C5aR ANTAGONISTS

Patent metadata

Field	Value
Publication number	US-2019060321-A1
Application number	US-201816030729-A
Country	US
Kind code	A1
Filing date	Jul 9, 2018
Priority date	Dec 22, 2008
Publication date	Feb 28, 2019
Grant date	—

Abstract

Compounds are provided that are modulators of the C5a receptor. The compounds are substituted piperidines and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activtation of C5a receptors.

First claim

1 . A compound having the formula

and pharmaceutically acceptable salts, hydrates and rotomers thereof; wherein
C 1 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R 2 substituents;
C 2 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R 2 substituents;
C 3 is selected from the group consisting of C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, heterocycloalkyl or heterocycloalkyl-C 1-4 alkyl, wherein the heterocycloalkyl group or portion has from 1-3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S, and each C 3 is optionally substituted with from 1-3 R 3 sub stituents;
each R 1 is independently selected from the group consisting of
halogen, —CN, —R c , —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR b C(O)R a , —NR b C( 0 ) 2 R c , —NR a —C(O)NR a R b , —NR a C(O)NR a R b , —NR a R b , —OR a , and —S(O) 2 NR a R b ; wherein each R a and R b is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R c is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of R a , R b and R c are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and
optionally when two R 1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring;
each R 2 is independently selected from the group consisting of halogen, —CN, —R f , —CO 2 R d , —CONR d R e , —C(O)R d , —OC(O)NR d R e , —NR e C(O)R d , —NR e C(O) 2 R f , —NR d C(O)NR d R e , —NR d C(O)NR d R e , —NR d R e , —OR d , and —S(O) 2 NR d R e ; wherein each R d and R e is independently selected from hydrogen, C 1-8 alkyl, and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and cyclic portions of R d , R e and R f are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups;
each R 3 is independently selected from the group consisting of halogen, —CN, —R i , —CO 2 R g , —CONR g R h , —C(O)R g , —OC(O)NR g R h , —NR h C(O)R g , —NR h C(O) 2 R i , —NR g C(O)NR g R h , —NR g R h , —OR g , —S(O) 2 NR g R h , —X 4 —NR g R h , —X 4 —CONR g R h , —X 4 —NR h C(O)R g , —NHR j and —NHCH 2 R j , wherein X 4 is a C 1-4 alkylene; each R g and R h is independently selected from hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R i is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each is selected from the group consisting of C 3-6 cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic and cyclic portions of R g , R h , R i and R j are optionally further substituted with from one to three halogen, methyl, CF 3 , hydroxy, amino, alkylamino and dialkylamino groups; and
X is hydrogen or CH 3 .

2 . The compound of claim 1 , wherein X is hydrogen.

3 - 5 . (cancelled)

6 . The compound of claim 1 , having the formula:

wherein
X 1 is selected from the group consisting of N, CH and CR 1 ;
the subscript n is an integer of from 0 to 2;
X 2 is selected from the group consisting of N, CH and CR 2 ; and
the subscript m is an integer of from 0 to 2.

7 . The compound of claim 1 , having the formula:

wherein
the subscript p is an integer of from 0 to 3;
X 1 is selected from the group consisting of N, CH and CR 1 ;
the subscript n is an integer of from 0 to 2;
X 2 is selected from the group consisting of N, CH and CR 2 ; and
the subscript m is an integer of from 0 to 2.

8 . The compound of claim 1 , having the formula:

9 . The compound of claim 1 , having the formula:

10 - 15 . (cancelled)

16 . The compound of claim 1 , wherein C 1 is selected from the group consisting of phenyl, pyridyl, indolyl and thiazolyl, each of which is optionally substituted with from 1 to 3 R 1 substituents.

17 . The compound of claim 1 , wherein C 2 is selected from the group consisting of phenyl, naphthyl, pyridyl and indolyl, each of which is optionally substituted with from 1 to 3 R 2 substituents.

18 . The compound of claim 1 , wherein C 3 is selected from the group consisting of C 3-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-2 alkyl, phenyl, pyridinyl, pyrazolyl, piperidinyl, pyrrolidinyl, piperidinylmethyl and pyrrolidinylmethyl, each of which is optionally substituted with from 1 to 3 R 3 substituents.

19 - 23 . (cancelled)

24 . The compound of claim 1 , wherein C 3 is selected from the group consisting of:

25 - 26 . (cancelled)

27 . A pharmaceutical composition comprising a compound a pharmaceutically acceptable carrier and a compound having formula

and pharmaceutically acceptable salts, hydrates and rotomers thereof; wherein
C 1 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R 1 substituents;
C 2 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected

Assignees

• Chemocentryx Inc

Inventors

• Fan Pingchen
• Greenman Kevin Lloyd
• Leleti Manmohan Reddy
• Li Yandong
• Powers Jay
• Tanaka Hiroko
• Yang Ju
• Zeng Yibin

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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

• A61P37/06

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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/04

  Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents · CPC title