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 activtation of C5a receptors.

What is claimed is: 
     
         1 . A method for treating a human having a disease or disorder involving pathologic activation of C5a receptors selected from the group consisting of tissue graft rejection, hyperacute rejection of transplanted organs, rheumatoid arthritis, lupus nephritis, vasculitis, Wegener's granulomatosis, microscopic polyangiitis, autoimmune hemolytic and thrombocytopenic states, immunovasculitis, and glomerulonephritis, comprising administering to the human an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or rotamer thereof; wherein 
         C 1  is phenyl optionally substituted with from 1 to 3 R 1  substituents; 
         C 2  is phenyl optionally substituted with from 1 to 3 R 2  substituents; 
         C 3  is phenyl optionally substituted with from 1 to 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; 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 —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 1-4  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 1  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; and 
         X is hydrogen or CH 3 . 
       
     
     
         2 . The method of  claim 1 , wherein the disease or disorder is lupus nephritis. 
     
     
         3 . The method of  claim 1 , wherein the disease or disorder is vasculitis. 
     
     
         4 . The method of  claim 1 , wherein the disease or disorder is immunovasculitis. 
     
     
         5 . The method of  claim 1 , wherein the disease or disorder is tissue graft rejection or hyperacute rejection of transplanted organs. 
     
     
         6 . The method of  claim 1 , wherein the disease or disorder is Wegener's granulomatosis. 
     
     
         7 . The method of  claim 1 , wherein the disease or disorder is microscopic polyangiitis. 
     
     
         8 . The method of  claim 1 , wherein the disease or disorder is autoimmune hemolytic and thrombocytopenic states. 
     
     
         9 . The method of  claim 1 , wherein the disease or disorder is glomerulonephritis. 
     
     
         10 . The method of  claim 1 , wherein the disease or disorder is rheumatoid arthritis. 
     
     
         11 . A method for treating a human having a disease or disorder involving pathologic activation of C5a receptors selected from the group consisting of tissue graft rejection, hyperacute rejection of transplanted organs, rheumatoid arthritis, lupus nephritis, vasculitis, Wegener's granulomatosis, microscopic polyangiitis, autoimmune hemolytic and thrombocytopenic states, immunovasculitis, and glomerulonephritis, comprising administering to the human an effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or rotamer thereof. 
       
     
     
         12 . The method of  claim 11 , wherein the disease or disorder is lupus nephritis. 
     
     
         13 . The method of  claim 11 , wherein the disease or disorder is vasculitis. 
     
     
         14 . The method of  claim 11 , wherein the disease or disorder is immunovasculitis. 
     
     
         15 . The method of  claim 11 , wherein the disease or disorder is tissue graft rejection or hyperacute rejection of transplanted organs. 
     
     
         16 . The method of  claim 11 , wherein the disease or disorder is Wegener's granulomatosis. 
     
     
         17 . The method of  claim 11 , wherein the disease or disorder is microscopic polyangiitis. 
     
     
         18 . The method of  claim 11 , wherein the disease or disorder is autoimmune hemolytic and thrombocytopenic states. 
     
     
         19 . The method of  claim 11 , wherein the disease or disorder is glomerulonephritis. 
     
     
         20 . The method of  claim 11 , wherein the disease or disorder is rheumatoid arthritis.