US 2025/0042853 A1Published application

Bicyclic compound and application thereof

AssigneeBetta Pharmaceuticals Co., Ltd.

InventorsRongwen YANG, Yun SUN, Jian ZHANG, Xuegang YI, Teng MA, Yu WANG, Pingping WANG, Lieming DING, Hong LAN, Jiabing WANG

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Abstract

The present invention relates to a compound as shown in formula (I). The present invention also provides a composition and preparation containing the compound, and a method for using and preparing the compound.

Claims34

Dependent claims

A compound as shown in formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof,

wherein represents a single bond or double bond;
X1, X2, X3 and X4 are each independently selected from C or N, and at least one of X1, X2, X3 and X4 is N;
W is selected from C, N, O or S;
R1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C6-C10 aryl, 5- to 18-membered heteroaryl, C5-C10 cycloalkyl, or 5- to 10-membered heterocyclyl;
wherein the 5- to 18-membered heteroaryl and 5- to 10-membered heterocyclyl contain 1, 2 or 3 heteroatoms each independently selected from N, O and S;
the C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C6-C10 aryl, 5- to 18-membered heteroaryl, C5-C10 cycloalkyl and 5- to 10-membered heterocyclyl can be optionally substituted with one or more substituents selected from H, halogen, —OH, —CN, oxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C5 cycloalkyl, C2-C6 alkynyl, C1-C6 haloalkyl, cyano-substituted C1-C6 alkyl, cyano-substituted C1-C6 haloalkyl, C1-C6 haloalkoxy, —C1-C6 alkylene-ORc, —C1-C6 alkylene-C═O—Rc, —NO2, —ORc, —SRc, —NRaRb, —C(═O)Rc, —C(═O)ORc, —C(═O)NRaRb, —NC(═O)Rc, —S(═O)Rc, —S(═O)2Rc, —S(═O)2NRaRb, —S(═O)(═NRa)Rb, —P(═O)RaRb or —P(═S)RaRb;
R3 is selected from H, deuterium, halogen, —NO2, —NRaRb, —CN, —OH, C1-C10 alkyl, C2-C10 alkenyl, C1-C5 haloalkyl, C1-C10 alkoxy, —O—C(═O)—C1-3 alkyl, —C(═O)—O—C1-3 alkyl or C2-C10 alkynyl, wherein the C1-C10 alkyl, C2-C10 alkenyl, C1-C5 haloalkyl, C1-C10 alkoxy, —O—C(═O)—C1-3 alkyl, —C(═O)—O—C1-3 alkyl, and C2-C10 alkynyl can be optionally substituted with one or more substituents selected from H, halogen, —CN, —OH, amino, C1-C5 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C1-C5 haloalkyl;
R4 and R5 are each independently selected from H, halogen, —NO2, —OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C5 cycloalkyl and 3- to 6-membered heterocyclyl;
the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C5 cycloalkyl and 3- to 6-membered heterocyclyl can be optionally substituted with one or more substituents selected from H, halogen, —CN, —OH, amino, oxo, C1-C5 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C1-C5 haloalkyl;
or R4 and R5 together form oxo;
or R4 and R5 together with the C atom to which they are attached form substituted or unsubstituted cyclopropyl;
R6 is selected from H, —CN, halogen, —NO2, —OH, —NO2, —NRaRb, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C5 cycloalkyl and 3- to 6-membered heterocyclyl;
the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C5 cycloalkyl and 3- to 6-membered heterocyclyl can be optionally substituted with one or more substituents selected from H, halogen, —CN, —OH, amino, oxo, C1-C5 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C1-C5 haloalkyl;
or two R6 together with the C atom to which they are attached form substituted or unsubstituted C3-C5 cycloalkyl or 3- to 5-membered heterocyclyl;
or R6 and R5 together with the C atom to which they are attached form substituted or unsubstituted C3-C4 cycloalkyl;
Rf is absent or selected from H, —CN, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, oxo, or —NRaRb;
the C1-C10 alkyl, C1-C10 haloalkyl and C3-C10 cycloalkyl can be optionally substituted with one or more substituents selected from H, halogen, —CN, —OH, amino, C1-C5 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C1-C5 haloalkyl;
R1 is selected from —C1-C6 alkylene-C(═O)Rc, —C1-C6 alkylene-C(═O)ORc, —C2F5, —C(═O)Rc, —C(═O)ORc, —SR, —S(═O)Rc, —S(═O)2R, or —S(═O)(═NRa)Rc, wherein the C1-C6 alkylene can be optionally substituted with one or more substituents selected from H, halogen, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy;
Ra and Rb are each independently selected from H, CN, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl or 5- to 10-membered heteroaryl;
Rc is selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C6 cycloalkyl and —NRaRb, wherein the C1-C10 alkyl, C1-C10 alkoxy and C3-C6 cycloalkyl can be optionally substituted with one or more substituents selected from H, halogen, CN, —NH2, oxo, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl;
n is 0 or 1;
m is 0, 1, 2, 3 or 4;
provided that the compound is not:
3-fluoro-5-(4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
3-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile;
3-(3-((difluoromethyl) sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile;
1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
(S)-5-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;
1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((S)-methylsulfoxyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((R)-methylsulfoxyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
3-fluoro-5-(5-fluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
(S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
2-chloro-5-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;
and
1-(3-chloro-5-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol.

34 more elements

A compound, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, wherein the compound is selected from:

1) 5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2,3-difluorobenzonitrile;
2) 5,5-difluoro-1-(4-fluoro-3-(fluoromethyl)phenyl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
3) (S)-4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile;
4) (S)-5-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;
5) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
6) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol;
7) (S)-3-((S)-(difluoromethyl)sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
8) (S)-3-((R)-(difluoromethyl) sulfinyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
9) 5-(5,5-difluoro-4-hydroxyl-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;
10) (S)-5-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;
11) (S)-5-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;
12) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
13) (S)-2-((5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile;
14) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
15) 2-(1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetamide;
16) (S)-3-(ethylsulfonyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
17) 5-(3-(cyanodifluoromethyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;
18)N—(((S)-1-(3-cyano-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)(methyl)(oxo)-16-sulfino)cyanamide;
19) (S)-2-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)acetonitrile;
20) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
21) (S)-3-((difluoromethyl) sulfonyl)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
22) (S)-5-(3-((difluoromethyl)sulfonyl)-2,5,5-trifluoroether-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;
23) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
24) 1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
25) 1-(3-chloro-4-fluorophenyl)-3-((difluoromethyl) sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol;
26) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl) sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol;
27) (S)-2-chloro-5-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
28) (S)-2-chloro-5-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
29) (S)-4-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile;
30) (S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-((fluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
31) (S)-4-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile;
32) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
33) (S)-1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
34) (S)-4-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile;
35) (S)-4-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile;
36) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(trifluoromethyl)benzonitrile;
37) (S)-1-(3-chloro-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
38) (S)-4-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile;
39) (S)-4-(3-((difluoromethyl)sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile;
40) (S)-2-chloro-5-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
41) 4-(5,5-difluoro-4-hydroxyl-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile;
42) (S)-4-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile;
43) (S)-2-(difluoromethyl)-4-(3-((difluoromethyl) sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
44) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(difluoromethyl)benzonitrile;
45) (S)-4-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile;
46) (S)-4-(5,5-difluoro-4-hydroxyl-3-(perfluoroethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)phthalonitrile;
47) 2-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)-2-fluoroacetonitrile;
48) ethyl (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetate;
49) (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetonitrile;
50) (S)-2-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-2,2-difluoroacetamide;
51) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(thiazol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
52) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
53) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(oxazol-2-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
54) (S)-2-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl) sulfonyl)-2,2-difluoroacetonitrile;
55) 2-(((S)-5,5-difluoro-1-(4-fluoro-3-(trifluoromethyl)phenyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl)-2-fluoroacetonitrile;
56) (S)-(1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)dimethylphosphine oxide methyl;
57) 2-(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)sulfonyl) propanenitrile;
58) (S)-1-((1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl) sulfonyl)cyclopropane-1-nitrile;
59)N—(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)(methyl)(oxo)-16-sulfino)cyanamide;
60) ethyl (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate;
61) (R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
62) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;
63) (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5-fluoro-4,5,6,7-tetrahydro-1H-indol-4-ol;
64) (4S,5S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl) sulfonyl)-5-fluoro-4,5,6,7-tetrahydro-1H-indol-4-ol;
65) (R)-2-(difluoromethyl)-4-(4-hydroxyl-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
66) (S)-4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-3-fluorobenzonitrile;
67) (4S)—1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl) sulfinyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
68) (S)-1-((R)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
69) (S)-1-((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
70) (S)-1-(2,4-difluorobenzyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
71) (S)-2-((5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)methyl)-5-fluorobenzonitrile;
72) (S)-1-(2,4-difluorophenyl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
73)N—(((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)(oxy)(trifluoromethyl)-16-sulfino)cyanamide;
74)N-((difluoromethyl)((S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-3-yl)(oxo)-16-sulfino)cyanamide;
75) (S)-2-(5-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorophenyl)acetonitrile;
76) (S)-4-(5,5-difluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(fluoromethyl)benzonitrile;
77) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((fluoromethyl) sulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol;
78) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol;
79) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol;
80) (S)-1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-1,4,5,6-tetrahydrocyclopentadiene[b]pyrrol-4-ol;
81) (S)-5-(5,5-difluoro-4-hydroxyl-3-((trifluoromethyl)sulfonyl)-5,6-dihydrocyclopentadiene[b]pyrrol-1(4H)-yl)-yl2-fluorobenzonitrile;
82) (S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroindol-8-ol;
83) (S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7,7-difluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol;
84) (7R,8S)-3-(3-(difluoromethyl)-4-fluorophenyl)-7-fluoro-1-((trifluoromethyl)sulfonyl)-5,6,7,8-tetrahydroindolizin-8-ol;
85) 1-(3-(difluoromethyl)-4-fluorophenyl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-1,4,5,7-tetrahydropyran[3,4-b]pyrrol-4-ol;
86) 2-(difluoromethyl)-4-((4S,5R)-3-((difluoromethyl)sulfonyl)-5-fluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
87) 2-(difluoromethyl)-4-((4S,5R)-5-fluoro-4-hydroxyl-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
88) (S)-5,5-difluoro-1-(imidazo[1,2-a]pyridin-8-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
89) (4S,5R)-1-(3-(difluoromethyl)-4-fluorophenyl)-5-fluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
90) (S)-8-(5,5-difluoro-3-((fluoromethyl)sulfonyl)-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluoro-1-naphthonitrile;
91) (S)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1-(4-fluoro-5,6,7,8-tetrahydronaphthalen-1-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
92) (S)-5,5-difluoro-1-(quinolin-8-yl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
93) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
94) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
95) (4S)-1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-3-((difluoromethyl) sulfonyl)-5,5-difluoro-4,5,6,7-tetrahydro-1H-indol-4-ol;
96) 1-(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-5,5-difluoro-3-((fluoromethyl) sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
97) (4S)—1-(5,7difluoro-2,3-dihydro-1H-inden-1-yl)-5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
98) (4S)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
99) (4S)-5,5-difluoro-3-(methylsulfonyl)-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
100) 5,5-difluoro-3-((fluoromethyl)sulfonyl)-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
101) (4S)-3-((difluoromethyl) sulfonyl)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
102) (4S)-5,5-difluoro-1-(5,6,7,8-tetrahydroquinolin-8-yl)-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
103) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxyl-3-((trifluoromethyl)thio)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
104) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxyl-3-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
105) 2-fluoro-5-(5-fluoro-4-hydroxyl-3-(trifluoromethyl)-4,7-dihydropyran[3,4-b]pyrrol-1(5H)-yl)benzonitrile;
106) 2-fluoro-5-(2,5,5-trifluoro-4-hydroxyl-3-(thien-2-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
or
107) 2-(difluoromethyl)-4-(5-fluoro-4-hydroxyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile.

105 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/706,666Filed 3 Nov 2022
Priority: WO PCT/CN2021/1282392 Nov 2021
Published: 6 Feb 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

A61P 35/00
Antineoplastic agents
C07D 209/22
Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals: with…
A61K 31/403
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: condensed with…
A61K 31/407
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: condensed with other…

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Abstract

A compound as shown in formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof,

wherein represents a single bond or double bond;
X1, X2, X3 and X4 are each independently selected from C or N, and at least one of X1, X2, X3 and X4 is N;
W is selected from C, N, O or S;
R1 is selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C6-C10 aryl, 5- to 18-membered heteroaryl, C5-C10 cycloalkyl, or 5- to 10-membered heterocyclyl;
wherein the 5- to 18-membered heteroaryl and 5- to 10-membered heterocyclyl contain 1, 2 or 3 heteroatoms each independently selected from N, O and S;
the C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C6-C10 aryl, 5- to 18-membered heteroaryl, C5-C10 cycloalkyl and 5- to 10-membered heterocyclyl can be optionally substituted with one or more substituents selected from H, halogen, —OH, —CN, oxo, amino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C5 cycloalkyl, C2-C6 alkynyl, C1-C6 haloalkyl, cyano-substituted C1-C6 alkyl, cyano-substituted C1-C6 haloalkyl, C1-C6 haloalkoxy, —C1-C6 alkylene-ORc, —C1-C6 alkylene-C═O—Rc, —NO2, —ORc, —SRc, —NRaRb, —C(═O)Rc, —C(═O)ORc, —C(═O)NRaRb, —NC(═O)Rc, —S(═O)Rc, —S(═O)2Rc, —S(═O)2NRaRb, —S(═O)(═NRa)Rb, —P(═O)RaRb or —P(═S)RaRb;
R3 is selected from H, deuterium, halogen, —NO2, —NRaRb, —CN, —OH, C1-C10 alkyl, C2-C10 alkenyl, C1-C5 haloalkyl, C1-C10 alkoxy, —O—C(═O)—C1-3 alkyl, —C(═O)—O—C1-3 alkyl or C2-C10 alkynyl, wherein the C1-C10 alkyl, C2-C10 alkenyl, C1-C5 haloalkyl, C1-C10 alkoxy, —O—C(═O)—C1-3 alkyl, —C(═O)—O—C1-3 alkyl, and C2-C10 alkynyl can be optionally substituted with one or more substituents selected from H, halogen, —CN, —OH, amino, C1-C5 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C1-C5 haloalkyl;
R4 and R5 are each independently selected from H, halogen, —NO2, —OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C5 cycloalkyl and 3- to 6-membered heterocyclyl;
the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C5 cycloalkyl and 3- to 6-membered heterocyclyl can be optionally substituted with one or more substituents selected from H, halogen, —CN, —OH, amino, oxo, C1-C5 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C1-C5 haloalkyl;
or R4 and R5 together form oxo;
or R4 and R5 together with the C atom to which they are attached form substituted or unsubstituted cyclopropyl;
R6 is selected from H, —CN, halogen, —NO2, —OH, —NO2, —NRaRb, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C5 cycloalkyl and 3- to 6-membered heterocyclyl;
the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C5 cycloalkyl and 3- to 6-membered heterocyclyl can be optionally substituted with one or more substituents selected from H, halogen, —CN, —OH, amino, oxo, C1-C5 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C1-C5 haloalkyl;
or two R6 together with the C atom to which they are attached form substituted or unsubstituted C3-C5 cycloalkyl or 3- to 5-membered heterocyclyl;
or R6 and R5 together with the C atom to which they are attached form substituted or unsubstituted C3-C4 cycloalkyl;
Rf is absent or selected from H, —CN, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, oxo, or —NRaRb;
the C1-C10 alkyl, C1-C10 haloalkyl and C3-C10 cycloalkyl can be optionally substituted with one or more substituents selected from H, halogen, —CN, —OH, amino, C1-C5 alkyl, C1-C6 alkoxy, C2-C6 alkenyl or C1-C5 haloalkyl;
R1 is selected from —C1-C6 alkylene-C(═O)Rc, —C1-C6 alkylene-C(═O)ORc, —C2F5, —C(═O)Rc, —C(═O)ORc, —SR, —S(═O)Rc, —S(═O)2R, or —S(═O)(═NRa)Rc, wherein the C1-C6 alkylene can be optionally substituted with one or more substituents selected from H, halogen, cyano, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy;
Ra and Rb are each independently selected from H, CN, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10 aryl or 5- to 10-membered heteroaryl;
Rc is selected from C1-C10 alkyl, C1-C10 alkoxy, C3-C6 cycloalkyl and —NRaRb, wherein the C1-C10 alkyl, C1-C10 alkoxy and C3-C6 cycloalkyl can be optionally substituted with one or more substituents selected from H, halogen, CN, —NH2, oxo, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C3-C6 cycloalkyl;
n is 0 or 1;
m is 0, 1, 2, 3 or 4;
provided that the compound is not:
3-fluoro-5-(4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
3-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile;
3-(3-((difluoromethyl) sulfonyl)-5,5-difluoro-4-hydroxyl-4,5,6,7-tetrahydro-1H-indol-1-yl)-5-fluorobenzonitrile;
1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
1-(3-chloro-5-fluorophenyl)-5,6-difluoro-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
(S)-5-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)-2-fluorobenzonitrile;
1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((S)-methylsulfoxyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-((R)-methylsulfoxyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
3-fluoro-5-(5-fluoro-4-hydroxyl-3-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indol-1-yl)benzonitrile;
(S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-(methylsulfonyl)-2-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indol-4-ol;
2-chloro-5-(5,5-difluoro-4-hydroxyl-3-(methylsulfonyl)-5,6-dihydrocyclopenta[b]pyrrol-1(4H)-yl)benzonitrile;
and
1-(3-chloro-5-fluorophenyl)-3-((difluoromethyl)sulfonyl)-5,5-difluoro-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-4-ol.

34 more elements

Facts

Application

18/706,666Filed 3 Nov 2022

Priority

WO PCT/CN2021/1282392 Nov 2021

Published

6 Feb 2025

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

A61P 35/00
Antineoplastic agents
C07D 209/22
Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals: with…
A61K 31/403
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: condensed with…
A61K 31/407
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: condensed with other…