Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors

Abstract

Enantiomerically pure compound of formula 1 are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.

1 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is CH 
 R 1  is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane, azitidine or phenyl group; and each hydrogen in R 1  is optionally substituted by R 3 ; 
 each R 3  is independently halogen, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 3-12  cycloalkyl, C 6-12  aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n OR 4 , —(CR 6 R 7 ) n C(O)NR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6  or —NR 4 S(O) p R 5 , each hydrogen in R 3  is optionally substituted by R 8 , and R 3  groups on adjacent atoms may combine to form a C 6-12  aryl, 5-12 membered heteroaryl, C 3-12  cycloalkyl or 3-12 membered heteroalicyclic group; 
 each R 4 , R 5 , R 6  and R 7  is independently hydrogen, halogen, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, C 3-12  cycloalkyl, C 6-12  aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R 4 , R 5 , R 6  and R 7  bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R 4 , R 5 , R 6  and R 7  bound to the same carbon atom may be combined to form a C 3-12  cycloalkyl, C 6-12  aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R 4 , R 5 , R 6  and R 7  is optionally substituted by R 8 ; 
 each R 8  is independently halogen, C 1-12  alkyl. C 2-12  alkenyl, C 2-12  alkynyl, C 3-12  cycloalkyl, C 6-12  aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —NH 2 , —CN, —OH, —O—C 1-12  alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12  aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic) or —O—(CH 2 ) n (5-12 membered heteroaryl); and each hydrogen in R 8  is optionally substituted by R 11 ; 
 each R 11  is independently halogen, C 1-12  alkyl, C 1-12  alkoxy, C 3-12  cycloalkyl, C 6-12  aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —O—C 1-12  alkyl, —O—(CH 2 ) n C 3-12  cycloalkyl, —O—(CH 2 ) n C 6-12  aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic), —O—(CH 2 ) n (5-12 membered heteroaryl) or —CN, and each hydrogen in R 11  is optionally substituted by halogen, —OH, —CN, —C 1-12  alkyl which may be partially or fully halogenated, —O—C 1-12  alkyl which may be partially or fully halogenated, —CO, —SO or —SO 2 ; 
 each m is independently 0, 1 or 2; 
 each n is independently 0, 1, 2, 3 or 4; 
 each p is independently 1 or 2; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein R 1  is pyrazole, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 2 , wherein R 3  is 3-12 membered heteroalicyclic, or a pharmaceutically acceptable salt thereof. 
     
     
         4 . An enantiomerically pure compound selected from the group consisting of 5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine; 5-iodo-3-[(R)1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 5-bromo-3-[1(R)-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine; 4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoic acid; (4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-piperazin-1-yl-methanone; 4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester; 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[4-(piperazin-1-ylcarbonyl)phenyl]pyridin-2-amine; 4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide; (4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}phenyl)methanol; 4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}-N-[3-(dimethylamino)propyl]-N-methylbenzamide; tert-butyl 4-(4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}benzoyl)piperazine-1-carboxylate; 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine; 1-[4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidin-1-yl]-2-hydroxy-ethanone; 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrazin-2-ylamine; 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrazol-4-yl)-pyrazin-2-ylamine; 1-[4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidin-1-yl]-2-hydroxy-ethanone; 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyrazin-2-ylamine; 1-[4-(4-{5-amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidin-1-yl]-2-dimethylamino-ethanone; 3-[(R)-1-(2-chloro-3,6-difluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine; or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.