Title of Invention

NAPHTHALENE DERIVATIVES AS CYTOCHROME P450 INHIBITORS

Abstract Compounds of the formula (I); and pharmaceutically acceptable salts thereof, wherein n1, n2, n3, n4, G 1,Q1, Z, R1, R2, R3, R4a, R4b, R5a, and R5b are defined herein, inhibit the cytochrome P450RAI enzyme and are useful for the treatment and/or prevention of various diseases and conditions which respond to treatment by retinoids and by naturally occurring retinoic acid.
Full Text

NAPHTHYLENE DERIVATIVES AS CYTOCHROME P450 INHIBITORS
BACKGROUND OF THE INVENTION
[1] The present invention is directed to novel heteroaryl-naphthalenyl-
alkylamines, their salts, processes for their preparation, and compositions comprising them. The novel compounds of this invention are useful in inhibiting the cytochrome P450RAI enzyme (Cyp26) in animals, including humans, for the treatment and/or prevention of various diseases and conditions that respond to treatment by retinoids and by naturally occurring retinoic acid.
[2] Retinoic acid, retinoid-like compounds, and pharmaceutical
compositions comprising retinoic acid or rectinoid-like compounds as the active ingredient are known in the art to play a significant role in the regulation and differentiation of epithelial cells. Such regulatory and differentiating effects, which include the ability to promote cell differentiation, apoptosis, and the inhibition of cell proliferation, make retinoic acid and retinoid compounds useful agents in tumor therapy and in treating such conditions as skin-related diseases. Retinoids and retinoid compounds are known as agents for treating skin-related diseases such as actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses, keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus; for preventing, treating, and reversal of glucocorticoid, age, and photo damage to the skin. Retinoids and retinoid compounds are also known as topical anti-microbial and skin antipigmentation agents. Retinoids, with their ability to serve as differentiating agents, redirect cells towards their normal phenotype and therefore may reverse or suppress developing malignant lesions or prevent cancer invasions altogether. Therefore, retinoid compounds are useful for the prevention and treatment of cancerous and precancerous conditions, including, for example, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, colon, bladder, cervix, uterus, stomach, lung, esophagus, blood and lymphatic system, larynx, oral cavity, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes, and in the treatment of Kaposi's sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, for example, proliferative vitreoretinopathy, retinal detachment, corneopathies such as dry eye, as well as in the treatment^ndprevenBoiTof various cardiovascular^iseasesr

dry eye, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulation tissue plasminogen activator. Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil®, diseases associated with the immune systems, including use of the present compounds as immunosuppresant and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. Retinoid compounds have also been discovered to be useful in treating type II non-insulin dependent diabetes mellitus (NDDDM).
[3] Several compounds having retinoid-like activity are marketed under
appropriate regulatory approvals in the United States of America and elsewhere as
medicants for the treatment of several diseases responsive to treatment with retinoids,
Retinoic acid (RA) itself is a naturally occurring retinoid, the biologically most active
metabolite of vitamin A, is biosynthesized and present in a multitude of human and
mammalian tissues and is known to play a crucial role in the regulation of gene
expression, cellular differentiation, proliferation of epithelial cells, and other
important biological processes in mammals including humans.
[4] Retinoids have demonstrated reversal of malignant growth in vivo and
in vitro and are effective as chemopreventive agents, Retinoids could successfully be used to treat oral leukoplakia, a potentially premalignant mucosal lesion, and the occurrence of second primary tumors following head and neck squamous cell carcinoma (HNSCC) could be inhibited or delayed. These second primary tumors, which occur at an incidence rate of 2-3% per year, are a major cause of death after surgical resection of early-stage head and neck cancer. Retinoid therapy has also been explored in the treatment of glioma tumors, primary and metastatic melanoma cells, and has shown anti-metastatic activities in rat invasive prostate adenocarcinoma cells. Retinoid leukemia therapy works through terminal differentiation"^dlBrevOTtual~

apoptotic death of leukemic cells and has been shown to result in complete remissiun
in up to 90% of patients with Acute Promyelocytic Leukemia (APL).
[5] Although treatment with retinoids is highly successful in inducing
complete remission in APL, if maintained on retinoids alone, most patients will relapse within a few months. The clinical use of retinoic acid in the treatment of cancer has been significantly hampered by the prompt emergence of resistance, which is believed to be caused by increased retinoic acid metabolism. Retinoic acid is metabolized by Cyp26Al (Cyp26), an inducible cytochrome P450 enzyme, that inactivates RA by oxidation of RA to 4-HO-atRA, 8-HO-atRA, and 4-oxo-atRA The tightly controlled negative feedback mechanism limits the availability of RA and thereby limits its biological activity. Compounds have been identified that inhibit Cyp26 and therefore RA metabolism and have shown to enhance the antiproliferative effects of RA and cause an increase in endogenous levels of RA in plasma and in tissues.
[6] Cyp26 inhibitors, also known as retinoic acid metabolism-blocking
agents (RAMBAs), are known and include, for example, Liarozole (Liazal™) and Rl 16010. Such Cyp26 inhibitors have demonstrated therapeutic benefits in dennatological and cancerous conditions in vitro, in vivo, and in clinical settings. In several preclinical tumor models, Liarozole displayed antitumoral properties which correlated with decreased endogenous retinoic acid metabolism and therefore, an increase in RA accumulation within tumor cells. In cancer patients, Liarozole has been shown to increase the half-life of orally administered RA and 13-cis-RA. Unfortunately, one of the limitations of Liarozole and many Cyp26 inhibitors described in the literature was their lack of specificity. Liarozole as well as other Cyp26 inhibitors inhibit other cytochrome P450-mediated reactions and are limited due to their lack of specificity towards other cytochrome P450 enzymes. This lack of specificity might explain the limited risk benefit ratio (the activity/toxicity ratio was considered insufficient by the FDA) observed in prostate cancer patients in the Liarozole phase in clinical trials. Therefore, there is clearly a need within retinoid therapy for Cyp26 inhibitors (RAMBA's) that are highly potent and selective that have greater selectivity to other cytochrome P450 enzymes, fewer side effects, and favorable drug-like properties including sufficient water solubility, bioavailability, sufficient pharmacokinetic properties, extraction ratios, and limited toxicity to balance

the activity/toxicity ratio and for use in the treatment of various dennatological and cancerous conditions.
[7] The present invention shows highly potent and selective novel
heteroaryl-naphthalenyl-alkylamines Cyp26 inhibitors that provide therapeutic benefits in the treatment or prevention of the diseases and conditions which respond to treatment by retinoids or are controlled by natural retinoic acid. The perceived mode of action of these compounds is that by inhibiting the Cyp26 enzyme (CP450RAI [cytochrome P450 retinoic acid inducible]) that has been proven in the art to catabolyze natural retinoic acid, endogenous retinoic acid level is elevated to a level where desired therapeutic benefits are attained. The endogenous levels of all natural and synthetic retinoids which are metabolized by Cyp26 would be expected to increase from inhibition of Cyp26 by the novel heteroaryl-naphthalenyl-alkylamines Cyp26 inhibitors described in this invention. Co-administration with a composition of the natural or synthetic retinoids with the compounds, or pharmaceutically acceptable salts thereof, disclosed in this invention can increase the level of retinoids. The co-administration of the natural and synthetic retinoids, which are catabolized by Cyp26, with at least one compound disclosed in this invention is a method for treating skin-related or cancerous diseases to yield higher endogenous levels of the retinoids. The compounds of this invention are active at nanomolar concentrations and selectively and potently inhibit enzymes involved in retinoic acid catabolism and therefore result in the effective modulation of desirable levels of atRA.
[8] The following publications describe or relate to the role of Cyp26
inhibitors and their ability to slow the catabolism of retinoic acid, thereby increasing endogenous retinoic acid levels, and their potential for the treatment of dermatological diseases and cancers:
[9] Altucci, L. etal. "Retinoic Acid-induced Apoptosis in Leukemia Cells
is Mediated by Paracrine Action of Tumor-Selective Death Ligand Trail", Nature Med. 2001, 7, 680-686;
[10] Altucci, L.; Gronemeyer, H. "The Promise of Retinoids to Fight
Against Cancer", Nature Reviews (Cancer), 2001,1, 181-193;
[11] Winum, J. Y.; et al. "Synthesis of New Targretin® Analogues that
Induce Apoptosis in Leukemia HL-60 Cells", Bioorganic & Medicinal Chemistry Letters. 2002. 12.3529-3532.

[12] Kuijpers, et. al. "The Effects of Oral Liarozole on Epidermal
Proliferation and Differentiation in Severe Plaque Psoriasis are Comparable with
Those of Acitretin", British Journal of Dermatology, 1998. 139, 380-389;
[13] Van Wauwe, et. al. "Liarozole, an Inhibitor of Retinoic Acid
Metabolism, Exerts Retinoid-Mimetic Effects in Vivo", The Journal of Pharmacology
and Experimental Therapeutics, 1992, 261, 773-779.
[14] Haque, M; Andreola, F.; DeLuca, L. M. "The Cloning and
Characterization of a Novel Cytochrome P450 Family, Cyp26, with Specificity
towards Retinoic Acid", NutriRev. 1999,56, 84-85.
[15] Wouters, W. et. al. "Effects of Liarozole, a New Antitumoral
Compound and Retinoic Acid-Induced Inhibition of Cell Growth and on Retinoic
Acid Metabolism in MCF-7 Breast Cancer Cells", Cancer Res, 1992,52,2841-2846;
[16] Freyne, E. et. al. "Synthesis of Liazal™, a Retinoic Acid Metabolism
Blocking Agents (RAMBA) with Potential Clinical Applications in Oncology and
Dermatology", Bioorganic & Medicinal Chemistry Letters, 1998, [17] Miller, W, H. "The Emerging Role of Retinoids and Retinoic Acid
Metabolism Blocking Agents in the Treatment of Cancer", Cancer, 1998,83, 1471-
1482;
[18] Van Heusden J. et al. "Inhibition of all-TRANS-retinoic Acid
Metabolism by Rl 16010 Induces Antitumor Activity", Br. J. Cancer, 2002,56(4),
605-611;
[19] Debruyne, F. J. M. et. al. "Liarozole-A Novel Treatment Approach for
Advanced Prostate Cancer: Results of a Large Randomized Trial versus
Cyproterone", Urology, 1998, 52,72-81;
[20] De Coster, R. et. al. "Experimental Studies with Liarozole (R75251):
An Antitumor Agent which Inhibits Retinoic Acid Breakdown", J. Steroid Biochem.
Molec. Biol 1992,43, 197-201;
[21] Njar, V. C. O.; Brodie, A M. H. "Inhibitors of Cytochrome P450
Enzymes: Their Role in Prostate Cancer Therapy", I Drugs, 1999,1,495-506;
[22] Miller, V. A.; Rigas, J. R.; Muindi, J. F. R.; Tong, W. P.;
Venkatraman, E.; Kris, M. G.; Warrell Jr. R. P. "Modulation of all-trans-retinoic acid
pharmacokinetics by liarozole", Cancer Chemother. Pharmacol 1994, 34, 522-526;
[23] Muindi, J.; Frankel, S. R.; Miller Jr. W. H.; Jakubowski, A.;
Scheinberg, D. A.; Young, C. W.; Dmitrovsld, E.; Warrell, Jr. R/P. "Continuous

treatment with all-trans-retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid 'resistance1 in patients with acute promyelocytic leukemia'\ Blood. 1992, 79,299-303;
[24] Muindi, J F.; Scher, H, L; Rigas, J. R.; Warrell Jr. R. P.; Young, C. W.
"Elevated plasma lipid peroxide content correlates with rapid plasma clearance of all-trans-retinoic acid in patients with advanced cancer", Cancer Res. 1994,54,2125-2128.
[25] U.S. Patent No. 6,303,785Bl describes inhibitors of cytochrome
P450RAL International Patent Publication No. WO 99/29674 describes inhibitors of retinoic acid metabolism. International Patent Publication No. WO 01/30762A1 describes imidazol-4-ylmethanols used as inhibitors of steroid C17-20 Lyase.
[26] U.S. Patent Nos. 6,291,677 and 6,124,330 and International Patent
Publication No. WO 02/03912 A2 describe inhibitors of cytochrome P450RAI. International Application No. PCTYUS00/11833 describes PPAR agonists or antagonists. International Patent Publication No. WO 02/06281 describes selective |33 adrenergic receptor agonists. International Patent Publication No. WO 01/068647 describes an antiviral agent. International Patent Publication No. WO 01/062234 describes a farnesyl protein transferase inhibitor. International Patent Publication No. WO 01/055155 describes compounds which have antibacterial activities. International Patent Publication No. WO 01/044170 describes adamantine derivatives. International Patent Publication No. WO 01/000615 describes benzimidazoles. International Patent Publication No. WO 00/069843 describes compounds for the treatment of inflammations. International Patent Publication No. WO 00/043384 describes aromatic heterocyclic ureas as anti-inflammatory agents. Japanese Patent Publication No. JP 01/43635 describes benzimidazole compositions and derivatives. International Patent Publication No. WO 99/40092 describes GABAa agonists, antagonists or inverse agonists. International Patent Publication No. WO 99/376609 describes virucides used against cytomegalovirus. German Patent Publication No. DE 75/6388 describes substituted 2-aryl-4-amino-quinazolines. International Patent Publication No. WO 98/54168 describes 2-oxoimidazole derivatives. International Patent Publication No. WO 98/23593 describes inhibitors of apolipoprotein B and/or

microsomal triglyceride transfer protein. U.S. Patent No. 5,852,213 describes matrix metalloproteinase inhibitors of the MMP enzyme. U.S. Patent No. 5,834,483 and International Patent Publication No. WO 97/37665 describes endothelin antagonists. International Patent Publication No. WO 97/24117 describes substituted hydroxamic acid compounds. International Patent Publication No. WO 95/29689 describes N-carboxyalkyl derivatives. U.S. Patent No. 5,461,162 describes N-acyl auxilliary compounds. European Patent Publication No. 611,776 describes pseudopeptides with antiviral activity. European Patent Publication No. 569,220 describes organic sulfonamides. European Patent Publication No. 545,376 describes guanidinothiazoles. German Patent No. DE 4,201,435 describes trifluoromethyl ketones. German Patent No. DE 4,138,820 describes compounds used as herbicides. International Patent Publication No. WO 91/19717 describes phosphodiesterase inhibitors. European Patent Publication No. EP 437,729 describes peptide retroviral protease inhibitors. European Patent Publication No. EP 412,350 describes peptides as renin inhibitors. International Patent Publication No. WO 89/10919 describes carbostyril derivatives. International Patent Publication No. WO 00/064888 describes diaryl carboxylic acids and derivatives. WO 99/47497 describes naphthyl and indolyl acylsulfonamides. German Patent No. DE 4304650 describes benzimidazoles, xanthines, and analogs. International Patent Application No. PCT/CA99/00212 describes compounds used for treating or preventing prostaglandin mediated diseases.
SUMMARY OF THE INVENTION
[27] The present invention relates to compounds represented by Formula I:

and pharmaceutically accepted salts thereof. The compounds of Formula I inhibit cytochrome P450RAI enzyme and are useful for the treatment and/or prevention of various diseases and conditions that respond to treatment by retinoids and by naturally occurring retinoic acid.











[43] In an embodiment of this aspect, a compound is represented by
Formula I, or a pharmaceutically acceptable salt thereof, wherein X is a substituted imidazolyl or substituted triazolyl; R1 is hydrogen; and the other variables are as described above.
[44] In a second aspect of the present invention, a compound is represented
by Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is oxygen, and the other variables are as described above.
[45] In an embodiment of this second aspect, a compound of the invention
is represented by Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein:
[46] X is an unsaturated heterocycle selected from pyrrolyl, pyrazolyl,
imidazolyl, triazolyl, tetrazolyl, thiazole, or pyridinyl, any of which is optionally substituted with one or more independent R66 substituents;
[47] R2 and R3 are each independently Co-ioalkyl, C2-ioalkenyl, C2-ioalkynyl,
Ci-ioalkoxyCi.ioalkyl, CMoalkoxyC2-ioalkenyl, Ci-ioalkoxyC2.ioalkynyl, Ci-loalkylthioCi.ioalkyl, Ci-ioalkylthioC2-ioalkenyl, Ci-ioalkylthioC2-ioalkynyl, cycloC3. salkyl, cycloC3-8alkenyl, cycloCs-salkylCi-ioalkyl, cycloCs-salkenylCi-ioalkyl, cycloC3. 8alkylC2-ioalkenyl, cycloC3-salkenylC2-ioalkenyl, cycloC3-8alkylC2-ioalkynyl, cycloC3-salkenylC2.ioalkynyl, heterocyclyl-Co-ioalkyl, heterocyclyl-C2-ioalkenyl, heterocyclyl-C2-ioalkynyl, Ci-ioalkylcarbonyl, C2-ioalkenylcarbonyl, C2-loalkynylcarbonyl, Ci.ioalkoxycarbonyl, Ci.ioalkoxycatbonylCi-ioalkyl, monoC]. ealkylaminocarbonyl, diCi^alkylaminocarbonyl, mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or Ci.ioalkyl(aryl)aminocarbonyl, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cuoalkoxy, -SO2NR71R81, or -NR71R81 substituents; or aiyl-Cwoalkyl, aryl-C2.ioalkenyl, or aryl-C2-ioalkynyl, any of which is optionally substituted with one or more













































































[ 142] 1 -[(6-Benzyloxy-naphthalen-2-y l)-( 1 -methyl-pyrrolidin-2-yl)-methyl]-
lH-imidazole.
[143] Unless otherwise stated, the connections of compound name moieties
are at the rightmost recited moiety. That is, the substituent name starts with a
terminal moiety, continues with any bridging moieties, and ends with the connecting
moiety. For example, hetarylthioCMalkyl has a heteroaryl group connected through a
thio sulfur to a CM alkyl that connects to the chemical species bearing the substituent
[144] As used herein, for example, "Co^alkyl" is used to mean an alkyl
having 0-4 carbons - that is, 0, 1, 2,3, or 4 carbons in a straight or branched
configuration. An alkyl having no carbon is hydrogen when the alkyl is a terminal
group. An alkyl having no carbon is a direct bond when the alkyl is a bridging
(connecting) group.
[145] In all embodiments of this invention, the term "alkyl" includes both
branched and straight chain alkyl groups. Typical alkyl groups are methyl, ethyl, n-
propyl, isopropyl, n-butyl, sec-butyl, isobutyl, terf-butyl, w-pentyl5 isopentyl, «-hexyl,
w-heptyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl,
eicosyl and the like.
[146] The term "halo" refers to fluoro, chloro, bromo or iodo.
[147] The term "haloalkyl" refers to an alkyl group substituted with one or
more halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl,
trifluoromethyl, perfluoropropyl, 8-chlorononyl and the like,
[148] The term "cycloalkyl" refers to a cyclic aliphatic ring structure,
optionally substituted with alkyl, hydroxy and halo, such as cyclopropyl,
methylcyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyl, cyclohexyl, 4-
chlorocyclohexyl, cycloheptyl, cyclooctyl and the like.
[149] The term "alkylcarbonyloxyalkyl" refers to an ester moiety, for
example acetoxymethyl, n-butyryloxyethyl and the like.
[150] The term "alkynylcarbonyl" refers to an alkynylketo functionality, for
example propynoyl and the like.
[151] The term "hydroxyalkyl" refers to an alkyl group substituted with one
or more hydroxy groups, for example hydroxymethyl, 2,3-dihydroxybutyl and the
like.

[152] The term "alkylsulfonylalkyl" refers to an alkyl group substituted with
an alkylsulfonyl moiety, for example mesylmethyl, isopropylsulfonylethyl and the
like.
[153] The term "alkylsulfonyl" refers to a sulfonyl moiety substituted with an
alkyl group, for example mesyl, n-propylsulfonyl and the like.
[154] The term "acetylaminoalkyl" refers to an alkyl group substituted with
an amide moiety, for example acetylaminomethyl and the like.
[155] The term "acetylaminoalkenyl" refers to an alkenyl group substituted
with an amide moiety, for example 2-(acetylamino)vinyl and the like.
[156] The term "alkenyl" refers to an ethylenically unsaturated hydrocarbon
group, straight or branched chain, having 1 or 2 ethylenic bonds, for example vinyl,
allyl, 1-butenyl, 2-butenyl, isopropenyl, 2-pentenyl and the like.
[157] The term "haloalkenyl" refers to an alkenyl group substituted with one
or more halo groups.
[158] The term "cycloalkenyl" refers to a cyclic aliphatic ring structure,
optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds
such as methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl,
cyclohexenyl, 1,4-cyclohexadienyl and the like.
[159] The term "alkynyl" refers to an unsaturated hydrocart>on group,
straight or branched, having 1 or 2 acetylenic bonds, for example ethynyl, propargyl
and the like.
[160] The term "haloalkynyl" refers to an alkynyl group substituted with one
or more halo groups.
[161] The term "alkylcarbonyl" refers to an alkylketo functionality, for
example acetyl, «-butyryl and the like.
[162] The term "alkenylcarbonyl" refers to an alkenylketo functionality, for
example, propenoyl and the like.
[163] The term "aryl" refers to phenyl or naphthyl which may be optionally
substituted. Typical aryl substituents include, but are not limited to, phenyl, 4-
chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-
methylphenyl, 3-methyphenyl, 4-methyIphenyl, 4-ethylphenyl, 2-methyl-3-
methoxyphenyl, 2,4-dibromophenyl? 3,5-difluorophenyl, 3,5-dimethylphenyl, 2,4,6-
trichlorophenyl, 4-methoxyphenyl, naphthyl, 2-chloronaphthyl, 2,4-dimethoxyphenyl,
4-(trifluoromethyl)phenyl and 2-iodo-4-methylphenyl.



defined hereinbefore, forming a bridging portion of the aryl-alkynyl moiety, for
example 3-phenyl-l-propynyl and the like.
[169] The terms "aryl-oxy" or "aryloxy" are used to describe a terminal aryl
group attached to a bridging oxygen atom. Typical aryl-oxy groups include phenoxy,
3,4-dichlorophenoxy and the like.
[170] The terms "aryl-oxyalkyl" or "aryloxyalkyl" are used to describe a
group wherein an alkyl group is substituted with an aryl-oxy group, for example
pentafluorophenoxymethyl and the like.
[171] The terms "hetaryl-oxy" or "heteroaiyl-oxy" or "hetaryloxy" or
"heteroaryloxy" are used to describe a terminal hetaryl group attached to a bridging
oxygen atom. Typical hetaryl-oxy groups include 4,6-dimethoxypyrimidin-2-yloxy
and the like.
[172] The terms "hetarylalkyl" or "heteroarylalkyl" or "hetaryl-alkyl" or
"heteroaiyl-alkyl" are used to describe a group wherein the alkyl chain can be
branched or straight chain with the heteroaryl portion, as defined hereinbefore,
forming a bridging portion of the heteroaralkyl moiety, for example 3-furylmethyl,
thenyl, furfuryl and the like.
[173] The terms "hetarylalkenyl" or "heteroarylalkenyl" or "hetaryl-alkenyl"
or "heteroaryl-alkenyl" are used to describe a group wherein the alkenyl chain can be
branched or straight chain with the heteroaryl portion, as defined hereinbefore,
forming a bridging portion of the heteroaralkenyl moiety, for example 3-(4-pyridyl)-
1-propenyl.
[174] The terms "hetarylalkynyl" or "heteroarylalkynyl1* or
"hetaryl-alkynyl" or "heteroaiyl-alkynyl" are used to describe a group wherein the
alkynyl chain can be branched or straight chain with the heteroaryl portion, as defined
hereinbefore, forming a bridging portion of the heteroaralkynyl moiety, for example
4-(2-thienyl)-1 -butynyl.
[175] The term "heterocyclyl" refers to a substituted or unsubstituted 3-10
membered saturated ring containing one, two or three heteroatoms, preferably one or
two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a
bicyclic ring system containing up to 10 atoms including at least one heteroatom
selected from oxygen, nitrogen and sulfur wherein the ring containing the heteroatom
is saturated. Examples of heterocyclyls include, but are not limited to,





[197] The term "haloalkoxy" refers to an alkoxy group substituted with one
or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy,
perfluoroisobutoxy and the like.
[198] The term "alkoxyalkoxyalkyl" refers to an alkyl group substituted with
an alkoxy moiety which is in turn substituted with a second alkoxy moiety, for
example methoxymethoxymethyl, isopropoxymethoxyethyl and the like.
[199] The term "alkylthio" includes both branched and straight chain alkyl
groups attached to a bridging sulfur atom, for example methylthio.
[200] The term "haloalkylthio" refers to an alkylthio group substituted with
one or more halo groups, for example trifluoromethylthio.
[201] The term "alkoxyalkyl" refers to an alkyl group substituted with an
alkoxy group, for example isopropoxymethyl.
[202] The term "alkoxyalkenyl" refers to an alkenyl group substituted with
an alkoxy group, for example 3-methoxyallyl.
[203] The term "alkoxyalkynyl" refers to an alkynyl group substituted with
an alkoxy group, for example 3-methoxypropargyl.
[204] The term "alkoxycarbonylalkyl" refers to a straight chain or branched
alkyl substituted with an alkoxycarbonyl, for example ethoxycarbonylmethyl, 2-
(methoxycart>onyl)propyl and the like.
[205] The term "alkoxycarbonylalkenyl" refers to a straight chain or
branched alkenyl as defined hereinbefore substituted with an alkoxycarbonyl, for
example 4-(ethoxycarbonyl)-2-butenyl and the like.
[206] The term "alkoxycarbonylalkynyl" refers to a straight chain or
branched alkynyl as defined hereinbefore substituted with an alkoxycarbonyl, for
example 4-(ethoxycarbonyl)-2-butynyl and the like,
[207] The term "haloalkoxyalkyl" refers to a straight chain or branched alkyl
as defined hereinbefore substituted with a haloalkoxy, for example 2-
chloroethoxymethyl, trifluoromethoxymethyl and the like.
[208] The term "haloalkoxyalkenyl" refers to a straight chain or branched
alkenyl as defined hereinbefore substituted with a haloalkoxy, for example 4-
(chloromethoxy)-2-butenyl and the like.
[209] The term "haloalkoxyalkynyl" refers to a straight chain or branched
alkynyl as defined hereinbefore substituted with a haloalkoxy, for example 4-(2-
fluoroethoxy)-2-butynyl and the like.

[210] . The term "alkylthioalkyl" refers to a straight chain or branched alkyl as
defined hereinbefore substituted with an alkylthio group, for example
methylthiomethyl, 3-(isobutylthio)heptyl and the like.
[211] The term "alkylthioalkenyl" refers to a straight chain or branched
alkenyl as defined hereinbefore substituted with an alkylthio group, for example 4-
(methylthio)-2-butenyl and the like.
[212] The term "alkylthioalkynyl" refers to a straight chain or branched
alkynyl as defined hereinbefore substituted with an alkylthio group, for example 4-
(ethylthio)-2-butynyl and the like.
[213] The term "haloalkylthioalkyl" refers to a straight chain or branched
alkyl as defined hereinbefore substituted with an haloalkylthio group, for example 2-
chloroethylthiomethyl, trifluoromethylthiomethyl and the like,
[214] The term "haloalkylthioalkenyl" refers to a straight chain or branched
alkenyl as defined hereinbefore substituted with an haloalkylthio group, for example
4-(chloromethylthio)-2-butenyl and the like.
[215] The term "haloalkylthioalkynyl" refers to a straight chain or branched
alkynyl as defined hereinbefore substituted with a haloalkylthio group, for example 4-
(2-fluoroethylthio)-2-butynyl and the like.
[216] The term "dialkoxyphosphorylalkyl" refers to two straight chain or
branched alkoxy groups as defined hereinbefore attached to a pentavalent
phosphorous atom, containing an oxo substituent, which is in turn attached to an
alkyl, for example diethoxyphosphoiylmethyl.
[217] The term "oligomer" refers to a low-molecular weight polymer, whose
number average molecular weight is typically less than about 5000 g/mol, and whose
degree of polymerization (average number of monomer units per chain) is greater than
one and typically equal to or less than about 50.
[218] Compounds described herein contain one or more asymmetric centers
and may thus give rise to diastereomers and optical isomers. The present invention
includes all such possible diastereomers as well as their racemic mixtures, their
substantially pure resolved enantiomers, all possible geometric isomers, and
phannaceutically acceptable salts thereof. The above Formula I is shown without a
definitive stereochemistry at certain positions. The present invention includes all
stereoisomers of Formula I and phannaceutically acceptable salts thereof. Further,
mixtures of stereoisomers as well as isolated specific stereoisomers are also included.

During the course of the synthetic procedures used to prepare such compounds, or in
using racemization or epimerization procedures known to those skilled in the art, the
products of such procedures can be a mixture of stereoisomers.
[219] Within the enantiomers of the compounds, both the syn and anti
isomers involving the X and G1 substituent show activity. It was found that the syn isomer is more active than the anti isomer and thus, is the preferred isomer. Furthermore, it is preferable that there be dual chiral centers at the X and G1 attachment positions.
[220] The invention also encompasses a pharmaceutical composition that is
comprised of a compound of Formula I in combination with a phannaceutically acceptable carrier.
[221] Preferably the composition is comprised of a phannaceutically
acceptable carrier and a non-toxic therapeutically effective amount of a compound of
Formula I as described above (or a phannaceutically acceptable salt thereof).
[222] Moreover, within this preferred embodiment, the invention
encompasses a pharmaceutical composition for the treatment of disease by inhibiting the cytochrome P450RAI enzyme, resulting in regulation and differentiating of epithelial cells, comprising a phannaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above (or a phannaceutically acceptable salt thereof).
[223] The term "phannaceutically acceptable salts" refers to salts prepared
from phannaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from phannaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium slats. Salts derived from phannaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other phannaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choiine, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-

dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylameine, trimethylamine, tripropylamine, tromethamine and the like.
[224] When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from pharmaceutically acceptable
non-toxic acids, including inorganic and organic acids. Such acids include, for
example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,
phosphoric, succinic, sulfizric, tartaric, p-toluenesulfonic acid and the like. Preferred
are citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfiiric and tartaric
acids. Particularly preferred are formic and hydrochloric acid.
[225] The pharmaceutical compositions of the present invention comprise a
compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
[226] In practice, the compounds represented by Formula I, or
pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid,

as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
[227] Thus, the pharmaceutical compositions of this invention may include a
pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
[228] The pharmaceutical carrier employed can be, for example, a solid,
liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
[229] In preparing the compositions for oral dosage form, any convenient
pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microciystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
[230] A tablet containing the composition of this invention may be prepared
by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules,

optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
[231] For example, a formulation intended for the oral administration to
humans may contain from about 0.5xng to about 5g of active agent, compounded with
an appropriate and convenient amount of carrier material which may vary from about
5 to about 95 percent of the total composition. Unit dosage forms will generally
contain between from about lmg to about 2g of the active ingredient, typically 25mg,
50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg.
[232] Pharmaceutical compositions of the present invention suitable for
parenteral administration may be prepared as solutions or suspensions of the active
compounds in water. A suitable surfactant can be included such as, for example,
hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid
polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be
included to prevent the detrimental growth of microorganisms.
[233] Pharmaceutical compositions of the present invention suitable for
injectable use include sterile aqueous solutions or dispersions. Furthermore, the
compositions can be in the form of sterile powders for the extemporaneous
preparation of such sterile injectable solutions or dispersions. In all cases, the final
injectable form must be sterile and must be effectively fluid for easy syringability.
The pharmaceutical compositions must be stable under the conditions of manufacture
and storage; thus, preferably should be preserved against die contaminating action of
microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene
glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
[234] Pharmaceutical compositions of the present invention can be in a form
suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream

or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
[235] Pharmaceutical compositions of this invention can be in a form
suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
[236] In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
[237] Generally, dosage levels on the order of from about O.Olmg/kg to
about 150mg/kg of body weight per day are useful in the treatment of the above-
indicated conditions, or alternatively about 0.5 mg to about 7g per patient per day. For
example, dermatological diseases and cancers may be effectively treated by the
administration of from about 0.01 to 50mg of the compound per kilogram of body
weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
[238] It is understood, however, that the specific dose level for any particular
patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. BIOLOGICAL ASSAYS
[239] The efficacy of the Examples of the invention, compounds of Formula
I, as inhibitors of Cyp26 were demonstrated and confirmed by a number of pharmacological in vitro assays. The following assays and their respective methods have been carried out with the compounds according to the invention. Activity possessed by compounds of Formula I may be demonstrated in vivo.
In vitro biochemical assay

[240] The compounds of Formula I can inhibit CYP26 activity. In vitro
biochemical assay was performed using microsomal preparations from T47D cells induced to express CYP26. Enzymatic activity was measured as the conversion of the radiolabeled substrate to its metabolites, 4-OH RA (4-hydroxy all trans retinoic acid) and 4-oxo RA (4-oxy retinoic acid) by separation on a C18 HPLC column. Inhibition of CYP26 activity in the presence of variable naphthalene analog concentrations was used to determine the ICso's.
Methods
Microsomal Preparation from T47D cells
[241] T47D cells were grown in RPMI1640 containing 10% FBS and 1%
P/S, plated and treated 16-25 hours later with 5uM atRA and allowed to incubate for an additional 48 hours before cell harvest. Cells were washed twice with lxPBS and scraped from plates. Cells were pelleted and resuspended in homogenization buffer (0.1M Tris-Cl, pH7.4, 0.1M DTT, 0.2mM EDTA, 1.15% w/vKCl, O.lmM PMSF and 20% v/v glycerol). Microsomes were prepared by differential centrifugation of homogenized cells. Homogenate was spun at 17,000g and the supernatant spun again at 100,000g. The pellet was resuspended in 25mM potassium phosphate, pH7.4,20% v/v glycerol and stored at -80 °C.
HPLC Biochemical CYP26 Assay
[242] Enzymatic assays were performed in a total volume of 100 pL in a
reaction mixture composed of 100 mM Tris pH7.4,150 mM KC1,10 mM MgCl2) 2 mM NADPH, 40 nM 3H-atRA, and varying concentrations of novel compound dissolved in DMSO such that the concentration in the reaction is 1% final, and 20 p.g of T47D microsomes. The reactions were incubated at 37 °C for 30 min in the dark. The reaction was stopped by the addition of 125 pL of acetonitrile, mixed and spun at 10,000g for 10 min. The supernatant was removed and atRA and metabolites were separated on a C18 Waters Spherisorb column with an in line radiometric detector with a flow rate of 1 mL/min at detected at 350 nM. The gradient used was the mixture of 60 mM Ammonium Acetate, pH 5.2/30%CH3OH, solvent A and solvent B (CH3OH). A 30-50% gradient of CH3OH was run for 8 min followed by a 50-99% CH3OH gradient for 4 min and 99% CH3OH for 2 min.

Inhibition of Cell Proliferation in vitro
[243] The novel naphthalene analogs inhibit the proliferation of breast cancer
and prostate cells in vitro. Experiments were conducted on T47D breast cancer cell line and on the AT6.1 rat prostate adenocarcinoma cell line.
Methods
[244] T47D cells were grown in RPMI1640 containing 10% FBS and
1%P/S. Cells were plated into 96 well culture plates (2000 cells per well) in 100 pL of same medium. After attachment for 16-24 h, the vehicle (DMSO), or atRA alone (at concentrations of 1 nM to 1 p.M)> or atRA at these concentrations in combination with vaiying concentration of novel compound were added to triplicate wells (/. Biol Chem. 1997,272(22), 17921-17928). Medium/treatments were repeated 3 days after the first treatment and measure of the decrease in cell proliferation was measured 48 hours later using CellTiter-Glo™ (Promega).
[245] The method described above was also used for AT6.1 cells except that
cells were plated at 1500 cells per well and treatment was performed once with measure of the decrease in cell proliferation 72 h post treatment. AT6.1 cells were grown in RPMI 1640 containing 10% FBS, 1% P/S and 250 nM Dexamethasone.
CYP3A4 Assay
[246] Enzymatic assays to measure the inhibition of CYP3A4 activity was
determined in lOOul volume in a 96 well plate by the use of a fluorescence substrate
(BD, Gentest). Compounds were tested at various concentrations in a reaction that
contained 200mM Potassium Phosphate buffer, pH 7.4,200mM NADPH and 50uM
7-benzyloxy-4-(trifluoromethyl)-coumarin. The reaction was incubated at 37°C for
45 minutes followed by the addition of 37ul of 0.5M Tris Base to terminate the
reaction. The plates were read at excitation/emission of 405/53 5nm, respectively.
[247] All Examples showed inhibition of Cyp26. The following Examples
showed efficacy and activity by inhibiting Cyp26 in the biochemical assay in the range from about 5|iM to below lOnM. The most preferred Examples are selective towards Cyp26. It is preferred that the ratio of the IC50 value of Cyp3A4 activity to the IC50 value of Cyp26 activity of 10:1 or greater, or 100:1 or greater. EXPERIMENTAL
[248] In Schemes 1-29 below showing how to synthesize compounds of this
invention and Tables 1-5 below listing various representative compounds of this

invention, the following abbreviations are used: Me for methyl, Et for ethyl, lPr or *Pr
for isopropyl, n-Bu for n-butyl, t-Bu for terf-butyl, Ac for acetyl, Ph for phenyl, 4C1-
Ph or (4Cl)Ph for 4-chlorophenyl, 4Me-Ph or (4Me)Ph for 4-methylphenyl, (p-
CH3O)Ph for/?-methoxyphenyl5 (p-NO2)Ph forp-nitrophenyl, 4Br-Ph or (4Br)Ph for
4-bromophenyl, 2-CF3-Ph or (2CF3)Ph for 2-trifluoromethylphenyl, DMAP for 4-
(dimethylamino)pyridine, DCC for 1,3-dicyclohexylcarbodiimide, EDC for l-(3-
dimethylaminopropyl>3-ethylcarbodiimide hydrochloride, HOBt for 1-
hydroxybenzotriazole, HO At for l-hydroxy-7-azabenzotriazole, CDI for 1,1'-
carbonyldiimidazole, CDT for l,r-carbonyldi(l,2,4-triazole),DEAD for diethlyl
azodicarboxylate, DIAD for diisopropyl azodicarboxylate, DBAD for di-tert-butyl
azodicarboxylate, FBS for fetal bovine serum, P/S for Penicillin/Streptomycin, DTT
for dithiothreitol, EDTA for ethylenediaminetetraacetic acid, PMSF for
phenylmethanesulfonyl fluoride, Tris for trimethamine, NADPH for beta
nicotinamide adenine dinucleotide phosphate reduced, and Bn for benzyl.
[249] The following schematic processes show certain compounds which are
useful as intermediates in the formation of Cyp26 inhibiting Examples. Such intermediates are included in the present invention.
[250] The compounds of Formula I of this invention and the intermediates
used in the synthesis of the compounds of this invention were prepared according to the following methods. Method A was used when preparing compounds of Formula I-A [compounds of Formula I where Rl equals H; R4a, R5a, R6a and R^ equal H; and Y equals O] as shown below in Scheme 1: Method A:


where X, R2, R3, G1, (Z%2, (CR4hK5h^ and (Q1)*, are as defined previously for compound of Formula I.
[251] In a typical preparation, a compound of Formula II was reacted with
CDI or CDT in a suitable solvent. Suitable solvents for use in the above process
included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and
the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; and
chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If
desired, mixtures of these solvents were used. The preferred solvent was dependent
upon the substrates employed and was selected according to the properties of the
substrates. The above process was carried out at temperatures between about -78 °C
and about 100 °C. Preferably, the reaction was carried out between 22 °C and about
80 °C. The above process to produce compounds of the present invention was
preferably carried out at about atmospheric pressure although higher or lower
pressures were used if desired. Substantially, equimolar amounts of reactants were
preferably used although higher or lower amounts were used if desired.
[252] The compounds of Formula II of Scheme 1 were prepared as shown
below in Scheme 2.


where R2, R3, G1, (Z)^, (CR^R5^, and (Q V> «« ** defined previously for compound of Formula I.
[253] In a typical preparation of a compound of Formula II, a compound of
Formula III was treated with a suitable reducing agent in a suitable solvent, where the
suitable reducing agents included boron-derived reducing agents such as, but not
limited to, sodium borohydride, lithium borohydride, borane, and the like; aluminum-
derived reducing agents such as lithium aluminum hydride, alane, lithium tri-tert-
butoxy-aluminum hydride, and the like; hydrogenation over a metal catalyst such as
palladium on carbon. The preferred reducing agent was sodium borohydride.
Suitable solvents for use in the above process included, but were not limited to, ethers
such as tetrahydrofixran (THF), glyme, and the like; alcoholic solvents such as
methanol, ethanol, isopropanol, and the like; however, the reactions were normally in
methanol. The above process was carried out at temperatures between about -78 °C
and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 20
°C. The above process to produce compounds of the present invention was preferably
carried out at about atmospheric pressure although higher or lower pressures could be
used if desired. Substantially, equimolar amounts of reactants were preferably used
although higher or lower amounts could be used if desired.
[254] The compounds of Formula III of Scheme 2 were prepared as shown
below in Scheme 3:


where R2, R3, G1, (Z)n2> (CR^R515)^, and (QV, are as defined previously for compound of Formula I, and A1 = OH, OTs, OMs or halo.
[255] In a typical preparation of a compound of Formula III (when A1 = halo
in compound of Formula V), a compound of Formula IV was reacted with a compound of Formula V (where A1 = halo) in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide PMSO); acetonitrile (CH3CN); chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent was DMF or CH3CN. Suitable bases for use in the above process included, but were not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases were used. The preferred base was sodium hydride or potassium terf-butoxide. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention

was preferably carried out at about atmospheric pressure although higher or lower pressures could be used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, one equivalent of base was used per equivalent of starting material of compound of Formula IV.
[256] In a typical preparation of a compound of Formula III (when A1 = OH
in compound of Formula V), a compound of Formula IV was reacted with a
compound of Formula V (where A1 = OH) in a suitable solvent in the presence
suitable reactants. Suitable solvents for use in the above process included, but were
not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like;
dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN);
chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If
desired, mixtures of these solvents were used, however, the preferred solvent was
THF. Suitable reactants for use in the above process included, but were not limited
to, triphenylphosphine and an azodicarboxylate (DIAD, DEAD, DBAD). The desired
reactants were triphenylphosphine and DIAD. The above process was carried out at
temperatures between about -78 °C and about 100 °C. Preferably, the reaction was
carried out between 0 °C and about 50 °C. The above process to produce compounds
of the present invention was preferably carried out at about atmospheric pressure
although higher or lower pressures were used if desired. Substantially, equimolar
amounts of reactants were preferably used although higher or lower amounts were
used if desired. Generally, one equivalent of triphenylphospine, DIAD and compound
of formula V was used per equivalent of starting material of compound of Formula
IV. The compounds of Formula V were generally commercially available or were
prepared according to known procedures {Tetrahedron Letters, 1999, 40, 5467-5470).
[257] The compounds of Formula IV of Scheme 3 were prepared as shown
below in Scheme 4:


where R2, R3, and G1 are as defined previously for compound of Formula I, and A2 = Ci^alkyl oraryl-Ci^alkyl.
[258] In a typical preparation of a compound of Formula IV, a compound of
Formula VI was reacted with suitable conditions to afford the conversion of A to H. Suitable reagents for use in the conversion of A2 to H in the above process included but were not limited to, pyridine-HCl, BBr3, AICI3, and HBr/Acetic acid. The preferred condition was treatment of compound of Formula VI with 48%aqHBr/acetic acid. The above process was carried out at temperatures between about 50 °C and about 150 °C Preferably, the reaction was carried out between 100 °C and about 120 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, an excess of 48%aqHBr/acetic acid was used per equivalent of starting material of compound of Formula VIII.
[259] The compounds of Formula VI of Scheme 4 were prepared as shown
below in Scheme 5:
Scheme 5

where R2, R3, and G1 are as defined previously for compound of Formula I, A2 = Ci-
ealkyl or aryl-Ci^alkyl, and A3 = suitable leaving group such as halo.
[260] In a typical preparation of a compound of Formula VI, a compound of
Formula VII was reacted with H-G1 in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like; aromatic solvents such as benzene and toluene; acetonitrile; chlorinated solvents such as methylene chloride (CH2CI2), carbon tetrachloride (CCU) or chloroform (CHCI3). If desired, mixtures of these solvents were used, however the preferred solvent was a mixture of methanol/chloroform. Suitable catalysts for use in the above process

included, but were not limited to, tetrabutylammonium iodide or Nal. If desired,
mixtures of these catalysts were used, however, the preferred catalyst was Nal.
Suitable bases for use in the above process included, but were not limited to, metal
hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or
potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide;
tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal
carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of
these bases were used, however, the preferred base was diisopropylethylamine or H-
G1 when G1 = NR7R8. The above process were carried out at temperatures between
about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C
and about 100 °C. The above process to produce compounds of the present invention
was preferably carried out at about atmospheric pressure although higher or lower
pressures were used if desired. Substantially, equimolar amounts of reactants were
preferably used although higher or lower amounts were used if desired. The catalyst
was normally used in lower amounts than that of both compounds of Formula VII and
H-G1. H-G1 is generally commercially available or was prepared according to known
procedures. Compound of Formula VII was prepared according to known literature
procedures (Sonawane, H. R.; et. al. Tetrahedron, 1994, 50 (4), 1243-1260).
[261] The compounds of Formula VII of Scheme 5 were prepared as shown
below in Scheme 6a:

wherein R and R are as defined previously for compound of Formula I, A = Ci-ealkyl or aryl-Ci^alkyl, and A3 and A5 = suitable leaving groups such as halo, and A4 = halo or OTf.
[262] In a typical preparation of a compound of Formula VII, a compound of
Formula VIII was reacted with a suitable organolithium reagent or metal catalyst

followed by reaction with a compound of Formula EX in a suitable solvent. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like; aromatic solvents such as benzene and toluene. If desired, mixtures of these solvents were used, however the preferred solvent was THF. Suitable organolithium or metal species for use in the above process included, but were not limited to organolithium species such as «-butyl lithium or /erf-butyl lithium; magnesium. The preferred metal catalyst was magnesium. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 100 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures could used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. The magnesium was normally used in excess amounts than that of compounds of Formula VIII. Compounds of Formula VIII and IX were generally commercially available or were prepared according to known procedures.
[263] Alternatively, the compounds of Formula VI of Scheme 5 were
prepared as shown below in Scheme 6b:

where R2, R3 and G1 are as defined previously for compound of Formula I, A2 = Ci_ ealkyl or aryl-Ci-ealkyl, and A4 = halo or OTf.
[264] In a typical preparation of a compound of Formula VI, a compound of
Formula VIII was reacted with a suitable organolithium reagent or metal catalyst followed by reaction with a compound of Formula X in a suitable solvent Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like; aromatic solvents such as benzene and toluene. If desired, mixtures of these solvents were used, however the preferred solvent was THF. Suitable organolithium or metal species for

use in the above process included, but were not limited to organolithium species such as «-butyl lithium or tert-butyl lithium; magnesium. The preferred organolithium species was terr-butyl lithium. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between -78 °C and about 50 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Compounds of Formula VIII and X were generally commercially available or were prepared according to known procedures.
[265] The compounds of Formula III of this invention and the intermediates
used in the synthesis of the compounds of this invention were prepared according to the following methods.
[266] Method B was used when preparing compounds of Formula III as
shown below in Scheme 7: Method B:

where R25 R3, G1, (Z)^, (CR4^5^, and (Q1)^, are as defined previously for compound of Formula I, and A3 = halo.
[267] In a typical preparation, according to Method B, Scheme 7, of a
compound of Formula III, a compound of Formula XI was reacted with H-G1 in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the

above process included, but were not limited to, ethers such as tetrahydrofuran (THF),
glyme, diethyl ether, dioxane and the like; aromatic solvents such as benzene and
toluene; acetonitrile; chlorinated solvents such as methylene chloride (CH2CI2),
carbon tetrachloride (CCI4) or chloroform (CHCI3). If desired, mixtures of these
solvents were used, however the preferred solvent was a mixture of acetonitrile.
Suitable catalysts for use in the above process include, but are not limited to,
tetrabutylammonium iodide or Nal. If desired, mixtures of these catalysts were used,
however, the preferred catalyst was Nal. Suitable bases for use in the above process
included, but were not limited to, metal hydrides such as sodium or potassium
hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal
hydroxides such as sodium or potassium hydroxide; tertiary amines such as
triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or
potassium carbonate; or pyridine. If desired, mixtures of these bases were used,
however, the preferred base was diisopropylethylamine or H-G1 when G1 = NR7R8.
The above process was carried out at temperatures between about -78 °C and about
100 °C. Preferably, the reaction was carried out between 0 °C and about 100 °C. The
above process to produce compounds of the present invention was preferably carried
out at about atmospheric pressure although higher or lower pressures were used if
desired. Substantially, equimolar amounts of reactants were preferably used although
higher or lower amounts were used if desired. The catalyst was normally used in
lower amounts than that of both compounds of Formula XI and H-G1. H-G1 is
generally commercially available or was prepared according to known procedures.
[268] The compounds of Formula XI of Scheme 7 was prepared as shown
below in Scheme 8:


where R2, R3, (Z)n2, (CR^R51^, and (Q3)n4, are as defined previously for compound of Formula I, and A3 = halo.
[269] In a typical preparation of a compound of Formula XI, a compound of
Formula XII was reacted with a suitable halogenating agent in a suitable solvent.
Suitable halogenating agents include Br2, CI2, //-bromosuccinimide, N-
chlorosuccinimide, sulfuryl chloride, and CuBr2. Suitable solvents for use in the
above process included, but were not limited to, ethers such as tetrahydrofuran (THF),
dioxane, glyme, diethyl ether, and the like; acetonitrile; chlorinated solvents such as
methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these
solvents were used, however, the preferred solvent was dioxane. The above process
was carried out at temperatures between about -78 °C and about 150 °C. Preferably,
the reaction was carried out between 80 °C and about 150 °C. The above process to
produce compounds of the present invention was preferably carried out at about
atmospheric pressure although higher or lower pressures were used if desired.
Substantially, equimolar amounts of reactants were preferably used although higher or
lower amounts were used if desired. Generally, two equivalents of CuBr2 were used
per equivalent of starting material of compound of Formula XII.
[270] The compounds of Formula XII of Scheme 8 were prepared as shown
below in Scheme 9:


where R2, R3, (Z)^, (CR^R5^, and (Q1)^ are as defined previously for compound of Formula I, and A1 = halo or OH.
[271] In a typical preparation of a compound of Formula XII (when A1 in
compound of Formula V equals halo), a compound of Formula XIII was reacted with a compound of Formula V (where A1 = halo) in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents were used. The preferred solvent was DMF or CH3CN. Suitable bases for use in the above process included, but were not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases were used. The preferred base was sodium hydride or potassium ter/-butoxide. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention

was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, one equivalent of base was used per equivalent of starting material of compound of Formula XIII.
[272] In a typical preparation of a compound of Formula XII (when A1 = OH
in compound of Formula V), a compound of Formula XIII was reacted with a compound of Formula V (where A1 = OH) in a suitable solvent in the presence suitable reactants. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofiiran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as rnethylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents were used, however, the preferred solvent was THF. Suitable reactants for use in the above process included, but were not limited to, triphenylphosphine and an azodicarboxylate (DIAD, DEAD, DBAD). The desired reactants were triphenylphosphine and DIAD. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, one equivalent of triphenylphospine, DIAD and compound of formula V was used per equivalent of starting material of compound of Formula XIII. The compounds of Formula V and XIII were generally commercially available or were prepared according to known procedures.
[273] Method C was used when preparing compounds of Formula I-B
[compounds of Formula I where R1 equals H, n1 = 1, R4a, R5a, R6a and R6* equal H, Y equals O, n4 = 1, and Q1 = CO2H] as shown below in Scheme 10: Method C:



[275] Method D was used when preparing salts of compounds of Formula I-
(HA6)n7 as shown below in Scheme 11: Method D:

where X, R1, R2, R3, G1, Y, (CR4aR5\i, (Z)n25 (CR4bR5b)n3, (Q1)**, R6a and R6* are as defined previously for compound of Formula I, n7 = 1 or 2, and A6 = counteranion to H including, for example, chloride or formate.
[276] In a typical preparation, according to Method D, of a compound of
Formula I-(HA6)n7, a compound of Formula I was reacted with a suitable acid, HA6, in a suitable solvent. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether and the like; acetonitrile; water; alcoholic solvents such as methanol, ethanol, and the like. If desired, mixtures of these solvents were used, however, the preferred solvents were either diethyl ether, methanol, or water. HA6 is a suitable pharmaceutically acceptable acid from which the respective mono or disalt of compound of Formula I-(HA6)n7 was formed. The above process was carried out at temperatures between about 0 °C and about 60 °C. Preferably, the reaction was carried out between 0 °C and about 25 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Acids HA6






[281] In a typical preparation of a compound of Formula II, a compound of
Formula XI was treated with a suitable reducing agent in a suitable solvent, where the suitable reducing agents included boron-derived reducing agents such as but not limited to sodium borohydride, lithium borohydride, borane, and the like; aluminum-derived reducing agents such as lithium aluminum hydride, alane, lithium tri-tert-butoxy-aluminum hydride, and the like; hydrogenation over a metal catalyst such as palladium on carbon. However, the preferred reducing agent was sodium borohydride. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; alcoholic solvents such as methanol, ethanol, isopropanol, and the like; however, the reactions are normally in methanol. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 20 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Once the reduction of the ketone to the alcohol was deemed complete, the reaction was then charged with HNR7R8 in a suitable solvent- Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF),

glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3); alcoholic solvents such as methanol, ethanol, isopropanol, and the like. If desired, mixtures of these solvents were used; however, the reactions were normally in methaaol. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 60 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were
*7 R
preferably used although higher or lower amounts were used if desired. HNR R was
used in excess in relation to compound of Formula XI and was generally
commercially available or was prepared according to known procedures.
[282] Alternatively, Method F was used when preparing compounds of
Formula I-A [compounds of Formula I where R1 equals H, R4a, R5a, R63 and R6** equal
H, and Y equals O] as shown below in Scheme 14.
Method F

l-A
where X, R2, R3, G1, (Z)^, (CR4bR5b)*3, and (Q1)^, are as defined previously for
compound of Formula I, and A1 = OH, OTs, OMs or halo.
[283] In a typical preparation, according to Method F, of a compound of
Formula I-A [compound of Formula I where R1 equals H, R4a, R5a, R6a and R6b equal

H, and Y equals O], a compound of Formula XIV was reacted with a compound of
Formula V (where A1 = halo) in a suitable solvent in the presence of a suitable base.
Suitable solvents for use in the above process included, but were not limited to, ethers
such as tetrahydroflxran (THF), glyme, and the like; dimethylformamide (DMF);
dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as
methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these
solvents were used. The preferred solvent was DMF or CH3CN. Suitable bases for
use in the above process included, but were not limited to, metal hydrides such as
sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides;
alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such
as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium
or potassium carbonate; or pyridine. If desired, mixtures of these bases were used.
The preferred base was sodium hydride or potassium terf-butoxide. The above
process was carried out at temperatures between about -78 °C and about 100 °C.
Preferably, the reaction was carried out between 0 °C and about 50 °C. The above
process to produce compounds of the present invention was preferably carried out at
about atmospheric pressure although higher or lower pressures were used if desired.
Substantially, equimolar amounts of reactants were preferably used although higher or
lower amounts were used if desired. Generally, one equivalent of base was used per
equivalent of starting material of compound of Formula XIV.
[284] In a typical preparation of a compound of Formula I-A [compound of
Formula I where R1 equals H, R4a, R5a, R6a and R6* equal H, and Y equals O], a compound of Formula XIV was reacted with a compound of Formula V (where A1 = OH) in a suitable solvent in the presence suitable reactants. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents were used, however, the preferred solvent was THF. Suitable reactants for use in the above process included, but were not limited to, triphenylphosphine and an azodicarboxylate (DIAD, DEAD, DBAD). The desired reactants were triphenylphosphine and DIAD. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention was preferably carried out at

about atmospheric pressure although higher or lower pressures were used if desired.
Substantially, equimolar amounts of reactants were preferably used although higher or
lower amounts were used if desired. Generally, one equivalent of triphenylphospine,
DIAD and compound of formula V was used per equivalent of starting material of
compound of Formula XIV. The compounds of Formula V were generally
commercially available or were prepared according to known procedures.
[285] The compounds of Formula XIV of Scheme 14 were prepared as
shown below in Scheme 15:

where X, R2, R3, and Gl are as defined previously for compound of Formula I.
[286] In a typical preparation of a compound of Formula XIV, a compound
of Formula XV was reacted with CDI or CDT in a suitable solvent. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents were used. The preferred solvent was dependent upon the substrates employed and was selected according to the properties of the substrates. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 22 °C and about 80 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired.
[287] The compounds of Formula XV of Scheme 15 were prepared as shown
in Scheme 16.


where R,R, and G are as defined previously for compound of Formula I.
[288] In a typical preparation of a compound of Formula XV, a compound of
Formula IV was treated with a suitable reducing agent in a suitable solvent, where the suitable reducing agents included boron-derived reducing agents such as but not limited to sodium borohydride, lithium borohydride, borane, and the like; aluminum-derived reducing agents such as lithium aluminum hydride, alane, lithium tri-tert-butoxy-aluminum hydride, and the like; hydrogenation over a metal catalyst such as palladium on carbon. The preferred reducing agent was sodium borohydride. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrdfuran (THF), glyme, and the like; alcoholic solvents such as methanol, ethanol, isopropanol, and the like; however, the reactions were normally performed in methanoL The above process was carried out at temperatures between about -78 °C and about 100 °C, Preferably, the reaction was carried out between 0 °C and about 20 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired.
[289] The compounds of Formula I-Z (compound of Formula I where R1 =
OH, X = heteroaryl, Y = O, nl = 1, and R6a, R6*, R4a and R5a = H) are prepared as shown in Scheme 17 following Reactions A-C.
Scheme 17


where X, R2, R3, G1, (Z%2, (CR4bR5b)n3, and (Q2)^, are as defined previously for compound of Formula I and A1 = suitable exchangeable group such as halo or triflate or a deprotonateable hydrogen atom, d = 0 or 1, R99 = suitable protecting group such as benzyl or trityl, and M = metal including lithium and magnesium; the salt of the metal shown by M can include for example, a metal halide such as magnesium chloride, magnesium bromide, or magnesium triflate.
[290] In a typical preparation of an intermediate of Formula XVII via
Reaction A, a compound of Formula XVI is treated with a suitable alkyl-lithium species or magnesium metal. Examples of such alkyl-lithium species include n-butyllithium, sec-butyllithium, or /erf-butyllithium. Examples of the alkyl-magnesium halide include ethylmagnesium bromide or methylmagnesium chloride. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofiiran (THF), diethyl ether, dioxane and the like; saturated

hydrocarbons such as hexane, pentane, and the like; aromatic hydrocarbons such as benzene or toluene. The above process is carried out at temperatures between about -40 °C and about 70 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used although higher or lower amounts are used if desired. In the case of the alkyl-lithium, the alkyl-lithium is used in an amount of 1 to 3 moles, preferably 1 to 1.5 moles per one mole of the starting material XVI.
[291] Following Reaction B, in a typical preparation of a compound of
Formula XVIII, the intermediate of Formula XVII is allowed to react with a compound of Formula HI. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), diethyl ether, dioxane and the like; saturated hydrocarbons such as hexane, pentane, and the like; an aromatic hydrocarbon such as benzene or toluene. The above process is carried out at temperatures between about -40 °C and about 70 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used although higher or lower amounts are used if desired.
[292] According to Reaction C, in a typical preparation of compound of
Formula I-Z, compound of Formula XVIII is treated under suitable deprotection conditions to afford the transformation of R99 into a hydrogen atom. For example, when d = 1 and R99 is a trityl group, deprotection is afforded under acidic or hydrogenolysis conditions. Examples of acidic conditions include the use of organic acids such as formic, acetic, or trifluoroacetic acid or the use of inorganic acids such as hydrochloric acid. Suitable solvents include alcohols, ethers, or halogenated solvents. The above process is carried out at temperatures between about -40 °C and about 70 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used although higher or lower amounts are used if desired. Examples of A!-X-(R99)d include, but are not limited to, the following heteroaryl groups:



solvents for use in the above process included, but were not limited to, ethers such as
tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like; aromatic solvents
such as benzene and toluene. Suitable organolithium or metal species for use in the
above process included, but were not limited to organolithium species such as «-butyl
lithium or terf-butyl lithium; magnesium. The above process is carried out at
temperatures between about -78 °C and about 70 °C. The above process to produce
compounds of the present invention is preferably carried out at about atmospheric
pressure although higher or lower pressures were used if desired. Substantially,
equimolar amounts of reactants are used although higher or lower amounts were used
if desired. Compounds of Formula VIII and XIX are generally commercially
available or is prepared according to known procedures. For example, compounds of
Formula XIX is prepared according to the methods described in Scheme 6b by
replacing compound of Formula VIE with compound of Formula XVI.
[295] The optically pure isomers, compounds of Formula I' and I", are
prepared as shown in Scheme 19 from (±)-syn-isomer, compound of Formula (±)-I-syn:











using an optically active acid or optically active base. When the desired enantiomers of Formula IF" and II"" are obtained in their respective diastereomeric salt form (compounds of Formula I-HA6 from the diastereomer salt method where HA6 = optically pure acid such as tartaric or mandelic acid), the enantiomers of Formula II"' and II"" are obtained in their respective free forms by neutralization of the reaction mixture.
[305] The compounds of Formula II', II", II"', and II"" of this invention
and the intermediates used in the synthesis of the compounds of this invention were prepared according Method G as shown below in Schemes 24-27. The optically pure compound of Formula II' is prepared as shown in Scheme 24 from optically pure compound of Formula Ila':
Method G:

where R2, R3, (Z)n2s (CR^R5^, and (Q1)^ are as defined previously for compound of Formula I; G1 = NR72R82 and Z55 = chiral auxiliary.
[306] In a typical preparation of compound of Formula II', a compound of
Formula Ila' (where OZ55 is taken together to equal O-(C=O)-R*, where R* is the chiral auxiliary) is reacted under typical reaction conditions to afford hydrolysis of an ester to an alcohol. Typical hydrolysis conditions involve HC1 in water or NaOH, KOH, or LiOH in water. Suitable solvents include water, THF, acetonitrile, or an alcohol such as methanol or ethanol. The above processes are carried out at temperatures between about -5 °C and about 100 °C. The above processes to produce



[309] The optically pure compound of Formula IF " is prepared as shown in
Scheme 26 from optically pure compound of Formula lib':

where R2, R3, (Z)n2, (CR4^51^, and (Q1)^ are as defined previously for compound of Formula I; G1 = NR72R82 and Z55 = chiral auxiliary.
[310] In a typical preparation of compound of Formula II'", a compound of
Formula lib' (where OZ55 is taken together to equal O-(C=O)-R*, where R* is the chiral auxiliary) is reacted under typical reaction conditions to afford hydrolysis of an ester to an alcohol. Typical hydrolysis conditions involve HC1 in water or NaOH, KOH, or LiOH in water. Suitable solvents include water, THF, acetonitrile, or an alcohol such as methanol or ethanol. The above processes are carried out at temperatures between about -5 °C and about 100 °C. The above processes to produce compounds of the present invention are carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used, however, an excess of HC1 or NaOH are used if desired.
[311] The optically pure compound of Formula II"" is prepared as shown in
Scheme 27 from optically pure compound of Formula lib":


where R2, R3, (Z)n2s (CR41^)^, and (Ql)n4 are as defined previously for compound of Formula I; Gl = NR72R82 and Z55 = chiral auxiliary.
[312] In a typical preparation of compound of Formula II'"\ a compound of
Formula lib" (where OZ55 is taken together to equal O-(C=O>R*, where R* is the chiral auxiliary) is reacted under typical reaction conditions to afford hydrolysis of an ester to an alcohol. Typical hydrolysis conditions involve HC1 in water or NaOH, KOH, or LiOH in water. Suitable solvents include water, THF, acetonitrile, or an alcohol such as methanol or ethanol. The above processes are carried out at temperatures between about -5 °C and about 100 °C. The above processes to produce compounds of the present invention are carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used, however, an excess of HC1 or NaOH are used if desired.
[313] The optically pure compounds of Formula Ha' and Ua" are prepared
as shown in Scheme 28 from the transformation of (±)-syn-compound of Formula II, into diastereomeric compounds of Formula Ha' and Ha", respectively:


where R2, R3, (Z)n2, (CR^R5**)^, and (Q1)^ are as defined previously for compound of Formula I; G1 = NR72R82 and Z55 = chiral auxiliary.
[314] In a typical preparation of diastereomerically resolved syn-compounds
of Formula Ha* and Ha", (±)-syn-compound of Formula II is reacted with a suitable chiral auxiliary and then the respective diastereomers, compounds of Formula Ha' and Ha", are separated by known methods such as recrystallization or chromatography. A typical reaction involves the treatment of (±)-syn-compound of Formula II with a suitable chiral auxiliary which contained a carboxylic acid or acid chloride moiety. Treatment of (±)-syn-compound of Formula II with an acid-based chiral auxiliary involves typical conditions for transforming an alcohol into an ester. These coupling conditions include, but are not limited to, DCC or EDC with a suitable catalyst such as DMAP, HOAT, or HOBT in a suitable solvent in the presence of a suitable base such as triethylamine or diisopropylamine. Treatment of (±)-syn-compound of Formula II with an acid chloride-based chiral auxiliary involves typical conditions for transforming an alcohol into an ester with an acid chloride such as an inert solvent and base. Typical chiral auxiliaries include, but are not limited to, suitably protected amino acid such as 7V-(ferr-butoxycarbonyl)-L-proline, iV-(terM>utoxycarbonyl)-D-

proline, (R)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetic acid, (S)-(-)-a-methoxy-a-(trifluoromethyl)phenylacetic acid, (R)-(+)-a-methoxy-a-(trifluoromethyl)pheiiylacetyl chloride, (S)-(-)-a-methoxy-oc-(trifluoromethyl)phenylacetyl chloride, (lR)-(+)-camphanic acid, (lS)-(-)camphanic acid, and (lS)-(-)-camphanic chloride. Suitable solvents for use in both of the above processes include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethyl formamide; dimethyl sulfoxide; halogenated solvents such as methylene chloride or chloroform. The above processes are carried out at temperatures between about -5 °C and about 100 °C. The above processes to produce compounds of the present invention are preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used if desired.
[315] The optically pure compounds of Formula lib' and lib" are prepared
as shown in Scheme 29 from the transformation of (±)-anti-compound of Formula II, into diastereomeric compounds of Formula lib' and lib", respectively:
Scheme 29

where R , R , (Z)n2, (CR R )n3, and (Q %* are as defined previously for compound of Formula I; G1 = NR72R82 and Z55 = chiral auxiliary.

[316] In a typical preparation of diastereomerically resolved anti-compounds
of Formula lib' and lib", (±)-anti-compound of Formula II is reacted with a suitable chiral auxiliary and then the respective diastereomers, compounds of Formula lib' and lib", are separated by known methods such as by recrystallization or by chromatography. A typical reaction involves the treatment of (±)-anti-compound of Formula II with a suitable chiral auxiliary which contained a carboxylic acid or acid chloride moiety. Treatment of (±)-anti-compound of Formula II with an acid-based chiral auxiliary involves typical conditions for transforming an alcohol into an ester. These coupling conditions include, but are not limited to, DCC or EDC with a suitable catalyst such as DMAP, HO AT, or HOBT in a suitable solvent in the presence of a suitable base such as triethylamine or diisopropylamine. Treatment of (^-anti-compound of Formula II with an acid chloride-based chiral auxiliary involves typical conditions for transforming an alcohol into an ester with an acid chloride such as an inert solvent and base. Typical chiral auxiliaries include, but are not limited to, suitably protected amino acid such as #-(terf-butoxycarbonyl)-L-proline, 7V-(/er/-butoxycarbonyl)-D-proline,(R)-(+)-a-methoxy-a-(trifluoromethyl)phenylaceticacid, (S)-(->a-methoxy-a-(trifluoromethyl)phenylacetic acid, (R)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetyl chloride, (S)-(->a-methoxy-a-(trifluoromethyl)phenylacetyl chloride, (lR)-(+)-camphanic acid, (lS)-(-)camphanic acid, and (lS)-(-)-camphanic chloride. Suitable solvents for use in both of the above processes include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethyl formamide; dimethyl sulfoxide; halogenated solvents such as methylene chloride or chloroform. The above processes are carried out at temperatures between about -5 °C and about 100 °C. The above processes to produce compounds of the present invention are preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used if desired.
[317] The following examples are intended to illustrate and not to limit the
scope of the present invention. Analytical HPLC Conditions:

















































































































































The compound of claim 10 wherein R2 and R3 are each independently
hydrogen, methyl, or ethyl.
21. The compound of claim 10 wherein
a) R2 is hydrogen; and
G1 and R3 taken together with the carbon atom to which they are attached form

wherein • is the carbon to which they are attached; or
b) R2 is hydrogen; and
G1 and R3 taken together with the carbon atom to which they are attached form

wherein • is the carbon to which they are attached, any of which is optionally substituted by 1-10 independent R67 substituents.
22. The compound of claim 3 wherein X is imidazole.
23. The compound of claim 11 wherein R is hydrogen and R is methyl.
24. The compound of claim 11 wherein R is hydrogen and R is ethyl.
25. The compound of claim 11 wherein R2 and R3 are both methyl.
26. The compound of claim 21 wherein nl and n2 are each 1 and Z is aryl.

























di(aryt)aminocarbon^ of which is optionally-
substituted with one or more independent halo, cyano, hydroxy, nitro, Ci.i0alkoxy, -S02N(Co^alkyl)(Co-4alkyl) or -N(Co^alkyl)(Co^alkyl) substituents; aryl-Co-ioalkyl, axyl-C2-ioalkenyl, or aryl-C2-ioalkynyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(C 38. A compound represented by Formula I-B:

in
or a pharmaceutically acceptable salt thereof, wherein:
R2 and R3 are each independently C0-ioalkyl, C2-ioalkenyl, C2-ioalkynyl, Ci-loalkoxyCi.ioalkyl, CMOalkoxyC2.ioalkenyl, Ci.i0alkoxyC2-ioalkynyl, CMOalkylthioCi. loalkyl, Ci.ioalkylthioC2-ioalkenyl, Ci.i0alkylthioC2-ioalkynyl, cycloC3^alkyl, cycloC3-salkenyl, cycloC3^alkylCi-ioalkyl, cycloCs-saUcenylCi-ioalkyl, cycloC3^alkylC2-loalkenyl, cycloC3-8alkenylC2-ioalkenyl, cycloC3-8alkylC2-ioalkynyl, cycloC3. 8alkenylC2-ioalkynyl, heterocyclyl-Co-ioalkyl, heterocyclyl-C2-ioalkenyl,









397 A pharmaceutical composition comprising a therapeutically effective" amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
40. The pharmaceutical composition of claim 39 wherein the pharmaceutical
composition is adapted for oral, rectal, topical, or parenteral administration.
41. The pharmaceutical composition of claim 39 wherein the pharmaceutical
composition is in the form of tablet, capsule, cachets, aerosol, cream, ointment, lotion,
powder, or suppository.
42. A method for treating dermatological or cancerous diseases in a mammal
by inhibiting cytochrome P450RAI enzyme comprising administrating to said
mammal a therapeutically effective amount of the compound according to claim 1, or
a pharmaceutically acceptable salt thereof.
43. A method for treating dermatological or cancerous diseases in a mammal
by inhibiting cytochrome P450RAI enzyme comprising administrating to said
mammal a therapeutically effective amount of a pharmaceutical composition
according to claim 39.
44. The method of claim 42 wherein said dermatological disease is psoriasis.
45. The method of claim 42 wherein said cancerous disease is leukemia,
breast cancer, prostate cancer, and solid tumors.
46. The method of claim 43 wherein said dermatological disease is psoriasis.
47. The method of claim 43 wherein said cancerous disease is leukemia,
breast cancer, prostrate cancer, and solid tumors.
48. A composition comprising a compound of claim 1, or a pharmaceutically
acceptable salt thereof, and at least one retinoid.

49. A method for treating sun-related or oiKAdus dliases coii^ramf the
step of co-administrating at least one retinoid, which are catabotized by Cyp26, with
at least one of a compound of claim 1 toyidd higher endogenous levels of said
ntinoids.
50. The compound of claim 1 having a ratio of die IC* value of Cyp3A4
activity to the IC» vahie of Cyp26 activity is 10:1 or greater.
51. The compound of claim 1 having a ratio of the IC» value activity to the K50 value ofCyp26 activity is 100: lor greater.
Dated this 6 day of January 2006

Documents:

0090-chenp-2006-abstract.pdf

0090-chenp-2006-claims.pdf

0090-chenp-2006-correspondnece-others.pdf

0090-chenp-2006-description(complete).pdf

0090-chenp-2006-form 1.pdf

0090-chenp-2006-form 3.pdf

0090-chenp-2006-form 5.pdf

0090-chenp-2006-pct.pdf

90-CHENP-2006 AMENDED CLAIMS 21-10-2010.pdf

90-CHENP-2006 AMENDED PAGES OF SPECIFICATION 21-10-2010.pdf

90-CHENP-2006 CORRESPONDENCE OTHERS 05-04-2010.pdf

90-CHENP-2006 EXAMINATION REPORT REPLY RECIEVED 21-10-2010.pdf

90-chenp-2006 form-1 21-10-2010.pdf

90-chenp-2006 form-3 21-10-2010.pdf

90-CHENP-2006 OTHER PATENT DOCUMENT 21-10-2010.pdf

90-chenp-2006 other patent document-1 21-10-2010.pdf

90-CHENP-2006 POWER OF ATTORNEY 21-10-2010.pdf

90-chenp-2006-description(complete)-1.pdf

abs-90-chenp-2006.jpg


Patent Number 244707
Indian Patent Application Number 90/CHENP/2006
PG Journal Number 52/2010
Publication Date 24-Dec-2010
Grant Date 16-Dec-2010
Date of Filing 06-Jan-2006
Name of Patentee OSI PHARMACEUTICALS, INC.
Applicant Address 58 SOUTH SERVICE ROAD, SUITE 110, MELVILLE, NEW YORK 11747,
Inventors:
# Inventor's Name Inventor's Address
1 SMITH, VANESSA WATLINGTON ROAD, OXFORD OX4 6LT,
2 NIGRO, ANTHONY 1 BIOSCIENCE PARK DRIVE, FARMINGDALE, NY 11735, USA
3 MULVIHILL, MARK 1 BIOSCIENCE PARK DRIVE, FARMINGDALE, NY 11735, USA
4 CESARIO, CARA 1 BIOSCIENCE PARK DRIVE, FARMINGDALE, NY 11735, USA
5 BECK, PATRICIA, ANNE 1 BIOSCIENCE PARK DRIVE, FARMINGDALE, NY 11735, USA
6 CASTELHANO, ARLINDO, L 1 BIOSCIENCE PARK DRIVE, FARMINGDALE, NY 11735, USA
PCT International Classification Number C07D 249/08
PCT International Application Number PCT/US04/22282
PCT International Filing date 2004-07-12
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/486,382 2003-07-10 U.S.A.