameters: HPLC Column: Zorbax 300 SB-C 18, 5 microns, 4.6 x 150 mm. HPLC Instrument: Agillent 1100 HPLC Reagent A: 0.1 %TFA/Water HPLC Reagent B: 0.05% TFA/CH3CN HPLC Method: 5%B to 100%B in 7 minutes.
The following compounds were prepared in this manner.
1 6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t. 5,194 mm.
1 6.chloro-9-(4,5-dimethoxy-2-nitro-benzyl)-9H-purin-2-ylamine. HPLC R.t. 5.194 min.
1 6-Chloro-9-(2,5-dichloro-benzyl)-9H-purin-2-ylamine. HPLC R.t. 5.846 min.
1 6-Chloro-9-(2,5-dichloro-benzyl)-9H-purin-2-ylamine. HPLC R,t. 5.982 min.6-Bromo-9-(3,4,5-trimethoxy-benzyl)9H-purin-2-ylamine. HPLC R.t. 4.947 min.
5 6-Chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purine. HPLC R.t. 5.327 min
5 6-Chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylatnine. HPLC R.t. 4.878 min.
5 6-Chloro-9^2,3,5-trifluoro-benzy])-9H-purm-2-ylamine. HPLC~R.t. 5.414 min.
5 6-Chloro-9-{3,5-dichloro-benzyl)-9H-purin-2-ylamine. HPLC R,t 6.074 min.
5 6-Chloro-9-(3,5-dimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t. 5.257 min.
5 9-(2-Bromo-3,5-dimethoxy-ben2yl)-6-chloro-9H-purin-2-ylamine. HPLC R.t. 6.026 min.
5 6-Chloro-9-(2,6-dibromo-3,5-dimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t 6.022 min.
5 6-chloro-9-(3-methoxy-benzyl)-9H-purin-2-ylainJne. HPLC R.t. 5.136 min.
5 6-Chloro-9-(2-chloro-,3,4-dimemoxy-benzyl)-9H-purin-2-y]amine. HPLC R.t. 5.445 min.
5 6-Chloro-9-(2,4-dimethoxy-3-methyl-benzyl)-9H-purin-2-ylamine. HPLC R.t. 5,435 min.
5 6-Cbloro-9-(6-chloro-benzo[l,3]dioxol-5-ylmethy])-9H-purin-2-ylamine. HPLC R.t. 5.506min.
5 6-Chloro-9-(4-methoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t. 5.067 min.
5 4-Chloro-l-(3,4,5-trimethoxy-benzyl)-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine. HPLC R,t. 5.683 min.
5 6-Bromo-9-(2-chloro-3,415-trimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t. 5.676 min.
5 6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine. HPLC R,t. 3.941.
6 9-(2-Bromo-4]5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine, HPLC R.t. 5.458 min.
21 4-Chloro-l-(4-methoxy-3J5-dimethyl-pyridin-2-ylmethyl)-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine. HPLC R.t 4,464 rain.
21 6-Chloro-9-(2J3-dimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t 5.200 min.
21 6-Chloro-9-(3,4-dimethoxy-ben2yl)-9H-purin-2-ylaniine. HPLC R.t 4.753 min.
21 4-(2-Amino-6-ch1oro-purin-9-ylmethyl)-benzoic acid methyl ester. HPLC JLt 5,052 min.
21 6-Chloro-9-(2-fluoro-4,5-dimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t. 4.939 min.
Example 60. Halogenation of purines.
To a solution of purine (6.6 mmoles) in acetate buffer/MeOH/THF or acetic acid or dichloromethane, bromine or N-chlorosuccim'mide or N-Iodosuccinimide (8.7 mmoles) was added. While bromination can be done at room temperature, chlorination and iodination can be done at 60C to 90 C in 2 hours. Same HPLC conditions as stated in Example 59 were used.
The following compounds were prepared in this manner:
1 8-Bromo-6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t 6.150 min.
1 8-Bromo-6-chloro-9-(3,4-dimethoxy-2-nitro-benzyl>9H-purin-2-ylamine. HPLC R.t. 6.040 min.
1 8-bromo-6-chloro-9-(3.4-dichloro-benzyl)-9H-purin-2-ylamine, HPLC R.t. 6.878 min.
1 6-Chloro-9-(2-chloro-3,4,5,-trmiethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t 5.616 min.
1 6-Chloro-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t.S.626 min.
1 6-Bromo-9-(2-brorao-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t. 5.793 min.
7 8-Bromo-9-(2-bromo-3,5-trimethoxy-benzyl)-6-chIoro-9H-purin-2-ylamine. HPLC R.t. 5.720 min.
7 9-(2-Bn)mo-3,4,5-trimethoxy-benzyl)-6-methoxy-9H-purine. HPLC R.t 5.987 min
7 9-(2,6-Dibromo-3,4,5-trimethoxy-benzyl)-6-methoxy-9H-purine. HPLC R.t. 6.676 min
7 9-(2-Bromo-3,4,5-trimeaioxy-benzyl)-6-methoxy-9H-purine. HPLC R.t. 6.248 min
7 9-(2,6-Dibromo-3r4J5-rrimethoxy-benzyl)-6-methoxy-9H-purine. HPLC R.t. 6.952 min
7 6)8-Dichloro-9-(2,6-dichloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t. 6.859 min
7 6-Chloro-9-(2,6-dichloro-3,4t5-trimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t. 6.100 min.
7 6-Chloro-9-(2-iodo-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t. 5.887 min.
Example 61. Displacement of 6-halogenated-purines.
6-haIogenated purines can be replaced by H, R, NHR, OR, SR using known procedures, e.g., as described in J. Med. Chem. 1999,42,2064-2086. Same HPLC conditions as stated in Example 59 were used.
The following compounds were prepared in this manner:
1 9-(3,4,5-Trimethoxy-benzyl)-9H-purin-2-ylamine. HPLC R.t 4.123 min.
1 2 -Amino -9-(2 -bromo-3,4,5 -rrimethoxy-benzyl)-9H-purine-6 -thiol. HPLC R.t. 4.931 min,
1 2-Amino.9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-6-ol. HPLC R,t. 4.610 min,
1 9-(2-Bromo-3,4,5-trimethoxy-benzyl)-6-ethylsulfanyl-9H-purin-2-ylamine. HPLC R.t. 6,039 min.
1 6-Methoxy-9-(3,4,5-trimethoxy-ben2yI)-9H-purine. HPLC R.t. 5.020 min,
1 9-(3,4,5-Trimethoxy-benzyl)-9H-purin-6-ylamme. HPLC R.t 4.248 min.
7 -(3,4,5-Trimethoxy-benzyl)-9H-purine-2,6-diainine. HPLC R.t. 4,209 min.
7 9-(2-Bromo-3,4,5-trimethoxy-benzy1)-6-methoxy-9H-purin-2-ylamine. HPLC R.t. 5.229 min.
7 9-(2-Bromo-3,4,5-trimethoxy-benzyl)-9H-purine-2,6-diamine. HPLC R.t 4.884 min.
7 6-Methoxy-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-yIamine. HPLC R.t. 4.489 min.
7 N-[9-(2-Bromo-3)4,5-trimethoxy-benzyl)-6-methoxy-9H-purin-2-yl]-N-methylacetamide. HPLC R.t. 6.178 min.
Example 62. Acylation of 2-amino-purines
2-amino-purine can be acylated in acetic anhydride with catalytic amount of concentrated sulfuric acid or in acetic acid and catalytic amount of fuming nitric acid at room temperature. Same HPLC conditions as stated in Example 59 were used.
The following compounds were prepared in this manner:
1 N-[6-C^loro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-yl]-acetamide. HPLC R.t. 5.744 min.
1 N-[9-(2-Bromo-3,4)5-trimethoxy-benzyl)-6-chloro-9H-purin-2-yl]-acetamide. HPLC R.t. 5.603 min.
Example 63. N-(9-(2-Bromo-3,4,5-triniethoxy-benzyl)-6-chlro-9H-purin-2-yl]-N-methylacetamide or Methylatton of compound 4.2.
To a suspension of compound 4.2 (Example 62 above) and iodomethane in DMF, NaH was added. Extraction with EtOAc and chromatography yield 5. HPLC R.t. 6.177 min.
Example 64. Synthesis of 6-raethyl purines
The title compound was obtained by suspended purine (0,19 mmole) and tetrakis(triphenylphosphino)-palladium (0.019 mmole) in dry THF (3mls) before treating with trimethylaluminum (2M in toluene, 0.44 mmole) under nitrogen. The solution was reftuxed for 3 hours before cooling down to room temperature. Diluted the reaction
mixture with toluene (5 mis) before quenching the reaction with methanol (0.5 mis) followed by ammonium chloride (1 mmole). The mixture was refluxed for 2 hours and filtered, while hot, on Celite. See./ Med. Chem, 1999,42(12), 2064-2086. The following compounds were prepared in this manner: 6,1 9-(2-Chloro-3,4,5-trimethoxy-benzyl)-6-methyI-9H-purin-2-yIamine. HPLCR.t. 4.800 min.
Example 65: 9-(4-Bromo-3,5-dimethyl-pyridin-2-yl)-6-chloro-9H-purin-2-ylamiDe
The title compound was obtained by alkylating 2-amino-6-chloropurine with 4-bromo-2-bromomemyl-3,5-dimerhyI-pyridine according to the general procedure 1.1. HPLC Rt: 5.301 min. 1H-NMR (CDC13): δ 8.19 The alkylating agent, 4-bromo-2-bromomethyl-3,5-dimethyl-pyridine, could itself be prepared by any of the following three methods:
Method 1
Step I: 2,3,5-Collidine-N-oxide
Oxidation of 2,3,5-collidine according to the general procedure 2.1 gave 2,3,5-coIIidine-N-oxide. Yield: 70%. HPLC Rt: 3.96 rnin. 1H-NMR (CDC13): δ 8.03 (s, 1H), 6.90 (s, 1H), 2.47 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H). m/z (%) 138.2 (M+l, 100%). Rf (20% MeOH/EtOAc): 0.35.
Step 2: 4-Bromo-2,3,5-collidine-N-oxide
2,3,5-collidine-N-oxide (1.3 g, 10 mmol) and K2CO3 (2.9 g, 20 mmol) were suspended in 10 mL of CCI4. Bromine (1 mL, 20 mmol) was added dropwise, and the reaction mixture was heated to reflux for 2 h. Work-up (EtOAc).and flash chromatography (10% MeOH/EtOAc) afforded the product as a solid (1.05 g, 51 % yield). HPLC Rt: 5.239 min. 1H-NMR (CDCI3): δ 8.06 (s, 'H), 2.56 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H). m/z (%) 216.2 (M+l, 100%), 218.2 (M+3,100%). Rf (20% MeOH/EtOAc): 0.45.
Step 3: Acetic acid 4-bromo-3,5-dimethyI-pyridin-2-yl methyl ester
4-Bromo-2,3,5-collidine-N-oxide (0.25g, 11 mmol) was dissolved in acetic anhydride (5 mL) and the solution was heated to reflux for 30 min. Work-up and flash chromatography (50% Hexane/EtOAc) afforded the product (0.27 g, 96% yield), Rf (50% Hexane/EtOAc): 0.70. HPLC Rt: 4.759 min. 1H-NMR (CDCl3): 5 8,26 (s, 1H), 5.27 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H).
Step 4: 4-Bromo-3,5-dimethyl-pyridin-2-yl methanol
A suspension of acetic acid 4-bromo-3,5-dimethyl-pyridin-2-yl methyl ester (0.26 gt 1.0 mmol) and K2CO3 (excess) in MeOH (5 mL) was heated to 50 °C for 15 min. Work-up (CHCb), filtration through a silica gel pad (eluent 100% EtpAc) and evaporation gave the title compound as a white solid (0.19 g, 88% yield). Rf (50% Hexane/EtOAc): 0.5. HPLC Rt: 3.80 min. 1H-NMR (CDCI3): 8 8.23 (s, 1H), 4.70 (s, 2H), 2.46 (s, 3H), 2.30 (s, 3H).
Step 5: 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine
The title compound was obtained from 4-bromo-3,5-dimethyl-pyridin-2-yl methanol according to the general procedure 2.5. HPLC Rt: 6.323 min. 1H-NMR (CDCl3): δ 8.22 (s, 1H), 4.63 (s, 2H), 2.52 (s, 3H), 2.40 (s, 3H).
Method 2:
Step 7: 2-chlorornethyl-3,5-dimethyl-pyridm-4-ol
The title compound was obtained by following the procedure described in the patent by Tarbit, etal. WO 99/10326.
Step 2; 4-bromo-2-chloromethyl-3,5-dimethyl pyridine
A neat mixture of 2-chloromethyl-3,5-dimethyl-pyridin-4-ol (8.2 g, 47.8 mmol) and POBr3 (60g, 209 mmol) was stirred at 130 °C for 3 h. The resulting viscous oil was cooled to r.t. and poured onto ice water. The pH was adjusted to 10 with solid KOH. Work-up (CHCI3), drying (MgS04) and evaporation afforded the title compound as a purple solid (8,7 g, 78% yield) which was used without purification. HPLC Rt: 6.028 min. 1H-NMR (CDCI3): 8.20 (s, 1H), 4.62 (s, 2H), 2.50 (s, 3H), 2.38 (s, 3H).
Method 3:
Step I: 4-biomo-2-chIoromethyl-3,5-dimethyl pyridine
A suspension of 2-chloromemy]-4-methoxy-3,5~dimethyl-pytidine (3.24 g, 14.6 mmol) in PBr3 (8.0 ml, 85.1 mmol, 5.8 equiv.) was heated to 80 °C under nitrogen. A catalytic amount of DMF (0.50 ml, 6.4 mmol, 0.44 equiv.) was added, whereupon the suspension rapidly turned into an orange solution. After 40 ruin., the reaction was still incomplete as judged by HPLC, The temperature was raised to 110 °C and the reaction was prolonged for 30 min, at which point it was complete. The mixture was poured over ice, made basic with cone. aq. NH4OH and extracted into EtOAc. Washing with water, drying (brine, MgSO4) and concentration gave the title compound as a pink solid (1.51 g, 44%) containing 10%of an impurity by lH-NMR. The crude was used without further purification. 1H-NMR (CDCl3) δ 8.19 (s, 1H), 4.59 (s, 2H), 2.48 (s, 3H), 2.37 (s, 3H).
Example 66: 9-(4-bromo-3,5-dimethyl-pyridin-2-yl methyl)-6-chloro-9H-purin-2-yjamine, phosphate salt
The title compound was obtained by treating 9-(4«bromo-3,5-dimethyl-pyridin-2-y] methyl)-6-chIoro-9H-purin-2-yIamine with H3PO4 according to the general procedure 2.7. HPLC Rt: 5.294 min. 1H-NMR (d6-DMSO): δ 8.12 (s, 1H), 8,09 (s, 1H), 6.83 (s, 2H), 5.47 (s, 2H), 2.49 (a, 3H), 2.29 (s, 3H)
Example 67: 9-(4-bromo-3,5-diiiiethyl-pyrtdin-2-yl methyl)-6-chloro-9H-purin-2-ylamine, hydrochloric acid salt
The title compound was obtained by treating 9-(4-bromo-3,5-dimethyI-pyridin-2-yl methyl)-6-chloro-9H-purin-2-ylamine with HCl according to the general procedure 2.7. HPLC Rt: 5.294 min. 1H-NMR (da-DMSO): δ 8.13 (s, 1H), 8.12 (s, IH), 5.47 (s, 2H), 5.47 (s, 2H), 2.49 (s, 3H), 2.30 (s, 3H).
Example 68: 9-(4-bromo-3r5-dimethyl-1-oxy-pyridin-2-yl methyl)-6-chloro-9H-purjn-2-ylamine
The title compound was obtained by oxidation of 9-(4-bromo-3,5-dimelhyl-pvridin-2-yI)-6-chloro-9H-purin-2-ylamine according to the general procedure 2.1,
HPLC Rt: 4.916 rain. 1H-NMR (CDC13): δ 8.46 (s, IH), 8.07 (s, IH), 5,57 (s, 2H), 5.03 (s, 2H), 2.81 (s, 3H), 2.35 (s, 3H).
Example 69: 6-bromo-9-(4-bromo-3,5-dhnethyl-pyridin-2-yl methyl) -9H-purin-2-ylamioe
A mixture of 6-bromo-9H-purin-2-ylamine (2.4 g, 11 mmol), 4-bromo-2-chIoromethyI-3,5-dimethyl pyridine (3.5 g, 15 mmol), K2CO3 (2.07 g, 15 mmol) and DMF (50 mL) was stirred at 50 °C for 2 h. Work-up and flash chromatography gave the title compound as a white solid (2.6 g, 56 %). HPLC Rt: 5.415 min. 1H-NMR (CDC13): 6 8.17 (s, 1H), 7.88 (3, IH), 5.38 (s, 2H), 5.05 (s, 2H), 2.51(s, 3H), 2.37 (s, 3H).
Example 70: 6-bronio-9-5-dimethyl-l-oxy-pyridin-2-yl methyl) -9H-purin-2-yiamine
The title compound was obtained by oxidation of 6-bromo-9-(4-hromo-3,5-dimethyl-pyridin-2-yl methyl) according to the general procedure 2.1 (52% yield). Rf (100% EtOAc): 0.1. HPLC Rt: 4.978 min. 1H-NMR(CDCI3): δ 8.47 (s, IH), 8.07 (s, : 1H), 5.56 (s, 2H), 5.06 (s, 2H), 2.81(s, 3H), 2.35 (s, 3H).
Example 71: 2-(2-Amino-6-chloro-purin-9-ylmethyl)-3,5-dlmethyl-pyridin-4-ol
The title compound was obtained by alkylating 6-chloro-9H-purin-2-ylamine with 2-chloromethyl-3,5-dimethylpyridin-4-ol according to the general procedure 1.1. HPLC Rt: 3.624min. 1H-NMR(d6-DMSO): δ 8.07 (s, IH), 7.47 (s, IH), 6.90 (s, 2H), 5.20(8, 2H), 2.00 (s, 3H), 1.86 (s, 3H).
Example 72: 6-Chloro-9-(4-ethoxy-3,5-dlmetnyl-pyridin-2-yImethyl)-9H-puridin-2-ylamtne
The title compound was obtained by O-alkylatjon of 2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol with ethyl iodide using the general procedure 2.6. HPLC Rt: 4.321 min. 'H-NMR (CDC13): δ 8.21 (s( IH), 7.90 (s, IH), 5.34 (s, 2H), 5.12 (s, 2H)( 3.90 (q, 2H), 2.31 (s, 3H) 2,26 (s, 3H), 1.44 (t, 3H).
Example 73: 9-(4-AIIylo.vy-3,5-dimethyl-pyridin-2-yImethyl)-6-chIoro-9H-purin-2-ylamine
The title compound was obtained by O-alkylation of 2-(2-anuno-6-chloro-purin-9-ylmcthyl)-3,5-dimethyl-pyridin-4-oI with allyll chloride using the general procedure 2.6. HPLC Rt: 4.417 min. 1H-NMR (CDCI3): δ 8.20 (s, 1H), 7.90 (s, IH), 6.03-6,10 (m, IH), 5.40-5.44 (dd, 1H), 5.34 (s, 2H), 5.29-5.32 (dd, IH), 5.19 (s, 2H), 4.34-4.36 (m, 2H), 2.30 Example 74: 6-Chloro-9-[4-{2-ethoxy-ethoxy)-3,5-dJmethyl-pyridin-2-y]metbyI]-9H-purln-2-ylaralne
The title compound was obtained by O-alkylation of 2-(2-aminc~6-chloro-purin-9-yImethyl)-3,5-dimethyl-pyridin-4-oI with ethoxyethyl chloride, using the general procedure 2.6. HPLC Rt: 4.388 min. lH-NMR (CDC13): δ 8.19 (s, IH), 7.89 (s, IH),
5.33 (s, 2H), 5.14 (s, 2H), 3.97-4.00 (t, 2H), 3.73-3.76 (t, 2H), 3.56-3.61 (q, 2H), 2.33 (s,
3H), 2.26 (s, 3H), 1.22-1.26 (t, 3H).
Example 75: 6-Chloro-9-(4-isopropoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-puriu-2-ylamine
The title compound was obtained by O-alkylation of 2-(2-amino-6-chloro-purin-9-yImethyl)-3,5-dimethyl-pyridin-4-ol with isopropyl iodide using the general procedure 2.6. HPLC Rt: 4.571 min. 1H-NMR (CDCI3): δ 8.17 (s, IH), 7.89 (s, IH), 5.32 (s, 2H), 5.06 (s, 2H), 4.20 (m, IH), 2,26 (s, 3H) 2.22 (s, 3H), 1.28-1.30 (d, 3H).
Example 76: 6-Cbloro-9-(4-cyclopropylmethoxy-3,5-dimethyI-pyridin-2-ylmethyl)-9H-purin-2-yIamine
The title compound was obtained by O-alkylation of 2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol with cyclopropylmethyl iodide using the general procedure 2.6. HPLCRt: 4.709 min. 1H-NMR (CDCI3): δ 8.20 (s, IH), 7.90 (s, IH),
5.34 (s, 2H), 5.09 (s, 2H), 3.68-3.70 (d, 2H), 2.32(s, 3H) 2.27 (s, 3H), 1.23-1.31 (m, IH),
0.63-0.68 (m, 2H), 0.30-O.33 (m, 2H).
Example 77; 6-chloro-9-[3,5-dimethyl-4-(3-methyI-butoxy)-pyrldiQ-2-ytmethyl]-9H-purin-2-ylamine
The title compound was obtained by O-alkylation of 2-(2-armno-6-chloro-purin-9-ylmethyl)-3,5~dimethyl-pyridin-4-ol with 3-methylbutyl bromide using the genera) procedure 2.6. HPLC Rt: 5.425 min. 1H-NMR (CDCl3): δ 8.21 (sf 1H), 7.90 (s, 1H),
5.34 (s, 2H), 5,07 (s, 2H), 3.82-3.86 (t, 2H), 2.31 (s, 3H) 2.26 (st 3H), 1.84-1.9r(m, 1H),
1.71-1.74 (q, 2H), 1.00 (s, 3H), 0.98 (s, 3H).
Example 78: 6-Chloro-9-(4-isobutoxy-3,5-dimetbyl-pyrldin-2-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by O-alkylation of 2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-ol with isobutyl bromide using the general procedure 2.6. HPLC Rt: 4.321 min. 1H-NMR (CDCI3): 8 8.21 (s, IH), 7.90 (s, 1H), 5.34 (s, 2H), 5.12 (s, 2H), 3.58-3.56 (d, 2H), 2.30 Example 79: Acetic acid 2-[2-(2-amino-6-chloro-purin-9-ylmethyl)-3,5-dimethyl-pyridin-4-yloxy]-ethyl ester
The title compound was obtained by O-alkylation of 2-{2-arnino-6-ch]oro-purin-9-ylmethy])-3,5-drmethyl-pyridin-4-ol with 2-bromoethyl acetate using the general procedure 2.6. HPLC Rt: 4.103 rain. 1H-NMR (CDCI3): δ 8.21 (s, 1H), 7.90 (s, 1H),
5.35 (s, 2H), 5.10 (s, 2H),4.42 (t, 2H), 4,05(t, 2H), 2.34 (s, 3H) 2.27 (s, 3H), 2.13 (s,
3H).
Example 80: Acetic acid 3-[2-(2-amlno-6-cntoro-purin-9-ylmetbyl)-3,$-dimethyI-pyridin-4-yIoxyJ-propyl ester
The title compound was obtained by O-alkylation of 2-(2-amino-6-chlon>purin-9-ylmethy1)-3,5-dimethyl-pyridm-4-ol with 2-chloropropyl acetate the general procedure 2,6, HPLC Rt: 4.414 rain. 1H-NMR (CDCI3): δ 8.21 (s, 1H), 7.91 (s, 1H), 5.34 (s, 211), 5.12 (s, 2H), 4.34 (t, 2H), 3.90 (t, 2B), 2.31 (s, 3H), 2.25 (s, 3H), 2.15 (m, IH), 2.09 (s, 3H).
Example 81: 6-Chloro-9-(3,S-dimethyl-4-propoxy-pyridin-2-ylmethyl)-9H-purln-2-
ylamine
The title compound was obtained by O-alkylation of 2-(2-amino-6-chIoro-purin-9-ylmethyl)-3,5-dimethyL-pyridin-4-ol according to the general procedure 2.6. HPLC Rt: 4.644 min. 1H-NMR (CDC13): 5 8.21 (s, 1H), 7.91 (s, 1H), 5,34 (s, 2H), 5.12 (s.2H), 3.80-3.76 (t, 2H), 2.31 (s, 3H),2.2 Example 82; 6-Chloro-9-(4-chlttro-3,5-dimethyl-pyrldia-2-ylmethyl)-9H-purin-2-
ylaralne
Step 1: 4-Chloro-2-chloromethyl-3,5-dimethyl pyridine
The title compound was obtained by treating 2-chIoromethyl-3,5-dimethyl-pyridin-4-oI with POCl3 according to the general procedure 2.4 (74% yield). HPLC Rt: 5.543 min. lH-NMR (CDC13): δ.24 (s, 1H), 4.71 (s, 2H), 2.48 (s, 3H), 2.36 (s, 3H).
Step 2: 6-chloro-9-(4-chloro-3,5-dimethyl-l-oxy-pyridm-2-yl methyl) -9H-purin-2-ylamine
A mixture of 6-chloro-9H-purin-2-yIamine (7 g, 41 mraol), 4-chloro-2-chloromethyl-3,5-dimethyl pyridine (8.2 g, 43 mmol), KaC03 (10 g, 72 mmol) and DMF (200 mL) was heated to 50 °C for 2 h. The reaction mixture was diluted with water (200 mL) and the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound as a beige solid (11.7 g, 88 % yield, 90% purity), HPLC Rt: 5.167 min. 1H-NMR (CDCI3): δ 8.24 (s, 1H), 7.90 (s, 1H), 5.40 (s, 2H), 5.07 (s, 2H), 2.49 (s,3H), 2.37 (s,3H).
Example 83; 6-Chloro-9-(4-chloro-3,5-dimethyl-1-oxy-pyrldin-2-yl methyl) -9H-purln-2-ylaniine
The title compound was obtained by oxidation of 6-chloro-9~(4-chloro-3,5-dimethyI-pyridin-2-ylmethyl)-9H-purin-2-ylamine according to the general procedure 2.1 (56% yield). HPLC Rt: 4.813 min. lH-NMR (d6-DMSO): δ 8.31 (s, 1H), 8.20 (s, ]H), 6.91 (s, 2H), 5.41 (s, 2H), 2.73 (s, 3H), 2.26 (s, 3H).
Examples 84: 6-Chloro-9-(3,5-dlmethyl-pyridin-2-yl methyl) -9H-purin-2-ylamine
Step I; Acetic acid 3,5-dimethyl-pyridin-2-yl methyl ester
The title compound was prepared from 2,3,5-collidine-N-oxide (see example 1) according to the general procedure 2,2. HPLC Rt: 2.916 min. 1H-NMR (CDCl3): δ 8.30 (s, 1H), 7.33 (s, 1H), 5.22 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 2.13 (s, 3H). -
Step 2: 3,5-Drrnethyl-pyridin-2-yl methanol
The title compound was obtained by deacetylarion of acetic acid 3,5-dimethyl-pyridin-2-yl methyl ester according to the general procedure 2.3. HPLC Rt: 2.909 min. 1H-NMR (CDC13): δ 8.24 (s, 1H), 7.30 (s, 1H), 4.85 (broad s, 1H), 4.67 (s, 2H), 2.33 (s,
3H), 2.20 (s, 3H).
Step 3: 2-Brornomethyl-3,5-dimethyl pyridine
The title compound was obtained from 3,5-dimethyl-pyridin-2-yl methanol according to the general procedure 2.5. HPLC Rt: 3.895 min. 1H-NMR (CDCl3): δ 8.3 (s, 1H), 7,3 (s, 1H), 4.61 (s, 2H), 2.41(s, 3H), 2,33 (s, 3H).
Step 4: 6-chloro-9-(3t5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 2-bromomethyl-3,5-dimethyl pyridine according to the general procedure 1.1. HPLC Rt: 3.760 min. 1H-NMR (CDC13): δ 8.21 (s, 1H), 7.89 (s, 1H), 7.30 (s, 1H), 5.32 (s, 2H), 5.05 (s, 2H), 2.36 (s, 3H), 2.29 (s, 3H).
Example 85: 6-Bromo-9-(4-methoxy-3,5-dlmethyI-pyrldin-2-ylmethyl)-9H-purin-2-ylamlne
The title compound was obtained by alkylation of 6-bromo-9H-purin-2-ylamine with 2-ch!oromethyl-4-mcthoxy-3,5-dimethylpyridine according to the general procedure 1.1. PLC Rt: 4.138. 1H-MMR (CDCI3): δ 8.21 (s, 1H), 7.91 (s, 1H), 5.34 (s, 2H), 5.12 (s, 2H), 3.77 (s, 3H), 2.32 (st 3H), 2.27 (s, 3H).). m/z (%) 363.2(M+1, 100%), 365.2 (M+3, 100%).
Example 86; 6-Bromo-9-(4-methoxy-3,S-dlmethyl-pyridln-2-ylmetIiyl)-9H-purin-2-ylamine, phosphate salt
The title compound was obtained by treating 6-bromo-9-(4-methoxy-3,S-dimethyl-pyridin-2-ylinethyl)-9H-purin-2-ylaniine with H3PO4 according to the general procedure 2.7. HPLC Rt: 4.138, 1H-NMR (d6-DMSO): δ 8.07 (s, 1H), S.02 (s, 1H), 6.84 (s, 2H), 5J5(s, 2H), 3.73 (s, 3H), 2.29 (s, 3H), 2.15 (s, 3H). ). xalz (%) 363.2(M+1, 100%), 365.2 (M+3,100%).
Example 87: 6-Bromo-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylatniae, hydrochloride salt
The title compound was obtained by treating 6-bromo-9-(4-niethoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylaraine with HC1 according to the general procedure 2.7. HPLC Rt: 4.138. ]H-NMR (d6-DMSO): δ 8.44 (s, 1H), 8.26 (s, 1H), 5.57 (s, 2H), 3.96 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H).
Example 88: 6-Bromo-9-{4-methoxy-3,5-dimethyl-l-oxy-pyrldin-2-ylmethyl)-9H-purio-2-ylamine
The title' compound was obtained by oxidation of 6-bromo-9-(4-niethoxy-3,5-dimethyI-pyridin-2-ylmethyl)-9H-purin-2-ylamine according to the general procedure 2.1. HPLC Rt: 4.439 mm. 1H-NMR {CDCI3): δ 8.55 (s, 1H), 8.06 (s, IH), 5.50 (s, 2H), 5.12 (s, 2H), 3.76 (s, 3H), 2.60 (s, 3H), 2,25 (s, 3H). m/z (%) 379.1 (M+l, 100%), 381.1
(M+3, 100%).
Example 89: 6-Chloro-9-(4-methoxy-3,5-dtmethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
Method 1
The title compound was obtained by alkylating 6-chloro-9H-purin-2-ylamine with 2-chloromethyl-4-methoxy-3,5-dimelhylpyridine (or its HC1 salt) according to the
general procedure 1,1.
Method 2
The title compound could also be obtained by O-methylation of 6-chloro-9-(4-hydroxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine according to the procedure 2.6 (KOH, Mel, DMF, 80 °C, 5 rain). HPLC Rt: 3.980 min, lH-NMR (CDC13): δ 8.19 (s, 1H), 7.88 (s, 1H), 5.32 (s, 2H), 5.07 (s, 2H), 3.75 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H).
Method 3
Step 1: (4-Methoxy-3,5-dimethyl-pyridin-2-yl)-methylamine
A solution of 2-chlorometiiyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride in 7N methanolic ammonia was placed in a pressure vessel and to 100 °C for 16 h. Concentration and flash chromatography gave the title compound as a greenish solid (76% yield). HPLCRt: 3.773 min. lH-NMR(CDCl3): δ 8.19 (s, 1H), 4.35 (s, 2H), 3.76
(s,3H), 2.24 (s,3H), 2.18 (s,3H),
Step 2: 6-Chloro-4-{4-methoxy-3,5-dimethyl-pyridin-2-y]methyl)-pyrimidine-2,4,5-triaraine
A solution of 4,6-dichloro-pyrimidine-2,5-diamine (see Seela et al, Helv. Chim. Acta. 1986, 69,1602-1613 and US Patent No. 5,917,042), 4-methoxy-3,5-dimethyl-pyridin-2-yl)-methylamineJ and Et3N in butanol was heated to reflux for 1 h to give the title compound. HPLC Rt; 3.761 min. 1H-NMR (CDCI3): δ 8.24 (s, 1H), 7.15 (s, 1H), 4.60 (s, 2H), 4.56-4.55 (d, 2H), 3.80 (s, 3H), 3.00 (s, 2H), 2,28 (s, 3H), 2.27 (s, 3H).
Step 3: Synthesis of 6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyI)-9H-purin-2-ylamine
The cyclization with trimethylorthoformate in presence of acid to prepare purines can be done. See similar reaction, example 48.
Example 90: 6-chioro-9-(4-methoxy-3,5-dimethyl-pyrldin-2-ylmethyl)-9H-purin-2-ylamine, phosphate salt
The title compound was obtained treating 6-chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine with H3PO4 according to the general procedure
2.7. HPLC Rt: 4.003 min. 1H-NMR (d6-DMSO): δ 8.06 (s, 1H), 8,03 (s, 1H), 6.83 (s,
2H), 5.36 (s, 2H), 3.74 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H).
Example 91: 6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine, sulphate salt
The title compound was obtained treating 6-cliloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine with H2SO4 according to the general procedure 2.7. HPLC Rt: 3.999 min. lH-NMR (d6-DMSO): δ 8.36 (s, lH)f 8.15 (s, 1H), 5.52 (s, 2H), 3.93 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3HJ.
Example 92: 6-Culoro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine, hydrochloride salt
The title compound was obtained treating 6-chloro-9-(4-methoxy-3,5~dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine with HC1 according to the general procedure 2.7. HPLC Rt: 4.093 min. 1H-NMR (d6-DMSO): δ 8.38 (s, 1H), 8.23 (s, 1H), 5.55 (s, 2H), 3.93 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H).
Example 93: 6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-y] amine, mesylate salt
The title compound was obtained treating 6-chIoro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamme with MeSO3H according to the general procedure 2.7. HPLC Rt: 4,093 min. 1H-NMR (d6-DMSO):δ 8.38 (s, 1H), 8.17 (s, 1H), 5.54 (s, 2H), 3.95 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H).
Example 94: N-[6-Chloro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)9H-purin-2-yl]-acetamide
A suspension of 6-chIoro-9-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-yIamine (80 mg, 0.25 mmol) in acetic acid anhydride (2.2 g) was treated with one drop of concentrated H2S04 and stirred at r.t. for 5 min. Work-up (EtOAc), drying (MgSOit) and evaporation gave the title compound as a white solid. HPLC Rt: 4.093
mm. 1H-NMR (CDCI3): δ 8.20 (s, 1H), 8.10 (s, 1H), 5.46 (s, 2H), 3.78 (s, 3H), 2.54 (s, 3H), 2.38 (s,3H), 2.27 (s,3H).
Example 95: 6-Chloro-9-(4-methoxy-3,5-(dimethyl-1-oxy-pyridin-2-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by oxidation of 6-chloro-9-(4-methoxy-3,5-dimethyI-pyridin-2-ylmethyl)-9H-purin-2-ylamine according to the general procedure 2.1. HPLC Rt: 4.435 min. lH-NMR (CDCI3): δ 8.55 (s, 1H), 8.06 (s, 1H), 5.52 (s, 2H), 5.07(a, 2H), 3.76 (s, 3H), 2,61 (s, 3H), 2.25 (s, 3H).). m/z (%) 335.1(M+1,100%), 337.1 (M+3, 34%).
Example 96: 6-Chloro-9-(4-methoxy-3,5-dimethyl-l-methoxy-pyridinium-2-methyI)-9H-purin-2-ylamine methyl sulfate salt
A suspension of 6-chloro-9-{4-methoxy-3,5-dimethyl-l-oxy-pyridin-2-ylmethyl)-9H-purin-2-ylamine (0.2 g, 0.56 mmol) in DCM (10 ml) was heated to reflux. Dimethyl sulfate (L12 ramol) was added dropwise (Tarbit WO 99/10326) and heating was continued for 3h. Filtration and washing (hot acetone) gave the title compound as a beige solid. HPLC Rt; 3.379 min. 1H-NMR (d6-DMSO): δ 9,68 (s, 1H), 9.40 (s, 1H), 5.85 (s, 2H), 4.42 (s, 3H), 4.15 (s, 3H), 4,12 (s, 3H), 2.70 (s, 3H), 2 .47 (s, 3H).
Example 97: 6-Chloro-9-(6-chIoro-4-methoxy-3,5-dlmethyl-pyrldIn-2-ylmethyl)-9H-puHn-2-yIatnine
Method 1
6-Chloro-9-(4-methoxy-3,5-dimethyl-1 -oxy-pyridin-2-ylmethyl)-9H-purin-2-ylamine was treated with POCl3 according to the general procedure 2.4. Flash chromatography gave the title compound as a white solid. HPLC Rt: 5,741 min. 1H-NMR (CDCl3); δ 7.94 (s, 1H), 5.29 (s, 2H), 5.05 (s, 2H), 3.74 (s, 3H)t 2.30 (s, 3H), 2.28 (5, 3H).
Method 2
Step I; 2-Chloromemyl-4-metooxy-3,S-dimethylpyridine-l-oxide
The title compound was obtained by oxidation of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine according to the general procedure 2.1. HPLC Rt: 4,462 min. 1H-NMR (CDCI3): δ 8.05 (s, III),4.93 (s, 2H), 3.77 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H).
Step 2: 2-Chloro-6-chloromethyl-4-methoxy-3,5-dimemylpyridine
The title compound was obtained by treating 2-chloromethyl-4-rrtethoxy-3,5-diniethylpyridine-l -oxide with POCl3 according to the general procedure 2.4. HPLC Rt: 6.757 min. 1H-NMR (CDCI3): δ 4.64 (s, 2H), 3.79 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H).
Step 3: 6-Chloro-9-(6-chloro)-4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 6-chloro-9H-purin-2-ylamine with 2-chloro-6-chloromethy]-4-methoxy-3,5-dimethylpyridine according to the general
procedure 1.1.
Example 98: 6-Chloro-9-(S-methoxy-4-methoxymethyl-6-methyl-pyridin-3-yl metbyI)-9H-purln-2-ylamlne
Step 1: Acetic acid 3-acetoxy-5-hydroxymethyl-2-methyl-pyridin-4-ylmethyl ester
The title compound was obtained by following the procedure reported by Morisawa et al. J. Med Chem. 1974,17, 1083-1086. HPLC Rt: 3.08 min. 1H-NMR (CDCl3): δ 8.41 (s, 1H), 5.20 (s, 2H), 4.80 (s, 2H), 2.40 (s, 3H), 2.38 (s, 3H), 2.03 (s,
3H).
Step 2: Acetic acid 3-acetoxy-5-bromomethyl-2-methyl-pyridin-4-
ylmethyl ester
The title compound was obtained from Acetic acid 3-acetoxy-5-hydroxymethyl-2-methyl-pyridin~4-yIjnethyl ester according to the general procedure 2.5. HPLC Rt: 5.332 min. 1H-NMR (CDC13): δ 8.43 (s, IH), 5.22 (s, 2H), 4.70 (s, 2H), 2.43 (s, 3H), 2.41 (s,3H), 2.06 (s,3H).
Step 3: 6-Chloro-9-(5-acetoxy-4-acetoxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6"-chloropurine with acetic acid 3-acetoxy-5-bromomethyl-2-methyl-pyridin-4-ylmethyl ester according to the general procedure 1.1. HPLC Rt: 4.498 min 1H-NMR (CDCl3): δ 8.42 (s, 1H), 7.74 (s, 1H), 5,43 (s, 2H), 5.10 (s, 2H), 5.07 (s, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 1.96 (s, HI).
Step 4: 6-Chloro-9-(5-hydroxy-4-hydroxymethyl-6-rnethyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine
A suspension of 6-chloro-9-(5-acetoxy-4-acetoxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-p«rin-2-ylamine and K2CO3 (excess) in MeOH was heated to SO °C for 15 min. Filtration, work-up (EtOAc) and purification by preparative TLC gave the title compound. HPLC Rt: 4.498 min. 1H-NMR (d6-DMSO) δ 8.08 (s, 1H), 7.74 (s, 1H), 6.95 (s, 1H), 5.31 (s, 2H), 4.74 (s, 2H), 2.31 (s, 3H).
Step 5: 6-Chloro-9-(5-methoxy-4-methoxyrnethyl-6-methyl-pyridin-3-
ylmethyl)-9H-purin-2-ylamine
A mixture of 6-chloro-9(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine, Mel, K2CO3 (excess) and DMF was heated to 50°C for 15 min. Work-up (EtOAc), drying (MgSO4), evaporation, and purification by preparative TLC gave the tide compound. HPLCRt: 5.446 min. 1H-NMR (CDCI3) δ S.35 (s, 1H), 7.70 (s, 1H), 5.35 (s, 2H), 5.25 (s, 2H), 5.15 (s, 2H), 3.80 (s, 3H) 2.59 (s, 3H), 1.970 (s,3H).
Example 99: Synthesis of 6-Chloro-9-(5-ethoxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-purin-2-ylatnine
A mixture of 6-chloro-9-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine (see previous example), Et[ (excess), K2CO3 (excess) and DMF was heated to 50 °C for 15 min. Work-up (EtOAc), drying (MgSO4), evaporation, and purification by preparative TLC gave the title compound. IIPLC Rt: 3.720 min. 1H-NMR(CDCl3)δ 8.27(s, lH),7.90(s, !H), 5.40 (s, 2H), 5.11 (s, 2H), 4,85 (d, 2H), 4.50 (t, 1H). 3.95 (q, 2H), 2.51 (s, 3H) 1.45(t, 3H).
Example 100: 6-Chloro-9-(3,5-dimethyl-4-aroino-pyridin-2-ylmethyl)-9H-puria-2-
ylamine
Step 1: 2-Bromomethyl-3,5-dimethyl-4-nitro-pyridine
The title compound was obtained from (3,5-dimethyl-4-nitio-pyridin-2-yl)-meihanol according to the general procedure 2.S. HPLC Rt; 6.206 rain. H-NMR (CDC13) 8 8.46 (s, 1H), 4.64 (s, 2H), 2.38 (s, 3H), 2.33 (s, 3H).
Step 2: 6-Chloro-9-(3,S-dimethyl-4-nitro-pyridin-2-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 2-bromomethyl-3,5-diinethyl4-nitro-pyridine according to the general procedure 1,1 HPLC Rt: 6.206 min. 1H-NMR (CDCI3) δ 8.40 (s, 1H), 7.94 (s, 1H), 5.40 (s, 2H)f 5.05 (s, 2H), 2.40 (s, 3H), 2.27 (a, 3H).
Step 3; 6-chloro-9-(3,5-dimethy]-4-amino-pyridin-2-ylmethyl)-9H-purin-2-ylamine
A suspension of 6-chloro-9-(4,6-dimethyl-5-mtro-pyridin-3-yIrnethyl)-9H-purin-2-y!amine and excess of sodium hydrosulfite (Na2S2O4) in methanol was stirred for 2 days at r,t. The MeOH was evaporated before extracting with EtOAc, Evaporation and purification by preparative TLC (100% EtOAc) gave the title compound. HPLC Rt: 3.544 min. 1H-NMR (CDCl3) δ 8.05 (s, 1H), 7.83 (s, 1H), 5.31 (s, 2H), 5.05 (s, 2H), 4.08 (s,2H), 2.12 (s,6H).
Example 101: 6-Chloro-9-(3-methoxy-5-metboxymethyl-4-methyl-pyridin-2-ylmethyI)-9H-purin-2-yIamlne
Step 1; 3-Methoxy-5-methoxymethyl-2,4-dimethyl-pyridine
The title compound was obtained by treating a solution of 5-hydroxymethyI-2,4-dimethyl-pyridin-3-o) hydrochloride (1 g, 5.2 mmol) in DMF with Mel (2.28 g, 15 mmol) and NaH (0.6 g, 50 mmol) for 1 h at 0 X. HPLC Rt: 2.835 min. 1H-NMR (CDC13) δ 8.16 (s, 1H), 4.44 (s, 2H), 3.75 (s, 3H), 3.41 (s, 3H), 2.53 (s, 3H), 2.32 (s, 3H).
Step 2: 3-Methoxy-5-methoxymethyl-2,4-dimethyl-pyrtdine 1-oxide
The title compound was obtained by oxidation of 3-methoxy-5-methoxymethyl-2,4-dimethyl-pyridme according to the general procedure 2.1, HPLC Rt: 4.181 min. !H-NMR(CDCI3) δ 8.18 (s, IH), 4.39 (s, 2H), 3.76 (s, 3H), 3.43 (s, 3H)t 2.52 (s, 3H), 2.46 (s, 3H).
Step 3: Acetic acid 3-methoxy-5-methoxymethyl-4-methyl-pyridin-2-yhnethyl ester
The title compound was obtained by treating 3-methoxy-5-methoxymethyl-2,4-dimethyl-pyridine 1 -oxide with ActO according to the general procedure 2.2. HPLC Rt: 4.062 min. 1H-NMR (CDC13) δ 8.32(s, IH), 5.27 {s, 2H), 4.47 (s, 2H), 3.80 (s, 3H), 3.43
(s,3H), 2.34 (s,3H), 2.25 (sf3H).
Step 4: (3-Methoxy-5-methoxynwthyl-4-methyl-pyridin-2-yI)-niethanol
The tide compound was obtained from acetic acid 3-methoxy-5-methoxymethy]-4-iiiethy]-pyridin-2-yIniethyl ester according to the genera) procedure 2.3. HPLC Rt: 3.465 min. lH-NMR (CDCl3) δ 8.22(s, IH), 4.75 (d, 2H), 4.47 (s, 2H)a 4.20 (t, IH), 3.77 (s, 3H), 3.43 (s, 3H), 2,34 (s, 3H).
Step 5: 2-Bromomethyl-3-methoxy-5-methoxymethyl-4-methyl-pyridine
The title compound was obtained from (3-methoxy-5-methoxymethyl-4-methyl-pyridin-2-yl)-methanol according to the general procedure 2.5. HPLC Rt: 4.498 min. lH-NMR (CDCl3) δ 8.22(s, IH), 4.695 (s, 2H), 4.42 (s, 2H), 3.S6 (s, 311), 3.40(s, 3H),
2.31 (8,3H).
Step 6: 6-Chloro-9-(3-methoxy-5-methoxymethyI-4-raethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkyktion of 2-araino-6-chloropurine with 2-bromomethyl-3-methoxy-5-methoxymethyl-4-rriethyl-pyridine according to the general procedure 1.1. HPLC Rt: 4.254 min. lH-NMR (CDC13) δ 8.210 (s, IH), 7.96 (s, IH), 5.40 (s, 2H), 5.05 (s, 2H), 4.42 (s, 2H ), 3.78 (s, 3H), 3.40 (s, 3H), 2.31 (s, 3H).
Example 102: 6-Chloro-9-(5-chIoro-6-methoxy-pyrldin-3-ylmethyl)-9H-purin-2-ylamine
Step /: (5-Chloro-6-methoxy-pyridin-3-y])-inethaitol
(5,6-Dichloro-pyridio-3-yl)-methaiw! was dissolved in a saturated solution of NaOMe in MeOH and heated to reflux overnight. Evaporation of MeOH, work-up (EtOAc) and evaporation gave the title compound. 1H-NMR (CDCl3) δ 8.03 (d, 1H), 7.72 (d, 1H), 4.65 (a, 2H), 4.04 (s, 3H).
Step 2: 5-Bromomethyl-3-chIoro-2-methoxy-pyridine
The title compound was obtained from (5-chloro-6-methoxy-pyridin-3-yl)-methanol according to the general procedure 2.5. 1H-NMR (CDCl3) δ 8 .05 (d, 1H), 7.70 (d, 1H),
4.42 Step 3: 6-Chloro-9-(5-chloro-6-methoxy-pyridin-3-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-arnino-6-chloropurine wife 5-bromomethyl-3-ch]oro-2-methoxy-pyridine according to the general procedure 1.1. HPLC Rt: 5.256 min. 1H-NMR (COCl3) δ 8.11(d, 1H), 7.78 (s, 1H), 7.63 (d, 1H), 5.19 (s, 2H), 5.16 (s, 2H), 4.04 (s, 3H),
Example 103: 6-chloro-9-(3,4-dimethoxy-pyrldin-2-ylmethyl)-9H-purln-2-ylamlne
The title compound was obtained by alkylation of 2-amino-6-chioropurine with 2-chloromethyl-3,4-dimethoxylpyridine hydrochloride according to the general procedure 1.1. HPLC Rt: 3.777 min. 1H-NMR(CDCl3): δ 8.19 (d, 1H), 7.95 (s, 1H), 6.82 (d, 1H), 5.39 (s, 2H)t 5.09 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H).
Example 104: 6-chloro-9-(3-methoxy-6-metliyl-pyrldiii-2-ylmethyl)-9H-purin-2-ylamine
Step I: (3-Methoxy-6-methyl-pyridin-2-yI)-methanol
The title compound was obtained by O-methylation of 2-hydroxyrnethyl-6-methyl-pyridin-3-ol according to the general procedure 2.6. HPLC Rt: 2.304 rain. 'H-NMR (CDCl3) δ 7.05-7.11 2.51 (s,3H).
Step 2: 2-Bromomethyl-3-methoxy-6-methyl-pyridine
The title compound was obtained from (3-Methoxy-6-methyl-pyridin-2-yl)-memanol according to the general procedure 2.5. HPLC Rt: 4.361. 1H-NMR (CDCl3) δ 7.06-7.12 (m, 2H), 4.61 (s, 2H), 3.89 (s, 3H), 2.49 (s, 3H).
Step 3: 6-chloro-9-(3-methoxy-6-m«thyI-pyridin-2-ylniethyl>9H-puriri-
2-ylamine
The title compound was obtained by alkylation of 2-armno-6-chIoropurine with 2-bromomethyl-3- methoxy-6-methylpyridme according to the general procedure 1.1. HPLC Rt: 3.777 min. 1H-NMR(CDC13): δ 7.92 (s, 1H), 7.11 (m, 2H), 5.39 (s, 2H), 5.15 (s,2H), 3.85 (s,3H), 2.45 (s,3H).
Example 105: 6-Cbloro-9-(S-metboxy-4,6-dimethyl-pyridln-3-ylmethyl)-9H-purin-2-ylamine
Step 1: (5-Methoxy-4,6-dimefliyl-pyridin-3-yl)-methanol
The title compound was obtained by O-methylation of 5-hydroxymethyl-2,4-dimethyl-pyridin-3-ol according to the general procedure 2.6. HPLC Rt: 3.114 min. ]H-NMR (CDCI3) δ 8.08 (s, 1H), 4.67 (s, 2H), 3.74 (a, 3H), 2.49 (s, 3H), 2.33 (s, 3H).
Step 2: 5-Bromomethyl-3-methoxy-2,4-dimerhyl-pyridine
The title compound was obtained from (5-methoxy-4,6-dimethyl-pyridin-3-yl)-methanol according to the general procedure 2.5. HPLC Rt: 2.873. 1H-NMR (CDCI3) δ 8.22 (s, 1H), 4.50 (s, 2H), 3.764(s, 3H), 2.54 (s, 3H), 2.37 (s, 3H).
Step 3: 6-Chloro-9--(5-methoxy-4,6-dimethyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 5-bromomethyl-3- methoxy~2>4-methylpyridine according to the general procedure 1.1. HPLC Rt: 3.7387 min. 1H-NMR (CDCl3): δ 8.25 (s, 1H), 7.63 (s, 1H), 5.39 (s, 2H), 5.11 Example 106: 9-(4-Methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-pnrin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 2-chloromethyl-4-methoxy-3,5-dimethyIpyridine hydrochloride according to the general procedure 1.1. HPLC Rt: 3.434 min. 1H-NMR(CDCIj): 8 8.75 (s, 1H), 8.25 (s, IB), 7.90 (s, 1H), 5.37(s, 2H), 5.07 (s, 2H), 3.77 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H).
Example 107: 6-Chloro-9-(3,5-dlmethoxy-4-methyl-benzyl)-9H-purin-2-ylamine
Step 1: (3,5-Dimethoxy-4-methyl-phenyl)-methanol
The title compound was obtained by reducing 3,5-dimethoxy-4-methyl-benzoic acid as described by Bhaskar et al. J. Org. Chem. 1991,56, 5964-5965. HPLC Rt: 5.352. 1H-NMR (CDCl3): δ 6,58(s, 2H), 4.68 (s, 2H), 3.85 (s, 6H), 2.10 (s, 3H).
Step 2: 5-Bromomethyl-l,3-diniethoxy-2-methyl-benzene
The title compound was obtained from (3,5-dimethoxy-4-methyl-phenyl)-methanol according to the general procedure 2.5. HPLC Rt: 7.200. 1H-NMR (CDC13): δ 6.59 (s, 2H), 4.51 (s, 2H), 3.86 (s, 3H),3.85 {s, 3H), 2.22 (s, 3H).
Step 3: 6-Chloro-9-(3,5-dimethoxy-4-methyl-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 5-bromomethyl-1,3-dimethoxy-4-methyl benzene according to the general procedure 1.1. HPLC Rt: 5.841 min. 1H-NMR (CDCl3): δ 7.75 (s, 1H), 6.46 (s, 1H), 5.21 (s, 2H), 5.07(s, 2H), 3.80 Example 108: 9-(2-Bromo-3,5-dimethoxy-4-methyl-benzyl)-6-chloro-9H-purin-2-
ylamine
The title compound was obtained by brominating 6-chloro-9-(3,5-dimethoxy-4-methyl-benzyl)-9H-purin-2-ylamine with bromine according to the genera! procedure 3.1. HPLC Rt: 6.222 min. 1H-NMR (CDCl3): δ 7.85 (s, 1H), 6.60 (s, 1H), 5.36 (s, 2H), 5.07(8,2H), 3.80 (s, 3H), 3.74 (s, 3H), 2.20 (s, 3H).
Example 109; 8-Bromo-9-(2-bromo-3,5-dimethoxy-4-methyl-benzyl)-6-chloro-9H-purtn-2-ylamine
The title compound was obtained by brominating 6-chloro-9-(3,5-dimethoxy-4-methyl-benzyl)-9H-purin-2-ylamine with excess bromine according to the general procedure 3.1. HPLC Rt: 7.040 min. 1H-NMR (CDCl3): δ 5.88 (s, 1H), 5.38 (s, 2H), 5.14(a, 2H), 3.83 (s, 3 H), 3.57 (s, 3H), 2.19 (s, 3H).
Example 110: 2,6-Dichioro-9-[4-methoxy-3,5-dlmethyl-pyridin-2-ylmethyl)-9H-purine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 2-chloromethyl-4-memoxy-3,5-dimethylpyridine (or its HC1 salt) according to the general procedure 1.1. HPLC Rt: 5.081 min, 1H-NMR (CDCI3): δ 8 .30 (s, 1H), 8.17 (s, 1H), 5.50 (s, 2H), 3.80 (5, 3H), 2.38 (s, 3H), 2.27 (s, 3H).
Example 111; 8-butyI-6-chlora-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylaittine
Step 1: 6-Chloro-N4-(3,4,5-trimethoxy-benzyl)-pyrunidine-2,4,5-
triamine
The title compound was obtained by refluxing 4,6-dichloro-pyrimidine-2,5-diamine (see Seela et al. Helv. Chim. Acta. 1986, 69,1602-1613 and US Patent No. 5,917,042), 3,4,-5-trimethoxybenzylamine,and Et3N in butanol or ethanol for 1 to 14 h. HPLC Rt: 4.327 min. 1H-NMR (CDCI3): δ 6.57 (s, 2H), 5.65 (t, 1H), 4.75 (s, 2H), 4.54 (d(2H), 3.86-3.87 (d,9H).
Step 2: 8-Butyl-6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-
ylamine
The title compound was obtained by following the procedure given in WO 98/39344. HPLC Rt: 5,971 min. 1H-NMR (CDC13): δ 6.34(s, 2H), 5.19 (s, 2H), 5.04 (s, 2H), 3.81 (s, 3H), 3.77 (s, 6H), 2.71-2.75 (t, 2H), 1.68-1.74 (m, 2H), 1.35-1.41 (m, 2H), 0.88-0.92 (t, 2H).
Example 112: 6-Chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 3,4,5-trimethoxybenzyl according to the general procedure 1.1. The title compound was also obtained by treating a solution of 6-chloro-N-4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2)4,5-triamine in triethyl orthoformate with a catalytic amount of cone. HC1 at r.t for 20 min. HPLC Rt: 4.906 min. 1H-NMR (CDC13): δ 7.76 (s, 1H), 6.51 (s, 2H), 5.18 (s, 2H), 5.12 (s,2H), 3.85 (s, 3H), 3.84 (s, 6H).
Example 113: Acetic add 4-(2-amino-6-chtoro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenyl ester
Step 1: Acetic acid 4-hydroxymethyl-2,6-dimethoxy-pheny] ester
A solution of acetic acid 4-formyl-2,6-dimethoxy-phenyl ester (25 mmol) in MeOH (100 mL) was treated with NaBH4 (1 equiv.) at 0 °C for 15 rnin. After quenching with acetone and evaporating the solvent, work-up (CH2O2) and evaporation gave the title compound as a white solid (85% yield), Rf (in EtOAc/Hexane 1:1): 0.5. 1H-NMR (CDCI3): 8 6.66 (s, 1H), 4.68-4.70 (d, 2H), 3.85 (s, 3H), 2.36 (s, 3H), 1.74 (t, 1H).
Step 2: Acetic acid 3-bromo-4-hydroxymethyl-2,6-dimethoxy-pheny]
ester
The title compound was obtained by brominafion of acetic acid 4-hydroxymethyl-2,6-dimethoxy-phenyI ester in AcOH/AcONa buffer according to the general procedure 3.1, Rf (EtOAc/Hexanc 1:3): 0.2. 1H-NMR (CDCl3): δ 7,01 (s, 1H), 4.75-4.76 (d, 2H), 3.86 (s, 3H), 3.85 (s, 3H ), 2.38 (st 3H), 2.05 (t, 1H).
Step 3: Acetic acid 3-bromo-4-bromomethyl-2,6-dimethoxy-phenyl ester
The title compound was obtained from Acetic acid 3-bromc-4-hydroxymethyl-2,6-dimethoxy-phenyl ester according to the general procedure 2.5. Rf ( EtOAc/Hexane 1:3): 0.8. 1H-NMR (CDCl3); δ 6.87 (s, lH)f 4.60 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H ), 2.36 (a, 3H).
Step 4: Acetic acid 4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenyl ester
The title compound was obtained by alleviation of 2-aimno-6-cbloropurine with acetic acid 3-bromo-4-bromomethyl-2,6-dimethoxy-phenyl ester according to the genera) procedure 1.1. HPLC Rt: 5.081 rain. lH-NMR (CDC13): δ 8.30 (s, 1H), 8.17 (831H), 5.50 (s, 2H), 3.80 (s, 3H), 2.3S (s, 3H)t 2.27 (s, 3H).
Example 314: 4-(2-amino-6-chloro-purin-9-ylmethy))-3-bromo-2,6-dimethoxy-phenol
The title compound was obtained by deacetylation of Acetic acid 4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-diraethoxy-phenyl ester (see previous example) in NH3/MeOH at r.t for 0.5 h or K5CO3 in methanol according to the general procedure 2.3. HPLC Rt: 4.912 min. 1H-NMR (CDCl3): δ 7.85 (s, 1H), 6.72 (s, 1H), 5.70 (s, 1H), 5.33 (s, 1H), 5.07 (s, 2H), 3,94 (s, 3H), 3.82 (s, 3H).
Example 115: 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
t The title compound was obtained by O-methylation of 4-(2-amino-6-chloro-
purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol (see previous example) according to the general procedure 2.6. The title compound could also be obtained by bromination of 6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine (see example 48) in acetate buffer according to the general procedure 3.1. HPLC Rt 5.742 min. 1H-NMR (CDCI3): δ 7.85 (s, IH), 6.66 (s, 1H), 5.32 (s, 2H), 5,11 (s, 211), 3.90 (s, 3H), 3.87 (s, 3H), 3.76 (s, 3H).
Example 116: 9-(4-allyloxy-2-bromo-3,5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylamtne
The title compound was obtained by alkylation of 4-(2-amino-6-calo:o-purin-9-ylmethyl)-3-bromo-2,6-dirnethoxy-phenol (see example 50) with 3-bromo-propene in DMF in the presence of K2CO3 at 70 δC for 0.25-1 h. HPLC Rt: 6.309 min. 1H-NMR (CDO3): δ 7-84 (s, 1H), 6.64 (s, 1H), 6.00-6.10 (m, 2H), 5.36-5,36 (m, 1H), 5.31 (s, 2H), 5.20-5,21 (m, 2H), 4.52-4.54 (m, 2H), 3.90 (s, 3H), 3.74 (s, 2H).
Example 117; 9-(2-bromo-4-chloromethoxy-3,5~dimethoxy-benzyl)-6-chloro-9H-purin-2-yIamfne
The title compound was obtained by alkylation of 4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol (see example 50) with chloroiodornethane in DMF in the presence of K2CO3 at 70 °C for 0.25-1 h. HPLC Rt: 6.109 min. 1H-NMR (CDC13): δ 7.87 (s, IB), 6.66 (s, 1H), 5.91 (s, 2H), 5,34 (s, 2H), 5.08 (s, 2H), 3.90 (s, 3H),3,76(s,3H).
Example US: 9-[2-bromo-4-(2-chloro-ethoxy}-3,5-dimthoxy-benzyl]-6-chloro~9H-
purin-2-ylamine
The title compound was obtained by alkylation of 4-(2-amino-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol (see example 50) with l-bromo-2-chloro-ethane in DMF in die presence of K2C03 at 70 °C for 0.25-1 h. HPLC Rt: 6.285 min. 'H-NMR (CDCl3): δ 7.86 (s, 1H), 6.67 (a, 1H)S 5.37 (s, 2H), 5.32 (a, 2H), 4.22-4.25 (t, 2H), 3.91 (s, 3H), 3.77-3.78 (t, 2H) 3.75 (s, 3H).
Example 119: 9-(2-bromo-4-cyclopropytmetboxy-3,5-dlmetboxy-beazyl)-6-chIoro-9H-pmin-2-ylamlne
The title compound was obtained by alkylation of 4-(2-amino-6-chloro-purin-9-y]niethyl)-3-bromo-2,6-dimethoxy-phenol (see example 50) with bromomethyl-cyclopropane in DMF in the presence of K2CO3 at 70°C for 0.25-1 h. HPLC: Rt: 6.512 min. 1H-NMR (CDC13): δ 7.86 (s, IH), 6.67 (s, 1H), 5,34 (s, 2H), 5.17 (a, 211), 3.95 (s, 3H)> 3.83-3.84 (d, 2H), 3.77 (s, 3H) 1.27(m, IK), 0.5S-0.62(m, 2H), 0.28-0,32 (m, 2H).Example 120: 9-(2-bromo-4-(ethoxy-3,5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
The title compound was obtained by alkylation of 4-(2-amino-6-chIoro-purin-9-y[methyl)-3-bromo-2,6-dimethaxy-phenol (see example 50) with EtI in DMF in the presence of K2CO3 at 70 °C for 0,25-1 h. HPLC Rt: 6.112 min. lH-NMR (CDC13): δ 7.84 (s, 1H), 6.65 (s, 1H), 5.31 (s, 2H), 5.13 (s, 2H), 4.04-4.09 Example 121: 9-(2-bromo-3,5-dimethoxy-4-propoxy-benzyl)-6-chloro-9H-purin-2-ylamine
The title compound was obtained by alkylation of 4-(2-ammo-6-chloro-purin-9-ylmethyl)-3-bromo-2,6-dimethoxy-phenol (see example 50) with PrI tn DMF in the presence of K2CO3 at 70 °C for 0.25-1 h. HPLC Rt: 6.594 min. 1H-NMR (CDCl3): δ 7.84 (s, 1H), 6.65 (s. 1H), 5.30 (s, 2H), 5.14 (s, 2H), 3.93-3.97 (t, 2H), 3.89 (s, 3H), 3.74 (a,3H), 1,72-1.81 (m,2H), 1.00-1.04 (t,3H)
Example 122: 9-(2-bromo-4-butoxy-3,5-dlmethoxy-benzyl)-6-chloro~9H-purin-2-ylamine
The title compound was obtained by alkylation of 4-(2-amtno-6-chloTo-purin-9-yImethyl)-3-bromo-2,6-dirnethoxy-phenol (see example 50) with Bui in DMF in the presence of KjC03 at 70 °C for 0.25-1 h. HPLC Rt: 6.594 min. 1H-NMR (CDCI3): δ 7,84 (s, 1H). 6.65 (s, 1H), 5.30 (s, 2H), 5,14 (s, 2H), 3.97-4.00 (t, 2H), 3.89 Example 123: 6-chloro-9-(3-methoxymethoxy-6-methyl-pyridln-2-ylmethyl)-9H-
purin-2-yIflmine
Step 1: (3-methoxymethoxy-6-raethyl-pyridin-2-yl)-methanol
The title compound was obtained by O-alkylation of 2-hydroxymethyl-6-methyl-pyridm-3-ol with chloromethyl methyl ether according to the general procedure 2.6. lH-NMR (CDCl3) δ 7.28-7.30 (d, 1H), 6.98-7.00 (d, 1H), 5.17 (s, 2H), 4.71 (s, 2H), 4.50 (s,
2H), 3.45 (s,3H), 2,49 Step 2: 2-Bromomethyl-3-methoxyroethoxy-6-methyl-pyridine
The title compound was obtained from (3-methoxyrnethoxy-6-methyl-pyridin-2-yl)-methanol according to the general procedure 2,5. 1H-NMR (CDCl3) δ 7.32-7.40 (d IH), 7.08-7.10 (d, 1H),5.30 (s, 2H), 4.67 (s, 2H), 3.55 (s, 3H), 2.54 Step 3: 6-Chloro-9-(3-methoxymemoxy-6-methyl-pyridin-2-yImethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 2-bromomethy]-3-methoxymethoxy-6-methyl-pyridine according to (he general procedure 1.1. HPLC Rt: 3.884 min. 1H-NMR (CDCl3): δ 7.92 (s, IH), 7.34-7.36 (d, 1H) 7.05-7.07 (d, IH), 5.39 (s, 2H), 5.17 (s, 2H), 5.06 (s, 2H), 3.40 (s, 3H), 2.44 (s, 3H).
Example 124; 3-(2-Amino-6-chloro-purin-9-ylmethyl)-3H-benzothiazole-2-tbloiie
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 3-chloromethyI-3H-berizothiazoIe-2-thione according to the general procedure I.I. HPLC Rt: 5.982 min. 1H-NMR (d6 -DMSO): δ 8.37 (s, IH), 8.25-8.28 (d, IH) 7.79-7.81 (d, IH), 7.54-7.56 (t, IH), 7.39-7.43 (m IH), 7.20 (s, 2H), 6.62 (i,2H), 3.34 (s, 3H).
Example 125: 6-Chloro-9-(2,5-dimethyl-beozyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 2-ch]orornethyl-l(4-dimethyl-benzene according to the general procedure 1.1. HPLC Rt: 5.920 min. 1H-NMR (d6-DMSO): δ 8.10 (s, IH), 7.10 (d, IH) 7.04 (d, IH), 6.95 (s, 2H), 6.65(3, IH), 5.23, (s, 2H), 3.34 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H).
Example 126: 6-chloro-9-isoquiaoIln-l-ylmethyl-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 1-bromomethyl-isoqviinoline according to the general procedure LI. HPLC Rt: 4.306 min. 1H-NMR(d6-DMSO): δ 8.43-8.45 (d, IH) 8.27-8.28 (d, IH), 8,20 (s, IH), 8.03-8.05 {d IH), 7.85-7.89 (m, 1H), 7.77-7.82 (m, 2H), 6.83 (s, 2H), 6.04 (s, 2H).
xample 127: 9-benzo[l,2,5]tbiadlazol-5-ylmethyl-6-chloro-9H-purid-2-ylamine
The title compound was obtained by alkylation of 2-arnino-6-chloropurine with 5-bromomethyl-benzo[l,2,5]thiadiazole according to the general procedure 1.1. HPLC Rt: 4.931 min. lH-NMR (d6-DMSO): δ 8.31 (s, 1H), 8.U (d, 1H), 7.87 (br. s, 1H), 7,70-7.67 (dd, 1H), 6.98 (br, s, 2H), 5.52 (s, 2H).
Example 128: 9-(l-methyl-lH-benzotriazol-5-ylmethyl)-6-chloro-9H-purin-2-ylantiue
The title compound was obtained by alkylation of 2-amino-6-cbJoropurine with 6-bromomethyl-l-methyl-lH-benzotriazole according to the general procedure 1.1. HPLC Rt: 4.295 min. 1H-NMR (d6-DMSO): 5 8.29 (s, IK), 7.95 (s, 1H), 7.86-7.84 (d, 1H), 7.55-7.53 (dd, 1H), 6.97 (s, 2H), 5.45 (s,2H),4.3 (s, 3H).
Example 129: 6-chloro-9-(6-chloro-benzo[l,2,5]thiadiazol-5-ylmethyl)-9H-purin-2-ylarnine
The title compound was obtained by alkylation of 2~arnino-6-cbJoropurine with 5-bromomethyl-6-chloro-benzo[l,2,5Jthiadiazole according to the general procedure 1.1. HPLC Rt: 5.400 min. 1H-MMR (ds-DMSO): δ 8.45 (s, 1H), 8.20 (s, 1H), 7.64 (s, 1H),
6.97 (s,2H), 5.55 (s,2H).
Example 130: 9-benzo[l,2,5]thiadia2ol-4-ylmethyl-6-chloro-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 4-bromomethyl-benzo[l,2,5]thiadia2io1e according to the general procedure 1.1. HPLC Rt: 5.027 min. 1H-NMR (d6-DMSO); δ 8,26 (s, IK), 8.04-8.07 (d, 1H), 7.68-7.64 (dd, 1H), 7.22-7.20 (dd, 1H), 6.93 (s, 2H), 5.79 (s, 2H).
Example 131: 6-chloro-9-(6-fluoro-4a,8a-diBydro-4H-benzoIl,3]dioxin-8-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 8-chloromethyl-6-fluoro-4a,8a-dihydro-4H-benzo[l,3]dioxine according to the general
procedure 1.1. HPLC Rt: 5.172 min. 1H-NMR (CDCI3):δ 7.84 (s, IH), 6.92-6.89 (dd, IH), 6.70-6.67 (dd, IH), 5.31 (s, 2H), 5.22 (s, 2H), 5.07 (s, 2H),4.90 (s, 2H).
Example 132: l-(3-(2-Amino-6-chloro-purin-9-ylmethyl)-4-methoxy-phenyl]-ethanone
The title compound was obtained by alkylation of 2-amino-6-chloropurine with l-(3-chloromethyl-4-methoxy-pheny])-ethanone according to the general procedure 1.1. HPLC Rt 4.887 min. 1H-NMR (CDCI3): δ 8.03-8.02 (d, 1H), 7.97-7.95 (dd, IH), 7.81 (s, 1H), 6.96-6.93 (d, IH), 5.25 (5, 2H), 5.08 (s, 2H), 3.93 Example 133: 6-chloro-9-(3-trifluoromethexy-benzyl)-9H~purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 1 -chIoromethyl-3-trifluoromethoxy-ben2ene according to the general procedure 1.1. HPLC Rt: 5.965 min, 1H-NMR (CDC13)'.δ 7.76 (s, IH), 7.39-7.37 (t, IH), 7.21-7.15 (m, 3H), 5.27 (s, 2H), 5,12 (s, 2H).
Example 134: 6-chloro-9-(2-fluoro-3-trifluorometbyl-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-anrino-6-chlaropurine with l-bromomethyl-2-fluoro-3-trifluoromethyl-benzene according to the general procedure 1.1. HPLC Rt: 4.841 min. lH-NMR (CDCI3): S 7.83 (s, IH), 7.63-7.59 (t, IH), 7.48-7.45(t, IH), 7.25-7.22 (t, IH), 5.36 (s, 2H), 5.12 (s, 2H).
Example 135: 6-Chloro-9-(2-fluoro-4,5-dimethoxy-benzyl)-9H-purin-2-ylamine
Step 1; (2-Fluoro-4,5-dimethoxy-phenyl)-methanol
A solution of 2-fluoro-4,5-dimethoxy-benzaIdehyde (6.0 rnmol) in MeOH (10 mL) was treated with NaBH4 (1.2 equiv.) at 0-23 "C for 0.5 h. After quenching with acetone and evaporating the solvent, work-up (CH2CI2), drying (MgSO4)) and evaporation gave the title compound as a crude oily product (94% yield). 1H-NMR (CDCI3): δ 6.90-6.88 (d, IH), 6.61-6.64 (d, 1H), 4.65-4.63 (d, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.00-1.94 (t, IH).
Step 2: 1 -Bromomethyt-2-fluoro-4,5-dimethoxy-benzcne
The title compound was obtained from (2-fluoro-4,5-dimethoxy-phenyl)-methanol according to the general procedure 2.5. 1H-NMR (CDCl3): δ 6.84-6.81 (d, 1H), 6,64-6.61 (d, IH), 4.52 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).
Step 3: 6-Chloro-9-(2-fluoro-4,5-dunethoxy-benzy)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 1 -bromomethyI-2-fluoro-4,5-dimethoxy-benzene according to the general procedure 1.1. HPLC Rt: 4.939 min, 1H-NMR (CDCl3): δ 7.79 (s, 1H), 6,88-6.85 (d, 1H), 6.69-6.66 (d, IH), 5,22 (s, 2H), 5.12 (s, 2H), 3.89 (s, 3H), 3,82 (s, 3H).
Example 136: 6-chloro-9-(2,3-dimethoxy-benzyl)-9H-purin-2-ylaraine
Step 1: l-BromomethyI-2,3-dimethoxy-benzene
The title compound was obtained from (2,3-dimethoxy-phenyl)-methanol according to the general procedure 2.5, 1H-NMR (CDCl3): δ 7.02-7.08 (t, IH), 6.95-6.98 (dd, IH), 6.87-6.91 (dd, IH), 4.57 (s, 2H), 3.92 (s, 3H), 3.86 (s, 3H).
Step 2: 6 The title compound was obtained by alkylation of 2-ammo-6-cbloropurine with l-bromomethyl-2,3-dirnethoxy-benzene according to the general procedure 1.1. HPLC Rt: 5.200.1H-NMR (CDCI3): δ 7.81 (s, IH), 7.02-7.08 (t, IH), 6.95-6.98(dd, IH), 6.87-6.91 (dd, IH), 5.28 (s, 2H), 5.12 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H).
Example 137: 6-chloro-9-(3,4~dimethoxy-benzyl)-9H-purin-2-ylamine
Step I: 4-Bromomethyl-l,2-dimethoxy-benzene
The title compound was obtained from (3,4-dimethoxy-pheny])-methanol according to the general procedure 2.5. 1H-NMR (CDCl3): δ 6.95-6.98 (dd, IH), 6.92-6.94 (d, IH), 6.7S-6.81 (d, IH), 4.51 (a, 2H), 3.92 (s, 3H)f 3.86 (s, 3H).
Step 2: 6-Chloro-9-(3,4-dimeaioxy-benzyl)-9H-purin-2-yamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 4-bromomethyl-1,2-dimethoxy-benzene according to the general procedure 1.1. HPLC Rfc 4.753.
1H-NMR(CDC13): δ 7.71 (s, 1H), 6.87 (s, 2H), 6.S2 (s, IH), 5.20 (s,2H),-5.12 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H).
Example 138; 9-{2-chloro-3,4,5-trimethoxy-beniyl)-6-methyl-9H-purin-2-ylamine
A suspension of 6-chloro-9-(2-chloro-3J4,5-trimethoxy-benzyl)-9H-purin-2-ylamine, see example 97) {0.2 mmol) and tetrakis(triphenylphosphino)-palladium (0,02 mtnol) in dry THF (3 mL) was treated with trimethylalumimtm (2M in toluene, 0.45 mmol) under nitrogen and heated to reflux for 3 h. The reaction mixture was cooled to r.t, diluted with toluene (5 mL) and quenched with methanol (0.5 mL) followed by ammonium chloride (1 mmol). The mixture was heated to reflux for 2 h and filtered, while hot, on Celite. See J. Med. Chem, 1999, 42, 2064-2086. TLC (100% EtOAc) Rf was 0.2. HPLC Rt: 4.800 min.
Example 139: 6-chloro-9-(2-chloro-4,5-dimethoxy-benmzyl)-9H-puriin-2-ylamine
Step I: (2-Chloro-4,5-dimethoxy-phenyl)-methanol
The title compound was obtained by chlorination of (3,4-dirnethoxy-phenyI)-methanol according to the genera! procedure 3.1. 1H-NMR (CDC13): δ 7.01 (s, 1H), 6.88 (s, IH), 4.75-4.73 (d, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 1.95-1.92 (t, 1H).
Step 2: l-Bromomethyl-2-chloro-4,5-dimethoxy-benzene
The title compound was obtained from (2-chloro-4,5-dimethoxy-phenyl)-methanol according to the general procedure 2.5. 1H-NMR (CDCl3): δ 6.92 (s, IH), 6.88 (s, IH), 4.60 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H).
Step 3: 6-Chloro-9-(2-ch1oio-4,5-dtmethoxy-benzyl)-9II-purin-2-ylamine
The title compound was obtained by alkyJatton of 2-amino-6-cliloropurine with l-broinomcthyl-2-chloro-4,5-dimethoxy-benzene according to the general procedure 1.1.
HPLC Rt: 5.366 min. lH-NMR (CDCl3): δ 7,81 (s, 1H), 7.28 (s, 1H), 6.92 (s, 1H), 5.30 (s, 2H), 5.15 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H).
Example 140; 6-chloro-9^2-iodo-4,5-diuictboxy-bci)zyI)-9H-purin-2-yla!mine
Step 1: 4-BromomethyI-l,2-dimethoxy-benzene
The title compound was obtained from (3,4-dimethoxy-phenyl)-methanol according to the general procedure 2.5. 1H-NMR (CDC13): δ 6.95-6.98 (dd, 1H), 6.92-6.94 (d, 1H), 6.78-6.81 (d, 1H), 4.51 (s, 2H), 3.92 (s, 3H), 3.86 (s, 3H).
Step 2: l-Bromomethyl-2-iodo-4,5-dimethoxy-benzene
The title compound was obtained by iodination of 4-bromomethyI-l ,2-diniethoxy-benzene according to the general procedure 3.1. 1H-NMR (CDCI3): δ 7.04 (s, 1H), 6.95 (g, 1H), 4.61 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H).
Step 3: 6-Chloro-9-(2-iodo-4f5-dimemoxy-benzyl)-9H-purin-2-ylaraine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 1 -bromomethyI-2-iodo-4,5-dimethoxy-benzene according to the general procedure 1.1. HPLC Rt; 5.470 min. 1H-NMR (CDCI3): δ 7.84 (s, 1H), 7.08 (a, 1H), 6.93 (a, 1H), 5.30 (a, 2H), 5.15 (s, 2H), 3.91 (s, 3H), 3.82 (s, 3H).
Example 141: 6-Bromo-9-(2-cbloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
Step 1: 2-Chloro-l-chloromethyl-3,4,5-trirnethoxy-benzene
The title compound was obtained by chlorination of 5-chloromethyl-l,2,3-trimethoxy-benzene according to the general procedure 3.1. 1H-NMR (CDCI3): δ 6.82 (s, 1H), 4.70 (a, 1H), 3.93 (a, 3H), 3.90 (s, 3H) 3.87 (a, 3H).
Step 2: Synthesis of 6-chIoro-9-(2-chIoro-3,4,5-trimemoxy-benzyl)-9H-purin-2-yIamine
The title compound was obtained by ailkylation of 6-bromoguanine with 2-chloro-1 -chloromethyl-3 4,5-rrimethoxy-ben2icne according to the general procedure 1,1, HPLC Rt; 5.676 min. 1H-NMR (CDCI3): δ 7.82 (s, HI), 6,70 (s, IH), 5.32 (a, 2H), 5.15 (s, 2H), 3.93 (5, 3H), 3.91 (a, 3H) 3.79 (s, 3H).
Example 142; 6-chIoro-9-(6-chaloro-benzo[l,3]dioxol-5-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 5-chloro-6-chloromethyl-benzo[l ,3]dioxoIe according to the general procedure 1. t. HPLC Rt 5.506 min. lH-NMR (CDCl3): δ 7.81 (s, IH), 6.88 (s, IH), 6.79 (s, IH), 5.98 (s, 2H), 5.25 (a, 2H), 5.13 (s, 2H).
Example 143: 6-chloro-9-(2,4-dimethoxy-3-methy1-benzyI)-9H-purin-2-ylamine
Step J: l-Bromomethyl-2,4-dimethoxy-3-methyl-benzene
The title compound was obtained from (2,4-diraethoxy-3-methyl-phenyl)-methanol according to the general procedure 2.5.
Step 2: e-Chloro-9-(2,4-dimethoxy-3--methyl-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with l-bromomemyl-2,4-dimethoxy-3-methyl-benzene according to the general procedure 1.1. HPLC Rt; 5.433 min. 1H-NMR (CDCl3): δ 7.76 (a, IH), 7.08-7.06 (d, IH), 6.60-6.62 (4, tH), 5.20 (s, 2H), 5.07 (a, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 2.17 (s, 3H).
Example 144: 6-chloro-9-(2-chloro-3,4-dimethoxy-benzyl)-9H-purin-2-ylamine
Step 1: t-BromomethyI-2-cbJoro-3,4-dimethoxy-benzene
The title compound was obtained from (2-chloro-3,4-dimeihoxy-phenyl)-methanol according to the general procedure 2.5.
Step 2: 6-Chloro-9-(2-chloro-3,4-dimeihoxy-benzyl)-9H-purin-2-ylaminc
The title compound was obtained by alkylation of 2-amino-6-chloropurine with l-bromomethyl-2-chloro-3,4-dimethoxy-benzene according to the general procedure 1,1. HPLC Rt: 5.633 min. 1H-NMR (CDCI3): δ 7.80 (s, 1H), 7.00-6.98 (d, 1H), 6.82-6.79 (d, IH), 5.31 (a, 2H), 5.08 (s, 2H), 3.88 (s, 3H), 3.88 (s, 3H),
Example 145: 6-chloro-9-(3-methoxy-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with l-bromomethyl-3-methoxyben2ene according to the general procedure 1.1. HPLCRt: 5.136 mm. 1H-NMR (CDCl3): δ 7.75 (s, IH), 7.30-7.28 (m. 1H), 6.88-6.85 (dd, IH), 6.84-6.82 (dd, IH), 6.80-6.79 (m, JH). 5.28 (s, 2H), 5.15 (s, 2H), 3.78 (s, 3H).
Example 146: 6-Chloro-9-(2,6-dibromo-3,5-dimethoxy-benzyl)-9H-pnrin-2-ylamine
Step J: 2-Bromo-i-chloromefayl-3,5-dimethoxy-benzene and 2,4-dibromo-3-chloromethyl-1,5-dtmethoxy-benzene
Bromination of l-chloromemyl-3,5-dimethoxy-benzene according to the general procedure 3.1 gave a mixture of the two title compounds, which were separated by flash chromatography. 1H-NMR of 2,4-dibromo-3-chloromethyl-1,5-dimethoxy-benzene (CDC13): 6 6.52 (s, IH), 5.02 (s, 2H), 3.93 (s, 6H). 2-bromo-I-chloromethyl-3,5-dimethoxy-benzene 1H-NMR (CDCl3): δ 6.67-6.67 (d, IH), 6.47-6.46 (d, IH), 4.80 (s, 2H), 3.85 (s,3H), 3.82 (s, 3H).
Step 2: 6-Chloro-9-(2,6-dibramo-3,5-dimethoxy-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-atnino-6-chIoropurme with 2J4-dibromo-3-chloromethyl-1,5-dimethoxy-benzene according to the general procedure 1.1. HPLC Rt: 6,022 ram. 1H-NMR(CDCl3):δ 7.46(s, IH),6.64(s, IH), 5.64 (s,2H), 5.14(s,2H),3.99(8,6H).
Example 147: 9-(2-Bromo-3,5-dimethoxy-benzyl)-6-chloro-9H-parltt-2-yIamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with
2-bromo-I -chloromethyl-3,5-dimethoxy-benzene (see previous example, step 1) according to the general procedure 1.1. HPLC Rt: 6.026 min. lH-NMR (CDCl3): δ 7.82 (s, IH), 6.48-6.47 (d, IH), 6.32-6.32 (d, IH), 5.35 (s, 2H), 5.09 (s, 2H), 3.90 (a, 3H), 3.73 (s, 3H).Example 148: 6-chloro-9-(3,5-dimethoxy-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with l-chloromethyl-3,5-dimethoxy-benzene according to the general procedure 1.1. HPLC Rt: 5.257 min. 1H-NMR (CDCl3): δ 7.79 (s, 1H), 6.44-6.42 (t, 1H), 6.41-6.39 (d, 2H), 5.22 (s, 2H), 5.15 (s, 2H), 3.80 (s, 6H).
Example 149: N-[6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-yl]-acetamide
A solution of 6-chloro-9-(3,4,5-triimethoxy-benzyl)-9H-purin-2-ylamine in acetic acid was treated with fuming HNO3 at 0 °C for 15 min. Work-up and preparative TLC (EtOAc:hexane 1:1) gave N-[6-chIoro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-yI]-acetamide. HPLC Rt: 5.744 min. 1H-NMR (CDCl3): δ 8.09 (s, 1H), 6.58 (s, 2H), 5.33 (s, 2H), 3.85 (s, 3H), 3.85 {s, 6H), 2,43 Example 150: 6-chloro-9-(2,5-dimetnoxy-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chIoropurine with l-chloromethyl-2,5-dimethoxy-benzene according to the general procedure 1.1. HPLC Rt: 5.291 min. 1H-NMR (CDCl3): δ 7.82 (s, 1H), 6.85-6.84 (d, 1H), 6.82-6.82 (d, 2H), 5.18 (a, 2H), 5.16 (s, 2H). 3.80 (s, 3H), 3.75 (s, 3H).
Example 151: 8-bromo-6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purin-2-ylamine
The title compound was obtained by bromination of 6-chloro-9-(2,5-dimethoxy-benzyl)-9H-purin-2-ylamine according to the general procedure 1.2. HPLC Rt: 6.150 min. 1H-NMR (CDCl3): S 6.83-6.78 (m, 2H), 6.37-6.36 (d, 1H), 5.31 (s, 2H), 5.13 (b, 2H), 3.83 (s,3H), 3.70 (s, 3H).
Example 152: 6-chloro-9-(4,5-dimethoxy-2-niiro-benzyl>9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 1 -bromomethyl-4,5-dimethoxy-2-tiitro-ben2iene according to the genera! procedure 1.1. HPLC Rt; 5.194 min. 1H-NMR (CDCl3): δ 7,98 (s, 1H), 7.74 (s, 1H), 6.79 (s, 1H), 5.67 >, 2H), 5.15 (s, 2H), 3.98 (s, 3H), 3.85 (s, 3H).Example 153: 8^bromo-6-chloro-9-(4,5-dimethoxy-2-nUio-bcnzyl)-9H-piirin-2-ylamine
The title compound was obtained by brominating 6-chloro-9-(4,5-dimethoxy-2-nitro-benzyl)-9H-purin-2-ylanime (see previous example) according to the general procedure 1.2. HPLC Rt: 6.040 min, 1H-NMRCCDCb): 5 7.74(a, 1H),6.I3 (s, 1H), 5.78 (s, 2H), 5.16 (a, 2H), 3.99 (s, 3H), 3.71 (s, 3H).
Example 154: 6-chloro-9-{2,5-dichloro-benzyI)-9H-purin-2-ylarnine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 2-bromomethyl-l,4-dichloro-benzene according to the general procedure I.I. HPLCRt: 5.846 min. 1H-NMR (CDC13): δ 7.82 (s, 1H), 7.38-7.36 (d, 1H), 7.28-7.26 (dd, 1H), 7.18-7.18 (d, 1H), 5.32 (s, 2H), 5.17 (s, 2H).
Example 155: 6-chloro-9-(2,3,5-trifluoro-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-arnino-6-chloropurine with l-bromomethyl-2,3,5-trifluoro-benzene according to the general procedure 1.1, HPLC Rt; 5.414 min. 1H-NMR (CDCl3): δ 7.82 (s, 1H), 6.98-6.89 (m, 1H), 6.82-6.75 (m. 1H), 5.30 (s,2H), 5.13 (s,2H).
Example 156: (2-amino-6-chloro-purin-9-yl)-(3,4,5-trimethoxy-phenyl)-methanone
A solution of 6-chIoro-9H-purin-2-ylamine in pyridine was treated with 3,4,5-trirnethoxybenzoyl chloride at r.t, for 2 h. Work-up and purification by preparative TLC (EtOAc:hexanel:I)gavethetitlecompound. HPLCRt: 5.305min. 1H-NMR (CDCI3): 5 8.24 (s, 1H), 7.13 (s, 2H), 5.36 (s, 2H), 3.99 (s, 3H), 3.88 (s, 6H).
Example 157: N-[9-(2-Bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-yl]-aceramide
A suspension of 9-(2-bromo-3,4,5-tTimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine (example 51) in acetic anhydride was treated with a catalytic amount of cone. H2SO4 at r.t. for 3 h. Work-up and purification by preparative TLC (EtOAc:hexanc 9:1)gave the title compound. HPLC Rt: 5.603 min. 1H-NMR (CDC13): δ 8.20 (s, 1H), 8.10 (s, 1H), 700 (s, 1H), 5.47 (s,2H), 3.92 (s, 3H)t 3.90(s, 3H), 3.86 (s,3H), 2,51 (s, 3H).
Example 158: N-[9-(2-bron»o-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-yl]-N-methyl-acetamide
A mixture of N-[9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-yl]-acetamide and NaH in DMF was stirred at r.t for 15 min, before adding Mel. Stirring was prolonged for 2 h at 50 "C. Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave foetitle compound HPLC Rt: 6.422 min. 1H-NMR (CDCI3): 5 8.20 (s, 1H), 6,80 (s, 1H), 5.45 (s, 2H), 3.93 (a, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.57 (s, 3H),2.51(s,3H).
Example 159: 6-chloro-9-(3,5-dicbloro-benzyl)-9H-purin-2-ylamine
Step 1: l-Bromomethyl-3,5-dichloro-benzene
The title compound was obtained from (3,5-dicbloro-phenyl)-rnethanol according to the general procedure 2.5.
Step 2: 6-chloro-9-(3,5-dichloro-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with l-bromomethyl-3,5-dichloro-benzene. HPLC Rt: 6,074 min. 1H-NMR (Acetone-d6): δ 8.12 (s, 1H), 7.45-7.43 (t, 1H), 7.72-7.42 (d, 2H), 6.30 (s, 2H), 5.40 Example 160: 6-chIoro-9-(3,4-dichloro-benzyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 4-bromomethyl-l,2-dichloro-benzene according to the general procedure l.l, HPLC Rt: 5,982 min. 1H-NMR (CDCl3): δ 7,76 (s, 1H), 7.48-7.45 (d, 1H), 7.40-7.39 (d, 1H), 7.12-7.10 (dd, 1H), 5.23 (a, 2H), 5.12 (s, 2H).
Example 161: 8-bromo-6-chloro-9-(3,4-dfcbIoro-benzyl)-9H-purin-2-ylainliie
The title compound was obtained by bromination of 6-chloro-9-(3,4-dichloro-benzyl)-9H-purin-2-ylaminc (sec previous example) according to the general procedure1.2. HPLC Rt: 6.878 min. 1H-NMR (CDC13); δ 7.45-7.43 (m, 2H), 7.17-7.14 (dd, 1H), 5.23 (s,2H), 5.12 (s,2H).
Example 162: 6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylainine
Chlorination of 6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine according to the general procedure 3.1 gave a mixture of the title compound and of 6-chloro-9-(2,6-dichloro-3,4f5-trimethoxy-benzyI)-9H--purin-2-ylaniirie. The two compounds were isolated by preparative TLC. HPLC Rt; 5.626 min. 1H-NMR (CDC13):
δ 7.83 (s, IH), 6.68 (s, 1H), 5.51 (s, 2H), 5.23 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H).
Example 163: 6-chloro-9-{2,6-dtchloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
See the previous example. HPLC Rt: 6.099 min. 1H-NMR (CDCI3): 5 7.57 (s, IH), 5.48 (st 2H), 5.12 (s,2H), 3.99 (s, 3H), 3.92 (s, 6H).
Example 164: 2-amino-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-6-ol
The title compound was obtained by heating a solution of 6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine (see example 98) in IN HC1 for 4 h. Solvent was evaporated and the residue was washed with EtOAc to give the title compound. HPLC Rt: 4.603 min. 1H-NMR (DMSO-d6): δ 7.82 (s, IH), 6.65 (s, IH), 6.60 (s, 2H), 5.15 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.69 (s, 3H).
Example 165: 6~bromo-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamtne
The title compound was obtained by alkylation of 6-bromoguanine with 3-chIoromethyl-3,4,5-trimethoxy benzene according to the general procedure 1.1. HPLC Rt: 4.947 min. 1H-NMR (CDCl3): δ 7.80 (s, IH), 6.50 (s, 2H), 5.20 (s, 2H), 5.18 (s, 2H), 3.85 (s, 3H), 3.84 (s, 6H).
Example 166: 6-bromo-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylainine
The title compound was obtained by bromination of 6-bromo-9-(3)4,5-trimethoxy-bcazyl)-9H-purin-2-ylamine (see previous example) according to the general procedure 3.1. HPLC Rt: 5.793 min. 1H-NMR (CDCl3): δ 7.88 (g, 1H), 6.68 (s, IH), 5.33 (s, 2H), 5.19 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3,79 (s, 3H).
Example 167: 9-(2-bron]0-3,4,5-trimethoxy-benzyl)-6-ethylsulfanyl-9H-purin-2-ylamine
A mixture of 6-bromo-9-(2-bromo-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine (see previous example), EtSH, K2CO3 and THF was placed in a pressure vessel and heated to 70 °C for 6 h, Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave the title compound. HPLC Rt: 6.039 min. 1H-NMR (CDCI3): δ 7.72 (s, 1H), 6.62 (s, IH), 5.30 (s, 2H), 4.98 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H), 3.35-3.29 (q, 2H), 1.44-1,41 (t,3H).
Example 168: 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-methoxy-9H-purln-2-ylamine
A solution of 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine (see example 51) in MeOH was treated with MeONa at reflux for 1 h. Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave the title compound. HPLC Rt: 5.229 min. 1H-NMR (CDCI3): δ 7.69 (sf IH), 6.58 (s, IH), 5.33 (s, 2H), 4.88 (s, 2H), 4.11 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 3.74 (s, 3H).
Example 169: 9-(2-bromo-3>4,S-trimethoxy-benzyl)-9H-purltie-2,6-diamine
A solution of 9-(2-bromo-3,4,5-trimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine (see example 51) in MeOH was treated with NH3 (7N in MeOH) in a pressure vessel at 90 °C for 16 h. Work-up and purification by preparative TLC (EtOAc:hexane 3:1) gave the title compound. HPLC Rt: 4.884 rain. 1H-NMR (DMSO-d6): δ 7.67 (s, 1H), 6.71 (s, 2H), 6.60 (s, IH), 5.84 (s, 2H), 5.17 (s, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.66 (s, 3H).
Example 170; 6-chloro-9-(2-iodo-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine
The title compound was obtained by iodination of 6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-y!aminc (see example 48) according to the general procedure 3.1, HPLC Rt: 5.887 min. lH-NMR (CDC13): δ 7.87 (s, 1H), 6.67 (s, 1H), 5.33 (s, 2H), 5.22 (s, 2H), 3.91 (s, 3H), 3,88 (s, 3H), 3.77 (s, 3H).
Example 171: 9-(2-bromo-3,5-dimetboxy-4-methoxymethoxy-benzyl)-6~chloro-9H-purin-2-ylamfne
The title compound was obtained by alkylation of 4-(2-amvno-6-chloro-purin-9-ylniethy])-3-bromo-2,6-dimethoxy-phenol (see example 50) chloromethyl methyl ether according to the general procedure 2.6 (NaOH, THF, r.t.) HPLC Rt: 5.817 min. 1H-NMR (CDCl3): δ 7.90 (s, 1H), 6.70 (s, 1H), 5.35 (s, 2H), 5.32 (s, 2H), 5.17 (s, 2H), 3.93
(s, 3H), 3.78 (s, 3H), 3.62 (s, 3H).
Example 172; 9-benzotliiazol-2-ylmethyI-6-chloro-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 2-bromomethyl-benzothiazole according to the general procedure 1.1. HPLC Rt: 5.055 min, 1H-NMR (DMSO-d6): δ 8.34 (s, 1H), 8.09-8.07 (dd, 1H), 7.98-7.96 (d, 1H), 7.53-7,50 (m, 1H), 7.47-7.43 (m, 1H), 7.01 (s, 2H), 5.81 (s, 2H).
Example 173: 6-chIoro-9-(4-methoxy-benzyl)-9H-purin-2-yIamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with l-chloromethyl-4-methoxy-benzene according to the general procedure 1.1. HPLC Rt: 5.067 min. 1H-NMR (CDCl3): δ 7.69 (s, 1H), 7.22-7.20 (d, 2H), 6.88-6.86 (d, 2H), 5.22 (s, 2H), 5.17 (st 2H), 3.79 (s, 3H).
Example 174: 9-(2-bromo-4,5-dimetboxy-benzyl)-6-chloro-9H-purin-2-ylamine
Step 1: (2-Bromo-4,5-dimcthoxy-phenyl)-methanol
The title compound was obtained by bromination of (3,4-dimethoxy-phenyl)-methanol according to the general procedure 3,1. lH-NMR (CDCl3): δ 7,03 (s, 1H), 7.03 (s, 1H), 4.70 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H)
Step 2: l-Bromomethyl-2-chloro-4,5-dimethoxy-benzene
The title compound was obtained from (2-bromo-4,5-dimethoxy-phenyI)-methanol according to the general procedure 2.5. lH-NMR (CDCl3): δ 7,03 (s, 1H), 6.94 (s, 1H), 4.60 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H)
Step 3: 9-(2-Bromo-4,5-dimethoxy-benzyl)-6-chloro-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chIoropurine with l-bromomethyl-2-chIoro-4,5-dimethoxy-benzene according to the general procedure 1.1. HPLC Rt; 5.458 min. 1H-NMR (CDCl3): δ 7.84 (s, 1H), 7.08 (s, 1H), 6.93 (s, 1H), 5.30 (s, 2H), 5.15 (s, 2H), 3.90 (s, 3H), 3,82 (s, 3H).
Example 175: 6-Chloro-9-(4-iodo-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
Step J: 2,3,5-Collidine-N-oxide
The title compound was obtained by oxidation of 2,3,5-colIidine according to the genera! procedure 2.1 (yield 70%). HPLC Rt: 3.964 min. 1H-NMR (CDCl3): δ 8.03 (s, 1H), 6.90 (s, 1H), 2.47 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H). m/z (%) 138.2 (M+l, 100%). Rf (20% MeOH/EtOAc) was 0.35.
Step 2; 2,3,5-Trimethyl-4-nitro-pyridine 1-oxide
A suspension of 2,3,5-colldine-N-oxide (3.77 g, 28 mmol) in cone. H2SO4 (8 mL) was cooled to 0 °C and fuming HNO3 (5 mL, 100 mmol) was added dropwise. The resulting transparent solution was stirred at 100 °C for 24 h, cooled to r.t., poured onto ice, and the pH was adjusted to 10. Work-up (CHCl3), drying (MgSO4), and evaporation gave the title compound, (97% yield, 97% purity). Rf (MeOH/EtOAc 1:9): 0.7. HPLC Rt: 4.756 min. 1H -NMR (CDCl3): δ 8.08 (s, 1H), 2,50 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). m/z (%) 183.1 (M+l, 100%).
Step 3: 2,3,5-Trimethy]-pyridin-4-ylamine-l-oxide hydrochloride
A suspension of 2,3>5-trimethyl-4-nitro-pyridinc 1-oxide (4.2g, 23 mmol) and 10% Pd/C (0.42 g) in cone. aq. HCI/EtOJ I {1:11) was treated with H2 (60 psi) at r.t. for 3 h. Filtration and evaporation gave the title compound as a slightly yellow solid. HPLC
Rt: 4.756 rain. 1H-NMR (DMSOd6): δ 8.2S (s, 1H), 7.24 (s, 2H), 2.50 (s, 3H), 2.12 (a,
3H), 2.11 (s, 3H). m/z (%) 153.2 (M+l, 100%).
Step 4: 4-Iodo-2,3,5-trimethyl-pyridtne-l-oxide
A solution of 2,3,5-Trimethy'-pyridin-4-ylamine-l -oxide hydrochloride (1,9 g, 10 mmol) HBF4 (20 mmol) in water (50 mL) was cooled to 0°C. A solution of NaNO (0.76 g, 11 mmol) in water (5 mL) was added dropwise to give a dark yellow solution which gradually gave a precipitate within 15 min. Potassium iodide (2.3 g, 1.39 x 10-02 mol) was added slowly in several portion to give a dark brown precipitate. The reaction mixture was stirred at r.t. for 5 min, and then heated to 60 °C for 10 min. The mixture was cooled to r.t. and the pH was adjusted to 10. Work-up (CHCl3), drying (MgSO4), evaporation, and flash chromatography gave the title compound. HPLC Rt: 5.579 min. 1H-NMR (CDCl3): δ 8.07 (s, 1H), 2.62 (s, 3H), 2.56 (s, 3H), 2.38 (s, 3H). m/z (%) 264.1 (M+l, 100%).
Step 5: Acetic acid 4-iodo-3,5-dimethyl-pyridin-2-ylmethyl ester
The title compound was obtained by treating 4-iodo-3,5-dimethyl-pyridine 1-oxide was with AC2O according to the general procedure 2.2. HPLC Rt: 2.913 min, 'H-NMR (CDC13); δ 8.26 (s, 1H), 5.32 (s, 2H), 2.47 (s, 3H), 2.41 (s, 3H), 2.24 (s, 3H). m/z {%) 306.0 (M+l, 100%).
Step 6: (4-Iodo-3,5-dimemyl-pyridin-2-yl)-methanol
The title compound was obtained by deacetylation of 4-iodo-3,5-dimethyl-pyridin-2-ylmethyl ester according to the general procedure 2.3. HPLC Rt: 3.773 min. 1H-NMR (CDCl3): δ 8.15 (s, 1HJ/4.70 (s, 2H), 2.46 (s, 3H), 2.40 (s, 3H). m/z (%) 264.1
(M+l, 100%).
Step 7: 2-Bromomethyl-4-iodo-3,5-dimethyl-pyridine
The title compound was obtained from (4-Iodo-3,5-dimethyl-pyridin-2-yl)-methanol according to the general procedure 2.5. HPLC Rt: 5.957 min, 1H-NMR (CDCI3): δ 8.14 (s, 1H), 4.67 (s, 2H), 2.59 (s, 3H), 2.45 (s, 3H). m/z (%)326.07 (M+l,
100%), 328,07 (M+l, 100%).
Step 8: 6-Chloro-9-(4-iodo-3,5-dimethyl-pyridin-2-yImethyl)-9H-purin-2-ytamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 2-bromomethyl-4-iodo-3,5-dimethyl-pyridine according to the general procedure 1.1. HPLC Rt: 5.361 min, 1H-NMR (CDC13); δ 8.08 (s, 1H), 7.86 (s, 1H), 5.41 (s, 2H), 5.04 (s, 2H), 2.57 (s, 3H), 2.41 (s, 3H).
Example 176: 6-chloro-9-{4-methyl-quinolin-2-ylmethyl)-9H-purin-2-ylamine
Step 1; 2,4-Dimethyl-quinoline 1-oxide:
The title compound was obtained by oxidation of 2,4-dimethyl-qumoline according to the general procedure 2.1. HPLC Rt 4.489 min. 1H-NMR (CDC13): δ, 8.89-8.07 (dd, 1H), 8.00-7.97 (dd, 1H), 7.82-7.79 (m, 1H), 7.69-7.65 (m, 1H), 7.20 (s, 1H), 2.73 (s,3H), 2.69 (s,3H).
Step 2; Acetic acid 4-methyl-quinolin-2-ylmethyl ester
The titie compound was obtained by treating 2,4-dimethyl-quinoIine-1-oxide with Ac20 according to the general procedure 2.2. HPLC Rt: 3.158 min. Rf(EtOAc/Hexane
1:1): 0.8.
Step 3: (4-Methyl-quinolin-2-yl)-methanol:
The title compound was obtained by deacetylation of acetic acid 4-methyl-quinolin-2-yiraethyl ester according to the general procedure 2.3. HPLC Rt: 3.715 min. 1H-NMR (CDCl3); δ, 8.0S-8.06 (dd, 1H), 8.00-7.97 (dd, 1H), 7.73-7,69 (m, 1H), 7.57-7.54 (m, 1H), 7,12 (s, 1H), 4.87 (s, 2H), 4.52 (s, 1H), 2.70 (s, 3H).
Step 4: 2-bromomethyl-4-niethyl-quinoline:
The title compound was obtained from (4-methyl-quinolin-2-yl)-metnanol according to the general procedure 2.5. HPLC Rt: 4.516 min. 1H-NMR(CDC13): δ, 8.07-8.05 (dd, 1H), 7.98-7.96 (dd, 1H), 7.73-7.69 (m, 1H), 7.58-7.54 (m, 1H), 7.40 (d, 1H), 4.66 (s,2H), 2.70 (s,3H).
Step 5: 6-chloro-9-(4-methyl-quinolm-2-ylmemyl)-9H-purin-2-ylamine
The title compound was obtained by alleviation of 2-ammo-6-chloropurine with 2-bromomethyl-4-methyI-quinoline according to the general procedure 1.1. HPLC Rt: 4.387 min. 1H-NMR (DMSO-d6): 5 8.31 (s, 1H), 8.11-8.09 (dd, 1H), 7.90-7.88 (dd, III), 7.77-7.74 (m, 1H), 7.66-7.62 (m, 1H), 7.27 (s, 1H), 6.91 (s, 2H) 5.58 (s, 2H), 2.68
(s, 3H).
Example 177: 6-bromo-9-(4-methyl-quinolin-2-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 6-bromoguanine with 2-bromomethyl-4-methyl-quinoline (see previous example) according to the general procedure 1.1. HPLC Rt: 4.489 min. 1H-NMR (DMSO-d6): δ 8.27 (s, 1H), 8.06-8.04 (dd, 1H), 7.85-7.83 (dd, 1H), 7.73-7.69 (m, 1H), 7.61-7.57 (m, 1H), 7.22 (s, 1H), 6.89 (s, 2H), 5,52 (s,2H), 2.64 (s,3H)
Example 178: 6-bronio-9-(4-metbyl-l-oxy-qulnolln-2-ylriiethyl)-9H-puriri-2-ylamtne
The title compound was obtained by oxidation of 6-bromo-9-(4-methyl-quinolin-2-ylmethyl)-9H-purin-2-yIamine (see previous example) according to the general procedure 2.1. HPLC Rt: 4.698 min. lH-NMR (DMSO-d6): δ 8.62-8.60 (dd, 1H), 8.27 (s, 1H), 8.12-8.10 (dd, 1H), 7.88-7.85 (m, 1H), 7.79-7.75 (m, 1H), 6.93 (s, 2H), 6.89 (s, 1H) 5.57 (s,2H), 2.64 (s,3H).
Example 179: 6-chloro-9-(3,5-dimethyl-4-methylsulfanyl-pyrldin-2-ylmethyl)-9H-purin-2-yIamine
Stepl: 2,3,5-Trimethyl-4-methylsulfanyl-pyridine l-oxide
A solution of 4-bromo-2,3,5-trimethyl-pyridine l-oxide in THF was treated in a pressure vessel with NaSMe at HO °C for 16 h. HPLC Rt: 5.303 min. 1H-NMR (CDCl3): δ 8.07 (s, 1H), 2.57 (s, 3H), 2.52 (s, 3H), 2.42 (s, 3H), 2,23 (s, 3H).
Step 2: Acetic acid 3,5-dimethyM-memylsulfanyI-pyridin-2-ylmethyl
ester
The title compound was obtained by treating 2,3,5-trimethyl-4-methylsulfanyl-pyridine 1-oxide with AcjO according to the general procedure 2.2. HPLC Rt: 4.341 min. 1H-NMR (CDCI3): δ 8.27 (s, 1H), 5.20 (s, 2H), 2,57 (3, 3H), 2.46 (s, 3H), 2.25 (s,
3H),2.10(s, 3H).
Step 3: (3,5-Dimethyl-4-methylsuIfanyl-pyridin-yl)-methanol:
The title compound was obtained by deacetylation of acetic acid 3,5-dimethyl-4-methy)sulfany]-pyridin-2-ylmethyl ester according to the general procedure 2.3. HPLC Rt; 3.921 min.
Step 4: 2-Bromomethyl-3,5-dimethyl-4-methylsuIfanyl-pyridine;
The compound was obtained from (3,5-dimethyI-4-methylsulfanyl-pyridin-2-yl)-methanol according to the general procedure 2.5. HPLC Rt: 4.905 min. 1HNMR (CDCI3): δ 8.26 (s, 1H), 4.59 (s, 2H), 2.62 (s, 3H), 2.47 (s, 3H), 2.27 (s, 3H), 2.10 (s, 3H). m/z (%): 246.13 (M+l, 96%), 248.09 (M+3, 100%).
Step 5: 6-Chloro-9-(3,5-dimethyl-4-methylsulfenyNpyridin-2-ylmethyl)-9H-purin-2-ylamine
The title compound was obtained by alkylation of 2-amino-6-chloropurine with 2-bromomethyl-3J5-dimethyl-4-methylsulfanyl-pyridine according to the general procedure 1.1. HPLC Rt: 4.611 min. 1H-NMR (CDC13): δ 8.24 (s, 1H), 7.87 (s, 1H), 5.36 (s, 2H), 5.00 (s, 2H), 2.61 (s, 3H), 2.47 (s, 3H), 2.26 (a, 3H).
Example 180: 6-chloro-9-(7-chloro-benzothiazol-2-ylmethyl)-9H-purio-2-ylamine
Step I; (2,3-dichloro-phenyl)-acetamide
A solution of 2,3-dichloroaniline (5.00g, 30.86 mmol) in pyridine (20 ml) was cooled to 0°C and treated with AcCl (4.85 g, 62 mrnol). The reaction mixture was stirred at r.t. for 1 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1% aqueous hydrochloric acid, water and brine, and dried over MgSO4. The solution was concentrated and recrystallized from EtOAc/hexane to
give (2,3-dichloro-phenyl)-acetamide (4.50 g, 22 mmol). HPLC Rt: 5.52 min. lH-NMR (CDC13): δ 8.35 (br. s, 1H), 7.7 (1H), 7,24 (1H), 7.23 (1H), 2.28 (s, 3H).
Step 2: (2,3-dichloro-phenyl)-thioacetamide
A solution of (2,3-dichloro-phenyl)-acetamide (4,50 g, 22 mmol,) in toluene (50 mt) was treated at r.L with P2S5 (9.80 g, 22 mmol). The reaction mixture was heated to 90°Cfor 1.5 h, cooled to r.t, and filtered. The solid was washed with ether and the washings were combined with the filtrate. The combined solutions were extracted twice with 10% aq. NaOH. The combined aqueous extracts were acidified at 0 °C with HO. The precipitate was collected and recrystallized from ethyl acetate/hexane to afford (2,3-dichloro-phenyl)-thioacetamide (3.40 g, 16 mmol). HPLC Rt: 5.91 min. 'H- NMR (CDCI3): S 8.80 (br. s, 1H, NH), 8.5 (d, 1H), 7.42 (d, 1H), 7.30 (t, 1H), 2.82 (s, 3H).
Step 3: 7-ChloTO-2-methyl-benzothiazole
A solution of (2,3-dichloro-phenyI)-thioacetamide (3.4 g, 15 mmol) in N-methyl-2-pyrrolidinone (25 ml) was treated with NaH (60% oil suspension, 0.74 g, 19 mmol) at r.t. The reaction mixture was heated to 150 "C for 30 min. Work-up (EtOAc), drying (brine, MgSO4), evaporation, and purification by flash chromatography afforded the title compound (2.4 g, 13 mmol). HPLC Rt; 6.65 min. 1H-NMR (CDC13): δ 7.87 (d, IH, J = 7.9 Hz, ph-H), 7.44 (t, IH, J - 7.9 Hz, ph-H), 7.35 (d, IH, J - 8.0 Hz, ph-H), 2.87 (s, 3H, CH3).
Step 4: 2-Bromomemyl-7-chIoro-benzofhiazole
A mixture of 7-chloro-2-methyl-benzothiazole (1.00 g, 5.45 mmol), N-bromosuccinimide (1.26 g, 7.08 mmol), benzoyl peroxide (0.1 g), and CCl4 (10 mL was heated to reflux under irradiation of a UV lamp for 14 h. The reaction mixture was cooled and filtered to remove the succinimide formed in the reaction, and the filtrate was evaporated to dryness. The resulting solid was purified by flash chromatography to give the title lamp (400 mg, 1.5 mmol). 1H-NMR (CDC13): δ 7.94 (d, 1H), 7.47 (t, 1H), 7.42 (d, 1H), 4.82 (s, 2H, CH2). HPLC Rt: 7.19 min.
Step 5: 6-Chloro-9-(7-chloro-benzothiazol-2-ylmethyl)-9H-purin-2-ylamine
A mixture of 2-bromomethyl-7-chloro-benzothiazole (60 mg, 0.2286 mmol), 2-amino-6-chloropurine (32 mg, 0.19 mmol), Cs2C03 (67.86 mg, 0.208 mmol), and DMF (2 ml) was heated to 40 'C for 1 h. The reaction was cooled to r.t and the solvent was removed on a rotary evaporator. The resulting solid was purified by preparative TLC to give the title compound (50 mg, 0.14 mmol). HPLC Rt: 5.81 min. 'H- NMR (CDC13): δ 8.0 (s, 1H), 7.95 (d, 1H), 7.48 (t, 1H), 7,43 (d, 1H), 5.69 (s, 2H), 5.17 (s, 2H).
Example 181: 6-Chloro-9-(3,4,5-trimethyl-pyridta-2-y)methyI)-9H-purin-2-ylaniine
Step I: 2,3,5-Collidine-N-oxide See Example 1, Method 1, step 1.
Step 2: 4-Bromo-2,3>5-collidine-N-oxide See Example 1, Method 1, step 2.
Step 3; 2,3,4,5-Tetramethyl-pyridine 1-oxide
4-Bromo-2,3J5-trimethyl-pyridine 1-oxide (2g, 9.2 mmole) and catalytic tetrakis(triphenylphosphino)-paIladium (80 mg, 4% by wt) in 20 mL of dry THF before treating with trimethylaluminum (2M in toluene, 15.2 mmole) tinder nitrogen. The solution was heated to reflux for 3 h, diluted with toluene (20 mL) before quenching the reaction with 4 mL of methanol followed by ammonium chloride (15 mmole). The mixture was refluxed for 2 h and filtered, while hot, on Celite. See J. Med. Chetn. 1999, 42(12), 2064-2086. HPLC Rt: 4.183 min. 1H-NMR (CDCl3): δ 8.05 (s, 1H), 2.55 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H).
Step 4: Acetic acid 3,4,5,-trimethyl-pyridin-2-ylmethyl ester
The compound was obtained by dissolving in acetic anhydride before bringing the reaction to reflux for 0.5 h as described in the general procedure 2.2. Quenching the reaction with water and extracting with chloroform yielded the titled product. HPLC Rt: 3.843 min. 1H-NMR (CDCI3): δ 8.20 (s, 1H), 5,22 (s, 2H), 2.26 (s, 3H), 2.25 (s, 3H), 2.21 (s,3H),2.11(s,3H).
Step 5: (3,4,5-Trimethyl-pyridin-2-yl)-methanol
The compound was obtained by hydrolysis of acetic acid 3,4,5-trimethyl-pyridin-2-ylmethyl ester in MeOH and K2CO3 at 50 °C for 0.5 h as described in the general procedure 2.3. After removing MeOH, the residue was dissolved in water and extracted with chloroform. HPLC Rt: 3.405 min. 1H-NMR (CDCl3): δ 8.18 (s, 1H), 5.00 (s, 1H), 4.67 (s, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 2.12 (s, 3H).
Step 6: 2-bromomethy]-3,4,5-trimethyl-pyridine
The compound was obtained from reacting (3,4,5-trimethyl-pyridin-2-yl)-methanol with triphenyl phosphine and carbon tetrabromide in dichloromethane as described in the general procedure 2.5. HPLC Rt: 3.979 min. 1H-NMR (CDCI3): δ 8.18 (s, 1H), 4.63 (s, 2H), 2.35 (s, 3H), 2.48 (s, 3H), 2.24 (s, 3H),
Step 7: 6-Chloro-9-(3,4,5-trimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
The compound was obtained by reacting 2-bromomethyl-3,4,5-trimethyl-pyridine with 6-chIoro-9H-purin-2-ylarnine in the presence of K2CO3 at 50 °C for 0,5 h as described in the general procedure 1.1. HPLC Rt: 3.903 min. 1H-NMR (CDCl3): δ 8.18 (s, 1H), 7.84 (s, 1H), 5.38 (s, 2H), 5.08 (st 2H), 2.29 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Example 182: 6-Bromo-9-(3,4,5-trimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
The compound was obtained by reacting 2-broraomethyl-3)415-trimethyI-pyridme (see example 117) with 6-bromo-9H-purin-2-ylaroine in the presence of K2CO3 in DMF for 0.5 h at 50 °C as described in the general procedure 1,1. HPLC Rt6; 4.045 min. *H-
NMR (CDCI3); 6 8.18 (s, 1H), 7.85 (s, 1H), 5.37 (s, 2H), 5.10 (s, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Example 183: 6-Bromo-9-(3,4,5-trimethyl-l-oxy-pyrldin-2-ylmethyl)-9H-purin-2-ylamine
The compound was obtained by the oxidation of 6-bromo-9-(3,4,5-trimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine with tn-CPBA in dichloromethane as described
in the general procedure2.1. HPLCRt 5,611 mm. 1H-NMR(CDCI3): δ 9.13 (s, 1H), S.OS (s, 1H), 5.91 (s, 2H), 2.70 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
BIOLOGY EXAMPLES
The biological activites of selected aminopurines were determined using four assays: the inhibition of binding of biotinylated geldamamycin (biotin-GM) to rHSP90, the Jysate binding ability, the HER2 degradation ability and the cytotoxity measurement. These assays have been described in Examples A, B, C and D in the previous sections. The biological activites are summarized in Table 6.
TABLE 6. Biological Activities of Selected Aminopurines of Formula II, Where R3=H
(Table Removed) - not determined
in. Preparation of Pvrazolopyrimtoines (Formula IIP
A. Materials and Methods
The chemical reagents used to create the novel products of the invention below are all available commercially, e.g., from Aldrich Chemical Co., Milwaukee, WI, USA, Otherwise their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein.
The final compounds were usually purified by preparative TLC (silica gel 60 A, Whatman Partisil PK6F) or flash chromatography (silica gel 60 A, EMD Chemicals) using EtOAc/hexane or MeOH/CHjClj as eluents. Rf s were measured using silica gel TLC plates (silica gel 60 A, EMD Chemicals). Analytical HPLC chromatograms were obtained using a C18 column (Agilent Zorbax 300SB-C18; 5 microns; 4.6 mm x 150 nvm). A gradient was applied between solvent A (0.1% TFA in H2O) and solvent B (0.5 % TFA in CH3CN) increasing the proportion of A linearly from 5% (t=0) to 100% (t=7.00 min), with a constant flow rate of 1 mL/min. The samples were diluted to typically 0.1-1 mg/mL in MeOH or CH3CN and the injection volumes were typically 10 uX. The column was not heated, and UV detection was effected at 254 nm. 1H-NMR spectra were recorded on a Bmker Avance 400 MHz spectrometer.
The chemical names were generated using the Beilstein Autonom 2, ] software,
B. General Procedures
1. General procedures to prepare and manipulate the pyrazolo[3.4-dlpyrimidine ring
General procedure 1.1: Alkylation of pyrazolo[3,4-d]pyrimidines at N-1
(Scheme Removed)4-Chloro~lH-pyrazolo[3,4-d]pyrimidin-6-ylamine was prepared as described in Seek, F.; Sleeker, H.Helv. Chim.Acta 1986, 69,1602-1613. A suspension of the 4-
Chloro-lH-pyrazo]o(3,4-d]pyrirmdin-6~ylamine (1 mmol), benzyl halide (1 mmol) and
K2C03 (1-3 mmol) in dry DMF (5 mL) was stiired at 22-70 °C for 0.5-16 h. Work-up
(EtOAc) and purification by preparative TLC or flash chromatography (EtOAc/hexane or
MeOH/CH2Cl2) yielded the pure N-1 alkylated product.
General procedure 1.2: Preparation of 3-alkylpyrazalo[3,4-djpyrimidines
Step 1: H2-Amino-4,6-dich]oro-pyrimidin-5-yl)-ethano]
A fine suspension of2-amino-4,6-dichIoro-pyriniidirie-5-carbaldehyde (3.0 g, 15 mmol); (Seela, F.; Stecker, H. Helv. Chim. Acta 1986, 69,1602) in THF was cooled to -78 °C. A 3M solution of MeMgBr in THF (25 mL, 75 mmol, 5 equiv.) was added over 3 h, keeping the internal temperature at -78 °C. The mixture was stirred for a further 0,5 h, quenched wim 100 ml H2O, and neutralized with aw, HC1. Extraction (EtOAc) gave 1-(2-aniino-4,6-dichloro-pyrimidin-S-yl)-ethanol as a pale yellow solid (2.5 g, 76%) which was used without further purification.
Step 2; l-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone
l-(2-Ammo4,6-dichloro-pyrinridin-5-yl)--ethanol (2.0 g, 9.6 mmol) was treated with MnO 2(20 g, 229 mmol, 24 equiv.) in 1,2-dichloroethane for 16 h at 70 °C. Filtration over celite and concentration gave l-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone as a pale orange solid (1.4 g, 6.7 mmol, 71%), which was used without further purification.
Step 3: 4-Chloro-3-memyl-lH-pyrazolo[3,4-d]pyrimidm-6-ylamine
l-(2-Amino-4,6-dichloro-pyrimidin-5-yl)-ethanone (200 mg, 0.97 mmol) was dissolved in CH2CI2 and treated with anhydrous hydrazine (31 mg, 0,97 mmol, 1 equiv.) at r.t. overnight. The precipitate was collected by filtration, washed with CH2G2, dissol-ved in DMSO (0.5 mL), and partitioned between EtOAc (100 mL) and water (25 mL), The organic layer was dried (brine, Na2SO4) and concentrated to afford the title compound as a white solid (95 mg, 0.52 mmol, 53%).
. General procedures to manipulate the pyridine ring
General procedure 2.1: Preparation of pyridine N-oxides
A solution of the pyridine derivative (1.0 mmol) in dichloromcthane or
chloroform (5 mL) was cooled by means of an ice-bath, treated with m-CPBA (I.I to 3
mmol) in three portions, and allowed to warm to r.t. The mixture was extracted with
dichloromethane and washed with aqueous NaOH, followed by water. Drying (Na2SO4)
and concentration afforded the pyridine N-oxide.
General procedure 2.2: Preparation of 2-{acetoxymethyl) pyridines
A solution of the 2-methyl pyridine N-oxide (1,0 mmol) in acetic anhydride (5
mL) was heated to reflux for 0,5 h. Work-up (EtOAc), drying (MgSO4), evaporation and
purification by preparative TLC or flash chromatography afforded the 2-(acetoxymethy])
pyridine.
General procedure 2.3: Preparation of 2-(hydroxymethyl)-pyridines
A suspension of 2-acetoxymethyl-pyridine derivative and solid K2CO3 in methanol was heated to 50°C for 5-30 min. Evaporation, work-up (EtOAc), and drying (MgSO4) afforded the 2-hydroxymethyl pyridine,
General procedure 2.4: Preparation of 2-fbromomethyl)-pyridines
A solution of 2-(hydroxymethyl)-pyridine (1.0 mmol) and triphenyl phosphine (1.2 mmol) in dichlotomethane or chloroform (5 mL) was cooled to 0 "C. A solution of CBr4 (1.5 mmol) in dichloromethane or chloroform was added dopwise, and the resulting mixture was stirred at 0 ^C for 0.5-1 h. Work-up followed and purification by flash chromatography afforded the 2-(bromomethyl)-pyridine.
General procedure 2.5: Preparation of 2-chIoropyridines
A suspension of 2-(hydroxymethyl)-pyridine(10 g) in POCI3 {30 mL) was stirred at 1l0°C for 1.5 h. The resulting viscous oil was cooled to r.t, and poured onto ice water (500 g). The pH was adjusted to 10 with solid KOH. Work-up (CHCI3), drying (MgSO4) and evaporation gave the 2-(chloromethyl)-pyridine, usually as a puple oil or solid, which was used without purification.
General procedure 2.6: Preparation of pyridinium salts
A solution of pyridine was heated in MeOH until it dissolved, A methanolic solution ofacid(1.0 equiv of e.g. HC1, MeOH) was added, and the solvent was evaporated to give the pyridinium salt.
3. General procedure to manipulate benzene rings
General procedure 3.1: Halogenation of benzene rings.
Variant 1: A solution of the aromatic compound in MeOH/THF/acetate buffer (IN in each AcOH and AcONa) was treated with B12 (1.3 eqmv)atr.t. for 5 min. The excess bromine and solvent were removed on a rotary evaporator. Work-up (CHCI3) and flash chromatography afforded the desired bromobenzene.
Variant 2: A solution of the aromatic compound (7 mmol) and n-halosuccinimide (NCS, NBS, or NIS, 1.06 equiv) in acetic acid (40 mL) was heated to 40-90 °C for 0.3-1 h. Evaporation, work-up (EtOAc) and flash chromatography afforded the desired halogenated benzene.
C. Preparation of Intermediates
Example 184. 2-Chloro-l-chloromethyl-3,4,5-trimethoxy-bettzene
The title compound was obtained by chlorination of 5-chloromethyl-l ,2,3-trimethoxy-benzene with NCS according to the general procedure 3.1. 1H-NMR (CDCI3): δ 6.82 (s, 1H), 4.70 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H) 3.87 (a, 3H).
Example 185. 2-chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine
(Scheme Removed)Step J: 2-Chloromemyl-4-methoxy-3,5-dimethyrpyridine-l-oxide
The title compound was obtained by oxidation of 2-chloromethyl-4-rnethoxy-3,5-dimethyl-pyriduie according to the general procedure 2.1. R.t.: 4.46 min. 1H-NMR (CDCI3): δ 8.05 (s, 1H), 4,93 (s, 2H), 3.77 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H).
Step 2: 2-Chloro-6-chtoromethyl-4-methoxy-3,5-dimethylpyridine
The title compound was obtained by treating 2-chloromethyl-4-methoxy-3,5-dimethylpyridine-1 -oxide with POCI3 according to the general procedure 2.5. R.t,: 6,757 min. 1H-NMR (CDCI3): δ 4.64 (s, 2H), 3.79 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H).
Example 186. 4-CMoro-2-chlormethyl-3,5-diraethyt-pyridine
The title compound was obtained by treating 2-chloromefliyl-3,5-dimethyl-pyridin-4-ol (Tarbit, et al. WO 99/10326) with POCl3 according in the same manner as the general procedure 2.5 (74% yield). R.t.: 5.54 min. 1H-NMR (CDCl3): 8.24 (s, 1H), 4,71 (s, 2H), 2.48 (s, 3H), 2.36 (s, 3H).
Example 187. 4-Bromo-2-bromomethyl-3,5-dimethyl-pyridine
4-Bromo-2-biomomethyI-3,5-dimethyl-pyridine was prepared by any of the following three methods:
Method 1
Step J: 2,3,5-Collidine-N-oxide
2,3,5-Colltdine-N-oxide was obtained by oxidation 012,3,5-001110^6 according to the general procedure 2.1 in 70% yield. R.t: 3,96 min, 1H-NMR (CDCI3): δ 8.03 (s, 1H), 6,90 (s, lH)t 2.47 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H). m/z (%) 138.2 (M+l, 100%).
Rf (20% MeOH/EtOAc): 0.35.
Step 2: 4-Bromo-2)3,5-collidine-N-oxide
2,3,5-collidine-N-oxide (1.3 g, 10 mmol) and K3C03 (2.9 g, 20 mmol) were suspended in 10 mL of CCl4. Bromine (1 mL, 20 mmol) was added dropwise, and the reaction mixture was heated to reflux for 2 h. Work-up (EtOAc) and flash chromatography (10% MeOH/EtOAc) afforded the title compound as a solid (1.05 g,
51% yield). RX: 5.24min. 1H-NMR (CDCl3): δ 8.06 (s, 1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.31 (s 3H m/z (% 2)6.2 (M+l, 100%),218.2 (M+3,100%). Rf(20%MeOH/EtOAc):
0.45.
Step 3: Acetic acid 4-bromo-3,5-dimethyl-pyridin-2-yl methyl ester
4-Bramo-2,3,5-conidine-N-oxide (0.25g, 11 mmol) was dissolved in acetic anhydride (5 mL) and the solution was heated to reflux for 30 min, Work-up and flash chromatography (50% Hexane/EtOAc) afforded the title compound (0.27 g, 96% yield). Rf(S0% Hexane/EtOAc): 0.70. R.t: 4.76 min. 1H-NMR (CDCI3): δ 8.26 (s,lH),5.27 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H).
Step 4: 4-Bromo-3,5-dmiethyl-pyridin-2-yl methanol
A suspension of acetic acid 4-bromo-3,5-dimethyl-pyridin-2-yl methyl ester (0.26 g, 1.0 mmol) and K2CO3 (excess) in MeOH (5 mL) was heated to 50 °C for 15 min. Work-up (CHCl3), evaporation, and filtration through a silica gel pad (eluent: 100% EtOAc) gave the title compound as a white solid (0.19 g, 88% yield). Rf (50% Hexane/EtOAc): O.S. R.t.: 3.80 min. 1H-NMR (CDCI3): δ 8.23 (s, lH),4.70(s,2H), 2.46 (a, 3H), 2.30 (s, 3H).
Step 5: 4-BTomo-2-biomomethyl-3,5-dimerhyl-pyridine
The title compound was obtained from 4-bromo-3,5-dimethyl-pyridin-2-yl methanol according to the general procedure 2.4. R,t: 6.32 min. 1H-NMR (CDCl3): δ 8.22 (s, 1H), 4.63 (s, 2H), 2.52 (s, 3H), 2.40 (s, 3H).
Method 2;
Step 1; 2-chloromethyl-3,5-dimethyl-pyridin-4-ol
The title compound was obtained by heating 2-chIoromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride in toluene as described in the patent by Tarbit, et at
WO 99/10326.
Step 2; 4-bromo-2-chloromethyl-3,5-dunethyl pyridine
A mixture of 2-chloromethyl-3,5-dimethyl-pyridin-4-ol (8,2 g, 47.8 mmol) and ?OBr3 (60g, 209 mmol) was stirred at 130°C for 3 h. The resulting viscous oil was
cooled to r.t and poured onto ice water. The pH was adjusted to 10 with solid KOH. Work-up (CHCI3), drying (MgSO4) and evaporation afforded the title compound as a purple solid (8.7 g, 78% yield) which was used without purification. R.t: 6.03 min. 'H-NMR (CDCl3): 8.20 (s, 1H), 4.62 (s, 2H), 2.50 (s, 3H), 2.38 (s, 3H).
Method 3:
4-bromo-2-chloromethyl-3,5-dimethyl pyridine
A suspension of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (3.24 g, 14.6 mmol) in PBrj (8.0 ml, 85.1 mmol, 5.8 equiv.) was heated to 80 °C under nitrogen. A catalytic amount of DMF (0.50 ml, 6.4 mmol, 0.44 equiv.) was added, whereupon the suspension rapidly turned into an orange solution. After 40 min., the reaction was still incomplete as judged by HPLC. The temperature was raised to 110 °C and the reaction was prolonged for 30 min, at which point it was complete. The mixture was poured over ice, made basic with cone. aq. NH4OH and extracted into EtOAc, Washing with water, drying (brine, MgS04) and concentration gave the title compound as a pink solid (1,51 g, 44%) containing 10% of an impurity by lH-NMR. The crude was used without further purification. 1H-NMR (CDCI3) δ 8.19 (s, 1H), 4.59 (s, 2H), 2.48 (s, 3H), 2.37 (s, 3H).
D. Preparation of final compounds
Example 188. 4-Chloro-l-{3,4,5-trimethoxy-benzyl)-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine
The title compound was obtained by alfcylation of 4-chloro-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine (See, F. Seela, Heterocycles 1985,23,2521; F. Seek, Helv. Chim. Acta 1986, 69,1602; R. O. Dempcy, PCT Publication No. WO 03/022859) with 5-ch!oromethyI-l,2,3-trimethoxy-benzene according to the general procedure 1.1. R.t. 5.68 min. 1H-NMR (CDCl3) δ 7.93 (s, 1H), 6.59 (s, 2H), 5.37 (or. s., 4H), 3.84 (s, 6H), 3.82 (s, 3H).'
Example 189. 4-Chloro-l-(2-chloro-3,4,5-trinethoxy-benzyl)-1H-pyrazolo[3,4-d)pyrfmidin-6-ylamine
The title compound was obtained by alkylation of 4-ch1oro-tH-pyrazolo[3)4-d]pyriraidm-6-ylamine with 2-chloro-l-chlorometfiyl-3,4,5-trimethoxy-beazene according to the general procedure 1.1. R,t. 6.44 min.1H-NMR (CDCl3) δ 7.95 (s, 1H), 6.36 (s, 1H), 5.51 (s, 2H), 5.24 (br. s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.70 (s, 3H).
Example 190. 4-Cbtoro-l-(4-methaxy-3,5-dimethyl-pyridin-2-yImethyI)-lH-pyrazolo [3,4-d] pyrimidin-6-ylamtne
A mixture of 4-chloro~lH-pyrazo1o[3,4-d]pyrimidin-6-ylairiine (1,76 g), 2-chlororaethyl-4-methoxy-3,5-dimethyI-pyridine hydrochloride {3.70 g), K2CO3 (5.17 g), and DMF (20 nil) was heated to 80 °C for 30 min, diluted with EtOAc, washed with water and brine, concentrated, and purified by flash chromatography to give the title compound as a white solid (0.57 g). R.t. 4.46 min. 1H-NMR (CDCl3) δ 8.10 (s, 1H), 7,89 (s, 1H), 5.53 (2H), 5.24 (br. s, 2H), 3.74 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Example 191. 4-Ch]oro-l-(6-chloro-4-methoxy-3,5-dimethyl-pyrldin-2-yimethyl)-lH-pyrazolo[3,4-d]pyr(midin-6-ylamine
A mixture of 4-chloro-lH-pyTazolo[3,4-d]pyrimidm-6-yIamine (124 mg), CS2CO3 (392 mg) and crude 2-chloro-6-chloromemyl-4-methoxy-3,5-dimethyI-pyridine (200 mg) in DMF (2 ml) was heated to 80 °C for 1 h, diluted with EtOAc and washed with water. Concentration and purification by preparative TLC (EtOAc) gave the title compound. R.t. 6.43 min. JH-NMR (CDClj) 5 7.86 (sf 1H), 5.48 (s, 2H), 5.37 (3,2H), 3.71 (s, 3H), 2.27 (s, 3H), 2.15 (s, 3H).
Example 192. 4-Chloro-l-(4-chloro-3,5-dimethyl-pyrdin-2-ylmethyl)-lH-pyrazolo(3,4-d]pyrimidin-6-ylamine
A mixture of 4-chloro-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine (158 mg), crude 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine (204 mg), CS2CO3 (660 mg) and DMF was heated to 80 °C for 1.5 h, diluted with EtOAc and washed with water. The crude material was concentrated and suspended in MeOH/DCM. Filtration gave a 2:1 mixture
of regioisomers which was farther purified by preparative silica gel plate (EtOAc 100%). The major (less polar) isomer corresponded to the title compound. R.t5.45min. 'H-NMR (CDC!3) δ 8.22 (a, 1H), 7,90 (s, 1H), 5.57 (s, 2H), 5,28 (s, 2H), 2.43 (s, 3H), 2.31
(s, 3H).
Example 193. 4-Chloro-l-(4-methoxy-3,5-dimethyH-oxy-pyridin-2-ylmethyl)-lH-pyrazolo [3,4-d] pyrimidin-6-ylaraine
A solution of 4-chloro-l-(4-methoxy-3,5-dimethyI-pyridin-2-ylmethyl)-lH-pyra2olo[3,4-d]pyrimidin-6-ylamine (50 mg) in CH2Cl2 (2 ml) was treated with m-CPBA (90 mg) for 10 min, diluted with CH2Cl2, washed with sat. aq. NaHC03,concentrated and re-crystallized from CHCl3/MeOH to give the title compound as a white solid. R.t 4.87 rain. !H-NMR (DMSO-d6) δ 8.06 (s, 1H), 7.89 (s. 1H), 7.36 (s, 2H), 5.55 (s, 2H), 3.72 (s, 3H), 2.30 (s, 3H), 2.18 (s, 3H).
Example 194. 4-Chloro-1-(3,4-dihloro-benzyl)-lH-pyrazolo[3,4-d]pyrimidin-6-ylamme
Tlie title compound was obtained by alkylation of 4-chloro-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine with 4-bromomethyl-l,2-dicWoro-benzene according to general procedure 1.1. R.t 6.89 min. 1H-NMR (CDC13) δ 7.90 (s, 1H), 7.39-7.37 (m, 2H), 7.26 (dd, 1H), 5.37 (s, 2H), 5.20 (br. s, 2H).
Example 195. 4-chloro-l-(2,5-diraethoxy-benzyl)-lH-pyrazolo(3,4-dJpyrimidid-6-ylamine
The title compound was obtained by alkylation of 4-chloro-lH-pyra2oIo[3,4-d)pyrimidin-6-yIamine with 2-chloromethyl-l ,4-dimethoxy-benzene according to general procedure 1.1. R.t6.0timin. 1H-NMR (CDCl3) δ 7,94 (s, 1H),6.85 (d, 1H), 6.75 (dd, 1H), 6,42 (dd, 1H), 5.48 (s, 2H), 5.24 (s, 2H), 3.82 (s, 3H), 3.70 (s, 3H).
Example 196. 4-Chloro-1-(4,5~dlmethoxy-2-nitro-benzyl)-lH-pyrazolo[3,4-d]pyriraidin-6-ylamine
The title compound was obtained by alkylation of 4-chloro-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine with l-bromomethyl-4,5-diinethoxy-2-nitro-benzene according togeneral procedure 1.1. R.t 5.99 min. 1H-NMR (DMSO-d6) δ 8.06 (s, 1H), 7.71 (a, 1H), 7.38 (br. s, 2H), 6.57 (s, 1H), 5.71 (s, 2H), 3.86 (s, 3H), 3.68 (s, 3H).
Example 197, l-(4-Bromo-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-lH-pyrazolo[3,4-dlpyrimidin-6-ylamine
The title compound was obtained by alkylation of 4-chlaro-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine according to general procedure 1.1. R.L 5.64 min. 1H-NMR (CDC13) δ 8.20 (s, 1H), 7.92 (s, 1H), 5.61 (s, 2H), 5.21 (br. s, 2H), 2.50 (s, 3H), 2.37 (s, 3H).
Example 198. l-(4-Bromo-3,5-dimethyl-l-oxy-pyridin-2-ylmethyl)-4-chloro-lH-pyrazolo [3,4-d]pyrimidin-6-ylamine
The title compound was obtained by oxidation of l-(4-brorno-3,5-dimethyl-pyridin-2-ylmethyl)-4-chloro-lH-pyrazolo[3J4-djpyrimidin-6-ylamine with m-CPBA according to general procedure 2.1. R.t 5.57 min. lH-NMR (CDC13) δ 8.23 (s, 1H), 7.90 (s, 1H), 7.38 (s, 2H), 5.64 (s, 2H), 2,50 (s, 3H), 2.30 (s, 3H).
Example 199, 4-Chloro-l-(2,3,6-trlfluoro-benzyl)-lH-pyrazolo[3,4-d]pyrimldin-6-ylamine
The title compound was obtained by alkylation of 4-chloro-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine with 2-bromomethyl-l,3,4-trifluoro-benzene according to general procedure 1.1. Rt. 7.12 min. 1H-NMR (CDCl3) δ 7.89(s, 1H), 7.25-7.05 (m, 1H), 6.95-6.85 (m, 1H), 5.53 (s, 2H), 5.49 (br. s, 2H).
Example 200, l-(2-Amino-4,6-dlchloro-pyrimidin-5-yl)-ethanol
The title compound was obtained by treatment of 2-Amitio-4-chloro-pyrimidine-5-carbaldehyde with MeMgBr according to general procedure 1.2. R.t.4.19min. 'H-NMR (DMSO-d6) δ 7.38 {a, 1H), 5.18 (bs, 2H), 5.15 (m, 1H), 3.56 (d, 3H).
Example 201. l-(2-Ami0O-4,6-dichloro-pyrimidln-5-yl)-ethanone
(Scheme Removed)The title compound was obtained by treatment of 1 -(2-Amrno-4,6-dichloro-pyrimidin-5-yl)-ethanol with Mn02 according to general procedure 1,2, R.t 5.23 min. 1H-NMR (DMSO-d6) δ 7.90 (a, 2H), 2.52 (s, 3H).
Example 202. 4-Chlor»-3-methyl-lH-pyrazoIo(3,4-dJpyrimidin-6-ylamine

The title compound was obtained by treatment of 1 -(2-Amino-4,6-dichIoro-pyrimidin-5-yl)-ethanone with hydrazine according to general procedure 1.2, R,t. 4.61 min. 1H-NMR(DMSO-d6) δ11.82 (Scheme Removed)(s, 1H), 8,16 (bs 2H), 2.46 (sf3H).
Example 203. 4-Chloro-3-ethy]-lH-pyrazolo[3,4-d]pyrlmidtn~6-ylaminc
The title compound was obtained by treating 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde by sequentially with EtMgCl, MnOj, and hydrazine according to general procedure 1.2. R.t. 4.55 min. lH-NMR (DMSO-dfi) δ 12.84 (s, 1H), 7.07 (s, 2H), 2.85
(nUH), 1.27-1,23 (m,3H).
Example 204. 4-Chloro-3-lsopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Scheme Removed)
The title compound was obtained by treating 2-amino-4,6-dichloro-pyrimidine-5-catbaldehyde sequentially with i-PrMgCI, MnOi and hydrazine according to general procedure 1.2. R.t. 6 t.10 min. 1H-NMR(DMSO-d6) δ 12.86 (s, lH),7.06(s, 2H), 1.29 (d, 6H).
Example 205. 4-Chloro-3-phenyl-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Scheme Removed)
The title compound was obtained by treating 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde sequentially with PhMgCl, Mn02 and hydrazine according to general procedure 1.2. R.t. 6.04 min. 1H-NMR (DMSO-d6) δ 13.04 ,7.19(bs,2H).
Example 206. 4-Chloro-l-{4-methoxy-3,5-dlmethyl-pyridin-2-ylmethyl)-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-3-methyI-lH-pyrazolo[3,4,-d]pyrimidin-6-ylamine with 2-chloromethyl-4-methoxy-3,5--dimethyl-
yridine according to general procedure 1.1. R.t 6.72 min. 1H-NMR (CDCI3) δ 8.20 (s, 1H), 5.47 (s, 2H), 5.26 (s, 2H), 3.76 (s, 2H), 2.58 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H).
Example 207. l-(4-Bromo-3,5-diiriethyl-l-oxy-pyridin-2-y]methyI)-4-chloro-3-methyl-lH-pyrazolo(3,4-d]pyrimidin-6-y)amine

The title compound w(Scheme Removed)as obtained by alkylation of 4-chloro-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine with 4-bromo-2-chloromethyl-3,5-dimethyl-pyridine 1-oxide according to general procedure 1.1. R.t. 5.90 min. 1H-NMR (DMSO-d6) δ 8.25 (s, 1H), 7.29 (s, 2H), 5.53 (s, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H).
Example 208. 4-chloro-l-(4-chloro-3,5-dimethyl-l-osy-pyridin-2-y[methyl)-3-metuyl-lH-pyrazolo(3,4-d]pyrimidia-6-yJamine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylaimne with4-chloro-2-chloromethyl-3,5-dimethyl-15 pyridine 1-oxide according to general procedure 1.1. R.t, 5.90mm, 1H-NMR(DMSO-d6) δ 8.25 (s, 1H), 7.30 (a, 2H), 5,54 (s, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H).
Example 209. 4-chloro-l-(4-chloro-3,5-dimethyl-pyridin-2-ylmethyl)-3-methyl-lH-pyrazolo [3,4-d] pyrlmidin-6-ylatnine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine with 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine according to general procedure 1,1. R.t. 5.63 min. 1H-NMR (CDCI3) δ 8.23 (s, 1H), 5.51 (s, 2H), 5.28 (br.s2H), 2.57 (s, 3H), 2.45 (s, 3H), 2.33 (s, 3H).
Example 210. 4-Chloro-3-metliyl-l-(3,4,5-trimethoxy-benzyl)-lH-pyrazolo[3,4-d)pyrimidin-6-y]amine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-3-methyl-lH-pyrazolo[3,4-d]pyiimidm-6-ylamine with 5-chloromethyl-l,2,3-triinetiioxy-benzene according to general procedure 1.1, R.t.6.72min. 1H-NMR (DMSO-d6) δ 7.30 (s, 2H), 6.57 (s, 2H), 5.22 (a, 2H), 3.71 (s, 6H), 3.62 (s, 3H), 2.47(s, 3H), 2.29 (s, 3H).
Example 211. l- (Scheme Removed)
The title compound was obtained by alkylation of 4»chloro-3-methyl-lH-pyrazolo[3,4-d]pyrimidin-6-ylamine with 4-bromo-2-chIoromethyl-3,5-dimetliyl-pyridine according to general procedure 1.1. R.t5.90min. 1H-NMR(DMSO-d«)58,15 (s, 1H), 7.22 (s, 1H), 5.46 (s, 2H), 2.42 (s, 6H), 2.30 (s, 3H).
Example 212, 4-Chloro-3-ethy(-l- (Scheme Removed)The title compound was obtained by alkylation of 4-chIoro-3-ethyI-lH-pyrazolo[3,4-d]pyrimidin-6-ylarnine with 2-chloromettiyl-4-methoxy-3,5-dimethyI-
pyridine according to genera! procedure 1.1. R.t6.02min. 1H-NMR (DMSO) 5 8.04 (s,lH), 719 (br. s, 2H), 5.39 (s, 2H), 3.71(s, 3H), 2.87-2.81 (m, 2H), 2.22 (s, 3H), 2.16
(s,3H), 1.21(m,3H).
Example 213, 4-Chloro-l-(4-chIoro-3,5-dlmetbyl-pytidln-2-yltnethyl>-3-etIiyI-lH-pyrazolo[3,4-dlpyrimidin-6-ylamine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-3-ethyMH-pyrazolo[3,4-d]pyrimidin-6-ylamine with4-chloro-2-chloromethyl-3,5-dimethyl~ pyridine according to general procedure 1.1. R.t 6.90 min. 1H-NMR (DMSO-de) 5 8.18 (s 1H), 7.21 (s, 1H), 5.47 (s, 2H), 2.87-2,81 (m, 2H), 2.39 (s, 3H), 2.27 (s, 3H), 1.21 (m,
3H).
Example 214. 4-Ch]oro-3-isopropyl-l-(4-metboxy-3,5-dlmethyl-pyridin-2-ylmethyl)-lH-pyrazolo[3,4-d]pyrim)din-6-y]amlne
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-3-iscrpropyl-I-(4-methoxy-3,5-dirnethyl-pyridm-2-yImetiiyl)-lH-pyi^zolop,4-d}pyrimidin-6-ylaminewith 2-ch]oromethyl-4-methoxy-3J5-diniethyl-pyridinc according to the general procedure 1.1. R.t. 5.75 min. 1H-NMR (DMSO-ds) 8 8.02 (s, 1H), 7.17 (br. 3,1H), 5.40 (s, 2H), 3.71 (s, 3H), 2.23 (s, 3H)t 2.16 (s, 3H), 1.26 (d, 6H).
Example 215. 4-Chloro-l-
The titie compound w(Scheme Removed)as obtained by alkylation of 4-chloro-3-phenyl-lH-pyrazolotS^-dJpyrimidin-e-ylaminewiihl-chloroniethyM-methoxy-S.S-dimethyl-pyridine according to general procedure 1.1. R.t 5.89 min. 1H-NMR{DMSO-d6)5 8.06 (s, 1H), 7.68-7.66 (m, 2H), 7.47-7.45 (m, 3H), 7.32 (br.s, 2H), 5.52 (s, 2H), 3.72 (s, 3H), 2.27 (s,3H), 2.16 (s,3H).
Example 216. 4-Cbloro-l-(4-chloro-3,5-diiaetliyl-pyrldin-2-yImethyI>3-pheiiyMH-pyrazolo [3,4-dlpyrimldin-^l-ylamine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-3-phenyl-lH-pyrazolo[3,4-d]pyriinidin-6-ylamine with 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine according to general procedure 1.1. R.t6.80min. 1H-NMR. (DMSO-de) S 8.20 (s, 1H), 7.67-7.65 (m, 2H), 7.47-7.45 (m, 3H), 7.34 (br.s, 2H), 5.61 (s, 2H), 2.43 (s, 3H), 2.27 (b, 3H).
Example 217. l-(4-Bromo-3,5-dimethyl-pyridln-2-ylmethyI)-4-chloro-3-phenyl-lH-pyrazolo [3,4-dIpyrliiiidJii-6-yIamine
(Scheme Removed)
The title compound was obtained by alkylation of 4-chloro-3-phenyl-lH-)yrazolo[3,4-d]pyrimidiit-6-ylaniinewith4-bM)mo-2-chloiomethyl-3,5-dimethyl-lyridine according to general procedure 1.1. R.t. 7.41 min. 5H-NMR (DMSO-d«) 5 8.15 .s, III), 7.67 (ra, 2H), 7.46 (m, 3H), 7.34 (br. s, 2H), 5.62 (s, 2H), 2.4 (sf 3H). 2.3 (s. 3m.
Example 218. 4-chloro-l-(4-chloro-3,5-dimetliyl-l-oxy-pyridln-2-yloiethy))-3-phenyl-lH-pyrazoIo[3,4-d]pyrinudIn-6-y)ainine
The title compound was obtained by alkylation of 4-chloro-3-phenyI-1H-pyrazolo[3,4-d3pyrimidin-6-ylamine with 4-chloro-2-chIoromethyL-3,5-dimethyl-pyridine 1-oxide according to general procedure 1,1. R.t. 7.50 min. 1H-NMRCDMSO-d6) 5 8.25 (s, 1H), 7.57 (s, 2H), 7.42 (m, 5H), 5,67 (s, 2H), 2.49 (s, 3H), 2.26 (s, 3H).
BIOLOGY EXAMPLES
The biological activites of selected pyrazolopyrimidines were determined using four assays: the inhibition of binding of biotinylated geldamamycin (biotin-GM) to rHSP90, the lysate binding ability, the HER2 degradation ability and the cytotoxity measurement. These assays have been described in Examples A, B, C and D in the previous sections. The biological activites are summarized in Table 7.
TABLE 1, Biological Activities of Pyrazolopurimidiue
(Table Removed)
ND = not determined
IV. Preparation of Triazolofvkimidines of Formula IV
A. Materials and Methods
The chemical reagents used to create the novel products of the invention below are all available commercially, e,g., from Aldrich Chemical Co., Milwaukee, "WL, USA. Otherwise their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein.
The final compounds were usually purified by preparative TLC (silica gel 60 A, Whatman Partisil PK6F) or flash chromatography (silica gel 60 A, EMD Chemicals) using EtOAc/hexane or MeOWCHtCh as eluents. Rf s were measured using silica gel TLC plates (silica gel 60 A, EMD Chemicals). Analytical HPLC chromatograins were obtained using a C18 column (Agilent Zorbax 300SB-C J 8; 5 microns; 4.6 mm x ] 50 mm). A gradient was applied between solvent A (0.1% TFA in H20) and solvent B (0.5% TFA in CH^CN) increasing the proportion of A linearly from 5% (K>) to 100% (t=7.00 min), with a constant flow rate of I mL/min. The samples were diluted to typically 0.1-1 mg/mL in MeOH or CH3CN and the injection volumes were typically uL. The column was not heated, and UV detection was effected at 254 ran. 1H-NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer.
The chemical names were generated using the Beilstein Autonom 2.1 software.
B. General Procedures
(Scheme Removed)
General Procedure 1: Displacement of chlorine wfttfr amines
Ref: Helv. Chim Acta. 1986, 69,1602-1613; US patent 5,917,042)
A mixture of benzyiamme derivative or aminomethyl pyridine derivative (5.88 mmole, 2.1 equivalents), triethylamine (1ml, 7.2 mmole) and 4,6-dichloro-pvrimidine-2,5-diamine (0.5 g, 2.8 mmole), was refluxed in n-BuOH or ethanol (10 mis) for 3 to 1B hours. The mixture was cooled to room temperature and was extracted with CHjClj. The organic layer was washed with water and dried with MgS04 to afford the crude product. The pyridinyl derivatives were purified by chromatography (100% EtOAc-10% MeOH/ EtOAc), whereas the benzylderivatives were used without further purification.
General Procedure 2: Cyclization to form triazolopyximidine ring
system
To a solution of e-chloro-l^-benzyl-pyrimidine^^.S-triamine derivatives or 6-chloro-N4-pyridin-2-ylmemyl-pyrirmdine-2,4,5-triamine derivatives (0.57 mmole) in 25%HOAc/H20, an aqueous solution of NaNQi (1.2 equivalents, 1ml) was added dropwise at O^C. The reaction mixture was stirred for 15 minutes at room temperature and filtered the crude product and purified by column chromatography using 75%EtOAc/Hexanes-100% EtOAc,
General Procedure 3: Aromatic ring halogenation
A mixture of 7-chloro-3-benzyI-3H-[I,2,3]tria2olo[4,5-d]pyrimid]n-5-ylamine derivatives (0.57 mmole) and NCS (N-cWorosuccinimide) or NBS (N-bromosuccinimide) orNIS (N-iodosuccinimide)(l,5 equivalents) in lOmlsHOAc was stirred at 50 °C for 1 to 15 hours to afford the crude corresponding halogcnated product which was purified by chromatography (50-75% EtOAc/Hexanes). General Procedure 4: N-oxide formation
A solution of the pyridine derivative (I mmol) in dichloromcthane or chloroform (5 mV) was cooled by means of an ice-bath, treated with m-CPBA (1,1 to 3 mmol) inthree portions, and allowed to warm to r.t. The mixture was extracted with dichloromethane and washed with aqueous NaOH, followed by water. Drying (Na3SO4) and concentration afforded the pyridine N-oxide.
Example 219. 7 Step 1: Synthesis of 2-ammomethyl4-methoxy-3,5-dimethyIpyridine:
A solution of 2-chlororaethyl-4-methoxy-3,5-dimethyl-pyridiiie HC1 (Aldrich 3.7g, 16.6 mraole) in 7N NHj/MeOH (Aldrich, 200mls) was refluxed in a steel bomb for 15 hours. Removed the solvent under reduced pressure, the residue was taken into 5% MeOH/CH2Cl2 and filtering it through a thin layer of silica gel afforded the product at 76% yield. HPLCRT was 2.850 rnin. 1HNMR(CDC13) 5 8.18 (s. 1H),4.32 (s,2H), 3.76 (s. 3H), 2.23 (s, 3H), 2.18 (s, 3H).
Step 2: Synthesis of 6-chloro-N4-(4-methoxy-3,5-drmethyl-pyridin-2-ylmethyl)-pyrimidine-2,4,5-triamine
A mixture of 4,6-dichloro-pyrimidine-2,5-dianiine and 2-aminomethyl-4-methoxy-3,5-dimethyl-pyridine was heated to reflux in n-BuOH for 3 h, following the general procedure 1. HPLC RT was 3.597 min. 1HNMR. (CDCi3} 8 8.22 (s, 1H), 7.12 (br. t, !H), 4.61 (s, 2H), 4.56-4.55 (d, 2H), 3,80 (s, 3H), 3.00 (s, 2H), 2.29 (s, 3H), 2.27 (s, 3H).
Step 3: Synthesis of 7-ch1oro-3-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidiri-5-yl8mine
A solution of 6-chloro-N4-(4-methoxy-3,5-dimethyl-pyridin-2-ylniethyl)-pyrimidine-2,4,5-triamme was treated with a cold aqueous solution of NaNO;, following the general procedure 2. HPLCRT was 3.597 min. 1HNMR (CDC13): δ 8.22(8,111), 7.12 (broad t, 1H), 4.61 (s, 2H), 4.56-4.55 (d, 2H), 3,80 (s, 3H), 3.00 (s, 2H), 2.29 (s,
3H),2.27(s,3H).Example 220. 7-CbIoro-3-(4-methoxy-3,5-dimethyI-l-oxy-pyrldIn-2-yl)-3H-[l,2,3]triazolo[4,5-dJpyrimidln-5-ylarnine
The compound was obtained by oxidation of 7-Chloro-3-(4-methoxy-3,5-
diinethyl-pyridin-2-ylmeLhyl)-3H-[l,2,3]uiazolo[4J5-d]pyrimidin-5-ylamine(see
j Example I) with m-CPBA (rn-chloroperoxybenzoic acid) in methylene chloride,
following the general procedure 4. HPLC RT was 4.780 min. 'KNMRfCDClaJiS 8.02 (s, 1H), 5.90 (s, 2H), 5.61 (s, 2H), 3.81 (s, 3H), 2.54 (s, 3H), 2.25(s, 3H).
Example 221. 7-chloro-3- Step 1: Synthesis of 6-chloro->TV4-methoxy-benzyl)-pyrimidine-2,4J5-triamine:
A mixture of 4,6-dichIoro-pyrimidine-2,5-diamine and l-aminomethyl-4-methoxybenzene was refluxed in n-BuOH for 15 h, following the general procedure 1. HPLC RT was 4.675 min. 1HNMR (CDCIj) 5 7.29-7.27 (d, 2H), 6.91-6.89 (d, 2H), 5.62 (br. t, 1H) 4.67 (s, 2H), 4.56-4.54 (d, 2H), 3.84 (s, 3H), 2.74 (s, 2H).
Step 2: Synthesis of 7-chloro-3-(4-methoxy-benzyl)-3H-
[l^^JtriazoIo^S-dJpyrmiidin-S-ylamine:
A solution of 6-cbloro-N4-(4-methoxy-phenyl)-pyrimidine-2,4,5"triarnine was treated with a cold aqueous solution of NaNOa, following the general procedure 2. HPLC RT was 5.7S4min. 1HNMR (CDCh): 5 7.37-7.35 (d,2H), 6.86-6.84 (d,2H), 5.57 (s, 2H), 5.39 (s,2H), 3.78 (s,3H).
Example 222. Synthesis of 7-c)Uoro-3-pyridin-2-ylmethyl-3H-ll,2,3]triazolo(4,5-d)pyrfmidln-5-ylamine
Step 1:6-chloro-N4-pyridin-2-ylrnethyl-pyrimidine-2,4,5-triamine
A mixture of 4,6-dichloro-pyrimidine-2]5-diamine and 2-aminomefhyl-pyridine was refluxed in n-BuOH for 15 h, following the general procedure 1. HPLC RT was 2.573 min. 1HNMR (CDC13) S 8.60-8.59 (m, 1H), 7.69-7.66 (m, 1H), 7.31-7.29 (m, 1H), 7.25-7.20 (m, 1H), 6.55 (br. t, 1H) 4.63 (s, 2H), 4.73-4.71 (d, 2H), 1.84 (s, 2H).
Step 2: Synthesis of 7-chloro-3-pyridin-2-ylmefhyl-3H-n,2,3]triazolo[4,5-d]pyrimidin-5-yIaniine:
A solution of 6-chloro-N4-pyridin-2-y1methyl-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaN02j following the general procedure 2. 1HNMR (CDCI3): δ 8.60-8.59 (m, 1H), 7.7l-7.67(m, 1H), 7.29-7,25 (m, 1H), 7.22-7.20 (m, 1H), 5.81 Example 223. Synthesis of 7-chIoro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3|triazolo[4,5-d]pyrimidin-5-ylaniine
Step 1: 6-chloro-N4-(3,4,5,-trimethoxy-benzyl)-pyrimidine-2,4,5,triamine
A mixture of 4f6-dicWoro-pyriraidine-2)5-4ianitne and l-anunomethyI-3,4-5-trimethoxybenzene in n-BuOH for 15 h, following the general procedure 1. HPLC RT was 4.458 min. (HNMR (CDCl3) 6 6.58 (s, 2H), 5.62 (bt. t, 1H) 4.72 (s, 2H), 4.56-4.54 (d, 2H), 3.88 (a, 6H), 3.86 (s, 3H), 2.77 (a, 2H).
Step 2: Synthesis of 7-chloro-3-(3,4,5-trhnethoxy-benzyl)-3H-
[lt2)3]tria2olo[4,5-d]pyrimidin-5-ylaraine):
A solution of 6 Example 224. Synthesis of 73H-[ 1,2,3]trlazolo [4,5-d] pyriiatdJn-5~y)amUte
Chlorinationof7-chloro-3-(3,4,5-ttimethoxy-benzyl)-3H-|[l^,3]triazolo[4,5-djpyriimdin-S-ylamme) (CF 2137) with NCS (1.5 equivalents) was done following the general procedure 3 to give 7-chloro-3-(2-chloro-3,4,5-trimethoxy-benzyIl)-3H-[l,2,3]triazolo[4,5-d]pyriraidin-5-ylamine: HPLC RT was 6.244min. 1HNMR (CDCl3): 3 6.53 (s, 1H), 5.70 (s, 2H), 5.48 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.75 (s,3H).
Example 225. 7-chloro-3-(2}6-dichloro-3,4,5-trimethoxy-benzyl)-3H-[l,2,31trinzoIoH,5-d]pyriniidia-S-ylamtne
Chlorination of 7-chIoro-3-(3J4)5-trimethoxy-benzyI)-3H-( 1,2,3]triazolo[4)5-d]pyrimidin-5-ylamine) with NCS (1.5 equivalents) was done following the general procedure 3 to give 7-Chloro-3-(2J6-dich]oro-3,4,5-triniethoxy-benzyl)-3H-[l,2,3]triazolo[4t5^]pyriraidin-5-ylamine: HPLC RT was 6.616rain. 1HNMR(CDCl3): δ 5.81 (s, 2H), 5.47 (s, 2H), 3.97 (s, 3H), 3.90(s, 6H).
Example 226. Synthesis of 7-chIoro-3-{2-bromo-3,4,5-trimethoxy-benzyl)-3H-[l,2,3|triazoIo[4,S-dJpyrimidin-5-ylamine
Brominationof 7-chloro-3-(3,4,5,-trimethoxy-benzyl)-3H-[1,2,3,]triazolo[4,5,-d]pyrimidin-5-ylamine) with NBS (1.5 equivalents) was done following the general procedure 3 to give 7-chloro-3-(2-bromo-3,4,5-trimethoxy-benzyl)-3H-[l,2,3]triazolot4,5-d]pyrimidin-5-ylamine HPLC RT was 6.541min. 1HNMR (CDCl3): δ 6.52 (s, 1H), 5,74(8,2H), 5.46 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.76 (8,311),
Example 227. 7-chloro-3-(2,6-dlbromo-3,4,5-trimethoxy-benzy])-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamine (CF 2564)
Bromination of 7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[l,2,3]triazolo[4J5-d]pyrimidin-5-ylamine) with NBS (1.5 equivalents) was done following the general procedure 3 to give 7-chloro-3-(2,6-dibromo-3,4f5-trimethoxy-beri2y])-3H-[l12,3jtriazolo[4,5-d]pyrimidin-5-ylamine:HPLC was 6.923rnio. lHNMR (CDCI3): δ 5.91 (s, 2H), 5.51 (s, 2H), 3.99 (s, 3H), 3.93(s, 6H),
Example 228. Synthesis of 7-chloro-3-{2-iodo-3J4,5-trimetboxy-beiizyl)-3H-[l,2,3]trfazolo[4,5-d]pyrimtdin-5-ylamLne
The titled compound was obtained from iodination of 7-chloro-3-{3,4,5-trimethoxy-benzyl)-3H-[ 1 f2,3]triazolo[4t5-d]pyrimidin-5-ylamine) with NIS (1.5 equivalents) following the general procedure 3. HPLC RT was 6.497mm. 1H NMR (CDCl3): δ 6.47 (s, III), 5.73(s, 2H), 5,44 (s, 2H), 3.92 (s, 3H), 3.88 (s, 311), 3.73 (s,3H).
Example 229. Synthesis of 7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3] triazoloH,5-d] pyrimidtu-5-ylamiiie
Step I: 6-chloro-N4-(3,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine
A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and l-aminomethyl-3, 5-dimethoxybenzene in n-BuOH for 15 h, following the general procedure 1, HPLC RT was 4.835 min. 1HNMR (CDCl) δ 6.46-6.47 (d, 2H), 6.38-6.37(d, 1H), 5.67 (br. t, 1H) 4.63 Step 2: Synthesis of 7-ehloro-3-(3,5-dimethoxy-benzyl)-3H-[1 ,2,3]triazolo[4, 5-d]pyrimidin-5-ylamin:
A solution of 6-chloro-N-{3,5-dimemoxy-benzyl)-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaNOi, following the general procedure 2. HPLC RT was 6.185min. 1HNMR (CDC13): S 6.54-6.53 (d, 2H), 6.41-6.40 (d, 1H), 5.58 (s, 2H), 5.54 (s, 2H), 3.78 (s,6H).
Example 230. Synthesis of 7-chloro-3-(2-chIoro-3,5-dimethoxy-benzyI)-3H-[l,2,3]triazolo[4,5-d]pyrimldin-5-ylamine
The titled compound was obtained by chlorination of 7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrirnidin-5-ylamine) with NCS (1.5 equivalents) in acetic acid at 50 °C for 1 h, following the general procedure 3. HPLC RT was 6.467min. 1HNMR (CDCl3): δ 6.50-6.49 (d, 1H), 6.18-6.17 (d, 1H), 5,77(s, 2H), 5,44 (s, 2H), 3.91 Example 232. Synthesis of 7-chloro-3-(2-bromo-3,5-dimethoxy-benzyl)-3H-
(1,2,3]tr iazolo [4,5-dJpyrtmldin-5-ylam( ne
The titled compound was obtained by bromination of 7-chloro-3-{3,5-dimethoxy-ben2y])-3H-[l,2t3]triazolo[4,5-d]pyrimidtn-5-y!amhie) withNBS (1.5 equivalents) in acetic acid at 50 °C during 1 h, following the general procedure 3. HPLC RT was 6.573min. 1HNMR(ds-DMSO): δ 7.74 (s, 2H), 6.70-6.69 (d, 1H), 6.23-6.22 (d, 1H), 5.63(8, 2H), 3.87 (s, 311), 3-71 (s, 3H),
Example 232, Synthesis of 7-chloro-3-(2-iodo-3,5~dimethoxy-benzyl)-3H-[1,2,3,]triazolo[4,5,6d]pyrimidin-5-ylamine
The titled compound was obtained by iodination of 7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamine) with NIS (1.5 equivalents) in acetic acid at 50 °C daring I h, following the general procedure 3. HPLC RT was 6.739min, 1HNMR (d6-DMSO): δ 7.75 (s, 2H), 6.61-6.60 (d, 1H), 6.15-6.14 (d,lH), S.58(s, 2H), 3.86 (s, 3H), 3.70 (s, 3H).
Example 233. Synthesis of 7-Chloro-3-(2,5-dim«thoxy-benzyl)-3H-
[l,2,3]triazolo[4,5-djpyrltnidin-5-ylamine
Step 1: 6-chloro-N4-(2,5-dunethoxy--benzyl)-pyrimidine-2,4,5-trianiine
A mixture of 4,6-dich!oro-pyrimidine-2,5-diamine and l-aminomethyl-2,5-dimethoxybenzene in n-BuOH for 15 h, following the general procedure 1. HPLC RT was 4.601min. 1HNMR (CDCl3) δ 6.91-6.90 (d, 1H), 6.82-6.80(m, 2H), 5.82 (br. t, 1H) 4.62 (s, 2H), 4.59-4,58 (d, 2H), 3.85 (s, 3H), 2.78 (s, 3H), 2.75 (s, 2H).
Step 2: Synthesis of 7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamine
A solution of 6-chloro-N4-(2,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaNO2, following the general procedure 2. HPLC RT was 6.130min. lHNMR (CDCl3): δ 6.84-6.83 (m,2H)> 6.64-6.63 (d, 1H), 5.67 (s, 2H)t 5.54 (s, 2H), 3.83 (a, 3H), 3.73 (s, 3H).
Exapmle 234. Synthesis of 7-chloro-3-(4-bromo-2,5-dimethoxy-benzyl)-3H-[1,2,3)triazo]o[4,5-dlpyrimidin-5-ylamine
The titled compound was obtained by bromination of 7-chloro-3-(2,5-dhnethoxy-benzyl)-3H-[l,2,3]triazolo(4,5-d]pyrimidm-5-ylamine)with-NBS (1,5 equivalents) in acetic acid at 50 °C during 1 h, following the general procedure 3. HPLC RT was 6.438min. 1HNMR(CDCl3): δ 7,11 (s, 1H), 6.80 (s, 1H), 5.63 (s,2H), 5.57 (S.2H), 3.82 (s,3H), 3,79 (s,3H).Example 235. Synthesis of 7~chioro-3-(3-chloro-2,5-dimethoxy-benzyl)-3H-[I,2,3]triazolo[4,5-d|pyrimidin-S-ylamine
The titled compound was obtained by chlorination of 7-chloro-3-(2,5-dinieth.oxy-benzyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamine) with NCS (1.5 equivalents) in acetic acid at 50 °C during 1 h, following the general procedure 3. HPLC RT was 6.392min. 1HNMR (CDCl3): δ 6 .91-6,90 (d, 1H), 6.67-6.66 (d, 1H), 5.70 (s,2H),
5.43(s, 2H), 3.92 (s, 3H), 3.73 (s, 3H).
BIOLOGY EXAMPLES
The biological activites of selected triazolopyrimidines were determined using four assays: the inhibition of binding of biotinylated geldamamycin (biotin-GM) to rHSP90, the lysate binding ability, the HER2 degradation ability and the cytotoxity measurement. These assays have been described in Examples A, B, C and D in the previous sections. The biological activites are summarized in Table 8.
TABLE 8. Biological Activities of Selected Triazolopyrimidines of Formula IV
(Table Removed)
ND x not determined
The foregoing examples are not limiting and are merely illustrative of various aspects and embodiments of the present invention. All documents cited herein are indicative of the levels of skill in the art to which the invention pertains and are incorporated by reference herein in their entireties. None, however, is admitted to be prior art.
One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as
those inherent therein. The methods and compositions described illustrate preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Certain modifications and other uses will occur to those skilled m the art, and are encompassed within the spirit of the invention, as defined by the scope of the claims,
The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described, or portions thereof. It is recognized mat various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modifications and variations of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims,
In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, e.g., genuses, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or subgenus, and exclusions of f individual members as appropriate, e.g., by proviso.

A compound of Formula A
(Scheme Removed)or tautomer or pharmaceutically acceptable salt or prodrug thereof, wherein X1 and X2 are the same or different and each is nitrogen or -CR6;
X3 is nitrogen or -CR3 wherein R3 is hydrogen, OH, a keto tautomer, -OR8, -CN, halogen, lower alkyl, or -C(O)R9;
X4 is nitrogen or a group CR6 when X3 is nitrogen, and X4 is -CR6R7 when X3 is -CR3;
R1 is halogen, -OR8, -SRB, or lower alkyl;
R2 is -NR8R10;
R4 is -(CH2)n- where n = 0-3; and
R5 is alkyl, aryl, heteroaryl, alicyclic, heterocyclic, all optionally bi-or tricyclic, and optionally substituted with H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, araalkyl, ary'nxyalkyl. alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -N3, -SR8, -ORB, -CN, -C03R9, -N02, or -NR8R10;
with the provisos that:
said compound is not one found or described in one or more of JP 10025294; US Patent 4,748,177; US Patent 4,748,177; US Patent 6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO 02/055083; European Journal of Medicinal Chemistry, 1994, 29(1), 3-9; and J, Het. Chem. 1990, 27(5), 1409;
-R4R5 is not a ribose or derivative thereof, or a sugar or derivative thereof;
-R4R5 is not a phosphonate or phosphonic acid, or substituted with phosphonate or phosphonic acid; and
when R4 is (CH2)n where n= 0 or 1, then R4 and R5 are not connected with '0








We Claim:
1. A compound represented by Formula IIC, or a tautomer or pharmaceutically acceptable salt thereof for treatment of HSP90 mediated disorder or cancer:
(Formula Removed)
wherein:
R1 is halogen; R2 is -NH2; R4 is -CHR12-; R3 is hydrogen;
R5 is aryl or heteroaryl wherein one ring nitrogen atom of the heteroaryl is optionally oxidized, and wherein: the aryl group is substituted with 3 to 5 substituents, the heteroaryl group is substituted with 3 to 5 substituents, and the substituents are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -N3, -SR8, -OR8, -CN, -C(O)R9, -NO2, -NR8R10, phosphonate and phosphonic acid; R8 is hydrogen, lower alkyl, lower aryl, or -C(O)R9; R9 is lower alkyl, lower aryl, lower heteroaryl, -NR10R10 or -OR11; R10 is independently hydrogen or lower alkyl; R11 is lower alkyl, lower aryl or lower heteroaryl; R12 is hydrogen or lower alkyl; provided that
when R5 is aryl, R5 is not an organo-metallic cyclopentadiene and
when R5 is phenyl, the substituents are not 3,5 di-halo.
2. The compound of claim 1, or a tautomer or pharmaceutically acceptable
salt thereof, wherein:
R1 is halogen;
R2 is -NH2;
R4 is-CHR12-;
R3 is hydrogen; and
R5 is aryl or heteroaryl wherein one ring nitrogen atom of the heteroaryl is optionally oxidized, and wherein
each of said aryl and heteroaryl groups is monocyclic or bicyclic, the aryl group is substituted with 4 to 5 substituents, and the heteroaryl group is substituted with 3 to 5 substituents.
3. The compound of claim 1, or a tautomer or pharmaceutically acceptable
salt thereof, wherein
R1 is chloro or bromo, R2 is -NH2, and
R5 is a phenyl having 3 to 5 substituents, a pyridyl having 3 to 5 substituents or an 1-oxy-pyridyl (N-oxy-pyridyl), each of which has 3 to 5 substituents.
4. A compound represented by Formula IID, or a tautomer or
pharmaceutically acceptable salt thereof:
(Formula Removed)
wherein:
R1 is halogen; R2 is -NH2; R3 is hydrogen;
R5 is aryl or heteroaryl wherein one ring nitrogen atom of the heteroaryl is optionally oxidized, and wherein the aryl group is substituted with 3 to 5 substituents, the heteroaryl group is substituted with 3 to 5 substituents, and the substituents are selected from the group of halogen, lower alky], lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -N3, -SR8, -OR8, -CN, -C(O)R9, -NO2, -NR8R10, phosphonate and phosphonic acid; R8 is hydrogen, lower alkyl, lower aryl, or -C(O)R9; R9 is lower alkyl, lower aryl, lower heteroaryl, -NR10R10or -OR11; R10 is independently hydrogen or lower alkyl; and R11 is lower alkyl, lower aryl or lower heteroaryl; provided that
when R5 is aryl, R5 is not an organo-metallic cyclopentadiene and when R5 is phenyl, the substituents are not 3,5 di-halo.
5. The compound of claim 4, or a tautomer or pharmaceutically acceptable
salt thereof, wherein:
R1 is halogen;
R2 is -NH2;
R3 is hydrogen; and
R5 is aryl or heteroaryl wherein one ring nitrogen atom of the heteroaryl is optionally oxidized, and wherein
each of the aryl and heteroaryl groups is monocyclic or bicyclic, the aryl group is substituted with 4 to 5 substituents, and the heteroaryl group is substituted with 3 to 5 substituents.
6. The compound of claim 4, or a tautomer or pharmaceutically acceptable salt thereof, wherein R1 is chloro or bromo, R2 is -NH2, and R5 is a phenyl having 3 to 5 substituents, a pyridyl having 3 to 5 substituents, or 1 -oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.
7. A compound selected from the group below, or a tautomer or
pharmaceutically acceptable salt thereof:
(Formula Removed)
8. A compound represented by one of the formulae below, or a tautomer or pharmaceutically acceptable salt thereof:
(Formula Removed)
A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and at least one compound according to claims 1-8.
9. A compound as claimed in claim 4 represented by the formula below:
(Formula Removed)
11. A compound as claimed in claim 4 represented by the formula below:
(Formula Removed)
12. A compound as claimed in claim 4 represented by the formula below, or a
tautomer or pharmaceutically acceptable salt thereof:
(Formula Removed)
13. A pharmaceutical composition as and when prepared by the compound as
claimed in claim 1 for treatment of HSP90 mediated disorder or cancer.
14. A compound as claimed in any of the above claims substantially as described in the specification and illustrated in the accompanying drawings.

Documents:

1585-delnp-2006-Abstract (18-11-2009).pdf

1585-DELNP-2006-Abstract-(05-05-2011).pdf

1585-DELNP-2006-Abstract-(07-03-2011).pdf

1585-delnp-2006-abstract.pdf

1585-delnp-2006-assignments.pdf

1585-delnp-2006-Claims (18-11-2009).pdf

1585-DELNP-2006-Claims-(05-05-2011).pdf

1585-DELNP-2006-Claims-(07-03-2011).pdf

1585-delnp-2006-claims.pdf

1585-DELNP-2006-Correspondence Others-(05-05-2011).pdf

1585-delnp-2006-Correspondence Others-(13-04-2011).pdf

1585-DELNP-2006-Correspondence-Others (06-11-2009).pdf

1585-delnp-2006-Correspondence-Others (18-11-2009).pdf

1585-delnp-2006-Correspondence-Others (19-11-2009)..pdf

1585-DELNP-2006-Correspondence-Others-(07-03-2011).pdf

1585-delnp-2006-correspondence-others-1.pdf

1585-delnp-2006-correspondence-others.pdf

1585-delnp-2006-Description (Complete) (18-11-2009).pdf

1585-DELNP-2006-Description (Complete)-(05-05-2011).pdf

1585-delnp-2006-description (complete).pdf

1585-delnp-2006-Drawings (18-11-2009).pdf

1585-delnp-2006-drawings.pdf

1585-delnp-2006-Form-1 (18-11-2009).pdf

1585-delnp-2006-form-1.pdf

1585-delnp-2006-form-18.pdf

1585-delnp-2006-form-2.pdf

1585-DELNP-2006-Form-3 (06-11-2009).pdf

1585-delnp-2006-Form-3-(13-04-2011).pdf

1585-delnp-2006-form-3.pdf

1585-delnp-2006-Form-5 (18-11-2009).pdf

1585-delnp-2006-form-5.pdf

1585-delnp-2006-pct-220.pdf

1585-delnp-2006-pct-237.pdf

1585-delnp-2006-pct-304.pdf

1585-delnp-2006-pct-308.pdf

1585-delnp-2006-pct-311.pdf

1585-delnp-2006-pct-402.pdf

1585-delnp-2006-pct-409.pdf

1585-delnp-2006-pct-416.pdf

1585-delnp-2006-Petition-137 (19-11-2009).pdf


Patent Number 248917
Indian Patent Application Number 1585/DELNP/2006
PG Journal Number 37/2011
Publication Date 16-Sep-2011
Grant Date 08-Sep-2011
Date of Filing 23-Mar-2006
Name of Patentee CONFORMA THERAPEUTICS CORPORATION
Applicant Address 9393 TOWNE CENTRE DR., SUITE 240, SAN DIEGO, CA 92121 (US).
Inventors:
# Inventor's Name Inventor's Address
1 HONG KEVIN D 5734 REDWOOD STREET, SAN DIEGO CALIFORNIA 92105 (US),
2 BIAMONTE MARCO A 11128 PORTOBELO DRIVE SAN DIEGO CALIFORNIA 92124 (US).
3 KASIBHATLA. SRINIVAS R. 13073 DRESSAGE LANE, SAN DIEGO, CALIFORNIA 92130 (US).
4 BOEHM MARCUS F 2811 MAPLE STREET, SAN DIEGO CALIFORNIA 92104 (US)
5 SHI JIANDONG 7556 CHARMANT DRIVE APT. # 1724, SAN DIEGO, CALIFORNIA 92122 (US).
6 NA NA
7 HURST DAVID 8082 RANCHO FANITA DRIVE, SANTEE, CALIFORNIA 92071, (US)
8 LE BRAZIDEC, JEAN-YVES 10170 WATERRIDGE CIRCLE# 142, SAN DIEGO, CALIFORNIA 92121(US).
9 ZHANG LIN 12455 BRICKELLIA STEET, SAN DIEGO, CALIFORNIA 92129 (US)
PCT International Classification Number A61K 31/00
PCT International Application Number PCT/US2004/031248
PCT International Filing date 2004-09-20
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/504,135 2003-09-18 U.S.A.
2 60/591,467 2004-07-26 U.S.A.