Substituted 3-amino-thieno[2,3-b] pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses

Abstract

Disclosed are methods of treating cancer by administration of compounds according to formula (I): wherein the variables R 1 , R 2 , R 3 and Z are described herein.

1 . A method of treating a cancer disease selected from lymphoid-, myeloid- and epithelial-derived malignancies, leukemia, lymphomas, breast cancer, gastric cancer, colorectal cancer, lung cancer, and pancreatic cancer, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to general formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is 
 (a) phenyl or heteroaryl selected from furanyl, thienyl, pyridyl, pyrrolyl, imidazolyl and benzofuranyl, optionally substituted with one to two R 4 ,  
 (b) heterocyclyl selected from 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl and 4-morpholinyl, optionally substituted with one to two groups selected from C 1-6 alkyl, —CO 2 C 1-5 alkyl, phenyl, benzyl, —OH and —C(O)heteroaryl, wherein the heteroaryl is selected from furanyl, thienyl, pyridyl and pyrrolyl,  
 (c) R 7 (CH 2 ) m O—,  
 (d) R 7 OCH 2 —,  
 (e) R 7 (CH 2 ) m NH—,  
 (f) R 7 (CH 2 ) p (CH═CH) m —,  
 (g) C 1-6 alkyl, optionally partially or fully halogenated and optionally substituted with one to two R 8 ,  
 (h) C 1-8 alkoxy, optionally partially or fully halogenated and optionally substituted with one to two R 8 ,  
 (i) C 1-8 alkylS(O) n —, optionally partially or fully halogenated and optionally substituted with one to two R 8 ,  
 (j) —N(R 5 )(R 6 ), or  
 (k) —C(O)NHR′, wherein R′ is R 7 , pyridyl or —CH 3 ;  
 
 R 2  is heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl, substituted with one to three R 4 ;  
 R 3  is —OH or —H;  
 R 4  is chosen from, C 1-6 alkoxy, hydroxyC 1-6 alkyl, halogen, —CN, —CO 2 H, —CO 2 C 1-6 alkyl, —S(O)C 1-6 alkyl, —S(O) n -p-tolyl, —NO 2 , —OH, —CF 3 , —N(R 5 )(R 6 ), —NHC(O)NHC 1-6 alkyl, —C(O)N(R 5 )(R 6 ), and R 9 ;  
 R 5  and R 6  are independently selected from H, C 1-6 alkyl, —C(O)C 1-6 alkyl, —SO 2 C 1-6 alkyl, phenyl, pyridyl, benzyl, piperidinyl, phenylethyl and (CH 3 ) 3 COC(O)—;  
 R 7  is a phenyl group optionally substituted with one or two groups selected from halogen, C 1-6 alkyl, —CN, —CO 2 C 1-6 alkyl, —C(O)NR 5 R 6 , —SO 2 NH 2 , —NO 2 , —OH, —NH 2 , —CF 3  and C 1-6 alkoxy, or R 7  is C 3-6 cycloalkyl, —CH 2 OH, naphthalene-2-yl, naphthalene-1-yl, pyridyl or thienyl;  
 R 8  is selected from oxo, —OH, —NR 4 R 5 , —CO 2 H and C 1-6 alkoxy;  
 R 9  is is a heteroaryl selected from the group of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl and methyl imidizolyl, carbanomethylsulfanyl, methoxypiperdinyl, methoxypyridinyl, bromopyridynyl and methoxypyrimidynyl;  
 m is 0 or 1;  
 n is 0, 1 or 2;  
 p is 0, 1, 2 or 3;  
 Z is a bond or —O—CH 2 —;  
 or a pharmaceutically acceptable salt, ester, tautomer, individual isomers, and mixtures of isomers thereof.  
 
     
     
         2 . The method of  claim 1  wherein said cancer disease is lympoid cancer.  
     
     
         3 . The method of  claim 1  wherein said cancer disease is myeloid- and epithelial-derived malignancies.  
     
     
         4 . The method of  claim 1  wherein said cancer disease is leukemia.  
     
     
         5 . The method of  claim 1  wherein said cancer disease is a lymphomas.  
     
     
         6 . The method of  claim 1  wherein said cancer isgastric cancer, colorectal cancer, lung cancer, and pancreatic cancer disease is breast cancer.  
     
     
         7 . The method of  claim 1  wherein said cancer is breast cancer.  
     
     
         8 . The method of  claim 1  wherein said disease is gastric cancer.  
     
     
         9 . The method of  claim 1  wherein said cancer is colorectal cancer.  
     
     
         10 . The method of  claim 1  wherein said cancer is lung cancer.  
     
     
         11 . The method of  claim 1  wherein said cancer is pancreatic cancer.  
     
     
         12 . The method of  claim 1  wherein said cancer is breast cancer.