Pyridine compound

Abstract

The present invention relates to a compound having RET kinase inhibiting action or a pharmaceutically acceptable salt thereof, useful in the treatment of diseases such as cancer.In particular a compound represented by the following general formula (I) as defined herein:ora pharmaceutically acceptable salt thereof.

1 - 21 . (canceled) 
     
     
         22 . A method of treating or preventing cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein A represents one of the following formulae (Ia) to (Id): 
       
       
         
           
           
               
               
           
         
         R 1  is a hydrogen atom or a C 1 -C 3  alkyl group, and 
         R 2  is a hydrogen atom or a C 1 -C 3  alkyl group; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 . The method of  claim 22 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         24 . The method of  claim 22  wherein the cancer is lung cancer, thyroid gland cancer, breast cancer, or colon cancer. 
     
     
         25 . The method of  claim 22 , wherein the cancer is non-small cell lung cancer. 
     
     
         26 . The method of  claim 22 , wherein the cancer is thyroid gland cancer. 
     
     
         27 . A pharmaceutically acceptable salt of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein A represents one of the following formulae (Ia) to (Id): 
       
       
         
           
           
               
               
           
         
         wherein R 1  represents a hydrogen atom or a C 1 -C 3  alkyl group, 
         R 2  represents a hydrogen atom or a C 1 -C 3  alkyl group, and 
         wherein the pharmaceutically acceptable salt is an organic acid salt. 
       
     
     
         28 . The pharmaceutically acceptable salt of  claim 27 , wherein the organic acid salt is an adipate, an acetate, a malate, a fumarate, a succinate, a citrate, an ascorbate, a tartrate, an oxalate or a maleate. 
     
     
         29 . The pharmaceutically acceptable salt of  claim 27 , wherein the organic acid salt is an adipate. 
     
     
         30 . The pharmaceutically acceptable salt of  claim 27 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The pharmaceutically acceptable salt of  claim 27 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         32 . A pharmaceutical composition comprising a pharmaceutically acceptable salt of  claim 27 , and one or more pharmaceutically acceptable excipients. 
     
     
         33 . A process for the preparation of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein A represents one of the following formulae (Ia) to (Id): 
       
       
         
           
           
               
               
           
         
         wherein R 1  represents a hydrogen atom or a C 1 -C 3  alkyl group, and 
         R 2  represents a hydrogen atom or a C 1 -C 3  alkyl group; 
         said process comprising the step of reacting an amine of formula (1) with a carboxylic acid of formula (2) to give a compound of Formula (I): 
       
       
         
           
           
               
               
           
         
         wherein the amine of formula (1) is: 
       
       
         
           
           
               
               
           
         
       
     
     
         34 . The process of  claim 33 , wherein the reacting step further comprises a coupling reagent. 
     
     
         35 . The process of  claim 34 , wherein the coupling reagent is dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and the hydrochloride thereof, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorphonium chloride (DMT-MM), hexafluorophosphate {{[(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy}-4-morpholinomethylene}dimethylammonium hexafluorophosphate (COMU), propylphosphonic anhydride (T3P), N,N′-carbonyldiimidazole (CDI), or diphenylphosphoryl azide (DPPA). 
     
     
         36 . The process of  claim 33 , wherein the process further comprises the step of preparing carboxylic acid (2) by reacting halo pyridine compound (3) with quinoline compound (4): 
       
         
           
           
               
               
           
         
         wherein P 1  is a hydrogen atom or a carboxylic acid protecting group, 
         B 1  is boronic acid, a boronic acid ester, boronic acid pinacolate, a trifluoroborate potassium salt, cyclic triolborate, or MIDA boronate, and 
         X 1  is a halogen atom. 
       
     
     
         37 . The process of  claim 36 , wherein P 1  is hydrogen, and B 1  is a boronic acid. 
     
     
         38 . The process of  claim 36 , wherein the halo pyridine compound (3) is 2-chloropyridin-5-ylacetic acid. 
     
     
         39 . The process of  claim 36 , wherein the reaction between halo pyridine compound (3) and quinoline compound (4) comprises a catalyst containing palladium. 
     
     
         40 . The process of  claim 39 , wherein the catalyst is tetrakis(triphenylphosphine)palladium(0), bis[tris(2-methylphenyl)phosphine]palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichlorobis(tri-o-tolylphosphine)palladium(II), dichlorobis(tricyclohexylphosphine)palladium(II), dichloro[2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (PEPSI (registered trademark)-IPr catalyst), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (SPhos Pd G1), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (XPhos Pd G1), chloro(triphenylphosphine)[2-(2′-amino-1,1′-biphenyl)]palladium(II), chloro[tri(o-tolyl)phosphine][2-(2′-amino-1,1′-biphenyl)]palladium(II), chloro[(tricyclohexylphosphine)-2-(2′-amino1,1′-biphenyl)]palladium(II) (PCy3 Pd G2), chloro[(tri t-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II) (P(tBu) 3  Pd G2), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) (SPhos Pd G2), chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos Pd G2), [2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (rac-BINAP Pd G3), (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (SPhos Pd G3), [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XantPhos Pd G3), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), palladium(II) acetate, Tris(dibenzylideneacetone)dipalladium(0), or a palladium carbon catalyst.