Benzamide derivatives useful as histone deacetylase inhibitors

Abstract

The invention concerns a compound of the formula (I) wherein Ring A is heterocyclyl; m is 0-4 and each R 1 is a group such as hydroxy, halo, trifluoromethyl and cyano; R 2 is halo and n is 0-2; and each R 4 is a group such as hydroxy, halo, trifluoromethyl and cyano; p is 0-4; and R 3 is amino or hydroxy; or pharmaceutically-acceptable salts or in-vivo-hydrolysable ester or amide thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by histone deacetylase.

1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 Ring A is piperidinyl, wherein nitrogen within the piperidinyl ring can be optionally substituted by K; 
 R 1  is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 -amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 -carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, aryl, aryloxy, arylC 1-6 alkyl, heterocyclic group, (heterocyclic group)C 1-6 alkyl, or a group (B-E-); wherein R 1 , including group (B-E-), may be optionally substituted on carbon by one or more W; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by J; 
 W is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 -amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 -carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, or a group (B′-E′-); wherein W, including group (B′-E′-), may be optionally substituted on carbon by one or more Y; 
 Y and Z are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 -amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 -carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl or N,N—(C 1-6 alkyl) 2 sulphamoyl; 
 G, J and K are independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 1-8 alkanoyl, C 1-8 alkylsulphonyl, C 1-8 alkoxycarbonyl, carbamoyl, N—(C 1-8 alkyl)carbamoyl, N,N—(C 1-8 alkyl)carbamoyl, benzyloxycarbonyl, benzoyl, phenylsulphonyl, aryl, arylC 1-6 alkyl or (heterocyclic group)C 1-6 alkyl; wherein G, J and K may be optionally substituted on carbon by one or more Q; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by hydrogen or C 1-6 alkyl; 
 Q is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 -amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 -carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonylamino, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, aryl, aryloxy, aryl C 1-6 alkyl, arylC 1-6 alkoxy, heterocyclic group, (heterocyclic group)C 1-6 alkyl, (heterocyclic group)C 1-6 alkoxy, or a group (B″-E″-); wherein Q, including group (B″-E″-), may be optionally substituted on carbon by one or more Z; 
 B, B′ and B″ are independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic group, (heterocyclic group)C 1-6 alkyl, phenyl or phenylC 1-6 alkyl; wherein B, B′ and B″ may be optionally substituted on carbon by one or more D; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from G; 
 E, E′ and E″ are independently selected from —N(R a )—, —O—, —C(O)O—, —OC(O)—, —C(O)—, —N(R a )C(O)—, —N(R a )C(O)N(R b )—, —N(R a )C(O)O—, —OC(O)N(R a )—, —C(O)N(R a )—, —S(O) r —, —SO 2 N(R a )—, —N(R a )SO 2 —; wherein R a  and R b  are independently selected from hydrogen or C 1-6 alkyl optionally substituted by one or more F and r is 0-2; 
 D and F are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 -amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 -carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl or N,N—(C 1-6 alkyl) 2 sulphamoyl; 
 m is 0, 1, 2, 3 or 4; wherein the values of R 1  may be the same or different; 
 R 2  is halo; 
 n is 0, 1 or 2; wherein the values of R 2  may be the same or different; 
 R 3  is amino or hydroxy; 
 R 4  is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkanoyl, C 1-3 alkanoyloxy, N—(C 1-3 alkyl)amino, N,N—(C 1-3 alkyl) 2 -amino, C 1-3 alkanoylamino, N—(C 1-3 alkyl)carbamoyl, N,N—(C 1-3 alkyl) 2 -carbamoyl, C 1-3 alkylS(O) a  wherein a is 0 to 2, C 1-3 alkoxycarbonyl, N—(C 1-3 alkyl)sulphamoyl, N,N—(C 1-3 alkyl) 2 sulphamoyl; 
 p is 0, 1 or 2; wherein the values of R 4  may be the same or different; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A compound of the formula (I) according to  claim 1  wherein:
 R 1  is a substituent on carbon and is selected from halo, amino, C 1-6 alkyl, C 1-6 alkoxy, N—(C 1-6 alkyl)amino, aryl, aryloxy, arylC 1-6 alkyl, heterocyclic group, (heterocyclic group)C 1-6 alkyl, or a group (B-E-); wherein R 1 , including group (B-E-), may be optionally substituted on carbon by one or more W; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by J;   W is hydroxy, mercapto, C 1-6 alkyl, C 1-6 alkoxy, N,N—(C 1-6 alkyl) 2 -amino or a group (B′-E′-); wherein W, including group (B′-E′-), may be optionally substituted on carbon by one or more Y;   Y and Z are independently selected from halo, nitro, cyano, hydroxy, C 1-6 alkoxy, N,N—(C 1-6 alkyl) 2 -amino or C 1-6 alkanoylamino;   G, J and K are independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 1-8 alkanoyl, aryl, arylC 1-6 alkyl or (heterocyclic group)C 1-6 alkyl; wherein G, J and K may be optionally substituted on carbon by one or more Q; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by hydrogen or C 1-6 alkyl;   Q is cyano, hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonylamino, aryl, aryloxy or a group (B″-E″-); wherein Q, including group (B″-E″-), may be optionally substituted on carbon by one or more Z;   B, B′ and B″ are independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic group, (heterocyclic group)C 1-6 alkyl, phenyl or phenylC 1-6 alkyl; wherein B, B′ and B″ may be optionally substituted on carbon by one or more D; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from G;   E, E′ and E″ are independently selected from —N(R a )—, —O—, —C(O)O—, —OC(O)—, —C(O)—, —N(R a )C(O)—, —N(R a )C(O)N(R b )—, —N(R a )C(O)O—, —OC(O)N(R a )—, —C(O)N(R a )—, —S(O) r —, —SO 2 N(R a )—, —N(R a )SO 2 —; wherein R a  and R b  are independently selected from hydrogen or C 1-6 alkyl optionally substituted by one or more F and r is 0-2;   D and F are independently selected from halo, C 1-6 alkoxy or N,N—(C 1-6 alkyl) 2 -amino.   
     
     
         3 . A compound of the formula (I) according to  claim 1  wherein m is 1. 
     
     
         4 . A compound of the formula (I) according to  claim 1  wherein R 2  is fluoro and n is 0 or 1. 
     
     
         5 . A compound of the formula (I) according to  claim 1  wherein R 3  is amino. 
     
     
         6 . A compound of the formula (I) according to  claim 1  wherein p is 0. 
     
     
         7 . A compound of formula (I) according to  claim 1  wherein:
 Ring A is piperidinyl, wherein nitrogen within the piperidinyl ring can be optionally substituted by K;   R 1  is a substituent on carbon and is selected from halo, amino, C 1-6 alkyl, C 1-6 alkoxy, N—(C 1-6 alkyl)amino, aryl, aryloxy, arylC 1-6 alkyl, heterocyclic group, (heterocyclic group)C 1-6 alkyl, or a group (B-E-); wherein R 1 , including group (B-E-), may be optionally substituted on carbon by one or more W; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by J;   W is hydroxy, mercapto, C 1-6 alkyl, C 1-6 alkoxy, N,N—(C 1-6 alkyl) 2 -amino or a group (B′-E′-); wherein W, including group (B′-E′-), may be optionally substituted on carbon by one or more Y;   Y and Z are independently selected from halo, nitro, cyano, hydroxy, C 1-6 alkoxy, N,N—(C 1-6 alkyl) 2 -amino or C 1-6 alkanoylamino;   G, J and K are independently selected from C 1-8 alkyl, C 2-8 alkenyl, C 1-8 alkanoyl, aryl, arylC 1-6 alkyl or (heterocyclic group)C 1-6 alkyl; wherein G, J and K may be optionally substituted on carbon by one or more Q; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by hydrogen or C 1-6 alkyl;   Q is cyano, hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonylamino, aryl, aryloxy or a group (B″-E″-); wherein Q, including group (B″-E″-), may be optionally substituted on carbon by one or more Z;   B, B′ and B″ are independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic group, (heterocyclic group)C 1-6 alkyl, phenyl or phenylC 1-6 alkyl; wherein B, B′ and B″ may be optionally substituted on carbon by one or more D; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from G;   E, E′ and E″ are independently selected from —N(R a )—, —O—, —C(O)O—, —OC(O)—, —C(O)—, —N(R a )C(O)—, —N(R a )C(O)N(R a )—, —N(R a )C(O)O—, —OC(O)N(R a )—, —C(O)N(R a )—, —S(O) r —, —SO 2 N(R a )—, —N(R a )SO 2 —; wherein R a  and R b  are independently selected from hydrogen or C 1-6 alkyl optionally substituted by one or more F and r is 0-2;   D and F are independently selected from halo, C 1-6 alkoxy or N,N—(C 1-6 alkyl) 2 -amino;   m is 0, 1, 2, 3 or 4; wherein the values of R 1  may be the same or different;   R 2  is fluoro or chloro;   n is 0, 1 or 2, wherein the values of R 2  may be the same or different;   R 3  is amino or hydroxy;   R 4  is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy or carbamoyl;   p is 0, 1 or 2, wherein the values of R 4  may be the same or different;   or a pharmaceutically acceptable salt thereof.   
     
     
         8 . A compound of formula (I) according to  claim 1  wherein:
 Ring A piperidinyl, wherein nitrogen within the piperidinyl ring can be optionally substituted by K;   R 1  is a substituent on carbon and is selected from fluoro, chloro, amino, methyl, ethyl, propyl, methoxy, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, phenyl, naphthylethyl, piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 2-(thiomethyl)-pyrimidin-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydropyran-2-ylmethyl, 1,2,5-thiadiazol-3-ylethyl, piperidin-1-ylmethyl, pyridin-2-ylmethyl, or a group (B-E-); wherein R 1 , including group (B-E-), may be optionally substituted on carbon by one or more W; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by J;   W is hydroxy, methyl, ethyl, ethoxy, N,N-(diethyl)amino, N,N-(dibutyl)amino, or a group (B′-E′-); wherein W, including group (B′-E′-), may be optionally substituted on carbon by one or more Y;   Y and Z are independently selected from fluoro, chloro, bromo, nitro, cyano, hydroxy, methoxy, N,N-(dimethyl)amino or methylcarbonylamino;   G, J and K are independently selected from methyl, ethyl, propyl, pentyl, 2-methylbutyl, butyl, acetyl, benzyl, 3-(pyrrol-1-yl)propyl or pyrrolidin-2-one-(5S)-methyl; wherein G, J and K may be optionally substituted on carbon by one or more Q; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by hydrogen or methyl;   Q is cyano, hydroxy, methoxy, ethoxy, methylcarbonyloxy, methoxycarbonyl, t-butoxycarbonylamino, phenyl or a group (B″-E″-); wherein Q, including group (B″-E″-), may be optionally substituted on carbon by one or more Z;   B, B′ and B″ are independently selected from methyl, ethyl, propyl, cyclohexyl, phenyl, benzyl, 1,2,3,4-tetrahydroquinolinyl, 3-morpholinopropyl, 2-morpholinoethyl, 2-pyrrolidin-1-ylethyl, 3-morpholinopropyl, 3-(4-methylpiperazin-1-yl)propyl, 2-piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, pyridin-3-ylmethyl or imidazol-1-ylpropyl; wherein B, B′ and B″ may be optionally substituted on carbon by one or more D; and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from G;   E, E′ and E″ are independently selected from —N(R a )—, —O—, —C(O)—, —NHC(O)—, —N(R a )C(O)O—; wherein R a  is hydrogen or methyl optionally substituted by one or more F;   D and F are independently selected from fluoro, methoxy or ethoxy;   m is 0, 1, or 2; wherein the values of R 1  may be the same or different;   R 2  is fluoro;   n is 0 or 1;   R 3  is amino;   R 4  is halo;   p is 0, 1 or 2, wherein the values of R 4  may be the same or different;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to  claim 1 , which process comprises of:
 (a) the reaction of a compound of the formula (II)   
       
         
           
           
               
               
           
         
       
       wherein X is a reactive group, with a compound of the formula (III) 
       
         
           
           
               
               
           
         
       
       wherein L 1  and L 2  are ligands;
 (b) the reaction of a compound of the formula (IV) 
 
       
         
           
           
               
               
           
         
       
       wherein L 1  and L 2  are ligands, with a compound of the formula (V) 
       
         
           
           
               
               
           
         
       
       wherein X is a reactive group; or
 (c) the reaction, in the presence of 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride, of a compound of the formula (VI) 
 
       
         
           
           
               
               
           
         
       
       with a compound of the formula (VII) 
       
         
           
           
               
               
           
         
       
       and thereafter if necessary:
 i) converting a compound of the formula (I) into another compound of the formula (I); and/or 
 ii) removing any protecting groups. 
 
     
     
         10 . A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to  claim 1  in association with a pharmaceutically-acceptable diluent or carrier. 
     
     
         11 . A method of treating cancer in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to  claim 1 . 
     
     
         12 . A compound of formula (I) according to  claim 1  wherein m is 0, 1 or 2; wherein the values of R 1  are the same or different, n is 0; R 3  is amino and p is 0.