6-5 fused rings as C5a inhibitors

Patent metadata

Field	Value
Publication number	US-10562896-B2
Application number	US-201815991703-A
Country	US
Kind code	B2
Filing date	May 29, 2018
Priority date	May 31, 2017
Publication date	Feb 18, 2020
Grant date	Feb 18, 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 0 is NH or C(O);
each of ring vertices A 1 and A 3 are independently selected from the group consisting of N, NH, CH, C(O) and C(R 4 );
each of ring vertices A 2 , A 5 and A 6 is independently selected from the group consisting of N, CH, and C(R 4 );
ring vertex A 4 is selected from the group consisting of N, N(C 1-4 alkyl), CH, and C(R 4 );
and no more than two of A 3 , A 4 , A 5 and A 6 are N;
each of the dashed bonds independently is a single or double bond;
R 1 is selected from the group consisting of heteroaryl, C 6-10 aryl, C 1-8 alkylene-heteroaryl, —C 1-8 alkylene-C 6-10 aryl, C 3-8 cycloalkyl, four to eight membered heterocycloalkyl, C 1-8 alkyl, C 1-8 haloalkyl, —C(O)NR 1a R 1b , and —CO 2 R 1a ; 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; 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, C 6-10 aryl, and —C 1-6 alkylene-C 6-10 aryl;
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 1-4 alkyl, C 1-4 haloalkyl and hydroxyl, and optionally two R 3 groups on the same carbon atom are combined to form oxo (═O);
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 alkyl-heterocycloalkyl, —C 1-8 alkyl-C 3-8 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 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-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 1-4 alkyl, and C 1-4 haloalkyl, or when attached to the same nitrogen atom R 5a and R 5b are combined with the nitrogen atom to form a five or six-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 0 , 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, when present, are 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 0 , A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is selected from the group consisting of

wherein m is 0, 1, 2, or 3.

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, C 1-4 haloalkyl, halogen, cyano, hydroxyl, —NH 2 , —CONR 4a R 4b , and —CO 2 R 4a ; and wherein the R 4 substituents, when present, are 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 0 , A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 as ring vertices is selected from the group consisting of:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of heteroaryl, C6-10 aryl, —C 1-6 alkylene-heteroaryl, —C 1-6 alkylene-C 6-10 aryl, four to eight membered heterocycloalkyl, C 3-8 cycloalkyl, C 1-8 alkyl, —C(O)NR 1a R 1b , and —CO 2 R 1a , wherein the heteroaryl group is a 5 or 6 membered aromatic ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S, and R 1 is optionally substituted with 1 to 3 R 5 substituents.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of pyridyl, pyrimidyl, pyrazinyl, thiadiazolyl, phenyl, benzyl, cyclopentyl, tetrahydropyranyl, —C(O)NR 1a R 1b , —CO 2 R 1a , and C 1-8 alkyl, wherein R 1 is optionally substituted with 1 to 3 R 5 substituents.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

each of which is optionally substituted with 1 or 2 R 5 substituents.

9. The compound of claim 8 , 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 1-8 alkyl-heterocycloalkyl, C 3-6 cycloalkyl, halogen, —CONR 5a R 5b , —NR 5a R 5b , —C 1-8 alkylene-NR 5a R 5b , and —CO 2 R 5a , each R 5a and R 5b is independently selected from the group consisting of hydrogen and C 1-4 alkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a 5 or 6-membered ring; and the heterocycloalkyl group is a 4 to 6 membered ring having from 1 to 3 heteroatoms as ring vertices selected from N, O and S.

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

11. The compound of claim 10 , wherein each R 5 is independently selected from the group consisting of cyclopropyl, isopropyl, isopropyloxy, OMe, Me, Cl, F, —CONH 2 , —CF 3 , —O—CF 3 ,

Assignees

• Chemocentryx Inc

Inventors

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

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title