Compounds as tyrosine kinase modulators

Abstract

The present invention is directed to novel compounds of Formula I. The compounds of the present invention are potent tyrosine kinase modulators, and are suitable for the treatment and prevention of diseases and conditions related to abnormal activities of tyrosine kinase receptors.

1 .- 10 . (canceled) 
     
     
         11 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Y is O; 
 the A ring is selected from the group consisting of phenyl and fluorophenyl; 
 Z is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         the B ring is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
       and
 R is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The compound of claim  1 , wherein the compound is selected from the group consisting of:
 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(2H-tetrazol-5-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;   7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2-b]pyridine-2-carboxamide;   ethyl (4-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazin-1-yl)acetate;   7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;   7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;   methyl rel-(2R,4S)-1-{3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate;   dimethyl 2,2′-({3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate;   N-(3-aminopropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;   tert-butyl {3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate;   N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;   7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide;   ethyl 4-{2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}piperazine-1-carboxylate;   ethyl 4-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}piperazine-1-carboxylate;   methyl ({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}amino)acetate;   dimethyl 2,2′-({3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}imino)diacetate;   dimethyl 2,2′-({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}imino)diacetate;   methyl 1-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)pyrrolidine-3-carboxylate;   ethyl (4-{[4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetyl}piperazin-1-yl)acetate;   ethyl [4-({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)piperazin-1-yl]acetate;   methyl ({2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}amino)acetate;   N-(2-aminoethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;   tert-butyl {2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]ethyl}carbamate;   7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;   N-(2,2-diethoxyethyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;   7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[3-(hydroxymethyl)piperidin-1-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;   7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-{3-[2-(hydroxymethyl)morpholin-4-yl]propyl}thieno[3,2-b]pyridine-2-carboxamide;   7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-hydroxypiperidin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;   methyl (2S,4R)-1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}-4-hydroxypyrrolidine-2-carboxylate;   N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;   7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(2-oxoethyl)thieno[3,2-b]pyridine-2-carboxamide;   methyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate;   7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide;   tert-butyl {3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate;   N-(3-aminopropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;   tert-butyl (4S)-5-(ethylamino)-4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoate;   (2S)-5-tert-butoxy-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]-5-oxopentanoic acid;   5-tert-butyl 1-methyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate;   1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylic acid;   tert-butyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylate;   7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide;   7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-hydroxypropyl)thieno[3,2-b]pyridine-2-carboxamide;   dimethyl (2S)-2-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]pentanedioate;   ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate;   ethyl 4-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate;   7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide;   7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-pyrrolidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide;   N-[2-(diethylamino)ethyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;   N-[3-(diethylamino)propyl]-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide;   Methyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;   7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylic acid;   N-ethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;   N,N-diethyl-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;   N-hydroxy-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;   N-(3-hydroxypropyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;   N-(2-hydroxyethyl)-7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxamide;   7-{3-[(3-methyl-2-furoyl)amino]phenoxy}-N-[2-(2H-tetrazol-5-yl)ethyl]thieno[3,2-b]pyridine-2-carboxamide;   3-hydroxypropyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;   2-hydroxyethyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;   2-methoxyethyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate;   Methyl [(3-{[(7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridin-2-yl)carbonyl]amino}propyl)amino]acetate;   Methyl 7-(3-((2-fluoro-5-methylphenyl)carbamoyl)phenoxy)thieno[3,2-b]pyridine-2-carboxylate;   7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxylic acid;   N-ethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide;   N,N-diethyl-7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridine-2-carboxamide; and   Methyl {[3-({[7-(3-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)thieno[3,2-b]pyridin-2-yl]carbonyl}amino)propyl]amino}acetate;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A pharmaceutical composition comprising a therapeutic effective amount of at least one compound of  claim 11 , or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 
     
     
         14 . The composition of  claim 13 , wherein the composition is in the form of tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, eye ointments, eye sprays, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic bioerodible implant, and non-bioerodible ophthalmic inserts and depots. 
     
     
         15 . A pharmaceutical composition comprising a therapeutic effective amount of at least one compound of  claim 12 , or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 
     
     
         16 . The composition of  claim 15 , wherein the composition is in the form of tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, eye ointments, eye sprays, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic bioerodible implant, and non-bioerodible ophthalmic inserts and depots.