Substituted 6,5-fused bicyclic heteroaryl compounds
View Patent ↗The present invention relates to substituted 6,5-fused bicyclic heteroaryl compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof.
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
each of R 1 , R 5 , R 9 , and R 10 , independently, is H or C 1 -C 6 alkyl;
each of R 2 , R 3 , and R 4 , independently, is -Q 1 -T 1 , in which Q 1 is a bond or C 1 -C 3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 1 is H, halo, hydroxyl, COOH, cyano, or R S1 , in which R S1 is C 1 -C 3 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C(O)O—C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, 4 to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R S1 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
R 6 is H, halo, C 1 -C 3 alkyl substituted with one or more -Q 2 -T 2 , C 2 -C 6 alkenyl, C 4 -C 6 cycloalkyl, C(O)H, OR a , —C(O)R a , phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, or 4 to 7-membered heterocycloalkyl, in which R a is C 1 -C 6 alkyl or 4 to 7-membered heterocycloalkyl, and each of the phenyl, the 5 to 6-membered heteroaryl, and the 4 to 7-membered heterocycloalkyl is optionally substituted with one or more -Q 2 -T 2 , wherein Q 2 is a bond or C 1 -C 3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 2 is H, halo, cyano, —OR c , —NR c R d , —(NR c R d R d ) + A − , —C(O)R c , —C(O)OR c ,—C(O)NR c R d , —NR d C(O)R c , —NR d C(O)OR c , —S(O) 2 R c , —S(O) 2 NR c R d , or R S4 , in which each of R c R d , and R d′ , independently is H or R S5 , A − is a pharmaceutically acceptable anion, each of R S4 and R S5 , independently, is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, or R c and R d , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom, and each of R S4 , R S5 , and the 4 to 7-membered heterocycloalkyl ring containing R c and R d , is optionally substituted with one or more -Q 3 -T 3 , wherein Q 3 is a bond or C 1 -C 3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 3 is selected from the group consisting of H, halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, 5 to 6-membered heteroaryl, OR e , COOR e , —S(O) 2 R e ,—NR e R f , and —C(O)NR e R f , each of R e and R f independently being H or C 1 -C 6 alkyl; or -Q 3 -T 3 is oxo; or -Q 2 -T 2 is oxo; or any two neighboring -Q 2 -T 2 , together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, and 5 to 6-membered heteroaryl; provided that -Q 2 -T 2 is not H; and
R 7 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 4 to 7-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 , wherein Q 5 is a bond, C(O), or C 1 -C 3 alkyl linker, and T 5 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, or 5 to 6-membered heteroaryl and T 5 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, and 5 to 6-membered heteroaryl except when T 5 is H, halo, hydroxyl, or cyano; or -Q 5 -T 5 is oxo;
provided that the compound is not
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2,5-dimethylthiophen-3-yl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide,
6-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide,
or
6-cyclopropyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide.
2. The compound of claim 1 , wherein R 6 is phenyl substituted with one or more -Q 2 -T 2 ; or R 6 is 5 to 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S and optionally substituted with one or more -Q 2 -T 2 , provided that the heteroaryl is not thiophenyl; or R 6 is halo, C 1 -C 3 alkyl substituted with one or more -Q 2 -T 2 , C 2 -C 6 alkenyl, C 4 -C 6 cycloalkyl, C(O)H, OR a , or —C(O)R a , in which R a is C 1 -C 6 alkyl or 4 to 7-membered heterocycloalkyl; or R 6 is 4 to 7-membered heterocycloalkyl optionally substituted with one or more -Q 2 -T 2 , in which -Q 2 -T 2 is oxo or Q 2 is a bond and T 2 is —OR c , —NR c R d , —C(O)R c , —C(O)OR c , —S(O) 2 R c , C 1 -C 6 alkyl, or 4 to 7-membered heterocycloalkyl, each of which is optionally substituted with one or more -Q 3 -T 3 when R c or R d is not H.
3. The compound of claim 1 , wherein R 7 is 5 to 6-membered heterocycloalkyl optionally substituted with one or more -Q 5 -T 5 .
4. The compound of claim 1 , wherein T 5 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, or 4 to 7-membered heterocycloalkyl; or Q 5 is a bond and T 5 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or 4 to 7-membered heterocycloalkyl; or Q 5 is CO and T 5 is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 3 -C 8 cycloalkyl, or 4 to 7-membered heterocycloalkyl; or Q 5 is C 1 -C 3 alkyl linker and T 5 is H or C 6 -C 10 aryl.
5. The compound of claim 1 , wherein each of R 2 and R 4 , independently is H or C 1 -C 6 alkyl optionally substituted with amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, or C 6 -C 10 aryl.
6. The compound of claim 1 , wherein R 1 is H.
7. The compound of claim 1 , wherein R 3 is H.
8. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
9. The compound of claim 2 , wherein R 6 is phenyl or a 5 to 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, which is substituted with one or more -Q 2 -T 2 .
10. The compound of claim 2 , wherein R 6 is phenyl which is substituted with one or more -Q 2 -T 2 .
11. The compound of claim 9 , wherein Q 2 is an unsubstituted C 1 -C 3 alkyl linker.
12. The compound of claim 9 , wherein T 2 is a 4- to 7-membered heterocycloalkyl optionally substituted with one or more -Q 3 -T 3 .
13. The compound of claim 1 , wherein Q 2 is an unsubstituted C 1 -C 3 alkyl linker.
14. The compound of claim 1 , wherein T 2 is a 4- to 7-membered heterocycloalkyl optionally substituted with one or more -Q 3 -T 3 .
15. The compound of claim 1 , wherein T 2 is —OR c , —NR c R d , —C(O)R c , —C(O)OR c , or —S(O) 2 R c .
16. The compound of claim 1 , wherein R 2 and R 4 are methyl.
17. The compound of claim 1 , wherein R 5 , R 9 , and R 10 is H.
18. A compound of claim 1 selected from:
Compound
Number
Structure
A-1
A-2
A-3
A-4
A-5
A-6
A-7
A-8
A-9
A-10
A-11
A-12
A-13
A-14
A-15
A-16
A-17
A-18
A-19
A-20
A-21
A-22
A-23
A-24
A-25
A-26
A-27
A-28
A-29
A-30
A-31
A-32
A-33
A-34
A-35
A-36
A-37
A-38
A-39
A-40
A-41
A-42
A-43
A-44
A-45
A-46
A-48
A-49
A-50
A-51
A-52
A-53
A-54
A-55
A-56
A-57
A-58
A-59
A-60
A-61
A-62
A-63
A-64
A-66
A-67
A-68
A-69
A-70
A-72
A-73
A-74
A-75
A-76
A-77
A-78
A-91
A-92
A-93
A-95
A-96
A-97
A-98
A-99
A-100
A-101
A-102
A-103
A-104
A-105
A-106
A-107
A-108
A-110
A-125
A-126
19. A compound of claim 1 selected from:
Compound
Number
Structure
B-1
B-2
B-4
B-5
B-6
B-7
B-8
B-9
B-10
B-11
B-14
B-15
B-16
B-17
B-19
B-20
B-21
B-23
B-24
B-25
B-27
B-28
B-29
B-30
B-31
B-32
B-33
B-34
B-35
B-36
B-37
B-38
B-39
B-40
B-41
B-42
B-43
B-44
B-45
B-46
B-47
B-48
B-49
B-50
B-51
B-52
B-53
B-54
B-55
B-56
B-57
B-58
B-59
B-60
B-61
B-62
B-63
B-64
B-65
B-66
B-67
B-68
B-69
B-70
B-71
B-72
B-73
B-74
B-75
B-76
B-77
B-78
B-79
B-80
B-81
B-82
B-83
B-84
B-85
B-86
B-87
B-88
B-89
B-92
B-94
B-95
B-96
B-98
B-99
B-100
B-101
B-102
B-103
B-104
B-105
B-106
B-107
B-108
B-110
B-112
B-113
B-115
B-116
B-118
B-119
B-122
B-123
B-126
B-129
B-130
B-131
B-137
B-138
B-139
B-142
B-143
B-144
B-145
B-146
B-148
B-151
B-152
B-153
B-156
B-164