Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4192—1,2,3-Triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles

Definitions

• 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.
• 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.
• 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,
• 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 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.
• 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 (NEDDM).
• NEDDM non-insulin dependent diabetes mellitus
• Retinoic acid 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.
• 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.
• HNSCC head and neck squamous cell carcinoma
• Retinoid leukemia therapy works through terminal differentiation and the eventual apoptotic death of leukemic cells and has been shown to result in complete remission in up to 90% of patients with Acute Promyelocytic Leukemia (APL).
• APL Acute Promyelocytic Leukemia
• 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.
• Cyp26Al Cyp26
• 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.
• Cyp26 inhibitors also known as retinoic acid metabolism-blocking agents (RAMBAs) are known and include, for example, Liarozole (LiazalTM) and Rl 16010.
• Liarozole LiazalTM
• Rl 16010 retinoic acid metabolism-blocking agents
• Such Cyp26 inhibitors have demonstrated therapeutic benefits in dermatological and cancerous conditions in vitro, in vivo, and in clinical settings.
• Liarozole displayed antitumoral properties which correlated with decreased endogenous retinoic acid metabolism and therefore, an increase in RA accumulation within tumor cells.
• Liarozole has been shown to increase the half-life of orally administered RA and 13-cis-RA.
• 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 III clinical trials.
• 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.
• CP450RAI cytochrome P450 retinoic acid inducible
• 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.
• RAMBA Blocking Agents
• WO 02/03912 A2 describe inhibitors of cytochrome P450RAI.
• International Application No. PCT/USOO/11833 describes PPAR agonists or antagonists.
• International Patent Publication No. WO 02/06281 describes selective ⁇ 3 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.
• 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.
• 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.
• 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.
• the present invention relates to a compound of Formula I:
• X is an unsaturated heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazole, or pyridinyb any of which is optionally substituted with one or more independent R 66 substituents;
• R 1 is a Co- 6 alkyl, -OR 7 , -SR 7 , or -NR 7 R 8 ;
• R 2 and R 3 are each independently Co-ioalkyl, C 2 _ ⁇ oalkenyb C 2 - ⁇ oalkynyb
• G 1 is -OR 72 , -SR 72 , -NR 72 R 82 (R 9 ) n5 , or G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, any of which is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or in the case of -NR 72 R 82 (R 9 ) n5 , R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C ⁇ - ⁇ 0 alkoxy, -SO
• Z is -aryl- -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,
• Q 1 is C 0 - 6 alkyb -OR 75 , -NR 75 R 85 (R 95 ) n6 , -CO 2 R 75 , -CONR 75 R 85 ,
• R 4a , R 4b , R 4c , R 5a , R 5b and R 5c are each independently a C 0 - ⁇ oalkyb C 2 .
• l oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 778 , -SO 2 NR 778 R 888 or -NR 778 R 888 substituents; or aryl-C 0 - ⁇ oalkyb aryl-C 2 - ⁇ oalkenyb or aryl-C 2 - 1 oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 778 , Ci-ioalkyl, C 2 - ⁇ oalkenyl, C - l oalkynyb haloCi-ioalkyb haloC 2 - ⁇ oalkenyb haloC 2 - ⁇ oalkynyb -COOH, Ci- 4 alkoxycarbonyb -CONR 778 R 888 , -SO 2 NR 778 R 888 or -NR 778 R
• R 83 , R 84 , R 85 , R 86 , R 87 , R 88 , R 888 , R 9 , R 95 , and R 98 are each independently C 0 - ⁇ 0 alkyb C 2 - ⁇ oalkenyb C 2 - 10 alkynyb C ⁇ - ⁇ oalkoxyC ⁇ - ⁇ oalkyb C ⁇ - ⁇ oalkoxyC 2 - 1 oalkenyb Ci- )0 alkoxyC 2 - ⁇ oalkynyb C ⁇ - ⁇ oalkylthioC ⁇ - ⁇ oalkyb C ⁇ - ⁇ oalkylthioC 2 - 1 oalkenyb Ci- ⁇ oalkylthioC 2 - l oalkynyb cycloC .
• Formula I or a pharmaceutically acceptable salt thereof, wherein X is a substituted imidazolyl or substituted triazolyb R 1 is hydrogen; and the other variables are as described above.
• 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.
• X is an unsaturated heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyb tetrazolyb thiazole, or pyridinyb any of which is optionally substituted with one or more independent R 65 substituents;
• R and R are each independently Co-ioalkyb C 2 - ⁇ oalkenyb C 2 - ⁇ oalkynyb
• Ci.ioalkoxyCi-ioalkyb C ⁇ - ⁇ 0 alkoxyC 2 - ⁇ 0 alkenyb C ⁇ - ⁇ oalkoxyC 2 - ⁇ oalkynyb
• Ci- loalkylthioQ-ioalkyb C ⁇ - ⁇ oalkylthioC 2 - ⁇ 0 alkenyb C ⁇ - ⁇ oalkylthioC 2 - ⁇ oalkynyb cycloC 3 - 8 alkyb cycloC 3 - 8 alkenyb cycloC 3 - 8 alkylC ⁇ - ⁇ oalkyb cyclod-salkenyld-ioalkyb cycloC 3 - 8 alkylC 2 - ⁇ 0 alkenyb cycloC 3 - 8 alkenylC 2 - ⁇ oalkenyb cycloC .
• G 1 is -OR 72 , -SR 72 , -NR 72 R 8 (R 9 ) n5 , or G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, any of which is optionally substituted with one or more independent R 57 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or in the case of-NR 72 R 82 (R 9 ) n5 , R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cwoalkoxy, -SO 2 NR 73
• Z is -aryl-, -arylalkyl- -aryloxy- -oxyaryl-, -arylalkenyl-,
• Q 1 is C 0 - 6 alkyb -OR 75 , -NR 75 R 85 (R 95 ) n6 , -CO 2 R 75 , -CONR 75 R 85 ,
• R 4b and R 5b are each independently a C 0 -ioalkyb C 2 - ⁇ oalkenyb C 2 .
• l oalkynyb C ⁇ - ⁇ 0 alkoxyC ⁇ - ⁇ 0 alkyb C ⁇ - ⁇ 0 alkoxyC 2 - ⁇ oalkenyb C ⁇ - ⁇ oalkoxyC 2 - ⁇ 0 alkynyb
• Ci- l oalkylthioCi-ioalkyb C ⁇ - ⁇ 0 alkylthioC 2 . ⁇ 0 alkenyb C ⁇ - ⁇ 0 alkylthioC 2 - ⁇ oalkynyb cycloC 3 . 8 alkyb cycloC 3 .
• l oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , -SO 2 NR 77 R 87 or -NR 77 R 87 substituents; or aryl-Co-i oalkyb aryl-C 2 - ⁇ oalkenyb or aryl-C 2 . ⁇ oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , C M oalkyb C 2 .
• R 85 , R 86 , R 87 , R 88 , R 888 , R 9 , R 95 , and R 98 are each independently C 0 - ⁇ 0 alkyb C 2 - loalkenyb C 2 - ⁇ 0 alkynyb C ⁇ - ⁇ oalkoxyC ⁇ - ⁇ oalkyb C ⁇ - ⁇ 0 alkoxyC 2 - ⁇ oalkenyb C ⁇ - ⁇ 0 alkoxyC 2 .
• l oalkynyb -COOH C ⁇ - 4 alkoxycarbonyb -CON(C 0 - 4 alkyl)(C 0 - ⁇ oalkyl), -SO 2 N(C 0 . 4 alkyl)(Co- 4 alkyl) or -N(Co- 4 alkyl)(Co- alkyl) substituents; or hetaryl-Co-i oalkyb hetaryl-C 2 - ⁇ oalkenyb or hetaryl-C 2 - ⁇ oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co- 4 alkyl), C ⁇ - ⁇ oalkyb C 2 .
• n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2.
• R 2 and R 3 are each independently Co-ioalkyb C 2 - ⁇ 0 alkenyb C 2 - ⁇ 0 alkynyb
• G 1 is -OR 72 , -SR 72 , -NR 72 R 82 (R 9 ) n5 , or G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or in the case of-NR 72 R 82 (R 9 ) n5 , R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more 7 81 71 81 independent halo, cyano, hydroxy, nitro, C ⁇ - ⁇ o
• Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,
• R 4b and R 5b are each independently a Co-ioalkyl, C 2 - ⁇ oalkenyl, C 2 - l oalkynyb C ⁇ - ⁇ oalkoxyC ⁇ - ⁇ oalkyb C ⁇ - ⁇ oalkoxyC 2 - ⁇ oalkenyb C ⁇ - ⁇ oalkoxyC 2 - ⁇ oalkynyb d- l oalkylthioC l -i oalkyb C ⁇ - ⁇ oalkylthioC 2 - ⁇ oalkenyb C ⁇ - ⁇ oalkylthioC 2 - ⁇ oalkynyb cycloC 3 - 8
• R 85 , R 86 , R 87 , R 88 , R 888 , R 9 , R 95 , and R 98 are each independently C 0 - ⁇ 0 alkyb C 2 .
• l oalkenyb C 2 - ⁇ 0 alkynyb C ⁇ - ⁇ oalkoxyC ⁇ - ⁇ oalkyb C ⁇ - ⁇ oalkoxyC 2 - ⁇ oalkenyb C ⁇ - ⁇ oalkoxyC 2 - l oalkynyb C ⁇ - ⁇ oalkylthioC ⁇ - ⁇ oalkyb C ⁇ - ⁇ 0 alkylthioC 2 - ⁇ 0 alkenyb C ⁇ - ⁇ 0 alkylthioC 2 - l oalkynyb cycloC 3 - 8 alkyb cycloC 3 - 8 alkenyb cycloC 3 - 8 alkylC ⁇ - ⁇ oalkyb cycloC 3 - 8 alkenyb cycloC 3
• n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2.
• R 2 and R 3 are each independently Q-ioalkyb C 2 - ⁇ oalkenyb C 2 - ⁇ oalkynyb
• G 1 is ⁇ OR 72 , -SR 72 , -NR 7 R 82 (R 9 ) n5 , or G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, any of which is optionally substituted with one or more independent R and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or in the case of-NR 72 R 82 (R 9 ) n5 , R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring,
• Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,
• Q 1 is Co- ⁇ alkyl, -OR 75 , -NR 75 R 85 (R 95 ) n6 , -CO 2 R 75 , -CONR 75 R 85 ,
• R and R 5 are each independently a Co-ioalkyb C 2 - ⁇ oalkenyb C 2 - loalkynyb C ⁇ - ⁇ 0 alkoxyC ⁇ - ⁇ 0 alkyb Ci-ioalkoxyd-ioalkenyb C ⁇ - ⁇ oalkoxyC 2 - ⁇ oalkynyb Ci- i 0 alkylthioCi-i 0 alkyb Ci.ioalkylthiod.ioalkenyb C ⁇ - ⁇ 0 alkylthioC 2 - ⁇ oalkynyb cycloC 3 - 8 alkyb cycloC 3 - 8 alkenyb cycloC 3 - 8 alkylC ⁇ - ⁇ 0 alkyb cycloC 3 .
• R 85 , R 86 , R 87 , R 88 , R 888 , R 9 , R 95 , and R 98 are each independently Co-ioalkyl, C 2 .
• Ci-ioalkylthioCi-joalkyb C ⁇ - ⁇ 0 alkylthioC 2 - ⁇ 0 alkenyb C ⁇ - ⁇ oalkylthioC 2 - loalkynyb cycloC 3 .
• loalkenylcarbonyb C 2 -ioalkynylcarbonyb Ci-ioalkoxycarbonyb C ⁇ - ⁇ oalkoxycarbonylC ⁇ - loalkyl, monoC ⁇ _ 6 alkylaminocarbonyb diC ⁇ - 6 alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or C ⁇ - ⁇ oalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C ⁇ - ⁇ oalkoxy, -SO 2 N(Co- 4 alkyl)(C 0 - 4 alkyl) or -N(C 0 - 4 alkyl)(C 0 - 4 alkyl) substituents; aryl-Co-i oalkyb aryl-C 2 - ⁇ oalkenyb or aryl-C 2 - ⁇ oalkynyb any of which
• 6 alkyb mono(aryl)aminoC ⁇ - 6 alkyb di(aryl)aminod- 6 alkyb or -N(Ci- 6 alkyl)-Ci.
• 6 alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co- 4 alkyl), Ci-ioalkyl, C 2 - ⁇ oalkenyl, C 2 - ⁇ oalkynyb haloC i-i oalkyb haloC 2 - ⁇ oalkenyb haloC - ⁇ oalkynyb -COOH, C ⁇ - 4 alkoxycarbonyb -CON(C 0 - alkyl)(Co- 4 alkyl), -SO 2 N(C 0 - 4 alkyl)(C 0 - 4 alkyl) or -N(C 0 - alkyl)(C 0 - 4 alkyl) substituent
• R and R 3 are each independently Co-ioalkyb C 2 - ⁇ oalkenyb C 2 - ⁇ oalkynyb
• Ci-ioalkoxyd-ioalkenyb C M0 alkoxyC 2 - ⁇ oalkynyb
• Ci- loalkylthioCi-ioalkyb C ⁇ - ⁇ 0 alkylthioC 2 - ⁇ oalkenyb C ⁇ - ⁇ oalkylthioC 2 - ⁇ oalkynyb cycloC 3 - 8 alkyb cycloC 3 - 8 alkenyb cycloC 3 - 8 alkylC ⁇ - ⁇ oalkyb cycloC 3 .
• loalkynyb C ⁇ - ⁇ 0 alkylcarbonyb C 2 - ⁇ oalkenylcarbonyb C 2 - loalkynylcarbonyb
• Ci-ioalkoxycarbonyb C ⁇ - ⁇ oalkoxycarbonylC ⁇ - ⁇ oalkyb monoCi- 6 alkylaminocarbonyb diC ⁇ - 6 alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or C ⁇ - ⁇ oalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C ⁇ - ⁇ oalkoxy, -SO 2 NR 71 R 81 , or -NR 71 R 81 substituents; or aryl-Co-i oalkyb aryl-C 2 - ⁇ 0 alkenyb or aryl-C 2 - l oalkynyb any of which is
• l oalkyb haloC 2 ⁇ oalkenyb haloC 2 - ⁇ oalkynyb -COOH, C ⁇ - 4 alkoxycarbonyb -CONR 71 R 81 , -SO 2 NR 71 R 81 or -NR 71 R 81 substituents; or heteroaryl-Co-ioalkyl, heteroaryl-C 2 - ⁇ oalkenyl, or heteroaryl-C 2 - ⁇ oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 71 , C M oalkyb C 2 .
• R and R taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent C ⁇ - 6 alkyl, halo, cyano, nitro, -OR 71 , -SO 2 NR 71 R 81 or -NR 71 R 81 substituents;
• G 1 is -OR 72 , -SR 72 , -NR 72 R 82 (R 9 ) n5 , or G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, any of which is optionally substituted one or more independent with R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or in the case of-NR 72 R 82 (R 9 ) n5 , R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C ⁇ - ⁇ 0 alkoxy, -SO 2
• Z is -aryl-, -arylalkyl-, -aryloxy- -oxyaryl-, -arylalkenyl-,
• Q 1 is Co- 6 alkyb -OR 75 , -NR 75 R 85 (R 95 ) n6 , -CO 2 R 75 , -CONR 75 R 85 ,
• R 4b and R 5b are each independently a Co-ioalkyb C 2 - ! oalkenyb C 2 . l oalkynyb d- ⁇ oalkoxyC ⁇ - ⁇ oalkyb C ⁇ - ⁇ oalkoxyC 2 - ⁇ oalkenyb C ⁇ - ⁇ oalkoxyC 2 . ⁇ oalkynyb Ci- l oalkylthioCi-ioalkyb Ci.ioalkylthioC 2 -ioalkenyb C ⁇ - ⁇ oalkylthioC 2 - ⁇ oalkynyb cycloC 3 - 8 alkyb cycloC 3 .
• R 83 , R 85 , R 86 , R 87 , R 88 , R 888 , R 9 , R 95 , and R 98 are each independently C 0 - ⁇ oalkyb C 2 .
• l oalkenyb C 2 - ⁇ 0 alkynyb Ci-ioalkoxyd-i oalkyb C ⁇ - ⁇ 0 alkoxyC 2 - ⁇ 0 alkenyb Ci-ioalkoxyd- l oalkynyb Ci-ioalkylthioCi-i oalkyb C ⁇ - ⁇ oalkylthioC 2 - ⁇ oalkenyb C ⁇ - ⁇ oalkylthioC 2 - l oalkynyb cycloC - 8 alkyb cycloC 3 .
• l oalkenylcarbonyb C 2 - ⁇ oalkynylcarbonyb Ci-ioalkoxycarbonyb C ⁇ - ⁇ oalkoxycarbonylC ⁇ - l oalkyl, monod- ⁇ alkylaminocarbonyb diC ⁇ - 6 alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or C ⁇ - ⁇ oalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C ⁇ - ⁇ 0 alkoxy, -SO 2 N(C 0 - alkyl)(C 0 - alkyl) or -N(Co- 4 alkyl)(
• 6 alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co- 4 alkyl), Ci-ioalkyl, C 2 - ⁇ oalkenyb C 2 . ⁇ oalkynyb haloCi-ioalkyb haloC-ioalkenyb haloC 2 - ⁇ oalkynyb -COOH, C ⁇ - 4 alkoxycarbonyb -CON(C 0 .
• n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2.
• the compounds of the present invention include compounds represented by Formula I above, or a pharmaceutically acceptable salt thereof, and
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents;
• R 1 , R 2 and R 3 are each independently Co-ioalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo
• R 4a , R 4b , R 5a , and R 5b are each independently a C 0 . i oalkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , -SO 2 NR 77 R 87 or -NR 77 R 87 substituents; or R 4a with R 5a , or R 4b with R 5 taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with R 69 ; or R 4a with R 5a , or R 4b with R 5b taken together with the respective carbon atom to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic ring, wherein said ring is optionally substituted with R ; and R 6a and R 6b are each independently hal
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents;
• R 1 , R 2 and R 3 are each independently C 0 . ⁇ oalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent
• R 4a and R 5a are each hydrogen;
• R 4b and R 5b are each independently C t wsalkyl, or R 4b with R 5b taken together with the respective carbon atom to which they are attached form a 3-10 membered saturated ring;
• R 4a and R 5a are each independently a C 0 - ⁇ 0 alkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , -SO 2 NR 77 R 87 or -NR 77 R 87 substituents; or R 4a with R 5a , wherein said ring is optionally substituted with R 69 ; or R 4a with R 5a taken together with the respective carbon atom to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic ring, wherein said ring is optionally substituted with R ; and R 6a and R 6b are each independently halo, -OR 78 , -NR 78 R 88 (R 98 ) n7 , -CO 2 R 78 , -CONR 78 R 88 , -NO 2 , -CN, -S(
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents
• R 1 , R 2 and R 3 are each independently Co-ioalkyl
• Y is oxygen
• Q 1 is Co- 6 alkyb -CO 2 R 75 , or -CONR 75 R 85
• R 4a , R 4b , R 5a , and R 5b are each independently a C 0 - ⁇ 0 alkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , -SO 2 NR 77 R 87 or -NR 77 R 87 substituents
• G is -NR R ; or G and R taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C ⁇ - ⁇ oalkoxy, -SO 2 NR 73 R 83 or -NR 73 R 83 substituents; Y is oxygen; Q 1 is C 0 - 6 alkyb -CO 2 R 75 , or
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents;
• R 1 and R 3 are each independently Co-ioalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring • 77 77 87 optionally is substituted with an R substituent; or R and R taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo
• R 4a , R 4b , R 5a , and R 5b are each independently a C 0 - i oalkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , -SO 2 NR 77 R 87 or -NR 77 R 87 substituents; or R 4a with R 5a , or R 4b with R 5b taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with R 69 ; or R 4a with R 5a , or R 4b with R 5b taken together with the respective carbon atom to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic ring, wherein said ring is optionally substituted with R 69 ; and R 6a and R 6b are each independently
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents;
• R is Co-ioalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 77 87 • substituent; or R and R taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy,
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents;
• R 1 is Co-ioalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic 77 saturated ring or heterocyclic unsaturated ring optionally is substituted with an R substituent; or
• R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano,
• R 4a , R 4b , R 5a , and R 5b are each independently a C 0 - ⁇ 0 alkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , -SO 2 NR 77 R 87 or -NR 77 R 87 substituents; or R 4a with R 5a , or R 4b with R 5b taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with R 69 ; or R 4a with R 5a , or R 4b with R 5b taken together with the respective carbon atom to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic ring, wherein said ring is optionally substituted with R 69 ; and R 6a and R 6b are each independently hal
• G is -NR R ; or G and R taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C ⁇ - ⁇ oalkoxy, -SO 2 NR 73 R 83 or -NR 73 R 83 substituents; Y is oxygen; Q 1 is C 0 - 6 alkyb -CO 2 R 75 , or
• R 4a , R 4b , R 5a , and R 5b are each independently a C 0 - loalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , -SO 2 NR 77 R 87 or -NR 77 R 87 substituents; or R 4a with R 5a , or R 4b with R 5 taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with R 69 ; or R 4a with R 5a , or R 4b with R 5b taken together with the respective carbon atom to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic ring, wherein said ring is optionally substituted with R 69 ; and R 6a and R 6b are each independently hal
• n2, n3, and n4 are each 1 and Z is aryl; or
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents;
• R 1 and R 3 are each independently Co-ioalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring * 77 77 87 optionally is substituted with an R substituent; or R and R taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo
• R 4a , R 4b , R 5a , and R 5b are each independently a C 0 . loalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , -SO 2 NR 77 R 87 or -NR 77 R 87 substituents; or R 4a with R 5a , or R 4b with R 5 taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with R 69 ; or R 4a with R 5a , or R 4b with R 5 taken together with the respective carbon atom to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic ring, wherein said ring is optionally substituted with R 69 ; and R 6a and R 6b are each independently halo,
• n2 is 1; n3 and n4 are each 0; and Z is aryl; or
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R substituents;
• R and R are ⁇ T ⁇ t 87 1 each independently Co-ioalkyl;
• G is -NR R ; or G and R taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring • 77 77 87 optionally is substituted with an R substituent; or R and R taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyan
• n2, n3, and n4 are each 1 and Z is aryl; and n3 is 0; or
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R substituents;
• R and R are each independently Co-ioalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or
• R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano,
• n2, n3, and n4 are each 1 and Z is aryl; and n3 is 0; or
• -NR R or G and R taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C ⁇ - ⁇ oalkoxy, -SO 2 NR 73 R 83 or -NR 73 R 83 substituents; Y is oxygen; Q 1 is -CO 2 R 75 or -CONR 75 R 85 ; R 4a , R
• -NR 72 R 82 or G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C]- ⁇ 0 alkoxy, -SO 2 NR 73 R 83 or -NR 73 R 83 substituents; Y is oxygen; Q 1 is -CO 2 R 75 or -CONR 75 R 85 ;
• -NR R or G and R taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C ⁇ - ⁇ oalkoxy, -SO 2 NR 73 R 83 or -NR 73 R 83 substituents; Y is oxygen; Q 1 is -CO 2 R 75 or -CONR 75 R 85 ; R 4a , R
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents;
• R 1 and R 3 are each independently Co-ioalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring 77 77 87 optionally is substituted with an R substituent; or R and R taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo,
• R 4a , R 4b , R 5a , and R 5b are each independently a C 0 - l oalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , -SO 2 NR 77 R 87 or -NR 77 R 87 substituents; or R 4a with R 5a , or R 4b with R taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with R 69 ; or R 4a with R 5a , or R 4b with R 5b taken together with the respective carbon atom to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic ring, wherein said ring is optionally substituted with R 69 ; and R 6a and R 6b are each independently
• nl and n2 are each 1; and Z is aryl; or
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents;
• R 1 and R 3 are each independently Co-ioalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring 77 77 87 optionally is substituted with an R substituent; or R and R taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo,
• R 4a , R 4b , R 5a , and R 5b are each independently a C 0 . i oalkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , -SO 2 NR 77 R 87 or -NR 77 R 87 substituents; or R 4a with R 5a , or R 4b with R taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted with R 69 ; or R 4a with R 5a , or R 4b with R 5 taken together with the respective carbon atom to which they are attached form a 3-10 membered saturated or unsaturated heterocyclic ring, wherein said ring is optionally substituted with R 69 ; and R 6a and R 6b are each independently halo
• nl and n2 are each 1; n3 and n4 are each 0; and Z is aryl; or
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents;
• R 1 and R 3 are each independently Co-ioalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring 77 77 87 optionally is substituted with an R substituent; or R and R taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano
• nl and n2 are each 1; Z is aryl; and Q 1 is -CO 2 R 75 ; or
• X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R 66 substituents;
• R 1 and R 3 are each independently Co-ioalkyl;
• G 1 is -NR 72 R 82 ; or
• G 1 and R 3 taken together with the carbon atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent R 67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R 72 substituent; or R 72 and R 82 taken together with the nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally substituted with one or more independent halo, cyano
• nl and n2 are each 1; Z is aryl; and Q 1 is -CO 2 H; and wherein, in each case, the other variables are as defined above for Formula I.
• the compounds of the present invention include:
• connection 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.
• substituent name starts with a terminal moiety, continues with any bridging moieties, and ends with the connecting moiety.
• hetarylthioC ⁇ - 4 alkyl has a heteroaryl group connected through a thio sulfur to a C ⁇ - 4 alkyl that connects to the chemical species bearing the substituent.
• 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
• alkyl includes both branched and straight chain alkyl groups. Typical alkyl groups are methyl, ethyl, n- propyl, isopropyb w-butyb -fec-butyb isobutyb tert-butyb «-pentyb isopentyb «-hexyb
• halo refers to fluoro, chloro, bromo or iodo.
• haloalkyl refers to an alkyl group substituted with one or more halo groups, for example chlorom ethyl, 2-bromoethyb 3-iodopropyb trifluoromethyb perfluoropropyb 8-chlorononyl and the like.
• cycloalkyl refers to a cyclic aliphatic ring structure, optionally substituted with alkyl, hydroxy and halo, such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyb cyclohexyb 4- chlorocyclohexyb cycloheptyb cyclooctyl and the like.
• alkylcarbonyloxyalkyl refers to an ester moiety, for example acetoxymethyl, «-butyryloxyethyl and the like.
• alkynylcarbonyl refers to an alkynylketo functionality, for example propynoyl and the like.
• hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, for example hydroxymethyb 2,3-dihydroxybutyl and the like.
• alkylsulfonylalkyl refers to an alkyl group substituted with an alkylsulfonyl moiety, for example mesylmethyb isopropylsulfonylethyl and the like.
• alkylsulfonyl refers to a sulfonyl moiety substituted with an alkyl group, for example mesyl, H-propylsulfonyl and the like.
• acetylaminoalkyl refers to an alkyl group substituted with an amide moiety, for example acetylaminomethyl and the like.
• acetylaminoalkenyl refers to an alkenyl group substituted with an amide moiety, for example 2-(acetylamino)vinyl and the like.
• 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, isopropenyb 2-pentenyl and the like.
• haloalkenyl refers to an alkenyl group substituted with one or more halo groups.
• cycloalkenyl refers to a cyclic aliphatic ring structure, optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyb cyclopentenyb cyclohexenyb 1,4-cyclohexadienyl and the like.
• alkynyl refers to an unsaturated hydrocarbon group, straight or branched, having 1 or 2 acetylenic bonds, for example ethynyb propargyl and the like.
• haloalkynyl refers to an alkynyl group substituted with one or more halo groups.
• alkylcarbonyl refers to an alkylketo functionality, for example acetyl, n-butyryl and the like.
• alkenylcarbonyl refers to an alkenylketo functionality, for example, propenoyl and the like.
• aryl refers to phenyl or naphthyl which may be optionally substituted.
• Typical aryl substituents include, but are not limited to, phenyl, 4- chlorophenyl, 4-fluorophenyb 4-bromophenyb 3-nitrophenyb 2-methoxyphenyb 2- methylphenyb 3-methyphenyb 4-methylphenyb 4-ethylphenyb 2-methyl-3- methoxyphenyb 2,4-dibromophenyb 3,5-difluorophenyb 3,5-dimethylphenyb 2,4,6- trichlorophenyb 4-methoxyphenyb naphthyb 2-chloronaphthyb 2,4-dimethoxy ⁇ henyb
• heteroaryl or “hetaryl” refer to a substituted or unsubstituted 3-10 membered unsaturated ring containing one, two, three or four heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a bicyclic unsaturated ring system containing up to 10 atoms including at least one one heteroatom selected from oxygen, nitrogen and sulfur.
• heterocyclic ring may be optionally substituted with up to two substituents.
• aryl-alkyl or "arylalkyl” are used to describe a group wherein the alkyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a bridging portion of the aryl-alkyl moiety.
• aryl-alkyl groups include, but are not limited to, optionally substituted benzyl, phenethyl, phenpropyl and phenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2- methylbenzyb 2-(3-fluorophenyl)ethyb 2-(4-methylphenyl)ethyb 2-(4- (trifluoromethyl)phenyl)ethyb 2-(2-methoxyphenyl)ethyb 2-(3-nitrophenyl)ethyb 2- (2,4-dichlorophenyl)ethyb 2-(3,5-dimethoxyphenyl)ethyb 3-phenylpropyb 3-(3- chlorophenyl)propyb 3-(2-methylphenyl)propyb 3-(4-methoxyphenyl)propyb 3-(4- (trifluoromethyl)phenyl)propyb 3-(2,4-dichlorophenyl
• aryl-cycloalkyl or "arylcycloalkyl” are used to describe a group wherein the aryl group is attached to a cycloalkyl group, for example phenylcyclopentyl and the like.
• aryl-alkenyl or "arylalkenyl” are used to describe a group wherein the alkenyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a bridging portion of the aralkenyl moiety, for example styryl (2-phenylvinyl), phenpropenyl and the like.
• aryl-alkynyl or "arylalkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a bridging portion of the aryl-alkynyl moiety, for example 3-phenyl-l-propynyl and the like.
• aryl-oxy or "aryloxy” are used to describe a terminal aryl group attached to a bridging oxygen atom.
• Typical aryl-oxy groups include phenoxy,
• 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.
• 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.
• heteroarylalkyl or “heteroarylalkyl” or “hetaryl-alkyl” or
• heteroaryl-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-furylmethyb thenyb furfuryl and the like.
• heteroarylalkenyl 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)-
• heteroaryl-alkynyl or “heteroaryl-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
• 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.
• heterocyclyls include, but are not limited to, tetrahydrofuranyb tetrahydrofuryb pyrrolidinyb piperidinyb 4-pyranyb tetrahydropyranyb thiolanyb mo ⁇ holinyb piperazinyb dioxolanyb dioxanyb indolinyl and 5-methyl-6-chromanyb
• heterocyclylalkyl or “heterocyclyl-alkyl” are used to describe a group wherein the alkyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinabove, forming a bridging portion of the heterocyclylalkyl moiety, for example 3-piperidinylmethyl and the like.
• heterocyclylalkenyl or “heterocyclyl-alkenyl” are used to describe a group wherein the alkenyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinbefore, forming a bridging portion of the heterocyclylalkenyl moiety, for example 2-mo ⁇ holinyl-l-propenyl.
• heterocyclylalkynyl or “heterocyclyl-alkynyl” are used to describe a group wherein the alkynyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinbefore, forming a bridging portion of the heterocyclylalkynyl moiety, for example 2-pyrrolidinyl-l-butynyb
• carboxylalkyl includes both branched and straight chain alkyl groups as defined hereinbefore attached to a carboxyl (-COOH) group.
• carboxylalkenyl includes both branched and straight chain alkenyl groups as defined hereinbefore attached to a carboxyl (-COOH) group.
• carboxylalkynyl includes both branched and straight chain alkynyl groups as defined hereinbefore attached to a carboxyl (-COOH) group.
• carboxylcycloalkyl refers to a carboxyl (-COOH) group attached to a cyclic aliphatic ring structure as defined hereinbefore.
• carboxylcycloalkenyl refers to a carboxyl (-COOH) group attached to a cyclic aliphatic ring structure having 1 or 2 ethylenic bonds as defined hereinbefore.
• cycloalkylalkyl or "cycloalkyl-alkyl” refer to a cycloalkyl group as defined hereinbefore attached to an alkyl group, for example cyclopropylmethyl, cyclohexylethyl and the like.
• cycloalkylalkenyl or “cycloalkyl-alkenyl” refer to a cycloalkyl group as defined hereinbefore attached to an alkenyl group, for example cyclohexylvinyl, cycloheptylallyl and the like.
• cycloalkylalkynyl or “cycloalkyl-alkynyl” refer to a cycloalkyl group as defined hereinbefore attached to an alkynyl group, for example cyclopropylpropargyl, 4-cyclopentyl-2-butynyl and the like.
• cycloalkenylalkyl or “cycloalkenyl-alkyl” refer to a cycloalkenyl group as defined hereinbefore attached to an alkyl group, for example 2-
• cycloalkenylalkenyl or “cycloalkenyl-alkenyl” refer to a cycloalkenyl group as defined hereinbefore attached to an alkenyl group, for example l-(cyclohexen-3-yl)allyl and the like.
• cycloalkenylalkynyl or “cycloalkenyl-alkynyl” refer to a cycloalkenyl group as defined hereinbefore attached to an alkynyl group, for example l-(cyclohexen-3-yl)propargyl and the like.
• carboxylcycloalkylalkyl refers to a carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkyl group as defined hereinbefore.
• carboxylcycloalkylalkenyl refers to a carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkenyl group as defined hereinbefore.
• carboxylcycloalkylalkynyl refers to a carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkynyl group as defined hereinbefore.
• carboxylcycloalkenylalkyl refers to a carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkyl group as defined hereinbefore.
• carboxylcycloalkenylalkenyl refers to a carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkenyl group as defined hereinbefore.
• carboxylcycloalkenylalkynyl refers to a carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkynyl group as defined hereinbefore.
• alkoxy includes both branched and straight chain terminal alkyl groups attached to a bridging oxygen atom. Typical alkoxy groups include methoxy, ethoxy, «-propoxy, isopropoxy, tert-butoxy and the like.
• haloalkoxy refers to an alkoxy group substituted with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy and the like.
• 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.
• alkylthio includes both branched and straight chain alkyl groups attached to a bridging sulfur atom, for example methylthio.
• haloalkylthio refers to an alkylthio group substituted with one or more halo groups, for example trifluoromethylthio.
• alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, for example isopropoxymethyb
• alkoxyalkenyl refers to an alkenyl group substituted with an alkoxy group, for example 3-methoxyallyl.
• alkoxyalkynyl refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyb
• alkoxycarbonylalkyl refers to a straight chain or branched alkyl substituted with an alkoxycarbonyb for example ethoxycarbonylmethyb 2-
• alkoxycarbonylalkenyl refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an alkoxycarbonyb for example 4-(ethoxycarbonyl)-2-butenyl and the like.
• alkoxycarbonylalkynyl refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an alkoxycarbonyb for example 4-(ethoxycarbonyl)-2-butynyl and the like.
• haloalkoxyalkyl refers to a straight chain or branched alkyl as defined hereinbefore substituted with a haloalkoxy, for example 2- chloroethoxymethyb trifluoromethoxymethyl and the like.
• haloalkoxyalkenyl refers to a straight chain or branched alkenyl as defined hereinbefore substituted with a haloalkoxy, for example 4-
• haloalkoxyalkynyl refers to a straight chain or branched alkynyl as defined hereinbefore substituted with a haloalkoxy, for example 4-(2- fTuoroethoxy)-2-butynyl and the like.
• alkylthioalkyl refers to a straight chain or branched alkyl as defined hereinbefore substituted with an alkylthio group, for example methylthiomethyb 3-(isobutylthio)heptyl and the like.
• alkylthioalkenyl refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an alkylthio group, for example 4-
• alkylthioalkynyl refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an alkylthio group, for example 4-
• haloalkylthioalkyl refers to a straight chain or branched alkyl as defined hereinbefore substituted with an haloalkylthio group, for example 2- chloroethylthiomethyb trifluoromethylthiomethyl and the like.
• haloalkylthioalkenyl refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an haloalkylthio group, for example
• haloalkylthioalkynyl refers to a straight chain or branched alkynyl as defined hereinbefore substituted with a haloalkylthio group, for example 4-
• 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 diethoxyphosphorylmethyl.
• oligomer refers to a low-molecular weight polymer, whose number average molecular weight is typically less than about 5000 g/mob 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.
• the invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula I in combination with a pharmaceutically acceptable carrier.
• the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of Formula I as described above (or a pharmaceutically acceptable salt thereof).
• 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 pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above (or a pharmaceutically acceptable salt thereof).
• salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
• the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanob ethanolamine, ethylenediamine, N-ethylmo ⁇ holine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, mo ⁇ holine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylame
• the compound of the present invention is basic, its co ⁇ esponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
• 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, sulfuric, tartaric, p-toluenesulfonic acid and the like.
• 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.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
• solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
• liquid carriers are sugar syrup, peanut oil, olive oil, and water.
• gaseous carriers include carbon dioxide and nitrogen.
• any convenient pharmaceutical media may be employed.
• 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, microcrystalline 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 earners are employed.
• tablets may be coated by standard aqueous or nonaqueous techniques.
• 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.
• a formulation intended for the oral administration to humans may contain from about 0.5mg 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.
• 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.
• 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 the 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.
• 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.
• 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.
• 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.
• 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.
• additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
• additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
• additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
• other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
• 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 0.5mg to about 7g per patient per day.
• 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.
• 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
• T47D cells were grown in RPMI 1640 containing 10% FBS and 1 %
• HPLC Biochemical CYP26 Assay Enzymatic assays were performed in a total volume of 100 ⁇ L in a reaction mixture composed of 100 mM Tris pH7.4, 150 mM KCb 10 mM MgCl 2 , 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 ⁇ 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 ⁇ L 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%CH 3 OH, solvent A and solvent B (CH 3 OH). A 30-50% gradient of CH 3 OH was run for 8 min followed by a 50-99% CH 3 OH gradient for 4 min and 99% CH 3 OH for 2 min.
• T47D breast cancer cell line and on the AT6.1 rat prostate adenocarcinoma cell line.
• 1%P/S 1%P/S.
• Cells were plated into 96 well culture plates (2000 cells per well) in 100 ⁇ L of same medium. After attachment for 16-24 h, the vehicle (DMSO), or atRA alone (at concentrations of 1 nM to 1 ⁇ M), or atRA at these concentrations in combination with varying concentration of novel compound were added to triplicate wells (J. Biol. Chem. 1997, 272(29), 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-GloTM (Promega).
• CYP3A4 Assay 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).
• 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 (CH 2 CI 2 ) or chloroform (CHC1 3 ). 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.
• R 2 , R 3 , G 1 , (Z) n2 , (CR 4b R 5b ) n3 , and (Q') n4 are as defined previously for compound of Formula I.
• 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 tetrahydrofuran (THF), glyme, and the like; alcoholic solvents such as methanob ethanob isopropanob and the like; however, the reactions were normally in methanob
• ethers such as tetrahydrofuran (THF), glyme, and the like
• alcoholic solvents such as methanob ethanob isopropanob and the like
• the reactions were normally in methanob
• 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
• 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 (DMSO); acetonitrile (CH 3 CN); chlorinated solvents such as methylene chloride (CH 2 C1 2 ) or chloroform (CHC1 3 ). If desired, mixtures of these solvents may be used.
• the preferred solvent was DMF or CH 3 CN.
• 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 tert-butoxide. The above process was carried out at temperatures between about -78 °C and about 100 °C.
• 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.
• one equivalent of base was used per equivalent of starting material of compound of Formula IV.
• 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 (CH 3 CN); chlorinated solvents such as methylene chloride (CH 2 C1 2 ) or chloroform (CHC1 3 ). If desired, mixtures of these solvents were used, however, the preferred solvent was THF.
• ethers such as tetrahydrofuran (THF), glyme, and the like
• DMF dimethylformamide
• DMSO dimethyl sulfoxide
• CH 3 CN acetonitrile
• chlorinated solvents such as methylene chloride (CH 2 C1 2 ) or chloroform (CHC1
• 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.
• Formula VI was reacted with suitable conditions to afford the conversion of A 2 to H.
• Suitable reagents for use in the conversion of A 2 to H in the above process included but were not limited to, pyridine-HCl, BBr 3 , A1C1 3 , and HBr/ Acetic acid.
• the preferred condition was treatment of compound of Formula VI with 48% aq HBr/acetic acid.
• the above process was carried out at temperatures between about 50 °C and about 150 °C.
• 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.
• an excess of 48% aq HBr/acetic acid was used per equivalent of starting material of compound of Formula VIII.
• Formula VII was reacted with H-G 1 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 (CH 2 C1 2 ), carbon tetrachloride (CC1 4 ) or chloroform (CHC1 3 ). If desired, mixtures of these solvents were used, however the preferred solvent was a mixture of methanol/chloroform.
• ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like
• aromatic solvents such as benzene and toluene
• chlorinated solvents such as methylene chloride (CH 2 C
• Suitable catalysts for use in the above process included but were not limited to, tetrabutylammonium iodide or Nab If desired, mixtures of these catalysts were used, however, the preferred catalyst was Nab 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.
• 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
• the above process were carried out at temperatures between about -78 °C and about 100 °C.
• 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-G 1 .
• H-G 1 is generally commercially available or was prepared according to known procedures.
• Formula VIII was reacted with a suitable organolithium reagent or metal catalyst followed by reaction with a compound of Formula IX 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 w-butyl lithium or tert-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.
• 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 VIH.
• Compounds of Formula VIII and IX were generally commercially available or were prepared according to known procedures.
• 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 tt-butyl lithium or tert-butyl lithium; magnesium.
• the prefe ⁇ ed organolithium species was tert-butyl lithium.
• the above process was carried out at temperatures between about -78 °C and about 100 °C.
• 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.
• a compound of Formula XI was reacted with H-G 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 (CH 2 C1 2 ), carbon tetrachloride (CC1 4 ) or chloroform (CHC1 3 ).
• ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like
• aromatic solvents such as benzene and toluene
• chlorinated solvents such as methylene chloride (CH 2 C1 2 ), carbon tetrachloride (CC1 4 ) or chloroform (CHC
• Suitable catalysts for use in the above process include, but are not limited to, tetrabutylammonium iodide or Nab If desired, mixtures of these catalysts were used, however, the preferred catalyst was Nab 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.
• 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
• the above process was carried out at temperatures between about -78 °C and about 100 °C.
• 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-G 1 .
• H-G 1 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:
• Formula XII was reacted with a suitable halogenating agent in a suitable solvent.
• suitable halogenating agents include Br 2 , Cl 2 , N-bromosuccinimide, N- chlorosuccinimide, sulfuryl chloride, and CuBr 2 .
• 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 (CH 2 C1 2 ) or chloroform (CHC1 ). If desired, mixtures of these solvents were used, however, the preferred solvent was dioxane.
• ethers such as tetrahydrofuran (THF), dioxane, glyme, diethyl ether, and the like
• chlorinated solvents such as methylene chloride (CH 2 C1 2
• 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 (CH 3 CN); chlorinated solvents such as methylene chloride (CH 2 C1 2 ) or chloroform (CHC1 3 ).
• 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 tert-butoxide. The above process was carried out at temperatures between about -78 °C and about 100 °C.
• 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.
• one equivalent of base was used per equivalent of starting material of compound of Formula XIH.
• 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 (CH 3 CN); chlorinated solvents such as methylene chloride (CH 2 C1 2 ) or chloroform (CHC1 3 ).
• 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.
• 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.
• 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; alcoholic solvents such as methanob ethanob and the like. If desired, mixtures of these solvents were used, however the preferred solvent was a mixture of water, THF, and methanob
• the basic conditions for use in the above process included alkoxides such as sodium or potassium alkoxides and alkali metal hydroxides such as sodium or potassium hydroxide in water.
• the acidic conditions for use in the above process included HCI in water.
• the above process was carried out at temperatures between about 0 °C and about 80 °C. Preferably, the reaction was carried out between 22 °C and about 70 °C.
• the above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures was used if desired. Substantially, equimolar amounts of reactants was preferably used although higher or lower amounts were used if desired. [275] Method D was used when preparing salts of compounds of Formula I-
• a compound of Formula I was reacted with a suitable acid, HA 6 , 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 methanob ethanob and the like. If desired, mixtures of these solvents were used, however, the prefe ⁇ ed solvents were either diethyl ether, methanob or water.
• HA 6 is a suitable pharmaceutically acceptable acid from which the respective mono or disalt of compound of Formula I- (HA 6 ) n7 was formed.
• the above process was carried out at temperatures between about 0 °C and about 60 °C.
• 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 HA 6 were generally commercially available or was be prepared according to known procedures.
• Suitable conditions included but were not limited to treating compound of Formula I-B with thionyl chloride, triphenylphosphine/carbon tetrachloride, CDI, or diphenylphosphorylazide to afford activated carbonyl species followed by treatment with HNR 7 R 8 .
• the preferred reaction condition was reaction of compound of Formula I-B with CDI followed by treatment with HNR 7 R 8 .
• 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; halogenated solvents such as chloroform or methylene chloride.
• mixtures of these solvents were used, however the preferred solvent was acetonitrile.
• the above process was carried out at temperatures between about 0 °C and about 80 °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.
• Suitable conditions include but are not limited to treating compound of Formula I-B and HNR 7 R 8 with coupling reagents such as DCC or EDC in conjunction with DMAP, HOBt, HO At and the like.
• 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; halogenated solvents such as chloroform or methylene chloride. If desired, mixtures of these solvents were used, however the preferred solvent was DMF.
• THF tetrahydrofuran
• DMSO dimethylformamide
• DMSO dimethyl sulfoxide
• acetonitrile halogenated solvents
• chloroform or methylene chloride halogenated solvents
• 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. Additionally, other suitable reaction conditions for the conversion of CO 2 H to 7 R
• CONR R can be found in Larock, R. C. Comprehensive Organic Transformations, 2 nd ed.; Wiley and Sons: New York, 1999, pp 1941-1949.
• R 2 , R 3 , A 3 , G 1 , (Z) n2 , (CR 4b R 5b ) n3 , and (Q 1 ) n4 are as defined previously for compound of Formula I.
• 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.
• 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 methanob ethanob isopropanob and the like; however, the reactions are normally in methanob
• ethers such as tetrahydrofuran (THF), glyme, and the like
• alcoholic solvents such as methanob ethanob isopropanob and the like
• the reactions are normally in methanob
• 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.
• 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 (CH CN); chlorinated solvents such as methylene chloride (CH 2 CI 2 ) or chloroform (CHC1 3 ); alcoholic solvents such as methanob ethanob isopropanob and the like.
• ethers such as tetrahydrofuran (THF), glyme, and the like
• DMF dimethylformamide
• DMSO dimethyl sulfoxide
• CH CN acetonitrile
• chlorinated solvents such as methylene chloride (CH 2 CI 2 ) or chloroform (CHC1 3 )
• alcoholic solvents such as methanob ethanob isopropanob and the like.
• 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 (CH 3 CN); chlorinated solvents such as methylene chloride (CH 2 C1 2 ) or chloroform (CHC1 ). If desired, mixtures of these solvents were used.
• the prefe ⁇ ed solvent was DMF or CH 3 CN.
• 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 prefe ⁇ ed base was sodium hydride or potassium tert-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.
• 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 (CH 3 C ⁇ ); chlorinated solvents such as methylene chloride (CH 2 C1 2 ) or chloroform (CHC1 ).
• 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.
• 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.
• X, R 2 , R 3 , and G 1 are as defined previously for compound of Formula I.
• 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 (CH 2 C1 2 ) or chloroform (CHC1 3 ). If desired, mixtures of these solvents were used.
• the prefe ⁇ ed 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.
• 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.
• Formula IN 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 tetrahydrofuran (THF), glyme, and the like; alcoholic solvents such as methanob ethanob isopropanob and the like; however, the reactions were normally performed in methanob
• ethers such as tetrahydrofuran (THF), glyme, and the like
• alcoholic solvents such as methanob ethanob isopropanob and the like
• the reactions were normally performed in methanob
• 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
• X, R 2 , R 3 , G 1 , (Z) n2 , (CR 4b R 5b ) n3 , and (Q') n4 are as defined previously for compound of Formula I and
• R 99 suitable protecting group such as benzyl or trityl
• 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.
• a compound of Formula XVI is treated with a suitable alkyl-lithium species or magnesium metal.
• alkyl-lithium species include n- butyllithium, -?ec-butyllithium, or tert-butyllithium.
• 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 tetrahydrofuran (THF), diethyl ether, dioxane and the like; saturated hydrocarbons such as hexane, pentane, and the like; aromatic hydrocarbons such as benzene or toluene.
• THF tetrahydrofuran
• diethyl ether 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.
• Formula XVIH the intermediate of Formula XVII is allowed to react with a compound of Formula III.
• 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.
• THF tetrahydrofuran
• 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
• compound of Formula XVIII is treated under suitable deprotection conditions to afford the transformation of R 99 into a hydrogen atom.
• deprotection is afforded under acidic or hydrogenolysis conditions.
• 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.
• a 1 -X-(R 99 ) d include, but are not limited to, the following heteroaryl groups:
• a compound of Formula VIII is first reacted with a suitable organolithium reagent or metal catalyst followed by reaction with a compound of Formula XLX 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.
• Suitable organolithium or metal species for use in the above process included, but were not limited to organolithium species such as n-butyl lithium or tert-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.
• Typical hydrolysis conditions involve HCI in water or NaOH, KOH, or LiOH in water.
• Suitable solvents include water, THF, acetonitrile, or an alcohol such as methanol or ethanob
• 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 HCI or NaOH are used if desired.
• Typical hydrolysis conditions involve HCI in water or NaOH, KOH, or LiOH in water.
• Suitable solvents include water, THF, acetonitrile, or an alcohol such as methanol or ethanob
• 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 HCI or NaOH are used if desired.
• Typical hydrolysis conditions involve HCI in water or NaOH, KOH, or LiOH in water.
• Suitable solvents include water, THF, acetonitrile, or an alcohol such as methanol or ethanob
• 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 HCI or NaOH are used if desired.
• 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.
• a suitable catalyst such as DMAP, HO AT, or HOBT
• a suitable solvent 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 N-(tert-butoxycarbonyl)-L-proline, N-(tert-butoxycarbonyl)-D- proline, (R)-(+)- ⁇ -methoxy- ⁇ -(trifluoromethyl)phenylacetic acid, (S)-(-)- ⁇ -methoxy- ⁇ -(trifluoromethyl)phenylacetic acid, (R)-(+)- ⁇ -methoxy- ⁇ - (trifluoromethyl)phenylacetyl chloride, (S)-(-)- ⁇ -methoxy- ⁇ - (trifluoromethyl)phenylacetyl chloride, (lR)-(+)-camphanic acid, (lS)-(-)camphanic acid, and (lS)-(-)-camphanic chloride.
• suitably protected amino acid such as N-(tert-butoxycarbonyl)-L-proline, N-
• 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.
• THF tetrahydrofuran
• glyme glyme
• 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.
• ( ⁇ )-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 N-(tert-butoxycarbonyl)-L-proline, N-(tert- butoxycarbonyl)-D-proline, (R)-(+)- ⁇ -methoxy- -(trifluoromethyl)phenylacetic acid, (S)-(-)- ⁇ -methoxy- ⁇ -(trifluoromethyl)phenylacetic acid, (R)-(+)- ⁇ -methoxy- ⁇ - (trifluoromethyl)phenylacetyl chloride, (S)-(-)- ⁇ -methoxy- ⁇ - (trifluoromethyl)phenylacetyl chloride, (lR)-(+)-camphanic acid, (lS)-(
• 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.
• THF tetrahydrofuran
• glyme glyme
• 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.
• the reaction mixture was charged with 5% HCI, the volume of THF was reduced in-vacuo, and water was added and the product was extracted with CH 2 CI 2 (3x). The combined organic layers were washed with water, brine, dried over MgSO 4 and concentrated in-vacuo.
• the crude solid was purified by silica gel chromatography (9:1 EtOAc:Hexanes), and recrystallized from MeOH to yield the title compound.
• the reaction mixture was concentrated in vacuo to a slurry and partitioned between CH 2 C1 2 and NaHCO 3 (sat), and the aqueous layer extracted with CH 2 C1 2 (5 ). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient of 6:1 CH 2 C1 2 :10% CH 3 OH in CH 2 C1 2 (1% Et 3 N) to 3:1 CH 2 C1 2 :10% CH 3 OH in CH 2 C1 2 (1% Et 3 N)) to afford the desired compound of Formula IH.
• the title compound was prepared as follows: A 0 °C solution of N-(tert-butoxycarbonyl)- L-proline (1.65 g, 7.66 mmol) in DCM (25 L) was charged with triethylamine (1.07 mL, 7.66 mmol) and diphenylphosphinic chloride (1.44 mL, 7.66 mmol), and allowed to warm to rt over 2 h.
• the title compounds were prepared as follows: A 0 °C solution of compound 1- 30 (0.43 g, 1.0 mmol) in THF (6 mL) was charged with LiAlH 4 (0.11 g, 3.0 mmol), heated to 50 °C for 3 h, cooled to rt, poured over ice, and extracted with EtOAc (3x). The organic layer was subsequently dried over Na 2 SO 4 , filtered, and concentrated in- vacuo.
• XI imidazol-l-yl
• X2 triazol-1-yl
• X3 triazol-3-yl

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