Substituted pyrrolidines as ros tyrosine kinase inhibitors

Abstract

The main purpose of the invention is to provide a novel aromatic heterocyclic derivative or a pharmaceutically acceptable salt thereof. Examples of the invention include aromatic heterocyclic derivatives represented by general formula [1] and pharmaceutically acceptable salts thereof. In formula [1]: R 1 represents phenyl optionally substituted with one or two groups selected from the group consisting of halogens, as well as alkyls and alkoxys optionally substituted by halogens; R 2 represents hydrogen, an alkyl, cycloalkyl, or alkoxy optionally substituted by a halogen, or a heteroaryl optionally substituted by an alkyl; X represents CR 3 , and Y represents N or CR 4 , or X represents N, and Y represents CR 4 ; and Z represents CR 5 or N.

1 - 11 . (canceled) 
     
     
         12 : A method of treating glioblastoma, non-small cell lung cancer, angiosarcoma, inflammatory myofibroblastic tumor, cholangiocarcinoma, gastric cancer, ovarian cancer, epithelioid hemangioendothelioma, colorectal cancer, liposarcoma, or Spitzoid neoplasms in a human, the method comprising the step of administering to the human a compound represented by the following formula [1], a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a pharmaceutically acceptable salt of an optical isomer thereof: 
       
         
           
           
               
               
           
         
         wherein
 R 1  represents phenyl which may be substituted with one or two groups selected from the group consisting of halogen, alkyl optionally substituted by halogen, and alkoxy; 
 R 2  represents hydrogen, alkyl optionally substituted by halogen, cycloalkyl, alkoxy, or heteroaryl optionally substituted by alkyl; 
 X represents CR 3 , and Y represents N or CR 4 , or X represents N, and Y represents CR 4 ; 
 R 3  represents hydrogen or alkyl; and 
 R 4  represents
 1) hydrogen, 
 2) alkyl which may be substituted with 1 to 3 groups selected from the group consisting of alkoxy and halogen, 
 3) cycloalkyl, 
 4) phenyl which may be substituted with one group selected from the group consisting of carbamoyl and alkylsulfonyl, 
 5) heteroaryl which may be substituted with one group selected from alkyl optionally substituted by hydroxy or alkoxy, halogen, hydroxy, and alkoxy, 
 6) carboxy, 
 7) alkyloxycarbonyl, or 
 8) carbamoyl which may be substituted with one or two groups selected from the group consisting of alkyl optionally substituted by hydroxy or alkoxy, alkylsulfonyl, saturated heterocyclic group optionally substituted by alkyl, and cycloalkyl optionally substituted by hydroxy or carboxy; and in the case where X represents N, and Y represents CR 4 , R 2  and R 4  may be taken jointly to form a group represented by the following formula, together with the carbon atom to which R 2  bonds as well as the carbon atom to which R 4  bonds: 
 
 
       
       
         
           
           
               
               
           
         
         wherein
 Q represents alkylcarbonyl or alkylsulfonyl; 
 Z represents CR 5  or N; and 
 R 5  represents alkyl, alkoxycarbonyl, halogen, or cyano. 
 
       
     
     
         13 : A method of treating glioblastoma, non-small cell lung cancer, angiosarcoma, inflammatory myofibroblastic tumor, cholangiocarcinoma, gastric cancer, ovarian cancer, epithelioid hemangioendothelioma, colorectal cancer, liposarcoma, or Spitzoid neoplasms in a human, the method comprising the step of administering to the human a compound selected from the group consisting of the following (1) to (71), a pharmaceutically acceptable salt thereof, an optical isomer thereof, or a pharmaceutically acceptable salt of an optical isomer thereof:
 (1) 2-({6-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrazin-2-yl amino)-1,3-thiazole-5-carbonitrile,   (2) 2-({5-methyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (3) 2-({5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-4,5′-bipyrimidin-6-yl}amino)-1,3-thiazole-5-carbonitrile,   (4) 4-{6-[(5-cyano-1,3-thiazol-2-yl)amino]-5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}benzamide,   (5) 2-({5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-6-(pyridin-3-yl)pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (6) methyl 6-[(5-cyano-1,3-thiazol-2-yl)amino]-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidine-4-carboxylate,   (7) 6-[(5-cyano-1,3-thiazol-2-yl)amino]-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidine-4-carboxylic acid,   (8) 2-({5-methyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (9) 2-({5-methoxy-6-methyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl)}amino)-1,3-thiazole-5-carbonitrile,   (10) 2-({5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (11) 2-({5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-6-(1,3-oxazol-5-yl)pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (12) 6-[(5-cyano-1,3-thiazol-2-yl)amino]-N-[(2R)-1-hydroxypropan-2-yl]-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidine-4-carboxamide,   (13) 2-({5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-6-[4-(methylsulfony)phenyl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (14) 2-({5-methoxy-2-[2-(2-methoxy-4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (15) 2-({6-(6-methoxypyridin-3-yl)-5-methyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (16) 2-({6-(6-hydroxypyridin-3-yl)-5-methyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (17) 2-({6-cyclopropyl-5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (18) 2-({5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (19) 2-({3-methyl-6-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (20) 2-({6-[2-(4-fluorophenyl)pyrrolidin-1-yl]-3-(1,3-oxazol-5-yl)pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (21) 2-({(6-[2-(4-fluorophenyl)pyrrolidin-1-yl]-3-(pyrimidin-5-yl)pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (22) 2-({3-cyclopropyl-6-[2-(2-methoxy-4-methylphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (23) 2-({3-cyclopropyl-6-[2-(2-methoxyphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (24) 2-({6-[2-(4-fluorophenyl)pyrrolidin-1-yl]-3-(furan-3-yl)pyrazin-2-yl}amino)-1,3-thaizole-5-carbonitrile,   (25) 2-({6-[2-(4-fluorophenyl)pyrrolidin-1-yl]-3-(pyridin-4-yl)pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (26) 2-({6-[2-(4-methylphenyl)pyrrolidin-1-yl]-4-(trifluoromethyl)pyridine-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (27) 2-({6-[2-(4-fluorophenyl)pyrrolidin-1-yl]-3-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (28) 3-methyl-6-[2-(4-methylphenyl)pyrrolidin-1-yl]-N-(5-methyl-1,3-thiazol-2-yl)pyrazine-2-amine,   (29) 2-({6-[2-(2-methoxy-4-methylphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (30) 6-[2-(4-chlorophenyl)pyrrolidin-1-yl]-3-cyclopropyl-N-(5-methyl-1,3-thiazol-2-yl)pyrazine-2-amine,   (31) 2-({6-[2-(3,5-dimethoxyphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (32) 2-({6-[2-(3-methoxy-4-methylphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (33) 3-cyclopropyl-6-[2-(4-methylphenyl)pyrrolidin-1-yl]-N-(5-methyl-1,3-thiazol-2-yl)pyrazine-2-amine,   (34) 2-({(3-cyclopropyl-6-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (35) 2-({6-[2-(4-chlorophenyl)pyrrolidin-1-yl]-3-cyclopropylpyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (36) 2-({6-[2-(4-methoxyphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (37) 2-({(6-[2-(3-methoxyphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (38) 2-[(6-{2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl}pyrazin-2-yl)amino]-1,3-thiazole-5-carbonitrile,   (39) 2-({3-cyclopropyl-6-[2-(4-fluorophenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (40) 2-({6-[2-(4-fluorophenyl)pyrrolidin-1-yl]-3-methylpyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (41) 2-({6-[2-(4-chlorophenyl)pyrrolidin-1-yl]-3-methylpyrazin-2-yl}amino)-1, 3-thiazole-5-carbonitrile,   (42) 2-({3,5-dimethyl-6-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (43) 2-({6-[2-(4-chlorophenyl)pyrrolidin-1-yl]-3-cyclopropyl-5-methylpyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (44) N-(5-ethyl-1,3-thiazol-2-yl)-6-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrazine-2-amine,   (45) 2-({6-[2-(3-methylphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (46) 2-({6-[2-(2-methylphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (47) 2-({6-[2-(4-chlorophenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (48) 2-({6-(2-fluoropyridin-3-yl)-5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (49) 2-({6-(6-fluoropyridin-3-yl)-5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (50) ethyl 2-({6-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrazin-2-yl}amino)-1,3-thiazole-5-carboxylate,   (51) 2-({5,6-dimethyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (52) 2-({6-[2-(4-fluorophenyl)pyrrolidin-1-yl]-3-(2-methylpyridin-4-yl)pyrazin-2-yl}amino)-1,3-thiazole-5-carbonitrile,   (53) 6-[(5-cyano-1,3-thiazol-2-yl)amino]-5-methyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-N-(1-methylpiperidin-4-yl)pyrimidine-4-carboxamide,   (54) 2-[(5-cyano-1,3-thiazol-2-yl)amino]-N,3-dimethyl-6-[2-(4-methylphenyl)pyrrolidin-1-yl]pyridine-4-carboxamide,   (55) N-(5-fluoro-1,3-thiazol-2-yl)-5-methoxy-6-methyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidine-4-amine,   (56) 2-({5-ethyl-6-(methoxymethyl)-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (57) 2-({5-methoxy-6-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (58) 2-({6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (59) 2-({5-methoxy-2′-methyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-4,5′-bipyrimidin-6-yl}amino)-1,3-thiazole-5-carbonitrile,   (60) 2-(4-{5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-6-(1,2,4-thiadiazol-5-ylamino)pyrimidin-4-yl}-1H-pyrazol-1-yl)ethanol,   (61) 6-[(5-cyano-1,3-thiazol-2-yl)amino]-N-(trans-4-hydroxycyclohexyl)-5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidine-4-carboxamide,   (62) trans-4-[({6-[(5-cyano-1,3-thiazol-2-yl)amino]-5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}carbonyl)amino]cyclohexanecarboxylic acid,   (63) 6-[(5-cyano-1,3-thiazol-2-yl)amino]-5-methoxy-N-(2-methoxyethyl)-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidine-4-carboxamide,   (64) 2-({5-methoxy-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-6-(6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (65) 2-[(5-cyano-1,3-thiazol-2-yl)amino]-3-cyclopropyl-6-[2-(4-methylphenyl)pyrrolidin-1-yl]pyridine-4-carboxamide,   (66) 6-[(5-cyano-1,3-thiazol-2-yl)amino]-5-ethyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-N-(methylsulfonyl)pyrimidine-4-carboxamide,   (67) 2-[(5-cyano-1,3-thiazol-2-yl)amino]-N-(4-hydroxycyclohexyl)-3-methyl-6-[2-(4-methylphenyl)pyrrolidin-1-yl]pyridine-4-carboxamide,   (68) 6-[2-(4-methylphenyl)pyrrolidin-1-yl]-4-(1-methyl-1H-pyrazol-4-yl)-N-(1,2,4-thiadiazol-5-yl)pyridine-2-amine,   (69) 2-({5-ethyl-6-methyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile,   (70) 2-({6-acetyl-2-[2-(4-methylphenyl)pyrrolidin-1-yl]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile, and   (71) 2-({2-[2-(4-methylphenyl)pyrrolidin-1-yl]-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile.