Pyrazolo fused heterocyclic compounds as ERK inhibitors
Disclosed herein is a compound of formula (I) and/or a pharmaceutically acceptable salt thereof that can serve as Erk inhibitors. They are potentially useful in the treatment of diseases treatable by inhibition of Erk, such as cancers. Also disclosed herein is a pharmaceutical composition, comprising a compound of formula I and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
1. A compound of formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
Z 1 and Z 2 are independently CH,
R 1 is H or alkyl,
R 2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein each of the aryl, cycloalkyl, alkyl, alkoxy, and heterocycloalkyl is optionally substituted with at least one group chosen from halo, hydroxyl, —CN, —CO 2 H, —CONR 3 R 4 , —SO 2 NR 3 R 4 , oxo, alkyl optionally substituted with at least one group chosen from halo and alkoxy, and alkoxy optionally substituted with at least one group chosen from halo and alkoxy, wherein the heteroaryl is substituted with at least one group chosen from halo, hydroxyl, —CN, —CO 2 H, —CONR 3 R 4 , —SO 2 NR 3 R 4 , alkyl optionally substituted with at least one group chosen from halo and alkoxy, and alkoxy optionally substituted with at least one group chosen from halo and alkoxy,
R 3 and R 4 are independently chosen from H and alkyl optionally substituted with at least one alkoxy, or R 3 and R 4 , together with the nitrogen to which they are attached form a heterocyclyl ring, wherein in the —SO 2 NR 3 R 4 group, R 3 and R 4 are not both H,
R 5 is independently chosen from H and alkyl optionally substituted with at least one alkoxy,
L 1 is a pyrrolidinyl which is optionally substituted with at least one group chosen from halo, —SO 2 alkyl, and alkyl, wherein the alkyl is optionally substituted with at least one group chosen from halo, hydroxyl, and alkoxy;
L 2 is
aryl optionally substituted with at least one group chosen from halo, —SO 2 alkyl, and alkyl, wherein the alkyl is optionally substituted with at least one group chosen from halo, hydroxyl, and alkoxy,
heteroaryl optionally substituted with at least one group chosen from halo, —SO 2 alkyl, and alkyl, wherein the alkyl is optionally substituted with at least one group chosen from halo, hydroxyl, and alkoxy,
cycloalkyl optionally substituted with at least one group chosen from halo, —SO 2 alkyl and alkyl, wherein the alkyl is optionally substituted with at least one group chosen from halo, hydroxyl and alkoxy,
heterocycloalkyl optionally substituted with at least one group chosen from halo, —SO 2 alkyl, and alkyl, wherein the alkyl is optionally substituted with at least one group chosen from halo, hydroxyl, and alkoxy, or
with indicating the point of attachment to the neighboring group,
L 3 is
H,
aryl optionally substituted with at least one group chosen from halo; alkyl optionally substituted with at least one group chosen from halo and alkoxy; aryl; heteroaryl; cycloalkyl; and heterocycloalkyl; wherein each of the last four groups: aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, is optionally substituted with at least one group chosen from alkyl, halo, aryl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, cycloalkyl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, heterocycloalkyl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, and heteroaryl optionally substituted with at least one group chosen from halo, alkyl and alkoxy,
heteroaryl optionally substituted with at least one group chosen from halo; alkyl optionally substituted with at least one group chosen from halo and alkoxy; aryl; heteroaryl; cycloalkyl; and heterocycloalkyl; wherein each of the last four groups: aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, is optionally substituted with at least one group chosen from alkyl, halo, aryl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, cycloalkyl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, heterocycloalkyl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, and heteroaryl optionally substituted with at least one group chosen from halo, alkyl and alkoxy,
cycloalkyl optionally substituted with at least one group chosen from halo; alkyl optionally substituted with at least one group chosen from halo and alkoxy; aryl; heteroaryl; cycloalkyl; and heterocycloalkyl; wherein each of the last four groups: aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, is optionally substituted with at least one group chosen from alkyl, halo, aryl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, cycloalkyl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, heterocycloalkyl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, and heteroaryl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, or
heterocycloalkyl optionally substituted with at least one group chosen from halo; alkyl optionally substituted with at least one group chosen from halo and alkoxy; aryl; heteroaryl; cycloalkyl; and heterocycloalkyl; wherein each of the last four groups: aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, is optionally substituted with at least one group chosen from alkyl, halo, aryl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, cycloalkyl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, heterocycloalkyl optionally substituted with at least one group chosen from halo, alkyl and alkoxy, and heteroaryl optionally substituted with at least one group chosen from halo, alkyl and alkoxy,
provided that when R 2 is a heterocycloalkyl, the heterocycloalkyl is not piperazinyl.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 is a phenyl, optionally substituted with at least one group chosen from halo and alkyl, wherein the alkyl is optionally substituted with at least one group chosen from halo and alkoxy.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is a heteroaryl chosen from pyridinyl, benzo[d]thiazole, and imidazolyl, each of which is substituted with at least one group chosen from alkyl, alkoxy, halo, hydroxyl, —CN, haloalkyl, —CO 2 H, —CONR 3 R 4 , and —SO 2 NR 3 R 4 .
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is a pyridinyl optionally substituted with at least one group chosen from alkyl, alkoxy, halo, hydroxyl, —CN, haloalkyl, —CO 2 H, —CONR 3 R 4 , and —SO 2 NR 3 R 4 .
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L 3 is H.
7. The compound of claim 1 , which is chosen from
N-((3R,4S)-4-(2-fluorophenyl)-1-methylpyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide,
N-((3S,4R)-4-(2-fluorophenyl)-1-methylpyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide,
a mixture of N-((3R,4S)-4-(2-fluorophenyl)-1-methylpyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide and N-((3S,4R)-4-(2-fluorophenyl)-1-methylpyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide,
N-((3R,4S)-4-(2-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide,
N-((3S,4R)-4-(2-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide,
a mixture of N-((3R,4S)-4-(2-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide and N-((3S,4R)-4-(2-chlorophenyl)-1-methylpyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide,
N-((3S,4R)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide,
N-((3R,4S)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide, and
a mixture of N-((3S,4R)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide and N-((3R,4S)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide;
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , which is chosen from
N-((3S,4R)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide,
N-((3R,4S)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide, and
a mixture of N-((3S,4R)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide and N-((3R,4S)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamide;
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.