Diaryl substituted 5,5-fused ring compounds as C5aR inhibitors

Patent metadata

Field	Value
Publication number	US-10759807-B2
Application number	US-201816226898-A
Country	US
Kind code	B2
Filing date	Dec 20, 2018
Priority date	Dec 22, 2017
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

The present disclosure provides, inter alia, Compounds of Formula (I)

or pharmaceutically acceptable salts thereof that are modulators of the C5a receptor. Also provided are pharmaceutical compositions and methods of use including the treatment of diseases or disorders involving pathologic activation from C5a and non-pharmaceutical applications.

First claim

What is claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein,
ring vertex a is N or C(R 2c ), ring vertex b is N or C(R 2d ), and ring vertex e is N or C(R 2e ), wherein no more than one of a, b and e is N;
X 1 is selected from the group consisting of a bond, C 1-8 alkylene, C(O), C(O)—C 1-4 alkylene, and S(O) 2 ;
R 1 is selected from the group consisting of
a) 5- to 10-membered heteroaryl having from 1 to 4 heteroatoms as ring vertices selected from N, O and S;
b) C 6-10 aryl;
c) C 3-8 cycloalkyl;
d) 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S; and
e) C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, —C(O)NR 1a R 1b , and —CO 2 R 1a ; wherein R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 6-10 aryl, and —C 1-6 alkylene-C 6-10 aryl;

wherein the group —X 1 —R 1 is optionally substituted with 1 to 5 R x substituents;
R 2a and R 2e are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, CN, and halogen, and at least one of R 2a and R 2e is other than hydrogen;
R 2b , R 2c , and R 2d are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, cyano, and halogen;
each R 3 is independently selected from the group consisting of hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 hydroxyalkyl, and optionally two R 3 groups on the same carbon atom are combined to form oxo (═O), and optionally two R 3 groups and the carbon atoms they are attached to form a 3-6 membered ring with 0-2 hetereoatoms as ring members selected from O, N, and S;
R 4 is independently selected from the group consisting of

each R 5 is independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, halogen, OH, CN, C(O)R 5a and CO 2 R 5a ; wherein each R 5a is independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
each R x is independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxy, C 2-4 alkenyl, C 3-6 cycloalkyl, CO 2 —C 1-4 alkyl, and CONH 2 ;
the subscript m is 0, 1, 2, 3 or 4; and
the subscript n is 0, 1, 2 or 3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is a bond.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is C(O).

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is C 1-8 alkylene.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is C(O)—C 1-4 alkylene or S(O) 2 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5- to 10-membered heteroaryl having from 1 to 4 heteroatoms as ring vertices selected from N, O and S; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.

9. The compound of claim 8 , wherein R 1 is selected from the group consisting of pyrazolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, thiadiazolyl and pyrazinyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having formula (Ia) or (Ib):

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6-10 aryl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.

12. The compound of claim 11 , wherein R 1 is phenyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3-8 cycloalkyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.

14. The compound of claim 13 , wherein R 1 is selected from the group consisting of cyclobutyl, cyclopentyl and cyclohexyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.

16. The compound of claim 15 , wherein R 1 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, —C(O)NR 1a R 1b , and —CO 2 R 1a ; wherein R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 6-10 aryl, and —C 1-6 alkylene-C 6-10 aryl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, and pyrazinyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring vertices a and b are CH; R 2b is H; ring vertex e is C(R 2e ), and R 2a and R 2e are independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, CN, and halogen.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring vertices a and b are CH; R 2b is H; ring vertex e is C(R 2e ), and R 2a and R 2e are independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and halogen.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 and each R 5 , when present, is independently selected from the group consisting of F, Cl, CN, C 1-4 alkyl and C 1-4 alkoxy.

22. The compo

Assignees

• Chemocentryx Inc

Inventors

• Fan Pingchen
• Lange Christopher W
• Lui Rebecca M
• Malathong Viengkham
• Mali Venkat Reddy
• Punna Sreenivas
• Singh Rajinder
• Zeng Yibin
• Zhang Penglie

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K31/4162

  condensed with heterocyclic ring systems · CPC title

• A61K9/10

  Dispersions; Emulsions · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61P37/06

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