EP1654236A1 - Naphthylene derivatives as cytochrome p450 inhibitors - Google Patents

Naphthylene derivatives as cytochrome p450 inhibitors

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Publication number
EP1654236A1
EP1654236A1 EP04756894A EP04756894A EP1654236A1 EP 1654236 A1 EP1654236 A1 EP 1654236A1 EP 04756894 A EP04756894 A EP 04756894A EP 04756894 A EP04756894 A EP 04756894A EP 1654236 A1 EP1654236 A1 EP 1654236A1
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alkyl
ring
syn
cycloc
ιoalkenyb
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German (de)
French (fr)
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Vanessa Smith
Anthony Nigro
Mark Mulvihill
Cara Cesario
Patricia Anne Beck
Arlindo Lucas Castelano
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OSI Pharmaceuticals LLC
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OSI Pharmaceuticals LLC
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    • 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

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  • Organic Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Enzymes And Modification Thereof (AREA)

Abstract

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

Description

NAPHTHYLENE DERIVATIVES AS CYTOCHROME P450 INHIBITORS
BACKGROUND OF THE INVENTION
[1] The present invention is directed to novel heteroaryl-naphthalenyl- alkylamines, their salts, processes for their preparation, and compositions comprising them. The novel compounds of this invention are useful in inhibiting the cytochrome P450RAI enzyme (Cyp26) in animals, including humans, for the treatment and/or prevention of various diseases and conditions that respond to treatment by retinoids and by naturally occurring retinoic acid.
[2] Retinoic acid, retinoid-like compounds, and pharmaceutical compositions comprising retinoic acid or rectinoid-like compounds as the active ingredient are known in the art to play a significant role in the regulation and differentiation of epithelial cells. Such regulatory and differentiating effects, which include the ability to promote cell differentiation, apoptosis, and the inhibition of cell proliferation, make retinoic acid and retinoid compounds useful agents in tumor therapy and in treating such conditions as skin-related diseases. Retinoids and retinoid compounds are known as agents for treating skin-related diseases such as actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses, keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus; for preventing, treating, and reversal of glucocorticoid, age, and photo damage to the skin. Retinoids and retinoid compounds are also known as topical anti-microbial and skin antipigmentation agents. Retinoids, with their ability to serve as differentiating agents, redirect cells towards their normal phenotype and therefore may reverse or suppress developing malignant lesions or prevent cancer invasions altogether. Therefore, retinoid compounds are useful for the prevention and treatment of cancerous and precancerous conditions, including, for example, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, colon, bladder, cervix, uterus, stomach, lung, esophagus, blood and lymphatic system, larynx, oral cavity, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes, and in the treatment of Kaposi's sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, for example, proliferative vitreoretinopathy, retinal detachment, corneopathies such as dry eye, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulation tissue plasminogen activator. Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as Minoxidil®, diseases associated with the immune systems, including use of the ' present compounds as immunosuppresant and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. Retinoid compounds have also been discovered to be useful in treating type II non-insulin dependent diabetes mellitus (NEDDM).
[3] Several compounds having retinoid-like activity are marketed under appropriate regulatory approvals in the United States of America and elsewhere as medicants for the treatment of several diseases responsive to treatment with retinoids. Retinoic acid (RA) itself is a naturally occurring retinoid, the biologically most active metabolite of vitamin A, is biosynthesized and present in a multitude of human and mammalian tissues and is known to play a crucial role in the regulation of gene expression, cellular differentiation, proliferation of epithelial cells, and other important biological processes in mammals including humans. [4] Retinoids have demonstrated reversal of malignant growth in vivo and in vitro and are effective as chemopreventive agents. Retinoids could successfully be used to treat oral leukoplakia, a potentially premalignant mucosal lesion, and the occurrence of second primary tumors following head and neck squamous cell carcinoma (HNSCC) could be inhibited or delayed. These second primary tumors, which occur at an incidence rate of 2-3% per year, are a major cause of death after surgical resection of early-stage head and neck cancer. Retinoid therapy has also been explored in the treatment of glioma tumors, primary and metastatic melanoma cells, and has shown anti-metastatic activities in rat invasive prostate adenocarcinoma cells. Retinoid leukemia therapy works through terminal differentiation 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). [5] Although treatment with retinoids is highly successful in inducing complete remission in APL, if maintained on retinoids alone, most patients will relapse within a few months. The clinical use of retinoic acid in the treatment of cancer has been significantly hampered by the prompt emergence of resistance, which is believed to be caused by increased retinoic acid metabolism. Retinoic acid is metabolized by Cyp26Al (Cyp26), an inducible cytochrome P450 enzyme, that inactivates RA by oxidation of RA to 4-HO-atRA, 8-HO-atRA, and 4-oxo-atRA. The tightly controlled negative feedback mechanism limits the availability of RA and thereby limits its biological activity. Compounds have been identified that inhibit Cyp26 and therefore RA metabolism and have shown to enhance the antiproliferative effects of RA and cause an increase in endogenous levels of RA in plasma and in tissues.
[6] Cyp26 inhibitors, also known as retinoic acid metabolism-blocking agents (RAMBAs), are known and include, for example, Liarozole (Liazal™) and Rl 16010. Such Cyp26 inhibitors have demonstrated therapeutic benefits in dermatological and cancerous conditions in vitro, in vivo, and in clinical settings. In several preclinical tumor models, Liarozole displayed antitumoral properties which correlated with decreased endogenous retinoic acid metabolism and therefore, an increase in RA accumulation within tumor cells. In cancer patients, Liarozole has been shown to increase the half-life of orally administered RA and 13-cis-RA. Unfortunately, one of the limitations of Liarozole and many Cyp26 inhibitors described in the literature was their lack of specificity. Liarozole as well as other Cyp26 inhibitors inhibit other cytochrome P450-mediated reactions and are limited due to their lack of specificity towards other cytochrome P450 enzymes. This lack of specificity might explain the limited risk benefit ratio (the activity/toxicity ratio was considered insufficient by the FDA) observed in prostate cancer patients in the Liarozole phase III clinical trials. Therefore, there is clearly a need within retinoid therapy for Cyp26 inhibitors (RAMBA's) that are highly potent and selective that have greater selectivity to other cytochrome P450 enzymes, fewer side effects, and favorable drug-like properties including sufficient water solubility, bioavailability, sufficient pharmacokinetic properties, extraction ratios, and limited toxicity to balance the activity/toxicity ratio and for use in the treatment of various dermatological and cancerous conditions.
[7] The present invention shows highly potent and selective novel heteroaryl-naphthalenyl-alkylamines Cyp26 inhibitors that provide therapeutic benefits in the treatment or prevention of the diseases and conditions which respond to treatment by retinoids or are controlled by natural retinoic acid. The perceived mode of action of these compounds is that by inhibiting the Cyp26 enzyme (CP450RAI [cytochrome P450 retinoic acid inducible]) that has been proven in the art to catabolyze natural retinoic acid, endogenous retinoic acid level is elevated to a level where desired therapeutic benefits are attained. The endogenous levels of all natural and synthetic retinoids which are metabolized by Cyp26 would be expected to increase from inhibition of Cyp26 by the novel heteroaryl-naphthalenyl-alkylamines Cyp26 inhibitors described in this invention. Co-administration with a composition of the natural or synthetic retinoids with the compounds, or pharmaceutically acceptable salts thereof, disclosed in this invention can increase the level of retinoids. The co- administration of the natural and synthetic retinoids, which are catabolized by Cyp26, with at least one compound disclosed in this invention is a method for treating skin- related or cancerous diseases to yield higher endogenous levels of the retinoids. The compounds of this invention are active at nanomolar concentrations and selectively and potently inhibit enzymes involved in retinoic acid catabolism and therefore result in the effective modulation of desirable levels of atRA.
[8] The following publications describe or relate to the role of Cyp26 inhibitors and their ability to slow the catabolism of retinoic acid, thereby increasing endogenous retinoic acid levels, and their potential for the treatment of dermatological diseases and cancers:
[9] Altucci, L. et.al. "Retinoic Acid-induced Apoptosis in Leukemia Cells is Mediated by Paracrine Action of Tumor-Selective Death Ligand Trail", Nature Med. 2001, 7, 680-686;
[10] Altucci, L.; Gronemeyer, H. "The Promise of Retinoids to Fight
Against Cancer", Nature Reviews (Cancer), 2001, 1, 181-193; [11] Winum, J. Y.; et. al. "Synthesis of New Targretin® Analogues that
Induce Apoptosis in Leukemia HL-60 Cells", Bioorganic & Medicinal Chemistry Letters, 2002, 12, 3529-3532. [12] Kuijpers, et. ab "The Effects of Oral Liarozole on Epidermal
Proliferation and Differentiation in Severe Plaque Psoriasis are Comparable with
Those of Acitretin", British Journal of Dermatology, 1998. 139, 380-389;
[13] Van Wauwe, et. al. "Liarozole, an Inhibitor of Retinoic Acid
Metabolism, Exerts Retinoid-Mimetic Effects in Vivo", The Journal of Pharmacology and Experimental Therapeutics, 1992, 261, 773-779.
[14] Haque, M.; Andreola, F.; DeLuca, L. M. "The Cloning and
Characterization of a Novel Cytochrome P450 Family, Cyp26, with Specificity towards Retinoic Acid", Nutri Rev. 1999, 56, 84-85.
[15] Wouters, W. et. al. "Effects of Liarozole, a New Antitumoral
Compound and Retinoic Acid-Induced Inhibition of Cell Growth and on Retinoic
Acid Metabolism in MCF-7 Breast Cancer Cells", Cancer Res, 1992, 52, 2841-2846;
[16] Freyne, E. et. al. "Synthesis of Liazal™, a Retinoic Acid Metabolism
Blocking Agents (RAMBA) with Potential Clinical Applications in Oncology and
Dermatology", Bioorganic & Medicinal Chemistry Letters, 1998, 8, 267-272;
[17] Miller, W. H. "The Emerging Role of Retinoids and Retinoic Acid
Metabolism Blocking Agents in the Treatment of Cancer", Cancer, 1998, 83, 1471-
1482;
[18] Van Heusden J. et. al. "Inhibition of aH-TRANS-retinoic Acid
Metabolism by Rl 16010 induces Antitumor Activity", Rr. J. Cancer, 2002, 86(4),
605-611;
[19] Debruyne, F. J. M. et. al. "Liarozole-A Novel Treatment Approach for
Advanced Prostate Cancer: Results of a Large Randomized Trial versus
Cyproterone", Urology, 1998, 52, 72-81;
[20] De Coster, R. et. al. "Experimental Studies with Liarozole (R75251):
An Antitumor Agent which Inhibits Retinoic Acid Breakdown", J. Steroid Biochem.
Molec. Biol. 1992, 43, 197-201;
[21] Njar, V. C. O.; Brodie, A. M. H. "Inhibitors of Cytochrome P450
Enzymes: Their Role in Prostate Cancer Therapy", I Drugs, 1999, 1, 495-506;
[22] Miller, V. A.; Rigas, J. R.; Muindi, J. F. R.; Tong, W. P.;
Venkatraman, E.; Kris, M. G.; Warrell Jr. R. P. "Modulation of all-trans-retinoic acid pharmacokinetics by liarozole", Cancer Chemother. Pharmacol. 1994, 34, 522-526;
[23] Muindi, J.; Frankeb S. R.; Miller Jr. W. H.; Jakubowskb A.;
Scheinberg, D. A.; Young, C. W.; Dmitrovski, E.; Warrell, Jr. R. P. "Continuous treatment with all-trans-retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid 'resistance' in patients with acute promyelocytic leukemia", Blood. 1992, 79, 299-303;
[24] Muindi, J F.; Scher, H. b; Rigas, J. R.; Warrell Jr. R. P.; Young, C. W.
"Elevated plasma lipid peroxide content correlates with rapid plasma clearance of all- trans-retinoic acid in patients with advanced cancer", Cancer Res. 1994, 54, 2125- 2128.
[25] U.S. Patent No. 6,303,785B1 describes inhibitors of cytochrome
P450RAI. International Patent Publication No. WO 99/29674 describes inhibitors of retinoic acid metabolism. International Patent Publication No. WO 01/30762A1 describes imidazol-4-ylmethanols used as inhibitors of steroid C 17-20 Lyase.
[26] U.S. Patent Nos. 6,291,677 and 6,124,330 and International Patent
Publication No. WO 02/03912 A2 describe inhibitors of cytochrome P450RAI. International Application No. PCT/USOO/11833 describes PPAR agonists or antagonists. International Patent Publication No. WO 02/06281 describes selective β3 adrenergic receptor agonists. International Patent Publication No. WO 01/068647 describes an antiviral agent. International Patent Publication No. WO 01/062234 describes a farnesyl protein transferase inhibitor. International Patent Publication No. WO 01/055155 describes compounds which have antibacterial activities. International Patent Publication No. WO 01/044170 describes adamantine derivatives. International Patent Publication No. WO 01/000615 describes benzimidazoles. International Patent Publication No. WO 00/069843 describes compounds for the treatment of inflammations. International Patent Publication No. WO 00/043384 describes aromatic heterocyclic ureas as anti-inflammatory agents. Japanese Patent Publication No. JP 01/43635 describes benzimidazole compositions and derivatives. International Patent Publication No. WO 99/40092 describes GABAa agonists, antagonists or inverse agonists. International Patent Publication No. WO 99/376609 describes virucides used against cytomegalovirus. German Patent Publication No. DE 75/6388 describes substituted 2-aryl-4-amino-quinazolines. International Patent Publication No. WO 98/54168 describes 2-oxoimidazole derivatives. International Patent Publication No. WO 98/23593 describes inhibitors of apolipoprotein B and/or microsomal triglyceride transfer protein. U.S. Patent No. 5,852,213 describes matrix metalloproteinase inhibitors of the MMP enzyme. U.S. Patent No. 5,834,483 and International Patent Publication No. WO 97/37665 describes endothelin antagonists. International Patent Publication No. WO 97/24117 describes substituted hydroxamic acid compounds. International Patent Publication No. WO 95/29689 describes N- carboxyalkyl derivatives. U.S. Patent No. 5,461,162 describes N-acyl auxilliary compounds. European Patent Publication No. 611,776 describes pseudopeptides with antiviral activity. European Patent Publication No. 569,220 describes organic sulfonamides. European Patent Publication No. 545,376 describes guanidinothiazoles. German Patent No. DE 4,201,435 describes trifluoromethyl ketones. German Patent No. DE 4,138,820 describes compounds used as herbicides. International Patent Publication No. WO 91/19717 describes phosphodiesterase inhibitors. European Patent Publication No. EP 437,729 describes peptide retroviral protease inhibitors. European Patent Publication No. EP 412,350 describes peptides as renin inhibitors. International Patent Publication No. WO 89/10919 describes carbostyril derivatives. International Patent Publication No. WO 00/064888 describes diaryl carboxylic acids and derivatives. WO 99/47497 describes naphthyl and indolyl acylsulfonamides. German Patent No. DE 4304650 describes benzimidazoles, xanthines, and analogs. International Patent Application No. PCT/CA99/00212 describes compounds used for treating or preventing prostaglandin mediated diseases.
SUMMARY OF THE INVENTION
[27] The present invention relates to compounds represented by Formula I:
and pharmaceutically accepted salts thereof. The compounds of Formula I inhibit cytochrome P450RAI enzyme and are useful for the treatment and/or prevention of various diseases and conditions that respond to treatment by retinoids and by naturally occurring retinoic acid. DETAILED DESCRIPTION OF THE INVENTION
[28] The present invention relates to a compound of Formula I:
[29] or a pharmaceutically acceptable salt thereof, wherein:
[30] 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 R66 substituents; [31] R1 is a Co-6alkyl, -OR7, -SR7, or -NR7R8;
[32] R2 and R3 are each independently Co-ioalkyl, C2_ιoalkenyb C2-ιoalkynyb
Cι-ιoalkoxyCι-ιoalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ιoalkoxyC2.1oalkynyb Cι_ loalkylthiod-ioalkyb C1-ιoalkylthioC2-ιoalkenyb Cι-ιoalkylthioC2.ιoalkynyb cycloC3- 8alkyb cycloC3-8alkenyb cycloC^salkylCMoalkyb cycloC .8alkenylCι-ιoalkyb cycloC - 8alkylC2-ιoalkenyb cycloC3.8alkenylC2-ιoalkenyb cycloC -8alkylC -1oalkynyb cycloC - 8alkenylC2-1oalkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C2.ιoalkenyb heterocyclyl-C2-ιoalkynyb Cι-ιoalkylcarbonyb C2-ιoalkenylcarbonyb C2- loalkynylcarbonyb Cι-ιoalkoxycarbonyb Ci-ioalkoxycarbonylCi-ujalkyb monoCi- 6alkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR71R81, or -NR71R81 substituents; or aryl-Co-ioalkyb aryl-C2-]0alkenyb or aryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Ci-ioalkyl, C .ιoalkenyl, C2-ιoalkynyb haloCi- loalkyb haloC2.ιoalkenyb haloC2.ιoalkynyb -COOH, CMalkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; or hetaryl-C0-ι0alkyb hetaryl-C2-ιoalkenyb or hetaryl-C2.ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Ci-ioalkyl, C2-ιc>alkenyb C - loalkynyb haloCi.ioalkyb haloC2-ιoalkenyb haloC -ιoalkynyb -COOH, Ci- 4alkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; [33] or R2 and R3 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 Cι-6alkyl, halo, cyano, nitro, -OR71, -SO2NR71R81 or -NR71R81 substituents;
[34] G1 is -OR72, -SR72, -NR72R82(R9)n5, or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or in the case of -NR72R82(R9)n5, R72 and R82 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, Cι-ι0alkoxy, -SO2NR73R83 or -NR73R83 substituents;
[35] Y is an oxygen atom, sulfur atom, -(C=O)N(R74)-, >CR4cR5c or
>NR74;
[36] Z is -aryl- -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,
-alkenylaryl-, -hetaryl-, -hetarylalkyl- -alkylhetaryl-, -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is optionally substituted with R68; [37] Q1 is C0-6alkyb -OR75, -NR75R85(R95)n6, -CO2R75, -CONR75R85,
-(C=S)OR75, -(C=O)SR75, -NO2, -CN, halo, -S(O)n6R75, -SO2NR75R85, -NR75(C=NR775)NR7775R85, -NR75(C=NR775)OR7775, -NR75(C=NR775)SR7775, -O(C=O)OR75, -O(C=O)NR75R85, -O(C=O)SR75, -S(C=O)OR75, -S(C=O)NR75R85, -S(C=O)SR75, -NR75(C=O)NR775R85, or -NR75(C=S)NR775R85; in the case of -NR75R85(R95)n6, R75 and R85 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, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR R or -NR76R86 substituents;
[38] R4a, R4b, R4c, R5a, R5b and R5c are each independently a C0-ιoalkyb C2. loalkenyb C2-ι0alkynyb d-ioalkoxyCi-ioalkyb Cι-ι0alkoxyC2-ι0alkenyb Cι-ιoalkoxyC2. loalkynyb Cι-ι0alkylthioCι-ι0alkyb Cι-ι0alkylthioC2-ι0alkenyb Cι-ι0alkylthioC - loalkynyb cycloC3-8alkyb cycloC3-8alkenyb cycloC -8alkylC1-ιoalkyb cycloC3- 8alkenylCι-ιoalkyb cycloC3-8alkylC2-!oalkenyb cycloC3-8alkenylC2-ι0alkenyb cycloC - 8alkylC2-ιoalkynyb cycloC3-8alkenylC2.ιoalkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or aryl-Co-ιcalkyb aryl-C -ιoalkenyb or aryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci-ioalkyl, C -ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2- loalkynyb -COOH, Cι-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or hetaryl-Co-ioalkyl, hetaryl-C2.ιoalkenyb or hetaryl-C2-ioalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci-ioalkyl, C2-ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC^oalkenyb haloC2- loalk nyl, -COOH, Cι-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or mono(aryl)aminoCι-6alkyb di(aryl)aminoCι.6alkyb or -N(Cι-6alkyl)-Cι_6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci-ioalkyl, C -ι0alkenyl, C2-ιoalkynyl, haloCi-ioalkyb haloC2-ιoalkenyb haloC2-i0alkynyb -COOH, Cι-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a or R4b with R5b, or R4c with R5c, 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 R69; or R4a with R5a, or R4b with R5b, or R4c with R5c, 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 R69; [39] R6a, R6b, R66, R67, R68, and R69 are each independently halo, -OR78,
-SH, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, Co-ioalkyl, C2-10alkenyb C2-ι0alkynyb Cι-ι0alkoxyCι-ι0alkyb Ci- ι0alkoxyC2-ιoalkenyb Cι-1oalkoxyC2-ιoalkynyb Cι-ιoalkylthioCι-ιoalkyb Ci- ι0alkylthioC2-ιoalkenyb Cι-10alkylthioC2-ιoalkynyb cycloC3.8alkyb cycloC3-8alkenyb cycloC3-8alkylCι-ιoalkyb cycloC . alkenylCι-1oalkyb cycloC3-8alkylC2-ιoalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC . alkylC2-ιoalkynyb cycloC -8alkenylC - loalkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C^oalkenyb or heterocyclyl-C2. loalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, -SO2NR778R888 or -NR778R888 substituents; or aryl-C0-ι oalkyb aryl-C2-ιoalkenyb or aryl-C2-1oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, Ci-ioalkyl, C2-ιoalkenyl, C - loalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, Ci- 4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or hetaryl-Co-i oalkyb hetaryl-C2-!oalkenyb or hetaryl-C2.ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, C\. loalkyl, C2-ιoalkenyl, C -!oalkynyb haloCι-ι oalkyb haloC2-ιoalkenyb haloC -ιoalkynyb -COOH, C,.4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or mono(Cι-6alkyl)aminoCι-6alkyl, di(Cι-6alkyl)aminoCι-6alkyl, mono(aryl)aminoCi.6alkyb di(aryl)aminoCι-6alkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, Ci-ioalkyl, C -ιoalkenyl, C2-ιoalkynyl, haloCι-ι oalkyb haloC -ιoalkenyb haloC2-ι0alkynyb -COOH, Cι-4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or in the case of-NR78R88(R98)n7, R78 and R88 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, Cι-ι0alkoxy, -SO2NR778R888 or -NR778R888 substituents; [40] R7, R71, R72, R73, R74, R75, R775, R7775, R76, R77, R78, R778, R8, R81, R82,
R83, R84, R85, R86, R87, R88, R888, R9, R95, and R98 are each independently C0-ι0alkyb C2-ιoalkenyb C2-10alkynyb Cι-ιoalkoxyCι-ιoalkyb Cι-ιoalkoxyC2-1oalkenyb Ci- )0alkoxyC2-ιoalkynyb Cι-ιoalkylthioCι-ιoalkyb Cι-ιoalkylthioC2-1oalkenyb Ci- ιoalkylthioC2- loalkynyb cycloC .8alkyb cycloC3-8alkenyb cyclod-salkylCi-] oalkyb cycloC3-8alkenylCι-ιoalkyb cycloC3-8alkylC2.ιoalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3-8alkylC2-ιoalkynyb cycloC3.8alkenylC2-ιoalkynyb heterocyclyl-Co-i oalkyb heterocyclyl-C2-ιoalkenyb heterocyclyl-C2-ιoalkynyb Cι-ιoalkylcarbonyb C - loalkenylcarbonyb C2-ιoalkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι- i oalkyb monoCj-όalkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, -ioalkoxy, -SO2N(C0.4alkyl)(Co-4alkyl) or -N(Co-4alkyl)(Co-4alkyl) substituents; aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Ci-ioalkyl, C2-ιoalkenyb C2-ιoalkynyb haloCι-ι oalkyb haloC2.ιoalkenyb haloC2- ,0alkynyb -COOH, Cι-4alkoxycarbonyb -CON(C0-4alkyl)(C0-ιoalkyl), -SO2N(C0- 4alkyl)(Co-4alkyl) or -N(Co-4alkyl)(Co-4alkyl) substituents; or hetaryl-Co-i oalkyb hetaryl-C2-ιoalkenyb or hetaryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Ci-ioalkyl, C - loalkenyl, C2-ιoalkynyl, haloCi-i oalkyb haloC -ιoalkenyb haloC2-ιoalkynyb -COOH, C!-4alkoxycarbonyb -CON(C0-4alkyl)(C0.4alkyl), -SO2N(C0- alkyl)(C0- alkyl) or -N(Co-4alkyl)(Co-4alkyl) substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(d- 6alkyl)aminoCι-6alkyl, mono(aryl)aminoCι-6alkyl, di(aryl)aminoCι-6alkyl, or -N(Cι-6alkyl)-Cι-6alkyl-aryl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Ci-ioalkyl, C2-ι0alkenyb C2-ι0alkynyb haloC i-i oalkyb haloC2-ιoalkenyb haloC2.ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CON(Co-4alkyl)(C0- alkyl), -SO2N(C0- alkyl)(C0- alkyl) or -N(C0-4alkyl)(C0-4alkyl) substituents; and [41] nl, n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2.
[42] In an aspect of the present invention, a compound is represented by
Formula I, or a pharmaceutically acceptable salt thereof, wherein X is an optionally substituted imidazolyl or optionally substituted triazolyb and the other variables are as described above. [43] In an embodiment of this aspect, a compound is represented by
Formula I, or a pharmaceutically acceptable salt thereof, wherein X is a substituted imidazolyl or substituted triazolyb R1 is hydrogen; and the other variables are as described above.
[44] In a second aspect of the present invention, a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is oxygen, and the other variables are as described above.
[45] In an embodiment of this second aspect, a compound of the invention is represented by Formula I-A:
I-A or a pharmaceutically acceptable salt thereof, wherein:
[46] 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 R65 substituents;
[47] R and R are each independently Co-ioalkyb C2-ιoalkenyb C2-ιoalkynyb
Ci.ioalkoxyCi-ioalkyb Cι-ι0alkoxyC2-ι0alkenyb Cι-ιoalkoxyC2-ιoalkynyb Ci- loalkylthioQ-ioalkyb Cι-ιoalkylthioC2-ι0alkenyb Cι-ιoalkylthioC2-ιoalkynyb cycloC3- 8alkyb cycloC3-8alkenyb cycloC3-8alkylCι-ι oalkyb cyclod-salkenyld-ioalkyb cycloC3- 8alkylC2-ι0alkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC .8alkylC2-ιoalkynyb cycloC - 8alkenylC2-ιoalkynyb heterocyclyl-Co-ιoalkyb heterocyclyl-C2-ιoalkenyb heterocyclyl-C2- loalkynyb Cι-ιoalkylcarbonyb C2-ιoalkenylcarbonyb C2- loalkynylcarbonyb Cι-ιoalkoxycarbonyb Ci-ioalkoxycarbonylCj-ioalkyb monoCi- 6alkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR71R81, or -NR71R81 substituents; or aryl-Co-i oalkyb aryl-C2-ι0alkenyb or aryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, -i oalkyb C2-ιoalkenyb C2-ιoalkynyb haloCi- loalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, C alkoxycarbonyb -CONR7,R81, -SO2NR71R81 or -NR71R81 substituents; or hetaryl-Co-i oalkyb hetaryl-C2-ιoalkenyb or hetaryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Cι-ιoalkyb C2.ιoalkenyb C2. loalkynyb haloCι-ι oalkyb halod-ioalkenyb haloC2-ι0alkynyb -COOH, C]. 4alkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; [48] or 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 Cι-6alkyb halo, cyano, nitro, -OR , -SO2NR71R81 or -NR71R81 substituents;
[49] G1 is -OR72, -SR72, -NR72R8 (R9)n5, or G1 and R3 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 R57 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or in the case of-NR72R82(R9)n5, R72 and R82 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, -SO2NR73R83 or -NR73R83 substituents;
[50] Z is -aryl-, -arylalkyl- -aryloxy- -oxyaryl-, -arylalkenyl-,
-alkenylaryl-, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-, -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is optionally substituted with R68; [51] Q1 is C0-6alkyb -OR75, -NR75R85(R95)n6, -CO2R75, -CONR75R85,
-(C=S)OR75, -(C=O)SR75, -NO2, -CN, halo, -S(O)n6R75, -SO2NR75R85, -NR75(C=NR775)NR7775R85, -NR75(C=NR775)OR7775, -NR75(C=NR775)SR7775, -O(C=O)OR75, -O(C=O)NR75R85, -O(C=O)SR75, -S(C=O)OR75, -S(C=O)NR75R85, -S(C=O)SR75, -NR75(C=O)NR775R85, or -NR75(C=S)NR775R85; in the case of -NR75R85(R95)n6, R75 and R85 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, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR R or -NR76R86 substituents;
[52] R4b and R5b are each independently a C0-ioalkyb C2-ιoalkenyb C2. loalkynyb Cι-ι0alkoxyCι-ι0alkyb Cι-ι0alkoxyC2-ιoalkenyb Cι-ιoalkoxyC2-ι0alkynyb Ci- loalkylthioCi-ioalkyb Cι-ι0alkylthioC2.ι0alkenyb Cι-ι0alkylthioC2-ιoalkynyb cycloC3. 8alkyb cycloC3.8alkenyb cycloC3.8alkylCι-ι0alkyb cycloC3.8alkenylCι-ι0alkyb cycloC3- 8alkylC2.ιoalkenyb cycloC -8alkenylC2-ιoalkenyb cycloC -8alkylC2-ιoalkynyb cycloC3. 8alkenylC2-ioalkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C2. loalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2.ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, CM oalkyb C2. i0alkenyb C2-ιoalkynyb haloCi-ioalkyb halod-ioalkenyb haloC2-1oalkynyb -COOH, Cι-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or hetaryl-Co-i oalkyb hetaryl-C -ιoalkenyb or hetaryl-C -ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci- loalkyl, C2-ιoalkenyb C2-ιoalkynyb haloCι-ι0alkyb haloC2-ι0alkenyb haloC2-ιoalkynyb -COOH, C alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι-6alkyl)aminoCι-6alkyb mono(aryl)aminoCι- 6alkyb di(aryl)aminoCι-6alkyb or -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci- loalkyl, C2-ι0alkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-10alkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or R4b with R5b, 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 R69; or R4b with R5b, 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 R69; [53] R66, R67, R68, and R69 are each independently halo, -OR78,
-NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, C0. loalkyb C2-ιoalkenyb C2-ιoalkynyb Cι-ιoalkoxyCι-ι0alkyb Cι-ιoalkoxyC2-ι0alkenyb Cι_ ι0alkoxyC2- loalkynyb Ci.ioalkylthioCi-ioalkyb Cι-ιoalkylthioC2-ιoalkenyb Ci- ι0alkylthioC2- loalkynyb cycloC3.8alkyb cycloC3-8alkenyb cycloC -8alkylCι-ιoalkyb cycloC .8alkenylCι-ι0alkyb cycloC -8alkylC2-ιoalkenyb cycloC3-8alkenylC2-ι0alkenyb cycloC3-8alkylC2-ιoalkynyb cycloC3-8alkenylC2-ιoalkynyb heterocyclyl-Co-i oalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C2-ιoalkynyb any of which is optionally 778 778 888 substituted with one or more independent halo, cyano, nitro, -OR , -SO NR R or -NR778R888 substituents; or aryl-Co-i oalkyb aryl-C2-ι0alkenyb or aryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, Ci-ioalkyl, C2_ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-,0alkynyb -COOH, Cι-4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or hetaryl-C0-ι oalkyb hetaryl-C2.10alkenyb or hetaryl-C2. loalkynyb any of which is optionally substituted with one or more independent halo, ■ 778 cyano, nitro, -OR , Ci-ioalkyl, C2.ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2. loalkenyb haloC2-ι0alkynyb -COOH, Cι-4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι- 6alkyl)aminoC ι -6alkyb mono(aryl)aminoC ι -6alkyb di(aryl)aminoC i .6alkyb -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, Ci-ioalkyl, C2-ιoalkenyb C2-ιoalkynyb haloCi- loalkyb haloC2-ιoalkenyb haloC2-ι0alkynyb -COOH, Cι-4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or in the case of -NR78R88(R98)n7, R78 and R88 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, Cι-ιoalkoxy, -SO2NR778R888 or -NR778R888 substituents;
[54] R7, R71, R72, R73, R75, R775, R7775, R76, R77, R78, R778, R8, R81, R82, R83,
R85, R86, R87, R88, R888, R9, R95, and R98 are each independently C0-ι0alkyb C2- loalkenyb C2-ι0alkynyb Cι-ιoalkoxyCι-ιoalkyb Cι-ι0alkoxyC2-ιoalkenyb Cι-ι0alkoxyC2. loalkynyb Cι-ι0alkylthioCι-ιoalkyb Cι-ιoalkylthioC2-ιoalkenyb Cι-ιoalkylthioC2. loalkynyb cycloC .8alkyb cycloC3.8alkenyb cycloC3.8alkylCι-ιoalkyb cycloC - 8alkenylCι-ι0alkyb cycloC3-8alkylC2-ιoalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3- 8alkylC2-ιoalkynyb cycloC3-8alkenylC2-ιoalkynyb heterocyclyl-C0-ιoalkyb heterocyclyl-C2-ιoalkenyb heterocyclyl-C2-ιoalkynyb Cι-ιoalkylcarbonyb C2- loalkenylcarbonyb C2-ιoalkynylcarbonyb Cι-ιoalkoxycarbonyb Ci-ioalkoxycarbonylCi- i oalkyb monoCι-6alkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ι0alkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO N(C0-4alkyl)(Co-4alkyl) or -N(Co-4alkyl)(C0-4alkyl) substituents; aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -©(Co^alkyl), Ci-ioalkyl, C2-]oalkenyb C -ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2. loalkynyb -COOH, Cι-4alkoxycarbonyb -CON(C0-4alkyl)(C0-ιoalkyl), -SO2N(C0. 4alkyl)(Co-4alkyl) or -N(Co-4alkyl)(Co- alkyl) substituents; or hetaryl-Co-i oalkyb hetaryl-C2-ιoalkenyb or hetaryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Cι-ιoalkyb C2. loalkenyb C2-ιoalkynyb halod-ioalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CON(C0. alkyl)(C0-4alkyl), -SO2N(C0-4alkyl)(C0- alkyl) or -N(Co-4alkyl)(Co-4alkyl) substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι- 6alkyl)aminoCι-6alkyb mono(aryl)aminoCι-6alkyb di(aryl)aminoCι-6alkyb or -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(C0.4alkyl), Cι-ιoalkyb C2.ιoalkenyb C2-ιoalkynyb haloC i-i oalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CON(C0- alkyl)(Co-4alkyl), -SO2N(C0-4alkyl)(C0-4alkyl) or -N(C0-4alkyl)(C0- alkyl) substituents; and
[55] n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2.
[56] In another embodiment of this second aspect, a compound of the invention is represented by Formula I-B:
or a pharmaceutically acceptable salt thereof, wherein: [57] X is substituted imidazolyl;
[58] R2 and R3 are each independently Co-ioalkyb C2-ι0alkenyb C2-ι0alkynyb
Cι-ιoalkoxyCι-ιoalkyb Cι-ιoalkoxyC2-ι0alkenyb Cι-ιoalkoxyC2-ιoalkynyb Ci- loalkylthioCi-ioalkyb Cι-ι0alkylthioC2-ιoalkenyb Cι-ιoalkylthioC2-ιoalkynyb cycloC3- 8alkyb cycloC3.8alkenyb cycloC3-8alkylCι-ι0alkyb cycloC3-8alkenylCι-ιoalkyb cycloC3- 8alkylC2-ιoalkenyb cycloC3-8alkenylC2-ι0alkenyb cycloC3-8alkylC2-ι0alkynyb cycloC3- 8alkenylC2- 10alkynyb heterocyclyl-C0-ι oalkyb heterocyclyl-C2.10alkenyb heterocyclyl-C2-ioalkynyb Cι-ιoalkylcarbonyb C2-ιoalkenylcarbonyb C2- loalkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι-ιoalkyb monoCi- 6alkylaminocarbonyb diC ι .6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR71R81, or -NR71R81 substituents; or aryl-C0-ι0alkyb aryl-C2-ι0alkenyb or aryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Ci-ioalkyl, C2-ιoalkenyl, C2-ιoalkynyl, haloCi- loalkyl, haloC -ιoalkenyl, haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; or hetaryl-C0-ι oalkyb hetaryl-C2-ιoalkenyb or hetaryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Cι-ι0alkyb C2-ιoalkenyb C2- loalkynyb haloCι-ι oalkyb haloC2-ιoalkenyb haloC2.ιoalkynyb -COOH, Ci- 4alkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; [59] or R2 and R3 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 Cι-6alkyl, halo, cyano, nitro, -OR71, -SO2NR71R81 or -NR71R81 substituents;
[60] G1 is -OR72, -SR72, -NR72R82(R9)n5, or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or in the case of-NR72R82(R9)n5, R72 and R82 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, Cι-ιoalkoxy, -SO2NR R or -NR R substituents;
[61] Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,
-alkenylaryl-, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-, -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is optionally substituted with R ; [62] R4b and R5b are each independently a Co-ioalkyl, C2-ιoalkenyl, C2- loalkynyb Cι-ιoalkoxyCι-ι oalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ιoalkoxyC2-ιoalkynyb d- loalkylthioC l-i oalkyb Cι-ιoalkylthioC2-ιoalkenyb Cι-ιoalkylthioC2-ιoalkynyb cycloC3- 8alkyb cycloC3-8alkenyb cycloC3-8alkylCι-ι oalkyb cycloC3-8alkenylCι-ιoalkyb cycloC - alkylC2-ιoalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3.8alkylC2-ιoalkynyb cycloC - 8alkenylC -ιoalkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C -ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or aryl-Co-ioalkyb aryl-C2-ι0alkenyb or aryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci-ioalkyl, C2. ioalkenyb C2-ι0alkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or hetaryl-Co-ioalkyb hetaryl-C2-ιoalkenyb or hetaryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci- loalkyl, C2.ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ι0alkynyb -COOH, Cι-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι-6alkyl)aminoCι-6alkyb mono(aryl)aminoC1- 6alkyb di(aryl)aminoCι-6alkyb or -N(Cι.6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci- loalkyl, C2-ιoalkenyb C2-ιoalkynyb haloCi-i oalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or R4b with R5b, 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 R69; or R4b with R513, taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated heterocyclic ring optionally substituted with R69; [63] R67, R68, and R69 are each independently halo, -OR78, -NR78R88(R98)n7,
-CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, C0-ι0alkyb C2- loalkenyb C2.ιoalkynyb Cι-ιoalkoxyCι.ιoalkyb Cι-ιoalkoxyC2-ι0alkenyb Cι-ι0alkoxyC2- loalkynyb Cι-ιoalkylthioCι-ιoalkyb Cι-ι0alkylthioC2-ιoalkenyb Cι-ι0alkylthioC2- loalkynyb cycloC3-8alkyb cycloC3.8alkenyb cycloC3-8alkylCι-ιoalkyb cycloC3- 8alkenylCι-ιoalkyb cycloC3-8alkylC2.ιoalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3- 8alkylC2- 1 oalkynyb cycloC3-8alkenylC2-ι oalkynyb heterocyclyl-C0. ι oalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C2-ioalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, -SO2NR778R888 or -NR778R888 substituents; or aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, Ci-ioalkyl, C2-ιoalkenyl, C2-ιoalkynyl, haloCi-ioalkyb haloC2_ιoalkenyb haloC2., oalkynyb -COOH, Cι_4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or hetaryl-Co-i oalkyb hetaryl-C2-ιoalkenyb or hetaryl-C - i oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, Ci-ioalkyl, C2.ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2. loalkenyb haloC2-ι oalkynyb -COOH, Cι-4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or mono(Cι-6alkyl)aminoCι.6alkyb di(Cι- 6alkyl)aminoC i -6alkyb mono(aryl)aminoC ι -6alkyb di(aryl)aminoC ι -6alkyb -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, Ci-ioalkyl, C2-ιoalkenyb C2-ιoalkynyb haloCi- ^alkyb haloC2-ιoalkenyb haloC2-ι0alkynyb -COOH, Cι-4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or in the case of -NR78R88(R98)n7, R78 and R88 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, optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR778R888 or -NR778R888 substituents;
[64] R7, R71, R72, R73, R75, R775, R7775, R76, R77, R78, R778, R8, R81, R82, R83,
R85, R86, R87, R88, R888, R9, R95, and R98 are each independently C0-ι0alkyb C2. loalkenyb C2-ι0alkynyb Cι-ιoalkoxyCι-ιoalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ιoalkoxyC2- loalkynyb Cι-ιoalkylthioCι-ιoalkyb Cι-ι0alkylthioC2-ι0alkenyb Cι-ι0alkylthioC2- loalkynyb cycloC3-8alkyb cycloC3-8alkenyb cycloC3-8alkylCι-ιoalkyb cycloC3- 8alkenylCι-ιoalkyb cycloC3.8alkylC2-ιoalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC . 8alkylC2-ioalkynyb cycloC3-8alkenylC2.ι oalkynyb heterocyclyl-C0-ι oalkyb heterocyclyl-C2. loalkenyb heterocyclyl-C2-ι oalkynyb Ci-ioalkylcarbonyb C2- loalkenylcarbonyb C2-ι0alkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι- i oalkyb monoCι-6alkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2N(Co-4alkyl)(Co-4alkyl) or -N(Co-4alkyl)(Co- alkyl) substituents; aryl-Co-ioalkyl, aryl-C2-ιoalkenyl, or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(C0-4alkyl), Ci-ioalkyl, C2-ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2. loalkynyb -COOH, Cι-4alkoxycarbonyb -CON(C0-4alkyl)(C0-ι0alkyl), -SO2N(C0- 4alkyl)(Co-4alkyl) or -N(Co-4alkyl)(Co-4alkyl) substituents; or hetaryl-Co-i oalkyb hetaryl-d-ioalkenyb or hetaryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), CM oalkyb C2. loalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CON(C0-4alkyl)(C0- alkyl), -SO2N(C0- alkyl)(C0- alkyl) or -N(Co-4alkyl)(Co-4alkyl) substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι- 6alkyl)aminoCι-6alkyb mono(aryl)aminoCι.6alkyb di(aryl)aminoCι-6alkyb or -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Cι-ι0alkyb C2-ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-!oalkenyb haloC2-ι oalkynyb -COOH, Cι-4alkoxycarbonyb -CON(Co- alkyl)(C0-4alkyl), -SO2N(C0- alkyl)(C0-4alkyl) or -N(C0-4alkyl)(C0-4alkyl) substituents; and [65] n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2.
[66] In a third aspect, an intermediate compound of the invention is represented by Formula II: II
or a pharmaceutically acceptable salt thereof, wherein:
[67] R2 and R3 are each independently Q-ioalkyb C2-ιoalkenyb C2-ιoalkynyb
Cι-ιoalkoxyC i-i oalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ιoalkoxyC2-ιoalkynyb Ci- ioalkylthioCi-i oalkyb Cι-ιoalkylthioC2.ιoalkenyb Cι-ιoalkylthioC2-ιoalkynyb cycloC . 8alkyb cycloC .8alkenyb cycloC -8alkylCι-ιoalkyb cycloC3-8alkenylCι-ιoalkyb cycloC3- 8alkylC2-ιoalkenyb cycloC -8alkenylC2-ιoalkenyb cycloC3-8alkylC2-ιoalkynyb cycloC3- 8alkenylC2-ιoalkynyb heterocyclyl-Co-ιoalkyb heterocyclyl-C2-ιoalkenyb heterocyclyl-C2-1oalkynyb Cι-ιoalkylcarbonyb C2-ιoalkenylcarbonyb C . loalkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι-ι oalkyb monoCi- 6alkylaminocarbonyb diCi -6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR71R81, or -NR71R81 substituents; or aryl-C0-ι0alkyb aryl-C2.ι0alkenyb or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Cι-ιoalkyb C2-ιoalkenyb C2-ιoalkynyb haloCi- loalkyl, haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; or heteroaryl-C0-i oalkyb heteroaryl-C2. loalkenyb or heteroaryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, C oalkyb C2. loalkenyb C2-ιoalkynyb haloCι-ι0alkyb haloC -ι0alkenyb haloC2-ι0alkynyb -COOH, CMalkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; [68] or 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).6alkyb halo, cyano, nitro, -OR71, SO2NR >71τ Rj 8δ1 or -NR 7"1rR>8δ1l substituents; [69] G1 is ^OR72, -SR72, -NR7 R82(R9)n5, or G1 and R3 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 R72 substituent; or in the case of-NR72R82(R9)n5, R72 and R82 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, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents;
[70] Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-,
-alkenylaryl-, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-, -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is optionally substituted with R68; [71] Q1 is Co-βalkyl, -OR75, -NR75R85(R95)n6, -CO2R75, -CONR75R85,
-(C=S)OR75, -(C=O)SR75, -NO2, -CN, halo, -S(O)n6R75, -SO2NR75R85, -NR75(C=NR775)NR7775R85, -NR75(C=NR775)OR7775, -NR75(C=NR775)SR7775, -O(C=O)OR75, -O(C=O)NR75R85, -O(C=O)SR75, -S(C=O)OR75, -S(C=O)NR75R85, -S(C=O)SR75, -NR75(C=O)NR775R85, or -NR75(C=S)NR775R85; in the case of -NR75R85(R95)n6, R75 and R85 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, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ι0alkoxy, -SO2NR76R86 or -NR76R86 substituents;
[72] R and R5 are each independently a Co-ioalkyb C2-ιoalkenyb C2- loalkynyb Cι-ι0alkoxyCι-ι0alkyb Ci-ioalkoxyd-ioalkenyb Cι-ιoalkoxyC2-ι oalkynyb Ci- i0alkylthioCi-i0alkyb Ci.ioalkylthiod.ioalkenyb Cι-ι0alkylthioC2-ιoalkynyb cycloC3- 8alkyb cycloC3-8alkenyb cycloC3-8alkylCι-ι0alkyb cycloC3.8alkenylCι-ι0alkyb cycloC3- 8alkylC2-ι0alkenyb cycloC3-8alkenylC2-ι0alkenyb cycloC3-8alkylC2-ι oalkynyb cycloC3- 8alkenylC2-ιoalkynyb heterocyclyl-C0-ι oalkyb heterocyclyl-C2-ι0alkenyb or heterocyclyl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR , Ci-ioalkyl, C2- loalkenyb C2-ιoalkynyb haloCι-ι oalkyb haloC2-ι0alkenyb haloC2-ι oalkynyb -COOH, -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or hetaryl-Co- loalkyl, hetaryl-C2-ιoalkenyl, or hetaryl-d-i oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR , Ci- loalkyl, C2-ιoalkenyl, C2-ιoalkynyb haloCi-ioalkyb haloC2-ι0alkenyb haloC2-ιoalkynyb -COOH, C,-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or mono(Cι-6alkyl)aminoCι-6alkyl, di(Cι-6alkyl)aminoCι-6alkyl, mono(aryl)aminoCι- 6alkyb di(aryl)aminoCι-6alkyb or -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci- loalkyl, C2-ιoalkenyl, C2.ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, d-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or R4b with R5b, taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, any of which is optionally substituted with R69; or R4b with R5b, taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated heterocyclic ring, any of which is optionally substituted with R69; [73] R7, R71, R72, R73, R75, R775, R7775, R76, R77, R78, R778, R8, R81, R82, R83,
R85, R86, R87, R88, R888, R9, R95, and R98 are each independently Co-ioalkyl, C2. loalkenyb C2-ιoalkynyb Cι-ιoalkoxyCι.ι oalkyb Cι_ιoalkoxyC2-ιoalkenyb Cι-ιoalkoxyC2- loalkynyb Ci-ioalkylthioCi-joalkyb Cι-ι0alkylthioC2-ι0alkenyb Cι-ιoalkylthioC2- loalkynyb cycloC3.8alkyb cycloC3.8alkenyb cycloC3.8alkylCι_ιoalkyb cycloC - 8alkenylCι-ιoalkyb cycloC3-8alkylC2-ι0alkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3- 8alkylC2-ιoalkynyb cycloC3-8alkenylC2_ιoalkynyb heterocyclyl-C0.ιoalkyb heterocyclyl-C2-ιoalkenyb heterocyclyl-C2.i oalkynyb Ci-ioalkylcarbonyb C2. loalkenylcarbonyb C2-ioalkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι- loalkyl, monoCι_6alkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2N(Co-4alkyl)(C0-4alkyl) or -N(C0-4alkyl)(C0-4alkyl) substituents; aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Cι-ιoalkyb C2.ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC -ιoalkenyb haloC2- loalkynyb -COOH, Cι-4alkoxycarbonyb -CON(Co-4alkyl)(C0-ι0alkyl), -SO2N(C0- 4alkyl)(C0-4alkyl) or -N(C0- alkyl)(C0^alkyl) substituents; or hetaryl-C0-ι oalkyb hetaryl-C2-ιoalkenyb or hetaryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -©(Co^alkyl), Ci-ioalkyl, C2. loalkenyb C2-ιoalkynyb haloCι-ι0alkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CON(C0-4alkyl)(C0-4alkyl), -SO2N(C0-4alkyl)(C0- alkyl) or -N(Co-4alkyl)(Co-4alkyl) substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι- 6alkyl)aminoCi.6alkyb mono(aryl)aminoCι-6alkyb di(aryl)aminod-6alkyb or -N(Ci-6alkyl)-Ci.6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Ci-ioalkyl, C2-ιoalkenyl, C2-ιoalkynyb haloC i-i oalkyb haloC2-ιoalkenyb haloC -ι oalkynyb -COOH, Cι-4alkoxycarbonyb -CON(C0- alkyl)(Co-4alkyl), -SO2N(C0-4alkyl)(C0-4alkyl) or -N(C0- alkyl)(C0-4alkyl) substituents; and [74] nl, n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2.
[75] In a fourth aspect, an intermediate compound of this invention is represented by Formula III:
III or a pharmaceutically acceptable salt thereof, wherein:
[76] R and R3 are each independently Co-ioalkyb C2-ιoalkenyb C2-ιoalkynyb
Cι-ιoalkoxyCι-ιoalkyb Ci-ioalkoxyd-ioalkenyb CM0alkoxyC2-ι oalkynyb Ci- loalkylthioCi-ioalkyb Cι-ι0alkylthioC2-ιoalkenyb Cι-ιoalkylthioC2-ιoalkynyb cycloC3- 8alkyb cycloC3-8alkenyb cycloC3-8alkylCι-ι oalkyb cycloC3.8alkenylCι-ι0alkyb cycloC3. 8alkylC2-ι0alkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3-8alkylC2-ιoalkynyb cycloC3- 8alkenylC2-ιoalkynyb heterocyclyl-Co-ιoalkyb heterocyclyl-C2-ι0alkenyb heterocyclyl-C2. loalkynyb Cι-ι0alkylcarbonyb C2-ιoalkenylcarbonyb C2- loalkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι-ιoalkyb monoCi- 6alkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR71R81, or -NR71R81 substituents; or aryl-Co-i oalkyb aryl-C2-ι0alkenyb or aryl-C2- loalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Cι-ι0alkyb C2-ιoalkenyb C2-ι0alkynyb haloCj. loalkyb haloC2.ιoalkenyb haloC2-ι oalkynyb -COOH, Cι-4alkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; or heteroaryl-Co-ioalkyl, heteroaryl-C2-ιoalkenyl, or heteroaryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, CM oalkyb C2. loalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb halod-ioalkynyb -COOH, Cι-4alkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; 7 1
[77] or 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 Cι-6alkyl, halo, cyano, nitro, -OR71, -SO2NR71R81 or -NR71R81 substituents;
[78] G1 is -OR72, -SR72, -NR72R82(R9)n5, or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or in the case of-NR72R82(R9)n5, R72 and R82 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, Cι-ι0alkoxy, -SO2NR73R83 or -NR73R83 substituents;
[79] Z is -aryl-, -arylalkyl-, -aryloxy- -oxyaryl-, -arylalkenyl-,
-alkenylaryl- -hetaryl-, -hetarylalkyl-, -alkylhetaryl- -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is optionally substituted with R68; [80] Q1 is Co-6alkyb -OR75, -NR75R85(R95)n6, -CO2R75, -CONR75R85,
-(C=S)OR75, -(C=O)SR75, -NO2, -CN, halo, -S(O)n6R75, -SO2NR75R85, -NR75(C=NR775)NR7775R85, -NR75(C=NR775)OR7775, -NR75(C=NR775)SR7775, -O(C=O)OR75, -O(C=O)NR75R85, -O(C=O)SR75, -S(C=O)OR75, -S(C=O)NR75R85, -S(C=O)SR75, -NR75(C=O)NR775R85, or -NR75(C=S)NR775R85; in the case of -NR75R85(R95)n6, R75 and R85 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, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR R or -NR76R86 substituents;
[81] R4b and R5b are each independently a Co-ioalkyb C2-!oalkenyb C2. loalkynyb d-ιoalkoxyCι-ιoalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ιoalkoxyC2.ι oalkynyb Ci- loalkylthioCi-ioalkyb Ci.ioalkylthioC2-ioalkenyb Cι-ιoalkylthioC2-ιoalkynyb cycloC3- 8alkyb cycloC3.8alkenyb cycloC3-8alkylCι-ιoalkyb cycloC3.8alkenylCι-ι oalkyb cycloC , 8alkylC2. loalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC -8alkylC2-ι oalkynyb cycloC3. alkenylC2- loalkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C2- loalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci-ioalkyl, C2- loalkenyb C -ιoalkynyb haloC 1-1 oalkyb halod-ioalkenyb haloC2-ιoalkynyb -COOH, C alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or hetaryl-Co-ioalkyl, hetaryl-C2-ιoalkenyb or hetaryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, C\. loalkyl, C2-ιoalkenyb d-ioalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, C alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or mono(Ci-6alkyl)aminoCi-6alkyb di(Cι-6alkyl)aminoCι-6alkyb mono(aryl)aminoCι- 6alkyb di(aryl)aminoCι-6alkyb or -N(Cι-6alkyl)-Cι.6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Cj. loalkyl, C2-ιoalkenyb C2-ιoalkynyb haloCMoalkyb haloC2.ιoalkenyb haloC2-ιoalkynyb -COOH, CMalkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or R4b with R5b, taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, any of which is optionally substituted with R69; or R4b with R5b, 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 ; [82] R67, R68, and R69 is a halo, -OR78, -NR78R88(R98)n7, -CO2R78,
-CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, C0-ι0alkyb C2-ι0alkenyb C2. loalkynyb Cι-ι0alkoxyCι-ι oalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ι0alkoxyC2.ι 0alkynyb Ci- loalkylthioCi-ioalkyb Cι-ιoalkylthioC2-ιoalkenyb Cι-ιoalkylthioC2-ι oalkynyb cycloC3- 8alkyb cycloC -8alkenyb cycloC3-8alkylCι-ι oalkyb cycloC3-8alkenylCι-ιoalkyb cycloC3- 8alkylC2- loalkenyb cycloC3.8alkenylC2-ιoalkenyb cycloC3-8alkylC2-ι oalkynyb cycloC3. 8alkenylC2.ι0alkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C2-ι0alkenyb or heterocyclyl-C2.ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, -SO2NR778R888 or -NR778R888 substituents; or aryl-Co- loalkyl, aryl-C _ιoalkenyb or aryl-C2_ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, Ci-ioalkyl, C2. loalkenyb C2-ιoalkynyb haloCi-i oalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, CMalkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or hetaryl-Co- loalkyl, hetaryl-C2-ioalkenyb or hetaryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, C- loalkyl, C2.ιoalkenyb C2-ιoalkynyb haloCι-ι0alkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, C alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι-6alkyl)aminoCι-6alkyb mono(aryl)aminoCι-6alkyb di(aryl)aminoCι-6alkyb -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, Cι-ιoalkyb C2-ιoalkenyb C2.ιoalkynyb haloCι-ι0alkyb haloC2-ιoalkenyb haloC2-i0alkynyb -COOH, Cι-4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or in the case of -NR78R88(R98)n7, R78 and R88 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, -SO2NR778R888 or -NR778R888 substituents; [83] R7, R71, R72, R73, R74, R75, R775, R7775, R76, R77, R78, R778, R8, R81, R82,
R83, R85, R86, R87, R88, R888, R9, R95, and R98 are each independently C0-ι oalkyb C2. loalkenyb C2-ι0alkynyb Ci-ioalkoxyd-i oalkyb Cι-ι0alkoxyC2-ι0alkenyb Ci-ioalkoxyd- loalkynyb Ci-ioalkylthioCi-i oalkyb Cι-ιoalkylthioC2-ιoalkenyb Cι-ιoalkylthioC2- loalkynyb cycloC -8alkyb cycloC3.8alkenyb cycloC3-8alkylCι-ιoalkyb cycloC3- 8alkenylCι-ι oalkyb cycloC -8alkylC2-ιoalkenyb cycloC .8alkenylC2-ιoalkenyb cycloC . 8alkylC2. i oalkynyb cycloC3.8alkenylC2. i oalkynyb heterocyclyl-C0. ι oalkyb heterocyclyl-C2-ιoalkenyb heterocyclyl-C2-ι oalkynyb Cι-ιoalkylcarbonyb C2. loalkenylcarbonyb C2-ιoalkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι- loalkyl, monod-όalkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ι0alkoxy, -SO2N(C0- alkyl)(C0- alkyl) or -N(Co-4alkyl)(C0.4alkyl) substituents; aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -©(Co^alkyl), Ci-ioalkyl, C2-ιoalkenyb C2_ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2. loalkynyb -COOH, CMalkoxycarbonyb -CON(C0.4alkyl)(C0-ιoalkyl), -SO2N(C0- 4alkyl)(Co-4alkyl) or -N(Co- alkyl)(Co-4alkyl) substituents; or hetaryl-Co-ioalkyb hetaryl-C2-ιoalkenyb or hetaryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), CM oalkyb C2. loalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, CMalkoxycarbonyb -CON(C0-4alkyl)(C0-4alkyl), -SO2N(C0-4alkyl)(C0-4alkyl) or -N(Co-4alkyl)(Co-4alkyl) substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι- 6alkyl)aminoCι-6alkyb mono(aryl)aminoCι-6alkyb di(aryl)aminoCι-6alkyb or -N(Cι-6alkyl)-Cι.6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Ci-ioalkyl, C2-ιoalkenyb C2.ιoalkynyb haloCi-ioalkyb haloC-ioalkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CON(C0.4alkyl)(Co- alkyl), -SO2N(C0- alkyl)(C0-4alkyl) or -N(C0-4alkyl)(C0- alkyl) substituents; and [84] n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2. [85] The compounds of the present invention include compounds represented by Formula I above, or a pharmaceutically acceptable salt thereof, and
[86] 1) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; or
[87] 2) wherein X is imidazolyl or triazolyb or
[88] 3) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents, and Q is
-CO2H or -CO2R75; or
[89] 4) wherein Y is oxygen; or
[90] 5) wherein Y is oxygen and X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; or
[91] 6) wherein Y is oxygen and X is imidazolyl or triazolyb or
[92] 7) wherein Y is oxygen and X is imidazolyl or triazolyl and Q1 is
-CO2H or -CO2R75; or
[93] 8) wherein Y is oxygen and R4a and R5a are each hydrogen; or
[94] 9) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1, R2 and R3 are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Ci-ioalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0. ealkyl, -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0. i oalkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, or R4b with R5 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 R69; or R4a with R5a, or R4b with R5b 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 R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ιOalkyl; or [95] 10) wherein X is imidazolyl or triazolyb R1 is hydrogen, R2 and R3 are each independently C0-ιoalkyl; G1 is -NR72R82; or G1 and R3 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 R67 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, hydroxy, nitro, Ci-ioalkoxy, -SO2NR7 R83 or -NR73R83 substituents; Y is oxygen; Q1 is -CO2R75 or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0-ioalkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5 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 R69; and R6a and R6b are each hydrogen; or
[96] 11) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1, R2 and R3 are each independently C0.ιoalkyl; G1 is -NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0. 6alkyl, -CO2R75, or -CONR75R85; R4a and R5a are each hydrogen; R4b and R5b are each independently a Co- 1 oalkyb any of which is optionally substituted with R69; or R4b with R5b 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 R69; or R4b with R5b 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 9; or [97] 12) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1, R2 and R3 are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 optionally is substituted with an R72 substituent; or R72 and R82 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, Ci-ioalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0. ealkyl, -CO2R75, or -CONR75R85; R4b and R5b are each independently Ctwsalkyl, or R4b with R5b taken together with the respective carbon atom to which they are attached form a 3-10 membered saturated ring; R4a and R5a are each independently a Co-ioalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, wherein said ring is optionally substituted with R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or Co-ioalkyl; or [98] 13) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R , R and R are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 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, hydroxy, nitro, Cι-,oalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0- βalkyl, -CO2R75, or -CONR75R85; R4a and R5a are each independently a C0-ι0alkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, wherein said ring is optionally substituted with R69; or R4a with R5a 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ι0alkyl; and R4b with R5b taken together with the respective carbon atom to which they are attached form a cyclopropyb cyclobutyb cyclopentyb or cyclohexyl ring; or [99] 14) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1, R2 and R3 are each independently C0-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Ci.ioalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0. 6alkyb -CO2R75, or -CONR75R85; R4a and R5a are each independently a C0-ι0alkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, wherein said ring is optionally substituted with R69; or R4a with R5a 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 R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ι0alkyl; and R4b and R5b are both ethyl or are both methyl or are independently ethyl or methyl; or [100] 15) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R substituents; R , R and R are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Ci-,oalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; R4a, R4b, R5a, and R are each independently a Co-ioalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or Co-ioalkyl; and Q1 is -CO2R75; or [101] 16) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1, R and R are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Ci-ioalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; R4a, R4b, R5a, and R5b are each independently a Co-ioalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5", or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or Co-ioalkyl; and Q1 is -CO2H; or
[102] 17) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1, R2 and R3 are each independently Co-ioalkyl; Y is oxygen; Q1 is Co-6alkyb -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0-ι0alkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or Co-ioalkyl; and G1 is di(Cι-6alkyl)amino; or [103] 18) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1, R and R 1 7S are each independently Co-ioalkyl; Y is oxygen; Q is Co-6alkyb -CO2R , or -CONR75R85; R4 , R4b, R5 , and R5b are each independently a Co-ioalkyl, any of which • 77 is optionally substituted with one or more independent halo, cyano, nitro, -OR , -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, or R4 with R5b 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 R69; or R4a with R5a, or R4 with R5b 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 9; and R a and R6 are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ι0alkyl; and G1 is dimethylamino, ethylmethylamino, diethylamino, or isopropylmethylamino; or [104] 19) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1 is 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0-6alkyb -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0-ι0alkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a , or R4b with R50 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ι0alkyl; and R2 and R3 are each independently hydrogen, methyl, or ethyl; or
[105] 20) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1 and R3 are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 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, hydroxy, nitro, Ci-ioalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0. 6alkyl, -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0- i oalkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a , or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-10alkyl; R2 is hydrogen; 1 1 and G and R taken together with the carbon atom to which they are attached form
0-3 wherein • is the carbon to which they are attached; or G1 and R3 taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, any of which is
optionally substituted by 1-10 independent R67 substituents; or [106] 21) wherein X is imidazole; or
[107] 22) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R is Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 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, nitro, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0-6alkyb -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a Co-ioalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a , or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ι0alkyl; and R2 is hydrogen and R3 is methyl; or
[108] 23) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1 is Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic 77 saturated ring or heterocyclic unsaturated ring optionally is substituted with an R substituent; or R72 and R82 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, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0.6alkyb -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0-ι0alkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ι0alkyl; and R2 is hydrogen and R3 is ethyl; or [109] 24) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1 is Co-ioalkyl; 1 77 87 1 1
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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0-6alkyb -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0-ι0alkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 9; and R a and R are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO NR78R88, or Co_10alkyl; and R2 is hydrogen and R3 are both methyl; or [110] 25) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent and R are each independently C0-ιoalkyl; G1 is -NR72R82; or G1 and R3 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 R67 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, hydroxy, nitro, Cι-,oalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0. βalkyl, -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0- loalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a , or R4b with R5 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ι0alkyl; R2 is hydrogen; and G and R taken together with the carbon atom to which they are attached form 0-3 wherein • is the carbon to which they are attached, or
G1 and R3 taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, any of which is
optionally substituted by 1-10 independent R67 substituents; and n2, n3, and n4 are each 1 and Z is aryl; or
[111] 26) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1 and R3 are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 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, hydroxy, nitro, d-ioalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0. 6alkyl, -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0. loalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a , or R4b with R5 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 R69; or R4a with R5a, or R4b with R5 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ι0alkyl; R2 is hydrogen; and G1 and R3 taken together with the carbon atom to which they are attached form 0-3 wherein • is the carbon to which they are attached, or
G1 and R3 taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, any of which is
optionally substituted by 1-10 independent R67 substituents; n2 is 1; n3 and n4 are each 0; and Z is aryl; or
[112] 27) wherein Z is aryl or aryloxy or oxyaryl; or
[113] 28) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R substituents; R and R are ι 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 R67 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, hydroxy, nitro, Cι-10alkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is -CO2R75; R4a, R4b, R5a, and R5b are each independently a Co-ioalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)π7R78, -SO2NR78R88, or C0-ι0alkyl; R2 is hydrogen; and G1 and R3 taken together with the carbon atom to which they are attached form
o-3 wherein • is the carbon to which they are attached, or
G1 and R3 taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, any of which is
optionally substituted by 1-10 independent R67 substituents; and n2, n3, and n4 are each 1 and Z is aryl; and n3 is 0; or
[114] 29) wherein 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; G1 is -NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Cι-ιoalkoxy, -SO2NR73R83 or -NR7 R83 substituents; Y is oxygen; Q1 is -CO2H; R4a, R4b, R5a, and R5b are each independently a C0-ι oalkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a ; or R4b with R5b 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 R69; or R4 with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ioalkyl; R2 is hydrogen; and G1 and R3 taken together with the carbon atom to which they are attached form
0-3 wherein • is the carbon to which they are attached, or
or G and R taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, any of which is
optionally substituted by 1-10 independent R67 substituents; and n2, n3, and n4 are each 1 and Z is aryl; and n3 is 0; or
[115] 30) wherein X is imidazolyl or triazolyb R1 is hydrogen; G1 is 77 87 1 1
-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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is -CO2R75 or -CONR75R85; R4a, R , R5a, and R5b are each independently a Co-ioalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each hydrogen; R2 is hydrogen; and R3 is methyl; or [116] 31) wherein X is imidazolyl or triazolyb R1 is hydrogen; G1 is
-NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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]-ι0alkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is -CO2R75 or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a Co-i oalkyb any of which is optionally 77 77 87 substituted with one or more independent halo, cyano, nitro, -OR , -SO2NR R or -NR77R87 substituents; or R4a with R5a, or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each hydrogen; R2 is hydrogen; and R is ethyl; or [117] 32) wherein X is imidazolyl or triazolyb R1 is hydrogen; G1 is 77 87 1 1
-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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is -CO2R75 or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a Co-ioalkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a , or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each hydrogen; and R and R3 are methyl; or
[118] 33) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1 and R3 are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 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, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0. ealkyl, -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0- loalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a , or R4b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ι0alkyl; R2 is hydrogen; and G1 and R3 taken together with the carbon atom to which they are attached form
0-3 wherein • is the carbon to which they are attached, or 1 1
G and R taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, any of which is
optionally substituted by 1-10 independent R67 substituents; nl and n2 are each 1; and Z is aryl; or
[119] 34) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1 and R3 are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 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, hydroxy, nitro, Ci-ioalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0. 6alkyl, -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a C0. i oalkyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a, or R4b 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 R69; or R4a with R5a, or R4b with R5 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-ι0alkyl; R2 is hydrogen; 1 1 and G and R taken together with the carbon atom to which they are attached form
0-3 wherein • is the carbon to which they are attached, or G1 and R3 taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, any of which is
optionally substituted by 1-10 independent R67 substituents; nl and n2 are each 1; n3 and n4 are each 0; and Z is aryl; or
[120] 35) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1 and R3 are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; R4a, R4b, R5a, and R5b are each independently a Co-ioalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or Co-ioalkyl; R2 is hydrogen; and G1 and R3 taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, or G1 and R3 taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, any of which is
optionally substituted by 1-10 independent R67 substituents; nl and n2 are each 1; Z is aryl; and Q1 is -CO2R75; or
[121] 36) wherein X is hetaryb imidazolyl, or triazolyb any of which is optionally substituted with one or more independent R66 substituents; R1 and R3 are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Ci-ioalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; R4a, R4b, R5a, and R are each independently a Co-ioalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a or R4b with R5b 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 R69; or R4a with R5 , or R4b with R5b 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 R69; and R6a and R6b are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or Co-ioalkyl; R2 is hydrogen; and G1 and R3 taken together with the carbon atom to which they are attached form
0-3 wherein • is the carbon to which they are attached, or 1 1
G and R, taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, any of which is
optionally substituted by 1-10 independent R67 substituents; nl and n2 are each 1; Z is aryl; and Q1 is -CO2H; and wherein, in each case, the other variables are as defined above for Formula I.
[122] The compounds of the present invention include:
[123] 3-[6-(2-Dimethylamino-l-imidazol-l-yl-propyl)-naphthalen-2-yloxy]-
2,2-dimethyl-propionic acid;
[124] 2-[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2- yloxymethyl]-2-ethyl-butyric acid;
[125] 1 -[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2- yloxymethyl]-cyclopropanecarboxylic acid;
[126] 1 - [6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2- yloxymethyl]-cyclobutanecarboxylic acid;
[127] 1 -[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2- yloxymethyl]-cyclopentanecarboxylic acid;
[128] 1 -[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2- yloxymethyl]-cyclohexanecarboxylic acid;
[129] 1 - {6-[ 1 -Imidazol- 1 -yl-2-(isopropylmethylamino)-propyl]-naphthalen-
2-yloxymethyl} -cyclopentanecarboxylic acid;
[130] 3-[6-(2-Diethylamino-l-imidazol-l-yl-propyl)-naphthalen-2-yloxy]-
2,2-dimethyl-propionic acid; [131] 3- {6-[ 1 -Imidazol- 1 -yl-2-(isopropylmethylamino)-propyl]-naphthalen-
2-yloxy} -2,2-dimethyl-ρropionic acid;
[132] 3- {6-[2-(Ethyl-methyl-amino)- 1 -imidazol- 1 -yl-propyl]-naphthalen-2- yloxy} -2,2-dimethyl-propionic acid;
[133] 3-[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2-yloxy]-
2,2-dimethyl-propionamide;
[ 134] 3 -[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2-yloxy]-
2,2,N-trimethyl-propionamide;
[135] 3-[6-(2-Dimethylamino-l -imidazol- 1 -yl-propyl)-naphthalen-2-yloxy]-
2,2,N,N-tetramethyl-propionamide;
[136] 3-[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-butyl)-naphthalen-2-yloxy] -
2,2-dimethyl-propionic acid;
[137] 4-[6-(2-Dimethylamino-l -imidazol- 1 -yl-propyl)-naphthalen-2- yloxymethyl]-benzoic acid;
[138] 3-[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2- yloxymethyl]-benzoic acid;
[139] 4-[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2- yloxymethyl] -benzamide;
[ 140] 4-[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2- yloxymethyl]-N-methyl-benzamide;
[141] 4-[6-(2-Dimethylamino-l-imidazol-l-yl-propyl)-naphthalen-2- yloxymethyl]-N,N-dimethyl-benzamide; and [142] l-[(6-Benzyloxy-naphthalen-2-yl)-(l-methyl-pyrrolidin-2-yl)-methyl]- lH-imidazole.
[143] Unless otherwise stated, the connections of compound name moieties are at the rightmost recited moiety. That is, the substituent name starts with a terminal moiety, continues with any bridging moieties, and ends with the connecting moiety. For example, hetarylthioCι-4alkyl has a heteroaryl group connected through a thio sulfur to a Cι-4 alkyl that connects to the chemical species bearing the substituent.
[144] As used herein, for example, "Co- alkyl" is used to mean an alkyl having 0-4 carbons - that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration. An alkyl having no carbon is hydrogen when the alkyl is a terminal group. An alkyl having no carbon is a direct bond when the alkyl is a bridging
(connecting) group.
[145] In all embodiments of this invention, the term "alkyl" includes both branched and straight chain alkyl groups. Typical alkyl groups are methyl, ethyl, n- propyl, isopropyb w-butyb -fec-butyb isobutyb tert-butyb «-pentyb isopentyb «-hexyb
«-heptyb isooctyb nonyb decyb undecyb dodecyb tetradecyb hexadecyb octadecyb eicosyl and the like.
[146] The term "halo" refers to fluoro, chloro, bromo or iodo.
[147] The term "haloalkyl" refers to an alkyl group substituted with one or more halo groups, for example chlorom ethyl, 2-bromoethyb 3-iodopropyb trifluoromethyb perfluoropropyb 8-chlorononyl and the like.
[148] The term "cycloalkyl" refers to a cyclic aliphatic ring structure, optionally substituted with alkyl, hydroxy and halo, such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, 2-hydroxycyclopentyb cyclohexyb 4- chlorocyclohexyb cycloheptyb cyclooctyl and the like.
[149] The term "alkylcarbonyloxyalkyl" refers to an ester moiety, for example acetoxymethyl, «-butyryloxyethyl and the like.
[150] The term "alkynylcarbonyl" refers to an alkynylketo functionality, for example propynoyl and the like.
[151] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, for example hydroxymethyb 2,3-dihydroxybutyl and the like. [152] The term "alkylsulfonylalkyl" refers to an alkyl group substituted with an alkylsulfonyl moiety, for example mesylmethyb isopropylsulfonylethyl and the like.
[153] The term "alkylsulfonyl" refers to a sulfonyl moiety substituted with an alkyl group, for example mesyl, H-propylsulfonyl and the like.
[154] The term "acetylaminoalkyl" refers to an alkyl group substituted with an amide moiety, for example acetylaminomethyl and the like.
[155] The term "acetylaminoalkenyl" refers to an alkenyl group substituted with an amide moiety, for example 2-(acetylamino)vinyl and the like.
[156] The term "alkenyl" refers to an ethylenically unsaturated hydrocarbon group, straight or branched chain, having 1 or 2 ethylenic bonds, for example vinyl, allyl, 1-butenyl, 2-butenyl, isopropenyb 2-pentenyl and the like.
[157] The term "haloalkenyl" refers to an alkenyl group substituted with one or more halo groups.
[158] The term "cycloalkenyl" refers to a cyclic aliphatic ring structure, optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyb cyclopentenyb cyclohexenyb 1,4-cyclohexadienyl and the like.
[159] The term "alkynyl" refers to an unsaturated hydrocarbon group, straight or branched, having 1 or 2 acetylenic bonds, for example ethynyb propargyl and the like.
[160] The term "haloalkynyl" refers to an alkynyl group substituted with one or more halo groups.
[161] The term "alkylcarbonyl" refers to an alkylketo functionality, for example acetyl, n-butyryl and the like.
[162] The term "alkenylcarbonyl" refers to an alkenylketo functionality, for example, propenoyl and the like.
[163] The term "aryl" refers to phenyl or naphthyl which may be optionally substituted. Typical aryl substituents include, but are not limited to, phenyl, 4- chlorophenyl, 4-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-dimethoxyρhenyb
4-(trifluoromethyl)phenyl and 2-iodo-4-methylphenyb [164] The terms "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. Examples of hetaryls include, but are not limited to, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, 4-, or 5-pyrimidinyb pyridazinyb triazolyb tetrazolyb imidazolyl, 2- or 3-thienyb 2- or 3-furyb pyrrolyb oxazolyb isoxazolyb thiazolyb isothiazolyb oxadiazolyb thiadiazolyb quinolyb isoquinolyb benzimidazolyb benzotriazolyb benzofuranyb and benzothienyb The heterocyclic ring may be optionally substituted with up to two substituents.
[165] The terms "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. Examples of 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)propyb 4-phenylbutyb 4-(4- chlorophenyl)butyb 4-(2-methylphenyl)butyb 4-(2,4-dichlorophenyl)butyb 4-(2- methoxphenyl)butyl and 10-phenyldecyl.
[166] The terms "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.
[167] The terms "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.
[168] The terms "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.
[169] The terms "aryl-oxy" or "aryloxy" are used to describe a terminal aryl group attached to a bridging oxygen atom. Typical aryl-oxy groups include phenoxy,
3,4-dichlorophenoxy and the like.
[170] The terms "aryl-oxyalkyl" or "aryloxyalkyl" are used to describe a group wherein an alkyl group is substituted with an aryl-oxy group, for example pentafluorophenoxymethyl and the like.
[171] The terms "hetaryl-oxy" or "heteroaryl-oxy" or "hetaryloxy" or
"heteroaryloxy" are used to describe a terminal hetaryl group attached to a bridging oxygen atom. Typical hetaryl-oxy groups include 4,6-dimethoxypyrimidin-2-yloxy and the like.
[ 172] The terms "hetarylalkyl" or "heteroarylalkyl" or "hetaryl-alkyl" or
"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.
[173] The terms "hetarylalkenyl" or "heteroarylalkenyl" or "hetaryl-alkenyl" or "heteroaryl-alkenyl" are used to describe a group wherein the alkenyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, forming a bridging portion of the heteroaralkenyl moiety, for example 3-(4-pyridyl)-
1-propenyl.
[174] The terms "hetarylalkynyl" or "heteroarylalkynyl" or
"hetaryl-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
4-(2-thienyl)- 1 -butynyl.
[ 175] The term "heterocyclyl" refers to a substituted or unsubstituted 3-10 membered saturated ring containing one, two or three heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a bicyclic ring system containing up to 10 atoms including at least one heteroatom selected from oxygen, nitrogen and sulfur wherein the ring containing the heteroatom is saturated. Examples of heterocyclyls include, but are not limited to, tetrahydrofuranyb tetrahydrofuryb pyrrolidinyb piperidinyb 4-pyranyb tetrahydropyranyb thiolanyb moφholinyb piperazinyb dioxolanyb dioxanyb indolinyl and 5-methyl-6-chromanyb
[176] The terms "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.
[177] The terms "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-moφholinyl-l-propenyl.
[178] The terms "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
[179] The term "carboxylalkyl" includes both branched and straight chain alkyl groups as defined hereinbefore attached to a carboxyl (-COOH) group.
[180] The term "carboxylalkenyl" includes both branched and straight chain alkenyl groups as defined hereinbefore attached to a carboxyl (-COOH) group.
[181] The term "carboxylalkynyl" includes both branched and straight chain alkynyl groups as defined hereinbefore attached to a carboxyl (-COOH) group.
[182] The term "carboxylcycloalkyl" refers to a carboxyl (-COOH) group attached to a cyclic aliphatic ring structure as defined hereinbefore.
[183] The term "carboxylcycloalkenyl" refers to a carboxyl (-COOH) group attached to a cyclic aliphatic ring structure having 1 or 2 ethylenic bonds as defined hereinbefore.
[184] The terms "cycloalkylalkyl" or "cycloalkyl-alkyl" refer to a cycloalkyl group as defined hereinbefore attached to an alkyl group, for example cyclopropylmethyl, cyclohexylethyl and the like.
[185] The terms "cycloalkylalkenyl" or "cycloalkyl-alkenyl" refer to a cycloalkyl group as defined hereinbefore attached to an alkenyl group, for example cyclohexylvinyl, cycloheptylallyl and the like. [186] The terms "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.
[187] The terms "cycloalkenylalkyl" or "cycloalkenyl-alkyl" refer to a cycloalkenyl group as defined hereinbefore attached to an alkyl group, for example 2-
(cyclopenten-l-yl)ethyl and the like.
[188] The terms "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.
[189] The terms "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.
[190] The term "carboxylcycloalkylalkyl" refers to a carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkyl group as defined hereinbefore.
[191] The term "carboxylcycloalkylalkenyl" refers to a carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkenyl group as defined hereinbefore.
[192] The term "carboxylcycloalkylalkynyl" refers to a carboxyl (-COOH) group attached to the cycloalkyl ring portion of a cycloalkylalkynyl group as defined hereinbefore.
[193] The term "carboxylcycloalkenylalkyl" refers to a carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkyl group as defined hereinbefore.
[194] The term "carboxylcycloalkenylalkenyl" refers to a carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkenyl group as defined hereinbefore.
[195] The term "carboxylcycloalkenylalkynyl" refers to a carboxyl (-COOH) group attached to the cycloalkenyl ring portion of a cycloalkenylalkynyl group as defined hereinbefore.
[196] The term "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. [197] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy and the like.
[198] The term "alkoxyalkoxyalkyl" refers to an alkyl group substituted with an alkoxy moiety which is in turn substituted with a second alkoxy moiety, for example methoxymethoxymethyl, isopropoxymethoxyethyl and the like.
[199] The term "alkylthio" includes both branched and straight chain alkyl groups attached to a bridging sulfur atom, for example methylthio.
[200] The term "haloalkylthio" refers to an alkylthio group substituted with one or more halo groups, for example trifluoromethylthio.
[201] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, for example isopropoxymethyb
[202] The term "alkoxyalkenyl" refers to an alkenyl group substituted with an alkoxy group, for example 3-methoxyallyl.
[203] The term "alkoxyalkynyl" refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyb
[204] The term "alkoxycarbonylalkyl" refers to a straight chain or branched alkyl substituted with an alkoxycarbonyb for example ethoxycarbonylmethyb 2-
(methoxycarbonyl)propyl and the like.
[205] The term "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.
[206] The term "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.
[207] The term "haloalkoxyalkyl" refers to a straight chain or branched alkyl as defined hereinbefore substituted with a haloalkoxy, for example 2- chloroethoxymethyb trifluoromethoxymethyl and the like.
[208] The term "haloalkoxyalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with a haloalkoxy, for example 4-
(chloromethoxy)-2-butenyl and the like.
[209] The term "haloalkoxyalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted with a haloalkoxy, for example 4-(2- fTuoroethoxy)-2-butynyl and the like. [210] The term "alkylthioalkyl" refers to a straight chain or branched alkyl as defined hereinbefore substituted with an alkylthio group, for example methylthiomethyb 3-(isobutylthio)heptyl and the like.
[211] The term "alkylthioalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an alkylthio group, for example 4-
(methylthio)-2-butenyl and the like.
[212] The term "alkylthioalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an alkylthio group, for example 4-
(ethylthio)-2-butynyl and the like.
[213] The term "haloalkylthioalkyl" refers to a straight chain or branched alkyl as defined hereinbefore substituted with an haloalkylthio group, for example 2- chloroethylthiomethyb trifluoromethylthiomethyl and the like.
[214] The term "haloalkylthioalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an haloalkylthio group, for example
4-(chloromethylthio)-2-butenyl and the like.
[215] The term "haloalkylthioalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted with a haloalkylthio group, for example 4-
(2-fluoroethylthio)-2-butynyl and the like.
[216] The term "dialkoxyphosphorylalkyl" refers to two straight chain or branched alkoxy groups as defined hereinbefore attached to a pentavalent phosphorous atom, containing an oxo substituent, which is in turn attached to an alkyl, for example diethoxyphosphorylmethyl.
[217] The term "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.
[218] Compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. [219] Within the enantiomers of the compounds, both the syn and anti isomers involving the X and G1 substituent show activity. It was found that the syn isomer is more active than the anti isomer and thus, is the preferred isomer. Furthermore, it is preferable that there be dual chiral centers at the X and G1 attachment positions.
[220] The invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula I in combination with a pharmaceutically acceptable carrier.
[221 ] Preferably 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). [222] Moreover, within this prefeπed embodiment, the invention encompasses a pharmaceutical composition for the treatment of disease by inhibiting the cytochrome P450RAI enzyme, resulting in regulation and differentiating of epithelial cells, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above (or a pharmaceutically acceptable salt thereof).
[223] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When 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-ethylmoφholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, moφholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylameine, trimethylamine, tripropylamine, tromethamine and the like.
[224] When the compound of the present invention is basic, its coπesponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Prefeπed are citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Particularly preferred are formic and hydrochloric acid. [225] The pharmaceutical compositions of the present invention comprise a compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
[226] In practice, the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
[227] Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
[228] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
[229] In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, 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. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
[230] A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
[231] For example, a formulation intended for the oral administration to humans may contain from about 0.5mg 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. [232] Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. [233] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against 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. [234] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
[235] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
[236] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
[237] Generally, dosage levels on the order of from about O.Olmg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above- indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, dermatological diseases and cancers may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day. [238] . It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. BIOLOGICAL ASSAYS
[239] The efficacy of the Examples of the invention, compounds of Formula
I, as inhibitors of Cyp26 were demonstrated and confirmed by a number of pharmacological in vitro assays. The following assays and their respective methods have been carried out with the compounds according to the invention. Activity possessed by compounds of Formula I may be demonstrated in vivo. In vitro biochemical assay [240] The compounds ofFormula I can inhibit CYP26 activity. In vitro biochemical assay was performed using microsomal preparations from T47D cells induced to express CYP26. Enzymatic activity was measured as the conversion of the radiolabeled substrate to its metabolites, 4-OH RA (4-hydroxy all trans retinoic acid) and 4-oxo RA (4-oxy retinoic acid) by separation on a C18 HPLC column. Inhibition of CYP26 activity in the presence of variable naphthalene analog concentrations was used to determine the IC5o's. Methods Microsomal Preparation from T47D cells [241 ] T47D cells were grown in RPMI 1640 containing 10% FBS and 1 %
P/S, plated and treated 16-25 hours later with 5uM atRA and allowed to incubate for an additional 48 hours before cell harvest. Cells were washed twice with lxPBS and scraped from plates. Cells were pelleted and resuspended in homogenization buffer (0.1M Tris-Cl, pH7.4, 0.1M DTT, 0.2mM EDTA, 1.15% w/v KCb O.lmM PMSF and 20% v/v glycerol). Microsomes were prepared by differential centrifugation of homogenized cells. Homogenate was spun at 17,000g and the supernatant spun again at 100,000g. The pellet was resuspended in 25mM potassium phosphate, pH7.4, 20% v/v glycerol and stored at -80 °C. HPLC Biochemical CYP26 Assay [242] Enzymatic assays were performed in a total volume of 100 μL in a reaction mixture composed of 100 mM Tris pH7.4, 150 mM KCb 10 mM MgCl2, 2 mM NADPH, 40 nM 3H-atRA, and varying concentrations of novel compound dissolved in DMSO such that the concentration in the reaction is 1% final, and 20 μg 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 μL of acetonitrile, mixed and spun at 10,000g for 10 min. The supernatant was removed and atRA and metabolites were separated on a C18 Waters Spherisorb column with an in line radiometric detector with a flow rate of 1 mL/min at detected at 350 nM. The gradient used was the mixture of 60 mM Ammonium Acetate, pH 5.2/30%CH3OH, solvent A and solvent B (CH3OH). A 30-50% gradient of CH3OH was run for 8 min followed by a 50-99% CH3OH gradient for 4 min and 99% CH3OH for 2 min. Inhibition of Cell Proliferation in vitro
[243] The novel naphthalene analogs inhibit the proliferation of breast cancer and prostate cells in vitro. Experiments were conducted on T47D breast cancer cell line and on the AT6.1 rat prostate adenocarcinoma cell line. Methods [244] T47D cells were grown in RPMI 1640 containing 10% FBS and
1%P/S. Cells were plated into 96 well culture plates (2000 cells per well) in 100 μL of same medium. After attachment for 16-24 h, the vehicle (DMSO), or atRA alone (at concentrations of 1 nM to 1 μM), 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-Glo™ (Promega).
[245] The method described above was also used for AT6.1 cells except that cells were plated at 1500 cells per well and treatment was performed once with measure of the decrease in cell proliferation 72 h post treatment. AT6.1 cells were grown in RPMI 1640 containing 10% FBS, 1% P/S and 250 nM Dexamethasone. CYP3A4 Assay [246] Enzymatic assays to measure the inhibition of CYP3A4 activity was determined in lOOul volume in a 96 well plate by the use of a fluorescence substrate (BD, Gentest). Compounds were tested at various concentrations in a reaction that contained 200mM Potassium Phosphate buffer, pH 7.4, 200mM NADPH and 50uM 7-benzyloxy-4-(trifluoromethyl)-coumarin. The reaction was incubated at 37°C for 45 minutes followed by the addition of 37ul of 0.5M Tris Base to terminate the reaction. The plates were read at excitation emission of 405/535nm, respectively. [247] All Examples showed inhibition of Cyp26. The following Examples showed efficacy and activity by inhibiting Cyp26 in the biochemical assay in the range from about 5μM to below lOnM. The most preferred Examples are selective towards Cyp26. It is prefeπed that the ratio of the IC5o value of Cyp3A4 activity to the IC5o value of Cyp26 activity of 10:1 or greater, or 100:1 or greater. EXPERIMENTAL
[248] In Schemes 1-29 below showing how to synthesize compounds of this invention and Tables 1-5 below listing various representative compounds of this invention, the following abbreviations are used: Me for methyl, Et for ethyl, 'Pr or 'Pr for isopropyb n-Bu for «-butyb t-Bu for tert-butyb Ac for acetyb Ph for phenyl, 4C1- Ph or (4Cl)Ph for 4-chlorophenyb 4Me-Ph or (4Me)Ph for 4-methyιphenyb (p- CH3O)Ph for/Mnethoxyphenyi, (p-NO2)Ph for -nitrophenyb 4Br-Ph or (4Br)Ph for 4-bromophenyb 2-CF3-Ph or (2CF3)Ph for 2-trifluoromethylphenyb DMAP for 4- (dimethylamino)pyridine, DCC for 1,3-dicyclohexylcarbodiimide, EDC for l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBt for 1- hydroxybenzotriazole, HO At for l-hydroxy-7-azabenzotriazole, CDI for 1,1'- carbonyldiimidazole, CDT for l,l'-carbonyldi(l,2,4-triazole), DEAD for diethlyl azodicarboxylate, DIAD for diisopropyl azodicarboxylate, DBAD for di-tert-butyl azodicarboxylate, FBS for fetal bovine serum, P/S for Penicillin/Streptomycin, DTT for dithiothreitol, EDTA for ethylenediaminetetraacetic acid, PMSF for phenylmethanesulfonyl fluoride, Tris for trimethamine, NADPH for beta nicotinamide adenine dinucleotide phosphate reduced, and Bn for benzyl. [249] The following schematic processes show certain compounds which are useful as intermediates in the formation of Cyp26 inhibiting Examples. Such intermediates are included in the present invention.
[250] The compounds of Formula I of this invention and the intermediates used in the synthesis of the compounds of this invention were prepared according to the following methods. Method A was used when preparing compounds of Formula I-A [compounds of Formula I where R1 equals H; R4a, R5a, R6a and R6b equal H; and Y equals O] as shown below in Scheme 1 : Method A:
Scheme 1
I-A where X, R R\ G1, (Z)n2, (CR ,44bDτR>'bDx)n3, and (Q')n4, are as defined previously for compound of Formula I.
[251] In a typical preparation, a compound of Formula II was reacted with
CDI or CDT in a suitable solvent. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; and chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHC13). If desired, mixtures of these solvents were used. The preferred solvent was dependent upon the substrates employed and was selected according to the properties of the substrates. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 22 °C and about 80 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. [252] The compounds of Formula II of Scheme 1 were prepared as shown below in Scheme 2. Scheme 2
II where R2, R3, G1, (Z)n2, (CR4bR5b)n3, and (Q')n4, are as defined previously for compound of Formula I.
[253] In a typical preparation of a compound of Formula II, a compound of
Formula III was treated with a suitable reducing agent in a suitable solvent, where the suitable reducing agents included boron-derived reducing agents such as, but not limited to, sodium borohydride, lithium borohydride, borane, and the like; aluminum- derived reducing agents such as lithium aluminum hydride, alane, lithium tri-tert- butoxy-aluminum hydride, and the like; hydrogenation over a metal catalyst such as palladium on carbon. The preferred reducing agent was sodium borohydride. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; alcoholic solvents such as methanob ethanob isopropanob and the like; however, 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 desired.
[254] The compounds of Formula III of Scheme 2 were prepared as shown below in Scheme 3: IV
(CR4bR5b)n3 (V) (Q1) n4
III where R2, R3, G1, (Z)n2, (CR4bR5b)n3, and (Q1)n4, are as defined previously for compound of Formula I, and A1 = OH, OTs, OMs or halo.
[255] In a typical preparation of a compound of Formula III (when A1 = halo in compound of Formula V), a compound of Formula IV was reacted with a compound of Formula V (where A1 = halo) in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as methylene chloride (CH2C12) or chloroform (CHC13). If desired, mixtures of these solvents may be used. The preferred solvent was DMF or CH3CN. Suitable bases for use in the above process included, but were not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases were used. The preferred base was sodium hydride or potassium 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. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures could be used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, one equivalent of base was used per equivalent of starting material of compound of Formula IV.
[256] In a typical preparation of a compound of Formula III (when A1 = OH in compound of Formula V), a compound of Formula IV was reacted with a compound of Formula V (where A1 = OH) in a suitable solvent in the presence suitable reactants. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as methylene chloride (CH2C12) or chloroform (CHC13). If desired, mixtures of these solvents were used, however, the preferred solvent was THF. Suitable reactants for use in the above process included, but were not limited to, triphenylphosphine and an azodicarboxylate (DIAD, DEAD, DBAD). The desired reactants were triphenylphosphine and DIAD. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, one equivalent of triphenylphospine, DIAD and compound of formula V was used per equivalent of starting material of compound of Formula IN. The compounds of Formula V were generally commercially available or were prepared according to known procedures (Tetrahedron Letters, 1999, 40, 5467-5470). [257] The compounds of Formula IV of Scheme 3 were prepared as shown below in Scheme 4: Scheme 4
IV VI where R2, R3, and G1 are as defined previously for compound of Formula I, and A2 = Cι-6alkyl or aryl-Cι.6alkyb
[258] In a typical preparation of a compound of Formula IV, a compound of
Formula VI was reacted with suitable conditions to afford the conversion of A2 to H. Suitable reagents for use in the conversion of A2 to H in the above process included but were not limited to, pyridine-HCl, BBr3, A1C13, and HBr/ Acetic acid. The preferred condition was treatment of compound of Formula VI with 48%aqHBr/acetic acid. The above process was carried out at temperatures between about 50 °C and about 150 °C. Preferably, the reaction was carried out between 100 °C and about 120 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, an excess of 48%aqHBr/acetic acid was used per equivalent of starting material of compound of Formula VIII.
[259] The compounds of Formula VI of Scheme 4 were prepared as shown below in Scheme 5: Scheme 5
VII VI
7 1 1 7 where R , R , and G are as defined previously for compound of Formula I, A = Ci- 6alkyl or aryl-Cι.6alkyb and A3 = suitable leaving group such as halo. [260] In a typical preparation of a compound of Formula VI, a compound of
Formula VII was reacted with H-G1 in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like; aromatic solvents such as benzene and toluene; acetonitrile; chlorinated solvents such as methylene chloride (CH2C12), carbon tetrachloride (CC14) or chloroform (CHC13). If desired, mixtures of these solvents were used, however the preferred solvent was a mixture of methanol/chloroform. Suitable catalysts for use in the above process included, but were not limited to, tetrabutylammonium iodide or 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. If desired, mixtures of these bases were used, however, the preferred base was diisopropylethylamine or H- G1 when G1 = NR7R8. The above process were carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 100 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. The catalyst was normally used in lower amounts than that of both compounds of Formula VII and H-G1. H-G1 is generally commercially available or was prepared according to known procedures. Compound of Formula VII was prepared according to known literature procedures (Sonawane, H. R.; et. al. Tetrahedron, 1994, 50 (4), 1243-1260). [261] The compounds of Formula VII of Scheme 5 were prepared as shown below in Scheme 6a: Scheme 6a
VIII VII
wherein R and R are as defined previously for compound of Formula I, A = Cι- 6alkyl or aryl-Cι-6alkyb and A3 and A5 = suitable leaving groups such as halo, and A4 = halo or OTf.
[262] In a typical preparation of a compound of Formula VII, a compound of
Formula VIII was reacted with a suitable organolithium reagent or metal catalyst followed by reaction with a compound of Formula 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. Preferably, the reaction was carried out between 0 °C and about 100 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures could used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. The magnesium was normally used in excess amounts than that of compounds of Formula VIH. Compounds of Formula VIII and IX were generally commercially available or were prepared according to known procedures.
[263] Alternatively, the compounds of Formula VI of Scheme 5 were prepared as shown below in Scheme 6b: Scheme 6b
VIII VI
where R , R and G are as defined previously for compound of Formula I, A = Ci- 6alkyl or aryl-Cι-6alkyb and A4 = halo or OTf.
[264] In a typical preparation of a compound of Formula Vb a compound of
Formula VIII was reacted with a suitable organolithium reagent or metal catalyst followed by reaction with a compound of Formula X in a suitable solvent. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like; aromatic solvents such as benzene and toluene. If desired, mixtures of these solvents were used, however the preferred solvent was THF. Suitable organolithium or metal species for use in the above process included, but were not limited to organolithium species such as tt-butyl lithium or tert-butyl lithium; magnesium. The prefeπed organolithium species was tert-butyl lithium. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between -78 °C and about 50 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Compounds of Formula VIII and X were generally commercially available or were prepared according to known procedures.
[265] The compounds of Formula III of this invention and the intermediates used in the synthesis of the compounds of this invention were prepared according to the following methods.
[266] Method B was used when preparing compounds of Formula III as shown below in Scheme 7:
Method B: Scheme 7
III where R2, R3, G1, (Z)n2, (CR4bR5b)n3, and (Q')n4, are as defined previously for compound of Formula I, and A = halo.
[267] In a typical preparation, according to Method B, Scheme 7, of a compound of Formula HI, 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 (CH2C12), carbon tetrachloride (CC14) or chloroform (CHC13). If desired, mixtures of these solvents were used, however the preferred solvent was a mixture of acetonitrile. Suitable catalysts for use in the above process include, but are not limited to, tetrabutylammonium iodide or 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. If desired, mixtures of these bases were used, 1 1 7 8 however, the preferred base was diisopropylethylamine or H-G when G = NR R . The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 100 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. The catalyst was normally used in lower amounts than that of both compounds of Formula XI and H-G1. H-G1 is generally commercially available or was prepared according to known procedures. [268] The compounds of Formula XI of Scheme 7 was prepared as shown below in Scheme 8:
Scheme 8
XI where R , R , (Z)n2, (CR >4br R>5b )n , and (Q )n4, are as defined previously for compound of Formula I, and A = halo.
[269] In a typical preparation of a compound of Formula XI, a compound of
Formula XII was reacted with a suitable halogenating agent in a suitable solvent. Suitable halogenating agents include Br2, Cl2, N-bromosuccinimide, N- chlorosuccinimide, sulfuryl chloride, and CuBr2. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), dioxane, glyme, diethyl ether, and the like; acetonitrile; chlorinated solvents such as methylene chloride (CH2C12) or chloroform (CHC1 ). If desired, mixtures of these solvents were used, however, the preferred solvent was dioxane. The above process was carried out at temperatures between about -78 °C and about 150 °C. Preferably, the reaction was carried out between 80 °C and about 150 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, two equivalents of CuBr2 were used per equivalent of starting material of compound of Formula XII. [270] The compounds of Formula XII of Scheme 8 were prepared as shown below in Scheme 9: Scheme 9
XIII
(CR4bR5 )n3 (V) 1 (Q1 ) n4 ~w& .
XII where R2, R3, (Z)n2, (CR4bR5b)n , and (Q1)n4, are as defined previously for compound of Formula I, and A = halo or OH.
[271] In a typical preparation of a compound of Formula XII (when A i1 i •n compound of Formula V equals halo), a compound of Formula XIII was reacted with a compound of Formula V (where A1 = halo) in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as methylene chloride (CH2C12) or chloroform (CHC13). If desired, mixtures of these solvents were used. The preferred solvent was DMF or CH3CN. Suitable bases for use in the above process included, but were not limited to,metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases were used. The preferred base was sodium hydride or potassium 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. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, one equivalent of base was used per equivalent of starting material of compound of Formula XIH.
[272] In a typical preparation of a compound of Formula XII (when A1 = OH in compound of Formula V), a compound of Formula XIII was reacted with a compound of Formula V (where A1 = OH) in a suitable solvent in the presence suitable reactants. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as methylene chloride (CH2C12) or chloroform (CHC13). If desired, mixtures of these solvents were used, however, the prefeπed solvent was THF. Suitable reactants for use in the above process included, but were not limited to, triphenylphosphine and an azodicarboxylate (DIAD, DEAD, DBAD). The desired reactants were triphenylphosphine and DIAD. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, one equivalent of triphenylphospine, DIAD and compound of formula V was used per equivalent of starting material of compound of Formula XIII. The compounds of Formula V and XIII were generally commercially available or were prepared according to known procedures.
[273] Method C was used when preparing compounds of Formula I-B
[compounds of Formula I where R1 equals H, n1 = 1, R4a, R5a, R6a and R6b equal H, Y equals O, n4 = 1, and Q1 = CO2H] as shown below in Scheme 10: Method C: Scheme 10
where X, R , R , G , (Z)n2, and (CR ,4bDrR,5 :'bD Λ)n3 are as defined previously for compound of Formula 1, and R7 = alkyl.
[274] In a typical preparation, according to Method C, of a compound of
Formula I-B [compounds of Formula I where R1 equals H, n1 = 1, R4a, R5a, R6a and R6b equal H, Y equals O, n4 = 1, and Q1 = CO2H], a compound of Formula I-A [compounds of Formula I where R1 equals H, n1 = 1, R4a, R5a, R6a and R6b equal H, Y equals O, n4 = 1, and Q1 = CO2R7] was reacted under basic or acidic conditions 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; 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-
(HA6)n7 as shown below in Scheme 11 : Method D: Scheme 11
(HA°)n7
I-(HA°)n7 where X, R1, R2, R3, G1, Y, (CR4aR5a)nι, (Z)n2, (CR4bR5b)n3, (Q R6a and R6b are as defined previously for compound of Formula I, n = 1 or 2, and A = counteranion to H including, for example, chloride or formate.
[276] In a typical preparation, according to Method D, of a compound of
Formula I-(HA6)n7, a compound of Formula I was reacted with a suitable acid, HA6, in a suitable solvent. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether and the like; acetonitrile; water; alcoholic solvents such as methanob ethanob and the like. If desired, mixtures of these solvents were used, however, the prefeπed solvents were either diethyl ether, methanob or water. HA6 is a suitable pharmaceutically acceptable acid from which the respective mono or disalt of compound of Formula I- (HA6)n7 was formed. The above process was carried out at temperatures between about 0 °C and about 60 °C. Preferably, the reaction was carried out between 0 °C and about 25 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Acids HA6 were generally commercially available or was be prepared according to known procedures.
[277] Method E was used when preparing compounds of Formula I-D
[compounds of Formula I where R1 equals H, n1 = 1, R4a, R5a, R6a and R6b equal H, Y equals O, n4 = 1, and Q1 = CONR7R8] as shown below in Scheme 12:
Method E: Scheme 12
where X, R2, R3, G1, (Z)n2, R7, R8 and (CR4bR5b)n3 are as defined previously for compound of Formula I.
[278] In a typical preparation, according to Method E, of a compound of
Formula I-D [compounds of Formula I where R1 equals H, n1 = 1, R4a, R5a, R6a and R6b equal H, Y equals O, n4 = 1, and Q1 = CONR7R8], a compound of Formula I-B [compounds of Formula I where R1 equals H, n1 = 1, R4a, R5a, R6a and R6b equal H, Y equals O, n4 = 1, and Q1 = CO2H] was reacted under suitable conditions with HNR7R8 to afford compound of formula I-D. 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 HNR7R8. The preferred reaction condition was reaction of compound of Formula I-B with CDI followed by treatment with HNR7R8. 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 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.
[279] Additionally, a typical preparation, according to Method E, of a compound of Formula I-D [compounds of Formula I where R1 equals H, n1 = 1, R4a, R5a, R6a and R6b equal H, Y equals O, n4 = 1, and Q1 = CONR7R8], a compound of Formula I-B [compounds of Formula I where R1 equals H, n1 = 1, R4a, R5a, R6a and R6b equal H, Y equals O, n4 = 1, and Q1 = CO2H] was reacted under typical amide formation conditions to afford compound of Formula I-D. Suitable conditions include but are not limited to treating compound of Formula I-B and HNR7R8 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. 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. Additionally, other suitable reaction conditions for the conversion of CO2H to 7 R
CONR R can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: New York, 1999, pp 1941-1949.
[280] Alternatively, the compounds of Formula II of Scheme 1 was prepared as shown in Scheme 13. Scheme 13
II where R2, R3, A3, G1, (Z)n2, (CR4bR5b)n3, and (Q1)n4, are as defined previously for compound of Formula I.
[281] In a typical preparation of a compound of Formula II, a compound of
Formula XI was treated with a suitable reducing agent in a suitable solvent, where the suitable reducing agents included boron-derived reducing agents such as but not limited to sodium borohydride, lithium borohydride, borane, and the like; aluminum- derived reducing agents such as lithium aluminum hydride, alane, lithium tri-tert- butoxy-aluminum hydride, and the like; hydrogenation over a metal catalyst such as palladium on carbon. However, the preferred reducing agent was sodium borohydride. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; alcoholic solvents such as methanob ethanob isopropanob and the like; however, 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. Once the reduction of the ketone to the alcohol was deemed complete, the reaction was then charged with HNR7R8 in a suitable solvent. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH CN); chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHC13); alcoholic solvents such as methanob ethanob isopropanob and the like. If desired, mixtures of these solvents were used; however, 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 60 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. HNR7R8 was used in excess in relation to compound of Formula XI and was generally commercially available or was prepared according to known procedures. [282] Alternatively, Method F was used when preparing compounds of
Formula I-A [compounds of Formula I where R1 equals H, R4a, R5a, R6a and R6b equal H, and Y equals O] as shown below in Scheme 14. Method F Scheme 14
XIV
I-A where X, R2, R3, G1, (Z)n2, (CR4bR5b)n , and (Q')n4, are as defined previously for compound of Formula I, and A1 = OH, OTs, OMs or halo.
[283] In a typical preparation, according to Method F, of a compound of
Formula I-A [compound of Formula I where R1 equals H, R 4a , r R>5a , R ,6oaa and R > 60bD equal H, and Y equals O], a compound of Formula XIV was reacted with a compound of Formula V (where A1 = halo) in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as methylene chloride (CH2C12) or chloroform (CHC1 ). If desired, mixtures of these solvents were used. The prefeπed solvent was DMF or CH3CN. Suitable bases for use in the above process included, but were not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases were used. The prefeπed 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. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, one equivalent of base was used per equivalent of starting material of compound of Formula X1N. [284] In a typical preparation of a compound of Formula I-A [compound of
Formula I where R1 equals H, R4a, R5a, R6a and R6b equal H, and Y equals O], a compound of Formula X1N was reacted with a compound of Formula V (where A1 = OH) in a suitable solvent in the presence suitable reactants. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CΝ); chlorinated solvents such as methylene chloride (CH2C12) or chloroform (CHC1 ). If desired, mixtures of these solvents were used, however, the preferred solvent was THF. Suitable reactants for use in the above process included, but were not limited to, triphenylphosphine and an azodicarboxylate (DIAD, DEAD, DBAD). The desired reactants were triphenylphosphine and DIAD. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, one equivalent of triphenylphospine, DIAD and compound of formula V was used per equivalent of starting material of compound of Formula XIV. The compounds of Formula V were generally commercially available or were prepared according to known procedures. [285] The compounds of Formula XIV of Scheme 14 were prepared as shown below in Scheme 15: Scheme 15
XIV XV
where X, R2, R3, and G1 are as defined previously for compound of Formula I. [286] In a typical preparation of a compound of Formula XIV, a compound of Formula XV was reacted with CDI or CDT in a suitable solvent. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; chlorinated solvents such as methylene chloride (CH2C12) or chloroform (CHC13). If desired, mixtures of these solvents were used. The prefeπed solvent was dependent upon the substrates employed and was selected according to the properties of the substrates. The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 22 °C and about 80 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired.
[287] The compounds of Formula XV of Scheme 15 were prepared as shown in Scheme 16. Scheme 16
IV xv where R ,2 , R , and G are as defined previously for compound of Formula I. [288] In a typical preparation of a compound of Formula XV, a compound of
Formula 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 The above process was carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out between 0 °C and about 20 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired.
[289] The compounds of Formula I-Z (compound of Formula I where R1
OH, X = heteroaryl, Y = O, nl = 1, and R , 6a , R ,6b , R ,4aa and R 5a H) are prepared as shown in Scheme 17 following Reactions A-C. Scheme 17 Reaction A -<R")d *■ M X (R9<>)d XVI XVII
Reaction B III
XVIII
Reaction C
I-Z
where X, R2, R3, G1, (Z)n2, (CR4bR5b)n3, and (Q')n4, are as defined previously for compound of Formula I and A1 = suitable exchangeable group such as halo or triflate or a deprotonateable hydrogen atom, d = 0 or 1, R99 = suitable protecting group such as benzyl or trityl, and M = metal including lithium and magnesium; the salt of the metal shown by M can include for example, a metal halide such as magnesium chloride, magnesium bromide, or magnesium triflate.
[290] In a typical preparation of an intermediate of Formula XVII via
Reaction A, a compound of Formula XVI is treated with a suitable alkyl-lithium species or magnesium metal. Examples of such alkyl-lithium species include n- butyllithium, -?ec-butyllithium, or tert-butyllithium. Examples of the alkyl- magnesium halide include ethylmagnesium bromide or methylmagnesium chloride. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), diethyl ether, dioxane and the like; saturated hydrocarbons such as hexane, pentane, and the like; aromatic hydrocarbons such as benzene or toluene. The above process is carried out at temperatures between about - 40 °C and about 70 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used although higher or lower amounts are used if desired. In the case of the alkyl- lithium, the alkyl-lithium is used in an amount of 1 to 3 moles, preferably 1 to 1.5 moles per one mole of the starting material XVI.
[291] Following Reaction B, in a typical preparation of a compound of
Formula 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. The above process is carried out at temperatures between about -40 °C and about 70 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used although higher or lower amounts are used if desired.
[292] According to Reaction C, in a typical preparation of compound of
Formula I-Z, compound of Formula XVIII is treated under suitable deprotection conditions to afford the transformation of R99 into a hydrogen atom. For example, when d = 1 and R99 is a trityl group, deprotection is afforded under acidic or hydrogenolysis conditions. Examples of acidic conditions include the use of organic acids such as formic, acetic, or trifluoroacetic acid or the use of inorganic acids such as hydrochloric acid. Suitable solvents include alcohols, ethers, or halogenated solvents. The above process is carried out at temperatures between about -40 °C and about 70 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used although higher or lower amounts are used if desired. Examples of A1-X-(R99)d include, but are not limited to, the following heteroaryl groups:
[293] Alternatively, the compounds of Formula XVII of Scheme 17 are prepared as shown below in Scheme 18: Scheme 18
VIII
XIX
XVII
where X, R2, R3, G1, (Z)n2, (CR4bR5b)n3, and (Q')n4 are as defined previously for compound of Formula I and A2 = Cι-6alkyl or aryl-Cι.6alkyb and A4 = halo or OTf, d = 0 or 1, R99 = suitable protecting group such as benzyl or trityl. [294] In a typical preparation of a compound of Formula XVH, 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. Substantially, equimolar amounts of reactants are used although higher or lower amounts were used if desired. Compounds of Formula VIII and XIX are generally commercially available or is prepared according to known procedures. For example, compounds of Formula XIX is prepared according to the methods described in Scheme 6b by replacing compound of Formula VIII with compound of Formula XVI. [295] The optically pure isomers, compounds of Formula F and I", are prepared as shown in Scheme 19 from (±)-syn-isomer, compound of Formula (±)-I- syn:
Scheme 19
(±) (I-syn)
+
where X, R1, R2, R3, G1, (CR4aR5a)nl, (Z)n2, (CR4bR5b)n3, R6a, R6b, and (Q')n4 are as defined previously for compound of Formula I.
[296] In a typical preparation of optically resolved syn-compounds of
Formula I' and I", (±)-syn-compound of Formula I is subjected to liquid chromatography method equipped with a chiral column or diastereomer salt method using an optically active acid or optically active base. When the desired enantiomers of Formula F or I" are obtained in their respective diastereomeric salt form (compounds of Formula I-(HA6)n7) from the diastereomer salt method where HA6 = optically pure acid such as tartaric or mandelic acid), the enantiomers of Formula F and I" are obtained in their respective free forms by neutralization of the reaction mixture. Additionally, compounds of Formula F and I" as diastereomeric salts are treated with HCI under suitable conditions to afford compounds of Formula I-(HA6)n7 where n7 = 2 and HA6 = HCI.
[297] The optically pure isomers, compounds of Formula F" and I"", are prepared as shown in Scheme 20 from (±)-anti-compound of Formula I: Scheme 20
(±) (I-anti)
+
where X, R1, R2, R3, G1, (CR4aR5a)nι, (Z)n2, (CR4bR5b)n3, R6a, R6b, and (Q')n4 are as defined previously for compound of Formula I.
[298] In a typical preparation of optically resolved anti-compounds of
Formula F" and I"", (±)-anti-compound of Formula I is subjected to liquid chromatography method equipped with a chiral column or diastereomer salt method using an optically active acid or optically active base. When the desired enantiomers of Formula F" and I"" are obtained in their respective diastereomeric salt form (compounds of Formula I-(HA6)n7) from the diastereomer salt method where HA6 = optically pure acid such asrtartaric or mandelic acid), the enantiomers of Formula F" and I"" are obtained in their respective free forms by neutralization of the reaction mixture. Additionally, compounds of Formula F" and I"" as diastereomeric salts are treated with HCI under suitable conditions to afford compounds of Formula I- (HA6)n7 where n7 = 2 and HA6 = HCI.
[299] The optically pure isomers, compounds of Formula IIF and III", are prepared as shown in Scheme 21 from (±)-compound of Formula III. Scheme 21
I II'
HI"
where R2, R3, (Z)n2, (CR4bR5b)n3, and (Q')n4 are as defined previously for compound of Formula I and G1 = NR72R82.
[300] In a typical preparation of optically resolved compounds of Formula
IIF and III", (±)-compound of Formula III is subjected to liquid chromatography method equipped with a chiral column or diastereomer salt method using an optically active acid. When the desired enantiomers of Formula IIF and III" are obtained in their respective diastereomeric salt form, compounds of Formula IIF and III" are obtained in their respective free non-salt forms by neutralization of the reaction mixture followed by extraction into a suitable organic solvent such as EtOAc or methylene chloride.
[301] The optically pure isomers, compounds of Formula IF and II", are prepared as shown in Scheme 22 from (±)-syn-compound of Formula II. Scheme 22
(±) (II-syn)
+
where R2, R3, (Z)n2, (CR4bR5b)n3, and (Q*)n4 are as defined previously for compound of Formula I and G1 = NR72R82.
[302] In a typical preparation of optically resolved syn-compounds of
Formula IF and II", (±)-syn-compound of Formula II is subjected to liquid chromatography method equipped with a chiral column or diastereomer salt method using an optically active acid or optically active base. When the desired enantiomers of Formula IF or II" are obtained in their respective diastereomeric salt form (compounds of Formula I-HA6 from the diastereomer salt method where HA6 = optically pure acid such as tartaric or mandelic acid), the enantiomers of Formula IF and II" are obtained in their respective free forms by neutralization of the reaction mixture.
[303] The optically pure isomers, compounds of Formula IF" and II"", are prepared as shown in Scheme 23 from (±)-anti-compound of Formula II. Scheme 23
(±) (II-anti)
+
,2 ,4br»5b- where R , R , (Z)n2, (CR R )n , and (Q )„4 are as defined previously for compound of Formula I and G1 = NR72R82.
[304] In a typical preparation of optically resolved anti-compounds of
Formula IF" and II"", (±)-anti-compound of Formula II is subjected to liquid chromatography method equipped with a chiral column or diastereomer salt method using an optically active acid or optically active base. When the desired enantiomers of Formula IF" and II"" are obtained in their respective diastereomeric salt form (compounds of Formula I-HA6 from the diastereomer salt method where HA6 = optically pure acid such as tartaric or mandelic acid), the enantiomers of Formula IF" and II"" are obtained in their respective free forms by neutralization of the reaction mixture.
[305] The compounds of Formula IF, II", IF", and II"" of this invention and the intermediates used in the synthesis of the compounds of this invention were prepared according Method G as shown below in Schemes 24 - 27. The optically pure compound of Formula IF is prepared as shown in Scheme 24 from optically pure compound of Formula Ha':
Method G: Scheme 24
where R2, R3, (Z)n2, (CR4bR5b)n3, and (Q')n4 are as defined previously for compound of Formula I; G1 = NR72R82 and Z55 = chiral auxiliary.
[306] In a typical preparation of compound of Formula IF , a compound of
Formula Ila' (where OZ55 is taken together to equal O-(C=O)-R*, where R* is the chiral auxiliary) is reacted under typical reaction conditions to afford hydrolysis of an ester to an alcohol. Typical hydrolysis conditions involve 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.
[307] The optically pure compound of Formula II" is prepared as shown in
Scheme 25 from optically pure compound of Formula Ha":
Scheme 25
where R2, R3, (Z)n2, (CR4bR5b)n3, and (Q')n4 are as defined previously for compound of Formula I; G1 = NR72R82 and Z55 = chiral auxiliary.
[308] In a typical preparation of compound of Formula II", a compound of
Formula Ila" (where OZ55 is taken together to equal O-(C=O)-R*, where R* is the chiral auxiliary) is reacted under typical reaction conditions to afford hydrolysis of an ester to an alcohol. Typical hydrolysis conditions involve 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. [309] The optically pure compound of Formula IF ' ' is prepared as shown in
Scheme 26 from optically pure compound of Formula lib': Scheme 26
where R ,2 , R , (Z)n2, (CR >4b- Rr> 5b- )n3, and (Q )n4 are as defined previously for compound of Formula I; G1 = NR72R82 and Z55 = chiral auxiliary.
[310] In a typical preparation of compound of Formula IF", a compound of
Formula lib' (where OZ55 is taken together to equal O-(C=O)-R*, where R* is the chiral auxiliary) is reacted under typical reaction conditions to afford hydrolysis of an ester to an alcohol. Typical hydrolysis conditions involve 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.
[311] The optically pure compound of Formula II"" is prepared as shown in
Scheme 27 from optically pure compound of Formula lib": Scheme 27
where R2, R3, (Z)n2, (CR4bR5b)n3, and (Q!)n4 are as defined previously for compound of Formula I; G1 = NR72R82 and Z55 = chiral auxiliary.
[312] In a typical preparation of compound of Formula IF"', a compound of
Formula lib" (where OZ55 is taken together to equal O-(C=O)-R*, where R* is the chiral auxiliary) is reacted under typical reaction conditions to afford hydrolysis of an ester to an alcohol. Typical hydrolysis conditions involve 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.
[313] The optically pure compounds of Formula Ila' and Ila' ' are prepared as shown in Scheme 28 from the transformation of (±)-syn-compound of Formula II, into diastereomeric compounds of Formula Ila' and Ila", respectively: Scheme 28
(±) (II-syn)
where R2, R , (Z)n2, (CR4bR5b)n3, and (Q!)n4 are as defined previously for compound of Formula I; G1 = NR72R82 and Z55 = chiral auxiliary.
[314] In a typical preparation of diastereomerically resolved syn-compounds of Formula Ila' and Ila", (±)-syn-compound of Formula II is reacted with a suitable chiral auxiliary and then the respective diastereomers, compounds of Formula Ila' and Ila", are separated by known methods such as recrystallization or chromatography. A typical reaction involves the treatment of (±)-syn-compound of Formula II with a suitable chiral auxiliary which contained a carboxylic acid or acid chloride moiety. Treatment of (±)-syn-compound of Formula II with an acid-based chiral auxiliary involves typical conditions for transforming an alcohol into an ester. These coupling conditions include, but are not limited to, DCC or EDC with a suitable catalyst such as DMAP, HO AT, or HOBT in a suitable solvent in the presence of a suitable base such as triethylamine or diisopropylamine. Treatment of (±)-syn-compound of Formula II with an acid chloride-based chiral auxiliary involves typical conditions for transforming an alcohol into an ester with an acid chloride such as an inert solvent and base. Typical chiral auxiliaries include, but are not limited to, suitably protected amino acid such as N-(tert-butoxycarbonyl)-L-proline, N-(tert-butoxycarbonyl)-D- proline, (R)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetic acid, (S)-(-)-α-methoxy- α-(trifluoromethyl)phenylacetic acid, (R)-(+)-α-methoxy-α- (trifluoromethyl)phenylacetyl chloride, (S)-(-)-α-methoxy-α- (trifluoromethyl)phenylacetyl chloride, (lR)-(+)-camphanic acid, (lS)-(-)camphanic acid, and (lS)-(-)-camphanic chloride. Suitable solvents for use in both of the above processes include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethyl formamide; dimethyl sulfoxide; halogenated solvents such as methylene chloride or chloroform. The above processes are carried out at temperatures between about -5 °C and about 100 °C. The above processes to produce compounds of the present invention are preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used if desired.
[315] The optically pure compounds of Formula lib' and lib" are prepared as shown in Scheme 29 from the transformation of (±)-anti-compound of Formula II, into diastereomeric compounds of Formula lib' and lib", respectively: Scheme 29
where R2, R3, (Z)n2, (CR4bR5b)n3, and (Q')n are as defined previously for compound of Formula I; G1 = NR72R82 and Z55 = chiral auxiliary. [316] In a typical preparation of diastereomerically resolved anti-compounds of Formula lib' and lib", (±)-anti-compound of Formula II is reacted with a suitable chiral auxiliary and then the respective diastereomers, compounds of Formula lib' and lib", are separated by known methods such as by recrystallization or by chromatography. A typical reaction involves the treatment of (±)-anti-compound of Formula II with a suitable chiral auxiliary which contained a carboxylic acid or acid chloride moiety. Treatment of (±)-anti-compound of Formula II with an acid-based chiral auxiliary involves typical conditions for transforming an alcohol into an ester. These coupling conditions include, but are not limited to, DCC or EDC with a suitable catalyst such as DMAP, HO AT, or HOBT in a suitable solvent in the presence of a suitable base such as triethylamine or diisopropylamine. Treatment of (±)-anti- compound of Formula II with an acid chloride-based chiral auxiliary involves typical conditions for transforming an alcohol into an ester with an acid chloride such as an inert solvent and base. Typical chiral auxiliaries include, but are not limited to, suitably protected amino acid such as N-(tert-butoxycarbonyl)-L-proline, N-(tert- butoxycarbonyl)-D-proline, (R)-(+)-α-methoxy- -(trifluoromethyl)phenylacetic acid, (S)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetic acid, (R)-(+)-α-methoxy-α- (trifluoromethyl)phenylacetyl chloride, (S)-(-)-α-methoxy-α- (trifluoromethyl)phenylacetyl chloride, (lR)-(+)-camphanic acid, (lS)-(-)camphanic acid, and (lS)-(-)-camphanic chloride. Suitable solvents for use in both of the above processes include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethyl formamide; dimethyl sulfoxide; halogenated solvents such as methylene chloride or chloroform. The above processes are carried out at temperatures between about -5 °C and about 100 °C. The above processes to produce compounds of the present invention are preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants are used if desired.
[317] The following examples are intended to illustrate and not to limit the scope of the present invention. Analytical HPLC Conditions: [318] Unless otherwise stated, all HPLC analyses were run on a Micromass system with a XTERRA MS C18 5μ 4.6 x 50mm column and detection at 254 nm. Table A below lists the mobile phase, flow rate, and pressure.
Table A
Semipreparative HPLC Conditions:
[319] Where indicated as "purified by Gilson HPLC", the compounds of interest were purified by a preparative/semipreparative Gilson HPLC workstation with a Phenomenex Luna 5μ C18 (2) 60 x 21 20MM 5μ column and Gilson 215 liquid handler (806 manometric module, 81 IC dynamic mixer, detection at 254 nm). Table B lists the gradient, flow rate, time, and pressure.
Table B
[320] Intermediate A-l (compound of Formula VI where R = CH3, R = H,
G1 = N(CH3)2, and A2 = CH3): A solution of 2-iodo-l-(6-methoxy-naphthalen-2-yl)- propan-1-one (compound of Formula VII, where R2 = CH3, R3 = H, A = 1, and A2 = CH3) (54 g, 161 mmol), dimethylamine (161 mL of a 2M solution in MeOH, 322 mmol), and diisopropylamine (28 mL, 161 mmol) in 500 mL of CHC13 and 500 mL of MeOH was stiπed at rt for 16 h. The reaction mixture was concentrated in-vacuo and partitioned between Na2CO3 (sat) and CH2CI2. The aqueous phase was extracted with CH2CI2 (4x), dried over Na2SO4 and concentrated in-vacuo. Intermediate A-l was deemed pure by 1HNMR and taken directly onto the next reaction. 'HNMR (CDCI3, 200 MHz) δ 1.31 (d, 3H, J= 7.0 Hz), 2.35 (s, 6H), 3.94 (s, 3H), 4.16 (q, 1H, J= 8.0 Hz), 7.15-8.56 (m, 6H); MS (ES) 258.0 (M+l).
[321] Intermediate A-2 (compound of Formula IV where R2 = CH3, R3 = H, and G1 = N(CH )2): A 2L rbf equipped with a reflux condensor, was charged with intermediate A-l (38 g, 148 mmol), 48% HBraq (800 mL) and glacial acetic acid (800 mL) and heated in an oil bath at 120 °C with stirring for 16 h. The reaction mixture was concentrated in-vacuo to as small a volume as possible, cooled in an ice bath and quenched with 8M NaOH. The cooled sluπy was then extracted with CH2C12 (7x). The organic layers were combined and filtered through a pad of celite. The filtrate was concentrated in-vacuo and the product was further purified by silica gel column chromatography (gradient of 5% CH3OH:CH2Cl2 with 1% Et3N per lOOmL of solvent to 10% CH3OH:CH2Cl2 with 1% Et3N per 100 mL of solvent) to afford the desired intermediate A-2 as a foamy brown solid. 'HNMR (CDC13, 200 MHz) δ 1.34 (d, 3H, J= 8.0 Hz), 2.39 (s, 6H), 4.22 (q, 1H, J= 8.0 Hz), 7.09-7.13 (m, 2H), 7.66 (d, 1H, J= 8.0 Hz), 7.82 (d, 1H, J= 8.0 Hz), 8.02 (dd, 1H, J= 2.0, 10.0 Hz), 8.52 (d, 1H, J= 2.0 Hz).
[322] Intermediate A-3 (compound of Formula VI where R = CH3, R =
CH3, A2 = CH3, and G1 = N(CH3)2): To a solution of the 2-bromo-6- methoxynaphthelene (2.37 g, 10 mmol) in THF (30 mL) at -78 °C, was charged with tBuLi (1.7 M, 11.16 mL, 20 mmol) over a period of 20 min. The reaction mixture was stiπed at -78 °C for 20 min, upon which time, neat 2-dimethylamino-2-methyl- propionitrile (1.23 g, 11.1 mmol) was added. The mixture was allowed to stir for an additional 30 min and then allowed to warm to rt. The mixture was charged with 2N H2SO4 (50 mL) and stiπed for 10 min. The THF layer was separated and the aqueous layer was extracted with ethyl acetate (2x40 mL). The aqueous layer was basified using 2N NaOH to pH 8.0 and was extracted with CH2C12 (3x40 mL). The CH2C12 extract was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give Intermediate A-3 as a pale yellow oil. MS (ES): m/z 271.96 [M+]; 1H NMR (CDC13, 400 MHz): δ 9.09 (d, J= 1.2 Hz, 1H), 8.35 (dd, J= 8.8, 4.0 Hz, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.62 (d, J= 8.8 Hz, 1H), 7.07 (dd, J= 8.8, 2.8 Hz, 1H), 7.03 (d, J= 2.8 Hz, 1H), 3.83 (s, 3H), 2.21 (s, 6H), 1.25 (s, 6H). [323] Intermediate A-4 (compound of Formula IN where R2 = CH3, R3 =
CH3, and G1 = Ν(CH3)2): A mixture of Intermediate A-3 (1.92 g, 7.11 mmol) and aq. HBr (48%, 30 mL) was charged with glacial acetic acid (30 mL) and heated to 120 °C for 16 h. The reaction mixture was cooled to rt and neutralized with 2N NaOH (up to pH 5.0) and saturated NaHCO3 (up to pH 7.0). The aqueous mixture was extracted with CH2C12 (4x40 mL) and the combined organics were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product as a brown oil. Purification of the crude product by column chromatography (10% MeOH/CH2Cl2) afforded Intermediate A-4. MS (ES): m/z 258.22 [M+H+]; 1H NMR (CDCb, 400 MHz) δ 9.17 (s, 1H), 8.39 (dd, J= 8.8, 2.0 Hz, 1H), 7.86 (d, J= 8.4 Hz, 1H), 7.63 (d, J= 8.8 Hz, 1H), 7.15 (s, 1H), 7.12 (dd, J= 8.4, 2.4 Hz, 1H), 2.29 (s, 6H), 1.34 (s, 6H).
[324] Intermediate A-5 (compound of Formula XII where R2 = CH3, R3 - H, n2 = 0, n3 = 1, R b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): A THF (160 mL) solution of l-(6-hydroxynaphthalen-2-yl)propan-l-one (10.0 g, 50.0 mmol), triphenylphosphine (20.0, 76.0 mmol), and methyl 2,2-dimethyl-3-hydroxypropionate (7.0 mL, 55.0 mmol) was evacuated, placed under a N2 arm, cooled in an ice bath and charged with DIAD (15.0 mL, 76.0 mmol) portionwise over 5 min. The mixture was allowed to warm to rt and then heated to 45 °C for 16 h. The reaction mixture was concentrated in vacuo to a dark oil and purified by silica gel column chromatography (5 to 10%) EtOAc/Hexanes). The white solids were recrystallized from hot hexanes to afford the desired Intermediate A-5. 1HNMR (CDC13, 400 MHz) δ 1.28 (t, 3H, J = 7.2 Hz), 2.33 (s, 6H), 1.38 (s, 6H), 3.12 (q, 1H, J= 7.2 Hz), 3.72 (s, 3H), 4.12 (s, 2H), 7.16 (m, 2H), 7.20 (dd, 1H, J= 2.5, 8.8 Hz), 7.76 (d, 1H, J= 8.6 Hz), 7.84 (d, 1H, J= 8.8 Hz), 8.01 (dd, 1H, J= 2.0, 8.6 Hz), 8.41 (s, 1H).
[325] Intermediate A-6 (compound of Formula XI where R2 = CH3, R3 = H, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, A3 = Br, and Q1 = CO2CH3): A 250 mL rbf containing Intermediate A-5 (8.60 g, 27.4 mmol) and CuBr2 (12.2 g, 54.7 mmol) was charged with dioxane (55 mL), evacuated, placed under a N2 atm, and heated to 110 °C for 16 h. The reaction mixture was concentrated in vacuo to a dark slurry and purified by silica gel column chromatography (5-10% EtOAc/Hexanes). The off white solids were recrystallized from hexanes/EtOAc to afford 9.36 g of Intermediate A-6 as off white solids. 1HNMR (CDC13, 400 MHz) δ 1.38 (s, 6H), 1.95 (d, 3H, J= 6.6 Hz), 3.77 (s, 3H), 4.12 (s, 2H), 5.44 (q, IH, J= 6.6 Hz), 7.16 (m, 2H), 7.21 (dd, IH, J= 2.4, 8.8 Hz), 7.77 (d, IH, J= 8.0 Hz), 7.86 (d, IH, J= 8.8 Hz), 8.03 (dd, IH, J = 2.4, 8.8 Hz), 8.49 (s, IH).
[326] Intermediate A-7 (compound of Formula XII where R2 = H, R3 = H, n2
= 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the procedures described in Intermediate A-5 above except for the substitution of l-(6-hydroxynaphthalen-2-yl)propan-l-one with l-(6-hydroxy- naphthalen-2-yl)ethanone. MS (ES) 301.0 (M+l).
[327] Intermediate A-8 (compound of Formula XI where R2 = H, R3 = H, n2
= 0, n3 - 1, R4b and R5b = CH3, n4 = 1, A3 = Br, and Q1 = CO2CH3): Intermediate A-7 (3.0 g, 9.99 mmol) and CuBr2 (4.9 g, 21.97 mmol) were dissolved in dioxane (35 ml) and heated at 100 °C for 20 h. The crude mixture was concentrated in vacuo, and water was added and extracted with CH2CI2 (3x). The organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10% EtOAc: Hexanes) to yield the desired product as a yellow solid. 1H NMR (CDC13, 400 MHz) δ 1.38 (s, 6H), 3.72 (s, 3H), 4.12 (s, 2H), 4.56 (s, 2H), 7.17-7.23 (m, 2H), 7.78 (d, IH, J= 8.8 Hz), 7.86 (d, IH, J= 9.2 Hz), 7.99 (dd, IH, J= 2.0, 6.4 Hz), 8.43 (s, IH).
[328] Intermediate A-9 (compound of Formula XII where R2 = CH3, R3 = H, n2 = 0, n3 = 1 , R4b and R5b along with the carbon to which they are attached form a cyclopentyl ring, n4 = 1, and Q1 = CO2E-): The title compound was prepared according to the procedures described for Intermediate A-5 above except for the substitution of methyl 2,2-dimethyl-3-hydroxypropionate with 1-hydroxymethyl cyclopentanecarboxylic acid ethyl ester. Η NMR (CDC13, 400 MHz) δ 1.22 (t, 3H, J = 8.0 Hz), 1.28 (t, 3H, J= 8.0 Hz), 1.72-1.82 (m, 6H), 2.19-2.22 (m, 2H), 3.11 (q, 2H, J= 8.0 Hz), 4.18 (m, 4H), 7.16-7.21 (m, 2H), 7.75 (d, 1H, J= 8.8 Hz), 7.83 (d, IH, J = 8.8 Hz), 8.00 (dd, IH, J= 2.0, 6.4 Hz), 8.40 (s, IH).
[329] intermediate A- 10 (compound of Formula XI where R2 = CH3, R3 = H, n2 = 0, n3 = 1, R4b and R5b along with the carbon to which they are attached form a cyclopentyl ring, n4 = 1, A3 = Br, and Q1 = CO2E-): The title compound was prepared according to the procedures described for Intermediate A-6 above except for the substitution of Intermediate 5 with Intermediate A-9. 1H NMR (CDC13, 400 MHz) δ 1.22 (t, 3H, J= 8.0 Hz), 1.72-1.75 (m, 6H), 1.95 (d, 3H, J= 6.4 Hz), 2.19-2.23 (m, 2H), 4.18 (q, 2H, J= 8.0 Hz), 5.44 (q, IH, J= 6.4 Hz), 7.11-7.21 (m, 2H), 7.77 (d, IH, 7= 8.8 Hz), 7.85 (d, IH, J= 8.8 Hz), 8.03 (dd, IH, 7= 2.0, 6.4 Hz), 8.48 (s, IH). [330] Intermediate A-l 1 (compound of Formula VII where R2 = CH2CH3, R3
= H, A = CI, A = CH3): The title compound was prepared as follows: A I L, three necked rbf, equipped with a N2 inlet and a reflux condenser, was charged with Mg turnings (7.70 g, 317 mmol) and dry THF (300 mL). 6-Bromo-2-methoxy- naphthalene (compound of Formula VIII where A4 = Br and A2 = CH3) (60.0 g, 253 mmol) was added portionwise over a period of 20 min. The reaction was evacuated and placed under a N2 atm and warmed gradually to 50 °C for 1 h. In another three necked flask equipped with a N2 inlet, dropping funnel and a septum was placed 2- chlorobutyryl chloride (compound of Formula IX where R2 = CH2CH , R3 = H, A3 = CI, A5 = CI) (64.0 g, 505 mmol) and dry THF (70 mL). The reaction mixture was cooled to -50 °C and the Grignard reagent as prepared above, was transfeπed by a cannula to the dropping funnel, under N2 pressure. The Grignard reagent was then added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature (rt) and stiπed for 16 h. 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 CH2CI2 (3x). The combined organic layers were washed with water, brine, dried over MgSO4 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. 1H NMR (CDCI3, 400 MHz) δ 1.11 (t, 3H, J=7.2 Hz), 2.04- 2.15 (m, IH), 2.18-2.29 (m, IH), 3.93 (s, 3H), 5.18-5.22 (m, IH), 7.16 (d, IH, 7= 2.4 Hz), 7.22 (dd, IH, 7= 6.0, 8.8 Hz), 7.79 (d, IH, 7= 8.8 Hz), 7.87 (d, IH, 7= 8.8 Hz), 8.02 (dd, IH, 7= 1.6, 8.8 Hz), 8.46 (s, IH).
[331] Intermediate A-12 (compound of Formula VI where R2 = CH2CH3, R3
= H, G1 = N(CH )2, and A2 = CH3) was prepared according to the procedures described for Intermediate A-l above except for the substitution of 2-iodo-l-(6- methoxy-naphthalen-2-yl)-propan-l-one with intermediate A-l 1. MS (ES) 271.7 (M+l). 1H NMR (CDC13, 400 MHz) δ 0.89 (t, 3H, 7= 7.4 Hz), 1.72-1.84 (m, IH), 1.91-2.02 (m, IH), 2.38 (s, 6H), 3.96 (s, 3H), 3.99-4.03 (m, IH), 7.15-7.21 (m, 2H), 7.77 (d, IH, 7= 9.0 Hz), 7.87 (d, IH, 7= 9.0 Hz), 8.07 (dd, IH, 7= 1.8, 9.6 Hz), 8.53 (s, IH).
[332] Intermediate A-13 (compound of Formula IN where R2 = CH2CH3, R3
= H, and G1 = Ν(CH3)2) was prepared according to the procedures described for Intermediate A-2 above except for the substitution of intermediate A-l with intermediate A-12. MS (ES) 258.3 (M+l).
[333] Following the general methods described hereinbefore, the following intermediates of Formula III as listed in Table 1 were prepared.
III
Table 1: Listing of Intermediates of Formula III
Compound R* R3 G' n2 Z n3 R4b Rft n4 Q1 1-1 CH3 H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 1-2 CH3 H N(CH3)2 4 Ph 0 - - 1 C02CH3 1-3 CH3 H N(CH3)2 3 Ph 0 - - 1 C02CH3 1-4 CH3 H N(CH3)2 4 Ph 1 H H 1 C02CH3 1-5 CH3 H N(CH3)2 0 - 1 CH3 CH3 1 CH3 1-6 CH3 H N(CH3)2 4 Ph 0 - - 1 OiBxi 1-7 CH3 H N(CH3)2 4 PhO 1 H H 1 C02CH3 1-8 CH3 H N(CH3)2 0 - 2 H H 1 OCH3 1-9 CH3 H N(CH3)2 4 Ph 0 - - 1 OCH3 1-10 CH3 H N(CH3)2 trans- 0 - - 0 ~ CH=CHPh 1-11 CH3 H N(CH3)2 4 Ph 0 - - CN 1-12 CH3 H N(CH3)2 4 Ph 0 - - N02 1-13 CH3 H N(CH3)2 0 - Et Et C02Et 1-14 CH3 H N(CH3)2 0 - CH2CH . ring C02Et 1-15 CH3 H N(CH3)2 0 - CH2CH2CH2 ring C02Et 1-16 CH3 H N(CH3)2 0 - CH2CH2OCH2CH2ring C02Et 1-17 CH3 H N(CH3)2 0 - CH2(CH2)3 ( ZH2 ring C02CH3 1-18 CH3 H N(CH3)2 0 - CH2(CH2)2 CH2 ring C02Et 1-19 CH3 H N(CH3)2 1 Ph 0 - - 0 - Compound R* R* G1 n2 Z n3 . R4b R5b n4 Q' 1-20 CH3 H N(CH2)20(CH2)2 ring 0 - 1 CH3 CH3 1 C02CH3 1-21 CH3 H N(Et)2 0 - 1 CH3 CH3 1 C02CH3 1-22 CH3 H N(CH3)cyclohexyl 0 - 1 CH3 CH3 1 C02CH3 1-23 CH3 H N(CH3)«-butyl 0 - 1 CH3 CH3 1 C02CH3 1-24 CH3 H N(CH3)zPr 0 - 1 CH3 CH3 1 C02CH3 1-25 CH3 H N(CH3)Ph 0 - 1 CH3 CH3 1 C02CH3 1-26 CH3 H N(CH2)4 0 - 1 CH3 CH3 1 C02CH3 1-27 CH3 CH3 N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 1-28 CH3 H N(CH3)Et 0 - 1 CH3 CH3 1 C02CH3 1-29 CH3 H N(CH3)2 0 - 0 - - 1 C02.Bu 1-30 A* 1 Ph 0 - - 0 - 1-31 Et H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 1-32 CH3 H N(CH3)ιPr 0 1 CH2(CH2)2 :CH2 ring 1 C02Et '
wherein A* = R2R3G* taken together with the carbon atom to which they are attached form:
where • is the carbon to which they are attached.
[334] General Synthetic Method A for the preparation of compounds of the Formula III: A THF (0.4 M) solution of compound of Formula IV (1 eq) (Intermediate A-2, A-4, or A-l 3), triphenylphosphine (1.1 eq), and compound of Formula V (1 eq) was evacuated, placed under a N2 atm, cooled in an ice bath and charged with DIAD (1 eq) portionwise over 5 min. The mixture was allowed to warm to rt and then heated to 45 °C for 16 h. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (gradient of 6:1 CH2C12:10% CH3OH in CH2C12 (1% Et3N) to 3:1 CH2C12:10% CH3OH in CH2C12 (1% Et3N)). [335] General Synthetic Method B for the preparation of compounds of the Formula III: An acetonitrile solution (0.5 M) of compound of Formula XI (1 eq) (Intermediate A-8 or A- 10) was charged with 1 eq. Nal and 3 eq. HG1 and allowed to stir at 40 °C for 16 h. The reaction mixture was concentrated in vacuo to a slurry and partitioned between CH2C12 and NaHCO3 (sat), and the aqueous layer extracted with CH2C12 (5 ). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient of 6:1 CH2C12:10% CH3OH in CH2C12 (1% Et3N) to 3:1 CH2C12:10% CH3OH in CH2C12 (1% Et3N)) to afford the desired compound of Formula IH.
[336] COMPOUND 1-1 (Compound of Formula III where R2 = CH3, R3 = H,
G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R = CH3, R = H, and G = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. 'HNMR (CDC13, 200 MHz) δ 1.18-1.35 (m, 9H), 3.68 (s, 3H), 4.10 (s, IH), 7.14-7.20 (m, 2H), 7.74 (d, IH, 7= 8.0 Hz), 7.84 (d, IH, J= 8.0 Hz), 7.74 (dd, IH, 7= 0.6, 4.4 Hz), 8.55 (s, IH).
[337] COMPOUND 1-2 (Compound of Formula III where R2 = CH3, R3 = H,
G1 = N(CH3)2, n2 = 1, Z = 4-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R = CH3, R = H, and G = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 1, Z = 4-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3. 'HNMR (CDCI3, 200 MHz) δ 1.30 (d, 3H, 7= 6.0 Hz), 2.33 (s, 6H), 3.91 (s, 3H), 4.15 (q, IH , 7= 6.0 Hz), 5.27 (s, 2H), 7.20-7.31 (m, IH), 7.56 (d, 2H, 7= 8.0 Hz), 7.74 (d, IH, 7= 8.4 Hz), 7.89 (d, IH, J= 8.8 Hz), 8.06-8.10 (m, 4H), 8.57 (s, IH); MS (ES) 391.9 (M+l).
[338] COMPOUND 1-3 (Compound of Formula III where R2 = CH3, R3 = H,
G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, n3 = 0, n4 = 1, and Q1 - CO2CH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IN, R2 = CH3, R3 = H, and G1 = Ν(CH3)2 and compound of Formula V, A1 = OH, n2 = 1, Z = 3-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3. 'HNMR (CDCI3, 200 MHz) δ 1.32 (d, 3H, J= 7.0 Hz), 2.36 (s, 6H), 3.94 (s, 3H), 4.18 (q, IH, 7= 6.6 Hz), 5.25 (s, 2H), 7.20-7.31 (m, IH), 7.44-7.52 (m, 2H), 7.68-7.78 (m, 2H), 7.89 (d, IH, 7= 10.0 Hz), 8.00-8.09 (m, 2H), 8.18 (s, IH), 8.56 (s, IH); MS (ES) 392.0 (M+l). [339] COMPOUND 1 -4 (Compound of Formula III where R2 = CH3, R3 = H,
G1 = N(CH3)2, n2 = 1, Z = 4-phenyl, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R = CH , R = H, and G1 = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 1, Z = 4-phenyl, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDC13, 200 MHz) δ 1.30 (d, 3H, 7= 8.0 Hz), 2.35 (s, 6H), 3.64 (s, 2H), 3.68 (s, 3H), 4.17 (q, IH, 7= 8.0 Hz ), 5.16 (s, 2H), 7.11 - 8.08 (m, 9H), 8.56 (s, IH); MS (ES) 405.9 (M+l). [340] COMPOUND 1 -5 (Compound of Formula III where R2 = CH3, R3 = H,
G1 - N(CH3)2, n2 = 0, n3 = 1, R4b and R5b - CH3, n4 = 1, and Q1 = CH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH )2 and compound of Formula V, A1 = OH, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CH3. Η NMR (CDC13, 200 MHz) δ 1.07 (s, 9H), 1.40 (d, 3H, 7= 6.2 Hz), 2.37 (s, 6H), 3.73 (s, 2H), 4.20 (q, IH, 7= 7.0 Hz), 7.11 (d, IH, 7= 2.2 Hz), 7.20 (dd, IH, 7= 2.6, 9.2 Hz). 7.47 - 7.58 (m, IH), 7.84 (d, IH, 7= 8.8 Hz), 7.88 (dd, IH, 7= 1.4, 8.2 Hz), 8.55 (s, IH).
[341] COMPOUND 1-6 (Compound of Formula III where R2 = CH3, R3 = H,
G1 = N(CH3)2, n2 = 1, Z = 4-phenyl, n3 = 0, n4 = 1, and Q1 = OtBu): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 1, Z = 4-phenyl, n3 = 0, n4 = 1, and Q1 = OtBu. 1HNMR (CDC13, 200 MHz) δ 1.30-1.36 (m, 12H), 2.35 (s, 6H), 4.17 (q, IH, 7 = 6.0 Hz), 5.14 (s, 2H), 7.01-7.07 (m, 2H), 7.24-7.30 (m, 2H), 7.36-7.41 (m, 2H), 7.73-7.90 (m, 2H), 8.05-8.10 (m, IH), 8.58 (s, IH); MS (ES) 406.0 (M+l). [342] COMPOUND 1-7 (Compound of Formula III where R2 = CH3, R3 = H,
G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 1, Z = 4-PhO, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3). 'HNMR (CDCI3, 200 MHz) δ 1.31 (d, 3H, J= 6.0 Hz), 2.34 (s, 6H), 3.80 (s, 3H), 4.17 (q, IH, 7= 6.0 Hz), 4.66 (s, 2H), 5.13 (s, 2H), 6.92-6.98 (m, 2H), 7.23-7.44 (m, 4H), 7.72-8.10 (m, 3H), 8.57 (s, IH); MS (ES)
422.0 (M+l).
[343] COMPOUND 1-8 (Compound of Formula III where R2 = CH3, R3 = H,
G' = N(CH3)2, n2 = 0, n3 = 2, R4b and R5b = H, n4 = 1, and Q1 = OCH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IN, R = CH3, R = H, and G = Ν(CH3)2 and compound of Formula V, A1 = OH, n2 = 0, n3 = 2, R4b and R5b = H, n4 = 1, and Q1 =
OCH3. MS (ES) 302.3 (M+l).
[344] COMPOUND 1-9 (Compound of Formula III where R2 = CH3, R3 = H,
G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OCH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 =
OCH3. MS (ES) 364.3 (M+l).
[345] COMPOUND 1-10 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z equals trans-CH=CHPh, n3 and n4 = 0): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 1, Z equals trans-CH=CHPh, n3 and n4 = 0.
MS (ES) 360.3 (M+l).
[346] COMPOUND 1-11 (Compound of Formula III where R2 = CH3, R3 -
H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CN): The title compound was prepared according to the General Synthetic Method A as described 1 above wherem compound of Formula IV, R = CH3, R = H, and G = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CN.
MS (ES) 359.3 (M+l).
[347] COMPOUND 1-12 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = NO2): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH )2 and compound of Formula V, A1 = OH, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 =
NO2. MS (ES) 381.3 (M+l).
[348] COMPOUND 1-13 (Compound of Formula in where R2 = CH3, R3 =
H, G' = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH2CH3, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 0, n3 = 1 , R4b and R5b = CH2CH3, n4 = 1, and Q1 = CO2Et. MS (ES) 400.3 (M+l).
[349] COMPOUND 1-14 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 370.3 (M+l).
[350] COMPOUND 1-15 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclobutyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH )2 and compound ofFormula V, A = OH, n = 0, n = 1, R and R are taken together with the carbon to which they are attached to equal a cyclobutyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 384.3 (M+l).
[351] COMPOUND 1-16 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R = CH3, R = H, and G = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, n4 = 1 , and Q1 = CO2CH3. MS (ES) 400.3 (M+l).
[352] COMPOUND 1-17 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IN, R2 = CH3, R3 = H, and G1 = Ν(CH3)2 and compound of Formula V, A1 = OH, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 412.3 (M+l).
[353] COMPOUND 1-18 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 398.2 (M+l).
[354] COMPOUND 1-19 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = Ph, n3 and n4 = 0): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 1, Z = Ph, n3 and n4 = 0. Η NMR (CDC13, 200 MHz) δ 1.32 (d, 3H, 7= 6.0 Hz), 2.37 (s, 6H), 4.21 (q, IH, 7= 6.0 Hz), 5.50 (s, 2H), 7.24-7.50 (m, 3H), 7.75 (d, 2H, 7- 10.0 Hz), 7.88 (d, 2H, 7= 8.0 Hz ), 8.04-8.09 (m, 2H), 8.58 (s, 2H); MS (ES) 334.2 (M+l).
[355] COMPOUND 1-20 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH2)2θ(CH2)2ring, n2 = 0, n3 = 1, R4b and R5 = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method B as described above wherein compound of Formula XI, R2 = CH3, R3 = H, A3 = Br, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3 and HG1 = HN(CH2)2O(CH2)2. MS (ES) 400.2 (M+l).
[356] COMPOUND 1-21 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(Et)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method B as described above wherein compound of Formula XI, R2 = CH3, R3 = H, A3 = Br, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3 and HG1 = HN(Et)2. MS (ES) 386.2 (M+l).
[357] COMPOUND 1-22 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)cyclohexyl, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method B as described above wherein compound of Formula XI, R2 = CH3, R3 = H, A3 = Br, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3 and HG1 = HN(CH3)cyclohexyl. MS (ES) 426.2 (M+l).
[358] COMPOUND 1-23 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)«-butyl, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method B as described above wherein compound of Formula XI, R2 = CH3, R3 = H, A3 = Br, n2 = 0, n3 = 1, R4b and R5 = CH3, n4 = 1, and Q1 = CO2CH3 and HG1 = HN(CH3)«-butyb MS (ES) 400.2 (M+l).
[359] COMPOUND 1-24 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)iPr, n2 - 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method B as described above wherein compound of Formula XI, R2 = CH3, R3 = H, A3 = Br, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3 and HG1 = HN(CH3)/Pr. MS (ES) 386.3 (M+l).
[360] COMPOUND 1 -25 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)Ph, n2 = 0, n3 = 1, R4 and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method B as described above wherein compound of Formula XI, R2 = CH3, R3 = H, A3 = Br, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3 and HG1 = HN(CH3)Ph. MS (ES) 420.2 (M+l).
[361] COMPOUND 1 -26 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH2)4, n2 = 0, n3 = 1, R4 and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method B as described above wherein compound of Formula XI, R2 = CH3, R3 = H, A3 = Br, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3 and HG1 = HN(CH2)4. MS (ES) 384.3 (M+l).
[362] COMPOUND 1 -27 (Compound of Formula III where R2 = CH3, R3 =
CH3, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH , R3 = CH , and G1 = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. 1HNMR (CDC13, 400 MHz) δ 1.31 (d, 6H, 7= 7.6 Hz), 1.37 (s, 6H), 2.29 (s, 6H), 3.70 (s, 3H), 4.10 (s, 2H), 7.12 - 7.26 (m, 2H), 7.68 (d, IH, 7= 8.8 Hz), 7.83 (d, IH, J= 8.8 Hz), 8.41 (dd, IH, 7= 2.0, 8.8 Hz), 9.14 (s, IH). [363] COMPOUND 1 -28 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)Et, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R2 = CH3, R3 = H, and G1 = N(CH3)Et and compound of Formula V, A1 = OH, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. MS (ES) 372.2 (M+l).
[364] COMPOUND 1 -29 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 0, n4 = 1, and Q1 = CO2tBu): The title compound was prepared as follows: An NN-dimethylformamide (25 mL) solution of intermediate A- 2 (3.00 g, 12.33 mmol) was charged with potassium tert-butoxide (L52g, 13.56 mmol) and allowed to stir at rt for 30 min. tert-Butyl bromoacetate (2.64 g, 13.56 mmol), compound of Formula V where A1 = Br, n2 = 0, n3 = 0, n4 = 1, and Q' = CO2tBu, was added dropwise and the reaction was allowed to stir for 24 h. The mixture was dissolved in EtOAc, washed with Νa2CO (sat) 2x, water 2χ, and brine l . The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo as a brown oil. Silica gel column chromatography (gradient of CH2C12 to 5% CH3OH:CH2Cl2 (containing 1 mL Et3N/100 mL of solvent) afforded the desired product as a brown oil. 'HNMR (CDC13, 200 MHz) δ 1.32 (d, 3H, 7= 6.0 Hz), 1.50 (s, 9H), 2.36 (s, 6H), 4.17 (q, IH, 7= 8.0 Hz), 4.66 (s, 2H), 7.08 (d, 2H, 7= 2.0 Hz), 7.28 (dd, IH, 7= 4.0, 8.0 Hz), 7.73 (d, IH, 7= 8.0 Hz), 7.89 (d, IH, 7= 8.0 Hz), 8.08 (dd, IH, 7= 4.0, 8.0 Hz), 8.58 (s, IH); MS (ES) 358.0 (M+l). [365] COMPOUND 1-30 (Compound of Formula III where R2, R3, and G1 are taken together to equal A* (see Table 1), n2 = 1, Z = Ph, n3 = 0, and n4 = 0): 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 solvent was removed in-vacuo, and the residual was partitioned between ethyl ether and H2O. The organic layer was subsequently washed with Νa2CO (2χ) and brine (lx), dried over Na2SO , filtered, and concentrated in- vacuo. The residual was dissolved in THF (25 mL) and cooled to -78 °C. Separately, a suspension of 2-bromo-6-benzyloxynaphthelene (1.20 g, 3.83 mmol) and Mg (0.140 g, 5.75 mmol) in THF (4.8 mL) was heated to 50 °C for 30 min, charged with CH3I (1 drop), maintained at 50 °C for an additional 30 min, heated to reflux for 30 min, cooled to rt, and added dropwise to the cooled mixed anhydride solution, which subsequently was allowed to warm to rt overnight with stirring. The solvent was removed in-vacuo, and the residual was partitioned between CH2C12 and 1 :1 phosphate buffer: IM citric acid. The organic layer was subsequently washed with Na2CO3 (2x) and brine (lx), dried over Na2SO4, filtered, and concentrated in-vacuo. The residual was subjected to chromatography (gradient of 95% hexanes:5% EtOAc to 80%) hexanes:20%> EtOAc) to afford the title compound as a white solid; mp 102- 104 °C; MS (ES) 432.13 (M+l).
[366] COMPOUND 1-31 (compound of Formula III where R2 = CH2CH3, R3
= H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. The title compound was prepared according to the General Synthetic Method A as described above wherein compound of Formula IV, R = CH2CH3, R = H, and G = N(CH3)2 and compound of Formula V, A1 = OH, n2 = 0, n3 = 1, R4 and R5 = CH3, n4 = 1, and Q1 = CO2CH3. Η NMR (CDC13, 400 MHz) δ 0.89 (t, 3H, 7.4 Hz), 1.38 (s, 6H), 1.78-1.79 (m, IH), 1.92-1.98 (m, IH), 2.38 (s, 6H), 3.71 (s, 3H), 3.97-4.01 (m, IH), 4.12 (s, 2H), 7.15 (d, IH, 7= 2.3 Hz), 7.18 (dd, IH, 7= 2.5, 8.9 Hz), 7.76 (d, IH, 7= 8.0 Hz), 7.86 (d, IH, 7= 8.0 Hz), 8.06 (dd, IH, J= 1.7, 8.6 Hz), 8.52 (s, IH). [367] COMPOUND 1-32 (Compound of Formula III where R2 = CH3, R3 =
H, G1 = N(CH3)tPr, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method A as 9 *ι I described above wherein compound of Formula IV, R = CH3, R = H, and G = N(CH3)iPr and compound of Formula V, A1 = OH, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 426.1 (M+l).
[368] Following the general methods described hereinbefore, the following intermediates of Formula II as listed in Table 2 were prepared. In the intermediate numbers, "a" denotes the syn amino alcohol and "b" denotes the anti amino alcohol with respect to G1. II
Table 2: Listing of Intermediates of Formula II Compound R* R3 G' n2 Z n3 R4b R5b n4 Q1 2-la CH3 H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 2-lb CH3 H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 2-2a CH3 H N(CH3)2 4 Ph 0 - - 1 C02CH3 2-2b CH3 H N(CH3)2 4 Ph 0 - - 1 C02CH3 2-3a CH3 H N(CH3)2 3 Ph 0 - - 1 C02CH3 2-3b CH3 H N(CH3)2 3 Ph 0 - - 1 C02CH3 2-4a CH3 H N(CH3)2 4 Ph 1 H H 1 C02CH3 2-4b CH3 H N(CH3)2 4 Ph 1 H H 1 C02CH3 2-5a CH3 H N(CH3)2 0 - 1 CH3 CH3 1 CH3 2-5b CH3 H N(CH3)2 0 - 1 CH3 CH3 1 CH3 2-6a CH3 H N(CH3)2 4 Ph 0 - - 1 OtBu 2-6b CH3 H N(CH3)2 4 Ph 0 - - 1 OtBu 2-7a CH3 H N(CH3)2 4 PhO 1 H H 1 C02CH3 2-7b CH3 H N(CH3)2 4 PhO 1 H H 1 C02CH3 2-8a CH3 H N(CH3)2 0 - 2 H H 1 OCH3 2-8b CH3 H N(CH3)2 0 - 2 H H 1 OCH3 2-9a CH3 H N(CH3)2 4 Ph 0 - - 1 OCH3 2-9b CH3 H N(CH3)2 4 Ph 0 - - 1 OCH3 2- 10a CH3 H N(CH3)2 trans- 0 - - 0 - CH=CHPh 2- 10b CH3 H N(CH3)2 trans- 0 - - 0 - CH=CHPh 2-l la CH3 H N(CH3)2 4 Ph 0 - - CN 2-1 lb CH3 H N(CH3)2 4 Ph 0 - - CN 2- 12a CH3 H N(CH3)2 4 Ph 0 - - N02 2- 12b CH3 H N(CH3)2 4 Ph 0 - - N02 2-13a CH3 H N(CH3)2 0 - 1 Et Et C02Et 2- 13b CH3 H N(CH3)2 0 - 1 Et Et C02Et 2-14a CH3 H N(CH3)2 0 - 1 CH2CH2 ring C02Et 2-14b CH3 H N(CH3)2 0 - 1 CH2CH2 ring C02Et Compound R* ' R3 G1 n2 z n3 Rih R3b n4 Q1 2-15a CH3 H N(CH3)2 0 - 1 CH2CH2CH2 πng C02Et 2- 15b CH3 H N(CH3)2 0 - 1 CH2CH2CH2 πng C02Et 2- 16a CH3 H N(CH3)2 0 - 1 CH2CH.OCH2CH2 πng C02CH3 2- 16b CH3 H N(CH3)2 0 - 1 CH2CH2OCH2CH2 πng C02CH3 2- 17a CH3 H N(CH3)2 0 - 1 CH2(CH2)3 CH2 nng C02Et 2- 17b CH3 H N(CH3)2 0 - 1 CH2(CH2)3CH2rrng C02Et 2-18a CH3 H N(CH3)2 0 - 1 CH2(CH2)2CH2 πng C02Et 2-18b CH3 H N(CH3)2 0 - 1 CH2(CH2)2CH2 πng C02Et 2- 19a CH3 H N(CH3)2 1 Ph 0 - - 0 - 2- 19b CH3 H N(CH3)2 1 Ph 0 - - 0 - 2-20a CH3 H N(CH2)20(CH2)3 πng 0 - 1 CH3 CH3 1 C02CH3 2-20b CH3 H N(CH2)20(CH2)2 πng 0 - 1 CH3 CH3 1 C02CH3 2-2 la CH3 H N(Et)2 0 - 1 CH3 CH3 1 C02CH3 2-2 lb CH3 H N(Et)2 0 - 1 CH3 CH3 1 C02CH3 2-22a CH3 H N(CH3)cyclohexyl 0 - 1 CH3 CH3 1 C02CH3 2-22b CH3 H N(CH3)cyclohexyl 0 - 1 CH3 CH3 1 C02CH3 2-23a CH3 H N(CH3)«-butyl 0 - 1 CH3 CH3 1 C02CH3 2-23b CH3 H N(CH3)n-butyl 0 - 1 CH3 CH3 1 C02CH3 2-24a CH3 H N(CH3 Pr 0 - 1 CH3 CH3 1 C02CH3 2-24b CH3 H N(CH3).Pr 0 - 1 CH3 CH3 1 C02CH3 2-25a CH3 H N(CH3)Ph 0 - 1 CH3 CH3 1 C02CH3 2-26a CH3 H N(CH2)4 nng 0 - 1 CH3 CH3 1 C02CH3 2-26b CH3 H N(CH2)4 rιng 0 - 1 CH3 CH3 1 C02CH3 2-27 CH3 CH3 N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 2-28a CH3 H N(CH3)Et 0 - 1 CH3 CH3 1 C02CH3 2-28b CH3 H N(CH3)Et 0 - 1 CH3 CH3 1 C02CH3 2-29a CH3 H N(CH3)2 0 - 0 - - 1 C02.Bu 2-29b CH3 H N(CH3)2 0 - 0 - - 1 C02tBu 2-30 H H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 2-3 la A2* 1 Ph 0 - - 0 - 2-3 lb A2* 1 Ph 0 - - 0 - 2-32a Et H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 2-32b Et H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 2-33a CH3 H N(CH3)ιPr 0 - 1 CH2(CH2)2 CH2 πng 1 C02Et 2-33b CH3 H N(CH3).Pr 0 - 1 CH2(CH2)2 CH2 ring 1 C02Et wherein A2* = R2R3G taken together with the carbon to which they are attached form:
where • is the carbon to which they are attached.
[369] General Synthetic Method C for the preparation of compounds of the Formula Ila/b: A solution of compound of Formula III (1 eq) in CH3OH (0.3M) was cooled to 0 °C. Sodium borohydride (1 eq) was added portionwise at 0 °C and the reaction mixture was allowed to warm to rt and stir for 1.5 h. The reaction mixture was concentrated in vacuo, partitioned between NaHCO3 and CH2C12, and the aqueous layer was extracted 5x with CH2C12. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (gradient of CH2CI2 to 5%> CH3OH:CH2Cl2 with 1% Et N) to afford the desired syn and anti isomers, a and b respectively, of compound of Formula II.
[370] COMPOUND 2-la (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. 'HNMR (CDCI3, 200 MHz) δ 0.72 (d, 3H, 7= 6.6 Hz), 1.36 (s, 6H), 2.34 (s, 6H), 2.63-2.68 (m, IH), 3.71 (s, 3H), 4.08 (s, 2H), 4.32 (d, IH, 7= 9.8 Hz), 7.11-7.14 (m, 2H), 7.26 (s, IH), 7.66- 7.74 (m, 3H); MS (ES) 360.0 (M+l).
[371] COMPOUND 2-lb (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH )2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. 1HNMR (CDCI3, 200 MHz) δ 0.85 (d, 3H, 7= 6.6 Hz), 1.36 (s, 6H), 2.34 (s, 6H), 2.63-2.68 (m, IH), 3.71 (s, 3H), 4.08 (s, 2H), 5.13 (d, 1H, 7= 3.6 Hz), 7.11-7.14 (m, 2H), 7.26 (s, IH), 7.66- 7.74 (m, 3H); MS (ES) 360.0 (M+l).
[372] COMPOUND 2-2a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z - 4-phenyb n3 = 0, n4 = 1, and Q1 = CO2CH3. 1HNMR (CDC13, 200 MHz) δ 0.73 (d, 3H, 7= 6.8 Hz), 2.33 (s, 6H), 2.61-2.68 (m, IH), 3.93 (s, 3H), 4.33 (d, IH, 7- 9.6 Hz), 5.24 (s, 2H), 7.16-7.24 (m, 2H), 7.37 (dd, IH, 7= 8.4 Hz, 1.2 Hz), 7.56 (d, 2H, 7 = 4.0 Hz), 7.66-7.77 (m, 3H), 8.06- 8.08 (m, 2H); MS (ES) 393.9 (M+l). [373] COMPOUND 2-2b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1 , Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CO2CH3. 1HNMR (CDC13, 200 MHz) δ 0.83 (d, 3H, 7= 6.8 Hz), 2.39 (s, 6H), 2.61-2.68 (m, IH), 3.93 (s, 3H), 5.10 (d, IH, 7- 3.2 Hz), 5.24 (s, 2H), 7.17-7.24 (m, 2H), 7.47 (dd, IH, 7= 2.0, 8.8 Hz), 7.56 (d, 2H, 7= 8.0 Hz), 7.66-7.77 (m, 3H), 8.06- 8.08 (m, 2H); MS (ES) 393.9 (M+l). [374] COMPOUND 2-3a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula H, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDC13, 200 MHz) δ 0.73 (d, 3H, 7= 6.6 Hz), 2.34 (s, 6H), 2.63 - 2.71 (m, IH), 3.93 (s, 3H), 4.33 (d, IH, 7= 9.4 Hz), 5.21 (s, 2H), 7.20 (s, IH), 7.24 (s, IH), 7.35 - 7.52 (m, 2H), 7.66 - 7.73 (m, 3H), 7.77 (s, IH), 8.00 - 8.04 (m, IH), 8.17 (s, IH); MS (ES) 394.0 (M+l). [375] COMPOUND 2-3b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described ^ 1 9 above wherein compound of Formula III, R = CH , R = H, G = N(CH3)2, n = 1, Z = 3-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDC13, 200 MHz) δ 0.89 (d, 3H, 7= 6.6 Hz), 2.45 (s, 6H), 2.94 - 3.02 (m, IH), 3.93 (s, 3H), 4.33 (d, IH, 7= 9.4 Hz), 5.21 (s, 2H), 7.20 (s, IH), 7.24 (s, IH), 7.35 - 7.52 (m, 2H), 7.66 - 7.73 (m, 3H), 7.77 (s, IH), 8.00 - 8.04 (m, IH), 8.17 (s, IH); MS (ES) 394.0 (M+l). [376] COMPOUND 2-4a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, R4b and R5 = H, n4 - 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3. Η NMR (CDC13, 200 MHz) δ 0.73 (d, 3H, 7= 6.6 Hz), 2.34 (s, 6H), 2.58 - 2.75 (m, IH), 3.65 (s, 2H), 3.70 (s, 3H), 4.35 (d, IH, 7= 10.0 Hz), 5.16 (s, 2H), 7.18 - 7.34 (m, 4H), 7.38 - 7.50 (m, 3H), 7.67 - 7.76 (m, 3H).
[377] COMPOUND 2-4b (Compound of Formula II where R2 = CH3, R3 =
H, G1 - N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, R4b and R5 = H, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDCI3, 200 MHz) δ 0.65 (d, 3H, 7= 6.6 Hz), 2.39 (s, 6H), 2.58 - 2.75 (m, IH), 3.65 (s, 2H), 3.70 (s, 3H), 4.35 (d, IH, 7= 10.0 Hz), 5.16 (s, 2H), 7.18 - 7.34 (m, 4H), 7.38 - 7.50 (m, 3H), 7.67 - 7.76 (m, 3H); MS (ES) 408.0 (M+l). [378] COMPOUND 2-5a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CH3. lH NMR (CDCI3, 200 MHz) δ 0.73 (d, 3H, 7= 3.6 Hz), 1.08 (s, 9H), 2.34 (s, 6H), 2.66 - 2.69 (m, IH), 3.71 (s, IH), 4.32 (d, 1H, 7= 10.0 Hz), 5.12 (s, 2H), 7.11 (s, IH), 7.16 (d, 1H, 7= 8.8 Hz), 7.35 (d, 1H, 7= 7.4 Hz), 7.45 (d, IH, 7= 8.4 Hz), 7.67 - 7.75 (m, 2H); MS (ES) 316.0 (M+l). [379] COMPOUND 2-5b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CH3. Η NMR (CDCI3, 200 MHz) δ 0.85 (d, 3H, 7= 3.6 Hz), 1.08 (s, 9H), 2.41 (s, 6H), 2.66 - 2.69 (m, IH), 3.71 (s, IH), 4.32 (d, IH, 7= 10.0 Hz), 5.12 (s, 2H), 7.11 (s, IH), 7.16 (d, IH, 7= 8.8 Hz), 7.35 (d, IH, 7= 7.4 Hz), 7.45 (d, IH, 7= 8.4 Hz), 7.67 - 7.75 (m, 2H); MS (ES) 316.0 (M+l). [380] COMPOUND 2-6a (Compound of Formula II where R2 = CH3, R3 =
H, G' = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OtBu): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OtBu. Η NMR (CDC13, 200 MHz) δ 0.73 (d, 3H, 7= 6.0 Hz), 1.36 (s, 9H), 2.34 (s, 6H), 2.63-2.72 (m, IH), 4.33 (d, IH, 7= 8.0 Hz), 5.11 (s, 2H), 7.00-7.04 (m, 2H), 7.20-7.23 (m, 2H), 7.36-7.49 (m, 3H), 7.69- 7.75 (m, 3H); MS (ES) 408.0 (M+l).
[381] COMPOUND 2-6b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OtBu): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OtBu. 1H NMR (CDC13, 200 MHz) δ 0.87 (d, 3H, 7- 6.0 Hz), 1.36 (s, 9H), 2.43 (s, 6H), 2.63-2.72 (m, IH), 5.11 (s, 2H), 5.16 (d, IH, 7= 4.0 Hz), 7.00-7.04 (m, 2H), 7.20-7.23 (m, 2H), 7.36-7.49 (m, 3H), 1.69-1.15 (m, 3H); MS (ES) 408.0 (M+l).
[382] COMPOUND 2-7a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDC13, 200 MHz) δ 0.73 (d, 3H, 7= 6.0 Hz), 2.34 (s, 6H), 2.64-2.72 (m, IH), 3.81 (s, 3H), 4.34 (d, IH, 7= 8.0 Hz), 4.65 (s, 2H), 5.10 (s, 2H) 6.92-6.96 (m, 2H), 7.17-7.21 (m, 2H), 7.39-7.46 (m, 3H), 7.68-7.75 (m, 3H); MS (ES) 424.0 (M+l).
[383] COMPOUND 2-7b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic 9 "\
Method C as described above wherein compound of Formula III, R = CH3, R = H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3. Η NMR (CDC13, 200 MHz) δ 0.90 (d, 3H, 7= 6.0 Hz), 2.46 (s, 6H), 2.64-2.72 (m, IH), 3.81 (s, 3H), 4.65 (s, 2H), 5.10 (s, 2H), 5.22 (d, IH, 7= 4.0 Hz), 6.92-6.96 (m, 2H), 7.17-7.21 (m, 2H), 7.39-7.46 (m, 3H), 1.68-1.15 (m, 3H); MS (ES) 424.0 (M+l).
[384] COMPOUND 2-8a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 2, R4b and R5b = H, n4 = 1, and Q1 = OCH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n = 2, R4b and R5b = H, n4 = 1, and Q1 = OCH3. MS (ES) 304.3 (M+l). [385] COMPOUND 2-8b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 2, R4b and R5b = H, n4 = 1, and Q1 = OCH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n' = 2, R4b and R5b = H, n4 = 1, and Q1 = OCH3. MS (ES) 304.3 (M+l). [386] COMPOUND 2-9a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OCH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OCH3. MS (ES) 366.4 (M+l). [387] COMPOUND 2-9b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 - OCH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z 4-phenyb n3 = 0, n4 = 1, and Q1 = OCH3. MS (ES) 366.4 (M+l).
[388] COMPOUND 2-10a (Compound of Formula II where R |2' - CH3, RJ =
H, G1 = N(CH3)2, n2 = 1, Z equals trans-CH=CHPh, n3 and n4 = 0): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 - H, G1 = N(CH3)2, n2 = 1, Z equals trans-CH=CHPh, n3 and n4 = 0. MS (ES) 362.3 (M+l). [389] COMPOUND 2-10b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z equals trans-CH=CHPh, n3 and n4 = 0): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IE, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z equals trans-CH=CHPh, n3 and n4 = 0. MS (ES) 362.3 (M+l). [390] COMPOUND 2-1 la/b (Compound of Formula II where R2 = CH3, R3
= H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CN): The title compounds were prepared as a mixture of syn and anti isomers according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CN. MS (ES) 361.2 (M+l). [391] COMPOUND 2-12a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = NO2): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = NO2. 1H NMR (CDC13, 400 MHz) δ 0.13 (d, 3H, 7= 6.4 Hz), 2.33 (s, 6H), 2.63 - 2.70 (m, IH), 4.33 (d, IH, 7= 12.0 Hz), 5.28 (s, 2H), 7.15 (d, IH, 7= 2.0 Hz), 7.21 (dd, IH, 7= 2.8, 8.8 Hz), 7.38 - 7.52 (m, 2H), 7.60 (d, 2H, 7= 8.4 Hz), 7.67 - 7.70 (m, 2H), 7.74 (s, IH), 7.75 - 7.78 (m, IH). [392] COMPOUND 2- 12b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = NO2): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = NO2. 1H NMR (CDC13, 400 MHz) δ 0.73 (d, 3H, 7= 6.4 Hz), 2.33 (s, 6H), 2.63 - 2.70 (m, IH), 4.33 (d, IH, 7= 12.0 Hz), 5.28 (s, 2H), 7.15 (d, IH, 7= 2.0 Hz), 7.21 (dd, IH, 7= 2.8, 8.8 Hz), 7.38 - 7.52 (m, 2H), 7.60 (d, 2H, 7= 8.4 Hz), 7.67 - 7.70 (m, 2H), 7.74 (s, IH), 7.75 - 7.78 (m, IH). [393] COMPOUND 2-13a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH2CH3, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4 and R5b = CH2CH3, n4 = 1, and Q1 = CO2Et. Η NMR (CDC13, 400 MHz) δ 0.72 (d, 3H, 7= 6.8 Hz), 0.85 (t, 6H, 7= 7.6 Hz), 1.26 (t, 3H, 7= 7.2 Hz), 1.78 - 1.83 (m, 4H), 2.33 (s, 6H), 2.63 - 2.71 (m, IH), 4.15 (s, 2H), 4.20 (q, 2H, 7= 6.4 Hz, 14.0 Hz), 4.33 (d, IH, 7= 9.6 Hz), 7.12 (dd, IH, 7= 2.8 Hz, 8.8 Hz), 7.19 (d, IH, 7= 2.4 Hz), 7.46 (d, IH, 7= 8.8 Hz), 7.69 -7.73 (m, 3H); MS (ES) 402.3 (M+l). [394] COMPOUND 2-13b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH2CH3, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH2CH3, n4 = 1, and Q1 = CO2Et. MS (ES) 402.3 (M+l).
[395] COMPOUND 2-14a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 - 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1 , R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, n4 = 1, and Q1 = CO2Et. 1H NMR (CDC13, 400 MHz) δ 0.73 (d, 3H, 7= 6.4 Hz), 1.09 (q, 2H, 7= 3.2 Hz), 1.22 (t, 3H, 7= 7.6 Hz), 1.39 (q, 2H, 7= 2.8 Hz), 2.34 (s, 6H), 2.63 - 2.71 (m, IH), 4.17 (q, 2H, 7= 7.2 Hz), 4.25 (s, 2H), 4.33 (d, IH, 7= 8.0 Hz), 7.13 (s, IH), 7.15 (d, IH), 7.45 (d, IH, 7= 8.4 Hz), 7.69 - 7.72 (m, 3H).
[396] COMPOUND 2-14b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH )2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 372.0 (M+l). [397] COMPOUND 2-15a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5 are taken together with the carbon to which they are attached to equal a cyclobutyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1 , R4b and R5b are taken together with the carbon to which they are attached to equal a cyclobutyl ring, n4 = 1, and Q1 = CO2Et. 1H NMR (CDC13, 400 MHz) δ 0.74 (d, 3H, 7= 6.6 Hz), 1.23-1.30 (m, 3H), 2.03 - 2.07 (m, 2H), 2.19 - 2.21 (m, 2H), 2.35 (s, 6H), 2.55 - 2.58 (m, 2H), 2.60 - 2.75 (m, IH), 4.17 - 4.24 (m, 2H), 4.31 - 4.38 (m, 3H), 7.15 (dd, IH, 7= 2.5 Hz, 8.8 Hz), 7.18 (d, IH, 7= 2.4 Hz), 7.48 (dd, IH, 7= 1.6 Hz, 8.6 Hz), 7.71 - 7.74 (m, 3H).
[398] COMPOUND 2-15b (Compound of Formula II where R2 = CH3, R3 =
H, G' = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclobutyl ring, n4 = 1, and Q1 = CO2Ef): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1 , R4b and R5b are taken together with the carbon to which they are attached to equal a cyclobutyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 386.3 (M+l). [399] COMPOUND 2- 16a (Compound of Formula II where R2 = CH3, R3 =
H, G' = N(CH3)2, n2 = 0, n3 - 1, R4b and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDC13, 400 MHz) δ 0.73 (d, 3H), 1.75 - 1.82 (m, 2H), 2.23 - 2.29 (m, 2H), 2.34 (s, 6H), 2.66 (m, IH), 3.57 - 3.64 (m, 2H), 3.75 (s, 3H), 3.86 - 3.93 (m, 2H), 4.12 (s, 2H), 4.34 (d, IH, 7= 9.8 Hz), 7.10 (s, IH), 7.13 (d, IH, 7= 2.6 Hz), 7.48 (dd, IH, 7= 1.4 Hz, 8.5 Hz), 7.68-7.76 (m, 3H).
[400] COMPOUND 2- 16b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5 are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, n4 = 1, and Q1 = CO2CH3. MS (ES) 402.2 (M+l). [401 ] COMPOUND 2- 17a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1 , R4b and R5 are taken together with the carbon to which they are attached to equal a cyclohexyl ring, n4 = 1, and Q1 = CO2Et. 1H NMR (CDC13, 400 MHz) δ 0.71 (d, 3H, 9.9 Hz), 1.23 (t, 3H, 7= 2.10), 1.30 - 1.36 (m, 2H), 1.47 - 1.51 (m, 3H), 1.52 - 1.64 (m, 3H), 2.20 - 2.23 (m, 2H), 2.35 (s, 6H), 2.67 - 2.71 (m, IH), 4.09 (s, 2H), 4.20 (q, 2H, 7= 7.1 Hz, 7.10), 4.34 (d, IH, 9.1 Hz), 7.11 (s, IH), 7.13 (d, IH, 7= 2.5 Hz), 7.47 (dd, IH, 7= 1.6 Hz, 8.5 Hz), 7.69 - 7.72 (m, 3H).
[402] COMPOUND 2- 17b (Compound of Formula II where R2 = CH3, R3 =
H, G1 - N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 - CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1 , R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 414.3 (M+l). [403] COMPOUND 2-18a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et. 1H NMR (CDC13, 400 MHz) δ 0.72 (d, 3H, 7= 6.6 Hz), 1.21 (t, 3H, J= 7.1 Hz), 1.63-1.82 (m, 6H), 2.16 - 2.21 (m, 2H), 2.34 (s, 6H), 2.65 - 2.69 (m, IH), 4.09 - 4.21 (m, 4H), 4.33 (d, IH, 7= 9.7 Hz), 7.10 (d, IH, J= 2.5 Hz), 7.13 (s, IH), 7.46 (dd, IH, 7= 1.6 Hz, 8.4 Hz), 7.64 - 7.71 (m, 3H).
[404] COMPOUND 2-18b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 400.3 (M+l). [405] COMPOUND 2- 19a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = Ph, n3 and n4 = 0): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1 , Z = Ph, n3 and n4 = 0. Η NMR (CDC13, 200 MHz) δ 0.74 (d, 3H, 7= 6.0 Hz), 2.35 (s, 6H), 2.68-2.76 (m, IH), 4.35 (d, 1H, 7= 10.0 Hz), 5.16 (s, 2H), 7.18-7.78 (m, 11H); MS (ES) 336.1 (M+l). [406] COMPOUND 2- 19b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 1, Z = Ph, n3 and n4 = 0): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = Ph, n3 and n4 - 0. Η NMR (CDCI3, 200 MHz) δ 0.98 (d, 3H, 7= 8.0 Hz), 2.62 (s, 6H), 2.68-2.76 (m, IH), 5.16 (s, 2H), 5.45 (broad d, IH), 7.18-7.78 (m, 1 IH); MS (ES) 336.1 (M+l). [407] COMPOUND 2-20a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH2)2O(CH2)2 ring, n2 = 0, n3 - 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic 9 ^
Method C as described above wherein compound of Formula III, R = CH3, R = H, G1 = N(CH2)2O(CH2)2 ring, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. Η NMR (CDC13, 400 MHz) δ 0.79 (d, 3H, 7= 6.8 Hz), 1.36 (s, 3H), 2.49- 2.54 (m, 2H), 2.64-2.70 (m, IH), 2.74-2.79 (m, 2H), 3.75 (s, 3H), 3.76-3.85 (m, 4H), 4.08 (s, 2H), 4.39 (d, IH, 7= 10.0 Hz), 7.11-7.14 (m, 2H), 7.44 (dd, IH, 7= 8.8 Hz, 1.6 Hz), 1.10-1.12 (m, 3H).
[408] COMPOUND 2-20b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH2)2O(CH2)2 ring, n2 = 0, n3 = 1, R4b and R5 = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH2)2O(CH2)2 ring, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. Η NMR (CDCI3, 400 MHz) δ 0.83 (d, 3H, 7= 6.8 Hz), 1.36 (s, 3H), 2.49- 2.54 (m, 2H), 2.64-2.70 (m, IH), 2.74-2.79 (m, 2H), 3.75 (s, 3H), 3.76-3.85 (m, 4H), 4.08 (s, 2H), 4.93 (d, IH, J= 4.0 Hz), 7.11-7.14 (m, 2H), 7.44 (dd, IH, 7= 8.8 Hz, 1.6 Hz), 7.70-7.72 (m, 3H).
[409] COMPOUND 2-2 la (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(Et)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH , R3 = H, G1 = N(Et)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. 1HNMR (CDC13, 400 MHz) δ 0.77 (d, 3H, 7= 6.8 Hz), 1.16 (t, 6H, 7= 7.2 Hz), 1.37 (s, 6H), 2.38-2.46 (m, 2H), 2.69-2.78 (m, 2H), 2.79-2.86 (m, IH), 3.71 (s, 3H), 4.08 (s, 2H), 4.32 (d, IH, 7 = 10.0 Hz), 7.12-7.15 (m, 2H), 7.47 (dd, IH, 7= 8.4 Hz, 1.6 Hz), 1.10-1.12 (m, 3H). [410] COMPOUND 2-21b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(Et)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(Et)2, n2 = 0, n3 - 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. 1HNMR (CDC13, 400 MHz) δ 0.92 (d, 3H, 7= 6.8 Hz), 1.05 (t, 6H, 7= 7.2 Hz), 1.36 (s, 6H), 2.53-2.54 (m, described above wherein compound of Formula III, R2 = CH3, R = H, G = N(CH3)«- butyb n2 = 0, n3 - 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. 1HNMR (CDC13, 400 MHz) δ 0.89 (d, 3H, 7= 7.2 Hz), 0.93 (t, 3H, 7= 7.2 Hz), 1.27-1.34 (m, 2H), 1.39 (s, 6H), 1.47-1.55 (m, 2H), 2.30 (s, 3H), 2.47-2.58 (m, 2H), 2.90-2.94 (m, IH), 3.73 (s, 3H), 4.10 (s, 2H), 4.99 (d, IH, 7= 3.6 Hz), 7.13-7.16 (m, 2H), 7.39 (dd, IH, 7 = 1.6, 8.4 Hz), 1.69-1.16 (m, 3H).
[415] COMPOUND 2-24a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)iPr, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)iPr, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. 1HNMR (CDC13, 400 MHz) δ 0.82 (d, 3H, 7= 6.8 Hz), 1.11 (d, 3H, 7= 7.6 Hz), 1.14 (d, 3H, 7 = 8.4 Hz), 1.36 (s, 6H), 2.26 (s, 3H), 2.84-2.88 (m, IH), 2.96-3.02 (m, IH), 3.71 (s, 3H), 4.08 (s, 2H), 4.25 (d, IH, 7= 9.2 Hz), 7.13-7.16 (m, 2H), 7.46 (dd, 1H, 7= 8.4 Hz, 1.6 Hz), 1.69-1.15 (m, 3H).
[416] COMPOUND 2-24b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)ιPr, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)iPr, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. 1HNMR (CDCI3, 400 MHz) δ 0.86 (d, 3H, 7= 6.8 Hz), 1.07 (d, 3H, 7= 6.4 Hz), 1.12 (d, 3H, 7 = 6.4 Hz), 1.39 (s, 6H), 2.21 (s, 3H), 2.99-3.02 (m, IH), 3.15-3.18 (m, IH), 3.70 (s, 3H), 4.10 (s, 2H), 4.95 (d, IH, 7= 4.0 Hz), 7.13-7.16 (m, 2H), 7.39 (dd, IH, 7= 8.4 Hz, 1.6 Hz), 7.69-7.75 (m, 3H).
[417] COMPOUND 2-25a (Compound of Formula II where R2 = CH3, R3 -
H, G1 = N(CH3)Ph, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)Ph, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 - CO2CH3. 1H NMR (CDC13, 400 MHz) δ 0.86 (d, 3H, 7= 6.8 Hz), 1.36 (s, 6H), 2.84 (s, 3H), 3.70 (s, 3H), 3.88-3.92 (m, IH), 4.68 (d, IH, 7= 9.6 Hz), 6.86-6.90 (m, IH), 7.05-7.08 (m, 2H), 7.13-7.16 (m, 2H), 7.28-7.33 (m, 2H), 7.56 (dd, IH, 7= 8.4 Hz, 1.6 Hz), 1.12-1.16 (m, 2H), 7.80 (s, IH). [418] COMPOUND 2-26a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH2)4 ring, n2 - 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH , R3 = H, G1 = N(CH2)4 ring, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. ]HNMR (CDC13, 400 MHz) δ 0.78 (d, 3H, 7= 6.4 Hz), 1.36 (s, 6H), 1.78-1.87 (m, 4H), 2.61-2.18 (m, 4H), 2.97-3.05 (m, IH), 3.70 (s, 3H), 4.08 (s, 2H), 4.36 (d, 1H, 7= 10.0 Hz), 7.11- 7.14 (m, 2H), 7.47 (dd, IH, 7= 8.4 Hz, 1.6 Hz), 1.69-1.13 (m, 3H). [419] COMPOUND 2-26b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH2)4 ring, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH , R3 = H, G1 = N(CH2)4 ring, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. 'HNMR (CDC13, 400 MHz) δ 0.81 (d, 3H, 7= 6.4 Hz), 1.36 (s, 6H), 1.82-1.89 (m, 4H), 2.58-2.61 (m, IH), 2.66-3.72 (m, 2H), 2.80-2.88 (m, 2H), 3.71 (s, 3H), 4.08 (s, 2H), 5.15 (d, IH, 7 = 2.4 Hz), 7.12-7.14 (m, 2H), 7.36 (dd, IH, 7= 8.4 Hz, 1.6 Hz), 1.61-1.14 (m, 2H), 7.77 (s, IH).
[420] COMPOUND 2-27 (Compound of Formula II where R2 = CH3, R3 =
CH3, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = CH3, G1 = N(CH3)2, n2 - 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. MS (ES) 374.3 (M+l).
[421] COMPOUND 2-28a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)Et, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)Et, n2 = 0, n3 = 1, R4b and R5 = CH3, n4 = 1, and Q1 = CO2CH3. 'HNMR (CDC13, 400 MHz) δ 0.74 (d, 3H, 7= 6.8 Hz), 1.16 (t, 3H, 7= 6.8 Hz), 1.36 (s, 6H), 2.29 (s, 3H), 2.41-2.49 (m, IH), 2.61-2.69 (m, IH), 2.71-2.78 (m, IH), 3.71 (s, 3H), 4.08 (s, 2H), 4.34 (d, IH, 7- 9.6 Hz), 7.11-7.14 (m, 2H), 7.46 (dd, IH, 7= 8.0 Hz, 1.6 Hz), 7.69-7.71 (m, 3H).
- [422] COMPOUND 2-28b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)Et, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2 CH3): The title compound was prepared according to the General Synthetic Method C as 9 ^ 1 described above wherein compound of Formula IH, R = CH3, R = H, G = N(CH3)Et, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2 CH3. 1HNMR (CDC13, 400 MHz) δ 1.04 (d, 3H, 7= 7.2 Hz), 1.30 (t, 3H, 7= 7.2 Hz), 1.36 (s, 6H), 2.65 (s, 3H), 2.88-2.93 (m, IH), 3.04-3.07 (m, IH), 3.23-3.27 (m, IH), 3.70 (s, 3H), 4.07 (s, 2H), 5.58 (s, IH), 7.09-7.13 (m, 2H), 7.44 (dd, IH, 7= 8.4 Hz, 1.6 Hz), 7.63- 7.70 (m, 2H), 7.79 (s, IH).
[423] COMPOUND 2-29a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 0, n4 = 1, and Q1 = CO2tBu): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 0, n4 = 1, and Q1 = CO2tBu. 'HNMR (CDC13, 200 MHz) δ 0.71 (d, 3H, 7- 6.6 Hz), 1.49 (s, 9H), 2.33 (s, 6H), 4.32 (d, IH, 7= 9.4 Hz), 4.62 (s, 2H), 7.04-7.06 (m, IH), 7.18-7.24 (m, IH), 7.34-7.49 (m, IH), 7.64-7.77 (m, 3H) MS (ES) 360.0 (M+l). [424] COMPOUND 2-29b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)2, n2 = 0, n3 = 0, n4 = 1, and Q1 = CO2tBu): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 0, n4 = 1, and Q' = CO2tBu. 'HNMR (CDC13, 200 MHz) δ 0.82 (d, 3H, 7= 6.6 Hz), 1.49 (s, 9H), 2.38 (s, 6H), 4.75 (s, 2H), 5.07 (d, IH, J = 3.6 Hz), 7.04-7.06 (m, IH), 7.18-7.24 (m, IH), 7.34-7.49 (m, IH), 7.64-7.77 (m, 3H); MS (ES) 360.0 (M+l). [425] COMPOUND 2-30 (Compound of Formula II where R2 = H, R3 = H,
G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared as follows: Intermediate A-8 (200 mg, 0.53 mmol) was dissolved in a 1 :1 mixture of CH2Cl2:CH3OH (2 mL) and cooled to 0 °C. The solution was charged with NaBH4 (30 mg, 0.79 mmol) and allowed to warm to rt. After 4 h, the reaction mixture was charged with 2M HN(CH3)2 in CH3OH (10 eq., 5.3 mmol) at rt. After 24 h, the reaction was concentrated in vacuo, partitioned between CH2C12 and sat. aq. NaHCO3, and the aqueous layer was extracted with CH2CI2 (3x). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (2% CH OH:CH2Cl2) to yield the desired product as a yellow gum. MS (ES) 346.0 (M+l). [426] COMPOUNDS 2-31 a and 2-3 lb (Compounds of Formula II where R2,
R3, and G1 are taken together to equal A2* (see Table 2), n2 = 1, Z = Ph, and n3 and n4 = 0): 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 LiAlH4 (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 Na2SO4, filtered, and concentrated in- vacuo. The residual was subjected to silica gel column chromatography (gradient of 100% CHC13 to 99% CHC13:1% CH3OH (NH3 sat.)) to afford the title compounds 2- 31a and 2-3 lb. Compound 2-3 la: white solid, mp 108-110 °C; Η NMR (CDC13, 400 MHz) δ 1.25-1.32 (m, IH), 1.61-1.77 (m, 3H), 2.34-2.40 (m, IH), 2.51 (s, 3H), 2.60-2.64 (m, IH), 3.15-3.19 (m, IH), 5.00 (d, IH, 7= 2.8 Hz), 5.18 (s, 2H), 7.22- 7.26 (m, 2H), 7.34-7.43 (m, 3H), 7.49 (d, 2H, 7= 7.6 Hz), 7.69 (d, IH, 7= 8.4 Hz), 7.76 (d, IH, 7= 8.8 Hz), 7.82 (s, IH); MS (ES) 348.31 (M+l), 330.28 (M-18, loss of -OH). Compound 2-3 lb: White solid, mp 84-87 °C; Η NMR (CDC13, 400 MHz) δ 1.76-1.81 (m, 3H), 1.82-1.94 (m, IH), 2.25 (s, 3H), 2.41-2.51 (m, IH), 2.84-87 (m, IH), 3.14-3.17 (m, IH), 4.49 (d, IH, 7= 5.2 Hz), 5.18 (s, 2H), 7.21-7.24 (m, 2H), 7.34 (d, IH, 7= 7.6 Hz), 7.40-7.50 (m, 5H), 7.70 (d, IH, 7= 8.8 Hz), 7.75 (d, IH, 7= 10.0 Hz), 7.78 (s, IH); MS (ES) 348.31 (M+l), 330.26 (M-18, loss of -OH). [427] COMPOUND 2-32a (Compound of Formula II where R2 = CH2CH3,
R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1 , R4b and R5b = CH3, n4 = 1 , and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH2CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. Η NMR (CDC13, 400 MHz) δ 0.58 (t, 3H, 7.6 Hz), 1.13-1.24 (m, IH), 1.36 (s, 6H), 1.50-1.61 (m, IH), 2.47 (s, 6H), 2.47-2.53 (m, IH), 3.71 (s, 3H), 4.08 (s, 2H), 4.27 (d, IH, 7= 9.6 Hz), 7.11-7.14 (m, 2H), 7.48 (dd, IH, 7= 1.5, 8.4 Hz), 1.69-1.12 (m, 3H). [428] COMPOUND 2-32b (Compound of Formula II where R2 = CH2CH3,
R3 = H, G1 = N(CH3)2, n2 = 0, n3 - 1, R b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH2CH , R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. Η NMR (CDCI3, 400 MHz) δ 0.81 (t, 3H, 7.5 Hz), 1.36 (s, 6H), 1.49-1.67 (m, IH), 2.59 (s, 6H), 2.84-2.89 (m, IH), 3.71 (s, 3H), 4.08 (s, 2H), 5.33 (d, IH, 7=3.1 Hz), 7.13 (s, IH), 7.15 (d, IH, 7= 2.4 Hz), 7.39 (dd, IH, 7= 1.6, 8.5 Hz), 7.70 (q, 2H, 7= 8.6 Hz), 7.8 (s, IH).
[429] COMPOUND 2-33a (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)tPr, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula IH, R2 = CH3, R3 = H, G1 = N(CH3)/Pr, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO Et. 1H NMR (CDCI3, 400 MHz) δ 0.84 (d, 3H, 7= 6.6 Hz), 1.12 (d, 3H, 7= 6.5 Hz), 1.16 (d, 3H, 7 = 6.5 Hz), 1.21 (t, 3H, 7= 7.1 Hz), 1.67 - 1.84 (m, 6H), 2.16 - 2.21 (m, 2H), 2.28 (s, 3H), 2.83 - 2.90 (m, IH), 2.94 - 3.04 (m, IH), 4.14 - 4.19 (m, 4H), 4.24 (d, IH, 7= 9.4 Hz), 7.10 - 7.13 (m, 2H), 7.46 (dd, IH, 7= 1.5 Hz, 8.6 Hz), 7.69 (s, IH), 7.71 (s, IH).
[430] COMPOUND 2-33b (Compound of Formula II where R2 = CH3, R3 =
H, G1 = N(CH3)ιPr, n2 = 0, n3 = 1, R4b and R5 are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula III, R2 = CH3, R3 = H, G1 = N(CH3)iPr, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 428.0 (M+l).
[431] Following the general methods described hereinbefore, the following compounds of Formula I (where R1 = H, n1 = 1, R6a = H, R6b = H, Y = O, R4a = H, R5a = H) as listed in Table 3 were prepared. In the EXAMPLE numbers, "a" denotes the syn isomer and "b" denotes the anti isomer, with respect to X and G1. XI = imidazol-1-yl, X2 = triazol-1-yb and X3 = triazol-3-yb
Table 3: Listing of Compounds of Formula I EX. R1 R3 G1 n2 z n3 R4b R5b n4 Q' X 3-la CH3 H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 XI 3-lb CH3 H N(CH3)2 0 - 1 CHj CH3 1 C02CH3 XI 3-2a CHj H N(CH3)2 1 4 Ph 0 - - 1 CO2CH3 XI 3-2b CH3 H N(CH3)2 1 4 Ph 0 - - 1 C02CH3 XI 3-3a CH3 H N(CH3)2 1 3 Ph 0 - - 1 C02CH3 XI 3-3b CH3 H N(CH3)2 1 3 Ph 0 - - 1 CO2CH3 XI 3-4a CH3 H N(CH3)2 1 4 Ph 1 H H 1 C02CH3 XI 3 -4b CHj H N(CH3)2 1 4 Ph 1 H H 1 C02CH3 XI 3-5a CH3 H N(CH3)2 0 - 1 CH3 CH3 1 CH3 XI 3-5b CH3 H N(CH3)2 0 - 1 CH3 CH3 1 CH3 XI 3-6a CH3 H N(CH3)2 1 4 Ph 0 - - 1 O.Bu XI 3-6b CH3 H N(CH3)2 1 4 Ph 0 - - 1 O.Bu XI 3-7a CH3 H N(CH3)2 1 4 PhO 1 H H 1 C02CH3 XI 3-7b CHj H N(CH3)2 1 4 PhO 1 H H 1 CO2CH3 XI 3-8a CH3 H N(CH3)2 0 - 2 H H 1 OCH3 X I 3-8b CH3 H N(CH3)2 0 - 2 H H 1 OCHj XI 3-9a CHj H N(CH3)2 1 4 Ph 0 - - 1 OCH3 XI 3-10a CH3 H N(CH3)2 1 trans- 0 - - 0 XI CH=CHPh 3- 10b CH3 H N(CH3)2 1 trans- 0 - - 0 XI CH=CHPh 3-l la CH3 H N(CH3)2 1 4 Ph 0 - - CN XI 3-l lb CH3 H N(CH3)2 1 4 Ph 0 - - CN X I 3-12a CH3 H N(CH3)2 1 4 Ph 0 - - N02 XI 3-13a CHj H N(CH3)2 0 - 1 Et Et C02Et XI 3- 14a CH3 H N(CH3)2 0 - 1 CH2CH ring C02Et XI 3-15a CH3 H N(CH3)2 0 - 1 CH2CH2CH2 ring C02Et X I 3-16a CH3 H N(CH3)2 0 - 1 CH2CH2OCH2CH2πng C02CH3 XI 3-17a CH3 H N(CH3)2 0 - 1 CH2(CH2)3CH2 ring C02Et XI 3-18a CH3 H N(CH3)2 0 - 1 CH2(CH2)2CH2 ring C02Et X I 3-19a CH3 H N(CH3)2 1 Ph 0 - - 0 XI 3-19b CH3 H N(CH3)2 1 Ph 0 - - 0 XI 3-20a CH3 H N(CH2)2θ(CH2)2 πng 0 - 1 CH3 CH3 1 C02CH3 XI 3-2 la CH3 H N(Et)2 0 - 1 CH3 CH3 1 C02CH3 XI EX. R2 R* G1 n2 z n3 R4b R5b n4 Q1 X 3-22a CH3 H N(CH3)cyclohexyl 0 - 1 CH3 CH3 1 C02CH3 XI 3-23a CH3 H N(CH3)«-butyl 0 - 1 CH3 CH3 1 C02CH3 XI 3-24a CH3 H N(CH3).Pr 0 - 1 CH3 CH3 1 C02CH3 XI 3-25a CH3 H N(CH2), ring 0 - 1 CH3 CH3 1 C02CHj XI 3-26a CH3 H N(CH3)Et 0 - 1 CH3 CH3 1 C02CH3 X I 3-27a CH3 H N(CH3)2 0 - 0 - - 1 C02.Bu XI 3-27b CH3 H N(CH3)2 0 - 0 - - 1 C02.Bu XI 3-28 CH3 CH3 N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 XI 3-29 H H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 XI 3-30a A2* 1 Ph 0 - - 0 XI 3-30b A2* 1 Ph 0 - - 0 XI 3-31a CH3 H N(CH3)2 0 - 1 CH2(CH2)2CH2 ring 1 C02Et X2 3-32a Et H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 XI 3-33a CH3 H N(CH3) Pr 0 - 1 CH2(CH2)3 :CH2 ring 1 C02Et X2
wherein A2* = R R G taken together with the carbon atom to which they are attached form:
where • is the carbon to which they are attached.
[432] General Synthetic Method D for the preparation of compounds of the Formula I: An acetonitrile solution (0.2M) of compound of Formula II (1 eq) was charged with l,l '-carbonyldiimidazole or 1,1-carbonylditriazole (2 eq) and allowed to stir at 70 °C for 10 h. The reaction mixture was quenched with water and sat. NaHCO3 and concentrated in vacuo to a slurry. The mixture was partitioned between CH C12 and NaHCO3 (sat) and the aqueous layer extracted with CH2C12 (5x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient of 2:1 CH2C12:4% CH3OH in CH2C12 (1% ~7 N NH3 in CH3OH) to 4% CH3OH in CH2C12 (1% ~7 N NH3 in CH3OH) to afford the desired compounds of Formula L [433 ] EXAMPLE 3 - 1 a (Compound of Formula I where X 1 = imidazol- 1 -yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. Η NMR (CDC13, 200 MHz) δ 0.79 (d, 3H, 7= 6.6 Hz), 1.35 (s, 6H), 2.27 (s, 6H), 3.46 - 3.55 (m, IH), 3.70 (s, 3H), 4.07 (s, 2H), 5.05 (d, 1H, 7= 10.6 Hz), 7.00 (s, 2H), 7.11 - 7.14 (m, IH), 7.17 (d, IH, 7= 5.2 Hz), 7.26 - 7.30 (m, IH), 7.65 (d, 2H, 7= 11.6 Hz), 7.72 (d, 2H, 7= 8.8 Hz); MS (ES) 410.0 (M+l).
[434] EXAMPLE 3- lb (Compound of Formula I where XI = imidazol- 1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R = CH3, R = H, G = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. Η NMR (CDCI3, 200 MHz) δ 0.90 (d, 3H, 7= 6.6 Hz), 1.35 (s, 6H), 2.21 (s, 6H), 3.55 - 3.63 (m, IH), 3.70 (s, 3H), 4.07 (s, 2H), 5.09 (d, IH, 7= 9.8 Hz), 7.01 (d, 2H, 7= 9.6 Hz), 7.10 (s, IH), 7.15 (d, IH, 7= 2.6 Hz), 7.40 (dd, IH, 7- 1.4 Hz, 8.6 Hz), 7.67 -7.71 (m, 4H); MS (ES) 410.0 (M+l).
[435] EXAMPLE 3-2a (Compound of Formula I where XI = imidazol-1-yb
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CO2 CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CO2CH3. 1HNMR (CDCI3, 200 MHz) δ 0.81 (d, 3H, 7= 8.0 Hz), 2.28 (s, 6H), 3.49-3.53 (m, IH), 3.93 (s, 3H), 5.06 (d, IH, 7= 8.0 Hz), 5.24 (s, 2H), 7.00 (s, 2H), 7.16 (d, IH, 7= 2.4 Hz), 7.27- 7.31 (m, 2H), 7.55 (d, 2H, 7= 8.0 Hz ), 1.65-1.15 (m, 4H), 8.07 (d, 2H, 7= 8.0 Hz); MS (ES) 375.9 (M+l).
[436] EXAMPLE 3 -2b (Compound of Formula I where XI = imidazol- 1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CO2CH3. Η NMR (CDCI3, 400 MHz) δ 0.90 (d, 3H, 7= 8.0 Hz), 2.23 (s, 6H), 3.58-3.62 (m, IH), 3.93 (s, 3H), 5.09 (d, IH, 7= 8.0 Hz), 5.24 (s, 2H), 7.01 (d, 2H, 7= 8.0 Hz), 7.15 (d, IH, 7= 2.4 Hz), 7.23-7.25 (m, 2H), 7.41-7.43 (m, IH), 7.55 (d, 2H, 7= 8.0 Hz), 1.65-1.14 (m, 3H), 8.07 (d, 2H, 7= 8.0 Hz); MS (ES) 375.9 (M+l). [437] EXAMPLE 3-3a (Compound of Formula I where XI = imidazol-1-yb
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDC13, 200 MHz) δ 0.80 (d, 3H, 7= 6.6 Hz), 2.28 (s, 6H), 3.47 - 3.55 (m, IH), 3.92 (s, 3H), 5.06 (d, IH, 7= 10.6 Hz), 5.21 (s, 2H), 6.75 (s, IH), 7.21 - 7.27 (m, IH), 7.36 - 7.45 (m, 3H), 7.59 (d, 2H, 7= 7.2 Hz), 7.73 - 7.87 (m, 4H), 7.93 (s, IH), 8.01 (s, IH); MS (ES) 443.9 (M+l).
[438] EXAMPLE 3-3b (Compound of Formula I where XI = imidazol-1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, n3 = 0, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDC13, 200 MHz) δ 0.91 (d, 3H, 7= 6.6 Hz), 2.21 (s, 6H), 3.55 - 3.65 (m, IH), 3.93 (s, 3H), 5.08 (d, IH, 7= 10.2 Hz), 5.21 (s, 2H), 6.83 (s, 1H), 7.23 (dd, IH, 7= 2.6, 8.8 Hz), 7.37 - 7.38 (m, 2H), 7.51 (t, IH, 7= 7.4 Hz), 7.68 - 7.91 (m, 7H), 8.05 (s, IH); MS (ES) 443.89.
[439] EXAMPLE 3-4a (Compound of Formula I where XI = imidazol-1-yb
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDC13, 200 MHz) δ 0.80 (d, 3H, 7= 6.6 Hz), 2.28 (s, 6H), 3.43 - 3.58 (m, IH), 3.64 (s, 2H), 3.70 (s, 3H), 5.05 (d, IH, 7 = 10.0 Hz), 5.15 (s, 2H), 6.99 (s, 2H), 7.17 - 7.33 (m, 5H), 7.42 (s, IH), 7.46 (s, IH), 7.65 - 7.73 (m, 4H); MS (ES) 458.0 (M+l).
[440] EXAMPLE 3 -4b (Compound of Formula I where X 1 = imidazol- 1 -yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method C as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3. Η NMR (CDC13, 200 MHz) δ 0.90 (d, 3H, 7- 6.6 Hz), 2.21 (s, 6H), 3.53 - 3.65 (m, IH), 3.64 (s, 2H), 3.69 (s, 3H), 5.10 (d, IH, 7 = 10.0 Hz), 5.15 (s, 2H), 7.01 (d, 2H, 7= 4.4 Hz), 7.18 - 7.26 (m, 3H), 7.29 (s, IH), 7.33 (s, IH), 7.41 - 7.45 (m, 2H), 7.65 - 7.73 (m, 4H); MS (ES) 458.0 (M+l).
[441] EXAMPLE 3-5a (Compound of Formula I where XI = imidazol-1-yb
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CH3. Η NMR (CDC13, 200 MHz) δ 0.80 (d, 3H, 7= 6.4 Hz), 3.69 (s, 9H), 2.28 (s, 6H), 3.49 - 3.53 (m, IH), 3.70 (s, 2H), 5.05 (d, IH, 7= 10.4 Hz), 7.00 (d, 2H, 7= 4.8 Hz), 7.09 (d, IH, 7= 2.0 Hz), 7.19 (dd, IH, 7= 2.4 Hz, 8.8 Hz) 7.29 (d, IH, 7= 1.6 Hz), 7.63 - 7.74 (m, 4H); MS (ES) 366.0 (M+l).
[442] EXAMPLE 3-5b (Compound of Formula I where XI = imidazol-1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CH ): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CH3. Η NMR (CDC13, 200 MHz) δ 0.90 (d, 3H, 7= 6.0 Hz), 1.07 (s, 9H), 2.12 (s, 6H), 3.57 - 3.61 (m, IH), 3.69 (s, 2H), 5.10 (d, IH, 7= 10 Hz), 7.00 (bs, IH), 7.03 (bs, IH), 7.08 (d, IH, 7= 2.0 Hz), 7.17 (dd, IH, 7 - 2.4 Hz, 9.2 Hz), 7.40 (dd, IH, 7= 1.0, 4.2 Hz), 7.66 - 7.70 (m, 4H); MS (ES) 366.02 (M+l).
[443] EXAMPLE 3-6a (Compound of Formula I where XI = imidazol-1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OtBu): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula IT, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OtBu. 1H NMR (CDCI3, 200 MHz) δ 0.81 (d, 3H, 7= 6.0 Hz), 1.36 (s, 9H), 2.21 (s, 6H), 3.47-3.63 (m, IH), 5.06 (d, 1H, 7= 6.0 Hz), 5.11 (s, 2H), 7.00-7.04 (m, 4H), 7.19-7.39 (m, 5H), 7.64-7.74 (m, 4H); MS (ES) 458.0 (M+l).
[444] EXAMPLE 3 -6b (Compound of Formula I where XI = imidazol- 1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OtBu): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z - 4-phenyb n3 = 0, n4 = 1, and Q1 = OtBu. Η NMR (CDC13, 200 MHz) δ 0.91 (d, 3H, 7= 6.0 Hz), 1.36 (s, 9H), 2.21 (s, 6H), 3.47-3.63 (m, IH), 5.06 (d, IH, 7= 6.0 Hz), 5.11 (s, 2H), 7.00-7.04 (m, 4H), 7.19-7.39 (m, 5H), 7.64-7.74 (m, 4H); MS (ES) 458.0 (M+l).
[445] EXAMPLE 3 -7a (Compound of Formula I where XI = imidazol- 1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDCI3, 200 MHz) δ 0.80 (d, 3H, 7= 6.6 Hz), 2.73 (s, 6H), 3.46- 3.55 (m, IH), 3.80 (s, 3H), 4.64 (s, 2H), 5.05 (d, IH, 7= 10.6 Hz), 5.09 (s, 2H), 6.90- 7.00 (m, 4H), 7.17-7.31 (m, 2H), 7.36-7.44 (m, 3H), 7.64-7.73 (m, 4H); MS (ES) 474.0 (M+l).
[446] EXAMPLE 3 -7b (Compound of Formula I where XI = imidazol- 1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula IT, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4b and R5b = H, n4 = 1, and Q1 = CO2CH3. 1H NMR (CDCI3, 200 MHz) δ 0.89 (d, 3H, 7= 6.6 Hz), 2.73 (s, 6H), 3.46- 3.55 (m, IH), 3.80 (s, 3H), 4.64 (s, 2H), 5.05 (d, IH, 7= 10.6 Hz), 5.09 (s, 2H), 6.90- 7.00 (m, 4H), 7.17-7.31 (m, 2H), 7.36-7.44 (m, 3H), 7.64-7.73 (m, 4H); MS (ES) 474.0 (M+l).
[447] EXAMPLE 3-8a (Compound of Formula I where XI = imidazol-1 -yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 2, R4b and R5b = H, n4 = 1 , and Q1 = OCH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula H, R = CH3, R = H, G = N(CH3)2, n2 = 0, n3 = 2, R4b and R5b = H, n4 = 1, and Q1 = OCH3. MS (ES) 354.3 (M+l).
[448] EXAMPLE 3-8b (Compound of Formula I where XI = imidazol-1-yl,
R2 - CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 2, R4b and R5b = H, n4 = 1 , and Q1 = OCH ): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 2, R4b and R5b = H, n4 = 1, and Q1 = OCH3. MS (ES) 354.3 (M+l).
[449] EXAMPLE 3 -9a (Compound of Formula I where XI = imidazol- 1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OCH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = OCH3. MS (ES) 416.3 (M+l). [450] EXAMPLE 3-10a (Compound of Formula I where XI = imidazol-1-yb R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z equals trans-CH=CHPh, n3 and n4 = 0): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z equals trans-CH=CHPh, n3 and n4 = 0. MS (ES) 412.3 (M+l). [451] EXAMPLE 3 - 10b (Compound of Formula I where X 1 = imidazol- 1 -yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z equals trans-CH=CHPh, n3 and n4 = 0): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 1, Z equals trans-CH=CHPh, n3 and n4 = 0. MS (ES) 412.3 (M+l). [452] EXAMPLE 3-1 la (Compound of Formula I where XI = imidazol-1-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CN): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CN. Η NMR (CDCI3, 400 MHz) δ 0.80 (d, 3H, 7= 6.4 Hz), 2.28 (s, 6H), 3.48 - 3.53 (m, IH), 5.06 (d, IH, 7 = 10.4 Hz), 5.24 (s, 2H), 7.00 (s, 2H), 7.14 (d, IH, J= 2.4 Hz), 7.24 (d, IH, 7= 2.4 Hz), 7.29 - 7.31 (m, IH), 7.59 (d, 2H, 7= 8.4 Hz), 7.62 (d, 2H, J = 2.4 Hz), 7.69 (d, 2H, 7 = 1.6 Hz), 7.71 - 7.76 (m, 2H).
[453] EXAMPLE 3-1 lb (Compound of Formula I where XI = imidazol-1-yι,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CN): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH )2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = CN. 1H NMR (CDCI3, 400 MHz) δ 0.91 (d, 3H, J= 6.4 Hz), 2.22 (s, 6H), 3.58 - 3.63 (m, IH), 5.10 (d, IH, 7 = 10.0 Hz), 5.28 (s, 2H), 7.01 (d, 2H, 7= 12.0 Hz), 7.14 (s, IH), 7.23 (s, IH), 7.43 (d, IH, 7 = 8.8 Hz) 7.64 - 7.76 (m, 6H), 8.26 (d, 2H, 7 = 7.2 Hz).
[454] EXAMPLE 3-12a (Compound of Formula I where XI = imidazol-1-yb
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = NO2): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula IT, R = CH3, R = H, G = N(CH )2, n2 = 1, Z = 4-phenyb n3 = 0, n4 = 1, and Q1 = NO2. Η NMR (CDC13, 400 MHz) δ 0.80 (d, 3H, 7= 6.4 Hz), 2.28 (s, 6H), 3.48 - 3.53 (m, IH), 5.06 (d, IH, 7 = 10.4 Hz), 5.24 (s, 2H), 7.13 (s, IH), 7.22 (dd, IH, 7= 2.4, 8.8 Hz), 7.42 (d, IH, J= 8.4 Hz), 7.57 - 7.59 (m, 2H), 7.67 - 7.75 (m, 8H).
[455] EXAMPLE 3-13a (Compound of Formula I where XI = imidazol-1-yb R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH2CH3, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH2CH3, n4 = 1, and Q1 = CO2Et. MS (ES) 452.3 (M+J).
[456] EXAMPLE 3-14a (Compound of Formula I where XI = imidazol-1-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, n = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 422.3 (M+l).
[457] EXAMPLE 3 - 15 a (Compound of Formula I where X 1 = imidazol-1-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclobutyl ring, n4 = 1 , and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclobutyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 436.3 (M+l). [458] EXAMPLE 3-16a (Compound of Formula I where XI = imidazol-1-yb R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, n4 = 1, and Q1 = CO CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, n4 = 1, and Q1 = CO CH3. MS (ES) 452.3 (M+l).
[459] EXAMPLE 3-17a (Compound of Formula I where XI = imidazol-1-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 464.2 (M+l).
[460] EXAMPLE 3-18a (Compound of Formula I where XI = imidazol-1-yb
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R = CH3, R = H, G = N(CH3)2, n2 = 0, n3 = 1, R b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 450.3 (M+l).
[461] EXAMPLE 3-19a (Compound of Formula I where XI = imidazol- 1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = Ph, n3 and n4 = 0): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula IT, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = Ph, n3 and n4 = 0. Η NMR (CDC13, 200 MHz) δ 0.80 (d, 3H, 7= 6.0 Hz), 2.21 (s, 6H), 3.47-3.55 (m, IH), 5.03 (d, IH, 7= 6.0 Hz), 5.17 (s, 2H), 7.00-7.74 (m, 14H); MS (ES) 386.1 (M+l).
[462] EXAMPLE 3- 19b (Compound of Formula I where XI = imidazol- 1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = Ph, n3 and n4 - 0): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula H, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = Ph, n3 and n4 = 0. 1H NMR (CDC13, 200 MHz) δ 0.91 (d, 3H, 7= 6.0 Hz), 2.21 (s, 6H), 3.47-3.55 (m, IH), 5.03 (d, IH, 7= 6.0 Hz), 5.17 (s, 2H), 7.00-7.74 (m, 14H); MS (ES) 386.1 (M+l).
[463] EXAMPLE 3-20a (Compound of Formula I where XI - imidazol-l-yl,
R2 = CH3, R3 = H, G1 = N(CH2)2O(CH2)2 ring, n2 = 0, n3 = 1, R4 and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R = CH3, R3 = H, G1 = N(CH2)2O(CH2)2 ring, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. MS (ES) 452.3 (M+l).
[464] EXAMPLE 3-21a (Compound of Formula I where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(Et)2, n2 = 0, n3 = 1, R4b and R5 = CH3, n4 = 1, and Q1 = CO CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(Et)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. MS (ES) 438.3 (M+l).
[465] EXAMPLE 3-22a (Compound of Formula I where XI = imidazol-l-yl,
R2 = CH3, R3 = H, G1 = N(CH3)cyclohexyl, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R = CH3, R3 = H, G1 = N(CH3)cyclohexyl, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. MS (ES) 478.2 (M+l).
[466] EXAMPLE 3 -23 a (Compound of Formula I where XI = imidazol-l-yl,
R2 = CH3, R3 = H, G1 = N(CH3)«-butyl, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic
Method D as described above wherein compound of Formula II, R = CH3, R = H, G = N(CH3)«-butyb n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. MS (ES) 425.2 (M+l).
[467] EXAMPLE 3 -24a (Compound of Formula I where XI = imidazol-l-yl,
R2 = CH3, R3 = H, G1 = N(CH3)/Pr, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)tPr, n2 = 0, n3 = 1, R4b and R5b - CH3, n4 = 1, and Q1 = CO2CH3. MS (ES)
438.2 (M+l).
[468] EXAMPLE 3-25a (Compound of Formula I where XI = imidazol-l-yl,
R2 = CH3, R3 = H, G1 = N(CH2)4, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH2)4, n2 = 0, n3 = 1, R4 and R5b = CH3, n4 = 1, and Q1 = CO2CH3. MS (ES)
436.3 (M+l).
[469] EXAMPLE 3 -26a (Compound of Formula I where X 1 = imidazol- 1 -yl,
R2 = CH3, R3 = H, G1 = N(CH3)Et, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2 CH ): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)Et, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2 CH3. MS (ES) 424.3 (M+l).
[470] EXAMPLE 3 -27a (Compound of Formula I where XI = imidazol-l-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 0, n4 = 1, and Q1 = CO2tBu): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 0, n4 = 1, and Q1 = CO2tBu. 1HNMR (CDC13, 200 MHz) δ 0.79 (d, 3H, 7= 6.6 Hz), 1.49 (s, 9H), 2.27 (s, 6H), 3.51-3.66 (m, IH), 4.61 (s, 2H), 5.20 (d, IH, 7= 4.0 Hz), 6.98-7.04 (m, 3H), 7.21 (dd, IH, 7= 2.6, 9.2 Hz), 7.41 (dd, IH, 7= 1.8, 8.4 Hz), 7.64-7.74 (m, 4H).
[471] EXAMPLE 3-27b (Compound of Formula I where XI = imidazol-l-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 0, n4 = 1, and Q1 = CO2tBu): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 0, n4 = 1, and Q1 = CO2tBu. 'HNMR (CDC13, 200 MHz) δ 0.89 (d, 3H, 7= 6.6 Hz), 1.49 (s, 9H), 2.20 (s, 6H), 3.51-3.66 (m, IH), 4.61 (s, 2H), 5.60 (d, IH, 7= 9.4 Hz), 6.98-7.04 (m, 3H), 7.21 (dd, IH, 7= 2.6, 9.2 Hz), 7.41 (dd, IH, 7= 1.8, 8.4 Hz), 7.64-7.74 (m, 4H).
[472] EXAMPLE 3-28 (Compound of Formula I where XI = imidazol-l-yl,
R2 = CH3, R3 = CH3, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = CH3, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. MS (ES) 424.3 (M+l).
[473 ] EXAMPLE 3-29 (Compound of Formula I where X 1 = imidazol- 1 -yl,
R2 = H, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1 , R4b and R5b = CH3, n4 = 1 , and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic 9 ^ 1
Method D as described above wherein compound of Formula II, R = H, R = H, G = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. Η NMR (CDC13, 400 MHz) δ 1.36 (s, 6H), 2.31 (s, 6H), 2.91-3.19 (m, 2H), 3.70 (s, 3H), 4.08 (s, 2H), 5.39-5.42 (m, IH), 7.00-7.23 (m, 5H), 7.55 (s, IH), 1.66-1.10 (m, 3H); MS (ES) 396.0 (M+l).
[474] EXAMPLE 3-30a (Compound of Formula I where XI = imidazol-l-yl,
R2, R3, and G1 are taken together to equal A2* (see Table 3), n2 = 1, Z = Ph, and n3 and n4 = 0): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, XI = imidazol-l-yl, R2, R3, and G1 are taken together to equal A2*, n2 = 1, Z = Ph, and n3 and n4 = 0. White solid, mp 124-126 °C; MS (ES) 398.18 (M+l).
[475] EXAMPLE 3-30b (Compound of Formula I where XI = imidazol-l-yl,
R2, R3, and G1 are taken together to equal A2* (see Table 3), n2 = 1, Z = Ph): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, XI = imidazol-l-yl, R2, R3, and G1 are taken together to equal A2*, n2 = 1, Z = Ph. White solid, mp 110-112 °C; MS (ES) 398.05 (M+l).
[476] EXAMPLE 3 -3 la (Compound of Formula I where X2 = triazol-1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1 , R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 451.2 (M+l).
[477] EXAMPLE 3-32a (Compound of Formula I where XI = imidazol-l-yl,
R2 = CH2CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH2CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CO2CH3. MS (ES) 424.2 (M+l). 1H NMR (CDC13, 400 MHz) δ 0.74 (t, 3H, 7= 7.4 Hz), 1.19-1.27 (m, IH), 1.36 (s, 6H), 1.45-1.56 (m, IH), 2.33 (s, 6H), 3.25-3.31 (m, IH), 3.70 (s, 3H), 4.07 (s, 2H), 5.12 (d, IH, 7= 10.0 Hz), 7.00 (s, IH), 7.05 (s, IH), 7.11 (d, IH, 7 = 2.3 Hz), 7.16 (dd, IH, 7= 2.5, 8.9 Hz), 7.37 (dd, IH, 7= 1.8, 8.5 Hz), 7.68-7.70 (m, 4H).
[478] EXAMPLE 3 -33a (Compound of Formula I where X2 = triazol-1-yl,
R2 = CH3, R3 = H, G1 = N(CH3)iPr, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et): The title compound was prepared according to the General Synthetic Method D as described above wherein compound of Formula II, R2 = CH3, R3 = H, G1 = N(CH3)ιPr, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, n4 = 1, and Q1 = CO2Et. MS (ES) 478.2 (M+l).
[479] Following the general methods described hereinbefore, the following compounds of Formula I-B as listed in Table 4 were prepared. In the EXAMPLE numbers, "a" denotes the syn isomer and "b" denotes the anti isomer, with respect to
X and G1. XI = imidazol-l-yl, X2 = triazol-1-yl, and X3 = triazol-3-yl.
Table 4: Listing of Compounds of Formula I-B EX. R2 R3 G1 n2 Z n3 R4b Rib X 4-la CH3 H N(CH3)2 0 - 1 CHj CHj XI 4-lb CHJ H N(CH3)2 0 - 1 CHj CHj XI 4-2a CHJ H N(CH3)2 1 4 Ph 0 - - XI 4-2b CHJ H N(CH3)2 1 4 Ph 0 - - XI
150 - EX. R2 R4b R4 G1 ιx2 z n3 R5b X 4-3a CHj H N(CH3)2 1 3 Ph 0 - - XI 4-3b CHJ H N(CH3)2 1 3 Ph 0 - - XI 4-4a CHj H N(CH3)2 1 4 Ph H H XI 4-4b CHJ H N(CH3)2 1 4 Ph H H XI 4-5a CHJ H N(CHj)2 0 - Et Et XI 4-6a CHJ H N(CH3)2 0 - CH2CH 2 ring XI 4-7a CHJ H N(CH3)2 0 - CH2CH2CH2 ring XI 4-8a CHJ H N(CH3)2 0 - CH2CH2OCH2CH2 ring XI 4-9a CHJ H N(CH3)2 0 - CH2(CH2)3 CH2 ring XI 4- 10a CHJ H N(CH3)2 0 - CH2(CH2)2 CH2 ring XI 4-l la CHJ H N(CH2)20(CH2)2 ring 0 - CHj CHj XI 4-12a CHJ H N(Et)2 0 - CHj CHj XI 4-13a CHJ H N(CH3)cyclohexyl 0 - CHj CHj XI 4-14a CHJ H N(CH3)«-butyl 0 - CHj CHJ XI 4-15a CHJ H N(CH3).Pr 0 - CHJ CHj XI 4- 16a CHJ H N(CH2)4 ring 0 - CHj CHj XI 4- 17a CHJ H N(CH3)Et 0 - CHj CHJ XI 4-18 CHJ C N(CH3)2 0 - CHj CHJ XI H 3 4-19 H H N(CH3)2 0 . 1 CHJ CHJ XI 4-20a CHj H N(CH3)2 0 - 1 CH2(CH2)2 CH2 ring X2 4-2 la Et H N(CH3)2 0 - 1 CHj CHJ XI 4-22a CHj H N(CH3) Pr 0 - 1 CH2(CH2)2 CH2 ring XI
[480] General Synthetic Method E for the preparation of compounds of the Formula I-B: A solution of compound of Formula I-C in THF was charged with 5 eq. NaOH in H2O and allowed to stir at 45 °C for 3 h. The reaction mixture was concentrated in vacuo to solids, taken up in minimal water, neutralized to pH 7 with 6 M HCI, and extracted with CH2C12. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting solids were purified by silica gel chromatography with 10% CH3OH in CHC1 to afford the desired compounds of Formula I-B.
[481] EXAMPLE 4- 1 a (Compound of Formula I-B where X 1 = imidazol- 1 - yl, R2 = CH3, R3 = H, G1 - N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and R7 = CH3. 'HNMR (CD3OD, 200 MHz) δ 0.85 (d, 3H, 7= 6.6 Hz), 1.32 (s, 6H), 2.30 (s, 6H), 3.81-3.98 (m, IH), 4.07 (s, 2H), 5.43 (d, IH, 7= 15 Hz), 6.97-7.22 (m, 3H), 7.35-7.60 ( , 2H), 7.23-7.96 (m, 3H), 8.20 (s, IH); MS (ES) 395.9 (M+l).
[482] EXAMPLE 4-lb (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 - N(CH3)2, n2 = 0, n3 = 1, and R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and R7 = CH3. 1HNMR (CD3OD, 200 MHz) δ 0.94 (d, 3H, J= 6.6 Hz), 1.32 (s, 6H), 2.30 (s, 6H), 3.81-3.98 (m, IH), 4.07 (s, 2H), 6.97-7.22 (m, 3H), 7.35-7.60 (m, 2H), 7.23-7.96 (m, 3H), 8.20 (s, IH); MS (ES) 395.9 (M+l).
[483] EXAMPLE 4-2a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb and n3 = 0): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, and R7 = CH3. 1H NMR (DMSO-c?6, 400 MHz) δ 0.85 (d, 3H, 7= 8.0 Hz), 2.39 (s, 6H), 4.15-4.40 (m, IH), 5.31 (s, 2H), 5.83 (d, IH, 7= 9.2 Hz), 7.30 (dd, IH, J= 9.2 Hz, 2.8 Hz), 7.15 (d, IH, 7= 2.0 Hz), 7.59 (d, 2H, 7= 8.4 Hz), 7.67 (d, 2H, 7= 8.8 Hz), 8.31 (d, 2H, 7= 8.8 Hz), 7.91-7.96 (m, 3H), 8.05 (s, IH), 9.05 (s, IH); MS (ES) 429.1 (M+l).
[484] EXAMPLE 4-2b (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb and n3 = 0): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 0, and R7 = CH3. 1H NMR (CD3OD, 200 MHz) δ 0.71 (d, 3H, 7= 6.4 Hz), 2.10 (s, 6H), 3.74-3.82 (m, IH), 5.27 (s, 2H), 5.34 (d, IH, 7= 11.0 Hz), 6.82 (s, IH), 7.23 (dd, IH, 7= 9.2 Hz, 2.6 Hz), 7.36-7.39 (m, 2H), 7.55 (d, 2H, 7= 8.0 Hz), 7.69 (d, 2H, 7= 3.8 Hz), 7.75-7.80 (m, 2H), 7.91-7.95 (m, 3H); MS (ES) 361.8 (M+l).
[485] EXAMPLE 4-3a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, and n3 = 0): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, n3 = 0, and R7 = CH3. 1H NMR (CDC13, 200 MHz) δ 0.66 (d, 3H, 7= 6.2 Hz), 2.15 (s, 6H), 3.65 - 3.83 (m, IH), 5.24 (s, 2H), 5.33 (d, IH, 7= 11.4 Hz), 6.75 (s, IH), 6.75 (s, IH), 7.21 - 7.27 (m, IH), 7.34 - 7.45 (m, 3H), 7.59 (d, 2H, 7- 7.2 Hz), 7.73 - 7.87 (m, 4H), 7.93 (s, IH), 8.01 (s, IH); MS (ES) 430.0 (M+l).
[486] EXAMPLE 4-3b (Compound of Formula I-B where XI = imidazol- 1 - yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, and n3 = 0): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 1, Z = 3-phenyl, n3 = 0, and R7 = CH3. 1H NMR (CDC13, 200 MHz) δ 0.71 (d, 3H, 7= 6.2 Hz), 2.09 (s, 6H), 3.74 - 3.83 (m, IH), 5.28 (s, 2H), 5.34 (d, IH, 7= 11.4 Hz), 6.83 (s, IH), 7.21 (d, IH, 7- 2.6 Hz), 7.25 (d, IH, 7= 2.6 Hz), 7.37 - 7.91 (m, 9H), 8.05 (s, IH); MS (ES) 430.0 (M+l).
[487] EXAMPLE 4-4a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, and R4b and R5b = H): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol- 1-yl, R = CH , R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, R4b and R5b = H, and R7 = CH3. Η NMR (CDCI3, 400 MHz) δ 0.77 (d, 3H, 7= 6.2 Hz), 2.19 (s, 6H), 3.46 - 3.70 (m, 3H), 5.00 - 5.18 (m, 3H), 7.02 (m, 2H), 7.15 - 7.36 (m, 6H), 7.62 - 7.69 (m, 3H), 7.89 (s, IH), 8.08 (s, IH), 11.26 (bs, IH).
[488] EXAMPLE 4-4b (Compound of Formula I-B where X 1 = imidazol- 1 - yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, and R4b and R5b = H): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-phenyb n3 = 1, R4b and R5b = H, and R7 - CH3. 1H NMR (CDCI3, 400 MHz) δ 0.90 (d, 3H), 2.24 (s, 6H), 3.46 - 3.70 (m, 3H), 5.00 - 5.18 (m, 3H), 7.02 (m, 2H), 7.15 - 7.36 (m, 6H), 7.62 - 7.69 (m, 3H), 7.89 (s, IH), 8.08 (s, IH), 11.26 (bs, IH).
[489] EXAMPLE 4-5a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, and R4b and R5b = CH2CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol- 1-yb R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH2CH3, and R7 = Et. MS (ES) 424.2 (M+l).
[490] EXAMPLE 4-6a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, and R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, and R7 = Et. MS (ES) 394.2 (M+l). [491] EXAMPLE 4-7a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, and R4b and R5b are taken together with the carbon to which they are attached to equal a cyclobutyl ring): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH , R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclobutyl ring, and R7 = Et. MS (ES) 408.6 (M+l). [492] EXAMPLE 4-8a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, and R4b and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-1-yb R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, and R7 = CH3. MS (ES) 438.3 (M+l). [493] EXAMPLE 4-9a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, and R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring, and R7 = Et. MS (ES) 436.2 (M+l). [494] EXAMPLE 4- 10a (Compound of Formula I-B where X 1 = imidazol- 1 - yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, and R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, and R7 = Et. MS (ES) 422.2 (M+l). [495] EXAMPLE 4-1 la (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH2)2O(CH2)2 ring, n2 = 0, n3 = 1, and R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH , R3 = H, G1 = N(CH2)2O(CH2)2 ring, n2 = 0, n3 = 1, R4b and R5b = CH3, and R7 = CH3. 'HNMR (CD3OD, 400 MHz) δ 0.92 (d, 3H, 7= 6.8 Hz), 1.36 (s, 6H), 2.45-2.52 (m, 2H), 2.75-2.80 (m, 2H), 3.48-3.69 (m, 4H), 3.69-3.73 (m, IH), 4.12 (s, 2H), 5.42 (d, IH, 7= 11.6 Hz), 6.99-7.00 (m, IH), 7.18 (dd, IH, J = 9.2 Hz, 3.2 Hz), 7.25 (d, IH, 7 = 4.0 Hz), 7.36-7.39 (m, IH), 7.55 (d, IH, 7= 9.2 Hz), 7.73-7.83 (m, 2H), 7.89 (s, IH), 8.04 (s, IH).
[496] EXAMPLE 4- 12a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(Et)2, n2 = 0, n3 = 1, and R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH , R3 = H, G1 = N(Et)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and R7 = CH3. 1HNMR (CD3OD, 400 MHz) δ 0.85 (d, 3H, 7= 6.8 Hz), 0.93 (t, 6H, 7= 6.8 Hz), 1.37 (s, 6H), 2.37-2.45 (m, 2H), 2.65-2.73 (m, 2H), 3.76-3.84 (m, IH), 4.09 (s, 2H), 5.35 (d, IH, 7= 11.2 Hz), 7.00 (s, IH), 7.15 (dd, IH, 7- 9.2 Hz, 2.4 Hz), 7.23 (d, IH, 7= 2.0 Hz), 7.37 (s, IH), 7.56 (d, IH, 7= 8.4 Hz), 7.77 (m, 2H), 7.90 (s, IH), 8.11 (s, IH). [497] EXAMPLE 4-13a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)cyclohexyl, n2 = 0, n3 = 1, and R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)cyclohexyl, n2 = 0, n3 = 1, R4b and R5b = CH3, and R7 = CH3. MS (ES) 464.2 (M+l).
[498] EXAMPLE 4-14a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)w-butyl, n2 = 0, n3 = 1, and R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)«-butyb n2 = 0, n3 = 1, R4b and R5b = CH3, and R7 = CH3. MS (ES) 438.1 (M+l).
[499] EXAMPLE 4- 15a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)iPr, n2 = 0, n3 = 1, and R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R = CH3, R3 = H, G1 = N(CH3 Pr, n2 = 0, n3 = 1, R4b and R5b = CH3, and R7 = CH3. MS (ES) 424.2 (M+l).
[500] EXAMPLE 4-16a (Compound of Formula I-B where XI = imidazol-l- yl, R2 - CH3, R3 = H, G1 = N(CH2)4 ring, n2 = 0, n3 = 1, and R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH2)4 ring, n2 = 0, n3 = 1, R4b and R5b - CH3, and R7 = CH3. MS (ES) 436.3 (M+l). MS (ES) 422.1 (M+l).
[501] EXAMPLE 4- 17a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)Et, n2 = 0, n3 = 1, and R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)Et, n2 = 0, n3 = 1, R4b and R5b - CH3, and R7 = CH3. 'HNMR (CD3OD, 400 MHz) δ 0.83 (d, 3H, 7= 6.8 Hz), 0.96 (t, 3H, 7= 6.8 Hz), 1.32 (s, 6H), 2.28 (s, 3H), 2.42-2.47 (m, IH), 2.60-2.65 (m, IH), 3.79-3.82 (m, IH), 4.08 (s, 2H), 5.39 (d, IH, 7= 10.8 Hz), 6.99 (s, IH), 7.14 (dd, IH, 7= 9.2 Hz, 2.4 Hz), 7.22 (d, IH, 7= 2.0 Hz), 7.36 (s, IH), 7.50 (d, IH, 7= 8.8 Hz), 1.13-1.11 (m, 2H), 7.86 (s, IH), 8.11 (s, lH).
[502] EXAMPLE 4-18 (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = CH3, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = CH3, R3 = CH3, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and R7 = CH3. MS (ES) 410.2 (M+l).
[503] EXAMPLE 4-19 (Compound of Formula I-B where XI = imidazol-l- yl, R2 = H, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, and R4b and RΛ = CH3): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R2 = H, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and R7 = CH3. 1H NMR (CDC13, 400 MHz) δ 1.37 (s, 6H), 2.29 (s, 6H), 2.99-3.20 (m, 2H), 4.06 (s, 2H), 5.44 (m, IH), 7.05 - 7.21 (m, 5H), 7.44 - 7.52 (m, 2H), 7.63 (d, IH, 7= 8.4 Hz), 7.74 (s, IH); MS (ES) 382.0 (M+l).
[504] EXAMPLE 4-20a (Compound of Formula I-B where X2 = triazol-1-yl,
R2 = CH3, R3 = H, G1 - N(CH3)2, n2 = 0, n3 = 1, and R4b and R5b = are taken together with the carbon to which they are attached to equal a cyclopentyl ring): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, X2 = triazol-1-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = are taken together with the carbon to which they are attached to equal a cyclopentyl ring, and R7 = Et. MS (ES) 423.3 (M+l). [505] EXAMPLE 4-21 a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH2CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3): The title compound was prepared according to the General Synthetic Method E as described ~X above wherein compound of Formula I-C, XI = imidazol-l-yl, R = CH2CH3, R = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and R7 = CH3. 1H NMR (CDC13, 400 MHz) δ 0.72 (t, 3H, 7= 7.4 Hz), 1.19-1.26 (m, IH), 1.38 (s, 6H), 1.47-1.54 (m, IH), 2.32 (s, 6H), 3.26-3.31 (m, IH), 4.08 (m, 2H), 5.08 (d, IH, 7= 10.1 Hz), 7.04 (d, 2H, 7= 8.2 Hz), 7.09 (d, IH, 7= 2.3 Hz), 7.13 (dd, IH, 7= 2.4, 8.9 Hz), 7.30 (dd, IH, 7= 1.6 Hz, 8.6 Hz), 7.62 (t, 3H, 7= 11.0 Hz), 7.84 (s, IH).
[506] EXAMPLE 4-22a (Compound of Formula I-B where XI = imidazol-l- yl, R2 = CH3, R3 = H, G1 = N(CH3)ΪPΓ, n2 = 0, n3 = 1, and R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring): The title compound was prepared according to the General Synthetic Method E as described above wherein compound of Formula I-C, XI = imidazol-l-yl, R = CH3, R3 = H, G1 - N(CH3)/Pr, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, and R7 = Et. MS (ES) 450.2 (M+l).
[507] Following the general methods described hereinbefore, the following compounds of Formula I-(HA6)n7 (where R1 = H, Y = O, nl = 1, R4a and R5a = H, R6a and R6b = H, n4 = 1) as listed in Table 5 were prepared. In the EXAMPLE numbers, "a" and "a"' denotes the syn isomer and "b" denotes the anti isomer with respect to X and G1. XI = imidazol-l-yl, X2 = triazol-1-yl, and X3 = triazol-3-yl.
I-(HA°)n7
Table 5: Listing of Compounds of Formula I-(HA )n7 EX. n2 n3 JE- R w X (HA°)n 5-la CH3 H N(CH3)2 0 - CHj CHj C02H XI HC02H 5- la' CHJ H N(CH3)2 0 - CHJ CHJ C02H XI (HC1)2 5-lb CHJ H N(CH3)2 0 - CHj CHJ C02H X I HCOjH 5 -2a CHj H N(CHj)2 1 4 Ph H H C02H X I HC02H 5-3a CHJ H N(CH3)2 0 - Et Et C02H XI (HC1)2 5 -4a CHJ H N(CH3)2 0 - CH2CH2 ring C02H X I (HC1)2 5-5a CHj H N(CHj)2 0 - CH2CH2CH2 ring C02H XI (HC1)2 5-6a CHJ H N(CHj)2 0 - CH2CH20CH2CH2ring C02H XI (HC1)2 5-7a CHj H N(CH3)2 0 - CH2(CH2)3CH2 ring C02H XI (HC1)2 5-8a CHJ H N(CH3)2 0 - CH2(CH2)2CH2 ring C02H XI (HC1)2 5-9a CHj H N(CH3).Pr 0 - CH2(CH2)2CH2 ring C02H XI (HC1)2 5-10a CHJ H N(Et)2 0 - CHj CHJ C02H XI (HC1)2 5-l la CHJ H N(CHj)cyclohexyl 0 - CHJ CHJ C02H XI (HC1)2 5- 12a CHJ H N(CH3)n-butyl 0 - CHJ CHJ C02H XI (HC1)2 5-13a CHJ H N(CH3)(Pr 0 - CHJ CHJ C02H XI (HC1)2 5-14a CHJ H N(CH3)Et 0 - CHJ CHJ C02H XI (HC1)2 5-15a CHJ H N(CH3)2 1 4 PhO H H C02H XI HC02H 5-16a CHJ H N(CH3)2 0 - 0 C02H XI (HC1)2 5- 16b CHJ H N(CH3)2 0 - 0 C02H XI (HC1)2 5-17 CHJ CHj N(CHj)2 0 - CHJ CHj C02H XI (HC1)2 5-18a CHJ H N(CH3)2 0 - CHJ CHJ CONH2 XI HC02H 5-19a CHJ H N(CHj)2 0 - CHJ CHJ CONHCHj XI HC02H 5 -20a CHJ H N(CH3)2 0 - CHJ CHJ CON(CH3)2 XI HC02H 5-21a CHJ H N(CH3)2 1 4 Ph 0 CONH2 XI HC02H 5-22a CHJ H N(CH3)2 1 4 Ph 0 CONH CHj XI HC02H 5-23a CHJ H N(CH3)2 1 4 Ph 0 CON(CH3)2 XI HC02H 5-24a Et H N(CH3)2 0 - 1 CH, CHj C02H XI (HC1)2 5-25a CHj H N(CHj)2 1 4 Ph 0 OH XI HC02H [508] General Synthetic Method F for the preparation of compounds of the Formula I-(HA6)n7: Compounds of Formula I were charged with 5 eq. 2N HCI in water and concentrated in vacuo to solids to afford compounds of the Formula I- (HC1)2. Compounds of Formula I could also be treated with formic acid in water followed by concentration in vacuo to afford compounds of Formula I-(HCO2H). Additionally, Compounds of Formula I were charged with 3 eq. 2N HCI in ether and concentrated in vacuo to solids to afford compounds of the Formula I-(HC1)2. [509] EXAMPLE 5-la (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b - CH3, Q1 = CO2H, and (HA6)n7 = HCO2H: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula 1, XI = imidazol- 1-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 - CO2H. 1H NMR (CD3OD, 200 MHz) δ 0.89 (d, 3H, 7= 6.6 Hz), 1.33 (s, 6H), 2.38 (s, 6H), 3.86 - 4.01 (m, IH), 4.09 (s, 2H), 5.42 (d, IH, 7= 11.0 Hz), 7.11 - 8.46 (m, 9H); MS (ES) 396.0 (M+l).
[510] EXAMPLE 5-la' (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H. 1H NMR (CD3OD, 400 MHz) δ 1.31 (d, 3H, 7= 6.1 Hz), 1.37 (s, 6H), 3.03 (s, 3H), 3.11 (s, 3H), 4.14 (s, 2H), 5.04 - 5.12 (m, IH), 6.28 (d, IH, 7= 11.3 Hz), 7.26 (dd, IH, 7= 2.4 Hz, 9.0 Hz), 7.32 (d, IH, 7= 2.2 Hz), 7.66 (dd, IH, 7= 1.9 Hz, 8.7 Hz), 7.73 (t, IH, 7= 1.7 Hz), 7.87 (d, IH, 7= 9.0 Hz), 3.94 (d, IH, 7= 8.6 Hz), 8.10 (s, IH), 8.21 (t, 1H, 7= 1.8 Hz), 9.62 (s, IH). [511] EXAMPLE 5-lb (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CO2H, and (HA6)n7 = HCO2H: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H. 1H NMR (CD3OD, 200 MHz) δ 0.93 (d, 3H, 7= 6.6 Hz), 1.33 (s, 6H), 2.30 (s, 6H), 3.91 - 4.00 (m, IH), 4.09 (s, 2H), 5.42 (d, IH, 7= 10.6 Hz), 6.96 (s, IH), 7.14 (dd, IH, 7= 2.6 Hz, 9.1 Hz), 7.22 (d, IH, 7- 2.6 Hz), 7.35 (s, IH), 7.58 - 7.94 (m, 5H); MS (ES) 395.9 (M+l). [512] EXAMPLE 5-2a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-Ph, n3 = 1, R4b and R5b = H, Q1 = CO2H, and (HA6)n7 = HCO2H: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 - N(CH3)2, n2 = 1, Z = 4-Ph, n3 = 1, R4b and R5b = H, and Q1 = CO2H. 1H NMR (CD3OD, 200 MHz) δ 0.93 (d, 3H, 7= 6.6 Hz), 2.42 (s, 6H), 3.90-3.99 (m, IH), 4.54 (s, 2H), 5.14 (s, 2H), 5.52 (d, IH, 7= 11.2 Hz), 6.97 (d, 2H, J= 8.4 Hz), 6.90 (d, IH, 7= 1.4 Hz), 7.25 (dd, IH, 7= 2.6 Hz, 6.6 Hz), 7.33-7.43 (m, 3H), 7.50-7.58 (m, 2H), 7.81 (d, 2H, 7= 8.8 Hz), 7.90-7.95 (m, IH), 8.37 (s, IH), 8.44 (s, IH); MS (ES) 460.0 (M+l).
[513] EXAMPLE 5-3a (Compound of Formula I-(HA6)π7 where X 1 = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R b and R5b = CH2CH3, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol- 1-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH2CH3, and Q1 = CO2H. Η NMR (CD3OD, 400 MHz) δ 0.89 (t, 6H, 7= 7.6 Hz), 1.29 (d, 3H, 7= 6.8 Hz), 1.81 (q, 4H, 7= 7.6 Hz), 3.01 (s, 3H), 3.09 (s, 3H), 3.30 (s, 2H), 5.06 - 5.11 (m, IH), 6.28 (d, IH, 7= 11.2 Hz), 7.23 (dd, IH, 7= 2.8, 9.2 Hz), 7.34 (d, IH, 7= 2.0 Hz), 7.67 (t, 2H, 7= 12.4 Hz), 7.85 (d, IH, 7= 9.2 Hz), 7.93 (d, 1H, 7= 8.8 Hz), 8.10 (s, IH), 8.20 (s, IH), 9.62 (s, IH). [514] EXAMPLE 5-4a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 - N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, Q1 = CO2H, and (HA6)n = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 - H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopropyl ring, and Q1 = CO2H. Η NMR (DMSO-<4, 400 MHz), δ 1.15 - 1.18 (m, 2H), 1.20 (d, 3H, 7= 6.5 Hz), 1.33 - 1.36 (m, 2H), 2.91 (s, 3H), 3.02 (s, 3H), 4.29 (s, 2H), 5.24 - 5.35 (m, IH), 6.51 (d, 1H, 7= 11.3 Hz), 7.36 (dd, 1H, 7 = 2.5, 8.9 Hz), 7.45 (d, 1H, 7= 2.4 Hz), 7.85 - 7.86 (m, 2H), 7.92 (d, IH, 7= 9.1 Hz), 8.00 (d, IH, 7= 8.9 Hz), 8.24 (s, IH), 8.39 (s, IH), 9.97 (s, IH), 10.39 (s, IH). [515] EXAMPLE 5-5a (Compound of Formula I-(HA6)n7 where XI = imidazol- 1-yb R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclobutyl ring, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the , General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclobutyl ring, and Q1 = CO2H. 1H NMR (DMSO-76, 400 MHz), δ 1.10 (d, 3H, 7= 7.61), 1.85 - 2.10 (m, 4H), 2.37 - 2.45 (m, 2H), 2.82 (s, 3H), 2.92 (s, 3H), 4.33 (s, 2H), 5.23 - 5.27 (m, IH), 6.46 (d, IH, 7= 11.0 Hz), 7.23 (dd, IH, 7= 2.5, 9.0 Hz), 7.44 (d, IH, 7= 2.4 Hz), 7.75 (s, IH), 7.78 - 7.83 (m, 2H), 7.91 (d, IH, 7= 8.7 Hz), 8.17 (s, IH), 8.33 (s, IH), 9.93 (s, IH), 10.36 (s, IH).
[516] EXAMPLE 5-6a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4 and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol- 1-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a 4-pyranyl ring, and Q1 = CO2H. ]H NMR (DMSO-- 400 MHz), δ 1.10 (d, 3H, 7= 6.8 Hz), 1.63 - 1.71 (m, 2H), 2.03 (d, 2H, 7= 13.6 Hz), 2.82 (s, 3H), 2.93 (s, 3H), 3.49 (t, 2H, 7= 10.4 Hz), 3.77 - 3.81 (m, 2H), 4.17 (s, 2H), 5.24 - 5.28 (m, IH), 6.47 (d, IH), 7.21 (dd, IH, 7= 2.4, 8.8 Hz), 7.42 (d, IH, J= 2.4 Hz), 7.75 - 7.84 (m, 2H), 7.91 (d, IH, 7 = 8.4 Hz), 8.18 (s, IH), 8.33 (s, IH), 9.94 (s, IH), 10.38 (s, IH). [517] EXAMPLE 5-7a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring, Q1 = CO2H, and (HA6)n = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3) , n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclohexyl ring, and Q1 = CO2H. Η NMR (CD3OD, 400 MHz) δ 1.34 (d, 3H, 7= 6.7 Hz), 1.54 - 1.69 (m, 8H), 2.18 - 2.26 (m, 2H), 3.06 (s, 3H), 3.14 (s, 3H), 4.18 (s, 2H), 5.05 - 5.14 (m, IH), 6.31 (d, IH), 7.28 (dd, IH, 7= 2.3, 9.1 Hz), 7.34 (s, IH), 7.69 (d, IH, 7= 8.7 Hz), 7.76 (s, IH), 7.89 (d, IH, 7= 8.9 Hz), 7.97 (d, IH, 7= 8.8 Hz), 8.13 (s, IH), 8.24 (s, IH), 9.65 (s, IH).
[518] EXAMPLE 5-8a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol- 1-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, and Q1 = CO2H. 1H NMR (CD3OD, 400 MHz) δ 1.29 (d, 3H, 7= 6.8 Hz), 1.75 - 1.83 (m, 6H), 2.14 - 2.23 (m, 2H), 3.00 (s, 3H), 3.07 (s, 3H), 4.19 (s, 2H), 5.01 - 5.09 (m, IH), 6.25 (d, IH, 7= 11.2 Hz), 7.22 (dd, IH, 7= 2.4, 8.8 Hz), 7.30 (d, IH, 7= 2.4 Hz), 7.63 (d, IH, 7= 8.8 Hz), 7.70 (s, IH), 7.84 (d, IH, 7= 9.2 Hz), 7.91 (d, IH, 7= 8.4 Hz), 8.07 (d, IH, 7= 1.6 Hz), 8.18 (d, IH, 7= 1.2 Hz), 9.59 (s, IH). [519] EXAMPLE 5-9a (Compound of Formula I-(HA6)n7 where XI = imidazol- 1-yl, R2 = CH3, R3 = H, G1 = N(CH3)ιPr, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)ιPτ, n2 = 0, n3 = 1, R4b and R5b are taken together with the carbon to which they are attached to equal a cyclopentyl ring, and Q1 = CO2H. lK NMR (CD3OD, 400 MHz) δ 1.12 - 1.16 (m, 3H), 1.31 - 1.76 (m, 8H), 2.08 (s, 3H), 2.92 - 2.98 (m, IH), 3.61 - 3.73 (m, IH), 4.09 (s, 2H), 6.27 (d, IH, 7= 7.5 Hz), 7.12 (dd, IH, 7= 2.3, 9.0 Hz), 7.20 (s, IH), 7.62 (s, 2H), 7.75 (d, IH, 7= 9.1 Hz), 7.80 - 7.82 (m, IH), 8.04 (s, IH), 8.19 (s, IH), 9.39 (s, IH). [520] EXAMPLE 5-10a (Compound of Formula I-(HA6)n7 where XI - imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH2CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH2CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H. 'HNMR (CD3OD, 400 MHz) δ 1.29 (d, 3H, 7= 6.8 Hz), 1.37 (s, 6H), 1.48-1.54 (m, 6H), 3.25-3.29 (m, IH), 3.61-3.66 (m, IH), 3.77-3.82 (m, IH), 4.14 (s, 2H), 5.00-5.04 (m, IH), 6.47 (d, IH, 7= 10.4 Hz), 7.25 (dd, IH, 7= 2.8, 9.2 Hz), 7.32 (d, IH, 7= 2.4 Hz), 7.72-7.76 (m, 2H), 7.88 (d, IH, 7= 9.2 Hz), 7.93 (d, IH, 7= 8.4 Hz), 8.19 (d, IH, 7= 1.6 Hz), 8.28-8.29 (m, IH), 9.67 (s, IH). [521 ] EXAMPLE 5- 11 a (Compound of Formula I-(HA6)n7 where X 1 = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)cyclohexyb n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)cyclohexyl, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H. 'HNMR (CD3OD, 400 MHz) δ 1.26-1.28 (m, 4H), 1.37 (s, 6H), 1.45-1.47 (m, 3H), 1.73-1.76 (m, 2H), 1.94-2.01 (m, 2H), 2.11-2.13 (m, IH), 2.49-2.57 (m, IH), 3.06 (s, 3H), 3.43-3.45 (m, IH), 4.13 (s, 2H), 5.08-5.11 (m, IH), 6.41 (d, 1H, 7= 11.2 Hz), 7.25 (dd, 1H, 7= 2.4, 8.8 Hz), 7.31 (d, IH, 7= 2.4 Hz), 1.12-1.15 (m, 2H), 7.87 (d, IH, 7= 9.2 Hz), 7.92 (d, IH, 7= 9.2 Hz), 8.12 (s, IH), 8.31 (s, IH), 9.51 (s, IH).
[522] EXAMPLE 5-12a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)«-Bu, n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)«-Bu, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H. 'HNMR (CD3OD, 400 MHz) δ 1.06 (t, 3H, 7= 7.2 Hz), 1.29-1.32 (m, 4H), 1.37 (s, 6H), 1.45-1.53 (m, 3H), 1.70-1.72 (m, IH), 3.07 (s, 3H), 3.04-3.09 (m, IH), 3.35-3.46 (m, IH), 4.13 (s, 2H), 6.36 (d, IH, 7= 11.2 Hz), 7.25 (dd, IH, 7= 2.4, 8.8 Hz), 7.32 (d, IH, 7= 2.4 Hz), 1.11-1.13 (m, 2H), 7.87 (d, IH, J= 8.8 Hz), 7.93 (d, IH, 7=8.4 Hz), 8.16 (s, IH), 8.28 (s, IH), 9.60 (s, IH). [523] EXAMPLE 5-13a (Compound of Formula I-(HA°)n7 where XI = imidazol- 1-yb R2 = CH3, R3 = H, G1 = N(CH3) Pr, n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)/Pr, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H. 'HNMR (CD3OD, 400 MHz) δ 1.28 (d, 3H, 7= 6.4 Hz), 1.37 (s, 6H), 1.51 (d, 3H, 7= 6.8 Hz), 1.58 (d, 3H, 7= 6.8 Hz), 3.08 (s, 3H), 3.76-3.83 (m, IH), 4.14 (s, 2H), 5.02-5.10 (m, IH), 6.42 (d, IH, 7= 10.8 Hz), 7.25 (dd, IH, 7= 2.4, 8.8 Hz), 7.31 (d, IH, 7= 2.4 Hz), 1.13-1.11 (m, 2H), 7.87 (d, IH, 7= 8.8 Hz), 7.92 (d, 1H, 7= 8.8 Hz), 8.18 (s, IH), 8.34 (s, IH), 9.54 (s, IH). [524] EXAMPLE 5-14a (Compound of Formula I-(HA6)n7 where XI = imidazol- 1-yb R2 = CH3, R3 = H, G1 = N(CH3)Et, n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)Et, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H. 1HNMR (CD3OD, 400 MHz) δ 1.26 (d, 3H, 7= 6.8 Hz), 1.33 (s, 6H), 1.48 (t, 3H, 7= 7.2 Hz), 3.03 (s, 3H), 3.36-3.41 (m, IH), 3.52-3.57 (m, IH), 4.11 (s, 2H), 5.06-5.10 (m, IH), 6.47 (d, IH, 7= 10.8 Hz), 7.20 (dd, IH, 7= 2.4, 8.8 Hz), 7.27 (s, IH), 1.68-1.11 (m, 2H), 7.84-7.90 (m, 2H), 8.21-8.34 (m, 2H), 9.68 (s, IH).
[525] EXAMPLE 5-15a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4a and R5b = H, Q1 = CO2H, and (HA6)n7 = HCO2H: The title compound was prepared according to the General Synthetic Method E followed by General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4a and R5b = H, Q1 = CO2H, compound of Formula I-B, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4a and R5b = H, and compound of Formula I-C, XI = imidazol- l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-PhO, n3 = 1, R4a and R5b = H, and R7 = CH3. 1H NMR (CD3OD, 200 MHz) δ 0.93 (d, 3H, 7= 6.6 Hz), 2.42 (s, 6H), 3.90-3.99 (m, IH), 4.54 (s, 2H), 5.14 (s, 2H), 5.52 (d, 1H, 7= 11.2 Hz), 6.97 (d, 2H, 7 = 8.4 Hz), 6.90 (d, IH, 7= 1.4 Hz), 7.25 (dd, IH, 7= 2.6 Hz, 6.6 Hz), 7.33-7.43 (m, 3H), 7.50-7.58 (m, 2H), 7.81 (d, 2H, 7= 8.8 Hz), 7.90-7.95 (m, IH), 8.37 (s, IH), 8.44 (s, IH); MS (ES) 460.0 (M+l).
[526] EXAMPLE 5-16a (Compound of Formula I-(HA6)n7 where XI = imidazol- 1-yb R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 0, Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared as follows: Compound 3-27a (100 mg, 0.24 mmol) in THF (500 μL) was charged with 2MHC1 (610 μL, 1.22 mmol) and allowed to stir at rt for 4 h. The mixture was concentrated in vacuo to afford compound 5-16a. 1HNMR (D2O, 200 MHz) δ 1.20 (d, 3H, 7= 6.6 Hz), 2.90 (s, 6H), 4.80 (s, 2H), 6.05 (d, IH, 7= 10.0 Hz), 7.17-7.22 (m, 2H), 7.5 (s, IH), 1.19-1.83 (m, 2H), 7.94 (d, 2H, 7= 6.0 Hz), 9.18 (s, IH); MS (ES) 354.2 (M+l). [527] EXAMPLE 5-16b (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 0, Q1 = CO2H, and (HA )n7 = (HC1)2: The title compound was prepared according to the procedures listed for compound 5- 16a above except for the substitution of compound 3-27b for compound 3-27a. 1HNMR (D2O, 200 MHz) δ 1.32 (d, 3H, J= 7.4 Hz), 2.90 (s, 6H), 4.80 (s, 2H), 7.17-7.22 (m, 2H), 7.5 (s, IH), 1.19-1.83 (m, 2H), 7.94 (d, 2H, 7= 6.0 Hz), 9.18 (s, IH); MS (ES) 354.3 (M+l).
[528] EXAMPLE 5-17 (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 - CH3, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CO2H, and (HA°)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = CH3, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H. MS (ES) 424.3 (M+l).
[529] General Synthetic Method G for the preparation of compounds of the Formula I-(HA6)n7 (Compound of Formula I where R1 equals H, R2 = CH3, R3 = H, G1 = N(CH3)2, n1 = 1, R4a, R5a, R6a and R6b equal H, Y equals O, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CONR7R8): An acetonitrile solution (0.3M) of compound of Formula I (1 eq) and l,l'-carbonyldiimidazole (2 eq) was refluxed at 80 °C for 16 h. HNR7R8 (solution in THF, 1.0 mmol) was added dropwise to the reaction mixture. After stirring for 3 h, the reaction mixture was concentrated in vacuo, partitioned between sat. NaHCO3 and CH2C12, and the aqueous layer extracted with CH2C1 (5 ). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by Gilson HLPC to afford compounds of Formula I-(HA6)n7. [530] EXAMPLE 5-18a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CONH2, and (HA6)n7 = HCO2H: The title compound was prepared according to the General Synthetic Method G as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H and HNR7R8 = NH3. MS (ES) 395.3 (M+l). [531] EXAMPLE 5-19a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CONHCH3, and (HA6)n = HCO2H: The title compound was prepared according to the General Synthetic Method G as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H and HNR7R8 = NH2CH3. Η NMR (CD3OD, 400 MHz) δ 0.90 (d, 3H, 7= 6.4 Hz), 1.32 (s, 6H), 2.40 (s, 6H), 2.74 (s, 3H), 3.90-3.98 (m, IH), 4.07 (s, 2H), 5.06 (d, IH, 7= 10.4 Hz), 7.17 (dd, IH, 7= 6.4 Hz, 2.4 Hz), 7.24 (d, IH, 7= 2.4 Hz), 7.51 (d, IH, 7= 8.8 Hz), 7.76-7.81 (m, 3H), 7.89 (s, IH), 8.39 (s, IH); MS (ES) 409.2 (M+l).
[532] EXAMPLE 5-20a (Compound of Formula I-(HA6)n7 where XI = imidazol- 1-yb R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, Q1 = CON(CH3)2, and (HA6)n7 = HCO2H: The title compound was prepared according to the General Synthetic Method G as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH3, and Q1 = CO2H and HNR7R8 = NH(CH3)2. MS (ES) 423.3 (M+l).
[533] General Synthetic Method H for the preparation of compounds of the Formula I-(HA6)n7 (Compound of Formula I where R1 equals H, R2 = CH3, R3 = H, G1 = N(CH3)2, n1 = 1, R4a, R5a, R6a and R6b equal H, Y equals O, n2 = 0, n3 = 1, R4b and R5b = CH3, n4 = 1, and Q1 = CONR7R8): A DMF solution of compound of Formula I (1 eq), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 7 o eq), HNR R ΗC1 (1.5 eq), and l-hydroxy-7-azabenzotriazole (0.5 eq) was charged with diisopropylethylamine (1.5 eq) dropwise and stiπed at rt for 16 h. Upon completion, the reaction mixture was concentrated in vacuo, partitioned between sat. NaHCO3 and CH2C12, and the aqueous layer extracted with CH2C12 (5x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by Gilson HLPC to afford compounds of Formula I-(HA6)n .
[534] EXAMPLE 5-21a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-Ph, n3 = 0, Q1 = CONH2, and (HA6)n7 = HCO2H: The title compound was prepared according to the General Synthetic Method H as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-Ph, n3 = 0, and Q1 = CO2H and HNR7R8 = NH3. MS (ES) 429.3 (M+l). [535] EXAMPLE 5-22a (Compound of Formula I-(HA6)n7 where XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-Ph, n3 = 0, Q1 = CONHCH3, and (HA6)n7 = HCO H: The title compound was prepared according to the General Synthetic Method H as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-Ph, n3 = 0, and Q1 = CO2H and HNR7R8 = NH2CH3 MS (ES) 443.3 (M+l). [536] EXAMPLE 5-23a (Compound of Formula I-(HA6)n7 where XI = imidazol- 1-yb R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-Ph, n3 = 0, Q1 = CON(CH3) , and (HA6)n = HCO H: The title compound was prepared according to the General Synthetic Method H as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-Ph, n3 = 0, and Q1 = CO2H and HNR7R8 = NH(CH3)2. 1H NMR (CD3OD, 400 MHz) δ 0.91 (d, 3H, 7= 6.8 Hz), 2.41 (s, 6H), 2.96 (s, IH), 3.09 (s, IH), 3.90-4.10 (m, IH), 5.26 (s, 2H), 5.53 (d, IH, 7= 11.6 Hz), 7.19 (s, IH), 7.27 (dd, IH, J= 2.4, 6.4 Hz), 7.33 (d, IH, 7= 2.8 Hz), 7.37 (d, IH, 7= 7.6 Hz), 7.47-7.54 (m, 4H), 7.60 (d, IH, 7= 7.6 Hz), 1.18-1.82 (m, 2H), 7.91 (s, IH), 8.46 (s, IH); MS (ES) 457.3 (M+l). [537] EXAMPLE 5-24a (Compound of Formula I-(HA°)n7 where XI = imidazol-l-yl, R2 = CH2CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4b and R5b = CH , Q1 = CO2H, and (HA6)n7 = (HC1)2: The title compound was prepared according to the General Synthetic Method F as described above wherein compound of Formula I, XI = imidazol-l-yl, R2 = CH2CH3, R3 = H, G1 = N(CH3)2, n2 = 0, n3 = 1, R4 and R5b = CH3, and Q1 = CO2H. Η NMR (CD3OD, 400 MHz) δ 0.81 (t, 3H, 7= 7.6 Hz), 1.37 (s, 6H), 1.63 - 1.75 (m, IH), 1.85 - 1.94 (m, IH), 3.02 (s, 3H), 3.10 (s, 3H), 4.11 (s, 2H), 5.06 - 5.11 (m, IH), 6.59 (d, IH, 7= 11.6 Hz), 7.17 (d, IH, 7= 2.8 Hz), 7.23 (dd, IH, 7= 2.4, 9.2 Hz), 7.42 (s, IH), 7.47 (s, IH), 7.74 (dd, IH, 7= 2.0, 8.8 Hz), 7.82 - 7.85 (m, 2H), 8.19 (s, IH), 8.35 (s, IH), 9.91 (s, IH). [538] EXAMPLE 5-25a (Compound of Formula I-(HA6)n7 where XI = imidazol- 1-yl, R2 = CH3, R3 = H, G1 = N(CH3)2, n2 = 1, Z = 4-Ph, n3 = 0, Q1 = OH, and (HA6)n7 = HCO H: A methylene chloride solution (1 mL) of compound 3-6a (20 mg, 0.044 mmol) was charged with trifluoroacetic acid and allowed to stir at rt for 16 h. Upon completion, the reaction mixture was concentrated in vacuo to solids, taken up in minimal water, and neutralized to pH 7 with sat. NaHCO3. The white solid that precipitated out of solution was filtered, washed with water, and purified on Gilson HPLC to afford the desired product as a white solid; Η NMR (CD3OD, 200 MHz) δ 0.83 (d, 3H, 7= 6.6 Hz), 2.30 (s, 6H), 3.70-3.79 (m, IH), 4.32 (s, 2H), 5.32 (d, IH, 7 = 10.6 Hz), 6.63 (d, 2H, J= 8.4 Hz), 6.90 (s, IH), 7.02 (d, 2H, 7= 8.8 Hz), 7.21 (d, IH, 7= 9.2 Hz), 7.28-7.31 (m, IH), 7.42 (d, IH, 7= 8.4 Hz), 7.68 (d, IH, 7= 9.2 Hz), 7.81-7.89 (m, 2H), 8.58 (s, 2H); MS (ES) 402.0 (M+l).

Claims

WHAT IS CLAIMED IS: 1. A compound represented by Formula I
or a pharmaceutically acceptable salt thereof wherein: 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 R66 substituents; R1 is a C0-6alkyb -OR7, -SR7, or -NR7R8; R2 and R3 are each independently Co-ioalkyl, C2-ιoalkenyb C2.1oalkynyb Ci- loalkoxyCi-ioalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ιoalkoxyC -ιoalkynyb Ci-ioalkylthioCi. loalkyb Cι-ιoalkylthioC2-ιoalkenyb Cι-ιoalkylthioC2-ιoalkynyb cycloC3.8alkyb cycloC . 8alkenyb cycloC .8alkylCι-ιoalkyb cycloC -8alkenylCι-ιoalkyb cycloC -8alkylC2- loalkenyb cycloC3-8alkenylC2.ιoalkenyb cycloC3-8alkylC2-ιoalkynyb cycloC3. 8alkenylC2-ioalkynyb heterocyclyl-Co-i oalkyb heterocyclyl-C -ιoalkenyb heterocyclyl-C2-ιoalkynyb Cι-ιoalkylcarbonyb C2- loalkenylcarbonyb C2- loalkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι-ιoalkyb monoCi- 6alkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR71R81, or -NR71R81 substituents; or aryl-Co-i oalkyb aryl-C -ι0alkenyb or aryl-C2.ioalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Ci-ioalkyl, C2-ιoalkenyl, C2-ιoalkynyl, haloCi- loalkyl, haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, CMalkoxycarbonyb -CONR7,R81, -SO2NR7,R81 or -NR71R81 substituents; or hetaryl-Co-ioalkyl, hetaryl-C2_ loalkenyb or hetaryl-C -ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Ci-ioalkyl, C -ιoalkenyl, C2-
- - loalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, Ci- 4alkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; or 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 Cι-6alkyl, halo, cyano, nitro, -OR71, -SO2NR71R81 or -NR71R81 substituents; G1 is -OR72, -SR72, -NR72R82(R9)n5, or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or in the case of -NR72R82(R9)n5, R72 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, nitro, C Oalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is an oxygen atom, sulfur atom, -(C=O)N(R74)-, >CR4cR5c or >NR74; Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-, -alkenylaryl- -hetaryl-, -hetarylalkyl-, -alkylhetaryl-, -hetarylalkenyl-, -alkenylhetaryl- or -aryl-, any of which is optionally substituted with R68; Q1 is C0.6alkyb -OR75, -NR75R85(R95)n6, -CO2R75, -CONR75R85, -(C=S)OR75, -(C=O)SR75, -NO2, -CN, halo, -S(O)n6R75, -SO2NR75R85, -NR75(C=NR775)NR7775R85, -NR75(C=NR775)OR7775, -NR75(C=NR775)SR7775, -O(C=O)OR75, -O(C=O)NR75R85, -O(C=O)SR75, -S(C=O)OR75, -S(C=O)NR75R85, -S(C=O)SR75, -NR75(C=O)NR775R85, or -NR75(C=S)NR775R85; in the case of -NR75R85(R95)n6, R75 and R85 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, d-ioalkoxy, -SO2NR76R86 or -NR76R86 substituents;
- R4a, R4b, R4c, R5a, R5b and R5c are each independently a C0-ι0alkyb C2. loalkenyb C2.ιoalkynyb Cι-ιoalkoxyCι-ι oalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ιoalkoxyC2. loalkynyb Ci-ioalkylthioCi-ioalkyb Cι-ιoalkylthioC2-ιoalkenyb Cι-ιoalkylthioC2- loalkynyb cycloC .8alkyb cycloC3.8alkenyb cycloC3.8alkylCι-ιoalkyb cycloC3- 8alkenylCι -loalkyb cycloC3.8alkylC2-ιoalkenyb cycloC .8alkenylC -ιoalkenyb cycloC3- 8alkylC2-ιoalkynyb cycloC3-8alkenylC -ιoalkynyb heterocyclyl-Co-i oalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C -ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci-ioalkyl, C2-ι0alkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2- loalkynyl, -COOH, CMalkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or hetaryl-Co-i oalkyb hetaryl-C2-ιoalkenyb or hetaryl-C2-ι0alkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci-ioalkyl, C2-ιoalkenyb C2-ιoalkynyl, haloCi-ioalkyb haloC2-ιoalkenyl, haloC2. loalkynyl, -COOH, CMalkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι-6alkyl)aminoCι-6alkyb mono(aryl)aminoC loalkyb di(aryl)aminoCι-6alkyb or -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Cι-ιoalkyb C2-ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-i0alkynyb -COOH, Cι-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a or R4b with R5b, or R4c with R5c, 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 R69; or R4a with R5a, or R4b with R5b, or R4c with R5c, 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 R69; nl, n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2; R6a, R6b, R66, R67, R68, and R69 are each independently halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, C0. loalkyl, C2.ι0alkenyb C2-ιoalkynyb Cι-ι0alkoxyCι-ι oalkyb Cι-ιoalkoxyC2-ι0alkenyb Ci- ιoalkoxyC2-ιoalkynyb Ci-ioalkylthioCi-ioalkyb Cι-ιoalkylthioC2-ιoalkenyb Ci- ιoalkylthioC2-ι oalkynyb cycloC3.8alkyb cycloC3-8alkenyb cycloC3-8alkylCι.ι oalkyb cycloC3-8alkenylCι-ιoalkyb cycloC3.8alkylC2-ιoalkenyb cycloC3.8alkenylC2-ιoalkenyb cycloC3-8alkylC2-ιoalkynyb cycloC3-8alkenylC2-ιoalkynyb heterocyclyl-Co-i oalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, -SO2NR778R888 or -NR778R888 substituents; or aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2.ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, 778 nitro, -OR , Ci-ioalkyl, C2-ιoalkenyl, C -ιoalkynyl, haloCi-ioalkyb haloC2.ιoalkenyb haloC2-,0alkynyb -COOH, Cι.4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or hetaryl-Co-i oalkyb hetaryl-C2.ιoalkenyb or hetaryl-C2. loalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, Ci-ioalkyl, C2-ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2- loalkenyb haloC2-ι0alkynyb -COOH, CMalkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or di(Cι- 6alkyl)aminoC i -6alkyb mono(aryl)aminoC ι .6alkyb di(aryl)aminoC i -6alkyb -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR , Ci-ioalkyl, C2-ιoalkenyl, C2-ιoalkynyb haloCi- loalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or in the case of -NR78R88(R98)n7, R78 and R88 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, Cι-ιoalkoxy, -SO2NR778R888 or -NR778R888 substituents; R7, R71, R72, R73, R74, R75, R775, R7775, R76, R77, R78, R778, R8, R81, R82, R83, R84, R85, R86, R87, R88, R888, R9, R95, and R98 are each independently C0-ι0alkyb C2- loalkenyb C2-ιoalkynyb Cι-ιoalkoxyCι-ι oalkyb Cι-ι0alkoxyC2-ιoalkenyb Cι-ιoalkoxyC2- loalkynyb Cι-ιoalkylthioCι-ιoalkyb Cι-ιoalkylthioC2.ιoalkenyb Cι-ιoalkylthioC2. loalkynyb cycloC .8alkyb cycloC3.8alkenyb cycloC3.8alkylCι-ι oalkyb cycloC - 8alkenylCι-ιoalkyb cycloC3.8alkylC2-ιoalkenyb cycloC -8alkenylC2-ιoalkenyb cycloC3- 8alkylC2-ιoalkynyb cycloC3.8alkenylC2-ι0alkynyb heterocyclyl-Co-i oalkyb heterocyclyl-C2-ιoalkenyb heterocyclyl-C2-ιoalkynyb Cι-ιoalkylcarbonyb C2. loalkenylcarbonyb C2-ιoalkynylcarbonyb Ci-ioalkoxycarbonyb Ci-ioalkoxycarbonylCi- loalkyb monoCi-όalkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2N(Co.4alkyl)(Co-4alkyl) or -N(Co-4alkyl)(C0.4alkyl) substituents; aryι-Co-ι oalkyb aryl-C2-ι0alkenyb or aryl-C _i oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co- alkyl), Ci-ioalkyl, C2-ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2- loalkynyb -COOH, CMalkoxycarbonyb -CON(C0-4alkyl)(C0-ι0alkyl), -SO2N(C0. 4alkyl)(Co-4alkyl) or -N(Co-4alkyl)(Co-4alkyl) substituents; or hetaryl-Co-i oalkyb hetaryl-C - loalkenyb or hetaryl-C .ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Ci-ioalkyl, C2. loalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2.ιoalkynyb -COOH, CMalkoxycarbonyb -CON(C0-4alkyl)(C0-4alkyl), -SO2N(C0- alkyl)(C0- alkyl) or -N(Co-4alkyl)(Co-4alkyl) substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι. 6alkyl)aminoCι-6alkyb mono(aryl)aminoCι-6alkyb di(aryl)aminoCι-6alkyb or -N(Ci-6alkyl)-Ci-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OfCo^alkyl), Cj-ioalkyb C2-ιoalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, CMalkoxycarbonyb -CON(Co- alkyl)(Co-4alkyl), -SO2N(C0-4alkyl)(C0-4alkyl) or -N(C0-4alkyl)(C0- alkyl) substituents.
2. The compound of claim 1 wherein X is imidazolyl or triazolyb any of which is optionally substituted with one or more independent R66 substituents.
3. The compound of claim 2 wherein X is imidazolyl or triazolyb
4. The compound of claim 2 wherein Q1 is -CO2H or -CO2R75.
5. The compound of claim 1 wherein Y is an oxygen atom.
6. The compound of claim 5 wherein X is imidazolyl or triazolyb any of which is optionally substituted with one or more independent R66 substituents.
7. The compound of claim 5 wherein X is imidazolyl or triazolyb
8. The compound of claim 5 wherein Q1 is -CO2H or -CO2R75.
9. The compound of claim 5 wherein R4a and R5a are each hydrogen.
10. The compound of claim 2 wherein R1, R2 and R3 are each independently Co-ioalkyl; G1 is -NR72R82; or G1 and R3 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 R67 and an N heteroatom of the heterocyclic saturated ring or heterocyclic unsaturated ring optionally is substituted with an R72 substituent; or R72 and R82 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, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Y is oxygen; Q1 is C0-6alkyl, -CO2R75, or -CONR75R85; R4a, R4b, R5a, and R5b are each independently a Co-ioalkyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5a or R4b with R5b 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 R69; or R4a with R5a, or R4b with R5b 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 R69; and R6a and R6 are each independently halo, -OR78, -NR78R88(R98)n7, -CO R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, or C0-,0alkyb
11. The compound of claim 10 wherein X is imidazolyl or triazolyl; R1 is hydrogen; R2 and R3 are each independently Co-ioalkyl; Q1 is -CO2R75 or -CONR75R85; and R6a and R6b are each independently a hydrogen atom.
12. The compound of claim 10 wherein R4a and R5a are each hydrogen; and R4b and R5b are each independently C0-ι0alkyl; or R4b with R5 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 R69; or R4b with R5b 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 R69.
13. The compound of claim 10 wherein R4b and R5b are each independently
Co-6alky Al,, oorr RR44bb wwiitthh RR55bb ttaakkeenn ttooggeetthheerr wwiitthh tthhee rreessppeecctive carbon atom to which they are attached form a 3-10 membered saturated ring.
14. The compound of claim 13 wherein R with R taken together with the respective carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring.
15. The compound of claim 13 wherein R4b and R5b are both ethyl, or are both methyl.
16. The compound of claim 10 wherein Q1 is -CO2R75.
17. The compound of claim 10 wherein Q is -CO2H
18. The compound of claim 10 wherein G is di(Cι-6alkyl)amino
19. The compound of claim 10 wherein G , 1 is dimethylamino, ethylmethylamino, diethylamino, or isopropylmethylamino.
20. The compound of claim 10 wherein R and R are each independently hydrogen, methyl, or ethyl.
21. The compound of claim 10 wherein a) R is hydrogen; and G1 and R3 taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached; or b) R is hydrogen; and G1 and R3 taken together with the carbon atom to which they are attached form
wherein • is the carbon to which they are attached, any of which is optionally substituted by 1-10 independent R67 substituents.
22. The compound of claim 3 wherein X is imidazole.
23. The compound of claim 11 wherein R is hydrogen and R is methyl.
24. The compound of claim 11 wherein R2 is hydrogen and R3 is ethyl.
25. The compound of claim 11 wherein R2 and R3 are both methyl.
26. The compound of claim 21 wherein nl and n2 are each 1 and Z is aryl.
27. The compound of claim 26 wherein n3 and n4 are each 0.
28. The compound of claim 1 wherein Z is -aryl- or -aryloxy- or -oxyaryl-.
29. The compound of claim 26 wherein Q1 is -CO2R75.
30. The compound of claim 29 wherein Q1 is -CO2H.
31. The compound of Formula I according to claim 1, selected from the group consisting of:
3-[6-(2-Dimethylamino-l-imidazol-l-yl-propyl)-naphthalen-2-yloxy]-2,2- dimethyl-propionic acid;
2-[6-(2-Dimethylamino-l-imidazol-l-yl-propyl)-naphthalen-2-yloxymethyl]-2- ethyl-butyric acid;
1 -[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2-yloxymethyl]- cyclopropanecarboxylic acid;
1 -[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2-yloxymethyl] - cyclobutanecarboxylic acid;
1 -[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2-yloxymethyl]- cyclopentanecarboxylic acid;
1 -[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2-yloxymethyl]- cyclohexanecarboxylic acid;
1 - {6-[ 1 -Imidazol- 1 -yl-2-(isopropylmethylamino)-propyl]-naphthalen-2- yloxymethyl} -cyclopentanecarboxylic acid;
3-[6-(2-Diethylamino-l-imidazol-l-yl-propyl)-naphthalen-2-yloxy]-2,2-dimethyl- propionic acid;
3- {6-[l -Imidazol- l-yl-2-(isopropylmethylamino)-propyl]-naphthalen-2-yloxy}- 2,2-dimethyl-propionic acid;
3- {6-[2-(Ethyl-methyl-amino)-l -imidazol- l-yl-propyl]-naphthalen-2-yloxy} -2,2- dimethyl-propionic acid;
3-[6-(2-Dimethylamino-l -imidazol- l-yl-propyl)-naphthalen-2-yloxy]-2,2- dimethyl-propionamide; 3-[6-(2-Dimethylamino-l-imidazol-l-yl-propyl)-naphthalen-2-yloxy]-2,2,N- trimethyl-propionamide;
3-[6-(2-Dimethylamino-l-imidazol-l-yl-propyl)-naphthalen-2-yloxy]-2,2,N,N- tetramethyl-propionamide;
3-[6-(2-Dimethylamino-l-imidazol-l-yl-butyl)-naphthalen-2-yloxy]-2,2-dimethyl- propionic acid;
4-[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2-yloxymethyl]- benzoic acid;
3-[6-(2-Dimethylamino-l-imidazol-l-yl-propyl)-naphthalen-2-yloxymethyl]- benzoic acid;
4-[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2-yloxymethyl] - benzamide;
4-[6-(2-Dimethylamino-l -imidazol- 1-yl-prop yl)-naphthalen-2-yloxymethyl]-N- methyl-benzamide;
4-[6-(2-Dimethylamino- 1 -imidazol- 1 -yl-propyl)-naphthalen-2-yloxymethyl] -N,N- dimethyl-benzamide; and l-[(6-Benzyloxy-naphthalen-2-yl)-(l-methyl-pyrrolidin-2-yl)-methyl]-lH- imidazole.
32. A compound according to claim 1 represented by Formula I:
or a pharmaceutically acceptable salt thereof, wherein
EX. R2 RJ G' n2 Z n3 R4k RΆ n4 Q1 X syn CH3 H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 XI anti CH3 H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 XI syn CH3 H N(CH3)2 4 Ph 0 - - 1 C02CH3 XI anti CH3 H N(CH3)2 4 Ph 0 - - 1 C02CH3 X I syn CH3 H N(CH3)2 3 Ph 0 - - 1 C02CH3 X I anti CH3 H N(CH3)2 3 Ph 0 - - 1 C02CH3 X I syn CH3 H N(CH3)2 4 Ph 1 H H 1 C02CH3 XI anti CH3 H N(CH3)2 4 Ph 1 H H 1 C02CH3 XI syn CH3 H N(CH3)2 0 - 1 CH3 CH3 1 CH3 XI EX R1 Ri G1 n2 z R4b R5b n3 n4 Q1 X anti CH3 H N(CH3)2 0 - 1 CH3 CH3 CH3 XI syn CH3 H N(CH3)2 1 4 Ph 0 - - OtBu XI anti CH3 H N(CH3)2 1 4 Ph 0 - - OtBu XI syn CH3 H N(CH3)2 1 4 PhO 1 H H C02CH3 XI anti CH3 H N(CH3)2 1 4 PhO 1 H H C02CH3 XI syn CH3 H N(CH3)2 0 - 2 H H 0CH3 XI anti CH3 H N(CH3)2 0 - 2 H H OCH3 XI syn CHj H N(CH3)2 1 4 Ph 0 - - OCH3 XI syn CH3 H N(CH3)2 1 trans- 0 - - 0 XI CH=CHPh anti CH3 H N(CH3)2 1 trans- 0 - - 0 XI CH=CHPh syn CH3 H N(CH3)2 1 4 Ph 0 - - 1 CN XI anti CH3 H N(CH3)2 1 4 Ph 0 - - 1 CN XI syn CH3 H N(CH3)2 1 4 Ph 0 - - 1 N02 XI syn CH3 H N(CH3)2 0 - 1 Et Et 1 C02Et XI syn CH3 H N(CH3)2 0 - 1 CH2CH . nng 1 C02Et XI syn CH3 H N(CH3)2 0 - 1 CH2CH2CH2 πng 1 C02Et XI syn CH3 H N(CH3)2 0 - 1 CH2CH2OCH2CH2 ππg 1 C02CH3 XI syn CH3 H N(CH3)2 0 - I CH2(CH2)3CH2 ring 1 C02Et XI syn CH3 H N(CH3)2 0 - 1 CH2(CH2)2CH2 ring 1 C02Et XI syn CH3 H N(CH3)2 1 Ph 0 - - 0 XI anti CH3 H N(CH3)2 1 Ph 0 - - 0 XI syn CH, H N(CH2)2θ(CH2)2 πng 0 - 1 CH3 CH3 1 C02CH3 XI syn CH3 H N(Et)2 0 - 1 CH3 CH3 1 C02CH3 XI syn CHj H N(CHj)cyclo exy! 0 - ] CH3 CH3 1 C02CH3 XI syn CH3 H N(CH3)n-butyl 0 - 1 CH3 CH3 1 C02CH3 XI syn CH3 H N(CH3).Pr 0 - 1 CH3 CH3 1 C02CH3 XI syn CH3 H N(CH2)4 ring 0 - 1 CH3 CH3 1 C02CH3 XI syn CH3 H N(CH3)Et 0 - 1 CH3 CH3 1 C02CH3 XI syn CH3 H N(CH3)2 0 - 0 - - 1 C02tBu XI anti CH3 H N(CH3)2 0 - 0 - - 1 C02tBu XI - CH3 CH3 N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 X I - H H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 XI
syn CH3 H N(CH3)2 0 1 CH2(CH2)2CH2 ring 1 C02Et X2 syn Et H N(CH3)2 0 1 CH3 CH3 1 C02CH3 XI EX R2 R3 G1 n2 Z n3 R4b R5b n4 Q1 X syn CH3 H N(CH3)ιPr 0 - 1 CH2(CH2)2CH2 ring 1 C02Et X2 and wherein XI is imidazol-l-yl, X2 is triazol-1-yl, and wherein
is R »2T R> 3r G- l taken together with the carbon (•) to which they are attached and
wherein the syn and anti configuration are with respect to X and G .
33. A compound represented by Formula I-B:
or a pharmaceutically acceptable salt thereof wherein EX R5 RJ G1 n2 z n3 R4b R5b X syn CH3 H N(CH3)2 0 - 1 CH3 CH3 XI anti CH3 H N(CH3)2 0 - 1 CH3 CH3 XI syn CH3 H N(CH3)2 1 4 Ph 0 - - XI anti CH3 H N(CH3)2 1 4 Ph 0 - - XI syn CH3 H N(CH3)2 1 3 Ph 0 - - XI anti CH3 H N(CH3)2 1 3 Ph 0 - - XI syn CH3 H N(CH3)2 1 4 Ph H H XI anti CH3 H N(CH3)2 1 4 Ph H H XI syn CH3 H N(CH3)2 0 - Et Et XI syn CH3 H N(CH3)2 0 - CH2CH2 πng XI syn CH3 H N(CH3)2 0 - CH2CH2CH2 ring XI syn CH3 H N(CH3)2 0 - CH2CH20CH2CH2 ring XI syn CH3 H N(CH3)2 0 - CH2(CH2)3CH2 πng XI syn CH3 H N(CH3)2 0 - CH2(CH2)2CH2 πng XI syn CH3 H N(CH2)20(CH2)2 ring 0 - CH3 CH3 XI syn CH3 H N(Et)2 0 - CH3 CH3 XI syn CH3 H N(CH3)cyclohexyl 0 - CH3 CH3 XI syn CH3 H N(CH3)n-butyl 0 - CH3 CH3 XI
- EX. R2 R3 G1 n2 Z n3 R4 R5b X syn CH3 H N(CH3)iPr 0 - I CH3 CH3 XI syn CH3 H N(CH2)4 ring 0 - CH3 CH3 XI syn CH3 H N(CH3)Et 0 - CH3 CH3 XI - CH3 CH3 N(CH3)2 0 - I CH3 CH3 XI - H H N(CH3)2 0 - CH3 CH3 XI . syn CH3 H N(CH3)2 0 - CH2(CH2): CH2 ring X2 syn Et H N(CH3)2 0 - CH3 CH3 XI syn CH3 H N(CH3)iPr 0 - CH2(CH2)2 CH2 ring XI and wherein XI is imidazol-l-yl and X2 is triazol-1-yl and wherein the syn and anti configuration are with respect to X and G1
34. A compound represented by Formula II:
II or a pharmaceutically acceptable salt thereof, wherein Compounds R1 R3 G' n2 Z n3 R4b R5b n4 Q1 syn CH3 H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 anti CH3 H N(CH3)2 0 - 1 CH3 CH3 1 C02CH3 syn CH3 H N(CH3)2 1 4 Ph 0 - - 1 C02CH3 anti CH3 H N(CH3)2 1 4 Ph 0 - - 1 C02CH3 syn CH3 H N(CH3)2 1 3 Ph 0 - - 1 C02CH3 anti CH3 H N(CH3)2 1 3 Ph 0 - - 1 C02CH3 syn CH3 H N(CH3)2 1 4 Ph 1 H H 1 C02CH3 anti CH3 H N(CH3)2 1 4 Ph 1 H H 1 C02CH3 syn CH3 H N(CH3)2 0 - 1 CH3 CH3 1 CH3 anti CH3 H N(CH3)2 0 - 1 CH3 CH3 1 CH3 syn CH3 H N(CH3)2 1 4 Ph 0 - - 1 O.Bu anti CH3 H N(CH3)2 1 4 Ph 0 - - 1 O.Bu syn CH3 H N(CH3)2 1 4 PhO 1 H H 1 C02CH3 anti CH3 H N(CH3)2 1 4 PhO 1 H H 1 C02CH3 syn CH3 H N(CH3)2 0 - 2 H H 1 OCH3 anti CH3 H N(CH3)2 0 - 2 H H 1 OCH3 Compounds R* R G1 n2 z n3 R4b R5 n4 Q' syn CH3 H N(CH3)2 1 4 Ph 0 - - OCH3 anti CH3 H N(CH3)2 1 4 Ph 0 - - OCH3 syn CH3 H N(CH3)2 1 trans- 0 - 0 CH=CHPh anti CH3 H N(CH3)2 1 trans- 0 - 0 CH=CHPh syn CH3 H N(CH3)2 1 4 Ph 0 - 1 CN anti CH3 H N(CH3)2 1 4 Ph 0 - - CN syn CH3 H N(CH3)2 1 4 Ph 0 - 1 N02 anti CH3 H N(CH3)2 1 4 Ph 0 - 1 N02 syn CH3 H N(CH3)2 0 - 1 Et Et 1 C02Et anti CH3 H N(CH3)2 0 - 1 Et Et 1 C02Et syn CH3 H N(CH3)2 0 - 1 CH2CH 2 ring 1 C02Et anti CH3 H N(CH3)2 0 - 1 CH2CH 2 ring C02Et syn CH3 H N(CH3)2 0 - 1 CH2CH2CH2 πng 1 C02Et anti CH3 H N(CH3)2 0 - 1 CH2CH2CH2 rιng C02Et syn CH3 H N(CH3)2 0 - 1 CH2CH2OCH2CH2 πng ] C02CH3 anti CH3 H N(CH3)2 0 - 1 CH2CH20CH2CH2 πng C02CH3 syn CH3 H N(CH3)2 0 - 1 CH2(CH2)3 CH2 ring ] C02Et anti CH3 H N(CH3)2 0 - 1 CH2(CH2)3 CH2πng C02Et syn CH3 H N(CH3)2 0 - 1 CH2(CH2)2 CH2 πng 1 C02Et anti CH3 H N(CH3)2 0 - 1 CH2(CH2)2 CH2 rmg C02Et syn CH3 H N(CH3)2 1 Ph 0 - ( ) anti CH3 H N(CH3)2 1 Ph 0 - ( ) syn CH3 H N(CH2)20(CH2)2 r.ng 0 - CH3 CH3 C02CH3 anti CH3 H N(CH2)20(CH2)2 πng 0 - CH3 CH3 C02CH3 syn CH3 H N(Et)2 0 - CH3 CH3 C02CH3 anti CH3 H N(Et)2 0 - CH3 CH3 C02CH3 syn CH3 H N(CH3)cyclohexyl 0 - CH3 CH3 C02CH3 anti CH3 H N(CH3)cyclohexyl 0 - CH3 CH3 C02CH3 syn CH3 H N(CH3)«-butyl 0 - CH3 CH3 C02CH3 anti CH3 H N(CH3)n-butyl 0 - CH3 CH3 C02CH3 syn CH3 H N(CH3).Pr 0 - CH3 CH3 1 C02CH3 anti CH3 H N(CH3).Pr 0 - CH3 CH3 C02CH3 syn CH3 H N(CH3)Ph 0 - CH3 CH3 1 C02CH3 syn CH3 H N(CH2)4 ring 0 - CH3 CH3 I C02CH3 anti CH3 H N(CH2)4 ring 0 - CH3 CH3 C02CH3 - CH3 CH3 N(CH3)2 0 - CH3 CH3 I C02CH3 syn CH3 H N(CH3)Et 0 - CH3 CH3 C02CH3 Compounds R R n2 n3 R W R w n4 anti CH3 H N(CH3)Et 0 1 CH3 CH3 1 C02CH3 syn CH3 H N(CH3)2 0 0 - - 1 C02?Bu anti CH3 H N(CH3)2 0 0 - - 1 C02.Bu H H N(CH3)2 0 1 CH3 CH3 1 C02CH3
syn Et H N(CH3)2 0 1 CH3 CH3 1 C02CH3 anti Et H N(CH3)2 0 1 CH3 CH3 1 C02CH3 syn CH3 H N(CH3)zPr 0 1 CH2(CH2)2CH2 ring 1 C02Et anti CH3 H N(CH3)/Pr 0 1 CH2(CH2)2CH2ring 1 C02Et
and wherein they are attached, and wherein the syn and anti configuration are with respect to the
-OH and G'
35. A compound represented by Formula III:
HI or a pharmaceutically acceptable salt thereof wherein R RJ n2 n3 R 4b~ R •5T n4 CH3 H N(CH3)2 0 - 1 CH3 CH3 C02CH3 CH3 H N(CH3)2 1 4 Ph 0 - - I C02CH3 CH3 H N(CH3)2 1 3 Ph 0 - - 1 C02CH3 CH3 H N(CH3)2 1 4 Ph 1 H H I C02CH3 CH3 H N(CH3)2 0 - 1 CH3 CH3 I CH3 CH3 H N(CH3)2 1 4 Ph 0 - - I OtBu Ri Rs G1 n2 z n3 R4b RΆ n4 Q1 CH3 H N(CH3)2 1 4 PhO 1 H H 1 C02CH3 CH3 H N(CH3)2 0 - 2 H H 1 OCH3 CH3 H N(CH3)2 1 4 Ph 0 - - 1 OCH3 CH3 H N(CH3)2 1 trans- 0 - - 0 - CH=CHPh CH3 H N(CH3)2 1 4 Ph 0 - - 1 CN CH3 H N(CH3)2 1 4 Ph 0 - - 1 N02 CH3 H N(CH3)2 0 - Et Et 1 C02Et CH3 H N(CH3)2 0 - CH2CH 2 ring 1 C02Et CH3 H N(CH3)2 0 - CH2CH2CH2 ring 1 C02Et CH3 H N(CH3)2 0 - CH2CH20CH2CH2 ring 1 C02Et CH3 H N(CH3)2 0 - CH2(CH2)3 CH2 ring 1 C02CH3 CH3 H N(CH3)2 0 - CH2(CH2)2 CH2ring 1 C02Et CH3 H N(CH3)2 1 Ph 0 - - 0 - CH3 H N(CH2)20(CH2)2 ring 0 - CH3 CH3 1 C02CH3 CH3 H N(Et)2 0 - CH3 CH3 1 C02CH3 CH3 H N(CH3)cyclohexyl 0 - CH3 CH3 1 C02CH3 CH3 H N(CH3)n-butyl 0 - CH3 CH3 1 C02CH3 CH3 H N(CH3)iPr 0 - CH3 CH3 1 C02CH3 CH3 H N(CH3)Ph 0 - CH3 CH3 1 C02CH3 CH3 H N(CH2)4 0 - CH3 CH3 1 C02CH3 CH3 CH3 N(CH3)2 0 - CH3 CH3 1 C02CH3 CH3 H N(CH3)Et 0 - CH3 CH3 1 C02CH3 CH3 H N(CH3)2 0 - 0 - - 1 C02tBu
and wherein is R >2τ R>3 G taken together with the carbon (•) to
which they are attached.
36. A compound represented by Formula I-(HA )n7:
I-(HA°)n7 wherein
EX. R2 R3 G1 n2 z n3 R4b R5b Q1 X (HA6)n7 syn CH3 H N(CH3)2 0 - CH3 CHj C02H XI HC02H syn CH3 H N(CH3)2 0 - CH3 CH3 C02H XI (HC1)2 anti CH3 H N(CH3)2 0 - CH3 CH3 C02H XI HC02H syn CH3 H N(CH3)2 1 4 Ph H H C02H XI HC02H syn CH3 H N(CH3)2 0 - Et Et C02H XI (HC1)2 syn CH3 H N(CH3)2 0 - CH2CH 2 ring C02H XI (HC1)2 syn CH3 H N(CH3)2 0 - CH2CH2CH2 ring C02H XI (HC1)2 syn CH3 H N(CH3)2 0 - CH2CH2OCH2CH2πng C02H XI (HC1)2 syn CH3 H N(CH3)2 0 - CH2(CH2)3CH2 ring C02H XI (HC1)2 syn CH3 H N(CH3)2 0 - CH2(CH2)2CH2 ring C02H XI (HC1)2 syn CH3 H N(CH3)ιPr 0 - CH2(CH2)2CH2 ring C02H XI (HC1)2 syn CH3 H N(Et)2 0 - CH3 CHj C02H XI (HC1)2 syn CH3 H N(CH3)cyclohexyl 0 - CH3 CH3 C02H XI (HC1)2 syn CH3 H N(CH3)n-butyl 0 - CH3 CH3 C02H XI (HC1)2 syn CH3 H N(CH3)ιPr 0 - CH3 CH3 C02H XI (HC1)2 syn CH3 H N(CH3)Et 0 - CH3 CH3 C02H XI (HC1)2 syn CH3 H N(CH3)2 1 4 Ph0 H H C02H XI HC02H syn CH3 H N(CH3)2 0 - 0 - - C02H XI (HC1)2 anti CH3 H N(CH3)2 0 - 0 - - C02H XI (HC1)2 - CH3 CH3 N(CH3)2 0 - CH3 CH3 C02H XI (HC1)2 syn CH3 H N(CH3)2 0 - CHj CH3 C0NH2 XI HC02H syn CH3 H N(CH3)2 0 - CH3 CH3 CONHCHj XI HC02H syn CH3 H N(CH3)2 0 - CHj CH3 C0N(CH3)2 XI HC02H syn CH3 H N(CH3)2 1 4 Ph 0 - - C0NH2 XI HC02H syn CH3 H N(CH3)2 1 4 Ph 0 - - CONH CH3 XI HC02H syn CH3 H N(CH3)2 1 4 Ph 0 - - CON(CH3)2 XI HC02H syn Et H N(CH3)2 0 - 1 CHj CHj C02H XI (HC1)2 syn CH3 H N(CH3)2 1 4 Ph 0 - - OH XI HC02H and wherein A is HCO2 " or CI" XI is imidazol-l-yl; R1 is hydrogen; Y is oxygen; nl is one; R ,4a and R >5a are each hydrogen; R6a and R6b are each hydrogen; n4 is one; and wherein the syn and anti configuration are with respect to X and G1.
37. A compound represented by Formula II:
II or a pharmaceutically acceptable salt thereof, wherein: R and R are each independently Co-ioalkyl, C2-ιoalkenyl, C2-ιoalkynyl, Ci- i0alkoxyC l-i oalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ι0alkoxyC2-ιoalkynyb Ci-ioalkylthioCi- loalkyb Cι-]oalkylthioC -ιoalkenyb Cι-ιoalkylthioC -ιoalkynyb cycloC3.8alkyb cycloC . 8alkenyb cycloC3-8alkylC].ιoalkyb cycloC -8alkenylCι-ιoalkyb cycloC -8alkylC2. loalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3.8alkylC2-ιoalkynyb cycloC3- alkenylC2-ι oalkynyb heterocyclyl-Co-i oalkyb heterocyclyl-C2-ιoalkenyb heterocyclyl-C2.ioalkynyb Cι-ιoalkylcarbonyb C2-ιoalkenylcarbonyb C2- loalkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι-ιoalkyb monoCi. 6alkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyl, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR71R81, or -NR71R81 substituents; or aryl-Co-i oalkyb aryl-C2.ι0alkenyb or aryl-C2- loalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Ci-ioalkyl, C2-!oalkenyb C -ιoalkynyb haloCi- loalkyb haloC -)0alkenyb haloC .ι oalkynyb -COOH, CMalkoxycarbonyb -CONR7IR81, -SO2NR7lR81 or -NR7,R81 substituents; or heteroaryl-C0-ι0alkyb heteroaryl-C2. loalkenyb or heteroaryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Ci-ioalkyl, C2- ioalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, CMalkoxycarbonyb -CONR71R81, -SO2NR7,R81 or -NR71R81 substituents; "X or 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, any of which is optionally substituted with one or more independent Cι-6alkyb halo, cyano, nitro, -OR71, -SO2NR71R81 or -NR71R81 substituents; G1 is -OR72, -SR72, -NR72R82(R9)n5, or G1 and R3 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 R72 substituent; or in the case of -NR72R82(R9)n5, R72 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, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-, -alkenylaryl-, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-, -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is optionally substituted with R ; Q1 is Qwsalkyl, -OR75, -NR75R85(R95)n6, -CO2R75, -CONR75R85, -(C=S)OR75, -(C=O)SR75, -NO2, -CN, halo, -S(O)n6R75, -SO2NR75R85, -NR75(C=NR775)NR7775R85, -NR75(C=NR775)OR7775, -NR75(C-NR775)SR7775, -O(C=O)OR75, -O(C=O)NR75R85, -O(C=O)SR75, -S(C=O)OR75, -S(C=O)NR75R85, -S(C=O)SR75, -NR75(C=O)NR775R85, or -NR75(C=S)NR775R85; in the case of -NR75R85(R95)n6, R75 and R85 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, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR76R86 or -NR76R86 substituents; R4b and R5b are each independently a Co-ioalkyl, C2-ιoalkenyl, C2-ιoalkynyl, d- loalkoxyCi-ioalkyl, Cι-ιoalkoxyC -ιoalkenyl, Cι-ιoalkoxyC2-ι oalkynyb Ci-ioalkylthioCi- loalkyb Cι-ιoalkylthioC2-ιoalkenyb Cι-ιoalkylthioC2-ι oalkynyb cycloC3.8alkyb cycloC3- 8alkenyb cycloC -8alkylC1-ιoalkyb cycloC3.8alkenylCι-ιoalkyb cycloC3-8alkylC2- loalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3-8alkylC2-ιoalkynyb cycloC - 8alkenylC2-ιoalkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C2.ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2.ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci-ioalkyl, C2- loalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, CMalkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or hetaryl-Co-ioalkyl, hetaryl-C2-ιoalkenyb or hetaryl-C -ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci- loalkyl, C2-ιoalkenyl, C -ιoalkynyl, haloCι-ι oalkyb haloC2.ιoalkenyb haloC2-ι oalkynyb -COOH, C alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or mono(Ci.6alkyl)aminoCi-6alkyb di(Cι-6alkyl)aminoCι-6alkyb mono(aryl)aminoCι- 6alkyb di(aryl)aminoCι-6alkyb or -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci- loalkyl, C2-ιoalkenyb C -ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, Cι-4alkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5 ; or R4b with R5b, or R4c with R5c, taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, any of which is optionally substituted with R69; or R4a with R5a, or R4b with R5b, or R4c with R5c, taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated heterocyclic ring, any of which is optionally substituted with R69; nl, n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2; p7 p71 p72 p73 p74 p75 p775 p7775 p76 p77 p78 p778 p 8 p 81 p82 p 83 p 85 1\. , K. , t . , K. , lx , -K. , J , i , K. , K. , . , 1\. , K. , 1\. , JΛ. , JΛ. , JΛ. ,
R86, R87, R88, R888, R9, R95, and R98 are each independently Co-ioalkyl, C2-ι0alkenyb C2-ιoalkynyb Cι-ιoalkoxyCι-ι0alkyb Cι-ι0alkoxyC2-ιoalkenyb Cι.ι0alkoxyC2-ιoalkynyb Cι-ιoalkylthioCι-ιoalkyb Cι-ιoalkylthioC2-ιoalkenyb Cι-ιoalkylthioC2-ιoalkynyb cycloC3-8alkyb cycloC3.8alkenyb cycloC3-8alkylCι-ι oalkyb cycloC3-8alkenylCι-ιoalkyb cycloC -8alkylC2-ιoalkenyb cycloC3-8alkenylC2-ι0alkenyb cycloC3-8alkylC2-ιoalkynyb cycloC -8alkenylC2-ιoalkynyb heterocyclyl-Co-i oalkyb heterocyclyl-C2-ιoalkenyb heterocyclyl-C2.ι oalkynyb Cι-ιoalkylcarbonyb C2-ιoalkenylcarbonyb C2. loalkynylcarbonyb Ci-ioalkoxycarbonyb Ci-ioaikoxycarbonyl -ioalkyb monoCi- 6alkylaminocarbonyb diC i -όalkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2N(Co-4alkyl)(C0- alkyl) or -N(C0-4alkyl)(C0-4alkyl) substituents; aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Ci-ioalkyl, C2-ιoalkenyl, C2-ιoalkynyb haloCι-ι oalkyb haloC2-ιoalkenyb haloC2-ι 0alkynyb -COOH, Ci- 4alkoxycarbonyb -CON(C0- alkyl)(C0-ιoalkyl), -SO2N(C0- alkyl)(C0-4alkyl) or -N(C0- alkyl)(Co-4alkyl) substituents; or hetaryl-Co-i oalkyb hetaryl-C2-ιoalkenyb or hetaryl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Ci-ioalkyl, C2-]oalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, Cι-4alkoxycarbonyb -CON(C0-4alkyl)(Co-4alkyl), -SO2N(C0- alkyl)(C0-4alkyl) or -N(C0-4alkyl)(C0- alkyl) substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι-6alkyl)aminoCι-6alkyb mono(aryl)aminoC1-6alkyb di(aryl)aminoCι-6alkyb or -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), Ci-ioalkyl, C2.ιoalkenyl, C2-ιoalkynyl, haloCi-ioalkyb haloC2- loalkenyb haloC2-ι oalkynyb -COOH, Cι-4alkoxycarbonyb -CON(Co-4alkyl)(Co- 4alkyl), -SO2N(C0- alkyl)(C0-4alkyl) or -N(C0- alkyl)(C0- alkyl) substituents.
38. A compound represented by Formula I-B:
HI or a pharmaceutically acceptable salt thereof, wherein: R2 and R3 are each independently Co-ioalkyl, C -ιoalkenyl, C2-!oalkynyb Ci- loalkoxyC l-i oalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ι0alkoxyC2-ιoalkynyb Ci-ioalkylthioCi- loalkyb Cι-ιoalkylthioC2-ιoalkenyb Cι-ιoalkylthioC2-ιoalkynyb cycloC3.8alkyb cycloC3- 8alkenyb cycloC3-8alkylCι-ιoalkyb cycloC3-8alkenylCι-ι0alkyb cycloC -8alkylC2- loalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3.8alkylC2-ιoalkynyb cycloC3- 8alkenylC2-ioalkynyb heterocyclyl-C0-ioalkyb heterocyclyl-C2-ιoalkenyb
- 189 heterocyclyl-C2-ioalkynyb Cι-ιoalkylcarbonyb C2-ιoalkenylcarbonyb C2- loalkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι-ιoalkyb monoCi- 6alkylaminocarbonyb diCι-6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or Cι-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR71R81, or -NR71R81 substituents; or aryl-Co-i oalkyb aryl-C2-ι0alkenyb or aryl-C2- loalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR71, Ci-ioalkyl, C2-ιoalkenyl, C2-ιoalkynyl, haloCi- loalkyl, haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, Cι-4alkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; or heteroaryl-Co-ioalkyl, heteroaryl-C2. loalkenyb or heteroaryl-C2-ιoalkynyb any of which is optionally 71 substituted with one or more independent halo, cyano, nitro, -OR , C oalkyb C2. loalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, CMalkoxycarbonyb -CONR71R81, -SO2NR71R81 or -NR71R81 substituents; or R2 and R3 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 Cι-6alkyl, halo, cyano, nitro, -OR71, -SO2NR71R81 or -NR71R81 substituents; G1 is -OR72, -SR72, -NR72R82(R9)n5, or G1 and R3 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 substituent; or in the case of-NR R (R )n5, R and R82 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, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR73R83 or -NR73R83 substituents; Z is -aryl-, -arylalkyl-, -aryloxy-, -oxyaryl-, -arylalkenyl-, -alkenylaryl-, -hetaryl-, -hetarylalkyl-, -alkylhetaryl-, -hetarylalkenyl-, -alkenylhetaryl-, or -aryl-, any of which is optionally substituted with R ; Q1 is Co-6alkyb -OR75, -NR75R85(R95)n6, -CO2R75, -CONR75R85, -(C=S)OR75, -(C=O)SR75, -NO2, -CN, halo, -S(O)n6R75, -SO2NR75R85, -NR75(C=NR775)NR7775R85, -NR75(C=NR775)OR7775, -NR75(C=NR775)SR7775, -O(C=O)OR75, -O(C=O)NR75R85, -O(C=O)SR75, -S(C=O)OR75, -S(C=O)NR75R85, -S(C=O)SR75, -NR75(C=O)NR775R85, or -NR75(C=S)NR775R85; in the case of -NR75R85(R95)n6, R75 and R85 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, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Cι-ιoalkoxy, -SO2NR76R86 or -NR76R86 substituents; R4b and R5 are each independently a Co-ioalkyl, C2-ιoalkenyl, C -ιoalkynyl, C . loalkoxyCi-ioalkyb Cι-ιoalkoxyC2-ιoalkenyl, Cι-ιoalkoxyC2-1oalkynyb Cj-ioalkylthioCi- loalkyb Cι-ιoalkylthioC2-1oalkenyb Cι-ιoalkylthioC2.ι oalkynyb cycloC3-8alkyb cycloC3- 8alkenyb cycloC3-8alkylCι-ιoalkyb cycloC3-8alkenylCι-ιoalkyb cycloC -8alkylC2- loalkenyb cycloC3.8alkenylC2-ιoalkenyb cycloC .8alkylC2-ιoalkynyb cycloC3- 8alkenylC2_ι oalkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C2-ιoalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, -SO2NR77R87 or -NR77R87 substituents; or aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, C 1-1 oalkyb C2- loalkenyb C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, CMalkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or hetaryl-Co- loalkyl, hetaryl-C2-ιoalkenyb or hetaryl-C -ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR 77 , C loalkyl, C2-ιoalkenyl, C2-ιoalkynyb haloCi-ioalkyb haloC∑-ioalkenyb haloC2-ιoalkynyb -COOH, CMalkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or mono(Cι-6alkyl)aminoCι-6alkyb di(Cι-6alkyl)aminoCι-6alkyb mono(aryl)aminoCι- 6alkyb di(aryl)aminoCι-6alkyb or -N(Cι.6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR77, Ci- loalkyl, C2-ιoalkenyl, C2-ιoalkynyb haloCi-ioalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, CMalkoxycarbonyb -CONR77R87, -SO2NR77R87 or -NR77R87 substituents; or R4a with R5 , or R4b with R5b, or R4c with R5c, taken together with the respective
- - carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated ring, any of which is optionally substituted with R69; or R4a with R5a, or R4b with R5b, or R4c with R5c, taken together with the respective carbon atom to which they are attached, form a 3-10 membered saturated or unsaturated heterocyclic ring, any of which is optionally substituted with R69; nl, n2, n3, n4, n5, n6, and n7 are each independently equal to 0, 1 or 2; R67, R68, and R69 is a halo, -OR78, -NR78R88(R98)n7, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)n7R78, -SO2NR78R88, Co-ioalkyl, C2-ι0alkenyl, C2-ι0alkynyb Ci- loalkoxyCi-ioalkyb Cι-ιoalkoxyC2-ιoalkenyb Cι-ιoalkoxyC2-ι oalkynyb C-ioalkylthioC- loalkyb Cι-ιoalkylthioC2-ιoalkenyb C-ioalkylthioC-ioalkynyb cycloC3-8alkyb cycloC3. salkenyb cycloC3-8alkylCι-ιoalkyb cycloC3- alkenylCι-ι oalkyb cycloC3-8alkylC2- loalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3-8alkylC2-ιoalkynyb cycloC3. 8alkenylC2- loalkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C2-ιoalkenyb or heterocyclyl-C2- loalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, -SO2NR778R888 or -NR778R888 substituents; or aryl-Co-i oalkyb aryl-C2-ιoalkenyb or aryl-C2-ιoalkynyb any of which is optionally • 77R substituted with one or more independent halo, cyano, nitro, -OR , Ci-ioalkyl, C2- loalkenyb C2-ιoalkynyb haloCi-i oalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, CMalkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or hetaryl-Co-i oalkyb hetaryl-C2-ιoalkenyb or hetaryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778, C- loalkyl, C2-ιoalkenyb C2-ιoalkynyb haloC-ioalkyb haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, CMalkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or mono(Cι-6alkyl)aminoCι-6alkyl, di(Cι-6alkyl)aminoC]-6alkyb mono(aryl)aminoCι-6alkyb di(aryl)aminoCι-6alkyb -N(Cι-6alkyl)-Cι-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, 77R
-OR , Ci-ioalkyl, C2-ιoalkenyl, C2-ιoalkynyb haloCι-ι oalkyb haloC2-ιoalkenyb haloC2-ιoalkynyb -COOH, CMalkoxycarbonyb -CONR778R888, -SO2NR778R888 or -NR778R888 substituents; or in the case of -NR78R88(R98)n7, R78 and R88 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, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C-ι0alkoxy, -SO2NR778R888 or -NR778R888 substituents; p 7 p71 p72 p73 p74 p75 p775 p 7775 p76 p77 p 78 p778 p 8 p 81 β 82 p 83 R 85 J , l , J\. , X\. , K. , l\. , l\. , is. , K. , K. , IS. , K. , Iv , J , K. , IS. , 1\. ,
R86, R87, R88, R888, R9, R95, and R98 are each independently C0-ι0alkyb C2-ι0alkenyb C-ioalkynyb Cι-ιoalkoxyCι-ιoalkyb C-ιoalkoxyC2-ιoalkenyb Cι-ιoalkoxyC2-ι oalkynyb Ci-ioalkylthioCi-ioalkyb C-ioalkylthioC-ioalkenyb Cι-ιoalkylthioC2-ιoalkynyb cycloC3.8alkyb cycloC3.8alkenyb cycloC3.8alkylC-ιoalkyb cycloC3.8alkenylC-ιoalkyb cycloC3-8alkylC2-ιoalkenyb cycloC3-8alkenylC2-ιoalkenyb cycloC3.8alkylC2-ι oalkynyb cycloC3-8alkenylC2-ιoalkynyb heterocyclyl-Co-ioalkyb heterocyclyl-C2-ιoalkenyb heterocyclyl-C2-ιoalkynyb C-ioalkylcarbonyb C2-ιoalkenylcarbonyb C2- loalkynylcarbonyb Ci-ioalkoxycarbonyb Cι-ιoalkoxycarbonylCι-ιoalkyb monoC- 6alkylaminocarbonyb diC i -6alkylaminocarbonyb mono(aryl)aminocarbonyb di(aryl)aminocarbonyb or C-ιoalkyl(aryl)aminocarbonyb any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C-ioalkoxy, -SO2N(CoMalkyl)(C0-4alkyl) or -N(C0-4alkyl)(C0-4alkyl) substituents; aryl-C0-ι oalkyb aryl-C2- loalkenyb or aryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), C-ioalkyl, C2-ιoalkenyl, C-ioalkynyb haloC-ioalkyb haloC2-ιoalkenyl, haloC-ioalkynyl, -COOH, C- 4alkoxycarbonyl, -CON(C0-4alkyl)(C0-ιoalkyl), -SO2N(C0-4alkyl)(C0-4alkyl) or -N(C0- 4alkyl)(Co-4alkyl) substituents; or hetaryl-Co-i oalkyb hetaryl-C-ioalkenyb or hetaryl-C2-ι oalkynyb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyl), C-ioalkyl, C2.ιoalkenyb C-ioalkynyb haloC-ioalkyb haloC2-ιoalkenyb haloC2-ι oalkynyb -COOH, CMalkoxycarbonyb -CON(Co-4alkyl)(C0- alkyl), -SO2N(C0- alkyl)(C0-4alkyl) or -N(C0-4alkyl)(Co-4alkyl) substituents; or mono(Cι-6alkyl)aminoCι-6alkyl, di(C-6alkyl)aminoC-6alkyb mono(aryl)aminoC-6alkyb di(aryl)aminoC-6alkyb or -N(C-6alkyl)-C-6alkyl-aryb any of which is optionally substituted with one or more independent halo, cyano, nitro, -O(Co-4alkyι), C-ioalkyl, C-ioalkenyl, C-ioalkynyb haloC-ioalkyb haloC2. loalkenyb haloC2-ιoalkynyb -COOH, C- alkoxycarbonyb -CON(Co-4alkyl)(Co- 4alkyl), -SO2N(C0-4alkyl)(C0-4alkyl) or -N(C0-4alkyl)(C0- alkyl) substituents.
39. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
40. The pharmaceutical composition of claim 39 wherein the pharmaceutical composition is adapted for oral, rectal, topical, or parenteral administration.
41. The pharmaceutical composition of claim 39 wherein the pharmaceutical composition is in the form of tablet, capsule, cachets, aerosol, cream, ointment, lotion, powder, or suppository.
42. A method for treating dermatological or cancerous diseases in a mammal by inhibiting cytochrome P450RAI enzyme comprising administrating to said mammal a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.
43. A method for treating dermatological or cancerous diseases in a mammal by inhibiting cytochrome P450RAI enzyme comprising administrating to said mammal a therapeutically effective amount of a pharmaceutical composition according to claim 39.
44. The method of claim 42 wherein said dermatological disease is psoriasis.
45. The method of claim 42 wherein said cancerous disease is leukemia, breast cancer, prostate cancer, and solid tumors.
46. The method of claim 43 wherein said dermatological disease is psoriasis.
47. The method of claim 43 wherein said cancerous disease is leukemia, breast cancer, prostrate cancer, and solid tumors.
48. A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one retinoid.
49. A method for treating skin-related or cancerous diseases comprising the step of co-administrating at least one retinoid, which are catabohzed by Cyp26, with at least one of a compound of claim 1 to yield higher endogenous levels of said retinoids.
50. The compound of claim 1 having a ratio of the IC5o value of Cyp3A4 activity to the IC5o value of Cyp26 activity is 10:1 or greater.
51. The compound of claim 1 having a ratio of the IC50 value of Cyp3A4 activity to the IC50 value of Cyp26 activity is 100:1 or greater.
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UA87822C2 (en) 2009-08-25
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CN1819996A (en) 2006-08-16
IL172812A0 (en) 2006-06-11
IS8223A (en) 2006-01-10
SG144941A1 (en) 2008-08-28
BRPI0412424A (en) 2006-09-05
AU2004257257A1 (en) 2005-01-27
MXPA06000401A (en) 2006-03-17
WO2005007631A1 (en) 2005-01-27
AU2004257257B2 (en) 2011-05-12
CA2532078A1 (en) 2005-01-27
RU2363696C2 (en) 2009-08-10
CN1819996B (en) 2010-10-27
JP4832295B2 (en) 2011-12-07
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