阅读说明：本技术 Ask1抑制剂化合物及其用途
(ASK1 inhibitor compounds and uses thereof
) 是由 塞谬尔·大卫·布朗 于 2018-12-31 设计创作，主要内容包括：本文描述了化合物,包括其药学上可接受的盐和溶剂化物,制备此类化合物的方法,包含此类化合物的药物组合物,以及使用此类化合物治疗非酒精性脂肪性肝炎和其他以功能失调的组织愈合和纤维化为特征的疾病的方法。(Described herein are compounds, including pharmaceutically acceptable salts and solvates thereof, methods of preparing such compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat non-alcoholic steatohepatitis and other diseases characterized by dysfunctional tissue healing and fibrosis.)
1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
wherein
Each R1Independently selected from hydrogen, halogen and C1-6An alkyl group;
R2selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
R3Selected from hydrogen, halogen, -CN and C1-6An alkyl group; or R2And R3Combined to form a mixture optionally substituted with one, two or three R 8A phenyl ring substituted with a substituent;
R4selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R5Independently selected from halogen, -CN and C1-6An alkyl group;
R5aselected from hydrogen and C1-6An alkyl group;
each R6Independently selected from hydrogen, C1-6Alkyl, -C1-6alkyl-O-C1-6Alkyl, -C1-6alkyl-C2-9heterocycle-C1-6alkyl-C2-9Heteroaryl group, C3-8Cycloalkyl and C2-9A heterocycle; or two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group;
each R7Independently selected from C1-6Alkyl radical, C3-8Cycloalkyl and C2-9A heterocycle;
each R8Independently selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R) 13)S(＝O)2R13；
Each R13Independently selected from hydrogen, C1-6Alkyl and C3-8A cycloalkyl group; or two R on the same heteroatom13Together with the heteroatom to which they are attached form C2-9A heterocycle;
each R14Independently selected from C1-6Alkyl and C3-8A cycloalkyl group;
p is 0, 1, 2 or 3; and is
q is 0, 1 or 2.
2. The compound of claim 1, having the structure of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
3. the compound of claim 1, having the structure of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:
4. the compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from hydrogen, halogen and C1-6An alkyl group.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is hydrogen.
6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is halogen.
7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is C1-6An alkyl group.
8. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is selected from C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13。
9. The compound of claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is selected from C2-9Heterocycle and C1-9A heteroaryl group; wherein C is2-9Heterocycle and C1-9Heteroaryl is optionally substituted with one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13。
10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is selected from C2-9Heterocycle and C1-9A heteroaryl group; wherein C is2-9Heterocycle and C1-9Heteroaryl is optionally substituted with one or two substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C 2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13。
11. The compound of claim 10, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from the group consisting of halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13。
12. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from halogen, C1-6Alkyl and C3-8A cycloalkyl group.
13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is composed of
Wherein R is11Is C1-6Alkyl or C3-6A cycloalkyl group.
14. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is composed of
Wherein each R12Independently hydrogen, halogen, CN, C1-6Alkyl or C3-6A cycloalkyl group; and is
m is 1 or 2.
15. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
16. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is C optionally substituted by one, two or three substituents6-10Aryl, the substituent being selected from the group consisting of halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13。
17. The compound of claim 16, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is phenyl optionally substituted by one or two substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13。
18. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-6Alkyl, -C1-6alkyl-O-C1-6Alkyl, -C1-6alkyl-C 2-9heterocycle-C1-6alkyl-C2-9Heteroaryl group, C3-8Cycloalkyl and C2-9A heterocycle; or two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group.
19. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is composed of
20. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is composed of
Wherein R is10Is C1-9A heteroaryl group.
21. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is-NHC (═ O) R7。
22. The compound of claim 21, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is composed of
23. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is-C (═ O) R7。
24. The compound of claim 23, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is composed of
25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is hydrogen.
26. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3Is C1-6An alkyl group.
27. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R2And R3Combined to form a mixture optionally substituted with one, two or three R8Phenyl ring substituted by a substituent.
28. The compound of claim 1, having the structure of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
wherein n is 0, 1, 2 or 3.
29. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein
n is 0.
30. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein
n is 1.
31. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein
n is 2.
32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein
R4Is selected from C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C 1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13。
33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein
R4Is selected from C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein said C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13。
34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt or solvate thereof, wherein
R4Is selected from C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein said C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13。
35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, wherein
R4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13。
36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein
R4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles;wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C1-6Alkyl and C3-8A cycloalkyl group.
37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein
R4Is composed of
38. The compound of claim 37, or a pharmaceutically acceptable salt or solvate thereof, wherein
R4Is composed of
39. The compound of claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein
R4Is composed of
40. The compound of claim 38, or a pharmaceutically acceptable salt or solvate thereof, wherein
R4Is composed of
41. The compound of claim 34, or a pharmaceutically acceptable salt or solvate thereof, wherein
R4Is composed of
42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein
43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
44. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed of
45. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed of
46. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed of
47. The compound of any one of claims 44-46, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
48. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed of
49. The compound of claim 48, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5aIs hydrogen.
50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt or solvate thereof, wherein each R1Is hydrogen.
51. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure:
52. a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure:
53. a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure:
54. a pharmaceutical composition comprising a compound of any one of claims 1-53, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
55. A method of treating non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-53, or a pharmaceutically acceptable salt or solvate thereof.
Background
Non-alcoholic steatohepatitis (NASH) is an extreme form of non-alcoholic fatty liver disease (NAFLD) whose condition resembles alcohol-induced liver damage associated with obesity and metabolic syndrome, rather than alcohol abuse. In NAFLD, triglycerides accumulate within the liver cells due to changes in the process of lipid synthesis, storage, movement or clearance, leading to steatosis. Although steatosis itself is generally not at high risk of being affected, in a proportion of NAFLD patients steatosis progresses to a condition involving inflammation, necrosis and fibrosis (hepatitis), a condition known as NASH. These NASH patients suffer from hepatocellular carcinoma (HCC, with a total risk of up to 7.6% in one study) and a significantly increased risk of cirrhosis (total risk of up to 25%), eventually leading to liver failure or death.
Current population-based studies indicate that at least 25% of the us population is afflicted with NAFLD, and about 25% of NAFLD patients will continue to develop NASH, which makes these conditions an important epidemiological factor leading to organ failure and cancer. Since these conditions are associated with obesity and metabolic diseases, their future prevalence may increase.
Disclosure of Invention
In one aspect, described herein are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, that inhibit apoptosis signal-regulated kinase 1(ASK 1).
In another aspect, presented herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
wherein
Is composed of
Each R1Independently selected from hydrogen, halogen and C1-6An alkyl group;
R2selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C 1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
R3Selected from hydrogen, halogen, -CN and C1-6An alkyl group; or R2And R3Combined to form a mixture optionally substituted with one, two or three R8A phenyl ring substituted with a substituent;
R4selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R5Independently selected from halogen, -CN and C1-6An alkyl group;
R5aselected from hydrogen and C1-6An alkyl group;
each R6Independently selected from hydrogen, C1-6Alkyl, -C1-6alkyl-O-C1-6Alkyl, -C1-6alkyl-C2-9heterocycle-C1-6alkyl-C2-9Heteroaryl group, C3-8Cycloalkyl and C2-9A heterocycle; or two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group;
each R7Independently selected from C 1-6Alkyl radical, C3-8Cycloalkyl and C2-9A heterocycle;
each R8Independently selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R13Independently selected from hydrogen, C1-6Alkyl and C3-8A cycloalkyl group; or two R on the same heteroatom13Together with the heteroatom to which they are attached form C2-9A heterocycle;
each R14Independently selected from C1-6Alkyl and C3-8A cycloalkyl group;
p is 0, 1, 2 or 3; and is
q is 0, 1 or 2.
In some embodiments are compounds of formula (I) having the structure of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
in some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ib):
in some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from hydrogen, halogen or C1-6An alkyl group. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is hydrogen. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2Is halogen. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is C1-6An alkyl group. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C2-9Heterocycle and C1-9A heteroaryl group; wherein C is2-9Heterocycle and C1-9Heteroaryl is optionally substituted with one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl group、C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2Is selected from C2-9Heterocycle and C1-9A heteroaryl group; wherein C is2-9Heterocycle and C1-9Heteroaryl is optionally substituted with one or two substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from the group consisting of halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from halogen, C1-6Alkyl and C3-8A cycloalkyl group. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2Is composed of
Wherein R is
11Is C
1-6Alkyl or C
3-6A cycloalkyl group. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
Wherein each R
12Independently hydrogen, halogen, CN, C
1-6Alkyl or C
3-6A cycloalkyl group; and m is 1 or 2. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines. In some embodiments, R
2Is C optionally substituted by one, two or three substituents
6-10Aryl, the substituent being selected from the group consisting of halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is phenyl optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2is-C (═ O) N (R)
6)
2And each R
6Independently selected from hydrogen, C
1-6Alkyl, -C
1-6alkyl-O-C
1-6Alkyl, -C
1-6alkyl-C
2-9heterocycle-C
1-6alkyl-C
2-9Heteroaryl group, C
3-8Cycloalkyl and C
2-9A heterocycle; or two R on the same heteroatom
6Together with the heteroatom to which they are attached form C
2-9Heterocyclic or C
2-9A heteroaryl group. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
Wherein R is10Is C1-9A heteroaryl group. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is-NHC (═ O) R7. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is composed of In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is-C (═ O) R7. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is composed of
In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
3Is hydrogen. In some embodiments are compounds of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2And R
3Combined to form a mixture optionally substituted with one, two or three R
8Phenyl ring substituted by a substituent.
In some embodiments are compounds of formula (I) having the structure of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
wherein n is 0, 1, 2 or 3.
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is4Is selected from C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C 1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is4Is selected from C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein said C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl radical、-C(＝O)R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is4Is selected from C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein said C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is 4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C1-6Alkyl and C3-8A cycloalkyl group. In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is4Is composed of
In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
4Is composed of
In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
4Is composed of
In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
4Is composed of
In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
4Is composed of
In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, which In
Is composed of
In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
5aIs hydrogen. In some embodiments are compounds of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is
1Is hydrogen.
In another aspect, described herein is a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
In another aspect, described herein is a method of treating non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), or (Ic), or a therapeutically effective amount of a pharmaceutically acceptable salt or solvate thereof.
Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.
Detailed Description
Apoptosis signal-regulated kinase 1(ASK1) is a ubiquitously expressed, serine/threonine-selective kinase of 1375 amino acids, a member of the mitogen-activated protein kinase (MAPK) family.
The MAPK pathway is one of the intracellular signaling systems that regulates essential cellular functions such as proliferation, motility, differentiation, stress response and apoptosis. Each MAPK pathway consists of three classes of protein kinases: MAPK kinase (MAP3K), MAPK kinase (MAP2K) and MAPK. MAP3K phosphorylates and therefore activates MAP2K, whereas activated MAP2K in turn phosphorylates and activates MAPK. Activated MAPK then translocates to the nucleus and regulates the activity of transcription factors to control gene expression.
ASK1 is a membrane proximal MAP3K (MAP-kinase) upstream of the pathway that plays an important role in the response of cells to environmental stress (e.g., the c-Jun and p38 pathways, which are known to respond to UV and oxidative damage), is a promising therapeutic target for NASH. ASK1, a positive regulator of mitochondrial apoptosis, is strictly regulated and activated by various cell injury signals such as inflammatory cytokines (e.g., TNFa and LPS), calcium, and intracellular sensors (e.g., redox sensors, thioredoxin and ER stress-responsive IRE1) acting on receptors.
Consistent with this role as an effector of stress signaling, ASK1 has been shown to be an important mediator of pathologically stress-induced liver tissue remodeling. In a mouse model of non-alcoholic liver injury, ASK 1-deficient mice exhibited resistance to diet-induced steatohepatitis and subsequent fibrosis. Human data are consistent with this role in guiding the response to diet-induced liver injury; ASK1 inhibitors (e.g., small molecule celecoxib (selonsertib)/GS-4997 in clinical trial NCT 02466516) have recently shown utility in phase II trials for nonalcoholic steatohepatitis (NASH) in affected patients, while NASH patients show up-regulation of ASK1 activity in a separate molecular assay.
Certain terms
Unless otherwise indicated, the terms used in this application (including the specification and claims) have the definitions given below. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The use of "or" and "means" and/or "unless stated otherwise. The terms "including" and other forms and equivalents, such as "comprises," "comprising," and "having," are not limiting; it is not intended to exclude what is excluded by the terms "consisting of … …" or "consisting essentially of … …". The section headings used herein are for organizational purposes only and are not to be construed as limiting the disclosure herein.
C1-xComprising C1-2、C1-3...C1-xWherein x is an integer. C1-xRefers to the number of carbon atoms in a given group (excluding optional substituents).
"amino" means-NH2A group.
"cyano" refers to the group-CN.
"nitro" means-NO2A group.
"oxa" refers to an-O-group.
"oxo" refers to an ═ O group.
"thio" refers to ═ S groups.
"imino" refers to an ═ N-H group.
"oximino" refers to the group ═ N-OH.
"alkyl" or "alkylene" refers to a compound consisting only of carbon and hydrogen atoms, free of unsaturation, having from 1 to 15 carbon atoms (e.g., C)1-15Alkyl) or a branched or unbranched hydrocarbon chain group. In certain embodiments, the alkyl group contains 1-13 carbon atoms (e.g., C)1-13Alkyl groups). In certain embodiments, the alkyl group contains 1 to 8 carbon atoms (e.g., C)1-8Alkyl groups). In other embodiments, the alkyl group contains 1 to 6 carbon atoms (e.g., C)1-6Alkyl groups). In other embodiments, the alkyl group contains 1 to 5 carbon atoms (e.g., C)1-5Alkyl groups). In other embodiments, the alkyl group contains 1 to 4 carbon atoms (e.g., C)1-4Alkyl groups). In other embodiments, the alkyl group contains 1 to 3 carbon atoms (e.g., C)1-3Alkyl groups). In other embodiments, the alkyl group contains 1 to 2 carbon atoms (e.g., C) 1-2Alkyl groups). In other embodiments, the alkyl group contains one carbon atom (e.g., C)1Alkyl groups). In other embodiments, the alkyl group contains 5 to 15 carbon atoms (e.g., C)5-15Alkyl groups). In other embodiments, the alkyl group contains 5 to 8 carbon atoms (e.g., C)5-8Alkyl groups). In other embodiments, the alkyl group contains 2 to 5 carbon atoms (e.g., C)2-5Alkyl groups). In other embodimentsIn embodiments, the alkyl group contains 3 to 5 carbon atoms (e.g., C)3-5Alkyl groups). In other embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specifically stated in the specification, an alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oximo (oximo), trimethylsilyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, -ORa、-SRa、-OC(O)-Rf、-N(Ra)2、-C(O)Ra、-C(O)ORa、-C(O)N(Ra)2、-N(Ra)C(O)ORf、-OC(O)-NRaRf、-N(Ra)C(O)Rf、-N(Ra)S(O)tRf(wherein t is 1 or 2), -S (O)tORa(wherein t is 1 or 2), -S (O)tRf(wherein t is 1 or 2) and-S (O) tN(Ra)2(wherein t is 1 or 2) wherein each RaIndependently is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each RfIndependently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl group.
"alkoxy" refers to a group bonded through an oxygen atom of the formula-O-alkyl, wherein alkyl is an alkyl chain as defined above.
"alkenyl" or "alkenylene" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, alkenyl groups contain 2 to 8 carbon atoms. In other embodiments, alkenyl groups contain 2 to 4 carbon atoms. The alkenyl group being linked to the remainder of the molecule by a single bond, e.g. vinyl, prop-1-enyl (i.e. allyl), but-1-enyl, pent-1, 4-Dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oximo (oximo), trimethylsilyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, -OR a、-SRa、-OC(O)-Rf、-N(Ra)2、-C(O)Ra、-C(O)ORa、-C(O)N(Ra)2、-N(Ra)C(O)ORf、-OC(O)-NRaRf、-N(Ra)C(O)Rf、-N(Ra)S(O)tRf(wherein t is 1 or 2), -S (O)tORa(wherein t is 1 or 2), -S (O)tRf(wherein t is 1 or 2) and-S (O)tN(Ra)2(wherein t is 1 or 2) wherein each RaIndependently is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each RfIndependently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl group.
"alkynyl" or "alkynylene" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from 2 to 12 carbon atoms. In certain embodiments, alkynyl groups contain 2 to 8 carbon atoms. In other embodiments, alkynyl groups have 2 to 4 carbon atoms. The alkynyl group is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, alkynyl groups are optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oximo (oximo), trimethylsilyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, -OR a、-SRa、-OC(O)-Rf、-N(Ra)2、-C(O)Ra、-C(O)ORa、-C(O)N(Ra)2、-N(Ra)C(O)ORf、-OC(O)-NRaRf、-N(Ra)C(O)Rf、-N(Ra)S(O)tRf(wherein t is 1 or 2), -S (O)tORa(wherein t is 1 or 2), -S (O)tRf(wherein t is 1 or 2) and-S (O)tN(Ra)2(wherein t is 1 or 2) wherein each RaIndependently is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each RfIndependently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl group.
"cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having from 3 to 15 carbon atoms. In certain embodiments, cycloalkyl groups contain 3 to 10 carbon atoms. In other embodiments, the cycloalkyl group contains 5 to 7 carbon atoms. The cycloalkyl group is attached to the rest of the molecule by a single bond. Cycloalkyl groups are saturated (i.e., contain only a single C-C bond) or partially unsaturated (i.e., contain one or more double or triple bonds). Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, cycloalkyl contains 3 to 8 carbon atoms (e.g., C)3-8Cycloalkyl groups). In other embodiments, the cycloalkyl group contains 3 to 7 carbon atoms (e.g., C) 3-7Cycloalkyl groups). In other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms (e.g., C)3-6Cycloalkyl groups). In other embodiments, the cycloalkyl group contains 3 to 5 carbon atoms (e.g., C)3-5Cycloalkyl groups). In other embodiments, the cycloalkyl group contains 3 to 4 carbon atoms (e.g., C)3-4Cycloalkyl groups). Partially unsaturated cycloalkyl groups, if they contain one or more double bonds, are also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo [ 2.2.1)]Heptylalkyl), norbornenyl, decahydronaphthyl, 7-dimethyl-bicyclo [2.2.1 ]]Heptalkyl, and the like. Except as described hereinAs otherwise specified in the specification, the term "cycloalkyl" is intended to include cycloalkyl groups optionally substituted with one or more substituents selected from: alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa、-Rb-OC(O)-Ra、-Rb-OC(O)-ORa、-Rb-OC(O)-N(Ra)2、-Rb-N(Ra)2、-Rb-C(O)Ra、-Rb-C(O)ORa、-Rb-C(O)N(Ra)2、-Rb-O-Rc-C(O)N(Ra)2、-Rb-N(Ra)C(O)ORa、-Rb-N(Ra)C(O)Ra、-Rb-N(Ra)S(O)tRa(wherein t is 1 or 2), -Rb-S(O)tORa(wherein t is 1 or 2), -R b-S(O)tRa(wherein t is 1 or 2) and-Rb-S(O)tN(Ra)2(wherein t is 1 or 2) wherein each RaIndependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, each RbIndependently is a direct bond or a linear or branched alkylene or alkenylene chain, and RcIs a linear or branched alkylene or alkenylene chain.
"aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by the removal of a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from 6 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e. it comprises a cyclic, delocalized (4n +2) pi-electron system according to houckel theory. Ring systems from which the aryl group is derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "aryl" (as in "aralkyl") is intended to include optionallyAn aryl group substituted with one or more substituents selected from: alkyl, alkenyl, alkynyl, halogen, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b-ORa、-Rb-OC(O)-Ra、-Rb-OC(O)-ORa、-Rb-OC(O)-N(Ra)2、-Rb-N(Ra)2、-Rb-C(O)Ra、-Rb-C(O)ORa、-Rb-C(O)N(Ra)2、-Rb-O-Rc-C(O)N(Ra)2、-Rb-N(Ra)C(O)ORa、-Rb-N(Ra)C(O)Ra、-Rb-N(Ra)S(O)tRa(wherein t is 1 or 2), -Rb-S(O)tORa(wherein t is 1 or 2), -Rb-S(O)tRa(wherein t is 1 or 2) and-Rb-S(O)tN(Ra)2(wherein t is 1 or 2) wherein each RaIndependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, each RbIndependently is a direct bond or a linear or branched alkylene or alkenylene chain, and RcIs a linear or branched alkylene or alkenylene chain.
"aryloxy" refers to a group bonded through an oxygen atom of the formula-O-aryl, wherein aryl is as defined above.
"aralkyl" means a group of the formula-Rc-a radical of an aryl radical, wherein RcIs an alkylene chain as defined above, e.g., methylene, ethylene, and the like. The alkylene chain portion of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for aryl.
"aralkyloxy" refers to a group bonded through an oxygen atom of the formula-O-aralkyl, wherein aralkyl is as defined above.
"aralkenyl" means a group of formula-Rd-a radical of an aryl radical, wherein RdIs an alkenylene chain as defined above. The aryl moiety of the aralkenyl group is optionally substituted as described above for aryl. The alkenylene chain portion of the aralkenyl group is optionally substituted as defined above for alkenylene.
"aralkynyl" means the formula-Re-a radical of an aryl radical, wherein ReIs an alkynylene chain as defined above. The aryl moiety of the arylalkynyl group is optionally substituted as described above for aryl. The alkynylene chain portion of the arylalkynyl group is optionally substituted as defined above for the alkynylene chain.
"heterocycloalkyl" refers to a stable 3 to 18 membered non-aromatic cyclic group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in the specification, a heterocycloalkyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, including fused, spiro, or bridged ring systems. The heteroatoms in the heterocycloalkyl group are optionally oxidized. In some embodiments, sulfur, if present, is substituted with — S-, -S (═ O) -or-S (═ O)2-in the form. If one or more nitrogen atoms are present, they are optionally quaternized. Heterocycloalkyl groups are fully saturated or partially unsaturated. In some embodiments, the heterocycloalkyl group is attached to the remainder of the molecule through any atom in the ring. Examples of such heterocycloalkyl groups include, but are not limited to, 1-dioxothiomorpholinyl, 1,2,3, 6-tetrahydropyridinyl, 1, 3-dioxolanyl, 1-oxothiomorpholinyl, 2H-pyranyl, 4H-pyranyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 3-azabicyclo [3.1.0 ]Hexyl, 3-azabicyclo [4.1.0]Heptyl, 3H-indolyl, 4-piperidinonyl, azetidinyl, aziridinyl, decahydroisoquinolinyl, diazaA group selected from the group consisting of a dihydrofuryl group, a dihydropyranyl group, a dihydrothienyl group, a dioxanyl group, a dioxolanyl group, a dithianyl group, a dithiacyclopentane group, a homopiperidinyl group, an imidazolidinyl group, an imidazolinyl group, an indolinyl group, an isothiazolinyl group, an isoxazolidinyl group, a dihydrofuranyl group, a dihydropyranyl group, a dihydrothienyl group, a dioxanyl group, a dioxolanyl group, a,Morpholinyl, octahydroindolyl, octahydroisoindolyl, oxaza
A group, an oxazolidonogroup, an oxazolidinyl group, an oxepanyl group, an oxetanyl group, a piperazinyl group, a piperidinyl group, a pyrazolidinyl group, a pyrazolinyl group, a pyrrolidinyl group, a pyrrolin-2-yl group, a pyrrolin-3-yl group, a quinolizinyl group, a quinuclidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a tetrahydrothienyl group, a tetrahydrothiopyranyl group, a thiaza group
Alkyl, thiazolidinyl, thienyl [1,3 ]]Dithianyl, thiepanyl, thietanyl, thiomorpholinyl, thiadecyl, and trithiahexonyl. Unless otherwise specifically stated in the specification, the term "heterocycloalkyl" is intended to include heterocycloalkyl groups as defined above optionally substituted with one or more substituents selected from: alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R
b-OR
a、-R
b-OC(O)-R
a、-R
b-OC(O)-OR
a、-R
b-OC(O)-N(R
a)
2、-R
b-N(R
a)
2、-R
b-C(O)R
a、-R
b-C(O)OR
a、-R
b-C(O)N(R
a)
2、-R
b-O-R
c-C(O)N(R
a)
2、-R
b-N(R
a)C(O)OR
a、-R
b-N(R
a)C(O)R
a、-R
b-N(R
a)S(O)
tR
a(wherein t is 1 or 2), -R
b-S(O)
tOR
a(wherein t is 1 or 2), -R
b-S(O)
tR
a(wherein t is 1 or 2) and-R
b-S(O)
tN(R
a)
2(wherein t is 1 or 2) wherein each R
aIndependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroCycloalkyl, heteroaryl or heteroarylalkyl, each R
bIndependently is a direct bond or a linear or branched alkylene or alkenylene chain, and R
cIs a linear or branched alkylene or alkenylene chain.
"heteroaryl" refers to a stable 3 to 18 membered aromatic ring group containing 1 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it comprises a cyclic, delocalized (4n +2) pi-electron system according to houckel's theory. Heteroaryl groups include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. In some embodiments, sulfur, if present, is substituted with — S-, -S (═ O) -or-S (═ O)2-in the form. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl group is attached to the rest of the molecule through any atom in the ring. Examples of such heteroaryl groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, furazanyl, furopyridinyl, furanyl, imidazolyl, indazolyl, indolizinyl, indolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, and triazolyl.
Illustrative examples of heteroaryl structures include groups corresponding to the following compounds (attached via C or N, as described below):
unless otherwise indicated in the specificationIn particular, the term "heteroaryl" is intended to include heteroaryl groups as defined above optionally substituted with one or more substituents selected from: alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa、-Rb-OC(O)-Ra、-Rb-OC(O)-ORa、-Rb-OC(O)-N(Ra)2、-Rb-N(Ra)2、-Rb-C(O)Ra、-Rb-C(O)ORa、-Rb-C(O)N(Ra)2、-Rb-O-Rc-C(O)N(Ra)2、-Rb-N(Ra)C(O)ORa、-Rb-N(Ra)C(O)Ra、-Rb-N(Ra)S(O)tRa(wherein t is 1 or 2), -Rb-S(O)tORa(wherein t is 1 or 2), -Rb-S(O)tRa(wherein t is 1 or 2) and-Rb-S(O)tN(Ra)2(wherein t is 1 or 2) wherein each RaIndependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, each RbIndependently is a direct bond or a linear or branched alkylene or alkenylene chain, and RcIs a linear or branched alkylene or alkenylene chain.
In some embodiments, the heterocycloalkyl or heteroaryl is attached to the carbon by a bond. In some embodiments, the heterocycloalkyl or heteroaryl is attached to the nitrogen by a bond. For example, in some embodiments, the heteroaryl pyrrolyl is linked to the nitrogen, pyrrol-1-yl, and in some embodiments, it is linked to the carbon, pyrrol-2-yl or pyrrol 3-yl by a bond.
"N-heterocycloalkyl" and "N-heteroaryl" refer to heterocycloalkyl and heteroaryl groups, respectively, as defined above that contain at least one nitrogen, and wherein the point of attachment of the heterocycloalkyl or heteroaryl group to the rest of the molecule is through the nitrogen atom in the heterocycloalkyl or heteroaryl group. The N-heterocycloalkyl or N-heteroaryl group is optionally substituted as described above for the heterocycloalkyl or heteroaryl group.
"C-heterocycloalkyl" and "C-heteroaryl" refer to heterocycloalkyl and heteroaryl groups, respectively, as defined above, and wherein the point of attachment of the heterocycloalkyl or heteroaryl group to the remainder of the molecule is through a carbon atom in the heterocycloalkyl or heteroaryl group. The C-heterocycloalkyl or C-heteroaryl group is optionally substituted as described above for the heterocycloalkyl or heteroaryl group.
"heteroaryloxy" refers to a group of formula-O-heteroaryl bonded through an oxygen atom, wherein heteroaryl is as defined above.
"Heteroarylalkyl" means a compound of the formula-Rc-a radical of heteroaryl, wherein RcIs an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkyl group is optionally substituted as defined above for heteroaryl.
"Heteroarylalkoxy" means a compound of the formula-O-Rc-a group of heteroaryl groups bonded via an oxygen atom, wherein RcIs an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkoxy group is optionally substituted as defined above for heteroaryl.
The term "halogen" or "halo" or "halide" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). In some embodiments, halogen is F or Cl. In some embodiments, halogen is F.
"haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above.
"haloalkoxy" means an alkoxy group as defined above substituted with one or more halo groups as defined above.
"fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl portion of the fluoroalkyl group is optionally substituted as described above for alkyl.
The term "bond" or "single bond" refers to a chemical bond between two atoms, or, when the atoms to which the bond is attached are considered part of a larger substructure, between two moieties. In one aspect, when a group described herein is a bond, the group referred to is absent, thereby allowing formation of a bond between the remaining defined groups.
The term "moiety" or "group" refers to a particular segment or functional group of a molecule. Chemical moieties are often considered chemical entities contained in or attached to a molecule.
The term "optionally substituted" or "substituted" means that the group referred to may be substituted with one or more additional groups individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halogen, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, and amino (including mono-and di-substituted amino), and protected derivatives thereof. In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH 2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl, -C (═ O) NH2-C (═ O) NH (alkyl), -C (═ O) N (alkyl)2、-S(＝O)2NH2、-S(＝O)2NH (alkyl), -S (═ O)2N (alkyl)2Alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthioAlkyl sulfoxides, aryl sulfoxides, alkyl sulfones, and aryl sulfones. In some embodiments, the optional substituents are independently selected from halogen, -CN, -NH2、-OH、-NH(CH3)、-N(CH3)2、-CH3、-CH2CH3、-CF3、-OCH3and-OCF3. In some embodiments, a substituted group is substituted with one or more of the foregoing groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic, saturated or unsaturated carbon atoms, except for aromatic carbon atoms) include oxo (═ O).
In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms defined as (R) -or (S) -according to absolute stereochemistry. Unless otherwise indicated, the present disclosure is intended to refer to all stereoisomeric forms of the compounds disclosed herein. If desired, the stereoisomers or mixtures enriched in a particular stereoisomer may be obtained by methods such as stereoselective synthesis and/or separation of stereoisomers by known methods, including the use of chiral chromatographic columns. When the compounds described herein contain olefinic double bonds, the present invention is intended to include both E and Z geometric isomers (e.g., cis or trans), unless otherwise indicated. Likewise, all possible isomers are also intended to be included, as well as racemic and optically pure forms thereof, and all tautomeric forms. The term "geometric isomer" refers to an E or Z geometric isomer (e.g., cis or trans) of an olefinic double bond. The term "positional isomers" refers to structural isomers around a central ring, such as the ortho, meta, and para isomers around the phenyl ring.
"tautomer" refers to molecules in which it is possible for a proton to move from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerism is likely to occur, there will be a chemical equilibrium of the tautomers. The exact ratio of tautomers depends on several factors including physical state, temperature, solvent and pH. Some examples of tautomeric equilibrium include:
"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and that the description includes both substituted aryl groups and unsubstituted aryl groups.
The methods and formulations described herein include the use of N-oxides (if appropriate) or pharmaceutically acceptable salts of compounds having the structure of formula (I), (Ia), (Ib) or (Ic), as well as active metabolites of these compounds having the same type of activity. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In other embodiments, the compounds described herein exist in unsolvated forms.
"pharmaceutically acceptable salts" include acid addition salts and base addition salts. The pharmaceutically acceptable salts of any of the pyrazole compounds described herein are intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, and the like. Also included are salts formed with the following organic acids: such as aliphatic mono-and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, malate, tartrate, mesylate, and the like. Also contemplated are Salts of amino acids such as arginate, gluconate, and galacturonate (see, e.g., Berge S.M et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science,66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.
"pharmaceutically acceptable base addition salts" refers to those salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from organic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, the following salts of organic bases: primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine (theobromine), purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al, supra.
The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no lasting adverse effect on the general health of the subject being treated.
The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof and an adjuvant (co-agent), are both administered to the patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that the active ingredients, e.g. a compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof and the co-agents, are administered to a patient as separate entities either simultaneously, together or sequentially with no specific intervening time constraints, wherein such administration provides effective levels of both compounds in the patient. The latter is also applicable to cocktail therapies, e.g., administration of three or more active ingredients.
The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalia class: humans, non-human primates, such as chimpanzees, and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.
The terms "treat," "treating," or "treatment" as used herein include alleviating, or ameliorating at least one symptom of a disease or condition, preventing an additional symptom, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, relieving a condition caused by a disease or condition, or stopping a symptom of a disease or condition prophylactically and/or therapeutically.
Compound (I)
In some embodiments, presented herein are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
wherein
Is composed of
Each R1Independently selected from hydrogen, halogen and C1-6An alkyl group;
R2selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl optionally substituted by one, twoSubstituted by one or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
R3Selected from hydrogen, halogen, -CN and C 1-6An alkyl group; or R2And R3Combined to form a mixture optionally substituted with one, two or three R8A phenyl ring substituted with a substituent;
R4selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R5Independently selected from halogen, -CN and C1-6An alkyl group;
R5aselected from hydrogen and C1-6An alkyl group;
each R6Independently selected from hydrogen, C1-6Alkyl, -C1-6alkyl-O-C1-6Alkyl, -C1-6alkyl-C2-9heterocycle-C1-6alkyl-C2-9Heteroaryl group, C3-8Cycloalkyl and C2-9A heterocycle; or two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group;
each R7Independently selected from C1-6Alkyl radical, C3-8Cycloalkyl and C2-9A heterocycle;
each R8Independently selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C 3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R13Independently selected from hydrogen, C1-6Alkyl and C3-8A cycloalkyl group; or two R on the same heteroatom13Together with the heteroatom to which they are attached form C2-9A heterocycle;
each R14Independently selected from C1-6Alkyl and C3-8A cycloalkyl group;
p is 0, 1, 2 or 3; and is
q is 0, 1 or 2.
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1Is hydrogen. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein one R1Is hydrogen and one R1Is C1-6An alkyl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1Is C1-6An alkyl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1Is halogen.
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from hydrogen, halogen and C1-6An alkyl group.
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2Is hydrogen.
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is halogen.
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is C1-6An alkyl group.
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl optionally substituted with one, two or three substituentsThe radicals being selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C2-9Heterocycle and C1-9A heteroaryl group; wherein C is2-9Heterocycle and C1-9Heteroaryl is optionally substituted with one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C 2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C2-9Heterocycle and C1-9A heteroaryl group; wherein C is2-9Heterocycle and C1-9Heteroaryl is optionally substituted with one or two substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from the group consisting of halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from halogen, C 1-6Alkyl and C3-8A cycloalkyl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is composed of
Wherein R is
11Is C
1-6Alkyl or C
3-6A cycloalkyl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
Wherein each R
12Independently hydrogen, halogen, CN, C
1-6Alkyl orC
3-6A cycloalkyl group; and m is 1 or 2. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines. In some embodiments, R
2Is C optionally substituted by one, two or three substituents
6-10Aryl, the substituent being selected from the group consisting of halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is phenyl optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2is-C (═ O) N (R)
6)
2And each R
6Independently selected from hydrogen, C
1-6Alkyl, -C
1-6alkyl-O-C
1-6Alkyl, -C
1-6alkyl-C
2-9heterocycle-C
1-6alkyl-C
2-9Heteroaryl group, C
3-8Cycloalkyl and C
2-9A heterocycle; or two R on the same heteroatom
6Together with the heteroatom to which they are attached form C
2-9Heterocyclic or C
2-9A heteroaryl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
Wherein R is
10Is C
1-9A heteroaryl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2is-NHC (═ O) R
7. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2is-C (═ O) R
7. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is hydrogen. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is C1-6An alkyl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is halogen.
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 2. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 1. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 0. In some casesIn one embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Selected from the group consisting of triazoles, imidazoles, and combinations thereof,Oxazole, isoxazole, oxadiazole and tetrazole; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are of formula (I) Or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed ofIn some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole moieties areOptionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments of formula (I)) A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed ofIn some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed ofAnd q is 2. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodimentsIs a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected fromC
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radicals、C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments, presented herein are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
wherein
Is composed of
Each R1Independently selected from hydrogen, halogen and C1-6An alkyl group;
R2selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R) 13)S(＝O)2R13；
R3Selected from hydrogen, halogen, -CN and C1-6An alkyl group; or R2And R3Combined to form a mixture optionally substituted with one, two or three R8A phenyl ring substituted with a substituent;
R4selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R5Independently selected from halogen, -CN and C1-6An alkyl group;
R5aselected from hydrogen and C1-6An alkyl group;
each R6Independently selected from hydrogen, C1-6Alkyl, -C1-6alkyl-O-C1-6Alkyl, -C1-6alkyl-C2-9heterocycle-C1-6alkyl-C2-9Heteroaryl group, C3-8Cycloalkyl and C2-9A heterocycle; or two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group;
each R7Independently selected from C1-6Alkyl radical, C3-8Cycloalkyl and C2-9A heterocycle;
each R8Independently selected from halogen, -CN, C1-6Alkyl, -C 1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R13Independently selected from hydrogen, C1-6Alkyl and C3-8A cycloalkyl group; or two R on the same heteroatom13Together with the heteroatom to which they are attached form C2-9A heterocycle;
each R14Independently selected from C1-6Alkyl and C3-8A cycloalkyl group;
p is 0, 1, 2 or 3; and is
q is 0, 1 or 2.
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is1Is hydrogen. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein one R1Is hydrogen and one R1Is C1-6An alkyl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is1Is C1-6An alkyl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is1Is halogen.
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from hydrogen, halogen and C1-6An alkyl group.
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2Is hydrogen.
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is halogen.
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is C1-6An alkyl group.
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C3-8CycloalkanesBase, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C2-9Heterocycle and C1-9A heteroaryl group; wherein C is2-9Heterocycle and C1-9Heteroaryl is optionally substituted with one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C 2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C2-9Heterocycle and C1-9A heteroaryl group; wherein C is2-9Heterocycle and C1-9Heteroaryl is optionally substituted with one or two substituents selected from halogen, -CN, C1-6Alkyl radical、-C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from the group consisting of halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from halogen, C 1-6Alkyl and C3-8A cycloalkyl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is composed of
Wherein R is
11Is C
1-6Alkyl or C
3-6A cycloalkyl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
Wherein each R
12Independently hydrogen, halogen, CN, C
1-6Alkyl or C
3-6A cycloalkyl group; and m is 1 or 2. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines. In some embodiments, R
2Is C optionally substituted by one, two or three substituents
6-10Aryl, the substituent being selected from the group consisting of halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is phenyl optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments is a compound of formula (Ia), orA pharmaceutically acceptable salt or solvate thereof, wherein R
2is-C (═ O) N (R)
6)
2And each R
6Independently selected from hydrogen, C
1-6Alkyl, -C
1-6alkyl-O-C
1-6Alkyl, -C
1-6alkyl-C
2-9heterocycle-C
1-6alkyl-C
2-9Heteroaryl group, C
3-8Cycloalkyl and C
2-9A heterocycle; or two R on the same heteroatom
6Together with the heteroatom to which they are attached form C
2-9Heterocyclic or C
2-9A heteroaryl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
Wherein R is
10Is C
1-9A heteroaryl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2is-NHC (═ O) R
7. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt thereofOr a solvate thereof, wherein R
2is-C (═ O) R
7. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is hydrogen. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is C1-6An alkyl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is halogen.
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 2. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 1. In some embodimentsIs a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 0. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia)Or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt thereofAn acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof,wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt thereofA salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed ofIn some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl radicalAnd condensed C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some casesIn an embodiment is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments, presented herein are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:
wherein
Is composed of
Each R1Independently selected from hydrogen, halogen and C1-6An alkyl group;
R2selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R 14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
R3Selected from hydrogen, halogen, -CN and C1-6An alkyl group; or R2And R3Combined to form a mixture optionally substituted with one, two or three R8A phenyl ring substituted with a substituent;
R4selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R5Independently selected from halogen, -CN and C1-6An alkyl group;
R5aselected from hydrogen and C1-6An alkyl group;
each R6Independently selected from hydrogen, C1-6Alkyl, -C1-6alkyl-O-C1-6Alkyl, -C1-6alkyl-C2-9heterocycle-C1-6alkyl-C2-9Heteroaryl group, C3-8Cycloalkyl and C2-9A heterocycle; or two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group;
each R7Independently selected from C1-6Alkyl radical, C3-8Cycloalkyl and C2-9A heterocycle;
each R8Independently selected from halogen, -CN, C 1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R13Independently selected from hydrogen, C1-6Alkyl and C3-8A cycloalkyl group; or two R on the same heteroatom13Together with the heteroatom to which they are attached form C2-9A heterocycle;
each R14Independently selected from C1-6Alkyl and C3-8A cycloalkyl group;
p is 0, 1, 2 or 3; and is
q is 0, 1 or 2.
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is1Is hydrogen. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein one R1Is hydrogen and one R1Is C1-6An alkyl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is1Is C1-6An alkyl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is1Is halogen.
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from hydrogen, halogen and C1-6An alkyl group.
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2Is hydrogen.
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is halogen.
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is C1-6An alkyl group.
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C2-9Heterocycle and C1-9A heteroaryl group; wherein C is2-9Heterocycle and C1-9Heteroaryl is optionally substituted with one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C 2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is selected from C2-9Heterocycle and C1-9A heteroaryl group; wherein C is2-9Heterocycle and C1-9Heteroaryl is optionally substituted with one or two substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from the group consisting of halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents Radical is selected from halogen, C1-6Alkyl and C3-8A cycloalkyl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is composed of
Wherein R is
11Is C
1-6Alkyl or C
3-6A cycloalkyl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
Wherein each R
12Independently hydrogen, halogen, CN, C
1-6Alkyl or C
3-6A cycloalkyl group; and m is 1 or 2. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines. In some embodiments, R
2Is C optionally substituted by one, two or three substituents
6-10Aryl, the substituent being selected from the group consisting of halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is phenyl optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2is-C (═ O) N (R)
6)
2And each R
6Independently selected from hydrogen, C
1-6Alkyl, -C
1-6alkyl-O-C
1-6Alkyl, -C
1-6alkyl-C
2-9heterocycle-C
1-6alkyl-C
2-9Heteroaryl group, C
3-8Cycloalkyl and C
2-9A heterocycle; or two R on the same heteroatom
6Together with the heteroatom to which they are attached form C
2-9Heterocyclic or C
2-9A heteroaryl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
Wherein R is
10Is C
1-9A heteroaryl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2is-NHC (═ O) R
7. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2is-C (═ O) R
7. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R
2Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is hydrogen. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is C1-6An alkyl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is halogen.
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 2. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 1. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 0. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl optionallySubstituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodimentsA compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted with one or two substituents selected from halogen, -CN, C,C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from triazoles and imidazolesOxazoles, isoxazoles, oxadiazoles and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments is a compound of formula (Ib)A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein triazole and imidazoleOxazole, isoxazole oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof,wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments of formula (I) b) A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or moreSubstituted by two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof Wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed ofIn some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments is a compound of formula (Ib)A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionallySubstituted by one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments is a compound of formula (Ib), orA pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereofWherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments, presented herein are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
wherein
Is composed of
Each R1Independently selected from hydrogen, halogen and C 1-6An alkyl group;
R4selected from hydrogen, halogen, -CN, -OH, -OR6、-SR6、-S(＝O)R7、-NO2、-N(R6)2、-S(＝O)2R7、-NHS(＝O)2R7、-S(＝O)2N(R6)2、-C(＝O)R7、-C(＝O)OR6、-OC(＝O)R7、-C(＝O)N(R6)2、-OC(＝O)N(R6)2、-NR6C(＝O)N(R6)2、-NR6C(＝O)R7、-NR6C(＝O)OR6、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R5Independently selected from halogen, -CN and C1-6An alkyl group;
R5aselected from hydrogen and C1-6An alkyl group;
each R6Independently selected from hydrogen, C1-6Alkyl, -C1-6alkyl-O-C1-6Alkyl, -C1-6alkyl-C2-9heterocycle-C1-6alkyl-C2-9Heteroaryl group, C3-8Cycloalkyl and C2-9A heterocycle; or two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group;
each R7Independently selected from C1-6Alkyl radical, C3-8Cycloalkyl and C2-9A heterocycle;
each R8Independently selected from halogen, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ O) R14、-C(＝O)OR13、-C(＝O)N(R13)2、-S(＝O)R14、-S(＝O)2R13、-S(＝O)2-N(R13)2、-N(R13)2、-N(R13)C(＝O)R14and-N (R)13)S(＝O)2R13；
Each R13Independently selected from hydrogen, C 1-6Alkyl and C3-8A cycloalkyl group; or two R on the same heteroatom13Together with the heteroatom to which they are attached form C2-9A heterocycle;
each R14Independently selected from C1-6Alkyl and C3-8A cycloalkyl group;
n is 0, 1, 2 or 3;
p is 0, 1, 2 or 3; and is
q is 0, 1 or 2.
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, whichEach R in1Is hydrogen. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein one R is1Is hydrogen and one R1Is C1-6An alkyl group. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is1Is C1-6An alkyl group. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R is1Is halogen.
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3.
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R is8Independently selected from halogen, C1-6Alkyl and C1-6A haloalkyl group. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R8Is halogen. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R8Is C1-6An alkyl group. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R8Is C1-6A haloalkyl group.
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some implementationsIn which is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 2. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 1. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And p is 0. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is selected from C
1-9Heteroaryl and fusedC
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof,wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments is A compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
p is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereofWherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaromatic compoundsRadicals and condensed C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof,wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl optionally substituted by oneSubstituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodimentsIs a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted with one or two substituents selected from halogen、-CN、C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is selected from threeOxazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereofArticle, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments of formula (II)(Ic) a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
q is 0, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 2. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 1. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
And q is 0. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein C is
1-6Alkyl radical, C
2-6Alkenyl radical, C
2-6Alkynyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl; wherein said C
1-9Heteroaryl and fused C
5-9Heteroaryl-cycloalkyl is optionally substituted by one or two substituents selected from halogen, -CN, C
1-6Alkyl radical、-C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles, and tetrazoles; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, -CN, C
1-6Alkyl, -C
1-6alkyl-OH, C
1-6Haloalkyl, C
3-8Cycloalkyl radical, C
2-9Heterocycle, C
6-10Aryl radical, C
1-9Heteroaryl, -C (═ O) R
14、-C(＝O)OR
13、-C(＝O)N(R
13)
2、-S(＝O)R
14、-S(＝O)
2R
13、-S(＝O)
2-N(R
13)
2、-N(R
13)
2、-N(R
13)C(＝O)R
14and-N (R)
13)S(＝O)
2R
13. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is selected from threeOxazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halogen, C
1-6Alkyl and C
3-8A cycloalkyl group. In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are of formula (Ic),or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt thereofOr a solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In some embodiments are compounds of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein
Is composed of
R
5aIs hydrogen, and R
4Is composed of
In another aspect, described herein are pharmaceutical compositions comprising a compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
In another aspect, described herein is a method of treating non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), or (Ic), or a therapeutically effective amount of a pharmaceutically acceptable salt or solvate thereof.
In another aspect, the compound of formula (I), (Ia), (Ib) or (Ic) is
Or a pharmaceutically acceptable salt or solvate thereof.
In another aspect, the compound of formula (I), (Ia), (Ib) or (Ic) is
Or a pharmaceutically acceptable salt or solvate thereof.
In another aspect, the compound of formula (I), (Ia), (Ib) or (Ic) is
Synthesis of Compounds
The compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in conjunction with the methods described herein. In addition, one of ordinary skill in the art of organic synthesis will recognize that the solvents, temperatures, and other reaction conditions set forth herein can vary from those described herein and provide the desired synthetic transformations or the conversion of a given starting material to a given product or intermediate.
The starting materials for the synthesis of the compounds described herein are synthetic or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, and the like. The compounds described herein and other related compounds having different substituents are synthesized using techniques and materials described herein or otherwise known, including those described in MARCH' S ADVANCED ORGANIC CHEMISTRY, 7 th edition, (Wiley 2013); those techniques and materials described IN Carey and Sundberg, advanced ORGANIC Chemistry 5 th edition, volumes A and B (Springer,2007) and Green and Wuts, Green' SPROTECTIVE GROUPS IN ORGANIC SYNTHESIS 4 th edition (Wiley 2007). The general methods of preparing the compounds can be modified using appropriate reagents and conditions in order to incorporate the various moieties found in the general formulae provided herein. Detailed descriptions of suitable techniques for the creation and removal of Protecting Groups are described in Greene and Wuts, Green's Protective Groups in Organic Synthesis, 4 th edition, John Wiley & Sons, New York, NY,2007 and Kocienski, Protective Groups, 3 rd edition, Thieme Verlag, New York, NY,2003, which are incorporated herein by reference for their disclosure.
Other forms of the Compounds
In one aspect, the compounds described herein have one or more stereocenters, and each stereocenter independently exists in the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric and epimeric forms, and appropriate mixtures thereof. The compounds and methods provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), entgegen (e), and zusammen (z) isomers and suitable mixtures thereof. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is performed using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by separation/resolution techniques based on solubility differences. In other embodiments, the separation of stereoisomers is performed by chromatography or by formation of diastereomeric salts or any combination thereof. Jean Jacques, Andre Collet, Samuel H.Wilen, "Enantiomers, Racemates And resolution," John Wiley And Sons, Inc., 1981. In some embodiments, the stereoisomers are obtained by stereoselective synthesis.
As used herein, "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not eliminate the biological activity or properties of the compound and is relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of a composition in which the compound is contained.
The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid. Pharmaceutically acceptable salts can also be obtained by reacting a compound described herein with a base to form a salt.
The compounds described herein may be formed and/or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) an acid addition salt formed by reacting the free base form of the compound with a pharmaceutically acceptable acid, said acid comprising: inorganic acids to form salts such as hydrochloride, hydrobromide, sulfate, phosphate, metaphosphate, and the like; or an organic acid to form a salt, such as acetate, propionate, hexanoate, cyclopentanepropionate, hydroxyacetate, pyruvate, lactate, malonate, succinate, malate, maleate, fumarate, trifluoroacetate, tartrate, citrate, benzoate, 3- (4-hydroxybenzoyl) benzoate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, 1, 2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, toluenesulfonate, 2-naphthalenesulfonate, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylate, glucoheptonate, 4' -methylenebis- (3-hydroxy-2-ene-1-carboxylic acid) salt, salt of a compound of formula (I), or a salt of a compound of formula (II), 3-phenylpropionate, pivalate, t-butyl acetate, lauryl sulfate, gluconate, glutamate, hydroxynaphthoate, salicylate, stearate, muconate, butyrate, phenylacetate, phenylbutyrate, valproate, and the like; (2) salts are formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., a lithium, sodium, or potassium salt), an alkaline earth metal ion (e.g., a magnesium or calcium salt), or an aluminum ion (e.g., an aluminum salt). In some cases, a compound described herein may coordinate with an organic base to form a salt, such as, but not limited to, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a tromethamine salt, an N-methylglucamine salt, a dicyclohexylamine salt, or a tris (hydroxymethyl) methylamine salt. In other instances, the compounds described herein may form salts with amino acids, such as, but not limited to, arginine salts, lysine salts, and the like. Acceptable inorganic bases for forming salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
It will be understood that reference to a pharmaceutically acceptable salt includes the solvent addition forms thereof. Solvates contain either stoichiometric or non-stoichiometric amounts of solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein may be conveniently prepared or formed in the procedures described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms.
In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as Such as respectively are2H、3H、13C、14C、l5N、18O、17O、31P、32P、35S、18F and36and (4) Cl. Compounds described herein and pharmaceutically acceptable salts, esters, solvates, hydrates or derivatives thereof containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention. Certain isotopically-labelled compounds, e.g. in which radioactive isotopes are incorporated, e.g.3H and14c, are useful in drug and/or substrate tissue distribution assays. Tritium (i.e. tritium3H) And carbon-14 (i.e.14C) Isotopes are particularly preferred for their ease of preparation and detectability. In addition, heavy isotopes (such as deuterium, i.e., deuterium) are employed due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements2H) Substitution offers certain therapeutic advantages. In some embodiments, the isotopically labeled compound, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method.
In some embodiments, the compounds described herein are labeled by other means including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent markers, or chemiluminescent markers.
Route of administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, aural, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, e.g., by direct injection of the compound into an organ, typically in a depot or sustained release formulation. In particular embodiments, the long acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate (intermediate) release formulation. In still other embodiments, the compounds described herein are administered topically.
Pharmaceutical composition/formulation
In some embodiments, the compounds described herein are formulated as pharmaceutical compositions. Pharmaceutical compositions are formulated in conventional manner using one or more pharmaceutically acceptable inactive ingredients which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The appropriate formulation will depend on the chosen route of administration. A summary of The pharmaceutical compositions described herein can be found, for example, in Remington, The Science and Practice of Pharmacy, 19 th edition (Easton, Pa., Mack publishing Company, 1995); hoover, John e., Remington's Pharmaceutical Sciences, Mack Publishing co, Easton, Pennsylvania 1975; liberman, h.a. and Lachman, l. eds, Pharmaceutical document Forms, Marcel Decker, New York, n.y., 1980; and pharmaceutical dosage Forms and Drug Delivery Systems, 7 th edition (Lippincott Williams & Wilkins,1999), the disclosures of which are incorporated herein by reference.
Provided herein are pharmaceutical compositions comprising a compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive ingredient. In some embodiments is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
In some embodiments, the compounds described herein are administered as a pharmaceutical composition in which the compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is mixed with other active ingredients, as in combination therapy. In other embodiments, the pharmaceutical composition comprises other pharmaceutical or medical agents, carriers, adjuvants, preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and/or buffers. In still other embodiments, the pharmaceutical composition comprises other therapeutically valuable substances.
As used herein, a pharmaceutical composition refers to a mixture of a compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, with other chemical components (i.e., pharmaceutically acceptable inactive ingredients) such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, permeation enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, or one or more combinations thereof. The pharmaceutical composition facilitates administration of the compound to a mammal.
The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. These compounds may be used alone or as components of a mixture in combination with one or more therapeutic agents.
The pharmaceutical formulations described herein are administered to a subject by a suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsed release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
Pharmaceutical compositions comprising a compound of formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt thereof, are prepared in a conventional manner, for example, and by way of example only, using conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression techniques.
The pharmaceutical composition will comprise at least one compound of formula (I), (Ia), (Ib) or (Ic) as active ingredient in free acid or free base form or in pharmaceutically acceptable salt form. In some embodiments, the compounds described herein exist in unsolvated forms or solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered disclosed herein.
The pharmaceutical compositions described herein comprising a compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, are formulated in any suitable dosage form, including but not limited to aqueous oral dispersions, liquids, gels, syrups, elixirs, syrups, suspensions, solid oral dosage forms, controlled release formulations, fast-melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, lozenges, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.
Pharmaceutical preparations for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In some embodiments, the push-fit capsules do not contain any other ingredients besides the capsule shell and the active ingredient. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, a stabilizer is added.
All formulations for oral administration are at dosages suitable for such administration.
In one aspect, a solid oral dosage form is prepared by combining a compound of (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, and one or more of the following: antioxidants, flavoring agents and carrier materials such as binders, suspending agents, disintegrants, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents and diluents.
In some embodiments, the solid dosage form disclosed herein is in the form of a tablet (including a suspension tablet, a fast-melt tablet, a chewable disintegrating tablet, a fast disintegrating tablet, an effervescent tablet, or a caplet), a pill, a powder, a capsule, a solid dispersion, a solid solution, a bioerodible dosage form, a controlled release formulation, a pulsatile release dosage form, a multiparticulate dosage form, a bead, a pellet, a granule. In other embodiments, the pharmaceutical formulation is in powder form. In still other embodiments, the pharmaceutical formulation is in the form of a tablet. In other embodiments, the pharmaceutical formulation is in the form of a capsule.
In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound of (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutical excipients to form a loosely blended (blend) composition. The loose blend is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. In some embodiments, the individual unit doses comprise a film coating. These formulations are prepared by conventional formulation techniques.
Conventional formulation techniques include, for example, one or a combination of the following: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) blending. Other methods include, for example, spray drying, pan coating, melt granulation, fluid bed spray drying or coating (e.g., wurster coating), tangential coating, top-spraying, tableting, extrusion, and the like.
In some embodiments, the tablet will comprise a film surrounding the final compressed tablet. In some embodiments, the film coating may provide delayed release of the compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, from the formulation. In other embodiments, the film coating aids in patient compliance (e.g.,a coating or a sugar coating). Comprises
The film coating of (a) typically comprises from about 1% to about 3% by weight of the tablet.
For example, capsules may be prepared by placing a loose blend of a formulation of the above compounds into a capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the formulation is placed in a standard gelatin or non-gelatin capsule, such as a capsule comprising HPMC. In other embodiments, the formulation is placed in a dispensing capsule, wherein the capsule is swallowed whole or the capsule is opened and the contents are dispensed onto food before the food is consumed.
In various embodiments, the granules of a compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, are dry blended with one or more excipients and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration, thereby releasing the formulation into the gastrointestinal fluids.
In still other embodiments, effervescent powders are also prepared. Effervescent salts have been used to disperse drugs in water for oral administration.
In some embodiments, the pharmaceutical solid oral dosage form is formulated to provide controlled release of the active compound. Controlled release refers to the release of the active compound from the dosage form into which it is incorporated over an extended period of time according to a desired profile. Controlled release profiles include, for example, sustained release, extended release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow for delivery of an agent to a subject according to a predetermined profile over an extended period of time. Such release rates may provide therapeutically effective levels of the agent over an extended period of time, thereby providing a longer period of pharmacological response while minimizing side effects as compared to conventional rapid release dosage forms. Such a longer reaction period provides a number of inherent benefits not attainable with corresponding short acting immediate release formulations.
In some embodiments, the solid dosage forms described herein are formulated as enteric-coated delayed release oral dosage forms, i.e., oral dosage forms of pharmaceutical compositions as described herein, which utilize an enteric coating to achieve release in the small or large intestine. In one aspect, the enteric-coated dosage form is a compressed or molded or extruded tablet/die (coated or uncoated) comprising granules, powders, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated. In one aspect, the enterically coated oral dosage form is in the form of a capsule comprising pellets, beads or granules.
The coating is applied using conventional coating techniques such as spray or pan coating. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until it reaches the desired local delivery site in the intestinal tract.
In other embodiments, the formulations described herein are delivered using a pulsed dosage form. The pulsatile dosage form can provide one or more immediate release pulses at a predetermined point in time after a controlled delay time or at a specific site. In one embodiment, the pulsed dosage form comprises at least two sets of particles (i.e., multiparticulates), each set comprising a formulation as described herein. The first group of particles provides a substantially immediate dose of the active compound when ingested by a mammal. The first set of particles may be uncoated or comprise a coating and/or a sealant. In one aspect, the second set of particles comprises coated particles. The coating on the second set of particles provides a delay of about 2 hours to about 7 hours after ingestion before release of the second dose. Suitable coatings for pharmaceutical compositions are described herein or in the art.
In some embodiments, there is provided a pharmaceutical formulation comprising granules of a compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, and at least one dispersing or suspending agent for oral administration to a subject. The formulation may be a powder and/or granules for suspension and when mixed with water a substantially homogeneous suspension is obtained.
In one aspect, the liquid dosage form for oral administration is in the form of an aqueous suspension selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels and syrups. See, for example, Singh et al Encyclopedia of Pharmaceutical Technology, 2 nd edition, pages 754 and 757 (2002). In addition to the granules of the compound of formula (I), (Ia), (Ib) or (Ic), the liquid dosage form comprises additives, such as: (a) a disintegrant; (b) a dispersant; (c) a humectant; (d) at least one preservative; (e) a viscosity enhancing agent; (f) at least one sweetener; and (g) at least one flavoring agent.
Buccal formulations comprising a compound of formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt thereof, are administered using a variety of formulations known in the art. For example, such formulations include, but are not limited to, U.S. Pat. nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, the buccal dosage forms described herein may further comprise a bioerodible (hydrolyzable) polymer carrier that also serves to adhere the dosage form to the buccal mucosa. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges or gels formulated in conventional manner.
In some embodiments, the compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is prepared as a transdermal dosage form. In one embodiment, the transdermal formulations described herein comprise at least three components: (1) formulations of a compound of formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt thereof; (2) a penetration enhancer; and (3) an aqueous adjuvant. In some embodiments, the transdermal formulation comprises additional components such as, but not limited to, gelling agents, creams, ointment bases, and the like. In some embodiments, the transdermal formulation further comprises a woven or nonwoven backing material to enhance absorption and prevent removal of the transdermal formulation from the skin. In other embodiments, the transdermal formulations described herein may be maintained in a saturated or supersaturated state to facilitate diffusion into the skin.
In one aspect, formulations suitable for transdermal administration of the compounds described herein employ transdermal delivery devices and transdermal delivery patches and may be lipophilic emulsions or buffered aqueous solutions dissolved and/or dispersed in a polymer or adhesive. In one aspect, such patches are configured for continuous, pulsed, or on-demand delivery of a medicament. Further, transdermal delivery of the compounds described herein may be achieved by means of iontophoretic patches and the like. In one aspect, transdermal patches provide controlled delivery of active compounds. In one aspect, the transdermal device is in the form of a bandage comprising a backing member, a reservoir containing the compound and optionally a carrier, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over an extended period of time, and means to immobilize the device on the skin (means).
In one aspect, the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous or intravenous injection. In one aspect, formulations suitable for intramuscular, subcutaneous or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), vegetable oils, and organic esters, such as ethyl oleate. In some embodiments, formulations suitable for subcutaneous injection contain additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
For intravenous injection, the compounds described herein are formulated in aqueous solutions, preferably in physiologically compatible buffers such as hanks 'solution, ringer's solution, or physiological saline buffer.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, suitable formulations include aqueous or non-aqueous solutions, preferably containing physiologically compatible buffers or excipients. Such excipients are known.
Parenteral injection may include bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In one aspect, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
In certain embodiments, delivery systems for pharmaceutical compounds may be employed, for example, liposomes and emulsions. In certain embodiments, the compositions provided herein may further comprise a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate, and dextran.
In some embodiments, the compounds described herein can be administered topically, and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, sticks, balms, creams, or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
Method of treatment
In some embodiments, described herein is a method of treating non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), or (Ic), or a therapeutically effective amount of a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a therapeutically effective amount of a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (Ia), or a therapeutically effective amount of a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (Ib), or a therapeutically effective amount of a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (Ic), or a therapeutically effective amount of a pharmaceutically acceptable salt or solvate thereof.
Combination therapy
In certain instances, it is suitable to administer at least one compound of formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.
In one embodiment, administration of an adjuvant enhances the therapeutic effectiveness of one of the compounds described herein (i.e., the adjuvant may have minimal therapeutic benefit by itself, but the overall therapeutic benefit to the patient is enhanced when combined with another therapeutic agent). Alternatively, in some embodiments, the benefit obtained by the patient is increased by administering one compound described herein and another therapeutic agent (also including a treatment regimen) that also has therapeutic benefit.
In a particular embodiment, a compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing greater overall benefit than either therapeutic agent administered alone.
In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be only additive of the two therapeutic agents, or the patient may experience a synergistic benefit.
In certain embodiments, when a compound disclosed herein is administered in combination with one or more additional agents, such as additional therapeutically effective drugs, adjuvants, and the like, different therapeutically effective doses of the compound disclosed herein will be used in formulating the pharmaceutical composition and/or in the treatment regimen. Therapeutically effective dosages of the drugs and other agents used in the combination treatment regimen may be determined by means similar to those set forth above for the active agents themselves. In addition, the prophylactic/therapeutic methods described herein include the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, the combination treatment regimen comprises a treatment regimen of: wherein the administration of the compound of formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt thereof, is initiated before, during or after treatment with the second agent and continues for any time during or after the end of treatment with the second agent. Also included are treatments: wherein the compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof and the second agent used in combination are administered simultaneously or at different times and/or with progressively decreasing or increasing intervals during the treatment period. Combination therapy further includes periodic treatments that are started and stopped at different times to assist in the clinical management of the patient.
It will be appreciated that the dosage regimen for treating, preventing or ameliorating a condition for which relief is sought will vary depending upon a variety of factors (e.g., the disease, disorder or condition from which the subject is suffering; the age, weight, sex, diet and medical condition of the subject). Thus, in some instances, the dosage regimen actually used will vary, and in some embodiments deviate from the dosage regimen described herein.
For the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of combination used, the particular drug used, the disease or condition being treated, and the like. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered either simultaneously or sequentially with one or more other therapeutic agents.
In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are provided in a single unified form, or in multiple forms (e.g., as a single pill or as two separate pills), by way of example only.
The compounds of formula (I), (Ia), (Ib) or (Ic), or pharmaceutically acceptable salts thereof, and the combination therapy are administered before, during or after the onset of the disease or condition, and the timing of administration of the composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to a subject having a predisposition to develop a condition or disease, in order to prevent the development of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject as soon as possible during or after the onset of symptoms. In particular embodiments, following detection or suspicion of the onset of a disease or condition, a compound described herein is administered as soon as possible, if feasible, for a period of time necessary to treat the disease. In some embodiments, the length of time required for treatment is not equal, and the length of treatment is adjusted to suit the specific needs of each subject. For example, in particular embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
