Novel spirolactone compounds
阅读说明：本技术 新的螺内酯化合物 (Novel spirolactone compounds ) 是由 熊豫生 关洪平 黄文君 于 2018-06-29 设计创作，主要内容包括：本申请提供了用作ACC1和/或ACC2的抑制剂的结构式(I)的螺内酯化合物。所述的螺内酯化合物可用于治疗与异常ACC1和/或ACC2活性相关的疾病或病症,例如非酒精性脂肪肝(NASH)、痤疮、肥胖症、糖尿病和癌症。本申请还提供了包括结构式I的螺内酯化合物的药学组成或其药学上可接受的盐的药物组合物。<Image he="455" wi="494" file="DDA0002340424780000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present application provides spirolactone compounds of structural formula (I) for use as inhibitors of ACC1 and/or ACC 2. The spirolactone compounds are useful for treating diseases or disorders associated with aberrant ACC1 and/or ACC2 activity, such as nonalcoholic fatty liver disease (NASH), acne, obesity, diabetes, and cancer. The present application also provides pharmaceutical compositions comprising a pharmaceutical composition of the spirolactone compounds of structural formula I or a pharmaceutically acceptable salt thereof.)
1. A compound of structural formula Ia or a pharmaceutically acceptable salt thereof,
wherein:
R1is hydrogen, halogen, cyano, optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl, optionally substituted C2-6Alkenyl, optionally substituted C2-6Alkynyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-6 membered heterocyclyl, NR10R11、COOR12、CONR13R14、CN、S(O)nR15OR OR16；
Wherein
R10And R11Each independently hydrogen, optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl, optionally substituted C1-6Alkanoyl, optionally substituted C3-6Cycloalkanoyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-6 membered heterocyclyl, COOR12Or CONR13R14；
R12、R13And R14Each independently hydrogen or optionally substituted C1-6An alkyl group;
n is 0,1 or 2;
R15is optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl or NR10R11；
R16Is hydrogen, optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl, optionally substituted C1-6Alkanoyl, optionally substituted C3-6Cycloalkanoyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-6 membered heterocyclyl or CONR13R14；
And R is3Is optionally substituted C6-10Aryl or optionally substituted 5-to 10-membered heteroaryl,
provided that when R is1When it is hydrogen, R3Not an optionally substituted phenyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having structural formula Ib,
wherein R is10And R11One is optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R10And R11One of which is an optionally substituted 5 or 6 membered heteroaryl.
4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R10And R11Is a 5-membered heteroaryl group having 2-4 ring nitrogen atoms, optionally substituted with 1 or 2 substituents independently selected from halogen, cyano and C1-4Alkyl substituents.
5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R10And R11One of which is pyrazolyl, triazolyl or tetrazolyl, each of which is optionally substituted by C1-4Alkyl substitution.
6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R10And R11One of them is
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1Is an optionally substituted 5-or 6-membered heteroaryl.
8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R1Is optionally substituted tetrazolyl or pyridyl.
9. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R1Is a pyridyl group, optionally substituted with a carboxylic acid group or a group convertible in vivo to a carboxylic acid group, or a salt thereof.
10. The compound of claim 7, or a pharmaceutically acceptable salt thereof, having structural formula Ic,
wherein R is20Is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl.
11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R20Is optionally substituted C1-6Alkyl (e.g. optionally substituted C)1-4Alkyl groups).
12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R20Is hydrogen or C1-4An alkyl group.
13. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R20Is composed ofWherein p is an integer from 1 to 500 (e.g., 1 to 10, 1 to 50, 1 to 100, etc., e.g., 1,2, or 3), R21Is hydrogen, Cl-4Alkyl (e.g., methyl) or oxygen protecting groups.
14. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R20Is composed of
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R3Is C6-10Aryl optionally substituted with 1-3 substituents independently selected from: halogen, hydroxy,Cyano, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group.
16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R3Is an optionally substituted 8-10 membered bicyclic heteroaryl.
17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R3Is naphthyl, benzimidazolyl, pyrrolopyridyl, pyrazolopyridinyl, indazolyl, indolyl, quinolinyl or isoquinolinyl, each of which is optionally substituted with one or more (e.g., 1-3) substituents independently selected from halogen, cyano, hydroxy, C optionally substituted with 1-3 halogens1-4Alkyl, C optionally substituted by 1-3 halogens1-4Alkoxy, C optionally substituted by 1-3 halogens3-6Cycloalkyl and C optionally substituted by 1-3 halogens3-6A cycloalkoxy group.
18. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R3Is composed of
Each of which is optionally substituted with 1-3 substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, ethyl, methoxy, trifluoromethoxy, ethoxy, and cyclopropyl.
19. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R3Is composed of
20. The compound of claim 1, wherein the compound is 1 ' - (4, 8-dimethoxy-2-naphthoyl) -7-isopropylspiro [ isochroman-3, 4 ' -piperidin ] -1-one (example 1), 1 ' - (4, 8-dimethoxyquinoline-2-carbonyl) -7-isopropylspiro [ isochroman-3, 4 ' -piperidin ] -1-one (example 2), 1 ' - (4, 8-dimethoxy-2-naphthoyl) -7-ethylspiro [ isochroman-3, 4 ' -piperidin ] -1-one (example 3), l ' - (4, 8-dimethoxyquinoline-2-carbonyl) -7-ethylspiro [ isochroman- 3,4 '-Piperidin-1-one (example 4), 1' - (4, 8-dimethoxy-2-naphthoyl) -7- ((1-methyl-1H-pyrazol-5-yl) amino) spiro [ isochroman-3, 4 '-piperidin ] -1-one (example 5), l' - (4, 8-dimethoxyquinoline-2-carbonyl) -7- ((1-methyl-1H-pyrazol-5-yl) amino) spiro [ isochroman-3, 4 '-piperidin ] -1-one (example 6), 7-isopropyl-l' - (2-methyl-1H-benzo [ d ] imidazole-6-carbonyl) spiro [ isochroman-3, 4 '-piperidin-1-one (example 7), 1' - (1H-indazole-5-carbonyl) -7-isopropylspiro [ isochroman-3, 4 '-piperidin ] -1-one (example 8), 7-isopropyl-1' - (1H-pyrrolo [3,2-b ] pyridine-2-carbonyl) -spiro [ isochroman-3, 4 '-piperidin ] -1-one (example 9), l' - (1H-indazole-6-carbonyl) -7-isopropylspiro- [ isochroman-3, 4 '-piperidin ] -1-one (example 10), 7-isopropyl-1' - (6-methoxyquinoline-3-carbonyl) spiro [ isochroman-3, 4 ' -piperidin-1-one (example 11), l ' - (2-ethyl-1H-benzo [ d ] imidazole-6-carbonyl) -7-isopropylspiro [ isochroman-3, 4 ' -piperidin ] -1-one (example 12), 7-isopropyl-1 ' - (3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazole-5-carbonyl) spiro [ isochroman-3, 4 ' -piperidin ] -1-one (example 13), methyl 5- (1 ' - (4, 8-dimethoxyquinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4 ' -piperidin ] -7-yl) nicotinate (example 14), 5- (l '- (4, 8-dimethoxyquinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidin ] -7-yl) nicotinic acid (example 15), 5- (1 '- (4, 8-dimethoxy-quinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidin ] -7-yl) nicotinic acid l- ((ethoxycarbonyl) oxy) ethyl ester (example 16), 5- (1 '- (4, 8-dimethoxyquinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidin ] -7-yl) nicotinic acid 2- (2- (2-methoxyethoxy) ethoxy) ethyl ester (example 17), 5- (1 '- (4, 8-dimethoxy-quinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidin ] -7-yl) nicotinic acid ethyl ester 2- (2-methoxyethoxy) ester (example 18), methyl 5- (l '- (8-cyclopropyl-4-methoxyquinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidin ] -7-yl) nicotinate (example 19), 5- (1 '- (8-cyclopropyl-4-methoxyquinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidin ] -7-yl) nicotinic acid (example 20), methyl 5- (l '- (1-cyclopropyl-4-methoxy-3-methyl-1H-indole-6-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidin ] -7-yl) nicotinate (example 21) or 5- (1 '- (1-cyclopropyl-4-methoxy-3-methyl-1H-indole-6-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidin ] -7-yl) nicotinic acid (example 22).
21. A pharmaceutical composition comprising a compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
22. A method of inhibiting one or more activities in a subject in need thereof, wherein the one or more activities are selected from the group consisting of acetyl-coa carboxylase (ACC1 and/or ACC2) activity, malonyl-coa production, adipogenesis, proliferation of sebocytes, proliferation of keratinocytes, proliferation of cells in the epidermis, dermis, and/or hypodermis (e.g., adipocytes, melanocytes, keratinocytes, squamous cells, mercker cells, langerhans cells, and skin stem cells), differentiation of fibroblasts into adipocytes in the cortex and/or subcutaneous layer, inflammation, and combinations thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21.
23. A method of treating a disease or disorder associated with abnormal sebocyte and/or keratinocyte activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21.
24. The method of claim 23, wherein the disease or disorder is acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, actinic keratosis, sebaceous adenomas, sebaceous cysts, sebaceous adenocarcinomas, squamous cell carcinoma, melanoma, rosacea, fibrofolliculoma in BHD syndrome, or a combination thereof.
25. The method of claim 23 or 24, wherein the compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21 is administered topically to a subject.
26. The method of any one of claims 23-25, further comprising treating the subject with one or more additional therapies effective to treat a disease or disorder associated with abnormal sebocyte and/or keratinocyte activity.
27. The method of any one of claims 23-25, further comprising administering to the subject a therapeutically effective amount of an antibiotic (e.g., tetracycline such as clindamycin, erythromycin, metronidazole, sulfacetamide or doxycycline and minocycline) or a retinoid (e.g., adapalene, isotretinoin, vitamin a, tazarotene or tretinoin) to treat acne and/or inflammation.
28. A method of treating non-alcoholic fatty liver disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 21.
29. The method of claim 28, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis (NASH).
30. The method of claim 28 or 29, further comprising administering to the subject a therapeutically effective amount of one or more additional agents to treat non-alcoholic fatty liver disease.
31. The method of claim 30, wherein the one or more additional agents is selected from the group consisting of angiotensin II receptor antagonists, Angiotensin Converting Enzyme (ACE) inhibitors, caspase inhibitors, cathepsin B inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulators, cholesterol solubilizing agents, diacylglycerol O-acyltransferase 1(DGAT1) inhibitors, dipeptidyl peptidase iv (dppiv) inhibitors, Farnesol X Receptor (FXR) agonists, galectin-3 inhibitors, glucagon-like peptide 1(GLPl) agonists, glutathione precursors, hepatitis c virus NS3 protease inhibitors, HMG CoA reductase inhibitors, 11 β -hydroxysteroid dehydrogenase (11 β -HSDl) inhibitors, IL- β antagonists, IL-6 antagonists, IL-10 agonists, IL-17 antagonists, ileal bile acid sodium cotransporter inhibitors, leptin analogs, 5-lipoxygenase inhibitors, gene oxygenase stimulators, lox inhibitors, lysine oxidase inhibitors (lpe) inhibitors, PPAR-2 kinase inhibitors, PPAR-05 inhibitors, PPAR kinase inhibitors, PPAR-2 kinase inhibitors, PPAR-1 inhibitors, PPAR-05 inhibitors, and combinations thereof.
32. The method of any one of claims 30-31, wherein the one or more additional agents is selected from acetylsalicylic acid, alistipen, 3 β -arachidonamido-7 α,12 α -di-hydroxy-5 β -cholestane-24-oic acid, atorvastatin, BLX-1002, seniviroc, 7- ((2R,4aR,5R,7aR) -2- ((3S) -1, 1-difluoro-3-methylpentyl) -2-hydroxy-6-oxooctahydrocyclopenta (b) pyran-5-yl) heptanoic acid, colesevelam, enrichexelon, enalapril, GFT-505, GR-MD-02, hydrochlorothiazide, ethyl eicosapentaenoate (ethyl eicosapentaenoate), IMM-124E, KD-025, linagliptin, liraglutide, mercaptocaptopril, MGL-3196, obeticholic acid, oxpocholic, olithic, PEG, gliclazide, glitazone, pioglitazone, oxypyr, trp-24, TRX-VBY, and combinations thereof.
33. A method of treating obesity and/or diabetes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21.
34. The method of claim 33, further comprising administering to the subject a therapeutically effective amount of one or more additional agents to treat obesity and/or diabetes.
35. The method of claim 34, wherein the one or more additional agents is selected from the group consisting of angiotensin II receptor antagonists, Angiotensin Converting Enzyme (ACE) inhibitors, caspase inhibitors, cathepsin B inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulators, cholesterol solubilizing agents, diacylglycerol O-acyltransferase 1(DGAT1) inhibitors, dipeptidyl peptidase iv (dppiv) inhibitors, Farnesol X Receptor (FXR) agonists, galectin-3 inhibitors, glucagon-like peptide 1(GLPl) agonists, glutathione precursors, hepatitis c virus NS3 protease inhibitors, HMG CoA reductase inhibitors, 11 β -hydroxysteroid dehydrogenase (11 β -HSDl) inhibitors, IL- β antagonists, IL-6 antagonists, IL-10 agonists, IL-17 antagonists, ileal bile acid sodium cotransporter inhibitors, leptin analogs, 5-lipoxygenase inhibitors, gene oxygenase stimulators, lox inhibitors, lysine oxidase inhibitors (lpe) inhibitors, PPAR-2 kinase inhibitors, PPAR-05 inhibitors, PPAR kinase inhibitors, PPAR-2 kinase inhibitors, PPAR-1 inhibitors, PPAR-05 inhibitors, and combinations thereof.
36. The method of any one of claims 34-35, wherein the one or more additional agents is selected from acetylsalicylic acid, alistipen, 3 β -arachidonamido-7 α,12 α -di-hydroxy-5 β -cholestane-24-oic acid, atorvastatin, BLX-1002, seniviroc, 7- ((2R,4aR,5R,7aR) -2- ((3S) -1, 1-difluoro-3-methylpentyl) -2-hydroxy-6-oxooctahydrocyclopenta (b) pyran-5-yl) heptanoic acid, colesevelam, enrichexelon, enalapril, GFT-505, GR-MD-02, hydrochlorothiazide, ethyl eicosapentaenoate (ethyl eicosapentaenoate), IMM-124E, KD-025, linagliptin, liraglutide, mercaptocaptopril, MGL-3196, obeticholic acid, oxpocholic, olithic, PEG, gliclazide, glitazone, pioglitazone, oxypyr, trp-24, TRX-VBY, and combinations thereof.
Technical Field
In various embodiments, the present invention relates generally to a novel class of spirolactone compounds, salts thereof, pharmaceutical compositions comprising the same, methods of synthesizing the same, and uses thereof.
Technical Field
Disclosure of Invention
In various embodiments, the present disclosure provides a spirolactone compound or a pharmaceutically acceptable salt thereof that may be an inhibitor of ACC1 and/or ACC 2. In some embodiments, the present disclosure also provides a pharmaceutical composition comprising the spirolactone compound or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure also provides methods of using the spironolactone compounds, or pharmaceutically acceptable salts thereof, to treat diseases or disorders associated with aberrant ACC1 and/or ACC2 activity, for example, non-alcoholic fatty liver disease (NASH), acne, obesity, diabetes, and cancer.
Some embodiments of the present disclosure relate to a compound of structural formula I:
wherein R is1、R2And R3As defined in the present application. In some embodiments, the compound of structural formula I is a compound of structural formula I-1, a compound of structural formula Ia, a compound of structural formula Ib, a compound of structural formula Ic, a compound of structural formulae II-1 to II-3, or a compound of structural formulae III-1 to III-6, as defined herein. In any of the embodiments described herein, the spirolactone compound may be: 1 '- (4, 8-dimethoxy-2-naphthoyl) -7-isopropylspiro [ isochroman-3, 4' -piperidine]-1-one (example 1), 1 '- (4, 8-Dimethoxyquinoline-2-carbonyl) -7-isopropylspiro [ isochroman-3, 4' -piperidine]-1-one (example 2), 1 '- (4, 8-dimethoxy-2-naphthoyl) -7-ethylspiro [ isochroman-3, 4' -piperidine]-1-one (example 3), 1 '- (4, 8-Dimethoxyquinoline-2-carbonyl) -7-ethylspiro [ isochroman-3, 4' -piperidine]-1-one (example 4), 1 '- (4, 8-dimethoxy-2-naphthoyl) -7- ((1-methyl-1H-pyrazol-5-yl) amino) spiro [ isochroman-3, 4' -piperidine]-1-one (example 5), 1 '- (4, 8-dimethoxyquinoline-2-carbonyl) -7- ((1-methyl-1H-pyrazol-5-yl) amino) spiro [ isochroman-3, 4' -piperidine]-1-one (example 6), 7-isopropyl-l' - (2-methyl-1H-benzo [ d)]Imidazole-6-carbonyl) spiro [ isochroman-3, 4' -piperidine]-1-one (example 7), 1 '- (1H-indazole-5-carbonyl) -7-isopropylspiro [ isochroman-3, 4' -piperidine]-1-one (example 8), 7-isopropyl-1' - (1H-pyrrolo [3, 2-b)]Pyridine-2-carbonyl) -spiro [ isochroman-3, 4' -piperidine]-1-one (example 9), l '- (1H-indazole-6-carbonyl) -7-isopropylspiro- [ isochroman-3, 4' -piperidine]-1-one (example 10), 7-isopropyl-1 '- (6-methoxyquinoline-3-carbonyl) spiro [ isochroman-3, 4' -piperidine]-1-one (example 11), l' - (2-ethyl-1H-benzo [ d)]Imidazole-6-carbonyl) -7-isopropylspiro [ isochroman-3, 4' -piperidine]-1-one (example 12), 7-isopropyl-1' - (3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d)]Imidazole-5-carbonyl) spiro [ isochroman-3, 4' -piperidine]-1-ketone (example 13), 5- (1' - (4,8-Dimethoxyquinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidine]-7-yl) nicotinic acid methyl ester (example 14), 5- (l '- (4, 8-dimethoxyquinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidine]-7-yl) nicotinic acid (example 15), 5- (1 '- (4, 8-dimethoxy-quinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidine]-7-yl) nicotinic acid l- ((ethoxycarbonyl) oxy) ethyl ester (example 16), 5- (1 '- (4, 8-dimethoxyquinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidine]-7-yl) nicotinic acid 2- (2- (2-methoxyethoxy) ethoxy) ethyl ester (example 17), 5- (1 '- (4, 8-dimethoxy-quinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidine]-7-yl) nicotinic acid 2- (2-methoxyethoxy) ethyl ester (example 18), 5- (l '- (8-cyclopropyl-4-methoxyquinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidine]-7-yl) nicotinic acid methyl ester (example 19), 5- (1 '- (8-cyclopropyl-4-methoxyquinoline-2-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidine]-7-yl) nicotinic acid (example 20), 5- (l '- (1-cyclopropyl-4-methoxy-3-methyl-1H-indole-6-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidine]-7-yl) nicotinic acid methyl ester (example 21) or 5- (1 '- (1-cyclopropyl-4-methoxy-3-methyl-1H-indole-6-carbonyl) -1-oxospiro [ isochroman-3, 4' -piperidine]-7-yl) nicotinic acid (example 22) or a pharmaceutically acceptable salt thereof.
Certain embodiments of the present disclosure relate to a pharmaceutical composition comprising a spirolactone compound of structural formula I (e.g., a compound of structural formula I-1, a compound of structural formula Ia, a compound of structural formula Ib, a compound of structural formula Ic, a compound of structural formulae II-1 to II-3, or a compound of structural formulae III-1 to III-6, or a compound of any of examples 1-22) as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises one or more additional active agents.
The pharmaceutical compositions described herein can be formulated for different routes of administration. In some embodiments, the pharmaceutical composition may be formulated for intravenous injection or infusion, oral administration, inhalation, or topical administration. In some embodiments, the pharmaceutical composition may be formulated in the form of a topical solution, lotion, shampoo, transdermal spray, topical film, foam, powder, paste, sponge, transdermal patch, tincture, oily patch, cream, gel, or ointment.
Certain embodiments of the present disclosure relate to a method of inhibiting ACC1 and/or ACC2 activity in a cell. In some embodiments, the method comprises contacting the cell with a spirolactone compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.
In some embodiments, the present disclosure also provides a method of inhibiting the following in a subject in need thereof: malonyl-coa production, adipogenesis in a cell (e.g., a sebocyte, adipocyte, or hepatocyte), proliferation of a cell (e.g., a sebocyte, a keratinocyte, an adipocyte, a melanocyte, a squamous cell, a merkel cell, a langerhans cell, or a skin stem cell in the epidermis, dermis, and/or hypodermis), differentiation of a fibroblast into an adipocyte, sebum production, or a combination thereof. In some embodiments, the subject is characterized as having a disease or disorder selected from the group consisting of: acne, seborrhea, sebaceous gland hyperplasia, seborrheic keratosis, sebaceous gland adenoma, sebaceous cyst, actinic keratosis, sebaceous adenocarcinoma, squamous cell carcinoma, melanoma, rosacea, fibrofolliculoma in BHD syndrome, and combinations thereof. In some embodiments, the subject is characterized as having non-alcoholic steatohepatitis (NASH). In some embodiments, the method comprises administering to the subject an effective amount of a spirolactone compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.
Certain embodiments of the present disclosure relate to a method of treating a disease or disorder associated with ACC1 and/or ACC2 in a subject in need thereof. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a spirolactone compound described herein (e.g., a compound of structural formula I-1, a compound of structural formula Ia, a compound of structural formula Ib, a compound of structural formula Ic, a compound of structural formulae II-1 to II-3, or a compound of structural formulae III-1 to III-6, or a compound of any of examples 1-22), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the methods further comprise treating a subject in need thereof with one or more additional therapies for the respective disease or disorder (e.g., a disease or disorder as described herein). Non-limiting diseases or disorders suitable for treatment with the methods described herein include skin diseases, such as diseases or disorders associated with abnormal sebocyte and/or keratinocyte activity (e.g., acne), non-alcoholic fatty liver disease (e.g., non-alcoholic fatty liver disease (NASH)), metabolic diseases or disorders (e.g., obesity or diabetes), and cancer.
Additional embodiments and advantages of the present disclosure are set forth in part in the description which follows and, in part, will be derived from the description, or may be learned by practice of the present disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.
Drawings
Some embodiments of the invention have been described by way of example only and with reference to the accompanying drawings. The drawings are described in detail below, with the emphasis instead being placed upon illustrating the embodiments of the invention.
FIG. 1 presents bar graphs showing that chronic treatment with an ACC inhibitor (e.g., example 14 or 20) reduces hepatic Triglycerides (TG) in C57BL/6J mice. Data are presented as mean ± standard error of mean. Statistical significance was determined by using ANOVA analysis, # p <0.01 relative to the vector.
Detailed Description
The present disclosure relates generally to a novel class of spirolactone compounds useful as ACC inhibitors (ACC1 and/or ACC2 inhibitors). In various embodiments, the present disclosure provides compounds, pharmaceutical compositions, methods and uses related to the novel spirolactone compounds described herein.
Spirolactone compounds
Certain embodiments of the present disclosure relate to novel spirolactone compounds. In some embodiments, the present disclosure provides a compound of structural formula I or a pharmaceutically acceptable salt thereof,
wherein:
R1and R2Each independently hydrogen, halogen, cyano, optionally substituted alkyl (e.g., optionally substituted C)1-6Alkyl), optionally substituted cycloalkyl (e.g., optionally substituted C)3-6Cycloalkyl), optionally substituted alkenyl (e.g., optionally substituted C)2-6Alkenyl), optionally substituted alkynyl (e.g., optionally substituted C)2-6Alkynyl), optionally substituted aryl (e.g., optionally substituted C)6-10Aryl), optionally substituted heteroaryl (e.g., optionally substituted 5-10 membered heteroaryl), optionally substituted heterocyclyl (e.g., optionally substituted 4-6 membered heterocyclyl), NR10R11、COOR12、CONR13R14、CN、S(O)nR15OR OR16；
Wherein
R10And R11Each independently hydrogen, optionally substituted alkyl (e.g., optionally substituted C1-6Alkyl), optionally substituted cycloalkyl (e.g., optionally substituted C)3-6Cycloalkyl), optionally substituted alkanoyl (e.g., optionally substituted C)1-6Alkanoyl), optionally substituted cycloalkanoyl (e.g., optionally substituted C)3-6Cycloalkanoyl), optionally substituted aryl (e.g., optionally substituted C)6-10Aryl), optionally substituted heteroaryl (e.g., optionally substituted 5-10 membered heteroaryl), optionally substituted heterocyclyl (e.g., optionally substituted 4-6 membered heterocyclyl), COOR12Or CONR13R14；
R12、R13And R14Each independently is hydrogen or optionally substitutedAlkyl (e.g., optionally substituted C)1-6Alkyl groups);
n is 0,1 or 2;
R15is optionally substituted alkyl (e.g., optionally substituted C)1-6Alkyl), optionally substituted cycloalkyl (e.g., optionally substituted C)3-6Cycloalkyl) or NR10R11；
R16Is hydrogen, optionally substituted alkyl (e.g. optionally substituted C)1-6Alkyl), optionally substituted cycloalkyl (e.g., optionally substituted C)3-6Cycloalkyl), optionally substituted alkanoyl (e.g., optionally substituted C)1-6Alkanoyl), optionally substituted cycloalkanoyl (e.g., optionally substituted C)3-6Cycloalkanoyl), optionally substituted aryl (e.g., optionally substituted C)6-10Aryl), optionally substituted heteroaryl (e.g., optionally substituted 5-10 membered heteroaryl), optionally substituted heterocyclyl (e.g., optionally substituted 4-6 membered heterocyclyl), or CONR13R14；
And R is3Is optionally substituted aryl (e.g., optionally substituted C)6-10Aryl) or optionally substituted heteroaryl (e.g., optionally substituted 5-10 membered heteroaryl),
with the proviso that when R1And R2When both are hydrogen, then R3Is not an optionally substituted phenyl group.
In some embodiments, R1And R2Are all hydrogen, provided that R3Is not an optionally substituted phenyl group. In some embodiments, R1And R2Only one of which is hydrogen, i.e. the benzene ring in formula I is monosubstituted. In some embodiments, R1And R2Are not hydrogen, i.e., the phenyl ring in formula I is disubstituted.
In some preferred embodiments, the compound of structural formula I is a compound of structural formula I-1:
wherein R is1、R2And R3As defined herein. In some embodiments, R1Is not hydrogen. In some embodiments, R1Is hydrogen.
In any of the embodiments described herein, R2May be hydrogen. For example, in some embodiments, the compound of structural formula I is a compound of structural formula Ia.
Wherein R is1And R3As defined herein. In some embodiments, R1Is not hydrogen. In some embodiments, R1Is hydrogen.
In some embodiments, R1Is halogen, such as F, Cl, Br or I. In some embodiments, R1Is CN. When R is1When halogen, the compounds of formula I (e.g., compounds of formula Ia) may also be useful as synthesis intermediates for the synthesis of other compounds via coupling reactions (e.g., palladium-mediated or copper-mediated coupling reactions), e.g., as R1A synthetic intermediate of a compound of formula I which is the following group: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, NR10R11、COOR12、CONR13R14、CN、S(O)nR15OR OR16。
In some embodiments, R1Is an optionally substituted alkyl group. In some embodiments, R1Is optionally substituted C1-6An alkyl group. In some preferred embodiments, R1Is optionally substituted C1-4An alkyl group. For example, in some embodiments, R1Can be C1-4Alkyl (e.g., methyl, ethyl, isopropyl, sec-butyl, tert-butyl). In some embodiments, R1Can be C optionally substituted with one or more (e.g., 1-3) substituents independently selected from1-4Alkyl groups: halogen (e.g., F) and C1-4An alkyl group. For example，R1May be C optionally substituted by 1 to 3 fluorine1-4Alkyl radicals, e.g. CF3、CF3CH2And the like.
In some embodiments, R1Is an optionally substituted alkoxy group. In some embodiments, R1Is optionally substituted C1-6An alkoxy group. In some preferred embodiments, R1Is optionally substituted C1-4An alkoxy group. For example, R1Can be C1-4Alkoxy (e.g., methoxy, ethoxy, isopropoxy, sec-butoxy, tert-butoxy). In some embodiments, R1Can be C optionally substituted with one or more (e.g., 1-3) substituents independently selected from1-4Alkoxy groups: halogen (e.g., F) and C1-4An alkyl group. For example, R1May be C optionally substituted by 1 to 3 fluorine1-4Alkoxy radicals, e.g. CF3O、CF3CH2O, and the like.
In some embodiments, R1Is an optionally substituted cycloalkyl group. In some embodiments, R1Is optionally substituted C3-6A cycloalkyl group. In some embodiments, R1Is C3-6A cycloalkyl group. In some embodiments, R1Is C optionally substituted with one or more (e.g., 1-3) substituents independently selected from3-6Cycloalkyl groups: halogen (e.g., F) and C1-4An alkyl group. For example, in some embodiments, R1Is cyclopropyl or cyclobutyl. In some embodiments, R1Is cyclopropyl or cyclobutyl optionally substituted by 1 to 3 fluorines.
In some embodiments, R1Is an optionally substituted cycloalkoxy group. In some embodiments, R1Is optionally substituted C3-6A cycloalkoxy group. In some embodiments, R1Is C3-6A cycloalkoxy group. In some embodiments, R1Is C optionally substituted with one or more (e.g., 1-3) substituents independently selected from3-6Cycloalkoxy group: halogen (e.g., F) and C1-4An alkyl group. For example, in some embodiments, R1Is cyclopropoxyOr cyclobutoxy. In some embodiments, R1Is cyclopropoxy or cyclobutoxy optionally substituted with 1-3 fluorines.
In some preferred embodiments, R1Is halogen, optionally substituted C1-6Alkyl, optionally substituted C1-6Alkoxy, optionally substituted C3-6Cycloalkyl or optionally substituted C3-6A cycloalkoxy group. In some preferred embodiments, R1Is C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl or C3-6Cycloalkoxy, each of which is optionally substituted with 1-3 substituents independently selected from: halogen and C1-4An alkyl group. In some preferred embodiments, R1Is C1-4Alkyl or C1-4Alkoxy, each of which is optionally substituted with 1-3 fluoro.
In some embodiments, R1Is optionally substituted aryl, e.g. optionally substituted C6-12Aryl (e.g., phenyl). In some embodiments, R1Is C optionally substituted with one or more (e.g., 1 or 2) substituents independently selected from6-12Aryl (e.g., phenyl): halogen, hydroxy, cyano, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group. In some embodiments, R1Is C optionally substituted with one or more (e.g., 1 or 2) substituents independently selected from6-12Aryl (e.g., phenyl): halogen (e.g. F, Cl), cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl and C3-6Cycloalkoxy, wherein alkyl, alkoxy, cycloalkyl and cycloalkoxy are each optionally substituted with 1-3 substituents independently selected from: halogen (e.g., F) and C1-4An alkyl group.
In some embodiments, R1Is an optionally substituted heteroaryl group. For example, in some embodiments, R1Is a 5-10 membered heteroaryl (e.g., as used herein) optionally substituted with one or more (e.g., 1 or 2) substituents independently selected fromPlease describe 5 or 6 membered heteroaryl): halogen, cyano, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group. In some embodiments, R1Is a 5-10 membered heteroaryl (e.g., a 5 or 6 membered heteroaryl as described herein) optionally substituted with one or more (e.g., 1 or 2) substituents independently selected from the group consisting of: halogen (e.g. F, Cl), cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl and C3-6Cycloalkoxy, wherein alkyl, alkoxy, cycloalkyl, and cycloalkoxy are each optionally substituted with 1-3 substituents independently selected from: halogen (e.g., F) and C1-4An alkyl group.
In some embodiments, R1 can be a 5-10 membered heteroaryl (e.g., a 5 or 6 membered heteroaryl as described herein, e.g., tetrazolyl, pyridyl, etc.), optionally substituted with one or more (e.g., 1 or 2) substituents independently selected from: halogen, hydroxy, cyano and COOR12Wherein R is12Is hydrogen or optionally substituted C1-6Alkyl, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group. In some embodiments, R1 can be an optionally substituted pyridyl (e.g., 2-, 3-, or 4-pyridyl). In some embodiments, the pyridyl may be optionally substituted with one or more (e.g., 1 or 2) substituents independently selected from the group consisting of: halogen, hydroxy, cyano and COOR12Wherein R is12Is hydrogen or optionally substituted C1-6Alkyl, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group. In some embodiments, the pyridyl group may be substituted with COOR12(e.g., COOH) substitution. In some embodiments, the pyridyl group can be substituted with COOH or a group that can be converted in vivo to a carboxylic acid group (or salt thereof). Suitable groups that can be converted in vivo to carboxylic acid groups (or salts thereof) include those known in the artSuch as esters, amides, and the like. Without wishing to be bound by theory, it is believed that the carboxylic acid functional group, such as a pyridyl carboxylic acid, may aid in the targeted delivery of compounds to the liver and thus may be particularly useful in the treatment of, for example, liver disease (e.g., NASH), with reduced systemic exposure being required.
In some embodiments, R1May be an optionally substituted 3-pyridyl group. For example, in some embodiments, the compound of structural formula I can be a compound of structural formula Ic:
wherein R is3And R20As defined herein. Suitable R for compounds of formula Ic20Including the group COOR20Are COOH (or a salt thereof) or those groups that can be converted to COOH (or a salt thereof) in vivo. In some embodiments, R20Can be hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl (e.g., optionally substituted C3-6Cycloalkyl groups). In some embodiments, R20May be optionally substituted C1-6Alkyl (e.g. optionally substituted C)1-4Alkyl groups). In some embodiments, R20May be hydrogen or optionally substituted C1-4Alkyl groups (e.g., methyl, ethyl, etc.). Various substituents for the alkyl or cycloalkyl groups may be used, including those that do not prevent the conversion of the ester group to a carboxylic acid group (or salt thereof) in vivo. Preferably, however, R is chosen20The groups, including any substituents, are such that the compound of structural formula Ic or the resulting cleavage by-product (i.e., not the spirolactone product produced) is not toxic or has acceptable toxicity to the subject user at therapeutically effective dosages. In some embodiments, the group COOR20May be a simple alkyl ester (e.g. methyl, ethyl or other C)1-4Alkyl esters).
In some embodiments, R20May include oligo-or polyethylene glycol chains. For example, in some embodiments, R20Can be
The methods discussed above are not limited to the spirolactone cores described herein. For example, it will be apparent to those skilled in the art in view of this disclosure that any ACC inhibitor may be modified to include a liver targeting moiety, such as a pyridyl group substituted with COOH or a group that can be converted in vivo to a carboxylic acid group (e.g., ester, amide, etc.), which is particularly useful for treating liver disease (e.g., NASH). In some embodiments, such ACC inhibitors may be engineered to include those described herein as being COOR20Substituted pyridyl, which may be a simple alkyl ester.
In some embodiments, R1Optionally substituted heterocyclic groups are also possible. For example, in some embodiments, R1Is a 4-6 membered heterocyclyl optionally substituted with one or more (e.g., 1 or 2) substituents independently selected from: halogen, oxo, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group. In some embodiments of the present invention, the substrate is,R1is a 4-6 membered heterocyclyl optionally substituted with one or more (e.g., 1 or 2) substituents independently selected from: halogen (e.g. F, Cl), C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl and C3-6Cycloalkoxy, wherein each of the alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with 1-3 substituents independently selected from the group consisting of: halogen (e.g., F) and C1-4An alkyl group.
In some preferred embodiments, R1Is NR10R11. For example, in some embodiments, the compound of structural formula Ia is a compound of structural formula Ib:
wherein R is10，R11And R3As defined herein. In some embodiments, R10And R11One is optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl (e.g., as described herein). In some embodiments, R10And R11One is a 5-membered heteroaryl (e.g., a 5-membered heteroaryl having 2-4 nitrogen atoms as described herein) optionally substituted with one or more (e.g., 1 or 2) substituents independently selected from the group consisting of: halogen, cyano and C1-4An alkyl group. For example, in some embodiments, R10And R11One is pyrazolyl, triazolyl or tetrazolyl. In some embodiments, R10And R11One is pyrazolyl, triazolyl or tetrazolyl, each of which is optionally substituted by 1 or 2 substituents independently selected from C1-4Alkyl (e.g., methyl or ethyl). In any of these embodiments, R10And R11Can be hydrogen or optionally substituted alkyl (e.g., C)1-4Alkyl groups such as methyl or ethyl). Other suitable R10And R11As described herein.
In some embodiments, R1Can be COOR12Or CONR13R14Wherein R is12、R13And R14As defined in the present application. For example, in some embodiments, R1Is COOR12And R is12May be hydrogen or optionally substituted alkyl. In some embodiments, R12May be hydrogen or optionally substituted C1-6Alkyl, e.g. C optionally substituted with one or more (e.g. 1-3) substituents independently selected from1-4Alkyl groups: halogen and C1-4An alkyl group. In some embodiments, R1Is CONR13R14And R is13And R14Each independently hydrogen or optionally substituted alkyl. In some embodiments, R13And R14Each independently hydrogen or optionally substituted C1-6Alkyl, e.g. C optionally substituted with one or more (e.g. 1-3) substituents independently selected from1-4Alkyl groups: halogen and C1-4An alkyl group.
In some embodiments, R1Can be S (O)nR15Wherein n and R15As defined in the present application. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R15Is an optionally substituted alkyl group. In some embodiments, R15Is optionally substituted C1-6Alkyl, e.g. C optionally substituted with one or more (e.g. 1-3) substituents independently selected from1-4Alkyl groups: halogen and C1-4An alkyl group. In some embodiments, R15Is an optionally substituted cycloalkyl group. In some embodiments, R15Is optionally substituted C3-6Cycloalkyl, e.g. C optionally substituted with one or more (e.g. 1-3) substituents independently selected from3-6Cycloalkyl groups: halogen and C1-4An alkyl group. In some embodiments, R15Is NR10R11，R10And R11Suitable groups of (a) are as described herein.
In some embodiments, R1Can be OR16Wherein R is16As defined in the present application. In some embodiments, R16Is H. In some preferred embodiments, R16Is optionally substituted alkyl (e.g., optionally substituted C)1-6Alkyl) or optionally substituted cycloalkyl (e.g., optionally substituted C)3-6Cycloalkyl) thus R1Is an optionally substituted alkoxy or cycloalkoxy group as described herein. Other suitable R16As described in the present application.
R for a compound of formula I (e.g., a compound of formula I-1, a compound of formula Ia, a compound of formula Ib, or a compound of formula Ic)3As described herein. In some embodiments, R3Is optionally substituted aryl, e.g. optionally substituted C6-10And (4) an aryl group. In some embodiments, R3Is C optionally substituted with one or more (e.g., 1-3) substituents independently selected from6-10Aryl: halogen, hydroxy, cyano, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group. In some embodiments, R3May be an optionally substituted phenyl group. In some embodiments, R3May be an optionally substituted bicyclic aryl group. For example, in some preferred embodiments, R3Is optionally substituted naphthyl. In some embodiments, R3Is naphthyl optionally substituted with 1-3 substituents independently selected from: halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl and C3-6Cycloalkoxy, wherein alkyl, alkoxy, cycloalkyl, and cycloalkoxy are each optionally substituted with 1-3 substituents independently selected from: halogen (e.g., F) and C1-4An alkyl group. In some embodiments, R3Is naphthyl optionally substituted with 1-3 substituents independently selected from: halogen, hydroxy, cyano, C optionally substituted by 1-3 halogens1-4Alkyl, C optionally substituted by 1-3 halogens1-4Alkoxy, C optionally substituted with 1-3 halogens3-6Cycloalkyl and C optionally substituted by 1-3 halogens3-6A cycloalkoxy group. In some embodimentsIn, R3Is naphthyl optionally substituted with 1-3 substituents independently selected from: fluorine, chlorine, hydroxyl, methyl, ethyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, and cyclopropyl.
In some embodiments, R3Optionally substituted heteroaryl groups are also possible. For example, in some embodiments, R3Is an optionally substituted 8-10 membered bicyclic heteroaryl. In some embodiments, R3Is an 8-10 membered bicyclic heteroaryl optionally substituted with one or more (e.g., 1-3) substituents independently selected from: halogen, cyano, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group. In some embodiments, R3Is optionally substituted benzimidazolyl, pyrrolopyridyl, pyrazolopyridyl, indazolyl, indolyl, quinolinyl or isoquinolinyl. In some embodiments, R3Is benzimidazolyl, pyrrolopyridyl, pyrazolopyridyl, indazolyl, indolyl, quinolinyl, or isoquinolinyl, each of which is optionally substituted with 1-3 substituents independently selected from: halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl and C3-6Cycloalkoxy, wherein each of alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with 1-3 substituents independently selected from the group consisting of: halogen (e.g., F) and C1-4An alkyl group. In some embodiments, R3Is benzimidazolyl, pyrrolopyridyl, pyrazolopyridyl, indazolyl, indolyl, quinolinyl, or isoquinolinyl, each of which is optionally substituted with 1-3 substituents independently selected from: halogen, hydroxy, cyano, C optionally substituted by 1-3 halogens1-4Alkyl, C optionally substituted by 1-3 halogens1-4Alkoxy, C optionally substituted with 1-3 halogens3-6Cycloalkyl and C optionally substituted by 1-3 halogens3-6A cycloalkoxy group. In some embodiments, R3Is benzimidazolyl, pyrrolopyridyl, pyrazolopyridyl, indazolyl, indolyl or quinolylOr isoquinolinyl, each optionally substituted with 1-3 substituents independently selected from: fluorine, chlorine, hydroxyl, methyl, ethyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, and cyclopropyl. Preferably, the substitution of heteroaryl groups herein does not result in the direct attachment of a halogen, cyano, or oxygen atom (e.g., from a hydroxyl, alkoxy, or cycloalkoxy group) to a ring heteroatom, such as a ring nitrogen atom of a heteroaryl group. Likewise, one skilled in the art will appreciate that when a compound is attached to a hydroxyl group at a carbon atom adjacent to a nitrogen ring atom, the compound may exist predominantly in one or more tautomeric forms. For example, 2-hydroxy substituted 1-methyl-benzimidazoles may exist predominantly in form B as shown below:
Is suitable for R3Various positions of the bicyclic aryl or heteroaryl groups of (a) can be used for attachment to the spirolactone nucleus, e.g., positions not immediately adjacent to the distal ring. For example, both 1-and 2-naphthyl are suitable for R3A group. In some embodiments, R3Preferably 2-naphthyl. Similarly, a quinolinyl group may have seven different points of attachment, each at positions 2-8
In any of the embodiments described herein, R3Optionally substituted naphthyl, quinolinyl, benzimidazolyl, pyrrolopyridinyl, indolyl or indazolyl:
in some embodiments, the naphthyl, quinolinyl, benzimidazolyl, pyrrolopyridinyl, indolyl, or indazolyl group is optionally substituted with one or more (e.g., 1-3) substituents independently selected from the group consisting of: halogen, cyano, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl and C3-6Cycloalkoxy, wherein each of the alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with one or more (e.g., 1-3) substituents independently selected from the group consisting of: halogen (e.g., F) and C1-4An alkyl group. In some embodiments, the naphthyl, quinolinyl, benzimidazolyl, pyrrolopyridinyl, indolyl, or indazolyl group is optionally substituted with one or more (e.g., 1-3) substituents independently selected from the group consisting of: halogen, cyano, hydroxy, C optionally substituted by 1-3 halogens1-4Alkyl, C optionally substituted by 1-3 halogens1-4Alkoxy, C optionally substituted with 1-3 halogens3-6Cycloalkyl and C optionally substituted by 1-3 halogens3-6A cycloalkoxy group. In some embodiments, the naphthyl, quinolinyl, benzimidazolyl, pyrrolopyridinyl, indolyl, or indazolyl group is optionally substituted with one or more (e.g., 1-3) substituents independently selected from the group consisting of: fluorine, chlorine, hydroxyl, methyl, trifluoromethyl, ethyl, methoxy, trifluoromethoxy, ethoxy and cyclopropyl. Preferably, the substitution of benzimidazolyl, pyrrolopyridyl, indolyl or indazolyl groups herein does not result in the direct attachment of a halogen, cyano or oxygen atom (e.g., from a hydroxyl, alkoxy or cycloalkoxy group) to a ring nitrogen atom.
In any of the embodiments described herein, R3Optionally substituted naphthyl or quinolyl:
in some embodiments, the naphthyl or quinolinyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl radicalsAnd C3-6Cycloalkoxy, wherein each of the alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with 1-3 substituents independently selected from the group consisting of: halogen (e.g., F) and C1-4An alkyl group. In some embodiments, the naphthyl or quinolinyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: halogen, cyano, C optionally substituted by 1-3 halogens1-4Alkyl, C optionally substituted by 1-3 halogens1-4Alkoxy, C optionally substituted with 1-3 halogens3-6Cycloalkyl and C optionally substituted by 1-3 halogens3-6A cycloalkoxy group. In some embodiments, the naphthyl or quinolinyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: fluorine, chlorine, hydroxyl, methyl, trifluoromethyl, ethyl, methoxy, trifluoromethoxy, ethoxy, and cyclopropyl.
In some embodiments, R3Can be
In any of the embodiments described herein, R3Can be as follows:
exemplary spirolactone compounds
Certain embodiments of the present disclosure relate to certain exemplary spirolactone compounds.
In some embodiments, the present disclosure provides compounds of structural formulae II-1 through II-3, or pharmaceutically acceptable salts thereof:
wherein R is3May be any of those substituents defined herein. For example, in some preferred embodiments, R3Is optionally substituted naphthyl. In some embodiments, R3Is optionally 1-Naphthyl substituted with 3 substituents independently selected from: halogen, cyano, C optionally substituted by 1-3 halogens1-4Alkyl, C optionally substituted by 1-3 halogens1-4Alkoxy, C optionally substituted with 1-3 halogens3-6Cycloalkyl and C optionally substituted by 1-3 halogens3-6A cycloalkoxy group. In some embodiments, R3Is naphthyl optionally substituted with 1-3 substituents independently selected from: fluorine, chlorine, hydroxyl, methyl, ethyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, and cyclopropyl. In some preferred embodiments, R3Is an optionally substituted quinolyl group. In some embodiments, R3Is quinolinyl optionally substituted with 1-3 substituents independently selected from the group consisting of: halogen, cyano, C optionally substituted by 1-3 halogens1-4Alkyl, C optionally substituted by 1-3 halogens1-4Alkoxy, C optionally substituted with 1-3 halogens3-6Cycloalkyl and C optionally substituted by 1-3 halogens3-6A cycloalkoxy group. In some embodiments, R3Is quinolinyl optionally substituted with 1-3 substituents independently selected from the group consisting of: fluorine, chlorine, hydroxyl, methyl, ethyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, and cyclopropyl.
In some embodiments, R in structural formulas II-1 through II-33Can be
Each of which is optionally substituted with 1-3 substituents independently selected from: fluorine, chlorine, hydroxyl, methyl, trifluoromethyl, ethyl, methoxy, trifluoromethoxy, ethoxy, and cyclopropyl.
In some embodiments, the present disclosure provides a compound of structural formula III-1 or a compound of structural formula III-2, or a pharmaceutically acceptable salt thereof:
wherein R is1And R2May be any of those substituents defined herein. In some embodiments, R in formula III-1 or formula III-22Is hydrogen.
In some embodiments, the present disclosure provides a compound of structural formula III-3 through III-6, or a pharmaceutically acceptable salt thereof:
wherein R is1And R2May be any of those substituents defined herein.
In some embodiments, R in any of structural formulas III-1 through III-61May be optionally substituted C1-4Alkyl groups, for example, methyl, ethyl, isopropyl or tert-butyl. In some embodiments, R in any of structural formulas III-1 through III-61May be optionally substituted C1-4Alkoxy, for example, methoxy, trifluoromethoxy, ethoxy or isopropoxy. In some embodiments, R in any of structural formulas III-1 through III-61Can be NR10R11. In some embodiments, R10And R11One is an optionally substituted 5 or 6 membered heteroaryl. In some embodiments, R10And R11One is a 5-membered heteroaryl having 2-4 ring nitrogen atoms, optionally substituted with 1 or 2 substituents independently selected from: halogen, cyano and C1-4An alkyl group. In some embodiments, R10And R11One of which is pyrazolyl, triazolyl or tetrazolyl, each of which is optionally substituted by C1-4Alkyl substitution. In any of these embodiments, R10And R11Can be hydrogen or C1-4Alkyl (e.g., methyl). For example, in some embodiments, R10And R11One is
In some embodiments, the present disclosure also provides any one of the compounds of examples 1-22 or a salt (e.g., a pharmaceutically acceptable salt) thereof. For example, in some embodiments, the present disclosure also provides:
Synthesis method
Certain embodiments of the present disclosure relate to methods of synthesizing spirolactone compounds described herein.
In some embodiments, the present disclosure provides a method of synthesizing a compound of structural formula I,
wherein R is1，R2And R3As defined herein. In some embodiments, the method comprises reacting a compound of structural formula S-1 or a salt thereof with an acid of structural formula S-2 or an activated form thereof (e.g., acid chloride, acid anhydride) to form a compound of structural formula I,
wherein R is1，R2And R3As defined herein. Suitable reagents and conditions for this conversion are known in the art and are exemplified in the examples section, e.g., using HATU ((1- [ bis (dimethylamino) methylene)]-1H-1,2, 3-triazolo [4,5-b]Pyridinium 3-oxide hexafluorophosphate)) and diisopropylamine.
In some embodiments, the method comprises contactingCompounds of the formula S-3 with R1G2Or another reagent to form a compound of formula I,
wherein G is1Is halogen (preferably Br or I), CN or NH2And R1、R2And R3As defined herein, wherein R1G2Are reagents that can react with structural formula S-3 under suitable conditions to form structural formula I. For example, in some embodiments, G1Is halogen, R1G2Can be an organozinc reagent, an organoboron reagent, an organotin reagent, for example, which can react with a compound of formula S-3 to form a compound of formula I under palladium or copper catalyzed coupling reaction conditions. In some embodiments, R1G2Is an amino compound in which G2Is H, and G1Is halogen, and for example, R1G2Can react with the compound of the structural formula S-3 under the condition of coupling reaction catalyzed by palladium or copper to form the compound of the structural formula I. In some embodiments, R2Is H. In some embodiments, the compound of formula S-3 is of formula S-3a, wherein G1And R3As defined herein, for example, in some embodiments of structural formula S-3a, G1Is halogen (e.g., Br or I),
in some embodiments, R1G2Is composed ofIn some embodiments, R1G2Is an organoboron reagent, organotin reagent or organometallic reagent (e.g. organozinc reagent), where G2Is a boronic acid or ester, a trisubstituted Sn or metal (e.g., Zn) ion, and in some embodiments, R1Can be optionally takenSubstituted aryl or optionally substituted heteroaryl (e.g., 5-or 6-membered heteroaryl, such as 2-, 3-or 4-pyridyl). Suitable coupling reaction conditions are known in the art and are exemplified in the examples section. In which G is1In some embodiments of CN, a compound of formula S-3 or S-3a may be reacted with another reagent, such as an azide, to form tetrazole as R in formula I or Ia1A group.
The compounds of formula S-1 can be readily obtained by one skilled in the art in light of the present disclosure. For example, certain compounds of structural formula S-1 can be prepared by scheme 1 below:
scheme 1
Wherein Pg1Being a nitrogen protecting group, e.g. benzyl, R100And R101Independently is hydrogen or C1-4Alkyl (e.g., methyl), and R1And R2As defined in the present application. In some embodiments, R100And R101Are all hydrogen. In some embodiments, R100And R101One is hydrogen, and R100And R101Another of (A) is C1-4Alkyl (e.g., methyl). Thus, for example, a compound of formula S-4 can be treated with a strong base such as n-BuLi and then reacted with a compound of formula S-5. Acid treatment under appropriate conditions (e.g., 50% acetic acid and concentrated H)2SO4) Thereafter, for example, refluxing for several hours gives the spiro-cyclic compound of the formula S-6. See, e.g., Yamato M. et al, "Spirocyclo [ isochroman piperidine ] inhibiting histamine release]Synthesis and Structure-activity relationship of analogs, "J.Med.Chem.24: 194-198(1981), the contents of which are incorporated herein by reference in their entirety. The compound of formula S-1 can be obtained by deprotecting the compound of formula S-6. For example, when Pg1In the case of benzyl, the hydrogenation reaction converts the compound of formula S-6 to the compound of formula S-1. Other suitable nitrogen protecting groups are known in the art, e.g., as in "organic synthesisProtecting group ", 4 th edition, p.g.m.wuts; greene, john willi, 2007 and references cited therein.
In some embodiments, the present disclosure provides a process for preparing compound B3 and a compound of structural formula S-1a, or a salt thereof, by, for example, scheme 2 below:
scheme 2
Wherein G is1Is halogen, for example Br or I or cyano. In some embodiments, the piperidine nitrogen in B1, B2, B3, and the compounds of structural formula S-1a may be protected with a nitrogen protecting group such as benzyl, Boc, and the like. Other suitable nitrogen protecting groups include those known in the art. For example, as "protecting groups in organic synthesis", 4 th edition. p.g.m.wuts; greene, john willi, 2007 and references cited therein. For example, compound B1 or a salt thereof obtainable by the process described in scheme 1 may be subjected to a nitration reaction (e.g. using HNO)3) To form compound B2 or a salt thereof, compound B2 (or an N-protected derivative thereof) can be reduced (e.g., hydrogenated with Pd/C) to form compound B3 or a salt thereof, or an N-protected derivative thereof. Compound B3 or a salt thereof, or an N-protected derivative thereof, can then be subjected to a halogenation reaction, such as conversion of the amine group to a halogen (e.g., Br or I) under typical sandmeyer conditions (e.g., diazotization followed by reaction with CuBr, CuCN or CuI). Compound B3 or a compound of formula S-1a can be reacted with an acid of formula S-2 or an activated form thereof (e.g., acid chloride, acid anhydride) to form certain compounds of formula S-3 a.
It will be apparent to those skilled in the art that conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, various protecting groups are "protecting groups in organic synthesis", 4 th edition. p.g.m.wuts; greene, john willi, 2007 and references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many reagents are available from commercial suppliers, such as Aldrich chemical Co., Ltd (Milwaukee, Wis., USA), Sigma (St.Louis, Mo.). Other reagents may be prepared by procedures such as those described in, or obvious modifications to, the following standard reference texts: fisetin and fisetin reagents for organic synthesis, volumes 1-15 (john willi and son, 1991), chemistry of carbon compounds by rodde, volumes 1-5 and supples (el saiville science publishers, 1989), organic reactions, volumes 1-40 (john willi and son, 1991), March advanced organic chemistry, (willi, 7 th edition), and comprehensive organic transformations by ralock (willi-publishers, 1999).
Pharmaceutical composition
Certain embodiments relate to a pharmaceutical composition comprising one or more spirolactone compounds of the present disclosure.
The pharmaceutical composition may optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a spirolactone compound of the present disclosure and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting examples of suitable excipients include, for example, encapsulating materials or additives such as absorption enhancers, antioxidants, binders, buffering agents, coating agents, colorants, diluents, disintegrants, emulsifiers, compatibilizers, fillers, flavorants, humectants, lubricants, flavorants, preservatives, propellants, mold release agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. Reference is also made to ramington, science and practice of pharmacy, 21 st edition, a.r. gennaro (lipicott, williams and wilkins, barthamo, Md., 2005; incorporated herein by reference), which discloses various excipients used in formulating pharmaceutical compositions and known techniques for preparing such compositions.
The pharmaceutical composition may include any one or more of the spirolactone compounds of the present disclosure. For example, in some embodiments, a pharmaceutical composition comprises a compound of any one of structural formula I, structural formula I-1, structural formula Ia, structural formula Ib, structural formula Ic, structural formulae II-1 through II-3, and structural formulae III-1 through III-6, or a compound of any one of examples 1-22, or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, the pharmaceutical composition comprises a compound of any one of examples 1-22, or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the pharmaceutical composition may comprise a compound that is:
or a pharmaceutically acceptable salt thereof.
The pharmaceutical compositions can be formulated for delivery by different routes, e.g., oral, parenteral, inhalation, topical, and the like.
In some embodiments, the pharmaceutical composition is formulated for oral administration. Oral formulations may be presented as discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granule; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for the preparation of compositions for oral administration are known in the art. Non-limiting examples of suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1, 3-butylene glycol, carbomer, castor oil, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato starch, povidone, propylene glycol, ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sodium lauryl sulfate, mannitol, soy bean oil, and mixtures thereof, Sucrose, surfactant, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof.
In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion). The parenteral formulation may be, for example, an aqueous solution, a suspension or an emulsion. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting examples of suitable excipients include, for example, 1, 3-butylene glycol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, ringer's solution, safflower oil, sesame oil, soybean oil, U.S. p. or isotonic sodium chloride solution, water and mixtures thereof.
In some embodiments, the pharmaceutical composition is formulated for inhalation. For example, inhalable formulations may be formulated, for example, as nasal sprays, dry powders or aerosols that can be administered by metered dose inhalers. Excipients for the preparation of inhaled formulations are known in the art. Non-limiting examples of suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, as well as mixtures of these substances. Sprays can further contain propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
In some embodiments, the pharmaceutical composition is formulated for topical administration. For example, the topical formulation may be in the form of: a topical solution, lotion, shampoo, transdermal spray, topical film, foam, powder, paste, sponge, transdermal patch, tincture, oily patch, cream, gel or ointment. Excipients for the preparation of topical formulations are known in the art. Non-limiting examples of suitable excipients include, for example, animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, and mixtures thereof.
For example, the topical formulations described herein may have one or more "lipophilic solvents" that act as carriers into the pilosebaceous unit. The lipophilic solvents useful in the present invention may be combined with water and/or lower chains (e.g., C)1-6) The alcohol is miscible. In some embodiments, the lipophilic solvent may be a glycol, for example, propylene glycol. In some embodiments, the lipophilic solvent can be a polyethylene glycol, e.g., an average molecular weight (e.g., M)nOr Mw) In the range of 200 to 20000 daltons. In some embodiments, the lipophilic solvent is a glycol ether, for example, diethylene glycol monoethyl ether (carbitol).
The topical formulations described herein may also have one or more "fillers". Non-limiting examples of useful fillers include water and lower (e.g., C)1-6) Alcohols, including ethanol, 2-propanol, and n-propanol. In some embodiments, the bulking agent is water, ethanol, and/or 2-propanol.
The topical formulations described herein may also have one or more "moisturizers" for providing a moisturizing effect. Non-limiting examples of useful humectants include glycerin, polyols, and silicone oils. In some embodiments, the topical formulation comprises one or more humectants selected from glycerin, propylene glycol, and cyclomethicone.
The topical formulations described herein may also have a gelling agent that increases the viscosity of the final formulation. In some embodiments, the gelling agent may also function as an emulsifier. Non-limiting examples of useful gelling agents include cellulosics, acrylate polymers and acrylate copolymers, such as hydroxypropyl cellulose, hydroxymethyl cellulose, pluronic PF127 polymer, carbomer 980, carbomer 1342 and carbomer 940. In some embodiments, the topical formulation comprises one or more gelling agents selected from the group consisting of: hydroxypropyl cellulose (f)
The topical formulations described herein may also have one or more antioxidants, free radical scavengers, and/or stabilizers. Non-limiting, useful examples include butylated hydroxytoluene, butylated hydroxyanisole, ascorbyl palmitate, citric acid, vitamin E acetate, vitamin E-TPGS, ascorbic acid, tocoferol, and propyl gallate.
The topical formulations described herein may also have one or more preservatives that exhibit antibacterial and/or antifungal properties. Non-limiting, useful examples include diazolidinyl urea, methylparaben, propylparaben, tetrasodium EDTA, and ethylparaben.
The topical formulations described herein may also have one or more chelating agents. Non-limiting examples of use herein include EDTA, disodium edetate, dipotassium edetate, cyclodextrin, trisodium edetate, tetrasodium edetate, citric acid, sodium citrate, gluconic acid, and potassium gluconate.
Various amounts of active ingredients and excipients are suitable for use in the topical formulations described herein. For example, in some embodiments, the topical formulation can comprise from about 0.001 wt% to about 5 wt% (e.g., from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 0.5 wt%) of the spironolactone of the present disclosure, based on the total weight of the formulation. In some embodiments, the topical formulation may include the following ingredients (in weight percent based on the total weight of the formulation):
the pharmaceutical compositions may include various amounts of the spirolactone compounds of the present disclosure, depending on various factors such as the intended use and potency of the compounds. For example, in some embodiments, the pharmaceutical composition may comprise a spirolactone compound of the present disclosure in an amount effective to inhibit ACC1 and/or ACC2 activity in cells in vitro, in cells in vivo, or in cells ex vivo. In some embodiments, the amount is effective to achieve about 10%, about 20%, about 50%, about 70%, about 90%, about 99% (or any range between the recited values) inhibition of ACC1 and/or ACC2 activity as compared to a control.
In some embodiments, the pharmaceutical composition can comprise an amount of a spirolactone compound of the present disclosure that, when administered to a subject (e.g., a human) in need thereof, is effective to inhibit one or more activities of the subject. In some embodiments, the one or more activities are selected from acetyl-coa carboxylase ACC1 and/or ACC2 activity; fat generation; proliferation of cells (e.g., adipocytes, melanocytes, keratinocytes, squamous cells, mercker cells, langerhans cells, or skin stem cells) in the epidermis, dermis, and/or hypodermis; proliferation of human dermal adipocytes; proliferation of human keratinocytes; differentiation of fibroblasts into adipocytes in the cortex and/or subcutaneous layer; sebum production; inflammation and combinations thereof. In some embodiments, the pharmaceutical composition may comprise an amount of a spirolactone compound of the present disclosure that, when administered to a subject (e.g., a human) in need thereof, is (a) effective to inhibit acetyl-coa carboxylase ACC1 and/or ACC2 activity in cells (e.g., sebocytes, adipocytes) of the subject; (b) effective to inhibit lipogenesis (e.g., lipogenesis of sebocytes, lipogenesis of adipocytes, etc.) in a subject; (c) effective to inhibit cell proliferation, e.g., proliferation of adipocytes, melanocytes, keratinocytes, squamous cells, merkel cells, langerhans cells, or skin stem cells in the epidermis, dermis, and/or hypodermis of a subject; (d) effective to inhibit proliferation of human dermal adipocytes in a subject; (e) effective to inhibit proliferation of human keratinocytes in a subject; (f) effective to inhibit differentiation of fibroblasts in the cortex and/or subcutaneous layer of a subject into adipocytes; (g) effective to inhibit sebum production in a subject; (h) effective to inhibit inflammation in a subject, or any combination thereof. In some embodiments, the subject is characterized as having a disease or disorder selected from the group consisting of: acne, seborrhea, sebaceous gland hyperplasia, seborrheic keratosis, sebaceous gland adenoma, sebaceous cyst, actinic keratosis, sebaceous adenocarcinoma, squamous cell carcinoma, melanoma, rosacea, fibrofolliculoma in BHD syndrome, and combinations thereof. In some embodiments, the subject is characterized as having NASH.
In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a spirolactone compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a spirolactone compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a spirolactone compound of the present disclosure is an amount effective to treat a disease or condition as described herein, and may depend on the recipient of the treatment, the disease or condition being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of the treatment, the potency of the compound, its rate of clearance, and whether it is co-administered with another drug.
The pharmaceutical compositions can be used to treat a variety of diseases or disorders. Non-limiting diseases or conditions suitable for such treatment include skin diseases (e.g., diseases or conditions associated with abnormal sebocyte and/or keratinocyte activity), non-alcoholic fatty liver diseases or conditions, metabolic diseases or conditions, and proliferative diseases such as cancer. Non-limiting suitable diseases or disorders associated with abnormal sebocyte and/or keratinocyte activity include, for example, acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, sebaceous adenoma, sebaceous cysts, actinic keratosis, sebaceous adenocarcinoma, squamous cell carcinoma, melanoma, rosacea, fibrofolliculoma in BHD syndrome, and combinations thereof. Non-limiting examples of suitable non-alcoholic fatty liver diseases or disorders include, for example, non-alcoholic fatty liver disease (NASH). Non-limiting examples of suitable metabolic diseases or disorders include, for example, obesity and/or diabetes.
In addition to the spirolactone compounds of the present disclosure, the pharmaceutical compositions may also include one or more active agents. The spironolactone compounds of the present disclosure and one or more active agents can be in a single dosage form (e.g., in a single pill, tablet, capsule, topical ointment, gel, paste, cream, etc.) or in separate dosage forms. For example, spirolactone compounds of the present disclosure may be in oral or topical formulations, while one or more active agents may be in the same formulation or in different oral or topical formulations. The spirolactone compounds of the present disclosure and one or more active agents may be included in a kit when in different dosage forms.
A variety of active agents may be combined with the spirolactone compounds of the present disclosure in pharmaceutical compositions. For example, in some embodiments, the one or more active agents are suitable for treating a disease or disorder associated with abnormal sebocyte and/or keratinocyte activity, such as acne. Non-limiting, useful examples include antibiotics (e.g., tetracycline such as clindamycin, erythromycin, metronidazole, sulfacetamide or doxycycline and minocycline), retinoids (e.g., adapalene, isotretinoin, vitamin a, tazarotene or tretinoin), and combinations thereof. In some embodiments, the one or more active agents are present in an amount effective to treat a disease or disorder associated with abnormal sebocyte and/or keratinocyte activity, such as acne.
Non-limiting examples of useful active agents include angiotensin II receptor antagonists, Angiotensin Converting Enzyme (ACE) inhibitors, caspase inhibitors, cathepsin B inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulators, cholesterol solubilizing agents, diacylglycerol O-acyltransferase 1(DGAT1) inhibitors, dipeptidyl peptidase IV (DPPIV) inhibitors, Farnesol X Receptor (FXR) agonists, galectin-3 inhibitors, glucagon-like peptide 1(GLPl) agonists, glutathione precursors, hepatitis C virus NS3 protease inhibitors, HMG CoA reductase inhibitors, 11 β -hydroxysteroid dehydrogenase (11-HSD) inhibitors, IL- β antagonists, IL-6 antagonists, IL-10 agonists, IL-17 antagonists, ileal protein inhibitors, bile acid kinase inhibitors, PEG-folate receptor agonists, PEG-4624 inhibitors, PEG-folate receptor agonists, PEG-94 inhibitors, PEG-O-acyl-transferase inhibitors, PEG-Arg-94 inhibitors, PEG-O-acyl transferase inhibitors, PEG-Arg-Asp-94 inhibitors, PEG-O-acyl transferase inhibitors, PEG-Arg-Asp-5 inhibitors, PEG-O-acyl transferase inhibitors, PEG-Arg-Asp-Arg-Asp-5, VEGF-Arg-3 inhibitors, PEG-Arg-Asp-Arg-3, PEG-Asp-Arg-Asp-and PEG-Asp-Arg-Asp-Ser-and PEG-Ser-3, PEG-Asp-and PEG-Asp-inhibitors.
Method of treatment
Spironolactone compounds of the present disclosure are useful for inhibiting ACC1 and/or ACC2 activity in a cell, and for treating a disease or disorder associated with ACC1 and/or ACC2 activity (e.g., a metabolic disease, a disease associated with abnormal sebum production, or non-alcoholic fatty liver disease).
In some embodiments, the present disclosure provides a method of inhibiting ACC1 and/or ACC2 activity in a cell. In some embodiments, the method comprises contacting a cell with an effective amount of a spirolactone compound of the present disclosure or a pharmaceutical composition described herein. In some embodiments, the cell can be in vitro (e.g., in vitro)Such as a human cell line), in vivo (e.g., a human cell in a human subject), or ex vivo (a human cell from a human subject). If administered systemically, and the respective compound's blood concentration (or local administration and local concentration) is near or above its respective IC50Values (taking protein binding into account) then the inhibitory effect on ACC1 and/or ACC2 activity in vivo can be detected or predicted.
In some embodiments, inhibiting the activity of ACC1 and/or ACC2 may also inhibit malonyl-coa production, adipogenesis, cell proliferation, fibroblast differentiation into adipocytes, sebum production, and/or inflammation in cells that are involved in diseases or disorders, such as diseases or disorders associated with abnormal sebocyte and/or keratinocyte activity (e.g., acne and other diseases described herein), metabolic diseases (e.g., obesity, diabetes and other diseases described herein), non-alcoholic steatoliver disease (e.g., NASH), and cancer.
Thus, in some embodiments, the present disclosure provides a method of inhibiting adipogenesis in a cell. In some embodiments, the method comprises contacting a cell (e.g., a human cell) with an effective amount of a spirolactone compound of the present disclosure or a pharmaceutical composition described herein. In some embodiments, the cell is a sebocyte, an adipocyte, or a hepatocyte.
In some embodiments, the present disclosure provides a method of inhibiting cell proliferation. In some embodiments, the method comprises contacting a cell (e.g., a human cell) with an effective amount of a spirolactone compound of the present disclosure or a pharmaceutical composition described herein. In some embodiments, the cell is an adipocyte, a melanocyte, a keratinocyte, a squamous cell, a merkel cell, a langerhans cell, and/or a skin stem cell. In some embodiments, the cell is an adipocyte, melanocyte, keratinocyte, squamous cell, merkel cell, langerhans cell, and/or skin stem cell in the epidermis, dermis, and/or hypodermis. In some embodiments, the cell is a human sebocyte cell. In some embodiments, the cell is a human keratinocyte.
In some embodiments, the present disclosure provides a method of inhibiting differentiation of fibroblasts (e.g., human fibroblasts) into adipocytes. In some embodiments, the method comprises contacting a fibroblast with an effective amount of a spironolactone compound of the present disclosure or a pharmaceutical composition described herein. In some embodiments, the method inhibits differentiation of fibroblasts in the cortex and/or subcutaneous layer into adipocytes.
In some embodiments, the present disclosure provides a method of inhibiting sebum production. In some embodiments, the method comprises contacting a sebocyte (e.g., a human sebocyte) with an effective amount of a spironolactone compound of the present disclosure or a pharmaceutical composition described herein.
In some embodiments, the present disclosure also provides a method of inhibiting ACC1 and/or ACC2 activity and one or more (e.g., 1,2,3, 4,5, 6, or all) activities in a subject (e.g., a human subject) in need thereof, wherein the one or more activities are selected from (a) lipogenesis in the subject (e.g., adipogenesis in sebocytes, adipogenesis in adipocytes, adipogenesis in hepatocytes, etc.); (b) cell proliferation in the epidermis, dermis and/or hypodermis of the subject, such as proliferation of adipocytes, melanocytes, keratinocytes, squamous cells, mercker cells, langerhans cells or skin stem cells; (c) proliferation of human dermal adipocytes of the subject; (d) proliferation of human keratinocytes in the subject; (e) differentiation of fibroblasts in the cortex and/or subcutaneous layer of the subject into adipocytes; (f) sebum production in the subject; (g) inflammation in a subject, and combinations thereof, comprising administering to the subject an effective amount of a spirolactone compound of the present disclosure or a pharmaceutical composition described herein. In some embodiments, the subject is characterized as having a disease or disorder selected from the group consisting of: acne, seborrhea, sebaceous gland hyperplasia, seborrheic keratosis, sebaceous gland adenoma, sebaceous cyst, actinic keratosis, sebaceous adenocarcinoma, squamous cell carcinoma, melanoma, rosacea, fibrofolliculoma in BHD syndrome, and combinations thereof.
In some embodiments, the present disclosure also provides a method of treating a disease or disorder associated with ACC1 and/or ACC2 in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a spirolactone compound of the present disclosure or a pharmaceutical composition described herein. A variety of diseases or conditions are associated with undesirable or aberrant (e.g., overactive) ACC1 and/or ACC2 activity and may be treated by the methods described herein.
Method for treating skin diseases
The skin is the largest organ of the human body and provides an interface between the external environment and the host. Lipids play a crucial role in the formation and maintenance of skin permeability and antimicrobial barriers. The normal function of the skin is maintained by a hydrophobic extracellular lipid matrix in the stratum corneum, which is composed mainly of ceramides, cholesterol and free fatty acids, which prevents the loss of water and electrolytes in the body. The sebaceous glands are the organs that produce and secrete sebum into the follicular duct, which reaches the surface of the skin to maintain the normal function of the skin as a barrier.
Acne vulgaris (acne) is a common skin disorder affecting many people. Acne is a chronic inflammatory skin disease that is manifested primarily as open or closed comedones (blackheads and whiteheads) and inflammatory lesions, including papules, pustules or nodules (also known as cysts). Zaenglein, A. et al, J. dermatological Association, 74:945-73 (2016). Key causative factors that play an important role in the development of acne are follicular hyperkeratosis, microbial colonization by propionibacterium acnes, sebum production, and complex inflammatory mechanisms involving innate and acquired immunity. Acne can be of varying severity, such as mild, moderate and severe. The severity of the condition is affected by a number of factors, including seasonal and psychological effects.
Acne can be treated using a variety of therapies, such as moderate to severe acne. See, e.g., Zaenglein, A. et al, J. U.S. dermatological Association, 74:945-73 (2016). These therapies include, for example, (1) antibiotics (oral or topical) such as tetracycline, doxycycline, minocycline, methoxybenzylPyridine/sulfamethoxazole (TMP/SMX), trimethoprim, erythromycin, clindamycin, azelaic acid, dapsone, azithromycin, amoxicillin and cephalexin; (2) hormonal agents, such as combined oral contraceptives containing estrogen and progestin, e.g., ethinyl estradiol/norgestimate, ethinyl estradiol/norethindrone acetate/ferrous fumarate, ethinyl estradiol/drospirenone, and ethinyl estradiol/drospirenone/levomethyltetrahydrofolate; (3) oral retinoids, e.g. oral isotretinoin (A
Reduction of sebum production has also been described as a means of treating acne and the results show that acne can be significantly improved using non-retinoids which inhibit sebum production. See, e.g., U.S. patent No. 8,884,034, patented as Daynard, t. et al (2014), which cites Zouboulis, c.c. et al, "zileuton, an oral 5-lipoxygenase inhibitor, direct reduction of sebum production", journal of dermatology (2005), volume 210, pp.36-38; and Zouboulis, c.c. et al, "a new concept for acne treatment: preliminary studies using zileuton (an oral 5-lipoxygenase inhibitor), dermatology journal (2003), volume 139, pp.668-670.
The sebaceous glands are filled with mature sebocytes, which are mainly occupied by lipid droplets in the cytosol and undergo total secretion. In order to maintain the normal function of sebaceous glands, mature sebocytes are constantly regenerated from epidermal stem cells. Over-activation of sebocytes, including proliferation, differentiation and production of sebum, can cause various skin diseases, including acne, seborrhea, sebaceous gland hyperplasia, seborrheic keratosis, sebaceous gland adenoma, sebaceous gland cysts, actinic keratosis, sebaceous gland carcinoma, squamous cell carcinoma, melanoma, rosacea and fibrofolliculoma in BHD syndrome, among others.
Although lipid metabolism is active in the skin, the expression level and enzymatic activity of ACC in the skin (particularly in sebaceous glands) have not been fully elucidated. It is not known whether inhibition of ACC1 and/or ACC2 interferes with the development and progression of the above-mentioned skin diseases. US 2016/0220557 discloses ACC inhibitors for the treatment of acne. Recently, the phase 1 acne trial with PF-06423264 was terminated because of the nonsensical pharmacodynamic response shown. Further, although the Olumacostat Glasaretil showed phase II positive data, its primary endpoint was not reached in the phase III study. Although Olumacostat Glasaretin was proposed as a prodrug for (5- (tetradecyloxy) -2-furancarboxylic acid, a purported inhibitor of ACC, the effect observed for Olumacostat Glasaretin may not be due to inhibition of ACC.
Despite the above facts, the present inventors found that ACC protein is abundantly and specifically expressed in sebaceous glands of human skin. This result reveals for the first time the location of ACC proteins in human skin structures and provides evidence that inhibition of ACC in sebaceous glands by administering ACC inhibitors to the sebaceous glands (e.g. by local administration of ACC inhibitors) can inhibit lipid accumulation and the development of diseases associated with overproduction of lipids in sebocytes. Thus, in some embodiments, spirolactone compounds of the present disclosure may also be used to treat diseases or disorders associated with abnormal sebocyte and/or keratinocyte activity by, for example, topical administration. As shown in the examples section, representative exemplary spirolactone compounds of the present disclosure are inhibitors of ACC1 and/or ACC 2. Furthermore, representative exemplary spirolactone compounds of the present disclosure are shown to inhibit the activity of sebocytes, such as lipogenesis of sebocytes.
Accordingly, in some embodiments, the present disclosure provides a method of treating a disease or disorder associated with abnormal sebocyte and/or keratinocyte activity in a subject in need thereof. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a spirolactone compound of the present disclosure or a pharmaceutical composition described herein. Non-limiting suitable diseases or disorders associated with abnormal sebocyte and/or keratinocyte activity include, for example, acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, sebaceous adenoma, sebaceous cysts, actinic keratosis, sebaceous adenocarcinoma, squamous cell carcinoma, melanoma, rosacea, fibrofolliculoma in BHD syndrome, and combinations thereof. Various routes of administration are suitable, such as oral or topical administration. The methods can use the spirolactone compounds of the present disclosure as active agents, or they can be used in combination with another therapy. In some embodiments, the spironolactone compounds of the present disclosure are the only active agent administered to a subject for treating a disease or disorder associated with abnormal sebocyte and/or keratinocyte activity. In some embodiments, the method is a combination therapy, and further comprises treating the subject with one or more additional therapies effective to treat a disease or disorder associated with abnormal sebocyte and/or keratinocyte activity. When used in combination therapy, the spirolactone compounds of the present disclosure may be administered to a subject simultaneously, prior to, or after one or more other therapies. The spirolactone compounds of the present disclosure and one or more other therapies may be administered to a subject by the same or different routes. For example, in some embodiments, spirolactone compounds of the present disclosure may be administered topically, while one or more other therapies (e.g., other active agents) may be administered orally.
In some embodiments, the present disclosure provides a method of treating acne in a subject in need thereof. In some embodiments, the methods comprise administering (e.g., topically) a therapeutically effective amount of a spirolactone compound of the present disclosure or a pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the method is a combination therapy, and further comprises treating the subject with an additional therapy for acne. Any known therapy for treating acne may be used as part of the combination therapy, some of which are exemplified herein. For example, in some embodiments, the method further comprises administering to the subject an antibiotic (local or systemic), a retinoid (local or systemic), or a combination thereof. In some embodiments, the antibiotic is clindamycin, erythromycin, metronidazole, sulfacetamide, a tetracycline such as doxycycline and minocycline, or a combination thereof. In some embodiments, the retinoid is adapalene, isotretinoin, vitamin a, tazarotene, tretinoin, or a combination thereof. Other suitable antibiotics and retinoids are known in the art and are exemplified herein.
Methods of treating other diseases
Inhibition of ACC1 and/or ACC2 activity has also been found to be associated with and/or useful in the treatment of various metabolic diseases, non-alcoholic fatty liver disease and/or cancer. See, e.g., U.S. Pat. No. 8,288,405 and Griffith et al, J.Chem.Chem.57: 10512-10526(2014) (obesity, diabetes); harriman et al, Proc. Natl. Acad. Sci. USA 113: E1796-1805(2016) (non-alcoholic fatty liver disease (NASH), and Svensson et al, Nature 22, 1108-.
Accordingly, some embodiments of the present disclosure relate to the use of spironolactone compounds of the present disclosure or pharmaceutical compositions described herein to treat metabolic diseases, non-alcoholic fatty liver disease, and/or cancer. Various routes of administration are suitable, such as oral administration or topical administration. The methods can use the spirolactone compounds of the present disclosure as active agents, or be used in conjunction with another therapy. In some embodiments, the spirolactone compounds of the present disclosure are the only active agents administered to a subject to treat metabolic disease, non-alcoholic fatty liver disease, and/or cancer. In some embodiments, the method is a combination therapy, and further comprises treating the subject with one or more additional therapies effective to treat metabolic disease, non-alcoholic fatty liver disease, and/or cancer. When used in combination therapy, the spirolactone compounds of the present disclosure may be administered to a subject simultaneously with, prior to, or after one or more other therapies. The spirolactone compounds of the present disclosure and one or more other therapies may be administered to a subject by the same or different routes. For example, in some embodiments, spirolactone compounds of the present disclosure may be administered topically, while one or more other therapies (e.g., active agents) may be administered orally.
In some embodiments, the present disclosure provides a method of treating obesity and/or an obesity-related disorder (e.g., overweight, weight gain, or weight maintenance) in a subject in need thereof (e.g., a human subject). Obesity and overweight are generally defined by Body Mass Index (BMI), which is related to overall fat in the body and predicts the relative risk of disease. BMI is determined by dividing body weight (kilograms) by height (meters) squared (kg/m)2) To calculate. Overweight is generally defined as BMI 25-29.9kg/m2Obesity is generally defined as BMI 30kg/m2. See, e.g., the national heart, lung and blood association, clinical guidelines for the identification, assessment and treatment of overweight and obesity in adults, evidence report, Washington, d.c.: U.S. department of health and human services, NIH publication No. 98-4083 (1998). In some embodiments, the methods comprise administering (e.g., orally) a therapeutically effective amount of a spirolactone compound of the present disclosure or a pharmaceutical composition described herein to a subject in need thereof.
In some embodiments, the present disclosure also provides a method of treating diabetes and/or a diabetes-related disorder, such as type 1 (insulin-dependent diabetes mellitus, also referred to as "IDDM") and type 2 (non-insulin-dependent diabetes mellitus, also referred to as "NIDDM") diabetes, and the like, in a subject (e.g., a human subject) in need thereof. In some embodiments, the methods comprise administering (e.g., orally) a therapeutically effective amount of a spirolactone compound of the present disclosure or a pharmaceutical composition described herein to a subject in need thereof.
In some embodiments, the present disclosure also provides a method of treating a nonalcoholic fatty liver disease, such as NASH, in a subject in need thereof (e.g., a human subject). In some embodiments, the methods comprise administering (e.g., orally) to a subject in need thereof a therapeutically effective amount of a spirolactone compound of the disclosure (e.g., a compound of structural formula Ic or a compound of examples 14-22) or a pharmaceutical composition described herein.
In some embodiments, a method of treating obesity, obesity-related disorders, diabetes-related disorders, and/or non-alcoholic steatoliver disease may be a combination therapy, e.g., the method may comprise administering to a subject one or more other active agents in a therapeutically effective amount to treat the respective disease or disorder non-limiting useful drugs for the combination therapy include angiotensin II receptor antagonists, Angiotensin Converting Enzyme (ACE) inhibitors, caspase inhibitors, cathepsin B inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulators, cholesterol lytic agents, diacylglycerol O-acyltransferase 1(DGAT1) inhibitors, dipeptidyl peptidase iv (dppiv) inhibitors, Farnesol X Receptor (FXR) agonists, galectin-3 inhibitors, glucagon-like peptide 1(GLPl) agonists, glutathione precursors, hepatitis c virus NS3 protease inhibitors, HMG CoA reductase inhibitors, 11 β -hydroxysteroid dehydrogenase (lox dehydrogenase) inhibitors, PPAR 2-12-isoxaglicla-12, PPAR kinase inhibitors, PPAR 2-folate kinase inhibitors, PPAR 5-folate kinase inhibitors, PPAR 5-folate receptor agonists, PPAR kinase inhibitors, PPAR 3 agonists, PPAR kinase inhibitors, cholesterol-folate reductase inhibitors, PPAR kinase inhibitors, folate reductase inhibitors, PPAR 3 agonists, folate reductase inhibitors, folate reductase-folate reductase inhibitors, folate reductase kinase inhibitors, folate reductase kinase inhibitors, folate reductase kinase inhibitors, folate reductase kinase inhibitors, folate reductase kinase.
In some embodiments, the present disclosure also provides a method of treating cancer.
Exemplary embodiments
The present disclosure also provides the following exemplary embodiments E1-E52.
1. A compound of structural formula I, or a pharmaceutically acceptable salt thereof,
wherein:
R1and R2Each independently hydrogen, halogen, cyano, optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl, optionally substituted C2-6Alkenyl, optionally substituted C2-6Alkynyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-6 membered heterocyclyl, NR10R11、COOR12、CONR13R14、CN、S(O)nR15OR OR16；
Wherein
R10And R11Each independently hydrogen, optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl, optionally substituted C1-6Alkanoyl, optionally substituted C3-6Cycloalkanoyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-6 membered heterocyclyl, COOR12Or CONR13R14；
R12,R13And R14Each independently hydrogen or optionally substituted C1-6An alkyl group;
n is 0,1 or 2;
R15is optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl or NR10R11；
R16Is hydrogen, optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl, optionally substituted C1-6Alkanoyl, optionally substituted C3-6Cycloalkanoyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-6 membered heterocyclyl or CONR13R14；
And R is3Is optionally substituted C6-10Aryl or optionally substituted 5-10 membered heteroaryl,
with the proviso that when R1And R2When both are hydrogen, then R3Is not an optionally substituted phenyl group.
2. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein R1Is halogen, optionally substituted C1-6Alkyl, optionally substituted C1-6Alkoxy, optionally substituted C3-6Cycloalkyl or optionally substituted C3-6A cycloalkoxy group.
3. The compound of E1 or E2, or a pharmaceutically acceptable salt thereof, wherein R1Is C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl or C3-6Cycloalkoxy, each of which is optionally substituted with 1-3 independently selected substituents from: halogen and C1-4An alkyl group.
4. The compound of any one of E1-3, or a pharmaceutically acceptable salt thereof, wherein R1Is C1-4Alkyl or C1-4Alkoxy, each of which is optionally substituted with 1-3 fluoro.
5. Such as E1, or a pharmaceutically acceptable salt thereof, wherein R1Is a 5-10 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from: halogen, cyano, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group.
6. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein R1Is a 4-6 membered heterocyclyl optionally substituted with 1 or 2 substituents independently selected from: halogen, oxo, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group.
7. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein R1Is NR10R11。
8. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R10And R11One is optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl.
9. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R10And R11One is a 5-membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from: halogen, cyano and C1-4An alkyl group.
10. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R10And R11One is a 5-membered heteroaryl having 2 to 4 ring nitrogen atoms, optionally substituted with 1 or 2 substituents independently selected from: halogen, cyano and C1-4An alkyl group.
11. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R10And R11One is pyrazolyl, triazolyl or tetrazolyl, each of which is optionally substituted by 1 or 2 substituents independently selected from C1-4Alkyl substituents.
12. The compound of any one of E1-11, or a pharmaceutically acceptable salt thereof, wherein R2Is H.
13. Such as any one of E1-12The compound of item (1), or a pharmaceutically acceptable salt thereof, wherein R3Is C optionally substituted with 1-3 substituents independently selected from6-10Aryl: halogen, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl, and optionally substituted C3-6A cycloalkoxy group.
14. The compound of any one of E1-12, or a pharmaceutically acceptable salt thereof, wherein R3Is an optionally substituted 8-10 membered bicyclic heteroaryl.
15. The compound of any one of E1-12, or a pharmaceutically acceptable salt thereof, wherein R3Is naphthyl or quinolinyl, each of which is optionally substituted with 1-3 substituents independently selected from: halogen, cyano, C optionally substituted by 1-3 halogens1-4Alkyl, C optionally substituted by 1-3 halogens1-4Alkoxy, C optionally substituted with 1-3 halogens3-6Cycloalkyl and C optionally substituted by 1-3 halogens3-6A cycloalkoxy group.
16. The compound of any one of E1-12, or a pharmaceutically acceptable salt thereof, wherein R3Is naphthyl or quinolinyl, each of which is optionally substituted with 1-3 substituents independently selected from: fluorine, chlorine, hydroxyl, methyl, ethyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy and cyclopropyl.
17. A compound of structural formula Ia, or a pharmaceutically acceptable salt thereof,
wherein:
R1is hydrogen, halogen, cyano, optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl, optionally substituted C2-6Alkenyl, optionally substituted C2-6Alkynyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-6 membered heterocyclyl, NR10R11,COOR12,CONR13R14,CN,S(O)nR15OR OR16；
Wherein
R10And R11Each independently hydrogen, optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl, optionally substituted C1-6Alkanoyl, optionally substituted C3-6Cycloalkanoyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-6 membered heterocyclyl, COOR12Or CONR13R14；
R12,R13And R14Each independently hydrogen or optionally substituted C1-6An alkyl group;
n is 0,1 or 2;
R15is optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl or NR10R11；
R16Is hydrogen, optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl, optionally substituted C1-6Alkanoyl, optionally substituted C3-6Cycloalkanoyl, optionally substituted C6-10Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-6 membered heterocyclyl or CONR13R14；
And R is3Is optionally substituted C6-10Aryl or optionally substituted 5-to 10-membered heteroaryl,
with the proviso that when R1When it is hydrogen, then R3Is not an optionally substituted phenyl group.
18. The compound of E17, or a pharmaceutically acceptable salt thereof, wherein R1Is optionally substituted C1-4An alkyl group.
19. The compound of E17 or E18, or a pharmaceutically acceptable salt thereof, wherein R1Is methyl, ethyl, isopropyl or tert-butyl.
20. The compound of E17, or a pharmaceutically acceptable salt thereof, wherein R1Is optionally substituted C1-4An alkoxy group.
21. The compound of E20, or a pharmaceutically acceptable salt thereof, wherein R1Is methoxy, trifluoromethoxy, ethoxy or isopropoxy。
22. The compound of E17, having structural formula Ib,
wherein R is10And R11One is optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl.
23. The compound of E22, or a pharmaceutically acceptable salt thereof, wherein R10And R11One is an optionally substituted 5 or 6 membered heteroaryl.
24. The compound of E22, or a pharmaceutically acceptable salt thereof, wherein R10And R11One is a 5-membered heteroaryl group having 2-4 ring nitrogen atoms, optionally substituted by 1 or 2 substituents selected from halogen, cyano and C1-4Alkyl substituents.
25. The compound of E22, or a pharmaceutically acceptable salt thereof, wherein R10And R11One of which is pyrazolyl, triazolyl or tetrazolyl, each of which is optionally substituted by C1-4Alkyl substitution.
26. The compound of E22, or a pharmaceutically acceptable salt thereof, wherein R10And R11One isAnd R is10And R11The other of (a) or (b) is hydrogen or methyl.
27. The compound of any one of E17-26, or a pharmaceutically acceptable salt thereof, wherein R3Is C optionally substituted with 1-3 substituents independently selected from6-10Aryl: halogen, cyano, optionally substituted C1-4Alkyl, optionally substituted C1-4Alkoxy, optionally substituted C3-6Cycloalkyl and optionally substituted C3-6A cycloalkoxy group.
28. The compound of any one of E17-26, or a pharmaceutically acceptable salt thereof, wherein R3Is an optionally substituted 8-10 membered bicyclic heteroaryl.
29. The compound of any one of E17-26, or a pharmaceutically acceptable salt thereof, wherein R3Is naphthyl or quinolinyl, optionally substituted with 1-3 substituents independently selected from the group consisting of: halogen, cyano, C optionally substituted by 1-3 halogens1-4Alkyl, C optionally substituted by 1-3 halogens1-4Alkoxy, C optionally substituted with 1-3 halogens3-6Cycloalkyl and C optionally substituted by 1-3 halogens3-6A cycloalkoxy group.
30. The compound of any one of E17-26, or a pharmaceutically acceptable salt thereof, wherein R3Is composed of
31. The compound of any one of E17-26, or a pharmaceutically acceptable salt thereof, wherein R3 is
32. The compound of any one of E17-26, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
33. a pharmaceutical composition comprising a compound of any one of E1-32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
34. The pharmaceutical composition of E33, formulated for intravenous injection or infusion, oral administration, inhalation, or topical administration.
35. The pharmaceutical composition of E33 or E34, formulated in the form of: topical solutions, lotions, shampoos, transdermal sprays, topical films, foams, powders, pastes, sponges, transdermal patches, tinctures, oily plasters, creams, gels or ointments.
36. The pharmaceutical composition of any one of E33-35, comprising an amount of a compound of any one of E1-32, or a pharmaceutically acceptable salt thereof, effective to inhibit one or more activities of a human in need thereof, wherein the one or more activities are selected from the group consisting of acetyl-coa carboxylase ACC1 and/or ACC2 activity, adipogenesis, proliferation of cells in the epidermis, dermis, and/or hypodermis (e.g., adipocytes, melanocytes, keratinocytes, squamous cells, mercker cells, langerhans cells, or skin stem cells), proliferation of human dermal adipocytes, proliferation of human keratinocytes, differentiation of fibroblasts in the cortex and/or subcutaneous layer into adipocytes, sebum production, inflammation, and combinations thereof.
37. A method of inhibiting one or more activities selected from acetyl-coa carboxylase (ACC1 and/or ACC2) activity, malonyl-coa production, adipogenesis, proliferation of sebocytes, proliferation of keratinocytes, proliferation of cells in the epidermis, dermis, and/or hypodermis (e.g., adipocytes, melanocytes, keratinocytes, squamous cells, mercker cells, langerhans cells, and skin stem cells), differentiation of fibroblasts in the cortex and/or subcutaneous layer into adipocytes, inflammation, and combinations thereof, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any of E1-32 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of E33-36.
38. The method of E37, wherein the compound of any one of E1-32 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of E33-36 is administered topically to a subject.
39. A method of treating a disease or disorder associated with abnormal sebocyte and/or keratinocyte activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of E1-32, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of E33-36.
40. The method of E39, wherein the disease or disorder is acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, actinic keratosis, sebaceous adenomas, sebaceous cysts, sebaceous adenocarcinomas, squamous cell carcinoma, melanoma, rosacea, fibrofolliculoma in BHD syndrome, or a combination thereof.
41. The method of E39 or 40, wherein the disease or disorder is acne.
42. The method of any one of E39-41, wherein the compound of any one of E1-32 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of any one of E33-36 is administered topically to a subject.
43. The method of any one of E39-42, further comprising treating the subject with one or more additional therapies effective to treat a disease or disorder associated with abnormal sebocyte and/or keratinocyte activity.
44. The method of any one of E39-42, further comprising administering to the subject a therapeutically effective amount of an antibiotic (e.g., a tetracycline such as clindamycin, erythromycin, metronidazole, sulfacetamide or doxycycline and minocycline) or a retinoid (e.g., adapalene, isotretinoin, vitamin a, tazarotene or tretinoin) to treat acne and/or inflammation.
45. A method of treating non-alcoholic fatty liver disease (e.g., non-alcoholic fatty liver disease (NASH)) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of E1-32, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of E33-36.
46. The method of E45, further comprising administering to the subject one or more additional therapeutically effective amounts of a drug to treat non-alcoholic fatty liver disease.
47. The method of E45 or E46, wherein the one or more additional drugs is selected from the group consisting of an angiotensin II receptor antagonist, an Angiotensin Converting Enzyme (ACE) inhibitor, a caspase inhibitor, a cathepsin B inhibitor, a CCR2 chemokine antagonist, a CCR5 chemokine antagonist, a chloride channel stimulator, a cholesterol lytic agent, a diacylglycerol O-acyltransferase 1(DGAT1) inhibitor, a dipeptidyl peptidase iv (dppiv) inhibitor, a Farnesol X Receptor (FXR) agonist, a galectin-3 inhibitor, a glucagon-like peptide 1(GLPl) agonist, a glutathione precursor, a hepatitis c virus NS3 protease inhibitor, an HMG CoA reductase inhibitor, 11 β -hydroxysteroid dehydrogenase (11 β -HSDl) inhibitor, an IL- β antagonist, an IL-6 antagonist, an IL-10 agonist, an IL-17 antagonist, a sodium ileum cotransporter inhibitor, a leptin analog, a leptin-5-lipoxygenase inhibitor, a gene stimulator, a lox kinase inhibitor, a PPAR-5825 antagonist, a ghrelin kinase inhibitor, a ghrelin-3 inhibitor, a ghrelin agonist, a PPAR-3 inhibitor, a ghrelin kinase inhibitor, a ghrelin-3 inhibitor, a ghrelin-3 inhibitor, a statin inhibitor, a ghrelin inhibitor, a statin inhibitor, a PPAR-3 inhibitor, a ghrelin inhibitor, a statin, a ghrelin inhibitor, a inhibitor.
48. The method of any one of E46-47, wherein the one or more additional drugs is selected from acetylsalicylic acid, alistipen, 3 β -arachidonamido-7 α,12 α -di-hydroxy-5 β -cholestane-24-oic acid, atorvastatin, BLX-1002, seniviroc, 7- ((2R,4aR,5R,7aR) -2- ((3S) -1, 1-difluoro-3-methylpentyl) -2-hydroxy-6-oxooctahydrocyclopenta (b) pyran-5-yl) heptanoic acid, colesevelam, enrichexec, enalapril, GFT-505, bear GR-MD-02, hydrochlorothiazide, ethyl eicosapentaenoate (ethyl eicosapentaenoate), IMM-124E, KD-025, linagliptin, liraglutide, mercaptopyrithion, MGL-3196, obeticholic acid, oxelixocholic acid, PEG, cholestyrol, interleukin 376, pioglitazone, progastride, trexolone, shplate, TRX-102, TRX-VBY, and combinations thereof.
49. A method of treating obesity and/or diabetes in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of E1-32, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of E33-36.
50. The method of E49, further comprising administering to the subject one or more additional effective amounts of a drug to treat obesity and/or diabetes.
51. The method of E50, wherein the one or more additional drugs is selected from the group consisting of angiotensin II receptor antagonists, Angiotensin Converting Enzyme (ACE) inhibitors, caspase inhibitors, cathepsin B inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulators, cholesterol solubilizing agents, diacylglycerol O-acyltransferase 1(DGAT1) inhibitors, dipeptidyl peptidase iv (dppiv) inhibitors, Farnesol X Receptor (FXR) agonists, galectin-3 inhibitors, glucagon-like peptide 1(GLPl) agonists, glutathione precursors, hepatitis c virus NS3 protease inhibitors, HMG CoA reductase inhibitors, 11-hydroxysteroid dehydrogenase β (11 β -HSDl) inhibitors, IL- β antagonists, IL-6 antagonists, IL-10 agonists, IL-17 antagonists, ileal bile acid sodium cotransporter protein inhibitors, leptin analogs, 5-lipoxygenase inhibitors, gene oxygenase stimulators, lysine oxidase (lox 2) agonists, inhibitors, PPAR-9638 inhibitors, PPAR-g-t receptor kinase inhibitors, PPAR-2 kinase inhibitors, PPAR-t inhibitors, PPAR-2 kinase inhibitors, PPAR-2 kinase inhibitors, PPAR-3-HSDl-3 inhibitors, ghrelin-3 inhibitors, ghrelin inhibitors.
52. The method of any one of E50-51, wherein the one or more additional drugs is selected from acetylsalicylic acid, alistipen, 3 β -arachidonamido-7 α,12 α -di-hydroxy-5 β -cholestane-24-oic acid, atorvastatin, BLX-1002, seniviroc, 7- ((2R,4aR,5R,7aR) -2- ((3S) -1, 1-difluoro-3-methylpentyl) -2-hydroxy-6-oxooctahydrocyclopenta (b) pyran-5-yl) heptanoic acid, colesevelam, enrichexelon, enalapril, GFT-505, GR-MD-02, hydrochlorothiazide, ethyl eicosapentaenoate (ethyl eicosapentaenoate), IMM-124E, KD-025, linagliptin, thiolan, mercaptoursol-3196, obeticholic, olithic acid, PEG, cholestyril, glitazone, pirox-102, trexolone, shplate, TRX-VBY, and combinations thereof.
Definition of
It is understood that for all moieties and combinations thereof, the appropriate valency is maintained.
It should also be understood that a particular embodiment of a variable portion of the present application may be the same or different from another particular embodiment having the same identifier.
Suitable for R in the compounds of formula I (e.g., formula I-1, formula Ia, formula Ib, formula Ic, formula II-1 to formula II-3, or formula III-1 to formula III-6)1、R2And R3The groups of (a) are all independently selected. The embodiments described in the present invention may be combined. Such combinations are contemplated and within the scope of the invention. For example, it is contemplated for R1、R2And R3Embodiments of any of the above can be combined with those for R1、R2And R3Any other group is defined herein.
SymbolWhether used as a bond or displayed perpendicular to (or otherwise intersecting with) a bond, indicates the point at which the displayed moiety is attached to the rest of the molecule.
As used herein, the term "spirolactone compound of the present disclosure" refers to any of the compounds of structural formula I (e.g., structural formula I-1, structural formula Ia, structural formula Ib, structural formula Ic, structural formula II-1 to structural formula II-3, or structural formula III-1 to structural formula III-6) described herein, isotopically labeled compounds thereof, possible stereoisomers thereof (including diastereomers, enantiomers, and racemic mixtures), tautomers thereof, conformational isomers thereof, and/or pharmaceutically acceptable salts thereof (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). Hydrates and solvates of the spirolactone compounds of the present disclosure are considered compositions of the present disclosure, where the compounds are associated with water or a solvent, respectively.
As used herein, the phrases "administering," "administering" a compound or other variations of these phrases of a compound refer to providing the compound or a prodrug of the compound to an individual in need of treatment.
As used herein, the term "alkyl", used alone or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon (i.e., C) containing one to twelve carbon atoms1-12Alkyl) or a straight or branched aliphatic hydrocarbon of the specified number of carbon atoms (i.e., C)1Alkyl radicals such as methyl, C2Alkyl radicals such as ethyl, C3Alkyl groups such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is a straight chain C1-10An alkyl group. In another embodiment, the alkyl group is branched C3-10An alkyl group. In another embodiment, the alkyl group is a straight chain C1-6An alkyl group. In another embodiment, the alkyl group is branched C3-6An alkyl group. In another embodiment, the alkyl group is a straight chain C1-4An alkyl group. In another embodiment, the alkyl group is branched C3-4An alkyl group. In another embodiment, the alkyl group is a straight or branched chain C3-4An alkyl group. Non-limiting exemplary C1-10Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. Non-limiting exemplary C1-4Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl.
The term "optionally substituted alkyl", as used herein alone or as part of another group, means that the alkyl group as defined above is unsubstituted or substituted with one or more (e.g.,one, two OR three) substituents each independently selected from, for example, halogen (e.g., F), oxo, nitro, cyano, ORa、CO2Ra、OCO2Ra、OSO2NRbRc、SO3Ra、OSO3Ra、OS(O)nRe、NRbRc、C(＝O)NRbRc、OC(＝O)NRbRc、SO2NRbRc、OC(＝O)Rd、C(＝O)Rd、S(O)nRe、C(＝NRf)NRbRcAlkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, wherein alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl are each further optionally substituted with 1-5RgSubstituted, wherein n is 0,1 or 2, and Ra、Rb、Rc、Rd、Re、RfAnd RgAs defined in the present application. In one embodiment, the optionally substituted alkyl is substituted with three substituents, for example three fluoro. In one embodiment, the optionally substituted alkyl is substituted with one substituent. In one embodiment, the optionally substituted alkyl is substituted with two substituents.
As used herein, Ra、RdAnd ReEach independently at each occurrence of (A) is selected from hydrogen, C1–10Alkyl radical, C1–10Haloalkyl, C2–10Alkenyl radical, C2–10Alkynyl, C3–10Cycloalkyl, 3-14 membered heterocyclyl, C6–14Aryl and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0,1, 2,3, 4 or 5RgAnd (4) substituting the group.
As used herein, Rb、RcAnd RfEach of which is independently at each occurrence selected from hydrogen, nitro, cyano, ORaa、CO2Raa、SO3Raa、NRbbRcc、C(＝O)NRbbRcc、SO2NRbbRcc、OC(＝O)Rdd、C(＝O)Rdd、S(O)nRee、C(＝NRff)NRbbRcc、C1–10Alkyl radical, C1–10Haloalkyl, C2–10Alkenyl radical, C2–10Alkynyl, C3–10Cycloalkyl, 3-14 membered heterocyclyl, C6–14Aryl and 5-14 membered heteroaryl, or RbAnd RcOr R isfAnd RbAnd RcWherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0,1, 2,3, 4 or 5RgIs substituted with radicals in which n is 0,1 or 2, and Raa、Rbb、Rcc、Rdd、ReeAnd RffAs defined in the present application. In some embodiments, RbAnd RcAt least one of them is selected from hydrogen and C1–10Alkyl radical, C1–10Haloalkyl, C2–10Alkenyl radical, C2–10Alkynyl, C3–10Cycloalkyl, 3-14 membered heterocyclyl, C6–14Aryl and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0,1, 2,3, 4 or 5RgAnd (4) substituting the group. In some embodiments, RbAnd RcBoth are independently selected from hydrogen and C1–10Alkyl radical, C1–10Haloalkyl, C2–10Alkenyl radical, C2–10Alkynyl, C3–10Cycloalkyl, 3-14 membered heterocyclyl, C6–14Aryl and 5-14 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0,1, 2,3, 4 or 5RgAnd (4) substituting the group.
As used herein, RgIndependently at each occurrence, selected from halogen (e.g., F), nitro, cyano, ORaa、CO2Raa、NRbbRcc、C(＝O)NRbbRcc、SO2NRbbRcc、NRbb(SO2NRbbRcc)、OSO2NRbbRcc、NRbb(SO3Raa)、SO3Raa、OSO3Raa、NRbb(S(O)nRee)、O(S(O)nRee)、OC(＝O)Rdd、OCO2Raa、NRbbCO2Raa、OC(＝O)NRbbRcc、NRbb(C(＝O)Rdd)、C(＝O)Rdd、S(O)nRee、C(＝NRff)NRbbRcc、-NRhh-C(＝O)NRbbRcc、-NRhh-C(＝NRff)NRbbRcc、C1–6Alkyl radical, C1–6Haloalkyl, C2–6Alkenyl radical, C2–6Alkynyl, C3–10Cycloalkyl radical, C6–10Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0,1, 2,3, 4 or 5RggSubstituted by radicals, or two geminal RggThe substituents may together form ═ O or ═ S, where n is 0,1 or 2, and Raa、Rbb、Rcc、Rdd、Ree、Rff、RggAnd RhhAs defined in the present application.
As used herein, Raa、Rbb、Rcc、Rdd、Ree、RffAnd RhhEach of which is independently selected at each occurrence from hydrogen, C1–6Alkyl radical, C1–6Haloalkyl, C2–6Alkenyl radical, C2–6Alkynyl, C3–6Cycloalkyl, 4-6 membered heterocyclyl, C6–10Aryl and 5-10 membered heteroaryl, or RbbAnd Rcc、RffAnd Rhh、RffAnd RbbAnd RccOr R ishhAnd RbbAnd RccTogether form a 4-6 membered heterocyclyl or 5-10 membered heterocyclylHeteroaryl ring wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0,1, 2,3, 4 or 5RggAnd (4) substituting the group.
As used herein, RggIndependently at each occurrence, is selected from halogen (e.g., F), nitro, cyano, hydroxy, NH2、N(H)(C1–6Alkyl group), N (C)1–6Alkyl) (C1–6Alkyl group, N (H) (C)3–6Cycloalkyl), N (C)1–6Alkyl) (C3–6Cycloalkyl), N (C)3–6Cycloalkyl) (C)3–6Cycloalkyl), O-C1–6Alkyl radical, C1–6Alkyl radical, C1–6Haloalkyl, O-C1–6Haloalkyl, optionally substituted by 1-5 substituents independently selected from halogen, C1-4Alkyl and C3–6Cycloalkyl-substituted C3–6Cycloalkyl optionally substituted by 1-5 substituents independently selected from halogen, C1-4Alkyl and C3–6Cycloalkyl-substituted O-C3–6Cycloalkyl optionally substituted by 1-3 substituents independently selected from halogen, oxo, C1-4Alkyl and C3–6A 4-6 membered heterocyclyl substituted with a substituent selected from the group consisting of cycloalkyl, optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C1-4Alkyl and C3–6Cycloalkyl-substituted C6–10Aryl and optionally substituted by 1-5 substituents independently selected from halogen, cyano, C1-4Alkyl and C3–65-10 membered heteroaryl substituted with a substituent of cycloalkyl, or two geminal RggThe substituents may together form ═ O or ═ S.
As used herein, the term "cycloalkyl", used alone or as part of another group, refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing 1-3 rings, each ring having 3-12 carbon atoms (i.e., C)3-12Cycloalkyl) or have a specified carbon number. In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl is C3-8A cycloalkyl group. In another embodiment, the cycloalkyl is C3-6A cycloalkyl group. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, napthalenyl, adamantyl, cyclopentenyl and cyclohexenyl.
As used herein, the term "optionally substituted cycloalkyl", used alone or as part of another group, means that the cycloalkyl group as defined above is unsubstituted or substituted with one or more (e.g., one, two, or three) substituents each independently selected from, for example: halogen (e.g., F), oxo, nitro, cyano, ORa、CO2Ra、OCO2Ra、OSO2NRbRc、SO3Ra、OSO3Ra、OS(O)nRe、NRbRc、C(＝O)NRbRc、OC(＝O)NRbRc、SO2NRbRc、OC(＝O)Rd、C(＝O)Rd、S(O)nRe、C(＝NRf)NRbRcAlkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, wherein alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl are each further optionally substituted with 1-5RgSubstituted, wherein n is 0,1 or 2, and Ra、Rb、Rc、Rd、Re、RfAnd RgAs defined in the present application. In one embodiment, the optionally substituted cycloalkyl is substituted with three substituents. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent.
As used herein, the term "alkenyl", used alone or as part of another group, refers to an alkyl group as defined above that contains one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is C2-6An alkenyl group. In another embodiment, the alkenyl is C2-4An alkenyl group. Non-limiting exemplary alkenyl packetsIncluding ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
The term "optionally substituted alkenyl" as used herein, alone OR as part of another group, means that alkenyl as defined above is unsubstituted OR substituted with one OR more (e.g., 1,2, OR 3) substituents each independently selected from, for example, halogen (e.g., F), oxo, nitro, cyano, ORa、CO2Ra、OCO2Ra、OSO2NRbRc、SO3Ra、OSO3Ra、OS(O)nRe、NRbRc、C(＝O)NRbRc、OC(＝O)NRbRc、SO2NRbRc、OC(＝O)Rd、C(＝O)Rd、S(O)nRe、C(＝NRf)NRbRcAlkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, wherein alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl are each further optionally substituted with 1-5RgSubstituted, wherein n is 0,1 or 2 and Ra、Rb、Rc、Rd、Re、RfAnd RgAs defined in the present application.
As used herein, the term "alkynyl", used alone or as part of another group, refers to an alkyl group as defined above containing 1 to 3 carbon-carbon triple bonds. In one embodiment, the alkynyl group has a1 carbon-carbon triple bond. In one embodiment, the alkynyl group is C2-6An alkynyl group. In another embodiment, the alkynyl group is C2-4An alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.
The term "optionally substituted alkynyl", as used herein alone or as part of another group, means that the alkynyl group as defined above is unsubstituted or substituted with one or more (e.g., 1,2 or 3) substituentsSubstituted, each independently selected from, for example, halogen (e.g., F), oxo, nitro, cyano, ORa、CO2Ra、OCO2Ra、OSO2NRbRc、SO3Ra、OSO3Ra、OS(O)nRe、NRbRc、C(＝O)NRbRc、OC(＝O)NRbRc、SO2NRbRc、OC(＝O)Rd、C(＝O)Rd、S(O)nRe、C(＝NRf)NRbRcAlkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, wherein alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl are each further optionally substituted with 1-5RgSubstituted, wherein n is 0,1 or 2, and Ra、Rb、Rc、Rd、Re、RfAnd RgAs defined in the present application.
As used herein, the term "haloalkyl" used alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and/or iodine atoms. In preferred embodiments, the haloalkyl is an alkyl substituted with 1,2 or 3 fluorine atoms. In one embodiment, the haloalkyl is C1-10A haloalkyl group. In one embodiment, the haloalkyl is C1-6A haloalkyl group. In one embodiment, the haloalkyl is C1-4A haloalkyl group.
As used herein, the term "optionally substituted haloalkyl" used alone or as part of another group refers to an optionally substituted alkyl group substituted with one or more fluorine, chlorine, bromine, and/or iodine atoms.
As used herein, the term "alkoxy" used alone OR as part of another group refers to the formula ORa1Wherein R isa1Is an alkyl group. As used herein, the term "optionally substituted alkoxy" refers to the formula ORa1Wherein R isa1Is an optionally substituted alkyl group.
As used herein, the term "cycloalkoxy", used alone OR as part of another group, refers to the formula ORa1Wherein R isa1Is a cycloalkyl group. As used herein, the term "optionally substituted cycloalkoxy" refers to the formula ORa1Wherein R isa1Is an optionally substituted cycloalkyl group.
As used herein, the term "aryl" used alone or as part of another group refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 6 to 14 carbon atoms (i.e., C)6-14Aryl). In one embodiment, the aryl group is C6-12And (4) an aryl group. In one embodiment, the aryl group is selected from phenyl and naphthyl. In one embodiment, the aryl group is naphthyl.
The term "optionally substituted aryl" as used herein, alone OR as part of another group, means that the aryl group as defined above is unsubstituted OR substituted with 1-5 substituents each independently selected from, for example, halogen (e.g., F), nitro, cyano, ORa、CO2Ra、OCO2Ra、OSO2NRbRc、SO3Ra、OSO3Ra、OS(O)nRe、NRbRc、C(＝O)NRbRc、OC(＝O)NRbRc、SO2NRbRc、OC(＝O)Rd、C(＝O)Rd、S(O)nRe、C(＝NRf)NRbRcAlkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, wherein alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl are each further optionally substituted with 1-5RgSubstituted, wherein n is 0,1 or 2, and Ra、Rb、Rc、Rd、Re、RfAnd RgAs defined in the present application; or two of said substituents together form an optionally substituted cycloalkyl or an optionally substituted cycloalkyl fused to an arylA heterocyclyl ring of (a).
As used herein, the term "heteroaryl" or "heteroarene" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 5-14 ring atoms (i.e., 5-to 14-membered heteroaryl) and 1,2,3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur heteroatoms in one embodiment, the heteroaryl has 3 heteroatoms, e.g., 3 nitrogen atoms in another embodiment, the heteroaryl has 2 heteroatoms, e.g., 2 nitrogen atoms, 1 nitrogen atom, and 1 oxygen atom, or 1 nitrogen atom and 1 sulfur atom in another embodiment, the heteroaryl has 1 heteroatom, e.g., 1 nitrogen atom in another embodiment, the heteroaryl has 5 ring atoms, e.g., pyrazolyl in one embodiment, the heteroaryl has 6 ring atoms in another embodiment, e.g., pyridyl, non-limiting exemplary heteroaryl groups include thienyl, benzo [ b ] thienyl, naphtho [2,3-b ] thienyl, e.g., pyrazolyl, and 2-thienyl, e.g., 2-thienyl, 2-indolyl, e.g., 2-thienyl, 2,3, and 4-indolyl (e.g., 2-thienyl, 2, 3-thienyl, 3,2, 3, and 4-indolyl) as well as contemplated in one embodiment, 2,3, 4, 2,3, 2,3, 4, 2-thienyl, 2,3, 2,4, 2,4, and 4, 2-indolyl (e.g., indolyl) heteroaryl groups, 2,4, 2,4, 2-indolyl (e.g., indolyl, 4, 2-indolyl, 4, 2-indolyl, such as (e.g., 2-indolyl, 4-indolyl, 2-oxazolyl, 2, and 2, 2-oxazolyl, and 2, and 2, 2-4, 2-one, 2-oxazolyl, 2, and 2-one of the group, 2-oxazolyl, 2-one, 2,4, and 1, 2-one, 2-oxazolyl (with an (one of the group, 4, 2-4, 2-one of the group, 2-oxazolyl, one of an indolyl, 2-one of the group, 4, 2, one of the group of an indolyl, one of the.
The term "optionally substituted heteroaryl" as used herein, alone OR as part of another group, means that heteroaryl as defined above is unsubstituted OR substituted with one OR more (e.g., 1,2,3, 4, OR 5) substituents each independently selected from, for example, halogen (e.g., F), nitro, cyano, ORa、CO2Ra、OCO2Ra、OSO2NRbRc、SO3Ra、OSO3Ra、OS(O)nRe、NRbRc、C(＝O)NRbRc、OC(＝O)NRbRc、SO2NRbRc、OC(＝O)Rd、C(＝O)Rd、S(O)nRe、C(＝NRf)NRbRcAlkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, wherein alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl are each further optionally substituted with 1-5RgSubstituted, wherein n is 0,1 or 2, and Ra、Rb、Rc、Rd、Re、RfAnd RgAs defined in the present application; or two of said substituents together form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring fused to a heteroaryl.
As used herein, the term "heterocycle" or "heterocyclyl" used alone or as part of another group refers to a saturated or partially unsaturated (e.g., containing one or two double bonds) cyclic group containing one, two or three rings, having 3 to 14 rings (i.e., 3-to 14-membered heterocycles) and at least one heteroatom, each heteroatom being independently selected from oxygen, sulfur (including sulfoxides and sulfones) and/or nitrogen atoms, which may be quaternized the term "heterocyclyl" is meant to include cyclic urea groups such as imidazolidin-2-one, cyclic amide groups such as β -lactam, γ -lactam, δ -lactam and ε -lactam, and cyclic carbamate groups such as oxazolidin-2-one in one embodiment, heterocyclyl is a 4-, 5-, 6-, 7-or 8-membered ring group containing one ring and one or two oxygen and/or nitrogen atoms in one embodiment, heterocyclyl is a 5-or 6-membered ring group containing one ring and one or two nitrogen atoms in one embodiment, heterocyclyl is a 5-or 6-membered ring group containing one or two nitrogen atoms in one embodiment, heterocyclyl is a 5-or 8-membered ring group containing ring, and one or two nitrogen atoms in one embodiment, a 9-to 10-membered ring group containing nitrogen atoms or two nitrogen atoms in one embodiment, a 12-to 12-membered ring group, and a remaining portion of a molecule.
The term "optionally substituted heterocyclyl" as used herein, alone OR as part of another group, means that the heterocyclyl group as defined above is unsubstituted OR substituted with one OR more (e.g., 1,2,3, 4, OR 5) substituents each independently selected from, for example, halogen (e.g., F), oxo, nitro, cyano, ORa、CO2Ra、OCO2Ra、OSO2NRbRc、SO3Ra、OSO3Ra、OS(O)nRe、NRbRc、C(＝O)NRbRc、OC(＝O)NRbRc、SO2NRbRc、OC(＝O)Rd、C(＝O)Rd、S(O)nRe、C(＝NRf)NRbRcAlkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, wherein alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl are each further optionally substituted with 1-5RgSubstituted, wherein n is 0,1 or 2, and Ra、Rb、Rc、Rd、Re、RfAnd RgAs defined in the present application; or two of said substituents together form an optionally substituted aryl or optionally substituted heteroaryl ring fused to a heterocyclyl. Substitution can occur at any available carbon or nitrogen atom, and can form a spiro ring.
As used herein, the term "alkanoyl" used alone or as part of another group refers to the formula C (═ O) -Rd1Wherein R isd1Is an alkyl group. As used herein, the term "optionally substituted alkanoyl" used alone or as part of another group refers to C (═ O) -Rd1Wherein R isd1Is an optionally substituted alkyl group.
As used herein, the term "cycloalkanoyl", used alone or as part of another group, refers to the formula C (═ O) Rd1Wherein R isd1Is a cycloalkyl group. As used herein, the term "optionally substituted cycloalkanoyl" used alone or as part of another group refers to C (═ O) Rd1Wherein R isd1Is an optionally substituted cycloalkyl group.
As used herein, the term "salt" includes both internal and external salts. In some embodiments, the salt is an internal salt, i.e., a zwitterionic structure. In some embodiments, the salt is an external salt. In some embodiments, the external salt is a pharmaceutically acceptable salt with a suitable counterion. Suitable counterions for pharmaceutical use are known in the art.
As used herein, the terms "treat," "treating," "treatment," and the like refer to the elimination, reduction, or amelioration of a disease or disorder and its associated symptoms. Although not excluded, treating a disease or condition does not require complete elimination of the disease, condition, or symptom associated therewith. As used herein, the terms "treat," "treating," "treatment," and the like can include "prophylactic treatment," which refers to reducing the likelihood of recurrence of a disease or disorder in a subject who is not a disease or disorder but who is at risk of, or susceptible to, recurrence of a disease or disorder that has previously been controlled. The terms "treatment" and synonyms contemplate administration of a therapeutically effective amount of a compound described herein to a subject in need of treatment.
The terms "inhibit", "inhibition" or "inhibitor" refer to the ability of a compound to reduce, slow, stop or prevent the activity of a particular biological process (e.g., the activity of an accase relative to a vector in a cell).
The term "subject" (or alternatively referred to herein as "patient") as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
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