Complement pathway modulators and uses thereof

Abstract

The present invention provides a compound of formula I: a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

What is claimed is: 
     
         1 . A method of modulating complement alternative pathway activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound, or salt or tautomer thereof, according to Formula (I): 
       
         
           
           
               
               
           
         
         Wherein 
            is a single or double bond; 
         X is N; 
         Y is N(H); 
         one occurrence of R is cyano and the other occurrence of R is hydrogen or R 4 ; 
         R 1  is halogen, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, C 3 -C 6 cycloalkylC 1 -C 5 alkoxy, haloC 1 -C 6 alkoxy, S(O) p C 1 -C 6 alkyl, CH 2 NHC(O)C 1 -C 4 alkyl or OCH 2 C(O)R 7 ; 
         p is 0, 1, or 2; 
         R 2  is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 6 alkyl or halogen; 
         R 3  is hydrogen, halogen, cyano, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, CH 2 C(O)R 7 , phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, wherein the phenyl or heteroaryl is optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups, and wherein the alkyl and haloalkyl is optionally substituted with 0 or 1 hydroxy groups; 
         R 4  is 0, 1, or 2 substitutents independently selected at each occurrence from halogen and C 1 -C 6 alkyl; 
         R 5  is hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S; 
         or R 3  and R 5  taken in combination form a divalent —CH 2 —CH 2 — or —CH 2 —N(H)— group; 
         R 6  is hydrogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, mono- and di-C 1 -C 4 alkylamino, amino C 1 -C 6 alkylamino, [CR A   2 ] n R 7 , [CR A   2 ] n C(O)R 7 , O[CR A   2 ] n R 7 , NHC(O)C 1 -C 6 alkyl, NHS(O 2 )C 1 -C 6 alkyl, (CH 2 ) n R 9 , O(CH 2 ) n R 9 , C(O)R 7 , N(H)[CR A   2 ] n R 7 , O[CR A   2 ] n C(O)R 7 , N(H)[CR A   2 ] n C(O)R 7  or tetrazolyl; 
         or CR 5 R 6 , taken in combination, form a divalent carbonyl group, a divalent ═CH 2  group or cyclopropyl which cyclopropyl is optionally substituted by CO 2 H or CH 2 OH; 
         n is 1, 2, 3 or 4; 
         R A  is independently selected at each occurrence from hydrogen, halogen or C 1 -C 4 alkyl; 
         R 7  is hydroxy, C 1 -C 4 alkoxy, amino or mono- and di-C 1 -C 4 alkylamino; 
         R 8  is hydrogen or halogen; and 
         R 9  is a 5 member heteroaryl having 1 to 4 ring heteroatoms selected from N, O or S and optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups. 
       
     
     
         2 . A method of treating a disorder or a disease in a subject mediated by complement activation, in particular mediated by activation of the complement alternative pathway, wherein the method comprises administering to the subject a therapeutically effective amount of the compound, or salt or tautomer thereof, according to Formula (I): 
       
         
           
           
               
               
           
         
         Wherein 
            is a single or double bond; 
         X is N; 
         Y is N(H); 
         one occurrence of R is cyano and the other occurrence of R is hydrogen or R 4 ; 
         R 1  is halogen, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, C 3 -C 6 cycloalkylC 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, S(O) p C 1 -C 6 alkyl, CH 2 NHC(O)C 1 -C 4 alkyl or OCH 2 C(O)R 7 ; 
         p is 0, 1, or 2; 
         R 2  is C r C 6 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 6 alkyl or halogen; 
         R 3  is hydrogen, halogen, cyano, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, CH 2 C(O)R 7 , phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, wherein the phenyl or heteroaryl is optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups, and wherein the alkyl and haloalkyl is optionally substituted with 0 or 1 hydroxy groups; 
         R 4  is 0, 1, or 2 substitutents independently selected at each occurrence from halogen and C r  C 6 alkyl; 
         R 5  is hydrogen, C r C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S; 
         or R 3  and R 5  taken in combination form a divalent —CH 2 —CH 2 — or —CH 2 —N(H)— group; 
         R 6  is hydrogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, mono- and di-C 1 -C 4 alkylamino, amino C 1 -C 6 alkylamino, [CR A   2 ] n R 7 , [CR A   2 ] n C(O)R 7 , O[CR A   2 ] n R 7 , NHC(O)C 1 -C 6 alkyl, NHS(O 2 )C 1 -C 6 alkyl, (CH 2 ) n R 9 , O(CH 2 ) n R 9 , C(O)R 7 , N(H)[CR A   2 ] n R 7 , O[CR A   2 ] n C(O)R 7 , N(H)[CR A   2 ] n C(O)R 7  or tetrazolyl; 
         or CR 5 R 6 , taken in combination, form a divalent carbonyl group, a divalent ═CH 2  group or cyclopropyl which cyclopropyl is optionally substituted by CO 2 H or CH 2 OH; 
         n is 1, 2, 3 or 4; 
         R A  is independently selected at each occurrence from hydrogen, halogen or C 1 -C 4 alkyl; 
         R 7  is hydroxy, C 1 -C 4 alkoxy, amino or mono- and di-C 1 -C 4 alkylamino; 
         R 8  is hydrogen or halogen; and 
         R 9  is a 5 member heteroaryl having 1 to 4 ring heteroatoms selected from N, O or S and optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups. 
       
     
     
         3 . The method of  claim 2 , in which the disease or disorder is selected from the group consisting of age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, neural regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity. 
     
     
         4 . A method of treating age related macular degeneration comprising administering to a subject in need thereof an effective amount of a composition comprising a compound, or salt or tautomer thereof, according to Formula (I): 
       
         
           
           
               
               
           
         
         Wherein 
            is a single or double bond; 
         X is N; 
         Y is N(H); 
         one occurrence of R is cyano and the other occurrence of R is hydrogen or R 4 ; 
         R 1  is halogen, hydroxyl, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 5 alkoxy, haloC 1 -C 5 alkyl, hydroxyC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, C 3 -C 6 cycloalkylC 1 -C 5 alkoxy, haloC 1 -C 5 alkoxy, S(O) p C 1 -C 5 alkyl, CH 2 NHC(O)C 1 -C 4 alkyl or OCH 2 C(O)R 7 ; 
         p is 0, 1, or 2; 
         R 2  is C 1 -C 5 alkyl, C 1 -C 5 alkoxy, hydroxyC 1 -C 5 alkyl or halogen; 
         R 3  is hydrogen, halogen, cyano, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, CH 2 C(O)R 7 , phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, wherein the phenyl or heteroaryl is optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups, and wherein the alkyl and haloalkyl is optionally substituted with 0 or 1 hydroxy groups; 
         R 4  is 0, 1, or 2 substitutents independently selected at each occurrence from halogen and C 1 -C 6 alkyl; 
         R 5  is hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S; 
         or R 3  and R 5  taken in combination form a divalent —CH 2 —CH 2 — or —CH 2 —N(H)— group; 
         R 6  is hydrogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, mono- and di-C 1 -C 4 alkylamino, amino C 1 -C 6 alkylamino, [CR A   2 ] n R 7 , [CR A   2 ] n C(O)R 7 , O[CR A   2 ] n R 7 , NHC(O)C 1 -C 6 alkyl, NHS(O 2 )C 1 -C 6 alkyl, (CH 2 ) n R 9 , O(CH 2 ) n R 9 , C(O)R 7 , N(H)[CR A   2 ] n R 7 , O[CR A   2 ] n C(O)R 7 , N(H)[CR A   2 ] n C(O)R 7  or tetrazolyl; 
         or CR 5 R 6 , taken in combination, form a divalent carbonyl group, a divalent ═CH 2  group or cyclopropyl which cyclopropyl is optionally substituted by CO 2 H or CH 2 OH; 
         n is 1, 2, 3 or 4; 
         R A  is independently selected at each occurrence from hydrogen, halogen or C 1 -C 4 alkyl; 
         R 7  is hydroxy, C 1 -C 4 alkoxy, amino or mono- and di-C 1 -C 4 alkylamino; 
         R 8  is hydrogen or halogen; and 
         R 9  is a 5 member heteroaryl having 1 to 4 ring heteroatoms selected from N, O or S and optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups. 
       
     
     
         5 . The method of  claim 2 , in which the compound is a compound according to Formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 2 , in which R 4  is absent. 
     
     
         7 . The method of  claim 2 , in which R 3  is hydrogen, chloro or phenyl. 
     
     
         8 . The method of  claim 2 , in which R 3  is hydrogen. 
     
     
         9 . The method of  claim 2 , in which R 2  is methyl. 
     
     
         10 . The method of  claim 2 , in which R 1  is halogen, C 1 -C 4 alkyl, vinyl, cyclopropyl, C r  C 4 alkoxy, hydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkoxy, cyclopropylC 1 -C 4 alkoxy, haloC 1 -C 4 alkoxy or S(O) 2 C 1 -C 4 alkyl. 
     
     
         11 . The method of  claim 2 , in which R 1  is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyclopropyl, bromo or difluoromethoxy. 
     
     
         12 . The method of  claim 2 , in which R 5  is hydrogen, methyl, ethyl cyclopropyl or trifluoromethyl. 
     
     
         13 . The method of  claim 2 , in which R 6  is hydrogen, hydroxy, methoxy, amino, mono- and di-methylamino or CH 2 R 7 ; and
 R 7  is hydroxy, amino, N(H)CH 3  or N(CH 3 ) 2 .   
     
     
         14 . The method of  claim 2 , in which R 5  is methyl or trifluoromethyl;
 R 6  is hydroxy, methoxy, amino, methylamino or CH 2 R 7 ; and   R 7  is hydroxy, amino, N(H)CH 3  or N(CH 3 ) 2 .