Phenyl- and pyridopyrazole derivatives as inhibitors of DDR1
This invention relates to novel compounds and pharmaceutical compositions comprising novel isoquinolone compounds. More specifically, the invention relates to compounds useful as inhibitors of discoidin domain receptor 1 (DDR1) and discoidin domain receptor 2 (DDR2). The compounds are particularly useful in the treatment of cancer and fibrotic diseases.
1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein
Z 1 and Z 2 are each selected from —CR 8a — and —NR 8b —, wherein one of Z 1 and Z 2 is —CR 8a — and the other is —NR 8b —; and wherein the ring comprising Z 1 and Z 2 is a pyrazole;
X 1 is independently selected from CR 7a and N;
R 1 and R 2 are each independently selected at each occurrence from halo, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 , CONR 9 R 9 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 9 R 10 , C 1 -C 4 -alkyl substituted with OR 11 , C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl and cyclopropyl;
R 3 is independently selected from H and C 1 -C 4 -alkyl;
R 4 is independently selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 0 -C 4 -alkylene-R 4a ; wherein R 4a is independently selected from: C 3 -C 8 -cycloalkyl, phenyl, 5-, 6-, 9- or 10-membered heteroaryl and 4- to 10-membered heterocycloalkyl; wherein said heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; wherein said cycloalkyl or heterocycloalkyl group is optionally substituted with a single R 12 group and/or from 1 to 4 R 13 groups and wherein said phenyl or heteroaryl group is optionally substituted with a single R 12 group and/or from 1 to 3 R 14 groups;
or R 3 and R 4 , together with the nitrogen atom to which they are attached together form a 4- to 10-membered heterocycloalkyl group or a 5-, or 9-membered heteroaryl group; wherein said heterocycloalkyl or heteroaryl group may be monocyclic or bicyclic; wherein said heterocycloalkyl group is optionally substituted with a single R 12 group and/or from 1 to 4 R 13 groups and wherein said heteroaryl group is optionally substituted with a single R 12 group and/or from 1 to 3 R 14 groups;
R 5 is independently at each occurrence selected from H, halo and C 1 -C 4 -alkyl, or the two R 5 groups and the carbon atom to which they are attached may together form a C 3 -C 6 cycloalkyl ring;
R 6 is independently selected from H, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and cyclopropyl;
R 7 and R 7a are each independently selected from H, halo, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 , CONR 9 R 9 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 9 R 10 , C 1 -C 4 -alkyl substituted with OR 11 , C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl and cyclopropyl;
R 8a is independently selected from H, halo, nitro, cyano, NR 9 R 10 , OR 11 , SR 9 , SO 2 NR 9 R 9 , SO 2 R 9 , CO 2 R 9 , C(O)R 9 , CONR 9 R 9 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with NR 9 R 10 , C 1 -C 4 -alkyl substituted with OR 11 , C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl and C 0 -C 4 -alkylene-R 8c ;
R 8b is independently selected from H, C 1 -C 4 -alkyl, C 2 -C 4 -alkyl substituted with NR 9 R 10 , C 2 -C 4 -alkyl substituted with OR 11 , C 3 -C 4 -alkenyl, C 3 -C 4 -alkynyl, C 1 -C 4 -haloalkyl and C 0 -C 4 -alkylene-R 8c ;
R 8c is independently selected from C 3 -C 6 -cycloalkyl and 3- to 7-membered heterocycloalkyl; wherein said heterocycloalkyl group is attached to the C 0 -C 4 -alkylene via a carbon atom in the heterocycloalkyl ring; wherein said cycloalkyl or heterocycloalkyl group is optionally substituted with from 1 to 4 R 13 groups;
R 9 is independently at each occurrence selected from H and C 1 -C 4 -alkyl; or two R 9 groups, together with the nitrogen atom to which they are attached together form a C 5 -C 8 -heterocycloalkyl group optionally substituted with from 0 to 4 R 13 groups;
R 10 is independently at each occurrence selected from H, C 1 -C 4 -alkyl, C(O)—C 1 -C 4 -alkyl and S(O) 2 —C 1 -C 4 -alkyl; or R 9 and R 10 , together with the nitrogen atom to which they are attached together form a C 5 -C 8 -heterocycloalkyl group optionally substituted with from 0 to 4 R 13 groups;
R 11 is independently at each occurrence selected from H, C 1 -C 4 -alkyl, C(O)—C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl;
R 12 is independently selected from C 3 -C 6 -cycloalkyl, phenyl, 5- or 6-membered heteroaryl and 3- to 6-membered-heterocycloalkyl; wherein said cycloalkyl or heterocycloalkyl group is optionally substituted with from 1 to 4 R 13 groups and wherein said phenyl or heteroaryl group is optionally substituted with from 1 to 3 R 14 groups;
R 13 is independently at each occurrence selected from ═O, halo, nitro, cyano, NR 8 R 9 , OR 14 , SR 8 , SO 2 NR 8 R 8 , CO 2 R 8 , C(O)R 8 , CONR 8 R 8 , C 1 -C 4 -alkyl, C 1 -C 4 -alkyl substituted with OR 11 , C 1 -C 4 -alkyl substituted with NR 9 R 10 , C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, C 6 -C 10 -aryl, and C 3 -C 6 -cycloalkyl;
R 14 is independently at each occurrence selected from halo, nitro, cyano, NR 8 R 9 , OR 10 , SR 8 , SO 2 R 8 , SO 2 NR 8 R 8 , CO 2 R 8 , C(O)R 8 , CONR 8 R 9 , C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkyl substituted with OR 11 , C 1 -C 4 -alkyl substituted with NR 8 R 9 and cyclopropyl;
m is an integer selected from 0, 1, 2 and 3;
n is an integer selected from 0, 1 and 2;
wherein any of the aforementioned alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: halo, oxo, fluoro, nitro, cyano, NR a R b , OR a , SR a , CO 2 R a , C(O)R a , CONR a R a , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and cyclopropyl; wherein R a is independently at each occurrence selected from H, C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; and R b is independently at each occurrence selected from H, C 1 -C 4 -alkyl, C(O)—C 1 -C 4 -alkyl and S(O) 2 -C 1 -C 4 -alkyl.
2 . The compound of claim 1 wherein Z 1 is NR 8b and Z 2 is CH.
3 . The compound of claim 1 , wherein Z 1 is CR 8a and Z 2 is NH.
4 . The compound of claim 1 , wherein m is 0.
5 . The compound of claim 1 , wherein m is 1.
6 . The compound of claim 5 , wherein the single R 1 group is F and is situated ortho to NR 6 .
7 . The compound of claim 1 , wherein n is 0.
8 . The compound of claim 1 , wherein R 5 is at each occurrence H.
9 . The compound of claim 1 , wherein R 6 is H.
10 . The compound of claim 1 , wherein R 7 is H.
11 . The compound of claim 1 , wherein X 1 is N.
12 . The compound of claim 1 , wherein X 1 is CR 7a .
13 . The compound of claim 1 , wherein R 3 is H and R 4 is selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl and C 0 -C 4 -alkylene-R 4a .
14 . The compound of claim 13 , wherein R 4 is selected from C 1 -C 6 -alkyl and C 1 -C 6 -haloalkyl.
15 . The compound of claim 13 , wherein R 4 is R 4a .
16 . The compound of claim 15 , wherein R 4a is selected from C 3 -C 8 -cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl group is optionally substituted with from 1 to 4 R 13 groups.
17 . The compound of claim 15 , wherein R 4a is independently selected from: phenyl and 5- or 6-membered heteroaryl; wherein said phenyl or heteroaryl group is optionally substituted with a single R 12 group and/or from 1 to 3 R 14 groups.
18 . The compound of claim 1 , wherein R 3 and R 4 , together with the nitrogen atom to which they are attached together form a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with from 1 to 4 R 13 groups.
19 . The compound of claim 1 , wherein NR 3 R 4 has the formula
wherein
R 4b is at each occurrence selected from H and F; wherein at least two R 4b groups are F,
R 3a is independently selected from H and C 1 -C 4 -alkyl;
R 4c is independently selected from H, C 1 -C 4 -alkyl and C 4 -C 6 -cycloalkyl; or
R 3a and R 4c , together with the carbon and nitrogen to which they are attached, form a 4- to 6-membered heterocycloalkyl group.
20 . The compound of claim 1 , wherein the compound of formula (I) is selected from:
21 . A pharmaceutical composition, comprising a compound of claim 1 ; and a pharmaceutically acceptable excipient.
22 . A method of treating a disease or disorder selected from renal conditions, liver conditions, inflammatory conditions, cardiovascular conditions, acute and chronic organ transplant rejection, fibrotic diseases and cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .