ASK1 inhibitor compounds and uses thereof
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 2018-04-04 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、溶剂化物、代谢物、前药,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它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, solvates, metabolites, prodrugs thereof, methods of making 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 III, or a pharmaceutically acceptable salt or solvate thereof:
wherein
R1Is composed of
Z is O, S, C (═ O), N (R)8) Or C (R)9)2；
X is O or S;
R2is C3-6A cycloalkyl group;
R3selected from hydrogen, C1-6Alkyl and C3-6A cycloalkyl group;
each R4Independently selected from hydrogen, halo, C1-6Alkyl and C3-6A cycloalkyl group;
or a R4And another R2、R3Or R4Together with the atoms to which they are attached form a 5 or 6 membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5 or 6 membered ring is saturated, unsaturated or aromatic; and wherein said 5 or 6 membered ring is optionally substituted with one, two or three substituents selected from halo, -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 and C1-6An alkyl group;
R5aselected from hydrogen and C1-C6An alkyl group;
each R25Independently selected from 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 halo, -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 R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl, -C3-C8Cycloalkyl-phenyl and C2-9Heterocyclic ring wherein C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl, -C3-C8Cycloalkyl-phenyl and C2-9The heterocyclic ring is optionally substituted with one, two OR three substituents selected from halo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14(ii) a Or two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9Heteroaryl group, wherein C2-9Heterocyclic or C2-9Heteroaryl is optionally substituted with one, two OR three substituents selected from halo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14；
Each R7Independently selected from C1-C6Alkyl radical, C3-C8Cycloalkyl and C2-9Heterocyclic ring wherein C3-C8Cycloalkyl and C2-9The heterocyclic ring is optionally substituted with one, two OR three substituents selected from halo, oxo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ C)O)R14、-C(＝O)OR13and-N (R)13)C(＝O)R14；
Each R8Independently selected from hydrogen and C1-C6An alkyl group;
each R9Independently selected from hydrogen, halogen and C1-C6An alkyl group;
each R13Independently selected from hydrogen, C1-C6Alkyl and C3-C8A 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-C6Alkyl and C3-C8A cycloalkyl group;
n is 0, 1,2,3 or 4;
p is 0, 1,2 or 3; and is
q is 0, 1 or 2.
2. A compound having the structure of formula II, or a pharmaceutically acceptable salt or solvate thereof:
wherein
R1Is composed of
Z is O, S, C (═ O), N (R)8) Or C (R)9)2；
X is O or S;
R2is C3-6A cycloalkyl group;
R3selected from hydrogen, C1-6Alkyl and C3-6A cycloalkyl group;
each R4Independently selected from hydrogen, halo, C1-6Alkyl and C3-6A cycloalkyl group;
or a R4And another R2、R3Or R4Together with the atoms to which they are attached form a 5 or 6 membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5 or 6 membered ring is saturated, unsaturated or aromatic; and wherein said 5 or 6 membered ring is optionally substituted with one, two or three substituents selected from halo, -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 and C1-6An alkyl group;
R5aselected from hydrogen and C1-C6An alkyl group;
R25selected from 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 halo, -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 R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl 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-C6Alkyl and C3-C8A cycloalkyl group;
R8selected from hydrogen and C1-C6An alkyl group;
each R9Independently selected from hydrogen, halogen and C1-C6An alkyl group;
each R13Independently selected from hydrogen, C1-C6Alkyl and C3-C8A 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-C6Alkyl and C3-C8A cycloalkyl group;
n is 0, 1,2,3 or 4;
p is 0, 1,2 or 3; and is
q is 0, 1 or 2.
3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Is 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 halo, -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。
4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Is 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 halo, -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。
5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Is 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 halo, -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。
6. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Selected 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 halo, -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。
7. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Selected 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 halo, C1-6Alkyl and C3-8A cycloalkyl group.
8. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R25Is composed of
Wherein each R11Independently is C1-C6Alkyl or C3-C6A cycloalkyl group.
9. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Is composed of
Wherein each R12Independently of one another is hydrogen, halo, C1-C6Alkyl or C3-C6A cycloalkyl group; and m is 1 or 2.
10. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
11. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Selected from the group consisting of pyrimidine, pyrazine and pyridazine; wherein the pyrimidine, pyrazine and pyridazine are optionally substituted by one or two substituents selected from halo, C1-6Alkyl and C3-8A cycloalkyl group.
12. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Selected from halogen, -OR6、-N(R6)2、C1-6Alkyl, pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from halo, C1-6Alkyl and C3-8A cycloalkyl group.
13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Selected from halogen, -OR6、-N(R6)2、C1-6Alkyl and unsubstituted pyridine.
14. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl and C2-9A heterocyclic ring.
15. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Is composed of
16. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Is composed of
Wherein R is10Is C2-9A heteroaryl group.
17. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25is-C (═ O) N (R)6)2And two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9Heteroaryl group, wherein C2-9Heterocyclic or C2-9Heteroaryl is optionally substituted with one, two OR three substituents selected from halo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14。
18. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Is composed of
19. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25is-C (═ O) N (R)6)2And two R6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group.
20. The compound of claim 18 or 19, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25Is composed of
21. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein
R25is-OR6And R is6Is selected from C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl and-C1-C6Alkane (I) and its preparation method
radical-C2-9A heterocyclic ring.
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein
R1Is composed of
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein R1Is composed of
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R1Is composed of
25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R1Is composed of
26. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein
R1Is composed of
27. A compound having the structure of formula I, or a pharmaceutically acceptable salt or solvate thereof:
wherein
Is composed of
Z is O, S, C (═ O), N (R)8) Or C (R)9)2；
R1And R3Each independently selected 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 halo, -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；
R2Selected from hydrogen, halogen, -CN, -OH, -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 halo, -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(ii) a Wherein R is2And R3Not hydrogen at the same time;
each R4And each R5Independently selected from halogen, -CN and C1-6An alkyl group;
R5aselected from hydrogen and C1-C6An alkyl group;
each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl 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-C6Alkyl and C3-C8A cycloalkyl group;
R8selected from hydrogen and C1-C6An alkyl group;
each R9Independently selected from hydrogen, halogen and C1-C6An alkyl group;
each R13Independently selected from hydrogen, C1-C6Alkyl and C3-C8A 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-C6Alkyl and C3-C8A cycloalkyl group;
n is 0, 1 or 2;
p is 0, 1,2 or 3; and is
q is 0, 1 or 2.
28. The compound of claim 27, 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 halo, -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。
29. The compound of claim 27, 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 halo, -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。
30. The compound of claim 27, 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 being optionally substituted by oneOr two substituents selected from halo, -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。
31. The compound of claim 27, 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 halo, -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。
32. The compound of claim 27, 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 halo, C1-6Alkyl and C3-8A cycloalkyl group.
33. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is composed of
Wherein R is11Is C1-C6Alkyl or C3-C6A cycloalkyl group.
34. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is composed of
Wherein each R12Independently of one another is halo, C1-C6Alkyl or C3-C6A cycloalkyl group; and is
m is 1 or 2.
35. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
36. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl and C2-9A heterocyclic ring.
37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is composed of
38. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein
R2Is composed of
Wherein R is10Is heteroaryl.
39. The compound of any one of claims 27-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is hydrogen.
40. The compound of any one of claims 27-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R3Is C1-C6An alkyl group.
41. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3Is 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 halo, -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。
42. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3Is 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 halo, -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。
43. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3Is 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 halo, -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。
44. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3Selected 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 halo, -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。
45. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3Selected 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 halo, C1-6Alkyl and C3-8A cycloalkyl group.
46. The compound of claim 45, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3Is composed of
Wherein R is11Is C1-C6Alkyl or C3-C6A cycloalkyl group.
47. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3Is composed of
Wherein each R12Independently of one another is halo, C1-C6Alkyl or C3-C6A cycloalkyl group; and m is 1 or 2.
48. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
49. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl and C2-9A heterocyclic ring.
50. The compound of claim 49, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3Is composed of
51. The compound of claim 49, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3Is composed of
Wherein R is10Is heteroaryl.
52. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein
R3is-OR6And R is6Is selected from C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl and-C1-C6alkyl-C2-9A heterocyclic ring.
53. The compound of any one of claims 41-52, or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is hydrogen.
54. The compound of any one of claims 41-52, or a pharmaceutically acceptable salt or solvate thereof, wherein R2Is C1-C6An alkyl group.
55. The compound of any one of claims 27-54, or a pharmaceutically acceptable salt or solvate thereof, wherein
R1Is selected from C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl andcondensed 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 halo, -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。
56. The compound of claim 55, or a pharmaceutically acceptable salt or solvate thereof, wherein
R1Is 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 halo, -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。
57. The compound of claim 55, or a pharmaceutically acceptable salt or solvate thereof, wherein
R1Is 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 halo, -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。
58. The compound of claim 57, or a pharmaceutically acceptable salt or solvate thereof, wherein
R1Selected 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 halo, -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。
59. The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein
R1Selected from the group consisting of triazoles, imidazoles, oxazoles, isoxazoles, oxadiazoles and tetracyclinesAzole; wherein the triazole, imidazole, oxazole, isoxazole, oxadiazole and tetrazole are optionally substituted with one or two substituents selected from halo, C1-6Alkyl and C3-8A cycloalkyl group.
60. The compound of claim 59, or a pharmaceutically acceptable salt or solvate thereof, wherein
R1Is composed of
61. The compound of claim 60, or a pharmaceutically acceptable salt or solvate thereof, wherein
R1Is composed of
62. The compound of claim 57, or a pharmaceutically acceptable salt or solvate thereof, wherein
R1Is composed of
63. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt or solvate thereof, whereinIs composed of
64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
65. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt or solvate thereof, wherein
66. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt or solvate thereof, wherein
67. The compound of claim 65 or 66, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
68. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
69. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
70. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
71. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C (R)9)2。
72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt or solvate thereof, wherein each R9Is H.
73. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has one of the following structures:
74. the compound of claim 1,2, or 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has one of the following structures:
75. the compound of claim 1,2, or 27, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has one of the following structures:
76. a pharmaceutical composition comprising a compound according to any one of claims 1-75, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
77. 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 according to any one of claims 1-75, 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 is similar to 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 usually not at high risk of being affected, in a proportion of NAFLD patients steatosis progresses to inflammation (hepatitis), necrosis and fibrosis, 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 patients with NAFLD will continue to develop NASH, making 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 that inhibit ASK1, or a pharmaceutically acceptable salt or solvate thereof.
In one aspect, presented herein is a compound having the structure of formula I, or a pharmaceutically acceptable salt or solvate thereof:
wherein
Z is O, S, C (═ O), N (R)8) Or C (R)9)2；
R1And R3Each independently selected 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 halo, -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；
R2Selected from hydrogen, halogen, -CN, -OH, -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 halo, -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(ii) a Wherein R is2And R3Not hydrogen at the same time;
each R4And each R5Each independently selected from halogen, -CN and C1-6An alkyl group;
R5aselected from hydrogen and C1-C6An alkyl group;
each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl 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-C6Alkyl and C3-C8A cycloalkyl group;
R8selected from hydrogen and C1-C6An alkyl group;
each R9Independently selected from hydrogen, halogen and C1-C6An alkyl group;
each R13Independently selected from hydrogen, C1-C6Alkyl and C3-C8A 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-C6Alkyl and C3-C8A cycloalkyl group;
n is 0, 1 or 2;
p is 0, 1,2 or 3; and is
q is 0, 1 or 2.
In some embodiments, 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 halo, -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, 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 halo, -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, 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 halo, -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, 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 halo, -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, 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 halo, C1-6Alkyl and C3-8A cycloalkyl group. In some embodiments, R2Is composed of
In some embodiments, R2Is composed ofWherein R is12Is halo, C1-C6Alkyl or C3-C6A cycloalkyl group; and m is 1 or 2.
In some embodiments, R2Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
In some embodiments, R2is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl and C2-9A heterocyclic ring.
In some embodiments, R2Is composed of
In some embodiments, R2Is composed of
Wherein R is10Is heteroaryl.
In some embodiments, R3Is hydrogen. In some embodiments, R3Is C1-C6An alkyl group.
In some embodiments, R3Is 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 halo, -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, R3Is 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 halo, -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, R3Is 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 halo, -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, R3Selected 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 halo, -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, R3Selected 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 halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R3Is composed of
In some embodiments, R3Is composed of
In some embodiments, R3Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
In some embodiments, R3is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl and C2-9A heterocyclic ring.
In some embodiments, R3Is composed of
In some embodiments, R3Is composed of
In some embodiments, R3is-OR6And R is6Is selected from C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl and-C1-C6alkyl-C2-9A heterocyclic ring. In some embodiments, R2Is hydrogen. In some embodiments, R2Is C1-C6An alkyl group.
In some embodiments, R1Is 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 halo, -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, R1Is 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 halo, -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, R1Is 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 halo, -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, R1Selected 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 halo, -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, R1Selected 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 halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In another aspect, described herein is a compound of formula II, or a pharmaceutically acceptable salt or solvate thereof:
wherein
R1Is composed of
Z is O, S, C (═ O), N (R)8) Or C (R)9)2；
X is O or S;
R2is C3-6A cycloalkyl group;
R3is selected fromHydrogen, C1-6Alkyl and C3-6A cycloalkyl group;
each R4Independently selected from hydrogen, halo, C1-6Alkyl and C3-6A cycloalkyl group;
or a R4And another R2、R3Or R4Together with the atoms to which they are attached form a 5 or 6 membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5 or 6 membered ring is saturated, unsaturated or aromatic; and wherein said 5 or 6 membered ring is optionally substituted with one, two or three substituents selected from halo, -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 and C1-6An alkyl group;
R5aselected from hydrogen and C1-C6An alkyl group;
R25selected from 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 halo, -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 R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl 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-C6Alkyl and C3-C8A cycloalkyl group;
R8selected from hydrogen and C1-C6An alkyl group;
each R9Independently selected from hydrogen, halogen and C1-C6An alkyl group;
each R13Independently selected from hydrogen, C1-C6Alkyl and C3-C8A 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-C6Alkyl and C3-C8A cycloalkyl group;
n is 0, 1,2,3 or 4;
p is 0, 1,2 or 3; and is
q is 0, 1 or 2.
In another aspect, described herein is a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof:
wherein
Is composed of
R1Is composed of
Z is O, S, C (═ O), N (R)8) Or C (R)9)2；
X is O or S;
R2is C3-6A cycloalkyl group;
R3selected from hydrogen, C1-6Alkyl and C3-6A cycloalkyl group;
each R4Independently selected from hydrogen, halo, C1-6Alkyl and C3-6A cycloalkyl group;
or a R4And another R2、R3Or R4Together with the atoms to which they are attached form a 5 or 6 membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5 or 6 membered ring is saturated, unsaturated or aromatic; and wherein said 5 or 6 membered ring is optionally substituted with one, two or three substituents selected from halo, -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 and C1-6An alkyl group;
R5aselected from hydrogen and C1-C6An alkyl group;
each R25Independently selected from 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 halo, -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 R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl, -C3-C8Cycloalkyl-phenyl and C2-9Heterocyclic ring wherein C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl, -C3-C8Cycloalkyl-phenyl and C2-9The heterocyclic ring is optionally substituted with one, two OR three substituents selected from halo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14(ii) a Or two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9Heteroaryl group, wherein C2-9Heterocyclic or C2-9Heteroaryl is optionally substituted with one, two OR three substituents selected from halo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14；
Each R7Independently selected from C1-C6Alkyl radical, C3-C8Cycloalkyl and C2-9Heterocyclic ring wherein C3-C8Cycloalkyl and C2-9The heterocyclic ring is optionally substituted with one, two OR three substituents selected from halo, oxo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14；
Each R8Independently selected from hydrogen and C1-C6An alkyl group;
each R9Independently selected from hydrogen, halogen and C1-C6An alkyl group;
each R13Independently selected from hydrogen, C1-C6Alkyl and C3-C8A 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-C6Alkyl and C3-C8A cycloalkyl group;
n is 0, 1,2,3 or 4;
p is 0, 1,2 or 3; and is
q is 0, 1 or 2.
In some embodiments, R25Is 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, wherein C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl optionally substituted by one, two or threeSubstituted by a substituent selected from halo, -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, R25Is 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 halo, -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, R25Is 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 halo, -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, R25Selected 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 halo, -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, R25Selected 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 halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R25Is composed of
In some embodiments, R25Is composed of
In some embodiments, R25Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
In some embodiments, R25Selected from the group consisting of pyrimidine, pyrazine and pyridazine; wherein the pyrimidine, pyrazine and pyridazine are optionally substituted by one or two substituents selected from halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R25Selected from halogen, -OR6、-N(R6)2、C1-6Alkyl, pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R25Selected from halogen, -OR6、-N(R6)2、C1-6Alkyl and unsubstituted pyridine.
In some embodiments, R25is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl and C2-9A heterocyclic ring.
In some embodiments, R25Is composed of
In some embodiments, R25Is composed of
Wherein R is10Is heteroaryl.
In some embodiments, R25is-C (═ O) N (R)6)2And two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9Heteroaryl group, wherein C2-9Heterocyclic or C2-9Heteroaryl is optionally substituted with one, two OR three substituents selected from halo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14。
In some embodiments, R25Is composed of
In some embodiments, R25is-C (═ O) N (R)6)2And two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group.
In some embodiments, R25is-C (═ O) N (R)6)2And two R6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group.
In some embodiments, R25Is composed of
In some embodiments, R25is-OR6And R is6Is selected from C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl and-C1-C6alkyl-C2-9A heterocyclic ring.
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments of the present invention, the substrate is,
In some embodiments of the present invention, the substrate is,
In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, Z is C (R)9)2. In some embodiments, R9Is H.
In a further aspect, described herein are pharmaceutical compositions comprising a compound of formula I, formula II, or formula III, 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, formula II, or formula III, or a pharmaceutically acceptable salt or solvate. 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 pharmaceutical composition comprising a compound of formula I, formula II, or formula III, or a pharmaceutically acceptable salt or solvate, and at least one pharmaceutically acceptable excipient.
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 invention will become apparent to those skilled in the art from this detailed description.
Drawings
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
figure 1 shows a graph comparing the inhibition of the hERG potassium channel by compound 2 and compound 27 (compound 2 and compound 27, respectively), ASK1 inhibitor GS-4997, and the positive control Amitriptyline (Amitriptyline) described herein.
Detailed Description
ASK1 is the 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), and 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.
In addition to its apparent role in NASH, recent studies have also demonstrated that ASK1 may often play a key role in stress-induced tissue remodeling diseases. Loss of ASK1 targeted to the heart may improve resistance to ischemia, angiotensin II and pressure-induced pathological tissue remodeling. Furthermore, the widespread expression of this molecule and its central position upstream in the stress-induced signaling cascade suggests that inhibitors of this molecule can be widely used against dysfunctional tissue healing and fibrotic diseases.
Certain terms
Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions given below. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. In this application, the use of "or" and "means" and/or "unless stated otherwise. Furthermore, the use of the terms "including" and other forms, such as "comprises," "comprising," and "having," are not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. An "alkyl" group may have 1 to 15 carbon atoms (whenever appearing herein, a numerical range such as "1 to 15" refers to each integer in the given range; for example, "1 to 15 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms … … up to and including 15 carbon atoms, although the present definition also covers the presence of the term "alkyl" where no numerical range is specified). In one aspect, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and the like.
The term "alkenyl" refers to a class of alkyl groups in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula-c (r) ═ CR2Wherein R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments of the present invention, the substrate is,r is H or alkyl. Non-limiting examples of alkenyl groups include-CH ═ CH2、-C(CH3)＝CH2、-CH＝CHCH3、-C(CH3)＝CHCH3and-CH2CH＝CH2。
The term "alkynyl" refers to a class of alkyl groups in which at least one carbon-carbon triple bond is present. In one embodiment, an alkynyl group has the formula-C ≡ C-R, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. Non-limiting examples of alkynyl groups include-C.ident.CH, -C.ident.CCH3、-C≡CCH2CH3、-CH2C≡CH。
The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic group in which each atom (i.e., a backbone atom) that makes up the ring is a carbon atom. Cycloalkyl groups may be saturated or partially unsaturated. The cycloalkyl group may be fused to the aromatic ring and the point of attachment is on a carbon other than a carbon atom of the aromatic ring. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may be substituted or unsubstituted. Depending on the structure, cycloalkyl groups can be monovalent or divalent (i.e., cycloalkylene groups such as, but not limited to, cyclopropyl-1, 1-diyl, cyclobutyl-1, 1-diyl, cyclopentyl-1, 1-diyl, cyclohexyl-1, 4-diyl, cycloheptyl-1, 1-diyl, and the like). In one aspect, cycloalkyl is C3-C6A cycloalkyl group.
The term "aromatic" refers to a planar ring having a delocalized pi-electron system containing 4n +2 pi-electrons, where n is an integer. The aromatic ring is optionally substituted. The term "aromatic" includes cycloalkylaryl ("aryl", e.g., phenyl) and heterocycloaryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. The term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. Aryl is optionally substituted. Depending on the structure, the aryl group can be a monovalent group or a divalent group (i.e., arylene).
The term "heteroaryl" or "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include the following moieties:
A "heterocycle" or "heterocycloalkyl" group refers to a cycloalkyl group in which at least one carbon atom of the cycloalkyl group is replaced by nitrogen (substituted or unsubstituted, e.g., -NH-, -N (alkyl) -), oxygen (-O-), or sulfur (e.g., -S-, -S (═ O) -, or-S (═ O)2-) instead. The group may be fused to an aryl or heteroaryl group. In some embodiments, the heterocycloalkyl group is selected from oxazolidonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and indolinyl. The term heteroalicyclic also includes carbohydrates in all ring forms, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In one aspect, heterocycloalkyl is C2-C10HeterocycloalkanesAnd (4) a base. In another aspect, heterocycloalkyl is C4-C10A heterocycloalkyl group. In some embodiments, heterocycloalkyl groups contain 0-3N atoms in the ring. In some embodiments, heterocycloalkyl groups contain 0-3N atoms, 0-3O atoms, and 0-1S atoms in the ring.
The term "halo" or "halogen" or "halide" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). 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" refers to a particular segment or functional group of a molecule. Chemical moieties are often considered chemical entities embedded 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, halo, 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, -NH2、-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, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, and aryl sulfone. In some embodiments, the optional substituents are independentIs 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 certain embodiments, the compounds presented herein have one or more stereocenters, and each center independently exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms, and appropriate mixtures thereof. If desired, the stereoisomers are obtained by methods such as stereoselective synthesis and/or separation of stereoisomers via chiral chromatography columns. In some embodiments, halogen is F or Cl. In some embodiments, halogen is F.
The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also referred to as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of formula I, formula II, or formula III, as well as active metabolites of these compounds having the same type of activity. In some cases, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds shown herein. In certain embodiments, the compounds described herein are present in a solvate form with a pharmaceutically acceptable solvent such as water, ethanol, and the like. In other embodiments, the compounds described herein are present in the form of a non-solvate.
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, formula II or formula III, 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, formula II or formula III, or a pharmaceutically acceptable salt thereof, and the auxiliary 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 prophylactically and/or therapeutically alleviating, eliminating, 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.
Compound (I)
In one aspect, presented herein is a compound having the structure of formula I, or a pharmaceutically acceptable salt or solvate thereof:
wherein
Z is O, S, C (═ O), N (R)8) Or C (R)9)2；
R1And R3Each independently selected 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 halo, -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；
R2Selected from hydrogen, halogen, -CN, -OH, -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 halo, -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(ii) a Wherein R is2And R3Not hydrogen at the same time;
each R4And each R5Each independently selected from halogen, -CN and C1-6An alkyl group;
R5aselected from hydrogen and C1-C6An alkyl group;
each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl 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-C6Alkyl and C3-C8A cycloalkyl group;
R8selected from hydrogen and C1-C6An alkyl group;
each R9Independently selected from hydrogen, halogen and C1-C6An alkyl group;
each R13Independently selected from hydrogen, C1-C6Alkyl and C3-C8A 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-C6Alkyl and C3-C8A cycloalkyl group;
n is 0, 1 or 2;
p is 0, 1,2 or 3; and is
q is 0, 1 or 2.
In some embodiments, 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 halo, -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, 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 halo, -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, 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 halo, -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, 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 halo, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Alkyl halidesBase, 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, 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 halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R2Is composed of
In some embodiments, R2Is composed of
In some embodiments, R2Is composed of
In some embodiments, R2Is composed of
In some embodiments, R2Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
In some embodiments, R2is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl and C2-9A heterocyclic ring.
In some embodiments, R2Is composed of
In some embodiments, R2Is composed of
In some embodiments, R3Is hydrogen. In some embodiments, R3Is C1-C6An alkyl group.
In some embodiments, R3Is selected from C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl; wherein C is3-8Cycloalkyl radicals、C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl and fused C5-9Heteroaryl-cycloalkyl is optionally substituted by one, two or three substituents selected from halo, -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, R3Is 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 halo, -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, R3Is 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 halo, -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, R3Selected 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 halo, -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, R3Selected 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 halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R3Is composed of
In some embodimentsIn, R3Is composed of
In some embodiments, R3Is composed of
In some embodiments, R3Is composed of
In some embodiments, R3Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
In some embodiments, R3is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl and C2-9A heterocyclic ring.
In some embodiments, R3Is composed of
In some embodiments, R3Is composed of
In some embodiments, R3is-OR6And R is6Is selected from C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl and-C1-C6alkyl-C2-9A heterocyclic ring. In some embodiments, R2Is hydrogen. In some embodiments, R2Is C1-C6An alkyl group.
In some embodiments, R1Is 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 halo, -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, R1Is 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 halo, -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, R1Is 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 halo, -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, R1Selected 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 halo, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl, C3-8Cycloalkyl radical, C2-9Heterocycle, C6-10Aryl radical, C1-9Heteroaryl, -C (═ 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, R1Selected 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 halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
Wherein each R17Independently hydrogen, halo, -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(ii) a Each R18Independently hydrogen, halo, -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(ii) a v is 0, 1,2,3, 4,5 or 6; and w is 0, 1,2,3 or 4. In some embodiments, each R is17Independently hydrogen, halo, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl or C3-8A cycloalkyl group; each R18Independently hydrogen, halo, -CN, C1-6Alkyl, -C1-6alkyl-OH, C1-6Haloalkyl or C3-8A cycloalkyl group.
In some embodiments, each R is17Independently hydrogen, halo, -CN, C1-6Alkyl, -C1-6alkyl-OH or C1-6A haloalkyl group; each R18Independently hydrogen, halo, -CN, C1-6Alkyl, -C1-6alkyl-OH or C1-6A haloalkyl group.
In some embodiments, each R is17Independently hydrogen, halo, -CN or C1-6An alkyl group; each R18Independently hydrogen, halo, -CN or C1-6An alkyl group.
In some embodiments, R1Is composed of
In another aspect, described herein is a compound of formula II, or a pharmaceutically acceptable salt or solvate thereof:
wherein
R1Is composed of
Z is O, S, C (═ O), N (R)8) Or C (R)9)2；
X is O or S;
R2is C3-6A cycloalkyl group;
R3selected from hydrogen, C1-6Alkyl and C3-6A cycloalkyl group;
each R4Independently selected from hydrogen, halo, C1-6Alkyl and C3-6A cycloalkyl group;
or a R4And another R2、R3Or R4Together with the atoms to which they are attached form a 5 or 6 membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5 or 6 membered ring is saturated, unsaturated or aromatic; and wherein said 5 or 6 membered ring is optionally substituted with one, two or three substituents selected from halo, -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 and C1-6An alkyl group;
R5aselected from hydrogen and C1-C6An alkyl group;
R25selected from 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 halo, -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 R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl 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-C6Alkyl and C3-C8A cycloalkyl group;
R8selected from hydrogen and C1-C6An alkyl group;
each R9Independently selected from hydrogen, halogen and C1-C6An alkyl group;
each R13Independently selected from hydrogen, C1-C6Alkyl and C3-C8A 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-C6Alkyl and C3-C8A cycloalkyl group;
n is 0, 1,2,3 or 4;
p is 0, 1,2 or 3; and is
q is 0, 1 or 2.
In some embodiments, R25Is 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 halo, -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, R25Is 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 halo, -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, R25Is 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 halo, -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, R25Selected 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 halo, -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, R25Selected from the group consisting of pyrazole, imidazole, thiazole and pyridine; it is composed ofThe pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R25Is composed of
In some embodiments, R25Is composed of
In some embodiments, R25Is composed of
In some embodiments, R25Is composed of
Wherein R is12Is halo, C1-C6Alkyl or C3-C6A cycloalkyl group; and m is 1 or 2.
In some embodiments, R25Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
In some embodiments, R25is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl and C2-9A heterocyclic ring.
In some embodiments, R25Is composed of
In some embodiments, R25Is composed of
In some embodiments, R25is-C (═ O) N (R)6)2And two R6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group.
In some embodiments, R25Is composed of
In some embodiments, R25is-OR6And R is6Is selected from C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl and-C1-C6alkyl-C2-9A heterocyclic ring.
In some embodiments of the present invention, the substrate is,
In some embodiments of the present invention, the substrate is,is composed ofIn some embodiments of the present invention, the substrate is,
In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, Z is C (R)9)2. In some embodiments, R9Is H.
In some embodiments, R1Is composed of
Wherein R is2Is C3-6A cycloalkyl group; r3Selected from hydrogen, C1-6Alkyl and C3-6A cycloalkyl group; each R4Independently selected from hydrogen, halogen, C1-6Alkyl and C3-6A cycloalkyl group; or a R4And another R2、R3Or R4To which they are connectedThe atoms taken together form a 5 or 6 membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5 or 6 membered ring is saturated, unsaturated or aromatic; and wherein said 5 or 6 membered ring is optionally substituted with one, two or three substituents selected from halo, -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, R1Is composed of
Wherein R is3Is selected from C1-6Alkyl and C3-6A cycloalkyl group; and is
Each R4Independently selected from hydrogen, halogen, C1-6Alkyl and C3-6A cycloalkyl group.
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
A R4And another R2、R3Or R4Together with the atoms to which they are attached form a 5 or 6 membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5 or 6 membered ring is saturated, unsaturated or aromatic; and wherein said 5 or 6 membered ring is optionally substituted with one, two or three substituents selected from halo, -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, R1Is composed of
In some embodiments, R1Is composed of
In another aspect, described herein is a compound of formula III, or a pharmaceutically acceptable salt or solvate thereof:
wherein
R1Is composed of
Z is O, S, C (═ O), N (R)8) Or C (R)9)2；
X is O or S;
R2is C3-6A cycloalkyl group;
R3selected from hydrogen, C1-6Alkyl and C3-6A cycloalkyl group;
each R4Independently selected from hydrogen, halo, C1-6Alkyl and C3-6A cycloalkyl group;
or a R4And another R2、R3Or R4Together with the atoms to which they are attached form a 5 or 6 membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5 or 6 membered ring is saturated, unsaturated or aromatic; and wherein said 5 or 6 membered ring is optionally substituted with one, two or three substituents selected from halo, -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 and C1-6An alkyl group;
R5aselected from hydrogen and C1-C6An alkyl group;
each R25Independently selected from 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 halo, -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 R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl, -C3-C8Cycloalkyl-phenyl and C2-9Heterocyclic ring wherein C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl, -C3-C8Cycloalkyl-phenyl and C2-9The heterocyclic ring is optionally substituted with one, two OR three substituents selected from halo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14(ii) a Or two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9Heteroaryl group, wherein C2-9Heterocyclic or C2-9Heteroaryl is optionally substituted with one, two OR three substituents selected from halo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14；
Each R7Independently selected from C1-C6Alkyl radical, C3-C8Cycloalkyl and C2-9Heterocyclic ring wherein C3-C8Cycloalkyl and C2-9The heterocyclic ring is optionally substituted with one, two OR three substituents selected from halo, oxo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14；
Each R8Independently selected from hydrogen and C1-C6An alkyl group;
each R9Independently selected from hydrogen, halogen and C1-C6An alkyl group;
each R13Independently selected from hydrogen, C1-C6Alkyl and C3-C8A 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-C6Alkyl and C3-C8A cycloalkyl group;
n is 0, 1,2,3 or 4;
p is 0, 1,2 or 3; and is
q is 0, 1 or 2.
At one endIn some embodiments, R25Is 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 halo, -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, R25Is 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 halo, -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, R25Is 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 halo, -CN, C1-6Alkyl, -C1-6Alkyl radical-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, R25Selected 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 halo, -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, R25Selected 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 halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R25Is composed of
In some embodiments, R25Is composed of
Wherein R is11Is C1-C6Alkyl or C3-C6A cycloalkyl group.
In some embodiments, R25Is composed of
In some embodiments, R25Is composed of
In some embodiments, R25Selected from the group consisting of unsubstituted pyrazoles, unsubstituted imidazoles, unsubstituted thiazoles, and unsubstituted pyridines.
In some embodiments, R25Selected from the group consisting of pyrimidine, pyrazine and pyridazine; wherein the pyrimidine, pyrazine and pyridazine are optionally substituted by one or two substituents selected from halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R25Selected from halogen, -OR6、-N(R6)2、C1-6Alkyl, pyrazole, imidazole, thiazole and pyridine; wherein the pyrazole, imidazole, thiazole and pyridine are optionally substituted with one or two substituents selected from halo, C1-6Alkyl and C3-8A cycloalkyl group.
In some embodiments, R25Selected from halogen, -OR6、-N(R6)2、C1-6Alkyl and unsubstituted pyridine.
In some embodiments, R25is-C (═ O) N (R)6)2And each R6Independently selected from hydrogen, C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl, -C1-C6alkyl-C2-9heterocycle-C1-C6alkyl-C2-9Heteroaryl group, C3-C8Cycloalkyl and C2-9A heterocyclic ring.
In some embodiments, R25Is composed of
In some embodiments, R25Is composed of
Wherein R is10Is heteroaryl.
In some embodiments, R25is-C (═ O) N (R)6)2And two R on the same heteroatom6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9Heteroaryl group, wherein C2-9Heterocyclic or C2-9Heteroaryl is optionally substituted with one, two OR three substituents selected from halo, -OR8、-SR8、-N(R8)2、-C1-6Alkyl, -O-C1-6Alkyl, -C (═ O) R14、-C(＝O)OR13and-N (R)13)C(＝O)R14。
In some embodiments, R25Is composed of
In some embodiments, R25is-C (═ O) N (R)6)2And two R6Together with the heteroatom to which they are attached form C2-9Heterocyclic or C2-9A heteroaryl group.
In some embodiments, R25Is composed of
In some embodiments, R25is-OR6And R is6Is selected from C1-C6Alkyl, -C1-C6alkyl-O-C1-C6Alkyl and-C1-C6alkyl-C2-9A heterocyclic ring.
In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.
In some embodiments, Z is C (R)9)2. In some embodiments, Z is C (R)9)2And each R9Is H.
In some embodiments, Z is N (R)8). In some embodiments, Z is N (R)8) And each R8Is H. In some embodiments, Z is N (R)8) And each R8Is C1-C6An alkyl group.
In some embodiments of the present invention, the substrate is,
In some embodiments of the present invention, the substrate is,
In some embodiments, R1Is composed of
Wherein R is2Is C3-6A cycloalkyl group; r3Selected from hydrogen, C1-6Alkyl and C3-6A cycloalkyl group; each R4Independently selected from hydrogen, halogen, C1-6Alkyl and C3-6A cycloalkyl group; or a R4And another R2、R3Or R4Together with the atoms to which they are attached form a 5 or 6 membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5 or 6 membered ring is saturated, unsaturated or aromatic; and wherein said 5 or 6 membered ring is optionally substituted with one, two or three substituents selected from halo, -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, R1Is composed of
Wherein R is3Is selected from C1-6Alkyl and C3-6A cycloalkyl group; and is
Each R4Independently selected from hydrogen, halogen, C1-6Alkyl and C3-6A cycloalkyl group.
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
In some embodiments, R1Is composed of
Wherein X is N.
In some embodiments, R1Is composed of
A R4And another R2、R3Or R4Together with the atoms to which they are attached form a 5 or 6 membered ring optionally containing one or two heteroatoms selected from O, N and S; wherein the 5 or 6 membered ring is saturated, unsaturated or aromatic; and wherein said 5 or 6The ring is optionally substituted with one, two or three substituents selected from halo, -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, R1Is composed of
In some embodiments, R1Is composed of
In one aspect, presented herein are pharmaceutical compositions comprising a compound of formula I, formula II, or formula III, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
In one aspect, presented 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, formula II, or formula III, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments 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 pharmaceutically acceptable salt or solvate thereof. In some embodiments 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 II or a pharmaceutically acceptable salt or solvate thereof. In some embodiments 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 III or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the compounds disclosed herein are compounds of any one of compounds 1-89, or a pharmaceutically acceptable salt or solvate thereof.
In one aspect, the structure of the compounds described herein is selected from table 1.
Table 1:
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, the solvents, temperatures, and other reaction conditions illustrated herein may vary.
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 various substituents are synthesized using techniques and materials described herein or otherwise known, including those described in March, Advanced Organic Chemistry 4 th edition (Wiley 1992); carey and Sundberg, advanced Organic Chemistry 4 th edition, volumes A and B (Plenum 2000,2001) and Green and Wuts, protective groups in Organic Synthesis 3 rd edition (Wiley 1999). 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. A detailed description of suitable techniques for the creation and removal of protecting Groups is described in Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons, New York, NY,1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY,1994, the disclosures of which are incorporated herein by reference.
In some embodiments, compounds, such as compound 1, are prepared according to the route shown in scheme 1.
Scheme 1:
in some embodiments, a phenolic compound, such as 1A, is hydrazide with a suitable hydrazide reagent to provide a hydrazide phenolic compound, such as 1B. In some embodiments, a suitable hydrazide agent is hydrazine hydrate. In some embodiments, the hydrazide phenolic compound, such as 1B, is coupled with an appropriate formamide compound to provide a coupled hydrazide phenolic compound, such as 1C. In some embodiments, a suitable formamide compound is dimethylformamide dimethyl acetal. In some embodiments, the coupled hydrazide phenolic compound, such as 1C, is subjected to suitable reaction conditions to provide a polycyclic compound, such as 1D. In some embodiments, suitable reaction conditions include treatment with acetic acid. In some embodiments, the polycyclic compound is subjected to suitable reaction conditions to provide a compound, such as compound 1.
In one aspect, the compounds described herein are synthesized as described in the examples. Throughout the specification, groups and substituents thereof are selected by those skilled in the art to provide stable moieties and compounds.
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 described 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 compound with an optically active resolving agent to form a pair of diastereomeric compounds/salts, 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, separation of stereoisomers is performed by chromatography or by forming diastereomeric salts and separating by recrystallization or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H.Wilen, "Enantiomers, Racemates And solutions," 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 is understood that the resulting pharmaceutically acceptable salts include the solvent addition forms thereof. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed during crystallization with pharmaceutically acceptable 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 during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms.
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. Suitable formulations 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, Nineteenth Ed (Easton, Pa.: The Science and Practice of Pharmacy, Nineteenth 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, Marcel Decker, New York, N.Y.,1980, and Pharmaceutical document Systems, Wilppincott, all of which are incorporated herein by reference.
Provided herein are pharmaceutical compositions comprising a compound of formula I, formula II, or formula III, 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 thereof, and at least one pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a compound of formula II, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments is a pharmaceutical composition comprising a compound of formula III, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the compounds described herein are administered as a pharmaceutical composition in which a compound of formula I, formula II, or formula III, 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, formula II, or formula III, or a pharmaceutically acceptable salt thereof, with other chemical ingredients (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. The 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, formula II or formula III, 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 compressing processes.
The pharmaceutical composition will comprise at least one compound of formula I, formula II or formula III as the active ingredient in free acid or free base form or in pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides (if appropriate), crystalline forms, amorphous phases, and active metabolites of these compounds that have the same type of activity. 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 described herein are also considered disclosed herein.
The pharmaceutical compositions described herein comprising a compound of formula I, formula II, or formula III, 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 formula I, formula II, or formula III, 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 formula I, formula II, or formula III, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients to form a loosely blended (bulk 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, formula II, or formula III, or a pharmaceutically acceptable salt thereof, from the formulation. In other embodiments, the film coating aids in patient compliance (e.g.,
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, formula II, or formula III, 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 to release the formulation into gastrointestinal fluids 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.
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 granules of the active ingredient and/or other composition ingredients, 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 particles of a compound of formula I, formula II, or formula III, 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 particles of the compound of formula I, formula II or formula III, 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. In some embodiments, the aqueous dispersion may further comprise a crystallization inhibitor.
Buccal formulations comprising a compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt thereof, are administered using a variety of art-known formulations. 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, formula II, or formula III, 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) a formulation of a compound of formula I, formula II or formula III, 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, a compound of formula I, formula II, or formula III, 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.
Combination therapy
In certain instances, it may be suitable to administer at least one compound of formula I, formula II, or formula III, 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 itself have minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). 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, formula II, or formula III, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound of formula I, formula II, or formula III, 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, symptom, or condition being treated, the overall benefit experienced by the patient may simply be an 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 rhythmic 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 administration of the compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt thereof, begins 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, formula II or formula III, or a pharmaceutically acceptable salt thereof, and the second agent used in combination are administered simultaneously or at different times and/or at progressively decreasing or increasing intervals during the treatment period. Combination therapy also includes periodic therapies that start and stop at different times to aid in the clinical treatment of the patient.
It will be appreciated that the dosage regimen for treating, preventing or ameliorating the condition for which remission is sought may be modified depending on a variety of factors such as 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 further embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered 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 compound of formula I, formula II or formula III, or a pharmaceutically acceptable salt 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 compound-containing composition varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to a subject predisposed to developing 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 may vary, 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.
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