Pyrazole N-linked carbamoylcyclohexanoic acids as LPA antagonists

文档序号：1188959 发布日期：2020-09-22 浏览：21次中文

阅读说明：本技术 作为lpa拮抗剂的吡唑n-连接的氨基甲酰基环己基酸 (Pyrazole N-linked carbamoylcyclohexanoic acids as LPA antagonists ) 是由施琰郑泰华王莹于 2018-12-18 设计创作，主要内容包括：本发明提供式(I)化合物,或其立体异构体、互变异构体或药学上可接受的盐或溶剂合物,其中X1、X2、X3和X4各自独立地为CR6或N；其前提为X1、X2、X3或X4中不超过两者为N；Q2为N或NR5a；Q1和Q3之一为CR5,且另一者为N或NR5a；且所述虚线圈表示形成芳族环的任选键；Y1为O或NR3；Y2为-CO-、-SO2-或-S(O(NH)-；Y3为O或NR4a；其前提为(1)Y1和Y3不均为O,且(2)当Y2为C(O)时,Y1不为O；L为共价键或被0至4个R7取代的C1-4亚烷基；R1为(-CH2)aR9；a为整数0或1；R2各自独立地为卤素、氰基、羟基、氨基、C1-6烷基、C3-6环烷基、C4-6杂环基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基、烷氧基烷基、卤烷氧基烷基或卤烷氧基；n为整数0、1或2；R3和R4a独立地为氢、C1-6烷基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基；R4为C1-10烷基、C1-10卤烷基、C1-10氘代烷基、C1-10烯基、C3-8环烷基、6至10元芳基、3至8元杂环基、-(C1-6亚烷基)-(C3-8环烷基)、-(C1-6亚烷基)-(6至10元芳基)、-(C1-6亚烷基)-(3至8元杂环基)或-(C1-6亚烷基)-(5至6元杂芳基)；其中各个所述烷基、亚烷基、烯基、环烷基、芳基、杂环基和杂芳基其自身或作为其他部分的一部分独立地被0至3个R取代；或者,R3和R4与其所连接的N和O原子一起形成被0至3个R8取代的4至9元杂环部分；或者,(R3和R5a)或(R3和R5)与其所连接的原子一起形成被0至3个R8取代的5至8元杂环部分；R5a为氢、C1-6烷基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基；R5和R6各自独立地为氢、卤素、氰基、羟基、氨基、烷基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基；R7为卤素、氧代、氰基、羟基、氨基、C1-6烷基、C3-6环烷基、C4-6杂环基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基；R8各自独立地为氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6氘代烷基、C2-6烯基、C2-6炔基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基、卤烷氧基、苯基或5至6元杂芳基；或者,两个R8与其所连接的原子一起形成3至6元碳环或3至6元杂环部分,其各自独立地被0至3个R12取代；R9选自-CN、-C(O)OR10、-C(O)NR11aR11b、-CO-NH-CO-Re、-CO-NH-SO2-Re、-CO-NH-SO-Re、-SO2-OH、-SO2-NH-CO-Re、-P(O)(OH)2、四唑-5-基、-CH2-CO-NH-CO-Re、-CH2-CO-NH-SO2-Re、-CH2-CO-NH-SO-Re、-CH2-SO2-OH、-CH2-SO2-NH-CO-Re、-CH2-P(O)(OH)2、四唑-5-基亚甲基；Re为C1-6烷基、C3-6环烷基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基或卤烷氧基烷基；R10为氢或C1-10烷基；且R11a和R11b各自独立地为氢、C1-6烷基、C3-6环烷基、C4-6杂环基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基或卤烷氧基；且R12为卤素、氰基、羟基、氨基、C1-6烷基、烷基氨基、卤烷基、羟基烷基、氨基烷基、烷氧基烷基、卤烷氧基烷基、烷氧基、卤烷氧基、苯基或5至6元杂芳基。这些化合物为选择性的LPA受体抑制剂。<Image he="731" wi="700" file="DDA0002626130550000021.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein X 1 、X 2 、X 3 And X 4 Each independently isCR 6 Or N; provided that X is 1 、X 2 、X 3 Or X 4 Wherein no more than two are N; q 2 Is N or NR 5a ；Q 1 And Q 3 One is CR 5 And the other is N or NR 5a (ii) a And the dotted circles represent optional bonds forming aromatic rings; y is 1 Is O or NR 3 ；Y 2 is-CO-, -SO 2 -or-S (O (NH) -; Y) 3 Is O or NR 4a (ii) a Provided that (1) Y 1 And Y 3 Not all are O, and (2) when Y 2 When is C (O), Y 1 Is not O; l is a covalent bond or is substituted by 0 to 4R 7 Substituted C 1‑4 An alkylene group; r 1 Is (-CH) 2 ) a R 9 (ii) a a is an integer of 0 or 1; r 2 Each independently is halogen, cyano, hydroxy, amino, C 1‑6 Alkyl radical, C 3‑6 Cycloalkyl radical, C 4‑6 Heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl or haloalkoxy; n is an integer 0,1 or 2; r 3 And R 4a Independently of one another is hydrogen, C 1‑6 Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; r 4 Is C 1‑10 Alkyl radical, C 1‑10 Haloalkyl, C 1‑10 Deuterated alkyl, C 1‑10 Alkenyl radical, C 3‑8 Cycloalkyl, 6-to 10-membered aryl, 3-to 8-membered heterocyclyl, - (C) 1‑6 Alkylene group) - (C 3‑8 Cycloalkyl), - (C) 1‑6 Alkylene) - (6-to 10-membered aryl), - (C) 1‑6 Alkylene) - (3-to 8-membered heterocyclic group) or- (C) 1‑6 Alkylene) - (5-to 6-membered heteroaryl); wherein each of said alkyl, alkylene, alkenyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl is independently substituted with 0 to 3R on its own or as part of another moiety; or, R 3 And R 4 Together with the N and O atoms to which they are attached form a group defined by 0 to 3R 8 A substituted 4 to 9 membered heterocyclic moiety; or (R) 3 And R 5a ) Or (R) 3 And R 5 ) Together with the atom to which they are attached form a group consisting of 0 to 3R 8 A substituted 5 to 8 membered heterocyclic moiety; r 5a Is hydrogen, C 1‑6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; r 5 And R 6 Each independently is hydrogen, halogen, cyano, hydroxy, amino, alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; r 7 Is halogen, oxo, cyano, hydroxy, amino, C 1‑6 Alkyl radical, C 3‑6 Cycloalkyl radical, C 4‑6 Heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; r 8 Each independently is deuterium, halogen, hydroxy, amino, cyano, C 1‑6 Alkyl radical, C 1‑6 Deuterated alkyl, C 2‑6 Alkenyl radical, C 2‑6 Alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl or 5-to 6-membered heteroaryl; or, two R 8 Together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 3-to 6-membered heterocyclic moiety each independently substituted with 0 to 3R 12 Substitution; r 9 Selected from-CN, -C (O) OR 10 、‑C(O)NR 11a R 11b 、‑CO‑NH‑CO‑R e 、‑CO‑NH‑SO 2 ‑R e 、‑CO‑NH‑SO‑R e 、‑SO 2 ‑OH、‑SO 2 ‑NH‑CO‑R e 、‑P(O)(OH) 2 Tetrazol-5-yl, -CH 2 ‑CO‑NH‑CO‑R e 、‑CH 2 ‑CO‑NH‑SO 2 ‑R e 、‑CH 2 ‑CO‑NH‑SO‑R e 、‑CH 2 ‑SO 2 ‑OH、‑CH 2 ‑SO 2 ‑NH‑CO‑R e 、‑CH 2 ‑P(O)(OH) 2 Tetrazol-5-ylmethylene; r e Is C 1‑6 Alkyl radical, C 3‑6 Cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl or haloalkoxyalkyl; r 10 Is hydrogen or C 1‑10 An alkyl group; and R is 11a And R 11b Each independently is hydrogen, C 1‑6 Alkyl radical, C 3‑6 Cycloalkyl radical, C 4‑6 Heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; and R is 12 Is halogen, cyano, hydroxy, amino, C 1‑6 Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl or 5-to 6-membered heteroaryl. These compounds are selective LPA receptor inhibitors.)

1. A compound according to formula (I):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein

X¹、X²、X³And X⁴Each independently is CR⁶Or N; provided that X is¹、X²、X³Or X⁴Wherein no more than two are N;

Q²is N or NR^5a；

Q¹And Q³One is CR⁵And the other is N or NR^5a(ii) a And the dotted circles represent optional bonds forming aromatic rings;

Y¹is O or NR³；

Y²Is composed of

Y³Is O or NR^4a(ii) a The premise ofIs (1) Y¹And Y³Not all are O, and (2) when Y²When is C (O), Y¹Is not O;

l is a covalent bond or is substituted by 0 to 4R⁷Substituted C_1-4An alkylene group;

R¹is (-CH)₂)_aR⁹；

a is an integer of 0 or 1;

R²each independently is halogen, cyano, hydroxy, amino, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_4-6Heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl or haloalkoxy;

n is an integer 0,1 or 2;

R³and R^4aIndependently of one another is hydrogen, C_1-6Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

R⁴is C_1-10Alkyl radical, C_1-10Haloalkyl, C_1-10Deuterated alkyl, C_1-10Alkenyl radical, C_3-8Cycloalkyl, 6-to 10-membered aryl, 3-to 8-membered heterocyclyl, - (C)_1-6Alkylene group) - (C_3-8Cycloalkyl), - (C)_1-6Alkylene) - (6-to 10-membered aryl), - (C)_1-6Alkylene) - (3-to 8-membered heterocyclic group) or- (C)_1-6Alkylene) - (5-to 6-membered heteroaryl); wherein each of said alkyl, alkylene, alkenyl, cycloalkyl, aryl, heterocyclyl and heteroaryl is independently substituted with 0 to 3R on its own or as part of another moiety⁸Substitution; or, R³And R⁴Together with the N and O atoms to which they are attached form a group defined by 0 to 3R⁸A substituted 4 to 9 membered heterocyclic moiety; or (R)³And R^5a) Or (R)³And R⁵) Together with the atom to which they are attached form a group consisting of 0 to 3R⁸A substituted 5 to 8 membered heterocyclic moiety;

R^5ais hydrogen, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

R⁵and R⁶Each independently of the others is hydrogen, halogen, cyano, hydroxy, amino, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

R⁷is halogen, oxo, cyano, hydroxy, amino, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_4-6Heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

R⁸each independently is deuterium, halogen, hydroxy, amino, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl or 5-to 6-membered heteroaryl; or, two R⁸Together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 3-to 6-membered heterocyclic moiety each independently substituted with 0 to 3R¹²Substitution;

R⁹selected from-CN, -C (O) OR¹⁰、-C(O)NR^11aR^11b、

R^eIs C_1-6Alkyl radical, C_3-6Cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl or haloalkoxyalkyl;

R¹⁰is hydrogen or C_1-10An alkyl group; and

R^11aand R^11bEach independently is hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_4-6Heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; and

R¹²is halogen, cyano, hydroxy, amino, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl or 5-to 6-membered heteroaryl.

2. The compound of claim 1, wherein

The above-mentionedIs partially made of

A compound according to claim 1 or 2, wherein

The above-mentioned

Y⁴Is O or NH.

3. The compound of claim 1 or 2, wherein n is 0.

4. A compound according to any one of claims 1 to 3, wherein R¹Is CO₂H。

5. A compound according to any one of claims 1 to 4, wherein R⁵Is hydrogen.

6. A compound according to any one of claims 1 to 5, wherein R^5aIs C_1-4An alkyl group.

7. The compound according to any one of claims 1 to 6, wherein

R⁴Is C_1-10Alkyl radical, C_1-10Haloalkyl, C_3-6Cycloalkyl, - (C)_1-4Alkylene group) - (C_3-6Cycloalkyl) or benzyl; wherein said alkyl, alkylene, cycloalkyl and benzyl are each independently substituted with 0 to 3R⁸Substitution; and

R⁸each independently of the others is halogen, hydroxy, amino, cyano, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy or phenyl.

8. The compound according to any one of claims 1 to 7, represented by formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf):

R^7aeach independently of the others is hydrogen, halogen, cyano, hydroxy, amino, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_4-6Heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

f is an integer 1,2 or 3;

n is 0 or 1;

R³and R^4aEach independently is hydrogen or C_1-4An alkyl group;

R⁵and R^5aEach independently is hydrogen or C_1-4An alkyl group; or (R)³And R^5a) Or (R)³And R⁵) Together with the atoms to which they are attached form a 6-to 8-membered heterocyclic moiety; and

R¹、R²、n、R⁴、X¹、X²、X³and X⁴And in claims 1 to 7Any one of the definitions is the same.

9. The compound of claim 8, wherein X¹Is CR⁶Wherein R is⁶Is hydrogen or C_1-4An alkyl group.

10. A compound according to claim 8 or 9, wherein X³Is N.

11. A compound according to claim 8 or 9, wherein X¹、X²、X³And X⁴Is CR⁶Wherein R is⁶Each independently is hydrogen or C_1-4An alkyl group.

12. A compound according to any one of claims 8 to 11, wherein

The above-mentionedPart is selected from

R^6aEach independently is halogen, cyano, hydroxy, amino, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; and

d is an integer of 0,1 or 2.

13. The compound of claim 12, wherein

The above-mentionedPart is selected from

R⁶each independently of the others is hydrogen, halogen, cyano, hydroxy, amino, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy.

14. The compound of any one of claims 8 to 13, wherein f is 1.

15. The compound according to any one of claims 1 to 14, represented by formula (III):

R³is methyl;

R^5ais methyl; or, R³And R^5aTogether with the atoms to which they are attached form a 6 or 7 membered heterocyclic moiety; and

R¹、R⁴、X¹、X²、X³and X⁴As defined in any one of claims 1 to 15.

16. The compound of claim 15, wherein thePart is selected from

17. The compound of claim 15 or 16, wherein R¹Is CO₂H。

18. A compound according to any one of claims 15 to 17, wherein

The above-mentioned

And

R⁶is hydrogen, CH₃Or CH₂CH₃。

19. A compound according to any one of claims 15 to 18, wherein

R⁴Is C_3-10Alkyl radical, C_3-10Haloalkyl, C_3-6Cycloalkyl, - (C)_1-4Alkylene group) - (C_1-3Alkoxy), - (C)_1-4Alkylene group) - (C_3-6Cycloalkyl) or- (C)_1-4Alkylene) -phenyl; wherein said alkyl, alkylene, cycloalkyl and phenyl are each independently substituted with 0 to 3R⁸Substitution; and

R⁸each independently is halogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy.

20. A compound according to any one of claims 15 to 19, wherein

R⁴Is C_3-10Alkyl radical, C_3-10Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, - (CHR)^8a)_1-2-cyclopropyl, - (CHR)^8a) -cyclobutyl or-CH₂-a phenyl group; wherein said cyclopropyl and cyclobutyl are each substituted by 0 to 2R⁸Substituted, and said phenyl is substituted with 0 to 2 halogens selected from fluorine and chlorine;

R⁸each independently is methyl, ethyl, propyl or cyclopropyl; and

R^8aeach independently hydrogen or methyl.

21. A compound according to claim 1, selected from any one of the embodiments as described in the specification, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

22. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 21 or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.

23. A compound according to any one of claims 1 to 21, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, for use in therapy.

24. A compound according to any one of claims 1 to 21 or a stereoisomer, tautomer or pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition according to claim 22 for use in the treatment of the diseases related to lysophosphatidic acid receptor 1 (LPA)₁) Is a disease, disorder or condition associated with dysregulation.

25. A compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or a composition for use according to claim 24, wherein the disease, disorder or condition is pathological fibrosis, transplant rejection, cancer, osteoporosis or inflammation.

26. A compound for use according to claim 25, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, or a composition, wherein the pathological fibrosis is fibrosis of the lung, liver, kidney, heart, skin, eye or pancreas.

27. A compound for use according to claim 24, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, or a composition, wherein the disease, disorder or condition is Idiopathic Pulmonary Fibrosis (IPF), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, and systemic sclerosis.

28. A compound for use according to claim 25, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate or composition thereof, wherein the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, genitalia, urogenital tract, head, kidney, larynx, liver, lung, muscle tissue, cervical, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testis, or thyroid.

29. A compound according to any one of claims 1 to 21, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 22, for use in the treatment of fibrosis in a mammal in need thereof.

30. A compound for use according to claim 29, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof or a composition, wherein the fibrosis is Idiopathic Pulmonary Fibrosis (IPF), nonalcoholic steatohepatitis (NASH), chronic kidney disease, diabetic nephropathy, and systemic sclerosis.

31. A compound according to any one of claims 1 to 21, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 22, for use in the treatment of the following diseases, in a mammal in need thereof: pulmonary fibrosis (idiopathic pulmonary fibrosis), asthma, Chronic Obstructive Pulmonary Disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis (nonalcoholic steatohepatitis), skin fibrosis, intestinal fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, intestinal cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenon (Raynaud's phenomenon), or neuropathic pain.

Technical Field

The present invention relates to novel substituted pyrazole compounds, compositions containing the same, and methods of using the same, e.g., methods of using the same to treat disorders associated with one or more lysophosphatidic acid (LPA) receptors.

Background

Lysophospholipids are membrane-derived bioactive lipid mediators, one of the most medically important of which is lysophosphatidic acid (LPA). LPA is not a single molecular entity, but a group of endogenous structural variants of fatty acids of varying length and saturation (Fujiwara et al, J biol. chem.,2005,280, 35038-. The structural backbone of LPA is derived from glycerol-based phospholipids, such as Phosphatidylcholine (PC) or Phosphatidic Acid (PA).

LPA is a bioactive lipid (Signaling lipid) that modulates various cellular Signaling pathways by binding to the cognate 7-transmembrane domain G-protein coupled (GPCR) receptor (Chun, j., Hla, t., Spiegel, s., Moolenaar, w. editor, lysophospholipidic Receptors: Signaling and Biochemistry,2013, Wiley; ISBN: 978-0-470-. The currently known LPA receptor is designated LPA₁、LPA₂、LPA₃、LPA₄、LPA₅And LPA₆(Choi, J.W., Annu.Rev.Pharmacol.Toxicol.,2010,50, 157-35186; Kihara, Y. et al, Br.J.Pharmacol.,2014,171, 3575-3594).

LPA has long been known as a precursor for phospholipid biosynthesis in eukaryotic and prokaryotic cells, but LPA has only recently emerged as a signaling molecule that is rapidly produced and released by activated cells, especially platelets, to affect target cells by acting on specific cell surface receptors (see, e.g., Moolenaar et al, bioesys, 2004,26,870 & 881, and van Leewen et al, biochem. In addition to synthesis and processing into more complex phospholipids in the endoplasmic reticulum, LPA can be produced by hydrolysis of pre-existing phospholipids after cell activation; for example, the sn-2 position is usually deleted for a fatty acid residue due to deacylation, leaving only the sn-1 hydroxyl esterified to a fatty acid. In addition, the key enzyme in LPA production, autophagocyclin (lysoPLD/NPP2), can be the product of oncogenes, as autophagocyclin is upregulated in many tumor types (Brindley, d., j.cell biochem.2004,92,900-12). LPA concentrations in human plasma and serum, as well as in human bronchoalveolar lavage (BALF), have been reported, including measurements using sensitive and specific LC/MS and LC/MS procedures (Baker et al, anal. biochem.,2001,292, 287-295; onomato et al, j.lipid res.,2014,55, 1784-1796).

LPA affects a wide variety of biological responses ranging from induction of cell proliferation, stimulation of cell migration and neurite retraction, gap junction closure, and even myxobacteria chemotaxis (Goetzl et al, Scientific World J.,2002,2, 324-. As LPA responses in more and more cellular systems are tested, the body of knowledge about LPA biology is constantly growing. For example, it is known that in addition to stimulating cell growth and proliferation, LPA also promotes cell tone and cell surface fibronectin binding, an important event in wound repair and regeneration (Moolenaar et al, BioEssays,2004,26, 870-. More recently, anti-apoptotic activity has also been attributed to LPA, and PPAR γ has recently been reported to be a receptor/target for LPA (Simon et al, j.biol. chem.,2005,280, 14656-.

Fibrosis is the result of an uncontrolled tissue healing process that causes excessive accumulation and insufficient resorption of extracellular matrix (ECM), ultimately leading to end organ failure (rock, d.c. et al, New engl.j.med.,2015,372, 1138-1149). LPA has been reported₁The receptor is overexpressed in Idiopathic Pulmonary Fibrosis (IPF) patients. LPA (low pressure additive)₁Receptor knockout mice are protected from bleomycin-induced pulmonary fibrosis (Tager et al, Nature med.,2008,14, 45-54). LPA (low pressure additive)₁The antagonist BMS-986020 showed a significant decrease in the rate of FVC (forced vital capacity) decay in a 26-week clinical trial in IPF patients (Palmer et al, Chest,2018,154, 1061-1069). LPA pathway inhibitors (e.g., LPA)₁Antagonists) have been shown in rat models to be chemopreventive antifibrotic agents for the treatment of hepatocellular carcinoma (Nakagawa et al, Cancer Cell,2016,30, 879-890).

Thus antagonizing LPA₁The receptor may be useful in the treatment of fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, arterial fibrosis and systemic sclerosis, and thereby in the treatment of diseases caused by fibrosis (pulmonary fibrosis-idiopathic pulmonary fibrosis [ IPF)]Liver fibrosis-nonalcoholic steatosis hepatitis [ NASH]Renal fibrosis-diabetic nephropathy, systemic sclerosis-scleroderma, etc.).

Disclosure of Invention

The present invention provides novel substituted azole compounds, including stereoisomers, tautomers and pharmaceutically acceptable salts or solvates thereof, which are useful as antagonists against one or more lysophosphatidic acid (LPA) receptors, particularly LPA₁An antagonist of the receptor.

The invention also provides processes and intermediates useful for making the compounds of the invention.

The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

The compounds of the invention may be used to treat conditions in which LPA plays a role.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used in the preparation of medicaments for the treatment of conditions in which inhibition of the physiological activity of LPA is indicated, such as diseases in which the LPA receptor is involved, which are implicated in the etiology or pathology of the disease, or are otherwise associated with at least one symptom of the disease.

In another aspect, the invention relates to a method of treating fibrosis of organs (liver, kidney, lung, heart and the like and skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, regenerative failure, nonalcoholic steatohepatitis (NASH), liver hypofunction, liver bloodstream disorders, and the like), cell proliferative diseases [ cancer (solid tumors, solid tumor metastases, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma (Kaposi's ' ssarcoma), leukemia, Chronic Lymphocytic Leukemia (CLL), and the like) and invasive metastases of cancer cells, and the like ], inflammatory diseases (psoriasis, nephropathy, pneumonia, and the like), gastrointestinal diseases (irritable bowel disease (IBS), Inflammatory Bowel Disease (IBD), abnormal pancreatic secretion, and the like), A renal disease, a urinary tract-related disease (benign prostatic hyperplasia or symptoms associated with a neuropathy bladder disease, spinal cord tumors, herniated disks, spinal stenosis, symptoms derived from polyuria, a lower urinary tract disease (lower urinary tract obstruction, and the like), an inflammatory disease of the lower urinary tract, urinary pain, urinary frequency, and the like), a pancreatic disease, an abnormal angiogenesis-related disease (arterial obstruction, and the like), scleroderma, a brain-related disease (cerebral infarction, cerebral hemorrhage, and the like), neuralgia, peripheral neuropathy, and the like, an ocular disease (age-related macular degeneration (AMD), diabetic retinopathy, Proliferative Vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery scarring, and the like).

In another aspect, the invention relates to a method of treating a disease, disorder or condition, wherein LPA activation of at least one LPA receptor results in the symptoms or progression of the disease, disorder or condition. These diseases, disorders, or conditions can be derived from one or more of genetic, iatrogenic, immunological, infectious, metabolic, neoplastic, toxic, surgical, and/or traumatic etiologies.

In another aspect, the present invention relates to a method of treating renal fibrosis, pulmonary fibrosis, liver fibrosis, arterial fibrosis and systemic sclerosis comprising administering to a patient in need of such treatment a compound of the present invention as described above.

In one aspect, the invention provides methods, compounds, pharmaceutical compositions and medicaments described herein comprising LPA receptor antagonists, in particular, LPA₁An antagonist.

The compounds of the present invention may be used alone, in combination with other compounds of the present invention or in combination with one or more (preferably one to two) other agents.

These and other features of the present invention will be set forth in the expanded form as the disclosure continues.

Detailed Description

I. Compounds of the invention

In one aspect, the invention provides, inter alia, compounds of formula (I):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein

X¹、X²、X³And X⁴Each independently is CR⁶Or N; provided that X is¹、X²、X³Or X⁴Wherein no more than two are N;

Q²is N or NR^5a；

Q¹And Q³One is CR⁵And the other is N or NR^5a(ii) a And the dotted circles represent optional bonds forming aromatic rings;

Y¹is O or NR³；

Y²Is composed of

Y³Is O or NR^4a(ii) a Provided that (1) Y¹And Y³Not all are O, and (2) when Y²When is C (O), Y¹Is not O;

l is a covalent bond or is substituted by 0 to 4R⁷Substituted C_1-4An alkylene group;

R¹is (-CH)₂)_aR⁹；

a is an integer of 0 or 1;

n is an integer 0,1 or 2;

R³and R^4aIndependently of one another is hydrogen, C_1-6Alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

R⁴is C_1-10Alkyl radical, C_1-10Deuterated alkyl (fully or partially deuterated), C_1-10Haloalkyl, C_1-10Alkenyl radical, C_3-8Cycloalkyl, 6-to 10-membered aryl, 3-to 8-membered heterocyclyl, - (C)_1-6Alkylene group) - (C_3-8Cycloalkyl), - (C)_1-6Alkylene) - (6-to 10-membered aryl), - (C)_1-6Alkylene) - (3-to 8-membered heterocyclic group) or- (C)_1-6Alkylene) - (5-to 6-membered heteroaryl); wherein each of said alkyl, alkylene, alkenyl, cycloalkyl, aryl, heterocyclyl and heteroaryl is independently substituted with 0 to 3R on its own or as part of another moiety⁸Substitution; or, R³And R⁴Together with the N and O atoms to which they are attached form a group defined by 0 to 3R⁸A substituted 4 to 9 membered heterocyclic moiety; or (R)³And R^5a) Or (R)³And R⁵) Together with the atom to which they are attached form a group consisting of 0 to 3R⁸Substituted byA 5-to 8-membered heterocyclic moiety;

R^5ais hydrogen, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy;

R⁸each independently is deuterium, halogen, hydroxy, amino, cyano, C_1-6Alkyl radical, C_1-6Deuterated alkyl (fully or partially deuterated), C_2-6Alkenyl radical, C_2-6Alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl or 5-to 6-membered heteroaryl; or, two R⁸Together with the atoms to which they are attached form a 3-to 6-membered carbocyclic or 3-to 6-membered heterocyclic moiety each independently substituted with 0 to 3R¹²Substitution;

R⁹selected from-CN, -C (O) OR¹⁰、-C(O)NR^11aR^11b、

R^eIs C_1-6Alkyl radical, C_3-6Cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl or haloalkoxyalkyl;

R¹⁰is hydrogen or C_1-10An alkyl group;

R¹²is halogen, cyano, hydroxy, amino, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl or 5-to 6-membered heteroaryl.

In one embodiment of formula (I), X¹Is CR⁶Wherein R is⁶Is hydrogen or C_1-4Alkyl groups, for example, methyl.

In any of the preceding embodiments of formula (I), two R as substituents on the cycloalkyl or heterocyclyl group⁸Together forming a bridging portion.

In any of the preceding embodiments of formula (I), L is methylene.

In any of the preceding embodiments of formula (I),

is partially made of

In any of the preceding embodiments of formula (I),

part is selected from

And

Y⁴is O or NH.

In any of the preceding embodiments of formula (I), n is 0.

In any of the preceding embodiments of formula (I), R¹Is CO₂H。

In any of the preceding embodiments of formula (I),R⁵is hydrogen.

In any of the preceding embodiments of formula (I), R^5aIs C_1-4An alkyl group. In one embodiment, R^5aIs methyl.

In any of the preceding embodiments of formula (I), R⁴Is C_1-10Alkyl radical, C_1-10Haloalkyl, C_3-6Cycloalkyl, - (C)_1-4Alkylene group) - (C_3-6Cycloalkyl) or benzyl; wherein said alkyl, alkylene, cycloalkyl and benzyl are each independently substituted with 0 to 3R⁸Substitution; and R is⁸Each independently of the others is halogen, hydroxy, amino, cyano, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy or phenyl. The alkyl and alkylene groups are each independently linear or branched; and the methylene and phenyl moieties of the benzyl group are each independently substituted with 0 to 3R⁸And (4) substitution.

In one embodiment of the invention, the compound is represented by formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIf):

f is an integer 1,2 or 3;

n is 0 or 1;

R³and R^4aEach independently is hydrogen or C_1-4An alkyl group;

R¹、R²、n、R⁴、R⁵、R^5a、X¹、X²、X³and X⁴As defined above.

In one embodiment of formula (IIa) or (IIb), R¹Is CO₂H。

In any of the preceding embodiments of formula (IIa) or (IIb), X¹Is CR⁶Wherein R is⁶Is hydrogen or C_1-4An alkyl group. In one embodiment, X¹Is CH or CCH₃。

In any of the preceding embodiments of formula (IIa) or (IIb), X³Is N.

In any of the preceding embodiments of formula (IIa) or (IIb), X¹、X²、X³And X⁴Is CR⁶Wherein R is⁶Each independently is hydrogen or C_1-4An alkyl group. In one embodiment, X¹、X²、X³And X⁴Is CH.

In any of the preceding embodiments of formula (IIa) or (IIb),

part is selected from

R^6aEach independently is halogen, cyano, hydroxy, amino, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy; and

d is an integer of 0,1 or 2.

In any of the preceding embodiments of formula (IIa) or (IIb),

part is selected from

And

R⁶each independently of the others is hydrogen, halogen, cyano, hydroxy, amino, C_1-6Alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy.

In any of the preceding embodiments of formula (IIa) or (IIb), L is methylene or f is 1. In one embodiment, R^7aIs hydrogen.

In one embodiment of the invention, the compound is represented by formula (III):

R³is methyl;

R^5ais methyl; or, R³And R^5aTogether with the atoms to which they are attached form a 6 or 7 membered heterocyclic moiety; and

R¹、R⁴、X¹、X²、X³and X⁴As defined above.

In one embodiment of formula (III),

part is selected from

In any of the preceding embodiments of formula (III), R¹Is CO₂H。

In any of the preceding embodiments of formula (III),

part is selected from

And

R⁶is hydrogen, CH₃Or CH₂CH₃。

In any of the preceding embodiments of formula (III), R⁴Is C_3-10Alkyl radical, C_3-10Haloalkyl, C_3-6Cycloalkyl, - (C)_1-4Alkylene group) - (C_1-3Alkoxy), - (C)_1-4Alkylene group) - (C_3-6Cycloalkyl) or- (C)_1-4Alkylene) -phenyl; wherein said alkyl, alkylene, cycloalkyl and phenyl are each independently substituted with 0 to 3R⁸Substitution; and R is⁸Each independently is halogen, C_1-6Alkyl radical, C_3-6Cycloalkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy or haloalkoxy. The alkyl and alkylene groups are each independently linear or branched; and the methylene and phenyl moieties of the benzyl group are each independently substituted with 0 to 3R⁸And (4) substitution.

In any of the preceding embodiments of formula (III), R⁴Is C_3-10Alkyl radical, C_3-10Haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, - (CHR)^8a)_1-2-cyclopropyl, - (CHR)^8a) -cyclobutyl or-CH₂-a phenyl group; wherein said cyclopropyl and cyclobutyl are each substituted by 0 to 2R⁸Substituted, and said phenyl is substituted with 0 to 2 halogens selected from fluorine and chlorine; r⁸Each independently is methyl, ethyl, propyl or cyclopropyl; and R is^8aEach independently hydrogen or methyl.

In one embodiment of the invention, the compound is selected from any one of the examples as described in the specification, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

In another embodiment of the invention, the compound is selected from examples 1 to 44 as described in the specification, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

In one embodiment, LPA is used₁Functional antagonist assay, Compounds of the invention having hLPA₁IC₅₀The value is less than or equal to 5000 nM; in another embodiment, the compounds of the invention have hLPA₁IC₅₀The value is less than or equal to 1000 nM; in another embodiment, the compounds of the invention have hLPA₁IC₅₀The value is less than or equal to 500 nM; in another embodiment, the compounds of the invention have hLPA₁IC₅₀The value is less than or equal to 200 nM; in another embodiment, the compounds of the invention have hLPA₁IC₅₀The value is less than or equal to 100 nM; in another embodiment, the compounds of the invention have hLPA₁IC₅₀The value is less than or equal to 50 nM.

Other embodiments of the invention

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is an antagonist of at least one LPA receptor. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is LPA₁An antagonist. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is LPA₂An antagonist. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is LPA₃An antagonist.

In some embodiments, provided herein are compounds selected from active metabolites, tautomers, pharmaceutically acceptable salts, or solvates of compounds of formula (I).

In another embodiment, the present invention provides a composition comprising a compound of the present invention, or at least one of a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the invention provides a method of making a compound of the invention.

In another embodiment, the present invention provides an intermediate useful in the preparation of the compounds of the present invention.

In another embodiment, the invention provides a pharmaceutical composition further comprising an additional therapeutic agent.

In another embodiment, the present invention provides a method of treating a condition associated with LPA receptor mediated fibrosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention, or at least one of a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof. As used herein, the term "patient" encompasses all mammalian species.

In another embodiment, the present invention provides a method of treating a lysophosphatidic acid receptor 1 (LPA) in a patient in need thereof₁) A method of modulating a disease, disorder, or condition associated with dysregulation comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. In one embodiment of the method, the disease, disorder or condition is associated with pathological fibrosis, transplant rejection, cancer, osteoporosis or an inflammatory disorder. In one embodiment of the method, the pathological fibrosis is lung, liver, kidney, heart, dermis, eye or pancreas fibrosis. In one embodiment of the method, the disease, disorder or condition is Idiopathic Pulmonary Fibrosis (IPF), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, and systemic sclerosis. In one embodiment of the method, the cancer is a cancer of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, genitalia, urogenital tract, head, kidney, throat, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testis, or thyroid.

In another embodiment, the present invention provides a method of treating fibrosis in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. In one embodiment of the method, the fibrosis is Idiopathic Pulmonary Fibrosis (IPF), nonalcoholic steatohepatitis (NASH), chronic kidney disease, diabetic nephropathy, and systemic sclerosis.

In another embodiment, the invention provides a method of treating pulmonary fibrosis (idiopathic pulmonary fibrosis), asthma, Chronic Obstructive Pulmonary Disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis (nonalcoholic steatohepatitis), skin fibrosis, intestinal fibrosis, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, intestinal cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant rejection, scleroderma, ocular fibrosis, age-related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenon (Raynaud's phenomenon), or neuropathic pain in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of the invention, or a stereoisomer thereof, a pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier, a, The tautomer or pharmaceutically acceptable salt or solvate is administered to a mammal in need thereof.

As used herein, "treating" encompasses treating a disease state in a mammal (particularly, a human) and includes: (a) inhibiting, i.e., arresting the development of, the disease state; and/or (b) alleviating, i.e., causing regression of, the disease state. As used herein, "treating" or "treatment" also includes prophylactic treatment of a disease state to reduce and/or minimize the risk of the disease state and/or reduce the risk of relapse of the disease state by administering to a patient a therapeutically effective amount of a compound of the present invention, or at least one of a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof. Such prophylactic therapies may be selected for a patient based on factors known to increase the risk of developing a clinical disease state compared to the general population. For prophylactic treatment, the condition of the clinical disease state may or may not yet exist. Prophylactic therapy can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as therapy that reduces or minimizes the risk of the disease state in a patient who has not yet presented a clinical disease state, while secondary prevention is defined as minimizing or reducing the risk of relapse or secondary occurrence of the same or similar clinical disease state.

The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention encompasses all combinations of the preferred aspects of the invention mentioned herein. It is to be understood that any and all embodiments of the present invention may be combined with any other embodiment to describe additional embodiments. It should also be understood that each individual element of an embodiment is a separate embodiment of its own. Moreover, any element of one embodiment is intended to be combined with any and all other elements of any embodiment to describe another embodiment.

Chemistry

Throughout the specification and the claims which follow, the indicated chemical formula or name shall encompass all stereoisomers and optical isomers and racemates thereof (if such isomers exist). Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C ═ N double bonds, ring systems, and the like may also be present in the compounds, and all such stable isomers are contemplated in the present invention. The cis and trans (or E and Z) geometric isomers of the compounds of the invention have been described and can be isolated as mixtures of isomers or as isolated isomers. The compounds of the invention may be isolated in optically active or racemic forms. Optically active forms can be prepared by resolution of the racemic form or by synthesis from optically active starting materials. All processes for the preparation of the compounds of the invention and intermediates prepared therein are considered to be part of the invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the processing conditions, the end products of the invention are obtained in free (neutral) form or in salt form. Both free forms and salts of these final products are within the scope of the present invention. Thus, if desired, one form of the compound may be converted to another. Free base or acid can be converted into salt; the salt may be converted to the free compound or another salt; mixtures of isomeric compounds of the invention may be separated into individual isomers. The compounds of the invention, free forms and salts thereof, may exist in a variety of tautomeric forms, wherein hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms in the molecule are thus rearranged. It is to be understood that all tautomeric forms, insofar as they may exist, are included within the invention.

The term "stereoisomer" refers to isomers having the same composition, except for the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and do not overlap. The term "diastereomer" refers to a stereoisomer that is not a mirror image. The term "racemate" or "racemic mixture" refers to a composition comprised of equimolar amounts of two enantiomeric species, wherein the composition lacks optical activity.

The symbols "R" and "S" represent the configuration of the substituent around the chiral carbon atom. The isomer descriptors "R" and "S" are used as described herein to indicate the atomic configuration relative to the core molecule and are intended to be used as defined in the literature (IUPAC recommendation 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term "chiral" refers to a structural feature of a molecule that makes it impossible to overlap with its mirror image. The term "homochiral" refers to a state of enantiomeric purity. The term "optically active" refers to the degree to which a plane of polarized light is rotated with a chiral molecule or a non-racemic mixture of chiral molecules.

As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. While "alkyl" represents a monovalent saturated aliphatic group (such as ethyl), an "alkylene" represents a divalent saturated aliphatic group (such as ethylene). Examples of such applications areIn other words, "C₁To C₁₀Alkyl "or" C_1-10Alkyl "is intended to include C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉And C₁₀An alkyl group. "C₁To C₁₀Alkylene "or" C_1-10Alkylene "is intended to include C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉And C₁₀An alkylene group. Also, for example, "C₁To C₆Alkyl "or" C_1-6Alkyl "represents an alkyl group having 1 to 6 carbon atoms; and is "C₁To C₆Alkylene "or" C_1-6Alkylene "represents an alkylene group having 1 to 6 carbon atoms; and is "C₁To C₄Alkyl "or" C_1-4Alkyl "represents an alkyl group having 1 to 4 carbon atoms; and is "C₁To C₄Alkylene "or" C_1-4Alkylene "means an alkylene having 1 to 4 carbon atoms. An alkyl group may be unsubstituted or substituted, wherein at least one hydrogen is replaced by another chemical group. Exemplary alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When using "C₀Alkyl "or" C₀Alkylene "is intended to mean a direct bond. In addition, the term "alkyl" by itself or as part of another group, such as alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, and haloalkoxy, can be an alkyl group having 1 to 4 carbon atoms, or 1 to 6 carbon atoms, or 1 to 10 carbon atoms.

"heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced with a heteroatom (such as O, N or S). For example, if the alkyl carbon atom attached to the parent molecule is replaced with a heteroatom (e.g., O, N or S), the resulting heteroalkyl group is individually an alkoxy group (e.g., -OCH)₃Etc.), alkylamino (e.g., -NHCH₃、-N(CH₃)₂Etc.), or sulfanyl (e.g., -SCH)₃). If the non-terminal carbon atom of the alkyl group not attached to the parent molecule is replaced by a heteroatom (e.g. O, N or S), the resulting heteroalkyl group is each an alkyl ether (e.g. -CH)₂CH₂-O-CH₃Etc.), alkylaminoalkyl (e.g., -CH)₂NHCH₃、-CH₂N(CH₃)₂Etc.) or thioalkyl ethers (e.g., -CH₂-S-CH₃). If the terminal carbon atom of the alkyl group is replaced by a heteroatom (e.g., O, N or S), the resulting heteroalkyl group is each a hydroxyalkyl group (e.g., -CH)₂CH₂OH), aminoalkyl (e.g., -CH)₂NH₂) Or alkyl thiol groups (e.g. -CH)₂CH₂-SH). The heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. C₁-C₆Heteroalkyl means a heteroalkyl having 1 to 6 carbon atoms.

"alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either a straight or branched chain configuration, having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may be present at any stable point along the chain. For example, "C₂To C₆Alkenyl "or" C_2-6Alkenyl "(or alkenylene) is intended to include C₂、C₃、C₄、C₅And C₆An alkenyl group. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.

"alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either a straight or branched chain configuration having one or more, preferably one to three, carbon-carbon triple bonds that may be present at any stable point along the chain. For example, "C₂To C₆Alkynyl "or" C_2-6Alkynyl "(or alkynylene) is intended to include C₂、C₃、C₄、C₅And C₆An alkynyl group; such as ethynyl, propynyl, butynyl, pentynyl and hexynyl.

As used hereinBy "aralkyl" (also referred to as aralkyl), "heteroarylalkyl," "carbocyclylalkyl," or "heterocyclylalkyl" is meant an acyclic alkyl group in which a bond is made to a carbon atom (typically terminal or sp)³Carbon atom) is replaced by an aryl, heteroaryl, carbocyclyl or heterocyclyl group, respectively. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenyleth-1-yl, naphthylmethyl, 2-naphthyleth-1-yl, naphthobenzyl, 2-naphthophenyleth-1-yl, and the like. Arylalkyl, heteroarylalkyl, carbocyclylalkyl or heterocyclylalkyl groups may contain 4 to 20 carbon atoms and 0 to 5 heteroatoms, e.g., the alkyl moiety may contain 1 to 6 carbon atoms.

The term "benzyl" as used herein refers to a methyl group in which one hydrogen atom is replaced by a phenyl group, wherein the phenyl group may optionally be substituted by 1 to 5, preferably 1 to 3 groups: OH, OCH₃、Cl、F、Br、I、CN、NO₂、NH₂、N(CH₃)H、N(CH₃)₂、CF₃、OCF₃、C(＝O)CH₃、SCH₃、S(＝O)CH₃、S(＝O)₂CH₃、CH₃、CH₂CH₃、CO₂H and CO₂CH₃. "benzyl" can also be represented by the formula "Bn".

The term "alkoxy" or "alkyloxy" refers to an-O-alkyl group. "C₁To C₆Alkoxy "or" C₁₆Alkoxy "(or alkyloxy) is intended to include C₁、C₂、C₃、C₄、C₅And C₆An alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above having the specified number of carbon atoms attached through a sulfur bridge; such as methyl-S-and ethyl-S-.

The term "alkanoyl" or "alkylcarbonyl", as used herein by itself or as part of another group, refers to an alkyl group attached to a carbonyl group. For example, the alkylcarbonyl group may be substituted by alkyl-C (O) -substitutedAnd (4) showing. "C₁To C₆Alkylcarbonyl "(or alkylcarbonyl) is intended to include C₁、C₂、C₃、C₄、C₅And C₆alkyl-C (O) -groups.

The term "alkylsulfonyl" or "sulfonamide" as used herein by itself or as part of another group refers to an alkyl or amino group attached to a sulfonyl group. For example, the alkylsulfonyl group may be substituted by-S (O)₂R' represents, and the sulfonamide may be represented by-S (O)₂NR^cR^dAnd (4) showing. R' is C₁To C₆An alkyl group; and R is^cAnd R^dAs defined below for "amino".

The term "carbamate" as used herein by itself or as part of another group refers to an oxygen attached to an amide group. For example, the carbamate may be formed from N (R)^cR^d) -C (O) -O-and R^cAnd R^dAs defined below for "amino".

The term "amido", as used herein by itself or as part of another group, refers to an amine group attached to a carbonyl group. For example, the amide group may be represented by N (R)^cR^d) -C (O) -and R^cAnd R^dAs defined below for "amino".

The term "amino" is defined as-NR^c1R^c2Wherein R is^c1And R^c2Independently is H or C_1-6An alkyl group; or alternatively, R^c1And R^c2Together with the atoms to which they are attached form a 3-to 8-membered heterocyclic ring, which heterocyclic ring is optionally substituted with one or more groups selected from: halogen, cyano, hydroxy, amino, oxo, C_1-6Alkyl, alkoxy and aminoalkyl groups. When R is^c1Or R^c2(or both) are C_1-6When alkyl, the amino group may also be referred to as alkylamino. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, and the like. In one embodiment, amino is-NH₂。

The term "aminoalkyl" refers toAlkyl in which one hydrogen atom is replaced by an amino group. For example, aminoalkyl groups may be substituted with N (R)^c1R^c2) -alkylene-represents. "C₁To C₆"or" C_1-6"aminoalkyl (or aminoalkyl) is intended to include C₁、C₂、C₃、C₄、C₅And C₆An aminoalkyl group.

The term "halogen" or "halo" as used herein by itself or as part of another group refers to chlorine, bromine, fluorine and iodine, with chlorine or fluorine being preferred.

"haloalkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens. "C₁To C₆Haloalkyl "or" C_1-6Haloalkyl "(or haloalkyl) is intended to include C₁、C₂、C₃、C₄、C₅And C₆A haloalkyl group. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2, 2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" which is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms. The term "polyhaloalkyl" as used herein refers to an "alkyl" as defined above, such as polyfluoroalkyl, e.g. CF, including from 2 to 9, preferably from 2 to 5 halogen substituents (such as F or Cl, preferably F)₃CH₂、CF₃Or CF₃CF₂CH₂。

"haloalkoxy" or "haloalkyloxy" represents a haloalkyl group, as defined above, having the specified number of carbon atoms, connected by an oxygen bridge. For example, "C₁To C₆Haloalkoxy 'or' C_1-6Haloalkoxy "is intended to include C₁、C₂、C₃、C₄、C₅And C₆A haloalkoxy group. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2, 2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "sulfurHaloalkoxy "represents a haloalkyl group as defined above having the specified number of carbon atoms, connected by a sulfur bridge; such as trifluoromethyl-S-and pentafluoroethyl-S-. The term "polyhaloalkoxy" as used herein refers to an "alkoxy" or "alkyloxy" group as defined above, such as polyfluoroalkoxy, e.g. CF, comprising 2 to 9, preferably 2 to 5 halogen substituents (such as F or Cl, preferably F)₃CH₂O、CF₃O or CF₃CF₂CH₂O。

"hydroxyalkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more hydroxyl groups (OH). "C₁To C₆Hydroxyalkyl "(or hydroxyalkyl) is intended to include C₁、C₂、C₃、C₄、C₅And C₆A hydroxyalkyl group.

The term "cycloalkyl" refers to a cyclized alkyl group, including monocyclic, bicyclic, or polycyclic ring systems. "C₃To C₈Cycloalkyl radicals "or" C₃₈Cycloalkyl "is intended to include C₃、C₄、C₅、C₆、C₇And C₈Cycloalkyl groups, including monocyclic, bicyclic, and polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. The definition of "cycloalkyl" includes branched chain cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl, as well as spiro-and bridged cycloalkyl groups.

The term "cycloheteroalkyl" refers to a cyclized heteroalkyl group, including monocyclic, bicyclic, or polycyclic ring systems. "C₃To C₇Cycloheteroalkyl "or" C_3-7Cycloheteroalkyl "is intended to include C₃、C₄、C₅、C₆And C₇A cycloheteroalkyl group. Examples of cycloheteroalkyl groups include, but are not limited to, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl. The definition of "cycloheteroalkyl" includes branched cycloheteroalkyl groups such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridylmethyl, pyridazinylmethyl, pyrimidinylmethyl and pyrazinylmethylA oxazinyl methyl group.

As used herein, "carbocycle," "carbocyclyl," or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane (decahydronaphthalene), [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As indicated above, the definition of carbocycle also includes bridged rings (e.g., [2.2.2] bicyclooctane). Unless otherwise specified, preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term "carbocyclyl" is used, it is intended to include "aryl". When one or more carbon atoms connect two non-adjacent carbon atoms, a bridged ring results. Preferably the bridge is one or two carbon atoms. It should be noted that bridges always convert a single ring into a tricyclic ring. When a ring is bridged, the substituents described in that ring may also be present on the bridge.

Furthermore, as used herein by itself or as part of another group, the term "carbocyclyl" (including "cycloalkyl" and "cycloalkenyl") includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocycloalkyl, bicycloalkyl and tricycloalkyl groups containing a total of 3 to 20 carbon atoms forming the ring, preferably 3 to 10 carbon atoms or 3 to 6 carbon atoms forming the ring, and which may be fused to 1 or 2 aromatic rings as described for aryl, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, cycloheptyl, and the like,

Any of the groups may be optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and/or alkylthio and/or any alkyl substituent.

As used herein, the term "bicyclic carbocyclyl" is intended to mean a stable 9-or 10-membered carbocyclic ring system containing two fused rings and consisting of carbon atoms. In two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5-or 6-membered saturated, partially unsaturated, or unsaturated carbocyclic ring. The bicyclic carbocyclyl group may be attached to its pendant group at any carbon atom that results in a stable structure. The bicyclic carbocyclyl groups described herein may be substituted on any carbon if the resulting compound is stable. Examples of bicyclic carbocyclyl are, but not limited to, naphthyl, 1, 2-dihydronaphthyl, 1,2,3, 4-tetrahydronaphthyl, and indanyl.

As used herein, the term "aryl" as used herein by itself or as part of another group refers to monocyclic or polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons, including, for example, phenyl, naphthyl, anthryl, and phenanthryl. Aryl moieties are well known and described in, for example, Lewis, ed.J., ed., Hawley's Condensed Chemical Dictionary, 13 th edition, John Wiley&Sons, inc., New York (1997). In one embodiment, the term "aryl" denotes monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl, including 1-naphthyl and 2-naphthyl). For example, "C₆Or C₁₀Aryl "or" C_6-10Aryl "refers to phenyl and naphthyl. Unless otherwise specified, "aryl", "C₆Or C₁₀Aryl group "," C_6-10The aryl "or" aromatic residue "may be unsubstituted or substituted with 1 to 5 groups, preferably 1 to 3 groups, selected from-OH, -OCH₃、-Cl、-F、-Br、-I、-CN、-NO₂、-NH₂、-N(CH₃)H、-N(CH₃)₂、-CF₃、-OCF₃、-C(O)CH₃、-SCH₃、-S(O)CH₃、-S(O)₂CH₃、-CH₃、-CH₂CH₃、-CO₂H and-CO₂CH₃。

As used herein, the term "heterocycle", "heterocyclyl" or "heterocyclyl" is intended to mean a stable 3-, 4-, 5-, 6-or 7-membered monocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-or 14-membered polycyclic (including bicyclic and tricyclic) heterocycle that is saturated or partially unsaturated and contains carbon atoms and 1,2,3 or 4 heteroatoms independently selected from N, O and S; and includes any polycyclic group in which any of the above-defined heterocyclic rings is fused to a carbocyclic ring or an aryl (e.g., benzene) ring. That is, the terms "heterocycle", "heterocyclyl" or "heterocyclic group" include non-aromatic ring systems such as heterocycloalkyl and heterocycloalkenyl. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N → O and S (O))_pWherein p is 0,1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent (if defined)). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic ring described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may optionally be quaternized. Preferably, if the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heterocycle does not exceed 1. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, piperazinyl, piperidinyl, piperidonyl, piperonyl, pyranyl, morpholinyl, tetrahydrofuranyl, tetrahydroisoquinolinylAryl, tetrahydroquinolyl, morpholinyl, dihydrofuro [2,3-b ]]Tetrahydrofuran.

As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclyl" is intended to mean a stable 9-or 10-membered heterocyclic ring system containing two fused rings and consisting of carbon atoms and 1,2,3, or 4 heteroatoms independently selected from N, O and S. In two fused rings, one ring is a 5 or 6 membered monocyclic aromatic ring, comprising a 5 membered heteroaryl ring, a 6 membered heteroaryl ring or a benzo ring, each fused to the second ring. The second ring is a 5-or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated and which comprises a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, or a carbocyclic ring (with the proviso that if the second ring is carbocyclic, then the first ring is not a benzo ring).

The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The bicyclic heterocyclic groups described herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. Preferably, if the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heterocycle does not exceed 1. Examples of bicyclic heterocyclic groups are, but are not limited to, 1,2,3, 4-tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 5,6,7, 8-tetrahydro-quinolinyl, 2, 3-dihydro-benzofuranyl, chromanyl, 1,2,3, 4-tetrahydro-quinoxalinyl, and 1,2,3, 4-tetrahydro-quinazolinyl.

Also included in the definition of heterocycle are bridging rings. When one or more atoms (i.e., C, O, N or S) join two non-adjacent carbon or nitrogen atoms, a bridged ring results. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It should be noted that bridges always convert a single ring into a tricyclic ring. When a ring is bridged, the substituents described in that ring may also be present on the bridge.

As used herein, the term "heteroaryl" is intended to mean stable monocyclic and polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons that include at least one heteroatom ring member, such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolinyl, isoquinolinyl, thienyl, imidazoleA group selected from the group consisting of thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2, 4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolyl and benzodioxan. Heteroaryl is substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or another substituent (if defined)). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N → O and S (O))_pWherein p is 0,1 or 2).

Examples of heteroaryl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5, 2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoquinolinyl, thiocyaninyl, and benzthiazyl, Isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidylperidinyl (oxazolidinylperidinyl), oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, pyrazolidinyl, pyrazolopyridinyl, pyrazolidinyl, pyrazolopyridinyl, pyridooxazolinyl, pyrido, 2H-pyrrolyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalyl, quinuclidinyl, tetrazolyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, and xanthenyl.

Examples of 5-to 10-membered heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyrazolyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benzotetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxinyl, benzoxazolinyl, benzothiazolyl, benzisothiazolyl, isazoyl, isoquinolyl, octahydroisoquinolyl, isoxazolopyridyl, quinazolinyl, quinolyl, isothiazolopyridyl, thiazolopyridyl, oxazolopyridyl, imidazopyridyl, and pyrazolopyridyl. Examples of 5-to 6-membered heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. In some embodiments, the heteroaryl group is selected from benzothiazolyl, imidazopyridinyl, pyrrolopyridinyl, quinolinyl, and indolyl.

Unless otherwise indicated, "carbocyclyl" or "heterocyclyl" includes one to three other rings fused to a carbocyclic or heterocyclic ring (such as an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring), for example

And optionally may be substituted by 1,2 or 3 groups selected from: hydrogen, halogen, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, thiol, alkylthio, arylthio, heteroarylthio, arylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, trifluoromethylamino, alkoxycarbonyloxy, alkoxycarbonylamino, alkoxycarbonyla, Arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino, and arylsulfonylaminocarbonyl groups, and/or any of the alkyl substituents set forth herein.

When any of the terms alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is used as part of another group, the number of carbon atoms and ring members are as defined in the term itself. For example, alkoxy, haloalkoxy, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, alkylthio and the like each independently contain the same number of carbon atoms as defined for the term "alkyl", such as 1 to 4 carbon atoms, 1 to 6 carbon atoms, 1 to 10 carbon atoms and the like. Similarly, cycloalkoxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino, aralkylamino, arylamino, aryloxy, aralkoxy, heteroaryloxy, heteroarylalkoxy, and the like, each independently contain the same ring members as defined for the terms "cycloalkyl", "heterocyclyl", "aryl", and "heteroaryl", such as 3-to 6-membered, 4-to 7-membered, 6-to 10-membered, 5-or 6-membered, and the like.

According to conventions used in the art, keys pointing to bold lines as used in the structural formulae herein, such as

Bonds are depicted as points of attachment of moieties or substituents to the core or backbone structure.

According to protocols used in the art, waves or wave bonds in structural formulae, e.g.Are used to depict the stereocenters of symmetry of the carbon atoms to which X ', Y ' and Z ' are attached, and are intended to represent two enantiomers in a single figure. That is, structural formulae having bonds such as wavy bonds represent the various enantiomers individually, such asAnd racemic mixtures thereof. When a wave or wavy bond is attached to a double bond (such as C ═ C or C ═ N) moiety, it includes cis or trans (or E-and Z-) geometric isomers or mixtures thereof.

It is to be understood herein that if a carbocyclic or heterocyclic moiety can be bonded or otherwise attached to a given substrate through different ring atoms without indicating a particular point of attachment, all possible points are intended points, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" means 2-pyridyl, 3-pyridyl or 4-pyridyl, the term "thienyl" means 2-thienyl or 3-thienyl, and so on.

If a bond to a substituent is shown to intersect a bond connecting two atoms in a ring, such substituent may be bonded to any atom on the ring. If the listed substituents do not indicate that such substituents are bonded to atoms of the remainder of the specified formula compound, such substituents may be bonded through any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

One skilled in the art will recognize that the substituents and other moieties of the compounds of the present invention should be selected to provide a sufficiently stable compound to provide a pharmaceutically acceptable compound, which may be formulated as an acceptable stable pharmaceutical composition. Compounds of the invention having such stability are contemplated to be within the scope of the invention.

The term "counter ion" is used to denote negatively charged species such as chloride, bromide, hydroxide, acetate and sulfate. The term "metal ion" refers to an alkali metal ion such as sodium, potassium or lithium; and alkaline earth metal ions such as magnesium and calcium; and zinc and aluminum.

As referred to herein, the term "substituted" means that at least one hydrogen atom (attached to a carbon atom or heteroatom) is replaced with a non-hydrogen group, provided that the valency is maintained and the substitution results in a stable compound. When the substituent is oxo (i.e., ═ O), then 2 hydrogens on the atom are replaced. Oxo substituents are not present on the aromatic moiety. When a ring system (e.g. carbocyclic or heterocyclic) is referred to as being substituted with a carbonyl group or double bond, it is desirable that the carbonyl group or double bond is part of (i.e. within) the ring. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N). The term "substituted" with respect to alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, and heterocyclyl, respectively, means alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, and heterocyclyl, wherein one or more hydrogen atoms attached to a carbon atom or heteroatom are each independently replaced with one or more non-hydrogen substituents.

In the case of nitrogen atoms (e.g., amines) present on the compounds of the invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxide) to yield other compounds of the invention. Thus, the nitrogen atoms shown and claimed are considered to encompass the nitrogen shown and its N-oxide (N → O) derivatives.

When any variable occurs more than one time in any constituent or formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0,1, 2 or 3R groups, then the group is unsubstituted or substituted with up to three R groups when it is substituted with 0R groups, and R is independently selected at each occurrence according to the definition of R.

Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, the term "tautomer" as used herein refers to each of two or more isomers of a compound that are in equilibrium co-located, and are readily interchangeable by migration of atoms or groups within the molecule. For example, one skilled in the art will readily appreciate that 1,2, 3-triazole exists in two tautomeric forms, as defined above:

thus, the present invention is intended to encompass all possible tautomers, even when the structure depicts only one of them.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The compounds of the present invention may exist in the form of salts, which are also within the scope of the present invention. Pharmaceutically acceptable salts are preferred. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present invention wherein the parent compound is modified by making acid or base salts thereof. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media (such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. A list of suitable salts is found in Remington's pharmaceutical Sciences, 18 th edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

If the compounds of the invention have, for example, at least one basic center, they can form acid addition salts. These acid addition salts are formed, for example, by the following acids: strong mineral acids, such as mineral acids, for example sulfuric acid, phosphoric acid or hydrohalic acids; organic carboxylic acids, such as alkanecarboxylic acids having from 1 to 4 carbon atoms (e.g. acetic acid), which are unsubstituted or substituted, for example by halogen (e.g. chloroacetic acid), such as saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, such as amino acids (e.g. aspartic acid or glutamic acid or lysine or arginine) or benzoic acid; or organic sulfonic acids, such as (C)₁-C₄) Alkyl or aryl sulphonic acids, unsubstituted or substituted, for example by halogen, for example methyl sulphonic acid or p-toluene sulphonic acid. Corresponding acid addition salts with an additionally present basic center can also be formed if desired. The compounds of the invention having at least one acidic group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal salts or alkaline earth metal salts, for example sodium, potassium or magnesium salts; or salts with ammonia or organic amines, such as morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-or tri-lower alkyl amines, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or mono-, di-or trihydroxy lower alkyl amines, for example mono-, di-or triethanolamine. Furthermore, the corresponding internal salts may be formed. Also included are salts of the free compounds of formula (I) or pharmaceutically acceptable salts thereof which are not suitable for pharmaceutical use, but which are useful, for example, in isolation or purification.

Preferred salts of compounds of formula (I) containing a base include the monohydrochloride, bisulfate, methanesulfonate, phosphate, nitrate or acetate salts.

Preferred salts of the compounds of formula (I) containing an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.

Furthermore, the compounds of formula (I) may have a prodrug form. Any compound that is converted in vivo to yield a biologically active agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present invention. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see:

a) bundgaard, eds H, Design of produgs, Elsevier (1985), and Widder, K. et al, Methods in Enzymology,112:309-396, Academic Press (1985);

b) bundgaard, H.5, Chapter, "Design and Application of precursors", A textbook of Drug Design and Development, p. 113. 191, Krosgaard-Larsen, P. et al, Harwood A computer Publishers (1991);

c)Bundgaard,H.,Adv.Drug Deliv.Rev.,8:1-38(1992)；

d) bundgaard, h, et al, j.pharm.sci.,77:285 (1988); and

e) kakeya, n. et al, chem.pharm.ball., 32:692 (1984).

The compounds of the present invention contain a carboxyl group which can form a physiologically hydrolyzable ester which acts as a prodrug, i.e., a "prodrug ester", which is hydrolyzed in vivo to yield the compounds of the present invention per se. Examples of physiologically hydrolyzable esters of the compounds of the present invention include C₁To C₆Alkyl radical, C₁To C₆Alkylbenzyl, 4-methoxybenzyl, indanyl, phthaloyl, methoxymethyl, C_1-6alkanoyloxy-C_1-6Alkyl (e.g. acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C₁To C₆Alkoxy carbonyloxy-C₁To C₆Alkyl groups (e.g. methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1, 3-dioxol-4-yl) -methyl), and other well-known physiologically hydrolysable esters used in e.g. penicillin and cephalosporin technology. Such esters may be prepared by conventional techniques known in the art. The "prodrug ester" may be formed by reacting the carboxylic acid moiety of the compounds of the present invention with an alkyl or aryl alcohol, halide or sulfonate salt using procedures known to those skilled in the art. Such asEsters may be prepared by conventional techniques known in the art.

Prodrug preparations are well known in The art and are described, for example, in King, F.D. eds, Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); testa, B.et al, Hydrolysis in Drug and Prodrug metabolism, chemistry, biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); wermuth, C.G. eds, the practice of Medicinal Chemistry, Academic Press, San Diego, Calif. (1999).

The present invention is intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms having the same number of atoms but different mass numbers. As a general example, but not by way of limitation, isotopes of hydrogen include deuterium and tritium. Deuterium has one proton and one neutron in its nucleus and has twice the mass of ordinary hydrogen. Deuterium can be substituted by a group such as "²The symbol of H "or" D "indicates. The term "deuterated" as such or used herein to modify a compound or group means that one or more hydrogen atoms attached to a carbon are replaced with deuterium atoms. Carbon isotopes include¹³C and¹⁴C。

isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriately isotopically-labeled reagent in place of the unlabeled reagent originally employed. Such compounds have a variety of potential uses, for example as standards and reagents for determining the ability of a potential pharmaceutical compound to bind to a target protein or receptor or for imaging compounds of the invention that bind to biological receptors in vivo or in vitro.

By "stable compound" and "stable structure" is meant a compound that is sufficiently robust to withstand isolation to a suitable degree of purity from a reaction mixture and formulation into an effective therapeutic agent. Preferably, the compounds of the invention do not contain N-halogen, S (O)₂H or S (O) H groups.

The term "solvate" means a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in an ordered and/or disordered arrangement. Solvates may comprise stoichiometric or non-stoichiometric amounts of solvent molecules. "solvate" encompasses both solution phase and separable solvate. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. In general, solvation methods are known in the art.

Abbreviations

Abbreviations as used herein are defined as follows: "1 x" is once, "2 x" is twice, "3 x" is three times, "deg.c" is degrees celsius, "eq" is equivalents, "g" is grams, "mg" is milligrams, "L" is liters, "mL" is milliliters, "μ L" is microliters, "N" is equivalent concentrations, "M" is molar concentrations, "mmol" is millimoles, "min" is minutes, "h" is hours, "RT" is room temperature, "RT" is retention time, "RBF" is a round bottom flask, "atm" is atmospheric pressure, "psi" is pounds/square, "con" is concentrated, "RCM" is dead cycle metathesis, "sat" or "sat'd" is saturated, "SFC" is supercritical fluid spectra, "MW" is molecular weight mp, "melting point," ee "is enantiomeric excess," MS "or" Mass Spec, "ESI" is electrospray ionization Mass spectrometry HR "is high resolution, "HRMS" is high resolution Mass Spectrometry, "LCMS" is liquid chromatography Mass Spectrometry, "HPLC" is high pressure liquid chromatography, "RP HPLC" is reverse phase HPLC, "TLC" or "TLC" is thin layer chromatography, "NMR" is nuclear magnetic resonance Spectroscopy, "nOe" is Nuclear Overhauser Effect Spectroscopy, "" is "¹H "is proton," "is (delta)," S "is singlet," d "is doublet," t "is triplet," q "is quartet," m "is multiplet," br "is broad," Hz "is hertz (hertz), and" α "," β "," γ "," R "," S "," E "and" Z "are stereochemical designations familiar to those skilled in the art.

Me methyl group

Et Ethyl group

Pr propyl group

i-Pr isopropyl group

Bu butyl

i-Bu isobutyl group

t-Bu tert-butyl

Ph phenyl

Bn benzyl group

Boc or BOC tert-butoxycarbonyl

Boc₂Di-tert-butyl O dicarbonate

AcO or HOAc acetic acid

AlCl₃Aluminium trichloride

AIBN azobisisobutyronitrile

BBr₃Boron tribromide

BCl₃Boron trichloride

BEMP 2-tert-butylimino-2-diethylamino-1, 3-dimethylperhydro-1, 3, 2-diazaphospho-benzene

BOP reagent benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate

Burgs reagent (Burgess 1-methoxy-N-triethylammonio sulfonyl-formamidinate reagent)

CBz Phenylmethoxycarbonyl

DCM or CH₂Cl₂Methylene dichloride

CH₃CN or ACN acetonitrile

CDCl₃Deuterated chloroform

CHCl₃Chloroform

mCPBA or m-CPBA m-chloroperbenzoic acid

Cs₂CO₃Cesium carbonate

Cu(OAc)₂Cupric acetate (II)

Cy₂NMe N-cyclohexyl-N-methylcyclohexylamine

DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene

DCE 1, 2-dichloroethane

DEA diethylamine

Dess-Martin 1,1, 1-tris (acetoxy) -1, 1-dihydro-1, 2-benziodoxaoxolane-3- (1H) -one

DIC or DIPCDI diisopropylcarbodiimide

DIEA, DIPEA or Whini diisopropylethylamine

Grignard base (Hunig's base)

DMAP 4-dimethylaminopyridine

DME 1, 2-dimethoxyethane

DMF dimethyl formamide

DMSO dimethyl sulfoxide

cDNA complementary DNA

Dpp (R) - (+) -1, 2-bis (diphenylphosphino) propane

Duphos (+) -1, 2-bis ((2S,5S) -2, 5-diethylphospholanyl) benzene

EDC N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide

EDCI N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride

EDTA ethylene diamine tetraacetic acid

(S, S) -EtDuPhosRh (I) (+) -1, 2-bis ((2S,5S) -2, 5-diethylphospholane) benzene (1, 5-cyclooctadiene) rhodium (I) trifluoromethanesulfonate

Et₃N or TEA Triethylamine

EtOAc ethyl acetate

Et₂O Ether

EtOH ethanol

GMF glass microfiber filter

Grubbs II (1, 3-bis (2,4, 6-trimethylphenyl) -2-imidazolidinylidene) dichloro (phenylmethylene) (tricyclohexylphosphine) ruthenium

HCl hydrochloric acid

HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HEPES 4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid

Hex Hexane

HOBt or HOBT 1-hydroxybenzotriazole

H₂O₂Hydrogen peroxide

IBX 2-Ioloxybenzoic acid

H₂SO₄Sulfuric acid

Jones reagent (Jones CrO)₃In H₂SO₄2M solution reagent in aqueous solution

K₂CO₃Potassium carbonate

K₂HPO₄Dipotassium hydrogen phosphate (Potassium hydrogen phosphate)

KOAc Potassium acetate

K₃PO₄Tripotassium phosphate

LAH lithium aluminum hydride

LG leaving group

LiOH lithium hydroxide

MeOH methanol

MgSO₄Magnesium sulfate

MsOH or MSA methanesulfonic acid/methanesulfonic acid

NaCl sodium chloride

NaH sodium hydride

NaHCO₃Sodium bicarbonate

Na₂CO₃Sodium carbonate

NaOH sodium hydroxide

Na₂SO₃Sodium sulfite

Na₂SO₄Sodium sulfate

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NH₃Ammonia

NH₄Cl ammonium chloride

NH₄OH ammonium hydroxide

NH₄ ⁺HCO₂ ^-Ammonium formate

NMM N-methylmorpholine

OTf triflate or triflate

Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium (0)

Pd(OAc)₂Palladium acetate (II)

Pd/C Palladium/carbon

Pd(dppf)Cl₂[1,1' -bis (diphenylphosphino) -ferrocene]Palladium dichloride (II)

Ph₃PCl₂Triphenylphosphine dichloride

PG protecting group

POCl₃Phosphorus oxychloride

PPTS pyridinium p-toluenesulfonate salt

i-PrOH or IPA isopropyl alcohol

PS polystyrene

RT or RT Room temperature

SEM-Cl 2- (trimethylsilyl) ethoxymethyl chloride

SiO₂Silicon dioxide

SnCl₂Tin chloride (II)

TBAF tetra-n-butylammonium fluoride

TBAI tetra-n-butylammonium iodide

TFA trifluoroacetic acid

THF tetrahydrofuran

THP tetrahydropyrans

TMSCHN₂Trimethylsilyl diazomethane

TMSCH₂N₃Trimethylsilylmethyl azide

T3P propane phosphonic anhydride

TRIS TRIS (hydroxymethyl) aminomethane

pTsOH p-toluenesulfonic acid

Organisms, IV

Lysophospholipids are membrane-derived bioactive lipid mediators. Lysophospholipids include, but are not limited to, lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA), sphingosine-1-phosphate (S1P), Lysophosphatidylcholine (LPC), and Sphingomyelin Phosphoramidate (SPC). Lysophospholipids affect essential cellular functions including cell proliferation, differentiation, survival, migration, adhesion, invasion and morphogenesis. The function affects many biological processes including neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis.

LPA acts via specific G-protein coupled receptors (GPCRs) in autocrine and paracrine ways. L binds to its cognate GPCR (LPA)₁、LPA₂、LPA₃、LPA₄、LPA₅、LPA₆) LPA (a) activates intracellular signaling pathways to produce a variety of biological responses.

Quantitatively, lysophospholipids (such as LPA) are trace lipid species compared to their primary phospholipid counterparts (e.g., phosphatidyl choline, phosphatidyl ethanolamine, and sphingomyelin). LPA has a role as a biological effector molecule and has a range of different physiological effects such as (but not limited to) effects on blood pressure, platelet activation and smooth muscle contraction; and a variety of cellular effects including cell growth, cell rounding, axonal retraction, and actin stress fiber formation and cell migration. The effects of LPA are mainly mediated by receptors.

LPA receptor (LPA)₁、LPA₂、LPA₃、LPA₄、LPA₅、LPA₆) Activation by LPA mediates a series of downstream signaling cascades. This includes, but is not limited to, mitogen-activated protein kinase (MAPK) activation, Adenylate Cyclase (AC) inhibition/activation, phospholipase c (plc) activation/Ca²⁺Migration, peanut oil acid release, Akt/PKB activation, and activation of small GTPases, Rho, ROCK, Rac, and Ras. Other pathways affected by LPA receptor activation include, but are not limited to, cyclic adenosine monophosphate (cAMP), cell division cycle 42/GTP-binding protein (Cdc42), proto-oncogene serine/threonine-protein kinase Raf (c-Raf), proto-oncogene tyrosine protein kinase Src (c-Src), extracellular signal-regulated kinase (ERK), Focal Adhesion Kinase (FAK), guanine nucleotide exchange factor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin light chain ii (mlc ii), nuclear factor kB (NF-kB), N-methyl-D-aspartate (NMDA) receptor activation, phosphatidylinositol 3-kinase (PI3K), protein kinase a (pka), protein kinase c (pkc), (c, and (c), ras-related C3 botulinum toxin substrate 1(RAC 1). The actual pathway and endpoint achieved depend on a range of variables including receptor usage, cell type, extent of expression of receptor or signaling protein, and LPA concentration. Nearly all mammalian cells, tissues and organs co-express several LPA receptor subtypesWhich indicates that LPA receptors signal in a cooperative manner. LPA (low pressure additive)₁、LPA₂And LPA₃Has high amino acid sequence similarity.

LPA is produced by activated platelets, activated adipocytes, neuronal cells and other cell types. Serum LPA is produced by a variety of enzymatic pathways involving monoacylglycerol kinase, phospholipase a₁Secretory phospholipase A₂And lysophospholipase d (lysopld), including hometown chemokines. Several enzymes are involved in LPA degradation: lysophospholipase, lipid phosphate phosphatase, and LPA acyltransferase such as endocytosin (endothilin). LPA concentrations in human serum are estimated to be 1 to 5 μ M. Serum LPA binds to albumin, low density lipoprotein or other proteins, which may protect LPA from rapid degradation. LPA molecular species with different acyl chain lengths and degrees of saturation are naturally occurring and include 1-palmitoyl (16:0), 1-palmitoleoyl (16:1), 1-stearoyl (18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and 1-eicosatetraenoyl (arachidonyl) (20:4) LPA. A trace amount of alkyl LPA has similar biological activity as acyl LPA, and different LPA species activate LPA receptor subtypes with different efficacy.

LPA receptors

LPA₁(previously named VZG-1/EDG-2/mrec1.3) with three types of G protein G_i/o、G_qAnd G_12/13And (3) coupling. Through activation of these G proteins, LPA passes through LPA₁Induce a range of cellular responses including (but not limited to): cell proliferation, serum response module (SRE) activation, mitogen-activated protein kinase (MAPK) activation, Adenylate Cyclase (AC) inhibition, phospholipase C (PLC) activation, Ca²⁺Migration, Akt activation and Rho activation.

LPA was observed in adult mice₁Is specifically present in testis, brain, heart, lung, small intestine, stomach, spleen, thymus and skeletal muscle. Likewise, human tissues also express LPA₁(ii) a It is found in the brain, heart, lung, placenta, colon, small intestine, prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle, and thymus.

LPA₂(EDG-4) also binds to three types of G proteins (G)_i/o、G_qAnd G_12/13) Coupled to mediate LPA-induced cell signaling. LPA is observed in testis, kidney, lung, thymus, spleen and stomach of adult mice and in human testis, pancreas, prostate, thymus, spleen and peripheral blood leukocytes₂Expression of (2). LPA (low pressure additive)₂Is up-regulated in a variety of cancer cell lines, and several human LPAs with mutations in the 3' -untranslated region have been observed₂A transcriptional variant. LPA in mice₂Does not yet show a clear phenotypic abnormality, but normal LPA signaling has been demonstrated in primary culture of Mouse Embryonic Fibroblasts (MEFs) (e.g., PLC activation, Ca²⁺Migration and stress fiber formation). Generation of LPA1(-/-) LPA2(-/-) double-null mice showed a number of LPA-induced responses (which included cell proliferation, AC inhibition, PLC activation, Ca activation²⁺Migration, JNK and Akt activation, and stress fiber formation) were absent or severely reduced in the dual-empty MEF. Eliminating AC inhibition (AC inhibition at LPA)₁Almost disappeared in (-) MEF) all the reactions were exclusively in LPA₁(/ -) or LPA₂(/ -) MEF is partially affected. LPA (low pressure additive)₂Normal LPA-mediated signaling reactions are caused in at least some cell types (Choi et al, Biochemica et Biophysica acta2008,1781, pages 531 to 539).

LPA₃(EDG-7) is different from LPA₁And LPA₂In that it is capable of reacting with G_i/oAnd G_qCoupled, but with G_12/13No coupling and much less reaction to LPA species with saturated acyl chains. LPA (low pressure additive)₃Can mediate pleiotropic LPA-induced signaling, including PLC activation, Ca²⁺Migration, AC inhibition/activation, and MAPK activation. When stimulated by LPA, LPA₃Overexpression in neuroblastoma cells leads to axonal elongation, whereas LPA₁Or LPA₂Overexpression of (a) causes axonal contraction and cell rounding. LPA is observed in the testis, kidney, lung, small intestine, heart, thymus and brain of adult mice₃Expression of (2). In humans, it is found in the heart, pancreas, prostate, testis,Lung, ovary and brain (frontal cortex, hippocampus and amygdala).

And LPA₁、LPA₂And LPA₃In contrast, LPA₄(p2y₉/GPR23) has divergent sequences and more closely resembles the Platelet Activating Factor (PAF) receptor. LPA (low pressure additive)₄Mediating LPA induction of Ca²⁺Migration and cAMP accumulation, and functional coupling to G-proteins Gs for AC activation, as well as coupling to other G-proteins. LPA (low pressure additive)₄Genes are expressed in ovary, pancreas, thymus, kidney and skeletal muscle.

LPA₅(GPR92) is a member of the purine cluster (purinocluster) of GPCRs and is structurally related to LPA₄The most closely related. LPA (low pressure additive)₅Expressed in human heart, placenta, spleen, brain, lung and intestine. LPA (low pressure additive)₅Also shown to be highly expressed in the CD8+ lymphocyte compartment of the gastrointestinal tract.

LPA₆(p2y5) is a member of the purine cluster of GPCRs and is structurally related to LPA₄The most closely related. LPA (low pressure additive)₆Is an LPA receptor coupled to the G12/13-Rho signaling pathway and is expressed in the internal root sheath of human hair follicles.

Illustrative biological Activity

Wound healing

Normal wound healing occurs through a series of highly coordinated events in which cellular, soluble factors and matrix components act synergistically to repair damage. The healing response can be described as proceeding in four broadly overlapping phases: hemostasis, inflammation, proliferation and remodeling. Many growth factors and cytokines are released into the wound site to initiate and sustain the healing process of the wound.

When injured, the injured blood vessels activate platelets. Activated platelets play a key role in subsequent repair processes by releasing bioactive mediators to induce cell proliferation, cell migration, blood clotting, and angiogenesis. LPA is one such mediator released by activated platelets; it induces platelet aggregation and produces mitogenic/migratory effects on peripheral cells such as endothelial cells, smooth muscle cells, fibroblasts and keratinocytes.

LPA was applied topically to mouse skin wounds to promote the repair process (wound closure and increased new epithelial thickness) by increasing cell proliferation/migration without causing secondary inflammation.

Growth factors and cytokines activate dermal fibroblasts such that they subsequently migrate from the wound margin into the temporary matrix formed by fibrin clots, which subsequently proliferate and begin to restore the dermis by secreting and organizing the characteristic dermal extracellular matrix (ECM). The increased number of fibroblasts and the continuous deposition of ECM within the wound results in a matrix with increased rigidity, which is achieved by applying a small traction force to the newly formed granulation tissue. The increase in mechanical stress in combination with transforming growth factor beta (TGF β) induces α -smooth muscle actin (α -SMA) expression and subsequently transforms fibroblasts into myofibroblasts. Myofibroblasts promote granulation tissue remodeling by myofibroblast contraction and by the production of ECM components.

LPA regulates many important functions of fibroblasts in wound healing, including proliferation, migration, differentiation and contraction. Wound healing requires fibroblast proliferation in order to fill an open wound. In contrast, fibrosis is characterized by intense proliferation and accumulation of myofibroblasts that actively synthesize ECM and proinflammatory cytokines. LPA can increase or inhibit the proliferation of cell types that play an important role in wound healing, such as epithelial and Endothelial Cells (EC), macrophages, keratinocytes and fibroblasts. LPA (low pressure additive)₁The role in LPA-induced proliferation is provided by the following observations: from LPA₁Isolated fibroblasts from recipient-depleted mice have reduced proliferation under LPA stimulation (Mills et al, Nat Rev. cancer 2003; 3: 582-591). LPA induces cytoskeletal changes essential for fibroblast adhesion, migration, differentiation and contraction.

Fibrosis of fiber

Tissue injury initiates a complex series of host wound healing responses; if successful, these responses restore normal tissue structure and function. If not, these reactions can lead to tissue fibrosis and loss of function.

For most organs and tissues, fibrosis development involves a variety of events and factors. Molecules involved in the development of fibrosis include proteins or peptides (pro-fibrotic cytokines, chemokines, metalloproteinases, etc.) and phospholipids. Phospholipids involved in the development of fibrosis include Platelet Activating Factor (PAF), phosphatidyl choline, sphingosine-1 phosphate (S1P) and lysophosphatidic acid (LPA).

A variety of muscular dystrophies are characterized by progressive weakness and wasting of muscle tissue, as well as extensive fibrosis. It has been shown that LPA treatment of cultured myoblasts induces significant expression of Connective Tissue Growth Factor (CTGF). CTGF subsequently induces collagen, fibronectin and integrin expression and induces dedifferentiation of these myoblasts. LPA treatment of various cell types induces reproducible and high-level CTGF induction (j.p. pradere et al, LPA)₁receptor activating antibodies novel internal tissue fibrosis, J.Am.Soc.Nephrol.18(2007) 3110-.

It has been found that treatment by LPA exacerbates the expression of CTGF by gingival epithelial cells involved in the development of gingival fibromyxoma (a. kantarci et al, j. pathol.210(2006) 59-66).

LPA is associated with the progression of liver fibrosis. LPA induces astrocyte and hepatocyte proliferation in vitro. These activated cells are the main cell type responsible for the accumulation of ECM in the liver. In addition, LPA plasma levels are in rodents, in CCl₄Increased duration of induced liver fibrosis, or in humans, increased in hepatitis C virus-induced liver fibrosis (N.Watanabe et al, Plasma lysophospholipid acid level and serum autotaxin activity area involvement in relationship to relationship, Life Sci.81(2007) 1009-.

Increased Phospholipid concentrations in bronchoalveolar lavage fluids of bleomycin (bleomycin) injected rabbits and rodents have been reported (K.Kuroda et al, Phospholipid concentration in Lung fluid activator for pulmonary fibrosis, Inhal.Toxicol.18(2006)389 393; K.Yasuda et al, Lung 172 (1994)) 91-102.

LPA is associated with heart disease and myocardial remodeling. Serum LPA levels are increased following myocardial infarction in patients and LPA stimulates rat cardiac fibroblast proliferation and collagen production (Chen et al, FEBS Lett.2006, 8/21 days; 580(19): 4737-45).

Pulmonary fibrosis

In the lung, abnormal wound healing responses to injury contribute to the pathogenesis of fibrotic pulmonary disease. Fibrotic pulmonary diseases, such as Idiopathic Pulmonary Fibrosis (IPF), are associated with high morbidity and mortality.

LPA is an important mediator of fibroblast recruitment in pulmonary fibrosis. LPA and LPA₁Plays a key pathogenic role in pulmonary fibrosis. Fibroblast chemotactic activity plays an important role in the lungs of patients with pulmonary fibrosis. According to LPA₁Receptor-mediated vascular leakage and enhancement of fibroblast recruitment, both events promoting fibrosis, explain LPA₁Receptor-stimulated profibrotic effects. LPA-LPA₁The pathway has the role of mediating fibroblast migration and vascular leakage in IPF. The net result is an abnormal healing process characterized by this fibrotic condition.

LPA₁The receptor is the LPA receptor that is most highly expressed on fibroblasts from IPF patients. Furthermore, BAL obtained from IPF patients induces chemotaxis of human fetal lung fibroblasts, which is dually LPA₁-LPA₃The receptor antagonist Ki16425 blocks. LPA levels in bronchoalveolar lavage samples were shown to be higher than unexposed controls in a bleomycin-induced lung injury mouse experimental model. LPA (low pressure additive)₁Knockout mice are protected from fibrosis following bleomycin challenge with reduced fibroblast accumulation and vascular leakage. High LPA levels were observed in bronchoalveolar lavage samples of human subjects with IPF compared to healthy controls. Enhanced fibroblast chemotactic activity in these samples was inhibited by Ki16425, indicating that the LPA-LPA receptor pathway mediates fibroblast migration (Tager et al, Nature Medicine,2008,14, 45-54).

LPA-LPA₁The pathway is in pulmonary fibrosisIs critical in fibroblast recruitment and vascular leakage.

Activation of potential TGF- β by α v β 6 integrin plays a key role in the development of lung injury and fibrosis (Munger et al, Cell, Vol. 96, 319-jar 328, 1999). LPA-induced α v β 6 mediates TGF- β activation on human lung epithelial cells (Xu et al, am. J. Pathology,2009,174, 1264-jar 1279). LPA-induced α v β 6 mediated TGF- β activation by LPA₂Receptor mediation. LPA in epithelial and mesenchymal cells in the area of lung fibrosis in IPF patients compared to normal human lung tissue₂Receptor expression is enhanced. LPA-LPA₂The pathway contributes to the activation of the TGF- β pathway in pulmonary fibrosis in some embodiments, LPA is inhibited₂The compounds of (a) show efficacy in the treatment of pulmonary fibrosis. In some embodiments, inhibition of LPA alone₁Or LPA₂Compared with the compound (A), inhibit LPA₁And LPA₂All show improved efficacy in the treatment of pulmonary fibrosis.

Renal fibrosis

LPA and LPA₁Relates to the etiology of renal fibrosis. LPA has an effect on both proliferation and contraction of mesangial cells and is therefore associated with proliferative glomerulonephritis (c.n. inoue et al, clin. sci. (Colch.)1999,96, 431-. In animal models of renal fibrosis [ Unilateral Ureteral Obstruction (UUO)]In (1), the renal LPA receptor was found to function as LPA under basal conditions₂>LPA₃＝LPA₁>>LPA₄Expression order of (3). This model mimics the development of renal fibrosis in an accelerated manner, including nephritis, fibroblast activation, and accumulation of extracellular matrix in the tubulointerstitial matrix. Remarkable induction of LPA by UUO₁The receptor is expressed. In parallel, kidney LPA was produced in conditioned medium from kidney explants (3.3 doublings plus). The contralateral kidney did not exhibit significant changes in LPA release and LPA receptor expression. This suggests that the preconditions for the role of LPA in fibrosis are met: production of Ligand (LPA) and one of its receptors (LPA)₁Receptor) (J.P. Pradere et al, Biochimica et Biophysica Acta,2008,1781, 582-activated 587).

In LPA₁Receptor gene knock-out (LPA)₁In the mice of (-/-), the development of renal fibrosis was markedly attenuated. UUO mice and LPA treated with LPA receptor antagonist Ki16425₁The profile of the (-/-) mice was very similar.

LPA can be involved in intraperitoneal accumulation of monocytes/macrophages and LPA can induce expression of the profibrotic cytokine CTGF in primary cultures of human fibroblasts (j.s.koh et al, j.clin.invest.,1998,102, 716-one 727).

LPA treatment of mouse epithelial kidney cell line MCT induced rapid increase in expression of the profibrotic cytokine CTGF. CTGF plays a key role in UUO induction of tubulointerstitial fibrosis (TIF) and is involved in the profibrotic activity of TGF β. Co-treatment with the LPA receptor antagonist Ki16425 almost completely suppressed this induction. In one aspect, the profibrotic activity of LPA in the kidney results from a direct effect of LPA on renal cells involved in CTGF induction.

Hepatic fibrosis

LPA is involved in liver disease and fibrosis. Plasma LPA levels and serum hometown chemokines (enzymes responsible for LPA production) are elevated in models of liver damage in patients with hepatitis and animals associated with increased fibrosis. LPA also regulates liver cell function. Mouse hepatic stellate cell expression of LPA₁And LPA₂Receptor and LPA stimulate hepatic myofibroblast migration.

Fibrosis of eye

LPA is involved in eye wound healing. LPA can be detected in normal rabbit corneal epithelial cells, keratinocytes and endothelial cells₁And LPA₃Receptor, and LPA in post-injury corneal epithelial cells₁And LPA₃Expression is increased.

LPA and its homologues are present in the aqueous humor and lacrimal fluid of rabbit eyes, and these levels are increased in rabbit corneal injury models.

LPA induces actin stress fibers in rabbit corneal endothelial and epithelial cells and promotes corneal fibroblast contraction. LPA also stimulates proliferation of human retinal pigmented epithelial cells.

Cardiac fibrosis

LPA is involved in myocardial infarction and cardiac fibrosis. Increased serum LPA levels occur in patients after Myocardial Infarction (MI) and LPA stimulates proliferation of rat cardiac fibroblasts and collagen production (fibrosis). Both LPA1 and LPA3 receptors are highly expressed in human cardiac tissue.

Treatment of fibrosis

In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat or prevent fibrosis in a mammal. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat fibrosis of an organ or tissue in a mammal. In one aspect, is a method of preventing a fibrotic condition in a mammal, the method comprising administering to the mammal at risk of developing one or more fibrotic conditions a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In one aspect, the mammal has been exposed to one or more environmental conditions known to increase the risk of fibrosis of an organ or tissue. In one aspect, the mammal has been exposed to one or more environmental conditions known to increase the risk of pulmonary fibrosis, liver fibrosis, or kidney fibrosis. In one aspect, the mammal has a genetic predisposition to develop organ or tissue fibrosis. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to a mammal to prevent or minimize scarring after injury. In one aspect, the injury comprises surgery.

As used herein, the term "fibrosis" or "fibrotic disorder" refers to conditions associated with abnormal accumulation of cells and/or fibronectin and/or collagen and/or enhanced fibroblast recruitment, and includes (but is not limited to) fibrosis of individual organs or tissues, such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.

Exemplary diseases, disorders or conditions involving fibrosis include (but are not limited to): pulmonary diseases associated with fibrosis, for example idiopathic pulmonary fibrosis, pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation induced fibrosis, Chronic Obstructive Pulmonary Disease (COPD), scleroderma, chronic asthma, silicosis, asbestos-induced lung or pleural fibrosis, acute lung injury, and acute respiratory distress (including bacterial pneumonia induction, trauma induction, viral pneumonia induction, ventilator induction, non-pulmonary sepsis induction, and suction induction); chronic nephropathy associated with injury/fibrosis (kidney fibrosis), for example glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allograft and Alport syndrome (Alport); intestinal fibrosis, such as scleroderma, and radiation-induced intestinal fibrosis; liver fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, nonalcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection or virus-induced liver fibrosis (e.g., chronic HCV infection), and autoimmune hepatitis; head and neck fibrosis, e.g., radiation-induced; corneal scarring, such as LASIK (laser-assisted in situ keratomileusis), corneal transplantation, and trabeculectomy; hypertrophic scars and keloids, such as burn induction or surgery; and other fibrotic diseases such as sarcoidosis, scleroderma, spinal cord injury/fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.

In one aspect, a mammal suffering from one of the following non-limiting exemplary diseases, disorders, or conditions would benefit from therapy with a compound of formula (I): atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pneumonia, intestinal adhesion, bladder fibrosis and cystitis, fibrosis of the nasal passages, sinusitis, neutrophile sphere-mediated inflammation, and fibroblast-mediated fibrosis.

In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to a mammal suffering from or prone to developing fibrosis in an organ or tissue, together with one or more other agents useful in the treatment of fibrosis. In one aspect, the one or more agents include a corticosteroid. In one aspect, the one or more agents include an immunosuppressive agent. In one aspect, the one or more agents comprise a B cell antagonist. In one aspect, the one or more agents include uteroglobin (uteroglobin).

In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat a skin condition in a mammal. As used herein, the term "dermatological disorder" refers to a skin disorder. Such dermatological disorders include, but are not limited to, proliferative or inflammatory skin disorders such as atopic dermatitis, bullous disorders, collagen diseases, psoriasis, scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scars, hypertrophic scars, keloids, Kawasaki Disease, rosacea, Sjogren-LarssoSyndrome, and urticaria. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat systemic sclerosis.

Pain (due to cold or dampness)

Since LPA is released after tissue damage, LPA₁Plays an important role in the initiation of neuropathic pain. Different from LPA₂Or LPA₃，LPA₁Expressed in Dorsal Root Ganglia (DRGs) and dorsal root neurons. Use of antisense oligodeoxynucleotides (AS-ODN) for LPA₁And LPA₁The knockout mice found LPA-induced mechanical allodynia and hyperalgesia as LPA₁Mediated in a dependent manner. LPA (low pressure additive)₁And downstream Rho-ROCK activation plays a role in the initiation of neuralgic signaling. Pretreatment with Clostridium botulinum C3 extracellular enzyme (BoTXC3, Rho inhibitor) or Y-27632(ROCK inhibitor) completely abolished the abnormal pain and hyperalgesia in nerve injured mice. LPA also induced demyelination of dorsal roots, which was prevented by BoTXC 3. In LPA₁Knockout mice or AS-ODN injected wild-type miceBack root demyelination due to injury was not observed. LPA signaling appears to be as LPA₁And Rho-dependent means to induce important neuropathic pain markers such as protein kinase C γ (PKC γ) and voltage-gated calcium channel α 21 subunit (Ca α 21) (m.inoue et al, Initiation of neuropathically pain requiring receptor signaling, nat. med.10(2004) 712-718).

In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat pain in a mammal. In one aspect, the pain is acute pain or chronic pain. In another aspect, the pain is neuropathic pain.

In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat muscle fiber pain. In one aspect, muscle fiber pain results from the formation of fibrous scar tissue in contracting (spontaneous) muscles. Fibrosis binds the tissue and inhibits blood flow, producing pain.

Cancer treatment

Hemolytic phospholipid receptor signaling plays a role in the etiology of cancer. Lysophosphatidic acid (LPA) and its G-protein coupled receptor (GPCR) LPA₁、LPA₂And/or LPA₃Play a role in the development of several types of cancer. Initiation, progression and metastasis of cancer involve several parallel and sequential processes, including cell proliferation and growth, survival and anti-apoptosis, cell migration, infiltration of foreign cells into defined cell layers and/or organs, and promotion of angiogenesis. Controlling each of these processes caused by LPA signaling under physiological and pathophysiological conditions underscores the potential therapeutic usefulness of modulating LPA signaling pathways for the treatment of cancer, especially at the level of LPA receptors or ATX/lysoPLD. Autoclavatorins (ATX) are prometastases originally isolated from the conditioned medium of human melanoma cells that stimulate a variety of biological activities by LPA production, including angiogenesis and promoting cell growth, migration, survival and differentiation (Mol Cancer Ther 2008; 7(10): 3352-62).

LPA signals through its own GPCR, activating a variety of downstream effector pathways. Such downstream effector pathways play a role in cancer. LPA and its GPCRs are associated with cancer through the major oncogenic signaling pathways.

LPA contributes to tumorigenesis by increasing the mobility and invasiveness of cells. LPA has been implicated in the initiation or progression of ovarian cancer. LPA is present in significant concentrations (2-80 μ M) in the ascites of ovarian cancer patients. Ovarian cancer cells constitutively produce increased amounts of LPA, a precursor to ovarian epithelial cancer, compared to normal ovarian surface epithelial cells. Elevated LPA levels were also detected in plasma from patients with early stage ovarian cancer compared to controls. LPA receptor (LPA) as compared to normal ovarian surface epithelial cells₂And LPA₃) It is also overexpressed in ovarian cancer cells. LPA stimulates Cox-2 expression by transcriptional activation and post-transcriptional enhancement of Cox-2mRNA in ovarian cancer cells. Prostaglandins produced by Cox2 have been associated with a variety of human cancers, and pharmacological inhibition of Cox-2 activity reduces colon cancer progression and reduces the size and number of adenomas in patients with familial adenomatous polyposis. LPA is also involved in the initiation or progression of prostate, breast, melanoma, head and neck, intestinal (colorectal), thyroid and other cancers (Gardell et al, Trends in Molecular Medicine, Vol.12, stage 2, pp.65-75, 2006; Ishii et al, Annu. Rev. biochem,73, 321. sup. 354, 2004; Mills et al, nat. Rev. cancer,3, 582. sup. 591, 2003; Murph et al, Biochimica et Biophysica Acta,1781, 547. sup. 557, 2008).

The cellular response to LPA is mediated by lysophosphatidic acid receptors. For example, LPA receptors mediate the migration and invasion of pancreatic cancer cell lines: LPA (low pressure additive)₁And LPA₃(Ki16425) and LPA₁Antagonists of specific siRNA effectively block LPA and peritoneal fluid (ascites) migration in vitro in response to pancreatic cancer patients; ki16425 blocked the invasion activity of LPA-and ascites-induced high-peritoneal metastatic pancreatic cancer cell lines (Yamada et al, J.biol.chem.279,6595-6605,2004).

Colorectal cancer cell line exhibiting LPA₁mRNA is significantly expressed and responds to LPA by cell migration and the production of angiogenic factors. Overexpression of LPA receptors plays a role in the pathogenesis of thyroid cancer. LPA (low pressure additive)₃Originally cloned from prostate cancer cells, consistent with LPA's ability to induce autocrine proliferation of prostate cancer cells.

LPA has a stimulatory effect on cancer progression in many types of cancer. LPA is produced by and induces proliferation of prostate cancer cell lines. LPA to LPA₁Signaling induces human colon cancer DLD1 cells to proliferate, migrate, adhere and secrete angiogenic factors. In other human colon cancer cell lines (HT29 and WiDR), LPA enhances cell proliferation and secretion of angiogenic factors. In other colon cancer cell lines, LPA₂And LPA₃Receptor activation causes cell proliferation. Genetic or pharmacological manipulation of LPA metabolism, specific blockade of receptor signaling, and/or inhibition of downstream signaling pathways represent methods of cancer treatment.

LPA and other phospholipids have been reported to stimulate the expression of interleukin-8 (IL-8) in ovarian cancer cell lines. In some embodiments, high IL-8 concentrations in ovarian cancer are associated with poor initial response and poor prognosis, respectively, to chemotherapy. In animal models, expression of IL-8 and other growth factors, such as Vascular Endothelial Growth Factor (VEGF), is associated with increased tumorigenicity, ascites formation, angiogenesis, and invasiveness of ovarian cancer cells. In some aspects, IL-8 is an important regulator of cancer progression, drug resistance, and prognosis in ovarian cancer. In some embodiments, the compound of formula (I) inhibits or reduces IL-8 expression in ovarian cancer cell lines.

In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat cancer. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat malignant and benign proliferative diseases. In one aspect, the compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof are used to prevent or reduce tumor cell proliferation, carcinoma, invasion and metastasis of pleural mesothelioma (Yamada, Cancer sci.,2008,99(8), 1603-. In one aspect, is a method of treating cancer in a mammal, comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.

As used herein, the term "cancer" refers to an abnormal growth of cells that tends to proliferate in an uncontrolled manner and, in some cases, to metastasize (spread). Cancer types include, but are not limited to, solid tumors (such as tumors of the bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (thyroid), prostate, skin (melanoma or basal cell carcinoma)) or hematologic tumors (such as leukemia) at any stage of the disease, with or without metastasis.

Other non-limiting examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal carcinoma, appendiceal carcinoma, astrocytoma, atypical teratoid/rhabdoid tumors, basal cell carcinoma, bile duct carcinoma, bladder carcinoma, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumors, breast cancer, bronchial tumor, Burkitt lymphoma (Burkitt lymphoma), cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonic tumor, endometrial cancer, ependymoma, esophageal cancer, ewing sarcoma (ewing sarcoma) tumor family, eye cancer, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), Gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, liver cell (liver) cancer, hodgkin lymphoma (hodgkin lymphoma), hypopharynx cancer, intraocular melanoma, islet cell tumor (endocrine pancreas), kaposi's sarcoma (kaposi's sarcoma), kidney cancer, Langerhans ' cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, liver cancer, non-small lymphocytic leukemiaCell lung cancer, small cell lung cancer, Burkitt's lymphoma, cutaneous T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia: (macroblastinomoma), medulloblastoma, melanoma, mesothelioma, oral cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, epithelial cancer, ovarian germ cell tumor, ovarian low malignancy potential, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, mesodifferentiated pineal parenchymal tumor, pinealoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasmacytoma/multiple myeloma, pleuropulmonoblastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, neuroblastoma, melanoma, and melanoma, Salivary gland carcinoma, sarcoma, ewing ' S sarcoma family of tumors, sarcoma, kaposi ' S sarcoma, sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymus cancer, thyroid cancer, urinary tract cancer, uterine sarcoma, vaginal cancer, vulval cancer, waldenstrom ' S macroglobulinemia, Wilms tumor (Wilms tumor).

Increased concentrations of LPA and vesicles in ascites and breast Cancer effusions from ovarian Cancer patients indicate that they may be an early diagnostic marker, a prognostic indicator, or an indicator of response to therapy (Mills et al, nat. Rev. Cancer.,3, 582-. LPA concentrations in ascites samples were consistently higher than the matched plasma samples.

Respiratory and allergic disorders

In one aspect, LPA is the onset of respiratory diseaseThe causative agent of the disease mechanism. In one aspect, the respiratory disease is asthma. Pro-inflammatory effects of LPA include mast cell degranulation, smooth muscle cell contraction, and cytokine release by dendritic cells. Respiratory smooth muscle cells, epithelial cells, and lung fibroblasts all showed responses to LPA. LPA induces IL8 secretion by human bronchial epithelial cells. Increased concentrations of IL-8 are found in BAL fluid from patients with asthma, chronic obstructive pulmonary disease, pulmonary sarcoidosis, and acute respiratory distress syndrome, and IL-8 has been shown to exacerbate respiratory inflammation and respiratory remodeling in asthmatic patients. LPA (low pressure additive)₁、LPA₂And LPA₃The receptors have all been shown to contribute to LPA-induced IL-8 production. Studies to clone multiple GPCRs activated by LPA demonstrated the presence of LPA in the lung₁、LPA₂And LPA₃The mRNA of (J.J.A.Contos et al, mol.Pharmacol.58,1188-1196,2000).

Platelet-released LPA is activated at the site of injury and its ability to promote fibroblast proliferation and contraction is a feature of LPA as a mediator of wound repair. In the case of respiratory diseases, asthma is an inflammatory disease in which inappropriate respiratory tract "repair" processes cause the respiratory tract to undergo structural "remodeling". In asthma, cells of the respiratory tract undergo ongoing damage due to a variety of insults including allergens, pollutants, other inhaled environmental agents, bacteria and viruses, resulting in chronic inflammation characterized by asthma.

In one aspect, in asthmatic individuals, the release of normal repair mediators (including LPA) is increased or the effect of the repair mediators is inappropriately prolonged, resulting in inappropriate airway remodeling. The major structural features observed in asthma to remodel the airways include thickening of the reticular layer (basement membrane-like structure just beneath airway epithelial cells), increased number and activation of myofibroblast fibroblasts, thickening of the smooth muscle layer, increased number of mucus glands and mucus secretions, and changes in the connective tissue and capillary bed throughout the airway wall. In one aspect, LPA contributes to these structural changes in the respiratory tract. In one aspect, LPA is involved in acute respiratory hyperresponsiveness in asthma. The lumen of the remodeled asthmatic airway is narrower due to the thickening of the airway wall, and thus airflow is reduced. In one aspect, LPA contributes to long-term structural remodeling and acute hyperreactivity of the asthmatic respiratory tract. In one aspect, LPA causes an overreaction, which is an initial feature of acute exacerbations of asthma.

In addition to LPA-mediated cellular responses, several LPA signaling pathway components that lead to these responses are associated with asthma. EGF receptor upregulation is induced by LPA and is also found in asthmatic respiratory tract (m.amishima et al, am.j.respir.crit.care med.157,1907-1912,1998). Chronic inflammation is a contributor to asthma, and several transcription factors for LPA activation are known to be involved in inflammation (Ediger et al, Eur Respir J21: 759-.

In one aspect, LPA stimulates fibroblast proliferation and contraction and extracellular matrix secretion, leading to fibroproliferative features of other respiratory diseases, such as bronchiolar fibrosis found in chronic bronchitis, emphysema, and interstitial lung disease. Emphysema is also associated with mild fibrosis of the alveolar walls, a feature believed to represent an attempt to repair alveolar damage. In another aspect, LPA plays a role in fibrotic interstitial lung disease and bronchiolitis obliterans, where both collagen and myofibroblasts are increased. In another aspect, LPA is involved in several of the multiple syndromes that constitute chronic obstructive pulmonary disease.

LPA administered in vivo induces airway hyperreactivity, pruritic scratch response, eosinophilic and neutrophilic infiltration and activation, vascular remodeling and hyperalgesic flexor response. LPA also induces histamine release from mouse and rat mast cells. In acute allergic reactions, histamine induces various reactions such as smooth muscle contraction, plasma exudation and mucus production. Plasma leakage is important in the respiratory tract because leakage and subsequent edema of the airway wall lead to the development of airway hyperreactivity. Plasma exudation progresses to conjunctival swelling in ocular allergic conditions and nasal obstruction in allergic rhinitis (Hashimoto et al, J PharmacolSci 100,82-87,2006). In one aspect, LPA-induced plasma exudation is mediated by one or more LPA receptors, through histamine release by mast cells. In one aspect, the LPA receptor comprises LPA₁And/or LPA₃. At one isIn aspects, the compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof are useful for treating various allergic conditions in a mammal. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is used to treat a respiratory disease, disorder or condition in a mammal. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat asthma in a mammal. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat chronic asthma in a mammal.

As used herein, the term "respiratory disease" refers to a disease that affects organs involved in breathing, such as the nose, pharynx, larynx, eustachian tube, trachea, bronchi, lungs, associated muscles (e.g., diaphragm and intercostal muscles), and nerves. Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin (aspirin) -sensitive asthma, exercise-induced asthma, isocarbon dioxide hyperparathyroidism, childhood asthma, adult asthma, cough variant asthma, occupational asthma, steroid resistant asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis, and/or respiratory inflammation and cystic fibrosis, and hypoxia.

As used herein, the term "asthma" refers to any condition of the lungs characterized by changes in lung airflow associated with airway constriction due to any cause (internal, external or both; allergic or non-allergic). The term asthma may be used with one or more adjectives to indicate etiology.

In one aspect, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing chronic obstructive pulmonary disease in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, at least once. In addition, chronic obstructive pulmonary diseases include, but are not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and/or respiratory inflammation, and cystic fibrosis.

Nervous system

The nervous system is LPA₁The major locus of expression; it is regulated spatially and temporally throughout brain development. In mammals, oligodendroglial cells (myelinating cells in the Central Nervous System (CNS)) express LPA₁. In addition, Schwann cells (Schwann cells), the myelinating cells of the peripheral nervous system, also express LPA₁It relates to the regulation of schwann cell survival and morphology. These observations identify important functions of receptor-mediated LPA signaling in neurogenesis, cell survival and myelination.

Exposure of peripheral nervous system cell lines to LPA causes their processes to rapidly contract, causing cell rounding, which is mediated in part by polymerization of the actin cytoskeleton. In one aspect, LPA causes neuronal degeneration under pathological conditions when the blood brain barrier is compromised and serum components leak into the brain (Moolenaar, curr. opin. cell biol.7:203-10, 1995). Immortalized CNS neuroblast cell lines from the cerebral cortex also exhibit contractile responses to LPA exposure through Rho activation and myofibrillar protein interactions. In one aspect, LPA is associated with post-ischemic nerve injury (J.neurohem.61, 340, 1993; J.neurohem., 70:66,1998).

In one aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, useful in the treatment or prevention of a neurological disorder in a mammal. As used herein, the term "neurological disorder" refers to conditions that alter the structure or function of the brain, spinal cord or peripheral nervous system, including, but not limited to, Alzheimer's disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathy, Parkinson's disease, those diseases found after blunt or surgical trauma (including post-surgical cognitive dysfunction and spinal cord or brainstem injury), and neurological disorders such as degenerative disc disease and sciatica.

In one aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prevention of a CNS disorder in a mammal. CNS disorders include, but are not limited to, multiple sclerosis, parkinson's disease, alzheimer's disease, stroke, cerebral ischemia, retinal ischemia, post-operative cognitive dysfunction, migraine, peripheral neuropathy/neuralgia, spinal cord injury, cerebral edema, and head injury.

Cardiovascular disorders

The cardiovascular phenotype observed following targeted deletion of the lysophospholipid receptor reveals an important role for lysophospholipid signaling in vascular development and maturation, atherosclerotic plaque formation and heart rate maintenance (Ishii, i. et al, annu. rev. biochem.73,321-354,2004). Angiogenesis (the formation of new capillary networks from pre-existing vascular structures) is often initiated in wound healing, tissue growth and myocardial angiogenesis following ischemic injury. Peptide growth factors, such as Vascular Endothelial Growth Factor (VEGF), and lysophospholipids control the coordinated proliferation, migration, adhesion, differentiation and assembly of Vascular Endothelial Cells (VECs) and peripheral Vascular Smooth Muscle Cells (VSMCs). In one aspect, dysregulation of processes that mediate angiogenesis causes atherosclerosis, hypertension, tumor growth, rheumatoid arthritis, and diabetic retinopathy (Osborne, n. and Stainier, d.y.annu.rev.physiol.65,23-43,2003).

Downstream signaling pathways by lysophospholipid receptors include Rac-dependent lamellar projection formation (e.g., LPA)₁) And Rho-dependent stress fiber formation (e.g., LPA)₁) Which plays an important role in cell migration and adhesion. Dysfunction of vascular endothelial cells can shift the balance from vasodilation to vasoconstriction and cause hypertension and vascular remodeling, which are risk factors for atherosclerosis (Maguire, j.j. et al, Trends pharmacol. sci.26,448-454,2005).

In addition to its overall progression, LPA contributes to the early (barrier dysfunction and endothelial monocyte adhesion) and late stages (platelet activation and intra-arterial thrombosis) of atherosclerosis. In the morningIn the meantime, LPA from many sources accumulates in the foci and activates its cognate GPCR (LPA) expressed on platelets₁And LPA₃) (Siess, w.biochim.biophysis.acta1582, 204-215,2002; rother, E.et al, Circulation 108,741-747, 2003). This triggers platelet shape changes and aggregation, leading to intra-arterial thrombosis and potentially myocardial infarction and stroke. LPA can also be a mitogen and motor factor for VSMC and an activator of endothelial cells and macrophages to support its atherogenic activity. In one aspect, mammals suffering from cardiovascular disease benefit from LPA receptor antagonists to prevent thrombus and neointimal plaque formation.

In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat or prevent cardiovascular disease in a mammal.

As used herein, the term "cardiovascular disease" refers to diseases affecting the heart or blood vessels, or both, including (but not limited to): cardiac arrhythmias (either atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; disturbance of heart rate; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral obstructive arterial disease of a limb, organ or tissue; reperfusion injury following ischemia of the brain, heart or other organ or tissue; endotoxin, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; (ii) shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, insufficiency confined to a single organ or tissue.

In one aspect, provided herein is a method for preventing or treating vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis, and stroke, comprising administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition or medicament comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at least once.

In one aspect, provided herein is a method of reducing cardiac reperfusion injury following myocardial ischemia and/or endotoxic shock comprising administering to the mammal at least once an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, provided herein is a method for reducing vasoconstriction in a mammal comprising administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at least once.

In one aspect, provided herein is a method for reducing or preventing elevated blood pressure in a mammal comprising administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at least once.

Inflammation(s)

LPA has been shown to modulate immune responses by modulating the activity/function of immune cells such as T/B lymphocytes and macrophages. In activated T cells, LPA passes through LPA₁Activated IL-2 production/cell proliferation (Gardell et al, TRENDS in molecular Medicine Vol 12, No. 2, month 2 2006). Expression of LPA-induced inflammatory response Gene by LPA₁And LPA₃Mediation (Biochem Biophys Res Commun.363(4):1001-8, 2007). In addition, LPA regulates chemotaxis of inflammatory cells (Biochem Biophys Res Commun, 1993, 15; 193(2), 497). It is known that immune cells respond to proliferation and cytokine secretion activity of LPA (j. imuunol.1999,162,2049), platelet aggregation activity in response to LPA, monocyte migration acceleration activity, NF- κ B activation in fibroblasts, binding of fibronectin to the cell surface is enhanced, and the like. Thus, LPA is associated with various inflammatory/immune diseases.

In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to treat or prevent inflammation in a mammal. In one aspect, the LPA₁And/or LPA₃The antagonists of (a) are useful for treating or preventing an inflammatory/immune disorder in a mammal. In one aspect, the LPA₁The antagonist is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

Examples of inflammatory/immune disorders include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle diseases, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allograft or xenograft (organ, bone marrow, stem cells and other cells and tissues) transplant rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

Other diseases, disorders or conditions

According to one aspect, a method for treating, preventing, reversing, preventing or slowing the progression of (once it becomes clinically apparent) or treating a symptom associated with or associated with an LPA-dependent or LPA-mediated disease or condition is accomplished by administering to a mammal a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the subject has suffered from, or is at risk for developing, an LPA-dependent or LPA-mediated disease or condition at the time of administration.

In certain aspects, LPA is modulated, directly or indirectly, in a mammal by administering a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, at least once₁And (4) activity. Such modulation includes, but is not limited to, reduction and/or inhibition of LPA₁And (4) activity. In other aspects, LPA activity in a mammal is modulated (including reduced and/or inhibited), directly or indirectly, by administering a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, at least once. Such modulation includes, but is not limited to, reduction and/or inhibition of the amount and/or activity of LPA receptors. In one aspect, the LPA receptor is LPA₁。

In one aspect, LPA has a contractile effect on bladder smooth muscle cells isolated from the bladder and promotes the growth of prostate-derived epithelial cells (J.Urology,1999,162, 1779-. In another aspect, LPA constricts the urinary tract and prostate in vitro and increases the intraurethral pressure in vivo (WO 02/062389).

In certain aspects, is a method for preventing or treating eosinophilia and/or basophilia and/or dendritic cells and/or neutrophilia and/or monocytes and/or T cell recruitment comprising administering to a mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at least once.

In certain aspects, is a method of treating cystitis, including, for example, interstitial cystitis, comprising administering to the mammal at least once a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

According to one aspect, the methods described herein comprise diagnosing or determining whether a patient has an LPA-dependent or LPA-mediated disease or condition by administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and determining whether the patient is responsive to treatment.

In one aspect, provided herein are compounds of formula (I), pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, which are LPAs₁Antagonists and for use in treating patients suffering from one or more LPA-dependent or LPA-mediated conditions or diseases, including (but not limited to) pulmonary fibrosis, renal fibrosis, liver fibrosis, scarring, asthma, rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial pulmonary fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, cancer, pain, proliferative disorders and inflammatory conditions. In some embodiments, LPA-dependent conditions or diseases include those conditions or diseases in which an absolute or relative excess of LPA is present and/or observed.

In any of the preceding aspects, LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, organ fibrosis, asthma, allergic disorders, chronic obstructive pulmonary disease, pulmonary hypertension, pulmonary or pleural fibrosis, peritoneal fibrosis, arthritis, allergy, cancer, cardiovascular disease, adult respiratory distress syndrome, myocardial infarction, aneurysm, stroke, and cancer.

In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is used to improve reduced corneal sensitivity resulting from corneal surgery, such as laser-assisted in situ corneal reshaping surgery (LASIK) or cataract surgery, reduced corneal sensitivity resulting from corneal degeneration, and the symptoms of dry eye resulting therefrom.

In one aspect, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing ocular inflammation and allergic conjunctivitis, vernal keratoconjunctivitis, and papillary conjunctivitis in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, at least once.

In one aspect, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing hulgan disease or an inflammatory disease with dry eye in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, at least once.

In one aspect, LPA and LPA receptors (e.g., LPA)₁) The pathogenesis of osteoarthritis is implicated (Kotani et al, hum. mol. gene., 2008,17, 1790-. In one aspect, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing osteoarthritis in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, at least once.

In one aspect, the LPA receptor (e.g., LPA)₁、LPA₃) Contribute to the pathogenesis of rheumatoid arthritis (Zhao et al, mol. pharmacol.,2008,73(2), 587-. In one aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing lactationUse of rheumatoid arthritis in a mammal comprising administering to the mammal an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at least once.

In one aspect, the LPA receptor (e.g., LPA)₁) It helps to generate fat. (Simon et al, J.biol.chem.,2005, vol. 280, No. 15, p. 14656). In one aspect, provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for promoting adipose tissue formation in a mammal, comprising administering to the mammal an effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, at least once.

a. In vitro assay

Compounds of the invention for use as LPAs₁The effectiveness of the inhibitor may be at the LPA₁Functional antagonist assays were determined as follows:

will overexpress human LPA₁Chinese hamster ovary cells of (c) were plated overnight (15,000 cells/well) in DMEM/F12 medium (Gibco, cat # 11039) in poly-D-lysine coated 384-well microplates (Greiner bio-one, cat # 781946). After overnight culture, cells were loaded with calcium indicator dye (AAT bioquest inc, cat. No. 34601) for 30 minutes at 37 ℃. The cells were then equilibrated for 30 minutes relative to room temperature before analysis. Test compounds dissolved in DMSO were transferred to 384-well non-binding surface plates (Corning, Cat. No. 3575) using a LabcyteEcho sonic dispenser and assayed in assay buffer [1 XHBSS with calcium/magnesium (Gibco Cat. No. 14025-092), 20mM HEPES (Gibco Cat. No. 15630-080) and 0.1% BSA without fatty acids (Sigma Cat. No. A9205) ]]Diluted to a final concentration of 0.5% DMSO. The diluted compound was added to the cells by FDSS6000(Hamamatsu) at a final concentration in the range of 0.08nM to 5 μ M, followed by incubation at room temperature for 20 minutes, at which time LPA (AvantiPolar Lipids catalog No. 857130C) was added at a final concentration of 10nM to stimulate the cells. Compound IC₅₀Values are defined as the concentration of test compound that inhibits 50% of calcium flux induced by LPA alone. IC was determined by fitting the data to a 4-parameter logarithmic equation (GraphPad Prism, san Diego CA)₅₀The value is obtained.

b. In vivo analysis

LPA challenge and plasma histamine assessment.

Prior to LPA challenge, compounds were administered orally to CD-1 female mice for 2 hours. Mice were then dosed via the tail vein (IV) with 0.15mL of LPA-containing 0.1% BSA/PBS (2. mu.g/. mu.L). Just 2 minutes after LPA challenge, mice were euthanized by decapitation and trunk blood was collected. These samples were centrifuged together and individual 75 μ L samples were frozen at-20 ℃ until histamine analysis.

Plasma histamine analysis was performed by standard EIA (enzyme immunoassay) methods. Plasma samples were thawed and diluted 1:30 in PBS containing 0.1% BSA. The EIA protocol for histamine analysis as outlined by the manufacturer was followed (histamine EIA, Oxford Biomedical Research, EA # 31).

The LPA used in the analysis was formulated as follows: LPA (1-oleoyl-2-hydroxy-sn-glycero-3-phosphate (sodium salt), 857130P, Avanti Polar Lipids) was prepared at a total concentration of 2. mu.g/. mu.L in 0.1% BSA/PBS. 13mg of LPA was weighed and 6.5mL of 0.1% BSA was added, vortexed and sonicated for about 1 hour until a clear solution was obtained.

Pharmaceutical compositions, formulations and combinations

In some embodiments, a pharmaceutical composition is provided comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable inactive ingredient.

In some embodiments, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable inactive ingredient. In one aspect, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, inhalation, nasal administration, topical administration, ocular administration, or otic administration. In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drop, or ear drop.

In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutically active agents selected from the group consisting of: corticosteroids (such as dexamethasone (dexamethasone) or fluticasone (fluticasone)), immunosuppressive agents (such as tacrolimus (tacrolimus) and pimecrolimus (pimecrolimus)), analgesics, anticancer agents, anti-inflammatory agents, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists (such as montelukast or zafirlukast), leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase a₁Inhibitor, phospholipase A₂Inhibitors and lysophospholipase d (lysopld) inhibitors, homeotic chemokine inhibitors, decongestants, antihistamines (e.g. loratadine), mucolytics, anticholinergics, antitussives, expectorants, anti-infective agents (e.g. fusidic acid), especially for the treatment of atopic dermatitis), antifungal agents (e.g. clotrimazole, especially for atopic dermatitis), anti-IgE antibody therapy (e.g. omalizumab), β -2 adrenergic agonists (e.g. albuterol or salmeterol), other PGD2 antagonists acting on other receptors (such as DP antagonists), PDE4 inhibitors (e.g. cilomilast), drugs regulating cytokine production (e.g. TACE inhibitors), drugs regulating Th2 cytokine IL-4 and IL-5 activities (e.g. blocking monoclonal antibodies and soluble receptor), glitazone inhibitors (e.g. glitazone), and lipocalin inhibitors (e.g. ziprasidone), e.g. ziprasidone-5).

In some embodiments, the pharmaceutical composition further comprises one or more other anti-fibrotic agents selected from: pirfenidone (pirfenidone), nintedanib (nintedanib), thalidomide (thalidomide), carpuzumab (carpuzab), FG-3019, follistatin (fresolimumab), interferon alpha, lecithin superoxide dismutase, simtuzumab (simtuzumab), tandezetib (tanzisertib), talogumab (tralokinumab), hu3G9, AM-152, IFN-gamma-1 b, IW-151, PRM-151, PXS-25, pentoxifylline (pentoxifylline)/N-acetyl-cysteine, pentoxifylline/vitamin E, salbutamol sulfate (salbutamol sulfate), [ Sarr 9, Met (O2)11] -substance P, pentoxifylline, captopril (tranylcalciferol tartrate), garnetic acid (GFarlacertine), metformin hydrochloride (fetida), metformin hydrochloride (metformin hydrochloride), metformin hydrochloride (GFE-505), metformin hydrochloride (metformin hydrochloride), metformin hydrochloride (orotate), metformin hydrochloride (E-E (E), metformin hydrochloride (E), metformin hydrochloride), metformin (E-E), metformin (E), metformin (E-E) 11) -substance P, E (E), metformin (E, E (E, Moluomab-CD 3(muromonab-CD3), oltipraz (oltipraz), IMM-124-E, MK-4074, PX-102, RO-5093151. In some embodiments, there is provided a method comprising administering a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, to a human suffering from an LPA-dependent or LPA-mediated disease or condition. In some embodiments, the human has been administered one or more additional therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method further comprises administering one or more additional therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the one or more additional therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is selected from: corticosteroids (e.g., dexamethasone or fluticasone), immunosuppressants (e.g., tacrolimus and pimecrolimus), analgesics, anti-cancer agents, anti-inflammatory agents, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists (e.g., montelukast or zafirlukast), leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A₁Inhibitor, phospholipase A₂Inhibitors and lysophospholipase D (lysoPLD) inhibitors, homeotic chemokine inhibitors, decongestants, antihistamines (e.g. loratadine), mucolytics, anticholinergics, antitussives, expectorants, anti-infectives (e.g. fusidic acid, especially for the treatment of atopic dermatitis), antifungals (e.g. clotrimazole, especially for atopic dermatitis), anti-IgE antibody therapy (e.g. omalizumab), β -2 adrenergic agonists (e.g. albuterol or salmeterol), other PGD2 antagonists acting on other receptors (such as DP antagonists), PDE4 inhibitors (e.g. cilomilast), agents for modulating cytokine productionSubstances (e.g., TACE inhibitors), drugs that modulate the activity of the Th2 cytokines IL-4 and IL-5 (e.g., blocking monoclonal antibodies and soluble receptors), PPAR γ agonists (e.g., rosiglitazone and pioglitazone), and 5-lipoxygenase inhibitors (e.g., zileuton).

In some embodiments, the one or more other therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is an additional anti-fibrotic agent selected from: pirfenidone, nintedanib, thalidomide, carpuzumab, FG-3019, fullisozumab, interferon alpha, lecithin superoxide dismutase, octolizumab, tentatin, tarolizumab, hu3G9, AM-152, IFN-gamma-1 b, IW-001, PRM-151, PXS-25, pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E, albuterol sulfate, [ Sar9, Met (O2)11] -substance P, pentoxifylline, cysteamine bitartrate, obeticholic acid, Alramelto, GFT-505, ethyl eicosapentanate, metformin, metreleptin, Moluomamab-CD 3, oltipran, IMM-124-E, MK-4074, PX-102, RO-5093151.

In some embodiments, the one or more additional therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is selected from ACE inhibitors, ramipril (ramipril), AII antagonists, irbesartan (irbesartan), antiarrhythmics, dronedarone (dronedarone), PPAR α activators, PPAR γ activators, pioglitazone, rosiglitazone, prostaglandins, endothelin receptor antagonists, elastase inhibitors, calcium antagonists, beta blockers, diuretics, aldosterone receptor antagonists, eplerenone (eplerenone), renin inhibitors, Rho kinase inhibitors, soluble guanylate cyclase (sGC) activators, sGC sensitizers, PDE inhibitors, PDE5 inhibitors, NO donors, digitalis drugs, ACE/NEP inhibitors, statins, bile acid reabsorption inhibitors, PDGF antagonists, vasopressin antagonists, aquaretic agents, bile acid diuretics, vasopressin inhibitors, and combinations thereof, NHE1 inhibitors, factor Xa antagonists, factor XIIIa antagonists, anticoagulants, antithrombotic agents, platelet inhibitors, profibrotic agents, thrombin-activatable fibrinolysis inhibitors (TAFI), PAI-1 inhibitors, coumarins, heparins, thrombolipidic antagonists, serotonin antagonists, COX inhibitors, aspirin, therapeutic antibodies, GPIIb/IIIa antagonists, ER antagonists, SERMs, tyrosine kinase inhibitors, RAF kinase inhibitors, p38 MAPK inhibitors, pirfenidone, multiple kinase inhibitors, nintedanib, sorafenib (sorafenib).

In some embodiments, the one or more other therapeutically active agents other than a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is selected from Gremlin-1mAb, PA1-1 mAb, Promedior (PRM-151; recombinant human pentraxin-2); FGF21, TGF β antagonists, α v β 6 and α v β pan antagonists; FAK inhibitors, TG2 inhibitors, LOXL2 inhibitors, NOX4 inhibitors, MGAT2 inhibitors, GPR120 agonists.

The pharmaceutical formulations described herein can be administered to a subject in a variety of ways and by a variety of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, or transdermal routes of administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, extended release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered orally.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered topically. In such embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is formulated as a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, massage agents (rubs), spreading agents, sticks, medicated bandages, balms, creams, or ointments. Such pharmaceutical compositions may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered topically to the skin.

In another aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered by inhalation. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered by inhalation directly targeted to the pulmonary system.

In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is formulated for intranasal administration. Such formulations include nasal sprays, nasal sprays and the like.

In another aspect, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is formulated as eye drops.

Another aspect is the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a disease, disorder or condition, wherein the activity of at least one LPA receptor results in a pathology and/or symptomology of the disease or condition. In one embodiment of this aspect, the LPA is selected from LPA₁、LPA₂、LPA₃、LPA₄、LPA₅And LPA₆. In one aspect, the LPA receptor is LPA₁. In one aspect, the disease or condition is any disease or condition specified herein.

Any of the preceding aspects are further embodiments, wherein: (a) systemically administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; and/or (b) orally administering to the mammal an effective amount of a compound; and/or (c) administering intravenously to the mammal an effective amount of the compound; and/or (d) administering an effective amount of the compound by inhalation; and/or (e) administering an effective amount of the compound by nasal administration; or/and/or (f) administering to the mammal an effective amount of the compound by injection; and/or (g) topically administering to the mammal an effective amount of a compound; and/or (h) administering an effective amount of the compound by ocular administration; and/or (i) rectally administering to the mammal an effective amount of the compound; and/or (j) non-systemically or locally administering to the mammal an effective amount.

Any of the preceding aspects are other embodiments comprising a single administration of an effective amount of a compound, including wherein (i) the compound is administered once; (ii) administering the compound to the mammal multiple times over a one day period; (iii) continuously; or (iv) other embodiments in which the compound is administered sequentially.

Any of the foregoing aspects are other embodiments comprising multiple administrations of an effective amount of the compound, including wherein (i) the compound is administered continuously or intermittently, such as in a single dose; (ii) the interval time of multiple administrations is every 6 hours; (iii) administering the compound to the mammal every 8 hours; (iv) administering the compound to the mammal every 12 hours; (v) other embodiments of administering the compound to the mammal every 24 hours. In other or alternative embodiments, the method comprises a drug withdrawal period, wherein administration of the compound is suspended or the dose of the compound administered is temporarily reduced; at the end of the drug withdrawal period, compound administration is resumed. In one embodiment, the length of the drug withdrawal period varies from 2 days to 1 year.

Also provided is a method of inhibiting LPA physiological activity in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, there is provided an agent for treating an LPA-dependent or LPA-mediated disease or condition in a mammal comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In some cases, disclosed herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment of an LPA-dependent or LPA-mediated disease or condition.

In some cases, disclosed herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the treatment or prevention of an LPA-dependent or LPA-mediated disease or condition.

In one aspect, is a method for treating or preventing an LPA-dependent or LPA-mediated disease or condition in a mammal comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, LPA-dependent or LPA-mediated diseases or conditions include, but are not limited to, organ or tissue fibrosis, scarring, liver disease, dermatological conditions, cancer, cardiovascular disease, respiratory disease or conditions, inflammatory disease, gastrointestinal disease, kidney disease, urinary tract related disease, inflammatory disease of the lower urinary tract, urinary pain, urinary frequency, pancreatic disease, arterial occlusion, cerebral infarction, cerebral hemorrhage, pain, peripheral neuropathy, and muscle fiber pain.

In one aspect, the LPA-dependent or LPA-mediated disease or condition is a respiratory disease or condition. In some embodiments, the respiratory disease or condition is asthma, Chronic Obstructive Pulmonary Disease (COPD), pulmonary fibrosis, pulmonary hypertension, or acute respiratory distress syndrome.

In some embodiments, the LPA-dependent or LPA-mediated disease or condition is selected from idiopathic pulmonary fibrosis; cystic fibrosis; diffuse parenchymal lung diseases of different etiologies, including iatrogenic drug-induced fibrosis, occupational and/or environmentally induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, pulmonary alveolar proteinosis, langerhans cell granulomatosis (langerhans cell granulomatosis), pulmonary lymphangioleiomyelitis, genetic diseases (hursky-prake Syndrome), tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung diseases); radiation-induced fibrosis; chronic Obstructive Pulmonary Disease (COPD); scleroderma; bleomycin-induced pulmonary fibrosis; chronic asthma; silicosis; asbestos-induced pulmonary fibrosis; acute Respiratory Distress Syndrome (ARDS); kidney fibrosis; tubulointerstitial fibrosis; glomerulonephritis; focal segmental glomerulosclerosis; IgA nephropathy; hypertension; alport (Alport); intestinal fibrosis; liver fibrosis; cirrhosis of the liver; alcohol-induced liver fibrosis; toxicity/drug-induced liver fibrosis; hemochromatosis; nonalcoholic steatosis hepatitis (NASH); biliary tract injury; primary biliary cirrhosis; infection-induced liver fibrosis; viral-induced liver fibrosis; and autoimmune hepatitis; corneal scarring; hypertrophic scars; dipterex disease (Dupuytren disease), keloid, dermal fibrosis; cutaneous scleroderma; spinal cord injury/fibrosis; myelofibrosis; restenosis of the blood vessel; atherosclerosis; arteriosclerosis; wegener's granulomatosis; pelonetz, chronic lymphocytic leukemia, tumor metastasis, transplant organ rejection, endometriosis, neonatal respiratory distress syndrome, and neuropathic pain.

In one aspect, LPA-dependent or LPA-mediated diseases or conditions are described herein.

In one aspect, there is provided a method of treating or preventing organ fibrosis in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, the organ fibrosis comprises pulmonary fibrosis, renal fibrosis, or liver fibrosis.

In one aspect, there is provided a method of improving lung function in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In one aspect, the mammal has been diagnosed with pulmonary fibrosis.

In one aspect, the compounds disclosed herein are used to treat idiopathic pulmonary fibrosis (common interstitial pneumonia) in a mammal.

In some embodiments, the compounds disclosed herein are used to treat diffuse parenchymal interstitial lung disease in a mammal: iatrogenic drug induction, occupational/environmental (farmer's lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases (scleroderma and others), pulmonary alveolar proteinosis, langerhans' cell granulomatosis, pulmonary lymphangioleiomyomatosis, hermansky-prasuk syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease.

In some embodiments, the compounds disclosed herein are used to treat post-transplant fibrosis associated with chronic rejection in a mammal: obstructive bronchiolitis in lung transplants.

In some embodiments, the compounds disclosed herein are used to treat skin fibrosis in a mammal: scleroderma, discodermia, keloid.

In one aspect, the compounds disclosed herein are used to treat liver fibrosis with or without cirrhosis in a mammal: toxicity/drug induction (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus, HCV), non-alcoholic liver disease (NAFLD, NASH), metabolic and autoimmune diseases.

In one aspect, the compounds disclosed herein are used for treating renal fibrosis in a mammal: tubulointerstitial fibrosis, glomerulosclerosis.

In any of the preceding aspects directed to treating an LPA-dependent disease or condition, is a further embodiment comprising administering at least one additional agent in addition to the compound having the structure of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In various embodiments, the agents are administered in any order, including simultaneously.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, a compound provided herein is administered to a human.

In some embodiments, the compounds provided herein are administered orally.

In some embodiments, the compounds provided herein are useful as antagonists of at least one LPA receptor. In some embodiments, the compounds provided herein are used to inhibit the activity of at least one LPA receptor or to treat a disease or condition that would benefit from inhibition of at least one LPA receptor activity. In one aspect, the LPA receptor is LPA₁。

In other embodiments, the compounds provided herein are used for the inhibition of LPA₁Formulations of active agents.

There is provided an article of manufacture comprising packaging material, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof within the packaging material, and a label that indicates that the compound or composition or a pharmaceutically acceptable salt, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug or pharmaceutically acceptable solvate thereof, is useful for inhibiting the activity of at least one LPA receptor or for treating, preventing or alleviating one or more symptoms of a disease or condition that would benefit from inhibition of the activity of at least one LPA receptor.

General Synthesis, including scheme

The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of organic synthetic chemistry or variations thereof as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to, the following. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and materials used and for effecting the conversion. It will be appreciated by those skilled in the art of organic synthesis that the functional groups present on the molecule should be consistent with the proposed transformations. Sometimes, this requires a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain the desired compounds of the invention.

It will also be appreciated that another major consideration in the art in the planning of any synthetic route is the judicious choice of protecting groups for protecting the reactive functional groups present in the compounds of the invention. An authoritative explanation that describes many alternatives to a trained practitioner is Greene et al, (Protective Groups in organic Synthesis, fourth edition, Wiley-Interscience (2006)). The compounds of formula (I) can be prepared by the following schemes and exemplary methods described in the working examples, as well as the relevant published procedures used by those skilled in the art. Exemplary reagents and procedures for these reactions are presented below and in the working examples. Protection and deprotection of the protecting groups in the following methods can be performed by procedures generally known in the art (see, e.g., Wuts, p.g.m., Greene's protective groups in Organic Synthesis, 5 th edition, Wiley (2014)). General methods for organic synthesis and functional group transformation are found in: trost, B.M. et al, Comprehensive Organic Synthesis, selection, Strategy & Efficiency in model Organic Chemistry, Pergamon Press, New York, NY (1991); smith, M.B. et al, March's Advanced Organic Chemistry: Reactions, mechanics, and Structure 7 th edition, Wiley, New York, NY (2013); katritzky, A.R. et al, eds., comprehensive organic Functional groups Transformations II, 2 nd edition, Elsevier Science Inc., Tarrytown, NY (2004); larock, R.C., Comprehensive Organic Transformations, 2 nd edition, Wiley-VCH, New York, NY (1999), and references therein.

Scheme 1 describes the synthesis of N-carbamoylpyrazole-aryloxycyclohexanoic acids 14 and 15. Pyrazole 5-carboxylic acid 1 is reduced (e.g., by a 2-step 1-pot reaction, by reaction with an alkyl chloroformate followed by NaBH₄Reduced at low temperature or directly reacted with diborane) to give the corresponding pyrazole alcohol which is then protected to give pyrazole intermediate 2. Halogenation of pyrazole 2 preferably occurs at the 4-pyrazole position to give a protected halopyrazolol 3 which is then subjected to a Suzuki-Miyaura cross-linking reaction with an appropriately substituted 4-hydroxy-aryl/heteroaryl borane 4 to give the corresponding 4-hydroxy-aryl (heteroaryl) -pyrazole 5. Reaction of phenol/hydroxyheteroarene 5 with 3-hydroxycyclohexyl ester 6 under Mitsunobu reaction conditions (Kumara Swamy, K.C., chem.Rev., 2009, 109, 2551-2651) gives the corresponding pyrazole cycloalkyl ether ester 7. Deprotection of hydroxymethylpyrazole 7 affords cyclohexyl pyrazolol 8. Pyrazole alcohol 8 subsequently with PBr₃Reaction (or other mild brominating agents, e.g. CBr)₄/Ph₃P) to give the corresponding bromide 9. Pyrazole bromide 9 and NaN₃(or other azide equivalent reagents) to give pyrazole azide 10, which is reduced (e.g., with Ph)₃P/water for Staudinger reduction) to yield prazosin 11. Pyrazole N-H carbamic acid cyclohexyl ester 13 is obtained by reacting pyrazole azolamine 11 with an appropriate acylating agent 12, such as chloroformate or 4-nitrophenyl carbonate. Deprotection of cyclohexyl ester 13 affords NH-carbamoylmethylpyrazole-aryloxycyclohexane acid 14. Pyrazole NH-carbamic acid cyclohexyl ester 13 is treated with a suitable base (e.g., NaH) and then reacted with an alkyl halide (R)³X) reaction to give cyclohexyl pyrazole N, N-disubstituted carbamates which are subsequently deprotected to give N, N-dialkyl esters-carbamoylpyrazole-aryloxycyclohexanoic acid 15.

Scheme 1

Scheme 2 describes an alternative synthesis of N-carbamoylpyrazole-aryloxycyclohexanoic acids 14 and 15. The 4-hydroxy-aryl/heteroaryl halide 16 is reacted with 3-hydroxycyclohexyl ester 6 under Mitsunobu reaction conditions to give the corresponding 4-halo-aryl-oxy-cycloalkyl ester 17. Boronation of aryl/heteroaryl halides 17 (e.g., using pinacol ester of diboronic acid in the presence of a suitable palladium catalyst, see Ishiyama, T. et al, J.org.Chem.1995, 60, 7508-7510) gives aryl/heteroaryl boronates 18 (which can be converted to the corresponding boronic acids) which are then subjected to Suzuki-Miyaura coupling with halo-pyrazole protected alcohols 3 to give the corresponding oxycycloalkylpyrazole-aryl/heteroaryl esters 7. Cyclohexyl ester-pyrazole ether 7 is then converted to the N-carbamoylpyrazole-aryloxycyclohexanoates 14 and 15 by the same synthetic sequence as described in scheme 1.

Scheme 2

Scheme 3 depicts an alternative synthetic route to N-carbamoylpyrazole-aryloxycyclohexanoic acids 14 and 15. Metallation of suitably protected halo-pyrazolol 3 (e.g. with n-BuLi) with boronizing agent B (OR)₃Reaction to give pyrazole boronic ester 19. This pyrazole boronic ester 19 is then subjected to a Suzuki-Miyaura coupling reaction with the appropriate 4-hydroxyaryl/heteroaryl halide 16 to directly yield the 4-haloaryl/heteroaryl-pyrazole 5. Reaction of phenol/hydroxyheteroarene 5 with 3-hydroxycyclohexyl ester 6 under Mitsunobu reaction conditions affords the corresponding pyrazolyloxycycloalkyl ester 7, which is subsequently converted to N-carbamoylpyrazole-aryloxycyclohexanoates 14 and 15 by the same synthetic sequence as depicted in scheme 1.

Scheme 3

Scheme 4 describes the synthesis of N-carbamoylpyrazole-aryloxycyclohexanoates 14 and 15 via a synthetic route involving the initial preparation of the fully described pyrazole N-carbamate intermediate. Pyrazole alcohol 18 is deprotected and then the same 3-step sequence as described in scheme 1 is used (from alcohol 8 to amine 11 by treatment with PBr)₃Or CBr₄/Ph₃Conversion of P to bromide with NaN₃Replacement with bromide of (2), and with Ph₃Reduction of the azide in P/water) to yield the corresponding pyrazole amine 20. Pyrazolidine 20 is reacted with an appropriate acylating agent 12 (e.g. chloroformate or 4-nitrophenyl carbonate) to give pyrazole N-H carbamate 21. Halo-pyrazole carbamate 21 is then subjected to a Suzuki-Miyaura cross-linking reaction with an appropriately substituted 4-hydroxy-aryl/heteroaryl boronate/boronic acid 22 to give the corresponding hydroxyaryl/hydroxyheteroaryl pyrazole carbamate 23, which is then subjected to a Mitsunobu reaction with 3-hydroxycyclohexyl ester 6 to give the corresponding pyrazolyloxycycloalkyl ester 13. Pyrazole N-carbamate cycloalkyl ester 13 is then converted to N-carbamoylpyrazole-aryloxycyclohexanoates 15 and 16 by the same synthetic sequence as described in scheme 1.

Scheme 4

Scheme 5 describes the synthesis of pyrazole N-linked carbamate cyclohexyl acids 26 and 27. Cyclohexylether pyrazole-alcohol 8 is oxidized to pyrazole carboxylic acid 24 (e.g., directly to the acid with pyridinium dichromate, or via a two-step sequential oxidation of an aldehyde [ Swern oxidation or Dess-Martin periodinane, followed by NaClO₂Oxidation to acids, e.g. Lindgren, B.O., ActaChem.Scand.1973, 27, 888]). In the alcohol R⁴Curtius rearrangement of pyrazole acid 24 in the presence of-OH gives pyrazole NH-carbamate 25. Deprotection of pyrazole NH-carbamate cyclohexyl ester 25 affords pyrazole NH-carbamate cyclohexyl acid 26. Alternatively, pyrazole NH-Carbamate cyclohexyl ester25 deprotonation with a suitable base and reaction with an alkyl radical R³Halide reaction (as depicted in scheme 1) to afford pyrazole N, N-dialkylaminoacetate acid 26.

Scheme 5

Scheme 6 describes the synthesis of N-ureido-pyrazole-aryloxycyclohexanoates 30 and 32. Pyrazolidine 12 is reacted with carbamoyl chloride 29 (prepared, for example, from the reaction of secondary amine 28 with triphosgene) to give the corresponding ureido-pyrazolylcyclohexyl ester, which is subsequently deprotected to give ureido-isoxazolyl cyclohexyl acid 30. In a complementary synthetic route, isoxazolylamine 12 is reacted with triphosgene to give isoxazolecarbonyl chloride 31, which is reacted with primary amine R³-NH₂(or with a secondary amine 28) to give (after deprotection of the ester) the corresponding N-alkyl-ureido-pyrazolyloxycyclohexanoic acid 32 (the product with the secondary amine is N, N' -dialkylureido-pyrazolecarboxylic acid 30). Alternatively, pyrazolylamine 11 is reacted with an isocyanate R³NCO reaction, and obtaining the N-alkyl-ureido-pyrazole cyclohexyl acid 32 after ester deprotection.

Scheme 6

Scheme 7 describes the synthesis of N-carbamoylpyrazole-aryloxycyclohexanoic acids 38 and 39. The appropriately protected 1, 5-dialkyl-1H-pyrazole-4-carboxylate 33 is brominated to give the bromo-pyrazole 34. The bromopyrazole 34 is then subjected to a Suzuki-Miyaura coupling reaction with the aryl/heteroaryl borate ester 18 (or corresponding boronic acid) to give the corresponding oxycycloalkylpyrazole-aryl/heteroaryl ester 35. Selective deprotection of the pyrazole ester of 35 affords the corresponding pyrazolecarboxylic acid 36, which is subsequently reduced (e.g., by a 2-step 1-pot reaction, by reaction with an alkyl chloroformate followed by NaBH₄Reduction at low temperature or direct reaction with diborane as described in scheme 1) gives the corresponding pyrazolol 37. By the same synthetic sequence as described in scheme 1, cyclohexyl-pyrazolol37 is subsequently converted into the pyrazole N-carbamoylcyclohexanoic acids 38 and 39. Alternatively, cyclohexyl ester-pyrazolol 37 is subsequently also converted to pyrazole N-carbamate aryloxycyclohexanoates 40 and 41 by the same synthetic sequence as depicted in scheme 5.

Scheme 7

VII. examples

The following examples are provided as illustrative examples, as part of the scope of the invention, and specific embodiments, and are not intended to limit the scope of the invention. Abbreviations and chemical symbols have their usual and customary meaning unless otherwise indicated. Unless otherwise indicated, the compounds described herein have been prepared, isolated, and characterized, or can be prepared using the procedures disclosed herein, as well as other methods.

The reaction is carried out under an atmosphere of dry nitrogen (or argon), as appropriate. Anhydrous reaction using EM-derived

A solvent. Other reactions employ reagent grade or HPLC grade solvents. All commercial reagents were used as received unless otherwise stated.

Microwave reactions were performed in a microwave reaction vessel under microwave (2.5GHz) irradiation using a 400W Biotage Initiator instrument.

HPLC/MS and preparative/analytical HPLC methods employed in characterization or purification examples

Typically, NMR (nuclear magnetic resonance) spectra were obtained with a Bruker or JEOL 400MHz and 500MHz instrument in the indicated solvents. All chemical shifts (ppm) were reported relative to tetramethylsilane using solvent resonance as an internal standard.¹HNMR spectroscopic data are typically reported as follows: chemical shift, multiplicities (s ═ singlet, br ═ broad singlet, d ═ doublet, dd ═ doublet, t ═ triplet, q ═ quartet, sep ═ seph, m ═ multiplet, app ═ apparent), coupling constants (Hz) and integrals.

At d₆-DMSIn O collection¹In the examples of H NMR spectroscopy, a water suppression procedure is generally employed. This procedure effectively suppresses the water signal and any proton peak in the same interval (typically between 3.30-3.65 ppm) that would affect the overall proton integral.

The term HPLC refers to a Shimadzu high performance liquid chromatography apparatus using one of the following methods:

HPLC-1: sunfire C18 column (4.6X 150mm)3.5 μm, gradient 10 to 100% B: A for 12 min, followed by 3min residence time at 100% B.

Mobile phase A: water containing 0.05% TFA CH₃CN(95:5)

Mobile phase B: CH with 0.05% TFA₃CN Water (95:5)

TFA buffer pH 2.5; flow rate: 1 mL/min; wavelength: 254nm, 220 nm.

HPLC-2: xbridge Phenyl (4.6X 150mm)3.5 μm, gradient 10 to 100% B: A over 12 min, followed by 3min hold at 100% B.

Mobile phase A: water containing 0.05% TFA CH₃CN(95:5)

Mobile phase B: CH with 0.05% TFA₃CN Water (95:5)

TFA buffer pH 2.5; flow rate: 1 mL/min; wavelength: 254nm, 220 nm.

HPLC-3：Chiralpak AD-H，4.6×250mm，5μm。

Mobile phase: 30% EtOH-heptane (1: 1)/70% CO₂

Flow rate 40mL/min, 100 bar, 35 ℃; wavelength: 220nm

HPLC-4: waters Acquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particles;

mobile phase A: 5:95CH₃CN containing 10mM NH₄Water of OAc;

mobile phase B: 95:5CH₃CN with 10mM NH₄Water of OAc;

temperature: 50 ℃; gradient: 0-100% B for 3 minutes followed by 0.75 minutes at 100% B; flow rate: 1.11 mL/min; and (3) detection: UV at 220 nm.

HPLC-5: waters Acquity UPLC BEH C18, 2.1X 50mm, 1.7 μm particles;

mobile phase A: 5:95CH₃CN water containing 0.1% TFA;

mobile phase B: 95:5CH₃CN water containing 0.1% TFA;

temperature: 50 ℃; gradient: 0-100% B for 3 minutes followed by 0.75 minutes at 100% B; flow rate: 1.11 mL/min; and (3) detection: UV at 220 nm.

Intermediate 1: isopropyl trans-3- ((6- (5- (bromomethyl) -1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate

Intermediate 1A: 4-bromo-1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-pyrazole

At 0 ℃ the pTsOH.H₂O (0.050g, 0.262mmol) was added to a solution of (4-bromo-1-methyl-1H-pyrazol-5-yl) methanol (1.0g, 5.2mmol) and 3, 4-dihydro-2H-pyran (1.32g, 15.7mmol) in DCM (10 mL). The reaction was warmed to room temperature and stirred at room temperature overnight. The reaction was cooled to 0 ℃ and quenched with saturated aqueous NaHCO₃Neutralized to pH 7. The mixture was partitioned between DCM (10mL) and water (10mL), and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic extracts were dried (MgSO)₄) And concentrated in vacuo. The residue is chromatographed (SiO)₂(ii) a EtOAc/hexanes) to give the title compound (1.40g, 5.09mmol, 97% yield) as a colorless oil.¹H NMR(500MHz，CDCl₃)7.41(s，1H)，4.72(d，J＝12.9Hz，1H)，4.65(dd，J＝4.1，3.0Hz，1H)，4.58(d，J＝12.9Hz，1H)，3.93(s，3H)，3.88(ddd，J＝11.6，8.3，3.1Hz，1H)，3.57(dddd，J＝11.0，5.0，3.9，1.4Hz，1H)，3.49(d，J＝5.5Hz，2H)，1.85-1.75(m，1H)，1.75-1.66(m，1H)，1.66-1.48(m，4H)。LCMS，[M+H]⁺＝275.1。

Intermediate 1B: 1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

A mixture of intermediate 1A (469mg, 1.71mmol), KOAc (502mg, 5.11mmol), bis (pinacolato) diboron (649mg, 2.56mmol) in 1,4 dioxane (10ml) was diluted with N₂Degassing for 5 minutes. Addition of PdCl₂(dppf) (125mg, 0.170mmol) and the reaction was again run with N₂Degassing for 5 minutes. The reaction vessel was sealed and heated at 85 ℃ for 10 hours and then cooled to room temperature. The mixture was partitioned between EtOAc (10mL) and water (10mL) and the aqueous layer was extracted with EtOAc (3X10 mL). The combined organic extracts were dried (MgSO)₄) And concentrated in vacuo to give the crude title compound (717mg, 0.890mmol, 52.2% yield) as a yellow to colorless oil. LCMS, [ M + H ]]⁺＝323.1。

Intermediate 1C: trans-3- ((6-bromopyridin-3-yl) oxy) cyclohexane-1-carboxylic acid isopropyl ester

To 6-bromopyridin-3-ol (300mg, 1.72mmol), (+ -) -cis-3-hydroxycyclo-hexanecarboxylic acid isopropyl ester (353mg, 1.90mmol), Et at 0 ℃ over 15 minutes₃N (0.264mL, 1.90mmol) and Ph₃P (497mg, 1.90mmol) in THF (2mL) was added DIAD (0.369mL, 1.90mmol) dropwise. The reaction was stirred at room temperature overnight and then partitioned between EtOAc (5mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (5mL) and dried (MgSO)₄) And concentrated in vacuo. The crude product is chromatographed (SiO)₂(ii) a EtOAc/hexanes) to give the title compound (255mg, 0.745mmol, 43.2% yield) as a white solid.¹H NMR(500MHz，CDCl₃)8.07(d，J＝3.2Hz，1H)，7.36(d，J＝8.8Hz，1H)，7.14(dd，J＝8.7，3.1Hz，1H)，5.02(hept，J＝6.3Hz，1H)，4.61(dq，J＝8.7，5.3，4.2Hz，1H)，2.76(tt，J＝9.0，4.4Hz，1H)，2.03-1.51(m，8H)，1.24(dd，J＝6.3，1.9Hz，6H)。LCMS，[M+H]⁺＝342。

Intermediate 1D: trans-3- ((6- (1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-pyrazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid isopropyl ester

To a solution of intermediate 1B (717mg, 0.891mmol) in 1, 4-dioxane (2mL) was added 1C (254mg, 0.742mmol) and K₂HPO₄(388mg, 2.23mmol), second generation XPhos pre-catalyst (29mg, 0.037mmol) and water (2 mL). The mixture was evacuated in vacuo and then backfilled with Ar (3 ×). The mixture was stirred at 60 ℃ for 24 hours, then cooled to room temperature and stirred at room temperature for 24 hours. The mixture was extracted with EtOAC (3X 5mL) and dried (MgSO)₄) And concentrated in vacuo to give the crude product. The crude material was chromatographed (12g SiO₂Continuous gradient 0 to EtOAc in 100% hexanes over 12 min) to give the title compound (212mg, 0.417mmol, 56.2% yield) as a yellowish oil.¹H NMR(500MHz，CDCl₃)8.30(d，J＝2.9Hz，1H)，7.76(s，1H)，7.46-7.39(m，1H)，7.28-7.21(m，1H)，5.08-4.94(m，3H)，4.72(dd，J＝4.5，3.0Hz，1H)，4.65(tq，J＝5.5，2.8Hz，1H)，3.97(s，3H)，3.88(ddd，J＝11.3，7.9，3.2Hz，1H)，3.56-3.45(m，1H)，2.80(tt，J＝9.8，4.1Hz，1H)，2.09-1.48(m，14H)，1.24(dd，J＝6.3，1.8Hz，6H)。LCMS，[M+H]⁺＝458.1。

Intermediate 1E: isopropyl trans-3- ((6- (5- (hydroxymethyl) -1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylate

To a solution of intermediate 1D (212mg, 0.463mmol) in MeOH (5mL) was added PPTS (12mg, 0.046 mmol). Mixing the mixture at 60Heating for 4 hr, cooling to room temperature, and adding saturated aqueous NaHCO₃Quench (2mL) and concentrate in vacuo to remove MeOH. The residue was extracted with EtOAC (3 × 5 mL). The combined organic extracts were dried (MgSO)₄) And concentrated in vacuo. The crude product was chromatographed (4g SiO_2；Successive gradients of EtOAc in 0% to 100% hexanes, 12 min) gave the title compound (75mg, 0.201mmol, 43.3% yield) as a colorless oil.¹H NMR(500MHz，CDCl₃)8.15(d，J＝2.9Hz，1H)，7.66(s，1H)，7.43(d，J＝8.8Hz，1H)，7.26(dd，J＝8.8，2.9Hz，1H)，6.93(s，1H)，4.95(hept，J＝6.2Hz，1H)，4.65(s，2H)，4.58(dq，J＝5.8，2.8Hz，1H)，3.85(3，3H)，2.72(tt，J＝9.0，4.3Hz，1H)，1.99-1.46(m，8H)，1.17(dd，J＝6.3，2.3Hz，6H)。LCMS，[M+H]⁺＝374.2。

Intermediate 1

PBr was washed at 0 deg.C₃(0.040mL, 0.426mmol) was added to a solution of intermediate 1E (53mg, 0.142mmol) in DME (1.5 mL). The reaction was stirred at room temperature overnight, then cooled to 0 ℃ and quenched with saturated aqueous NaHCO₃Neutralized to pH 7. The mixture was partitioned between DCM (5mL) and water (3mL), and the aqueous layer was extracted with DCM (3 × 3 mL). The combined organic extracts were dried (MgSO)₄) And concentrated in vacuo. The residue is chromatographed (SiO)₂(ii) a EtOAc/hexanes) to give the title compound (55mg, 0.126mmol, 89% yield) as a white solid.¹H NMR(500MHz，CDCl₃)8.34(d，J＝2.8Hz，1H)，7.74(s，1H)，7.45(d，J＝8.8Hz，1H)，7.32-7.24(m，1H)，5.11(s，2H)，5.04(p，J＝6.2Hz，1H)，4.68(tt，J＝5.5，3.0Hz，1H)，3.96(s，3H)，2.80(dd，J＝9.4，4.2Hz，1H)，2.09-1.53(m，8H)，1.26(dd，J＝6.2，2.5Hz，6H)。LCMS，[M+H]⁺＝436.0。

Intermediate 2: isopropyl (1S,3S) -3- ((2- (5- (aminomethyl) -1-methyl-1H-pyrazol-4-yl) -4-methylpyrimidin-5-yl) oxy) cyclohexane-1-carboxylate

Intermediate 2A: (4-bromo-1-methyl-1H-pyrazol-5-yl) methanol

4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid (5.0g, 24.4mmol) and BH₃A mixture of THF (36.6mL of a 1M THF solution, 36.6mmol) in THF (50mL) was stirred at 50 ℃ for 2 days; LCMS at this point indicated the reaction was complete. The reaction was cooled to room temperature and carefully quenched with aq.1n HCl and stirred at room temperature for 1 hour, after which the mixture was extracted with EtOAc (3X 50 mL). The combined organic extracts were concentrated in vacuo. The residue is chromatographed (80g SiO₂(ii) a Successive gradients of EtOAc in 0% to 100% hexanes, 25 min) gave the title compound (3.60g, 18.9mmol, 77% yield) as a white solid. LCMS, [ M + H ]]⁺＝193.0。

Intermediate 2B: 4-bromo-1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-pyrazole

Reacting p-TsOH.H₂O (0.050g, 0.262mmol) was added to a solution of intermediate 2A (1.0g, 5.23mmol) and 3, 4-dihydro-2H-pyran (1.32g, 15.7mmol) in DCM (10mL) at 0 deg.C at room temperature. The reaction was warmed to room temperature and stirred at room temperature overnight. The mixture was cooled to 0 ℃ with saturated aqueous NaHCO₃Neutralized to pH 7 and then partitioned between DCM (10mL) and H₂O (10 mL). The aqueous layer was extracted with DCM (3 × 10 mL). The combined organic extracts were dried (MgSO)₄) And concentrated in vacuo. The residue is chromatographed (40g SiO₂(ii) a Successive gradients of EtOAc in 0% -80% hexanes over 14min) gave the title compound (1.4g, 5.09mmol, 97% yield) as a colorless oil.

¹H NMR(500MHz，CDCl₃)7.41(s，1H)，4.72(d，J＝12.9Hz，1H)，4.65(dd，J＝4.1，3.0Hz，1H)，4.58(d，J＝12.9Hz，1H)，3.93(s，3H)，3.88(ddd，J＝11.6，8.3，3.1Hz，1H)，3.57(dddd，J＝11.0，5.0，3.9，1.4Hz，1H)，3.49(d，J＝5.5Hz，2H)，1.85-1.75(m，1H)，1.75-1.66(m，1H)，1.66-1.48(m，4H)。LCMS，[M+H]⁺＝275.1。

Intermediate 2C: 1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole

Ar was bubbled vigorously through the stirring intermediates 2B (550mg, 2.00mmol), KOAc (589mg, 6.00mmol) and B₂Pin₂(761mg, 3.00mmol) in 1, 4-dioxane (10mL) for 5 minutes. Addition of Pd (dppf) Cl₂-CH₂Cl₂(163mg, 0.20mmol) and the reaction was flushed with argon and then heated to 100 ℃ for 16 h; LCMS analysis after 16 hours indicated the reaction was complete. The reaction mixture was cooled to room temperature and partitioned between CH₂Cl₂(20mL) and H₂O (10 mL); the resulting mixture was stirred vigorously. The organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The crude product was used in the next step without further purification.

Intermediate 2D: 2-bromo-4-methylpyrimidin-5-ol

A mixture of 2-chloro-4-methylpyrimidin-5-ol (500mg, 3.46mmol) and HBr (30 wt.% in HOAc; 3mL) was heated to 110 ℃ overnight, after which LCMS indicated the reaction was complete. The reaction mixture was cooled to room temperature, then poured onto ice and extracted with EtOAc (3X 50 mL). The combined organic extracts were washed with saturated aqueous Na₂CO₃Washed with water and brine, then dried (Na)₂SO₄) And concentrated in vacuo to give the title compound (630mg, 3.33mmol, 96% yield) as an off-white solid. LCMS, [ M + H ]]⁺＝189.1。

Intermediate 2: 4-methyl-2- (1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-pyrazol-4-yl) pyrimidin-5-ol

Bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (101mg, 0.14mmol), intermediate 2C (552mg, 1.71mmol), intermediate 2D (270mg, 1.43mmol), aq.2M Na, were placed in a microwave reactor₂CO₃(3.6mL, 7.14mmol) in MeCN (7mL) was heated at 100 deg.C for 1 hour, then cooled to room temperature and quenched with saturated aqueous NaHCO₃Diluted and extracted with EtOAc (3X 50 mL). The combined organic extracts were washed with brine and dried (Na)₂SO₄) And concentrated in vacuo. The crude product was chromatographed (80g SiO₂Continuous gradient 0% EtOAc in 90% hexanes) to give the title compound (250mg, 0.82mmol, 58% yield) as an off-white solid.¹H NMR(500MHz，CDCl₃)8.85(d，J＝1.42Hz，1H)，8.14(d，J＝1.41Hz，1H)，5.15(m，2H)，4.98(m，1H)，4.69(m，1H)，4.13(s，3H)，3.82(ddd，J＝11.33，7.90，3.08Hz，1H)，3.49(m，1H)，2.74(tt，J＝11.5，3.67Hz，1H)，2.15(m，1H)，1.98-1.50(m，13H)，1.20(m，6H)。[M+H]⁺＝305.1。¹H NMR(500MHz，DMSO-d6)8.17(s，1H)，7.86(s，1H)，5.26(d，J＝11.9Hz，1H)，5.09(d，J＝11.9Hz，1H)，4.77-4.69(m，1H)，3.87(s，3H)，3.85-3.77(m，2H)，2.37(s，3H)，1.73-1.39(m，6H)。

Intermediate 2F: isopropyl (1S,3S) -3- ((4-methyl-2- (1-methyl-5- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) -1H-pyrazol-4-yl) pyrimidin-5-yl) oxy) cyclohexane-1-carboxylate

(E) -diazene-1, 2-diylbis (piperidin-1-ylmethanone) (435mg, 1.73mmol), toluene (8mL) and Bu₃A mixture of P (0.43mL, 1.73mmol) was stirred at room temperature for 30 minutes, after which intermediate 2E (210mg, 0.6 mmol) was added in order9mmol) and isopropyl (1S,3R) -3-hydroxycyclohexane-1-carboxylate (231mg, 1.24 mmol). The reaction mixture was heated at 85 ℃ for 9 hours, after which LC/MS indicated the formation of the desired product. The reaction was cooled to room temperature and quenched with CH₂Cl₂Diluting; the mixture was filtered and the filtrate was concentrated in vacuo. The crude oily product was chromatographed (80g SiO₂(ii) a A continuous gradient of 0% to 90% EtOAc/Hex over 25min, 20min at 90%) gave the title compound (190mg, 0.40mmol, 58% yield) as a light yellow oil.¹H NMR(500MHz，CDCl₃)8.98(s，1H)，8.09(s，1H)，5.51(t，J＝6.90Hz，1H)，5.43(s，1H)，4.98(m，1H)，4.80(d，J＝6.88，2H)，4.07(s，3H)，2.72(tt，J＝11.5，3.67Hz，1H)，2.15(m，1H)，1.98-1.50(m，7H)，1.20(m，6H)。LCMS，[M+H]⁺＝473.2。

Intermediate 2G: isopropyl (1S,3S) -3- ((2- (5- (hydroxymethyl) -1-methyl-1H-pyrazol-4-yl) -4-methylpyrimidin-5-yl) oxy) cyclohexane-1-carboxylate

A solution of intermediate 2F (190mg, 0.40mmol) and PPTS (15mg, 0.06mmol) in MeOH (4mL) was heated at 60 deg.C overnight, then cooled to room temperature and concentrated in vacuo. Addition of saturated aqueous NaHCO₃And the mixture was extracted with EtOAc (3X25 mL). The combined organic extracts are washed with H₂O and brine, dried (MgSO)₄) And concentrated in vacuo. The crude product was chromatographed (40g SiO₂Continuous gradient 0% EtOAc in 100% hexanes) to give the title compound (140mg, 90% yield) as an off-white solid. LCMS, [ M + H ]]⁺＝389.2。

Intermediate 2H: isopropyl (1S,3S) -3- ((2- (5- (bromomethyl) -1-methyl-1H-pyrazol-4-yl) -4-methylpyrimidin-5-yl) oxy) cyclohexane-1-carboxylate

PBr was washed at 0 deg.C₃(0.09mL, 0.90mmol) was added to a solution of intermediate 2G (140mg, 0.36mmol) in DME (4 mL). The reaction was warmed to room temperature and stirred at room temperature overnight, then cooled to 0 ℃ and saturated aqueous NaHCO was carefully added₃To quench the reaction and adjust the pH to about 7. The mixture was partitioned between EtOAc (200mL) and H₂O (10 mL); the aqueous layer was extracted with EtOAc (3X10 mL). The combined organic extracts were dried (MgSO)₄) And concentrated in vacuo. The crude product was chromatographed (40g SiO₂(ii) a Continuous gradient 0% to 60% EtOAc: hexane over 20 min) to give the title compound (140mg, 0.31mmol, 86% yield) as a colorless oil. LCMS, [ M + H ]]⁺＝453.0。

Intermediate 2I: isopropyl (1S,3S) -3- ((2- (5- (azidomethyl) -1-methyl-1H-pyrazol-4-yl) -4-methylpyrimidin-5-yl) oxy) cyclohexane-1-carboxylate

To a solution of intermediate 2H (500mg, 1.11mmol) in DMF (2mL) was added NaN₃(72mg, 1.11mmol) and the reaction stirred at 80 ℃ for 1 hour; LCMS analysis at this point indicated the reaction was complete. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water (10mL each), and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The crude product was chromatographed (24g SiO₂(ii) a A continuous gradient of EtOAc in 0% to 100% hexanes over 12 min) gave the title compound (368mg, 0.890mmol, 80% yield) as a colorless oil. LCMS, [ M + H ]]⁺＝414.3。¹HNMR(500MHz，CDCl₃)8.25(s，1H)，8.14(s，1H)，5.09-5.03(m，1H)，5.02(s，2H)，4.74(dp，J＝5.2，2.7Hz，1H)，3.96(s，3H)，2.78(tq，J＝8.0，4.1Hz，1H)，2.52(s，3H)，2.15-1.57(m，8H)，1.27(dd，J＝6.3，2.5Hz，6H)。

Intermediate 2

Intermediate 2I (128 mg; 0.31mmol) and Ph₃P (81mg, 0.31mmol) in THF (2mL) and H₂A solution of O (0.7mL) was stirred at room temperatureAt night; LCMS analysis at this point indicated the reaction was complete. EtOAc/water was added and the mixture was stirred at rt for 15 min. The organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The residue is chromatographed (12g SiO₂(ii) a Continuous gradient 0% to 10% CH₂Cl₂MeOH in 20 minutes; flow rate 30mL/min) to give the title compound (97mg, 0.25mmol, 81% yield) as a light brown oil. LCMS, [ M + H ]]⁺＝388.2。

Intermediate 3: 3- (4- (((1S,3S) -3- (isopropoxycarbonyl) cyclohexyl) oxy) phenyl) -1, 5-dimethyl-1H-pyrazole-4-carboxylic acid

Intermediate 3A: 1, 5-dimethyl-1H-pyrazole-4-carboxylic acid methyl ester

To a 0 deg.C solution of 1, 5-dimethyl-1H-pyrazole-4-carboxylic acid (1.0g, 7.14mmol) in DCM/MeOH (7mL each) was added TMSCHN in 2M hexane₂(4.28mL, 8.56 mmol). The reaction mixture was stirred at 0 ℃ for 1 hour, then warmed to room temperature and stirred at room temperature overnight, then concentrated in vacuo. The crude product was chromatographed (80g SiO₂(ii) a Successive gradients of EtOAc in 0% to 50% hexanes over 20 min) gave the title compound (900mg, 5.84mmol, 82% yield). LCMS, [ M + H ]]⁺＝155.2。

Intermediate 3B: 3-bromo-1, 5-dimethyl-1H-pyrazole-4-carboxylic acid methyl ester

To a solution of intermediate 3A (1.10g, 7.14mmol) in MeCN (14.3mL) was added HOAc (4.1mL, 71.4mmol) and Br₂(0.44mL, 8.56 mmol). The reaction mixture was stirred at rt for 16 h, then washed with saturated aqueous sodium thiosulfate (20mL) and extracted with EtOAc (3 × 20 mL). Will mergeDrying (MgSO) of the organic extract₄) And (4) concentrating in vacuum. The crude product was chromatographed (80g SiO₂(ii) a Continuous gradient EtOAc in 0% to 50% hexanes over 20 min) to give the title compound (400mg, 25%).¹H NMR(400MHz，CDCl₃)3.79-3.71(m，3H)，3.68-3.60(m，3H)，2.45-2.33(m，3H)。

Intermediate 3C: (1S,3S) -3- (4-bromophenoxy) cyclohexane-1-carboxylic acid isopropyl ester

To a solution of 4-bromophenol (500mg, 2.89mmol) and isopropyl (1S,3R) -3-hydroxycyclohexane-1-carboxylate (538mg, 2.89mmol) in toluene (5.8mL) was added Bu dropwise₃P (2.20mL, 8.67mmol) and (E) -diazene-1, 2-diylbis (piperidin-1-ylmethanone) (2.20g, 8.67 mmol). The reaction mixture was heated at 50 ℃ for 2 hours and then cooled to room temperature. Hexane (6mL) was added to the mixture; the precipitated white solid was filtered off. The filtrate was concentrated in vacuo. The crude product was chromatographed (80g SiO₂(ii) a Successive gradients of EtOAc in 0% to 50% hexanes over 20 min) gave the title compound (400mg, 1.17mmol, 40.6% yield).¹H NMR(400MHz，CDCl₃)7.28-7.20(m，2H)，6.75-6.64(m，2H)，4.95-4.82(m，1H)，4.52-4.38(m，1H)，2.73-2.58(m，1H)，2.16-2.01(m，2H)，1.98-1.67(m，2H)，1.64-1.49(m，4H)，1.19-1.04(m，6H)。

Intermediate 3D: isopropyl (1S,3S) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) cyclohexane-1-carboxylate

To a mixture of intermediate 3C (1.3G, 3.8mmol), bis-pinacolato diboron (1.5G, 5.8mmol), KOAc (1.15G, 12mmol) in 1, 4-dioxane (8mL) was added Xphos Pd G2 precatalyst (76mg, 0.096mmol) at room temperature. The mixture was heated at 80 ℃ for 16 hours, then cooled to room temperature and usedSaturated aqueous NaHCO₃Washed (20mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried (Na)₂SO₄) And concentrated in vacuo. The crude product was chromatographed (80g SiO₂(ii) a Continuous gradient EtOAc in 0% to 50% hexanes over 20 min) to give the title compound (1.00g, 67%).¹H NMR(400MHz，CDCl₃)7.81-7.71(m，2H)，7.00-6.88(m，2H)，5.09-4.96(m，1H)，4.74-4.62(m，1H)，2.89-2.73(m，1H)，2.11-2.04(m，1H)，1.97-1.86(m，2H)，1.80-1.70(m，1H)，1.67-1.59(m，2H)，1.40-1.34(m，12H)，1.32-1.28(m，2H)，1.27-1.21(m，6H)。

Intermediate 3E: 3- (4- (((1S,3S) -3- (Isopropoxycarbonyl) cyclohexyl) oxy) phenyl) -1, 5-dimethyl-1H-pyrazole-4-carboxylic acid methyl ester

A mixture of intermediate 3D (32mg, 0.082mmol), intermediate 3B (19mg, 0.082mmol) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloro-palladium (II) (7mg, 8. mu. mol) in MeCN (1mL) and water (0.05mL) was stirred in a microwave reactor at 100 ℃ for 1 hour and then cooled to room temperature. The reaction mixture was diluted with water (25mL) and extracted with EtOAc (2 × 50 mL); the combined organic layers were washed with water and brine (50mL each) and dried (Na)₂SO₄) And concentrated in vacuo. The crude product was chromatographed (12g SiO₂(ii) a Successive gradients of EtOAc in 0% to 50% hexanes over 10 min) gave the title compound (20mg, 0.048mmol, 59.2% yield) as a clear oil.

¹H NMR(400MHz，CDCl₃)7.61-7.46(m，2H)，7.08-6.85(m，2H)，5.14-4.94(m，1H)，4.73-4.58(m，1H)，3.90-3.82(m，3H)，3.81-3.70(m，3H)，2.88-2.74(m，1H)，2.62-2.48(m，3H)，2.17-2.03(m，1H)，1.97-1.87(m，3H)，1.84-1.72(m，1H)，1.65-1.53(m，3H)，1.33-1.20(m，6H)。

Intermediate 3

Intermediate 3E (60mg, 0.145mmol) and LiI (97mg, 0.724mmol) in DMF (0.5mL) was heated in a microwave reactor at 180 ℃ for 30 minutes, then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC (C1830 x 100mm column; detection at 220 nm; flow rate 40 mL/min; continuous gradient 0% B to 100% B over 10 min +2min at 100% B residence time, where a is 90:10:0.1H₂O MeCN: TFA, and B90: 10:0.1MeCN: H₂TFA) to give the title compound (20mg, 0.050mmol, 34.5% yield). LCMS, [ M + H ]]⁺＝401.2。

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