5-5 fused rings as C5a inhibitors

Patent metadata

Field	Value
Publication number	US-10683294-B2
Application number	US-201815991747-A
Country	US
Kind code	B2
Filing date	May 29, 2018
Priority date	May 31, 2017
Publication date	Jun 16, 2020
Grant date	Jun 16, 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 1 is selected from the group consisting of N, CH, C(O) and C(R 4 );
ring vertex A 2 is selected from the group consisting of N, CH, and C(R 4 );
each of ring vertices A 3 , A 4 , A 5 and A 6 is independently selected from the group consisting of CH and C(R 4 );
each of the dashed bonds independently indicate a single or double bond;
R 1 is selected from the group consisting of —C 1-8 alkylene-heteroaryl, —C 1-8 alkylene-C 6-10 aryl, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)—C 1-8 alkyl, —C(O)—C 6-10 aryl, —C(O)-heteroaryl, —C(O)—C 3-6 cycloalkyl, —C(O)-heterocycloalkyl, —C(O)NR 1a R 1b , —SO 2 —C 6-10 aryl, —SO 2 -heteroaryl, —C(O)—C 1-8 alkylene-O-heteroaryl, —C(O)—C 1-8 alkylene-O—C 6-10 aryl, —C(O)—C 1-8 alkylene-O-heterocycloalkyl, —C(O)—C 1-8 alkylene-O—C 3-6 cycloalkyl, —C(O)—C 1-8 alkylene-heteroaryl, —C(O)—C 1-8 alkylene-C 6-10 aryl, —C(O)—C 1-8 alkylene-heterocycloalkyl, —C(O)—C 1-8 alkylene-C 3-6 cycloalkyl and —CO 2 R 1a ; the heterocycloalkyl is a 4 to 8 membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S; and the heteroaryl group is a 5 to 10 membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S;
wherein R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl;
wherein R 1 is optionally substituted with 1 to 5 R 5 substituents;
R 2a and R 2e are each 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;
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 C 1-6 alkyl, C 1-6 haloalkyl, halogen and hydroxyl, and optionally two R 3 groups on the same carbon atom are combined to form oxo (═O) or to form a three to five membered cycloalkyl ring;
each R 4 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, —O—C 1-6 haloalkyl, halogen, cyano, hydroxyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, —NR 4a R 4b , —CONR 4a R 4b , —CO 2 R 4a , —COR 4a , —OC(O)NR 4a R 4b , —NR 4a C(O)R 4b , —NR 4a C(O) 2 R 4b , and —NR 4a —C(O)NR 4a R 4b ;
each R 4a and R 4b is independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
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, —C 1-8 alkylene-heterocycloalkyl, —C 1-8 alkylene-C 36 cycloalkyl, C 3-6 cycloalkyl, heterocycloalkyl, halogen, OH, C 2-8 alkenyl, C 2-8 alkynyl, CN, C(O)R 5a , —NR 5b C(O)R 5a , —CONR 5a R 5b , —NR 5a R 5b , —C 1-8 alkylene-NR 5a R 5b , —S—C 1-6 alkyl, —C 1-6 alkylene-O—C 1-6 alkyl, —C 1-6 alkylene-S—C 1-6 alkyl, —OC(O)NR 5a R 5b , —NR 5a C(O) 2 R 5b , —NR 5a —C(O)NR 5b R 5b , and CO 2 R 5a ; wherein the heterocycloalkyl group is a 4 to 8 membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O, and S;
wherein each R 5a and R 5b is independently selected from the group consisting of hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when R 5a and R 5b are attached to the same nitrogen atom they are combined with the nitrogen atom to form a 5 or 6-membered ring having from 0 to 1 additional heteroatoms as ring vertices selected from N, O, or S; and
the subscript n is 0, 1, 2 or 3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring portion having A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is a bicyclic heteroaryl selected from the group consisting of

wherein m is 0, 1, 2 or 3; and wherein the R 4 substituents may be attached to any suitable carbon ring vertex of the bicyclic heteroaryl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring portion having A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is a bicyclic heteroaryl represented by the structure

wherein m is 0, 1, 2, or 3; and wherein the R 4 substituents may be attached to any suitable carbon ring vertex of the bicyclic heteroaryl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1-6 hydroxyalkyl, halogen, cyano, and —CO 2 R 4a ; and wherein the R 4 substituents may be attached to any suitable carbon ring vertex of the bicyclic heteroaryl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring portion having A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is a bicyclic heteroaryl selected from the group consisting of:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the ring portion having A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is a bicyclic heteroaryl selected from the group consisting of:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of —C 1-8 alkylene-heteroaryl, —C 1-8 alkylene-C 6-10 aryl, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)—C 1-8 alkyl, —C(O)—C 6-10 aryl, —C(O)-heteroaryl, —C(O)—C 3-8 cycloalkyl, —C(O)NR 1a R 1b , —SO 2 —C 6-10 aryl, —C(O)—C 1-8 alkylene-O—C 6-10 aryl, and —CO 2 R 1a ; wherein the heterocycloalkyl is a 4 to 8 membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S; and the heteroaryl group is a 5 to 10 membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S; and wherein R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, and C 1-s haloalkyl; and R 1 is optionally substituted with 1 to 5 R 5 substituents.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 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, C 3-6 cycloalkyl, halogen, OH, —NR 5a R 5b , and CO 2 R 5a , wherein each R 5a and R 5b is independently selected from the group consisting of hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 -phenyl optionally substituted by 1 to 3 R 5 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 -phenyl substituted by 1 or 2 R 5 , wherein each R 5 is independently C 1-4 haloalkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 -phenyl substituted by 1 or 2

Assignees

• Chemocentryx Inc

Inventors

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

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/4162

  condensed with heterocyclic ring systems · CPC title