Substituted nicotinamide derivatives as kinase inhibitors

Abstract

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.

We claim: 
     
         1 . A compound of formula I or II 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is hydrogen or NH 2 ; 
         R 2  is hydrogen or NH 2 ; 
         X is 
       
       
         
           
           
               
               
           
         
         Y is CH or N; 
         Ar 1  is, in formula I, a carbocyclic aryl or heteroaryl group, wherein said carbocyclic aryl or heteroaryl group may be optionally substituted with halogen, trihalomethyl, or lower alkyl; 
         Ar 1  is, in formula II, an aryl group, i.e. a carbocyclic group or heteroaryl group, further including prodrugs, pharmaceutically acceptable salts, racemic mixtures and enantiomers thereof; 
         R 3  is hydrogen, lower alkyl, 
       
       
         
           
           
               
               
           
         
         R 4  is hydrogen, lower alkyl, (CH 2 )—COOR 6  or (CH 2 )—COR 7 ; 
         R 5  is hydrogen or lower alkyl; 
         R 6  is hydrogen or lower alkyl; 
         R 7  is a substituted amine; 
         and n is 0, or an integer of from 1 to 6. 
       
     
     
         2 . A compound according to  claim 1  wherein X is —NH—C(O)—. 
     
     
         3 . A compound according to  claim 1  wherein Y is CH. 
     
     
         4 . A compound according to  claim 1  wherein the compound is of formula I and Ar 1  is selected from the group consisting of phenyl and furanyl and substituted derivatives thereof. 
     
     
         5 . A compound according to  claim 4  wherein said substituted derivatives are lower alkyl and/or halo-substituted phenyl and furanyl. 
     
     
         6 . A compound according to  claim 5  wherein Ar 1  is selected from the group consisting of 3-methyl-2-furanyl and 2-fluoro-5-methylphenyl. 
     
     
         7 . A compound according to  claim 1  wherein, R 2  is H. 
     
     
         8 . A compound according to  claim 1  wherein R 3  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound according to  claim 8  wherein R 3  is —C(O)N(R 4 )(R 5 ). 
     
     
         10 . The compound of  claim 1  wherein R 7  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1  wherein the compound is of formula II and said carbocyclic aryl or heteroaryl group is substituted with one or more alkoxy, halogen, trihaloalkyl, or lower alkyl radicals. 
     
     
         12 . The compound of  claim 1  wherein the compound is of formula II and wherein Ar 1  is selected from the group consisting of phenyl, oxazoyl, furanyl and alkyl, alkyloxy and halo-substituted phenyl, oxazoyl and furanyl. 
     
     
         13 . The compound of  claim 12  wherein Ar 1  is selected from the group consisting of
 3-methylfuranyl; 
 2-fluoro 5-methylphenyl; 
 4-chloro 5-t-butylphenyl; 
 3-methoxyphenyl; and 
 5-butyloxazoyl. 
 
     
     
         14 . A compound according to  claim 1  wherein said compound is selected from the group consisting of:
 1 tert-butyl 1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1λ 4 ,4-thiazinane-4-carboxylate 1-oxide, 
 5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-(1-oxido-1λ 4 ,4-thiazinan-1-ylidene)nicotinamide, 
 1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1λ 4 ,4-thiazinane-4-carboxamide 1-oxide, 
 ethyl 3-({[1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1-oxido-1λ 4 ,4-thiazinan-4-yl]carbonyl}amino)propanoate, 
 ethyl 4-({[1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1-oxido-1λ 4 ,4-thiazinan-4-yl]carbonyl}amino)butanoate, 
 3-({[1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1-oxido-1λ 4 ,4-thiazinan-4-yl]carbonyl}amino)propanoic acid, 
 4-({[1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1-oxido-1λ 4 ,4-thiazinan-4-yl]carbonyl}amino)butanoic acid, 
 N-[3-(3-hydroxypyrrolidin-1-yl)-3-oxopropyl]-1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1λ 4 ,4-thiazinane-4-carboxamide 1-oxide, 
 N-[4-(3-hydroxypyrrolidin-1-yl)-4-oxobutyl]-1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1λ 4 ,4-thiazinane-4-carboxamide 1-oxide; 
 N-{4-[(2,3-dihydroxypropyl)amino]-4-oxobutyl}-1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1λ 4 ,4-thiazinane-4-carboxamide 1-oxide, 
 ethyl({[1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1-oxido-1λ 4 ,4-thiazinan-4-yl]carbonyl}amino)acetate, 
 ({[1-({[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1-oxido-1λ 4 ,4-thiazinan-4-yl]carbonyl}amino)acetic acid, 
 tert-butyl 1-({[6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1λ 4 ,4-thiazinane-4-carboxylate 1-oxide, 
 6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-(1-oxido-1λ 4 ,4-thiazinan-1-ylidene)nicotinamide, 
 1-({[6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1λ 4 ,4-thiazinane-4-carboxamide 1-oxide, 
 tert-butyl 1-({[6-amino-5-({3-[(2-fluoro-5-methylbenzoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1λ 4 ,4-thiazinane-4-carboxylate 1-oxide, 
 6-amino-5-({3-[(2-fluoro-5-methylbenzoyl)amino]phenyl}ethynyl)-N-(1-oxido-1λ 4 ,4-thiazinan-1-ylidene)nicotinamide, 
 1-({[6-amino-5-({3-[(2-fluoro-5-methylbenzoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}imino)-1λ 4 ,4-thiazinane-4-carboxamide 1-oxide; 
 5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide, 
 6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide, 
 6-amino-5-({3-[(2-fluoro-5-methylbenzoyl)amino]phenyl}ethynyl)-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide, 
 6-amino-5-[(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenyl)ethynyl]-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide, 
 6-amino-5-{[3-({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)phenyl]ethynyl}-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide, 
 6-amino-5-[(3-{[(5-tert-butylisoxazol-3-yl)amino]carbonyl}phenyl)ethynyl]-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide, and 
 6-amino-5-[(3-{[(3-methoxyphenyl)amino]carbonyl}phenyl)ethynyl]-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide; 
 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof. 
 
     
     
         15 . A method for treating a disease related to unregulated tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or formula II of  claim 1 . 
     
     
         16 . The method of  claim 15  wherein said disease is selected from the group consisting of cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases. 
     
     
         17 . The method of  claim 16  wherein the blood vessel proliferative disorder is selected from the group consisting of diabetic retinopathy, exudative age-related macular degeneration, retinopathy of prematurity, pterigium, rosacea, arthritis and restenosis. 
     
     
         18 . The method of  claim 16  wherein the fibrotic disorder is selected from the group consisting of hepatic cirrhosis and atherosclerosis. 
     
     
         19 . The method of  claim 16  wherein the mesangial cell proliferative disorder is selected from the group consisting of glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies. 
     
     
         20 . The method of  claim 16  wherein the metabolic disease is selected from the group consisting of psoriasis, diabetes mellitus, wound healing, and neurodegenerative diseases. 
     
     
         21 . The method of  claim 16  wherein said disease is an ophthalmic disease. 
     
     
         22 . The method of  claim 21  wherein said ophthalmic disease is selected from the group consisting of pterygia, hyperemia related to an actively inflamed pterygia, recurrent pterygia following excisional surgery, prophylactic therapy to prevent recurrent pterygia post-excision, progressive pterygia approaching the visual axis, chronic low grade hyperemia associated with pterygia, corneal neovascularization, neovascular glaucoma, iris neovascularization, chronic allergic conjunctivitis, ocular rosacea, blepharoconjunctivitis, recurrent episcleritis, keratoconjunctivitis sicca, ocular graft vs host disease, diabetic retinopathy, diabetic macular edema, proliferative diabetic retinopathy, exudative or neovascular age-related macular degeneration, high-risk eyes with dry age-related macular degeneration, neovascular disease associated with retinal vein occlusion, neovascular disease associated with the following: pathologic myopia, pseudoxanthoma elasticum, optic nerve drusen, traumatic choroidal rupture, idiopathic etiologies, presumed ocular histoplasmosis syndrome, and retinopathy of prematurity. 
     
     
         23 . The Method of  claim 16  wherein said disease is a dermatological indication selected from the group consisting of sun burn, eczema, psoriasis and contact dermatitis. 
     
     
         24 . The compound of  claim 1  that is 5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The compound of  claim 1  that is 6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The compound of  claim 1  that is 6-amino-5-[(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenyl)ethynyl]-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The compound of  claim 1  that is 6-amino-5-[(3-{[(5-tert-butylisoxazol-3-yl)amino]carbonyl}phenyl)ethynyl]-N-(4-oxido-1,4λ 4 -oxathian-4-ylidene)nicotinamide, or a pharmaceutically acceptable salt thereof.