C5ar antagonists

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 activation of C5a receptors.

1 . A compound having the formula 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, hydrates and rotomers thereof; wherein 
         C 1  is heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said heteroaryl group is optionally substituted with from 1 to 3 R 1  substituents; 
         C 2  is selected from the group consisting of phenyl, naphthyl, pyridyl and indolyl wherein C 2  is optionally substituted with from 1 to 3 R 2  substituents; 
         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, and C 3  is optionally substituted with from 1-3 R 3  substituents; 
         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(O) 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, and is optionally substituted with one or two oxo; each R c  is independently selected from the group consisting of C 1-8  alkyl or heteroalkyl, 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 or heterocyclic ring; 
 
         each R 2  is independently selected from the group consisting of
 halogen, —CN, —NO 2 , —R f , —CO 2 R d , —CONR d R c , —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, and is optionally substituted with one or two oxo; each R f  is independently selected from the group consisting of C 1-8  alkyl or heteroalkyl, 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, and optionally when two R 2  groups are on adjacent atoms, they are combined to form a five- or six-membered ring; 
 
         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 , —C(O)R i , —OC(O)NR g R h , —NR h C(O)R g , —NR h CO 2 R i , —NR g C(O)NR g R h , —NR g R h , —OR g , —OR j , —S(O) 2 NR g R h , —X 4 —R j , —NH—X 4 —R j , —O—X 4 —R j , —X 4 —NR g R h , —X 4 —NHR j , —X 4 —CONR g R h , —X 4 —NR h C(O)R g , —X 4 —CO 2 R g , —O—X 4 —CO 2 R g , —NH—X 4 —CO 2 R g , —X 4 —NR h CO 2 R i , —O—X 4 —NR h CO 2 R i , —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 or heteroalkyl, 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 four-, 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 or heteroalkyl, C 1-8  haloalkyl, C 3-6  cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each R i  is selected from the group consisting of C 3-6  cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and S,S-dioxo-tetrahydrothiopyranyl, 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, C 1-4  alkoxy, C 1-4  alkoxy-C 1-4  alkyl, —C(O)O—C 1-8  alkyl, amino, alkylamino and dialkylamino groups, and optionally when two R 3  groups are on adjacent atoms, they are combined to form a five- or six-membered ring; and 
 
         X is hydrogen or CH 3 . 
       
     
     
         2 . The compound of  claim 1 , wherein X is hydrogen. 
     
     
         3 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein 
         X 1  is N; 
         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 N; 
         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 - 18 . (canceled) 
     
     
         19 . The compound of claim  16 , wherein each R 1  is independently selected from the group consisting of halogen, —CN, —R c , —NR a R b  and —OR a , and 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 pyrrolidine ring; each R c  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl and C 3-6  cycloalkyl, and wherein the aliphatic and cyclic portions of R a , R b  and R c  are optionally further substituted with from one to three 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. 
     
     
         20 . The compound of  claim 1 , wherein each R 2  is independently selected from the group consisting of halogen, —R f  and —OR d ; wherein each R d  is independently selected from hydrogen, C 1-8  alkyl, and C 1-8  haloalkyl; each R f  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl, C 3-6  cycloalkyl, heterocycloalkyl and heteroaryl, and wherein the aliphatic and cyclic portions of R d  and R f  are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups. 
     
     
         21 . The compound of claim  18 , wherein each R 3  is independently selected from the group consisting of
 halogen, —R i , —CO 2 R g , —CONR g R h , —NR h C(O)R g , —NR h C(O) 2 R i , —NR g R h , —OR g , —X 4 —R j , —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 1-3  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 1 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 R j  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   
     
     
         22 . The compound of  claim 20 , wherein C 2  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         23 . (canceled) 
     
     
         24 . The compound of  claim 1 , wherein C 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 1 , wherein C 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         26 - 29 . (canceled) 
     
     
         30 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         31 . A method for treating a mammal suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors, comprising administering to the mammal an effective amount of a compound of  claim 1 . 
     
     
         32 . A method of inhibiting C5a receptor-mediated cellular chemotaxis comprising contacting mammalian white blood cells with a C5a receptor modulatory amount of a compound of  claim 1 . 
     
     
         33 .- 39 . (canceled) 
     
     
         40 . A method of assaying a compound for C5a-receptor (C5aR) antagonistic activity, said method comprising
 (a) contacting the compound with cells expressing C5aR and a radiolabeled C5a to form a reaction mixture;   (b) aspirating the reaction mixture onto a GF/B glass filter pre-soaked in a polyethyleneimine solution;   (c) measuring the amount radioactivity remaining on the GF/B glass filter,
 wherein said method comprises performing steps (a)-(c) with a positive control sample having the structure according to  claim 1 .