Kinase inhibitors useful for the treatment of proliferative diseases

Abstract

The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of Raf kinases and disease polymorphs thereof. Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, non small cell lung cancer, and mesothelioma. Compounds of the present invention also find utility in the treatment of rheumatoid arthritis and retinopathies including diabetic retinal neuropathy and macular degeneration.

1 - 45 . (canceled) 
     
     
         46 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, secondary cancer growth arising from metastasis, diseases characterized by hyper-vascularization, inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, cardiovascular disease and diseases characterized by angiogenesis, comprising administering to an individual an effective amount of a compound or a salt thereof, of the formula IIa: 
       
         
           
           
               
               
           
         
         wherein Q1 is N and Q2 is CR3; 
         wherein E1 is; 
         wherein A is selected from the group consisting of phenyl, naphthyl, C3-C8-carbocyclyl, —CHR4R8; pyridinyl, and benzothienyl; 
         when A has one or more substitutable sp2-hybridized carbon atom, each respective sp2 hybridized carbon atom may be optionally substituted with a R3 substituent; 
         when A has one or more substitutable sp3-hybridized carbon atom, each respective sp3 hybridized carbon atom may be optionally substituted with a R3 substituent; 
         each Z3 is independently and individually selected from the group consisting of H, methyl, ethyl, isopropyl, C3-C4 carbocyclyl, halogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, and cyano; 
         wherein each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, and C3-C8carbocyclyl; 
         each R4 is independently and individually selected from the group consisting of C1-C4alkyl, branched C3-C5alkyl and C3-C5carbocyclyl; 
         each R8 is independently and individually selected from the group consisting of C3-C8carbocyclyl, and Z3-substituted phenyl; 
         R16 is independently and individually selected from the group consisting of hydrogen, methyl, ethyl, halogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, and C2-C3alkynyl; and 
       
     
     
         47 . The method of  claim 46 , wherein the compound has formula IIb. 
       
         
           
           
               
               
           
         
       
     
     
         48 - 66 . (canceled) 
     
     
         67 . The method of  claim 47 , wherein the compound has formula IIv; 
       
         
           
           
               
               
           
         
         wherein R16 is methyl, ethyl, cyano, -ethynyl, or halogen, and wherein the substituent Z3 can be in either of the fused phenyl rings comprising the naphthyl ring. 
       
     
     
         68 . The method of  claim 67 , wherein the compound has formula IIw: 
       
         
           
           
               
               
           
         
       
     
     
         69 . The method of  claim 67 , wherein the compound has formula IIx: 
       
         
           
           
               
               
           
         
         and wherein R16 is methyl, ethyl, cyano, -ethynyl or halogen. 
       
     
     
         70 . The method of  claim 47 , wherein the compound has formula IIy: 
       
         
           
           
               
               
           
         
         and wherein R16 is methyl, ethyl, cyano, -ethynyl, or halogen. 
       
     
     
         71 . The method of  claim 70 , wherein the compound has formula IIz: 
       
         
           
           
               
               
           
         
       
     
     
         72 . The method of  claim 70 , wherein the compound has formula IIaa: 
       
         
           
           
               
               
           
         
         wherein R16 is methyl, cyano, -ethynyl, or halogen. 
       
     
     
         73 . The method of  claim 47 , wherein the compound has formula IIbb: 
       
         
           
           
               
               
           
         
       
     
     
         74 . The method of  claim 73 , wherein the compound has formula IIcc: 
       
         
           
           
               
               
           
         
       
     
     
         75 . The method of  claim 73 , wherein the compound has formula IIdd: 
       
         
           
           
               
               
           
         
         wherein R16 is methyl, ethyl, cyano, -ethynyl or halogen. 
       
     
     
         76 . The method of  claim 47 , wherein the compound has formula IIee: 
       
         
           
           
               
               
           
         
         wherein R16 is methyl, ethyl, cyano, -ethynyl, or halogen. 
       
     
     
         77 . The method of  claim 76 , wherein the compound has formula IIff: 
       
         
           
           
               
               
           
         
       
     
     
         78 . The method of  claim 76 , wherein the compound has formula IIgg: 
       
         
           
           
               
               
           
         
         wherein R16 is methyl, ethyl, cyano, -ethynyl, or halogen. 
       
     
     
         79 . The method of  claim 47 , wherein the compound has formula IIhh: 
       
         
           
           
               
               
           
         
         wherein R16 is methyl, ethyl, cyano, -ethynyl, or halogen. 
       
     
     
         80 . The method of  claim 79 , wherein the compound has formula IIii: 
       
         
           
           
               
               
           
         
       
     
     
         81 . The method of  claim 79 , wherein the compound has formula IIjj 
       
         
           
           
               
               
           
         
         wherein R16 is methyl, cyano, -ethynyl, or halogen CCH fluorine or chlorine. 
       
     
     
         82 - 91 . (canceled) 
     
     
         92 . A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, secondary cancer growth arising from metastasis, diseases characterized by hyper-vascularization, inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, cardiovascular disease and diseases characterized by angiogenesis, comprising administering to an individual an effective amount of a compound selected from the group consisting of 1-(2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(2-fluro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(naphthalen-1-yl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, 7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(naphthalen-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, (4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-cyclohexylurea, 1-cyclohexyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-cyclohexylurea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(naphthalen-1-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl)-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-cyanophenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl-3-(2,3-difluorophenyl)urea, 1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-cyclohexylurea, 1-cyclopropyl-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, (R)-1-(2-fluoro-4-(methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(1-phenylethyl)urea, 1-(2-flouro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl))urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-methyl-5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(4-fluoro-5-(trifluoromethyl)pyridin-3-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-ylurea, 1-(5-(7-amino-1-methyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea, 1-cyclohexyl-3-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)urea, 1-cyclohexyl-3-(5-(1-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl) urea, 1-cyclohexyl-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea, 1-cyclohexyl-3-(2,4-difluoro-5-(1-methyl-7-(methylamino-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1-(4-cyano-2-fluoro-5-(1-methyl-7-(methylamino-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-cyclohexylurea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl-3-((1R,2R)-2-methylcyclohexyl)urea, 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-((1S,2S)-2-methylcyclohexyl)urea, and 1-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-((1r,4r)-4-methylcyclohexyl)urea. 
     
     
         93 . (canceled) 
     
     
         94 . (canceled) 
     
     
         95 . The method of  claims 46  or  92 , wherein the compounds of  claims 46  and  92  are combined with a pharmaceutically acceptable carrier, said carrier including an additive selected from the group including adjuvants, excipients, diluents, and stabilizers. 
     
     
         96 - 98 . (canceled)