Amino-derivatives as novel inhibitors of histone deacetylase

Abstract

This invention comprises the novel compounds of formula (I) wherein n, m, t, R 1 , R 2 , L, Q, X, Y, Z and have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

1 - 12 . (canceled) 
     
     
         13 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein 
         n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended; 
         m is 0, 1, 2 or 3 and when m is 0 then a direct bond is intended; 
         t is 0 or 1 and when t is 0 then a direct bond is intended; 
         each Q is nitrogen or 
       
       
         
           
           
               
               
           
         
         each X is nitrogen or 
       
       
         
           
           
               
               
           
         
         each Y is nitrogen or 
       
       
         
           
           
               
               
           
         
         each Z is —CH 2 — or —O—; 
         R 1  is —C(O)NR 3 R 4 , —N(H)C(O)R 7 , —C(O)—C 1-6 alkanediylSR 7 , —NR 8 C(O)N(OH)R 7 , —NR 8 C(O)C 1-6 alkanediylSR 7 , —NR 8 C(O)C═N(OH)R 7  or another Zn-chelating-group wherein R 3  and R 4  are each independently selected from hydrogen, hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl or aminoaryl;
 R 7  is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, arylC 1-6 alkyl, C 1-6 alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl; 
 R 8  is independently selected from hydrogen or C 1-6 alkyl; 
 
         R 2  is hydrogen, hydroxy, amino, hydroxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyloxy, arylC 1-6 alkyl, aminocarbonyl, hydroxycarbonyl, aminoC 1-6 alkyl, aminocarbonylC 1-6 alkyl, hydroxycarbonylC 1-6 alkyl, hydroxyaminocarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylaminoC 1-6 alkyl or di(C 1-6 alkyl)aminoC 1-6 alkyl; 
         -L- is a bivalent radical selected from C 1-6 alkanediyl, carbonyl, sulfonyl, or C 1-6 alkanediyl substituted with phenyl; 
       
       
         
           
           
               
               
           
         
       
       is a radical selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each s is independently 0, 1, 2, 3, 4 or 5;
 each R 5  and R 6  are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloC 1-6 alkyl; trihaloC 1-6 alkyloxy; C 1-6 alkyl; C 1-6 alkyl substituted with aryl and C 3-10 cycloalkyl; C 1-6 alkyloxy; C 1-6 alkyloxyC 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylsulfonyl; cyanoC 1-6 alkyl; hydroxyC 1-6 alkyl; hydroxyC 1-6 alkyloxy; hydroxyC 1-6 alkylamino; aminoC 1-6 alkyloxy; di(C 1-6 alkyl)aminocarbonyl; di(hydroxyC 1-6 alkyl)amino; (aryl)(C 1-6 alkyl)amino; di(C 1-6 alkyl)aminoC 1-6 alkyloxy; di(C 1-6 alkyl)aminoC 1-6 alkylamino; di(C 1-6 alkyl)aminoC 1-6 alkylaminoC 1-6 alkyl; arylsulfonyl; arylsulfonylamino; aryloxy; aryloxyC 1-6 alkyl; arylC 2-6 alkenediyl; di(C 1-6 alkyl)amino; di(C 1-6 alkyl)aminoC 1-6 alkyl; di(C 1-6 alkyl)amino(C 1-6 alkyl)amino; di(C 1-6 alkyl)amino(C 1-6 alkyl)aminoC 1-6 alkyl; di(C 1-6 alkyl)aminoC 1-6 alkyl(C 1-6 alkyl)amino; di(C 1-6 alkyl)aminoC 1-6 alkyl(C 1-6 alkyl)aminoC 1-6 alkyl; aminosulfonylamino(C 1-6 alkyl)amino; aminosulfonylamino(C 1-6 alkyl)aminoC 1-6 alkyl; di(C 1-6 alkyl)aminosulfonylamino(C 1-6 alkyl)amino; di(C 1-6 alkyl)aminosulfonylamino(C 1-6 alkyl)aminoC 1-6 alkyl; cyano; thiophenyl; thiophenyl substituted with di(C 1-6 alkyl)aminoC 1-6 alkyl(C 1-6 alkyl)aminoC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, C 1-6 alkylpiperazinylC 1-6 alkyl, hydroxyC 1-6 alkylpiperazinylC 1-6 alkyl, hydroxyC 1-6 alkyloxyC 1-6 alkylpiperazinylC 1-6 alkyl, di(C 1-6 alkyl)aminosulfonylpiperazinylC 1-6 alkyl, C 1-6 alkyloxypiperidinyl, C 1-6 alkyloxypiperidinylC 1-6 alkyl, morpholinylC 1-6 alkyl, hydroxyC 1-6 alkyl(C 1-6 alkyl)aminoC 1-6 alkyl, or di(hydroxyC 1-6 alkyl)aminoC 1-6 alkyl; furanyl; furanyl substituted with hydroxyC 1-6 alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C 1-6 alkyl; C 1-6 alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; piperidinylC 1-6 alkyloxy; morpholinyl; C 1-6 alkylmorpholinyl; morpholinylC 1-6 alkyloxy; morpholinylC 1-6 alkyl; morpholinylC 1-6 alkylamino; morpholinylC 1-6 alkylaminoC 1-6 alkyl; piperazinyl; C 1-6 alkylpiperazinyl; C 1-6 alkylpiperazinylC 1-6 alkyloxy; piperazinylC 1-6 alkyl; naphtalenylsulfonylpiperazinyl; naphtalenylsulfonylpiperidinyl; naphtalenylsulfonyl: C 1-6 alkylpiperazinylC 1-6 alkyl; C 1-6 alkylpiperazinylC 1-6 alkylamino; C 1-6 alkylpiperazinylC 1-6 alkylaminoC 1-6 alkyl, C 1-6 alkylpiperazinylsulfonyl; aminosulfonylpiperazinylC 1-6 alkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC 1-6 alkyl; di(C 1-6 alkyl)aminosulfonylpiperazinyl; di(C 1-6 alkyl)aminosulfonylpiperazinylC 1-6 alkyl; hydroxyC 1-6 alkylpiperazinyl; hydroxyC 1-6 alkylpiperazinylC 1-6 alkyl; C 1-6 alkyloxypiperidinyl; C 1-6 alkyloxypiperidinylC 1-6 alkyl; piperidinylaminoC 1-6 alkylamino; piperidinylaminoC 1-6 alkylaminoC 1-6 alkyl; (C 1-6 alkylpiperidinyl)(hydroxyC 1-6 alkyl)aminoC 1-6 alkylamino; (C 1-6 alkylpiperidinyl)(hydroxyC 1-6 alkyl)aminoC 1-6 alkylaminoC 1-6 alkyl; hydroxyC 1-6 alkyloxyC 1-6 alkylpiperazinyl; hydroxyC 1-6 alkyloxyC 1-6 alkylpiperazinylC 1-6 alkyl; (hydroxyC 1-6 alkyl)(C 1-6 alkyl)amino; (hydroxyC 1-6 alkyl)(C 1-6 alkyl)aminoC 1-6 alkyl; hydroxyC 1-6 alkylaminoC 1-6 alkyl; di(hydroxyC 1-6 alkyl)aminoC 1-6 alkyl; pyrrolidinylC 1-6 alkyl; pyrrolidinylC 1-6 alkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from C 1-6 alkyl or trihaloC 1-6 alkyl; pyridinyl; pyridinyl substituted with C 1-6 alkyloxy, aryloxy or aryl; pyrimidinyl; tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylC 1-6 alkyl; quinolinyl; indolyl; phenyl; phenyl substituted with ones two or three substituents independently selected from halo, amino, nitro, C 1-6 alkyl, C 1-6 alkyloxy, hydroxyC 1-4 alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC 1-4 alkyloxy, C 1-4 alkylsulfonyl, C 1-4 alkyloxyC 1-4 alkyloxy, C 1-4 alkyloxycarbonyl, aminoC 1-4 alkyloxy, di(C 1-4 alkyl)aminoC 1-4 alkyloxy, di(C 1-4 alkyl)amino, di(C 1-4 alkyl)aminocarbonyl, di(C 1-4 alkyl)aminoC 1-4 alkyl, di(C 1-4 alkyl)aminoC 1-4 alkylaminoC 1-4 alkyl, di(C 1-4 alkyl)amino(C 1-4 alkyl)amino, di(C 1-4 alkyl)amino(C 1-4 alkyl)aminoC 1-4 alkyl, di(C 1-4 alkyl)aminoC 1-4 alkyl(C 1-4 alkyl)amino, di(C 1-4 alkyl)aminoC 1-4 alkyl(C 1-4 alkyl)aminoC 1-4 alkyl, aminosulfonylamino(C 1-4 alkyl)amino, aminosulfonylamino(C 1-4 alkyl)aminoC 1-4 alkyl, di(C 1-4 alkyl)aminosulfonylamino(C 1-4 alkyl)amino, di(C 1-4 alkyl)aminosulfonylamino(C 1-4 alkyl)aminoC 1-6 alkyl, cyano, piperidinylC 1-4 alkyloxy, pyrrolidinylC 1-4 alkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC 1-4 alkyl, di(C 1-4 alkyl)aminosulfonylpiperazinyl, di(C 1-4 alkyl)aminosulfonylpiperazinylC 1-4 alkyl, hydroxyC 1-4 alkylpiperazinyl, hydroxyC 1-4 alkylpiperazinylC 1-4 alkyl, C 1-4 alkyloxypiperidinyl, C 1-4 alkyloxypiperidinylC 1-4 alkyl, hydroxyC 1-4 alkyloxyC 1-4 alkylpiperazinyl, hydroxyC 1-4 alkyloxyC 1-4 alkylpiperazinylC 1-4 alkyl, (hydroxyC 1-4 alkyl)(C 1-4 alkyl)amino, (hydroxyC 1-4 alkyl)(C 1-4 alkyl)aminoC 1-4 alkyl, di(hydroxyC 1-4 alkyl)amino, di(hydroxyC 1-4 alkyl)aminoC 1-4 alkyl, furanyl, furanyl substituted with —CH═CH—CH═CH—, pyrrolidinylC 1-4 alkyl, pyrrolidinylC 1-4 alkyloxy, morpholinyl, morpholinylC 1-4 alkyloxy, morpholinylC 1-4 alkyl, morpholinylC 1-4 alkylamino, morpholinylC 1-4 alkylaminoC 1-4 alkyl, piperazinyl, C 1-4 alkylpiperazinyl, C 1-4 alkylpiperazinylC 1-4 alkyloxy, piperazinylC 1-4 alkyl, C 1-4 alkylpiperazinylC 1-4 alkyl, C 1-4 alkylpiperazinylC 1-4 alkylamino, C 1-4 alkylpiperazinylC 1-4 alkylaminoC 1-6 alkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylC 1-4 alkyl, piperidinylaminoC 1-4 alkylamino, piperidinylaminoC 1-4 alkylaminoC 1-4 alkyl, (C 1-4 alkylpiperidinyl)(hydroxyC 1-4 alkyl)aminoC 1-4 alkylamino, (C 1-4 alkylpiperidinyl)(hydroxyC 1-4 alkyl)aminoC 1-4 alkylaminoC 1-4 alkyl, pyridinylC 1-4 alkyloxy, hydroxyC 1-4 alkylamino, hydroxyC 1-4 alkylaminoC 1-4 alkyl, di(C 1-4 alkyl)aminoC 1-4 alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC 1-4 alkyloxy, or thiophenylC 1-4 alkylamino; 
 each R 5  and R 6  can be placed on the nitrogen in replacement of the hydrogen; 
 aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl. 
 
     
     
         14 . A compound as claimed in  claim 13  wherein t is 0;
 R 1  is —C(O)NR 3 R 4 , —C(O)—C 1-6 alkanediylSR 7 , —NR 8 C(O)N(OH)R 7 , —NR 8 C(O)C 1-6 alkanediylSR 7 , —NR 8 C(O)C═N(OH)R 7  or another Zn-chelating-group wherein R 3  and R 4  are each independently selected from hydrogen, hydroxy, hydroxyC 1-6 alkyl or aminoC 1-6 alkyl;   R 2  is hydrogen, hydroxy, amino, hydroxyC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkyloxy, arylC 1-6 alkyl, aminocarbonyl, aminoC 1-6 alkyl, C 1-6 alkylaminoC 1-6 alkyl or di(C 1-6 alkyl)aminoC 1-6 alkyl;   -L- is a bivalent radical selected from C 1-6 alkanediyl, carbonyl or sulfonyl;   
       
         
           
           
               
               
           
         
       
       is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-1 g), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) or (a-51);
 s is 0, 1, 2, 3 or 4; 
 R 5  is hydrogen; halo; hydroxy; amino; nitro; trihaloC 1-6 alkyl; trihaloC 1-6 alkyloxy; C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylsulfonyl; hydroxyC 1-6 alkyl; aryloxy; di(C 1-6 alkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyC 1-6 alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C 1-6 alkyl; C 1-6 alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl; C 1-6 alkylmorpholinyl; piperazinyl; C 1-6 alkylpiperazinyl; hydroxyC 1-6 alkylpiperazinyl; C 1-6 alkyloxypiperidinyl; pyrazolyl; pyrazolyl substituted with one or two substituents selected from C 1-6 alkyl or trihaloC 1-6 alkyl; pyridinyl; pyridinyl substituted with C 1-6 alkyloxy, aryloxy or aryl; pyrimidinyl; quinolinyl; indole; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy or trifluoromethyl; and 
 R 6  is hydrogen; halo; hydroxy; amino; nitro; trihaloC 1-6 alkyl; trihaloC 1-6 alkyloxy; C 1-6 alkyl; C 1-6 alkyloxy; C 1-6 alkylcarbonyl; C 1-6 alkyloxycarbonyl; C 1-6 alkylsulfonyl; hydroxyC 1-6 alkyl; aryloxy; di(C 1-6 alkyl)amino; cyano; pyridinyl; phenyl; or phenyl substituted with one or two substituents independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy or trifluoromethyl. 
 
     
     
         15 . A compound as claimed in  claim 13  wherein n is 0, 1 or 2; m is 0, 1 or 2; each Q is 
       
         
           
           
               
               
           
         
       
       each X is nitrogen; R 1  is —C(O)NH(OH); R 2  is hydrogen L is a bivalent radical selected from carbonyl, sulfonyl, or C 1-6 alkanediyl substituted with phenyl; 
       
         
           
           
               
               
           
         
       
       is a radical selected from (a-1), (a-20) or (a-43); s is 0 or 1; and each R 5  is independently selected from hydrogen or phenyl. 
     
     
         16 . A compound as claimed in  claim 13  wherein n is 0, 1 or 2; m is 1 or 2; each Q is 
       
         
           
           
               
               
           
         
       
       each X is nitrogen; R 1  is —C(O)NH(OH); R 2  is hydrogen; -L- is a bivalent radical selected from carbonyl or sulfonyl; 
       
         
           
           
               
               
           
         
       
       is a radical selected from (a-1) or (a-20); each s is independently 0 or 1; and each R 5  is independently selected from hydrogen or aryl. 
     
     
         17 . A compound according to  claim 13  selected from the following compounds No. 1, No. 3, No. 5, No. 4, No. 14, No. 12, No. 7, No. 8 and No. 9. 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in  claim 13 . 
     
     
         19 . A process of preparing a pharmaceutical composition as claimed in  claim 18  wherein the pharmaceutically acceptable carriers and the compound are intimately mixed. 
     
     
         20 . The method of treating proliferative disease comprising administering to a patient in need of such treatment, an anti-proliferative disease-effective amount of a compound of  claim 13 . 
     
     
         21 . A process for preparing a compound as claimed in  claim 13 , characterized by reacting an intermediate of formula (II) with an appropriate acid, such as for example, trifluoro acetic acid, yielding a hydroxamic acid of formula (I-a), wherein R 1  is —C(O)NH(OH). 
       
         
           
           
               
               
           
         
       
     
     
         22 . A method of detecting or identifying a histone deacetylase (HDAC) in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound as defined in  claim 13  and a HDAC. 
     
     
         23 . A combination of an anti-cancer agents and a compound of  claim 13 .