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.

What is claimed is: 
     
         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 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 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 or heteroalkyl, 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  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 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, 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 j , —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 j  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 . 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. 
       
     
     
         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 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein R 3  is a member selected from the group consisting of —NR g R h , —NHR j  and —NHCH 2 R j . 
       
     
     
         15 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         wherein R 3  is a member selected from the group consisting of —X 4 —NR g R h , —X 4 —R j  and —X 4 —NR h COR g . 
       
     
     
         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 . 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 17 , 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 . The compound of  claim 19 , wherein C 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         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 . The compound of  claim 1 , wherein said compound is selected from the group in Table 1. 
     
     
         27 . The compound of  1 , having the formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         28 . The compound of  1 , having the formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         29 . The compound of  1 , having the formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         30 . 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 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 or heteroalkyl, 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  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 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, 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 b C(O)R g , —X 4 —NHC(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 j  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 . 
       
     
     
         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 . The method of  claim 31 , wherein the disease or disorder is an inflammatory disease or disorder. 
     
     
         34 . The method of  claim 33 , wherein the disease or disorder is selected from the group consisting of neutropenia, sepsis, septic shock, Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease, age-related macular degeneration, chronic obstructive pulmonary disorder, inflammation associated with burns, lung injury, osteoarthritis, atopic dermatitis, chronic urticaria, ischemia-reperfusion injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, tissue graft rejection, cancer and hyperacute rejection of transplanted organs. 
     
     
         35 . The method of  claim 31 , wherein the disease or disorder is a cardiovascular or cerebrovascular disorder. 
     
     
         36 . The method of  claim 35 , wherein the disease or disorder is selected from the group consisting of myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, artherosclerosis, traumatic central nervous system injury and ischemic heart disease. 
     
     
         37 . The method of  claim 31 , wherein the disease or disorder is an autoimmune disorder. 
     
     
         38 . The method of  claim 37 , wherein the disease or disorder is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis, lupus glomerulonephritis, psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, immunovasculitis, tissue graft rejection and hyperacute rejection of transplanted organs. 
     
     
         39 . The method of  claim 31 , wherein the disease or disorder is a pathologic sequelae associated with the group consisting of insulin-dependent diabetes, mellitus, lupus nephropathy, Heyman nephritis, membranous nephritis, glomerulonephritis, contact sensitivity responses, and inflammation resulting from contact of blood with artificial surfaces.