Substituted benzimidazoles and benzopyrazoles as ccr(4) antagonists

Patent metadata

Field	Value
Publication number	US-2016185756-A1
Application number	US-201514834836-A
Country	US
Kind code	A1
Filing date	Aug 25, 2015
Priority date	Dec 1, 2011
Publication date	Jun 30, 2016
Grant date	—

Abstract

Benzimidazole, benzopyrazole and benzotriazole compounds are provided which bind to CCR(4) and are useful for the treatment of diseases such as allergic diseases, autoimmune diseases, graft rejection and cancer.

First claim

What is claimed is:

1 . A compound having formula (I):

and pharmaceutically acceptable salts thereof wherein:
R 1 is a member selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, and halogen;
R 2 is a member selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, halogen, CN, and C 1-8 alkoxy; or optionally two R 2 groups on adjacent carbon atoms can be connected to form a 5 or 6 member ring (aliphatic or aromatic, heterocycle or carbocycle) which is optionally substituted with additional R 2 groups;
R 3 is a member selected from the group consisting of H, C 1-4 lower alkyl and C 1-4 haloalkyl;
R 4 is a member selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl and ═O;
the subscripts n are each independently selected from the group consisting of 0, 1, 2 and 3;
the subscript m is a member selected from the group consisting of 0, 1 and 2;
each A is independently C or N, and at least one A is N;
B is a member selected from the group consisting of a bond, C(O), C(O)NH, C(O)NR a , CH 2 C(O)NH, CH 2 C(O)NR a , NH and NR a ;
Q is a member selected from the group consisting of C, CH, N, O, S, S(O) and SO 2 ;
W, X, Y, and Z are independently C, CH, or N with the exception that Q and W may not be N in the same molecule;
R 5 and R 6 are each independently absent or are a member selected from the group consisting of H, OH, halogen, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 alkyl-NH 2 , —C(O)NR a R b , -alkylene-C(O)NR a R b , —CO 2 H and acid isosteres, -alkylene-CO 2 H and acid isosteres, -alkylene-NHC(O)NH 2 , —NR a R b , -alkylene-NR a R b , —C(O)OR a , -alkylene-C(O)OR a , CN, —C(O)R a , —SO 2 R a , and —N(R a )C(O)R b ;
R 7 is absent or a member selected from the group consisting of H, halogen, C 1-8 alkyl and C 1-8 haloalkyl;
R 8 is absent or a member selected from the group consisting of H, OH, NH 2 , NHR a , CN, C 1-4 aminoalkyl, C 1-4 hydroxyalkyl and C 1-4 alkyl;
R 9 is absent or a member selected from the group consisting of H, C 1-4 alkyl, C 1-8 haloalkyl, CN, and —CO 2 R a ;
R 19 is absent or a member selected from the group consisting of H, CF 3 , C 1-4 alkyl and CN; and wherein
R a and R b are selected from the group consisting of H, C 1-8 alkyl, heteroalkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 3-8 halocycloalkyl, and C 1-8 alkoxy.

2 . A compound of claim 1 , wherein the subscript m is 0 or 1.

3 . A compound of claim 2 , wherein the subscript m is 1, Y is N and X is selected from the group consisting of C and CH.

4 . A compound of claim 3 , wherein X is C, and B is C(O).

5 . A compound of claim 3 , wherein X is C, B is C(O) and the ring having Z as a ring vertex is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and cyclohexyl.

6 . A compound of claim 3 , wherein X is C, B is C(O) and the ring having Z as a ring vertex is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and cyclohexyl; and at least one of R 5 , R 6 and R 7 is other than hydrogen.

7 . A compound of claim 2 , 3 , 4 , 5 , or 6 , wherein each R 2 is selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl, and R 3 is methyl.

8 . A compound of claim 2 , wherein the subscript m is 1, Y is CH, and X is N.

9 . A compound of claim 8 , wherein B is C(O).

10 . A compound of claim 8 or 9 , wherein the ring having Z as a ring vertex is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and cyclohexyl.

11 . A compound of claim 8 or 9 , wherein the ring having Z as a ring vertex is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and cyclohexyl; each R 2 is selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl, and R 3 is methyl.

12 . A compound of claim 8 or 9 , wherein the ring having Z as a ring vertex is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and cyclohexyl; at least one of R 5 , R 6 and R 7 is other than hydrogen; each R 2 is selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl, and R 3 is methyl.

13 . A compound of claim 2 , wherein the subscript m is 1, Y is N, and X is N.

14 . A compound of claim 13 , wherein B is C(O).

15 . A compound of claim 14 , wherein B is C(O), and the ring having Z as a ring vertex is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and cyclohexyl.

16 . A compound of claim 14 , wherein B is C(O), and the ring having Z as a ring vertex is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and cyclohexyl, and at least one of R 5 , R 6 and R 7 is other than hydrogen.

17 . A compound of claim 13 , 14 , 15 or 16 , wherein each R 2 is selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl, and R 3 is methyl.

18 . A compound of claim 2 , having formula (Ia):

19 . A compound of claim 18 , wherein B is a bond.

20 . A compound of claim 18 , wherein B is C(O).

21 . A compound of claim 18 , wherein B is selected from the group consisting of C(O)NH and C(O)NR a .

22 . A compound of claim 18 , 19 , 20 or 21 , wherein each R 2 is selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl, and R 3 is methyl.

23 . A compound of claim 18 , 19 , 20 or 21 , wherein the ring having Z as a ring vertex is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and cyclohexyl; each R 2 is selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl; and R 3 is methyl.

24 . A compound of claim 18 , 19 , 20 or 21 , wherein the ring having Z as a ring vertex is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and cyclohexyl; at least one of R 5 , R 6 and R 7 is other than hydrogen; each R 2 is selected from the group consisting of fluoro, chloro, methyl and trifluoromethyl; and R 3 is methyl.

25 . A compound of claim 1 , having formula (Ib):

26 . A compound of claim 25 , wherein X is C.

27 . A compound of claim 25 , wherein X is C, and Y is N.

28 . A compound of claim 25 , wherein X is C, Y is N, and B is C(O).

29 . A compound of claim 25 , wherein X is N, Y is N, and B is C(O).

30 . A compound of claim 25 , 26 , 27 , 28 or 29 , wherein

Assignees

• Chemocentryx Inc

Inventors

• Leleti Manmohan Reddy
• Li Yandong
• Mali Venkat Reddy
• Powers Jay
• Yang Ju

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title