Inhibitors of histone deacetylase

Abstract

Disclosed are compounds which inhibit histone deacetylase (HDAC) enzymatic activity. Also disclosed are pharmaceutical compositions comprising such compounds as well as methods to treat conditions, particularly proliferative conditions, mediated at least in part by HDAC.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R is selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl substituted heteroaryl, alkyl and substituted alkyl; 
 R 12  is selected from the group consisting of —NR 14 OH, —OH, —NR 14 R 15 , —OR 14 , —(C 1 -C 6 )alkylene-SR 4 , —(C 1 -C 6 )alkylene-OR 14 , —(C 1 -C 6 )alkylene-NR 14 R 15 , —CF 3 ; 
 where R 14  and R 15  are independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )substituted alkyl, aryl, substituted aryl and where R 14  and R 15  together with the nitrogen atom bound thereto form a heterocyclic or substituted heterocyclic ring; 
 V, W, X, Y, and Z form a 5-membered heteroaryl where W, X, and Y are independently selected from ═C(R 11 )—, —N═, —N(R 14 )—, —O—, —S—, —S(O)—, and/or —S(O) 2 —, and V and Z independently form ═C(R 14 )— and/or >N— where R 14  is as defined above, provided that at least one of V, W, X, Y and Z is ═C(R 14 )—, and further provided that the ring formed by V, W, X, Y, and Z is not a thiophene; 
 R 11  is hydrogen or alkyl; 
 the ring defined by A above is selected from the group consisting of cycloakylene, substituted cycloalkylene, hetrocyclene, substituted heterocyclene, arylene, heteroarylene, -het-(L 2 ) b -het-, -het-(L 2 ) b -cyclo-, -cyclo-(L 2 ) b -het-, and -cyclo-(L 2 ) b -cyclo-; 
 where each b is independently 0 or 1; 
 L 2  is selected from the group consisting of a covalent bond, (C 1 -C 4 )alkylene, substituted (C 1 -C 4 )alkylene, —NH(C 1 -C 4 )alkylene, (C 1 -C 4 )alkyleneNH—, provided that the nitrogen atom of the —NH(C 1 -C 4 )alkylene and (C 1 -C 4 )alkyleneNH— group are not attached to a nitrogen atom in the het or in cyclo groups; 
 T is selected from the group consisting of —SO 2 —[(C 1 -C 3 )alkylene] p -, —[(C 1 -C 3 )alkylene] p -SO 2 —, —NR 16 SO 2 —[(C 1 -C 3 )alkylene] p —, —SO 2 NR 16 —[(C 1 -C 3 )alkylene] p -, —C(O)—[(C 1 -C 3 )alkylene] p -, —[(C 1 -C 3 )alkylene] p -C(O)—, —NR 6 C(O)—[(C 1 -C 3 )alkylene] p -, —C(O)NR 16 —[(C 1 -C 3 )alkylene] p -, —N(R 16 )—[(C 1 -C 3 )alkylene] p  and (C 1 -C 3 )alkylene where p is zero or one and R 16  is hydrogen, alkyl, aryl, or heteroaryl, provided that when T is connected to A at a nitrogen atom and T is —SO 2 NR 16 —[(C 1 -C 3 )alkylene] p —, —C(O)NR 16 —[(C 1 -C 3 )alkylene] p —, or —N(R 16 )—[(C 1 -C 3 )alkylene] p  then p is not zero; 
 Q is selected from the group consisting of a covalent bond, —O—, (C 1 -C 3 )alkylene, —C(O)—, —SO 2 —, —NR 1 C(O)NR 1 —, —NR 1 C(O)—, —C(O)NR 1 —, —(C 1 -C 3 -alkylene) p NR 1 — and —NR 1 —(C 1 -C 3 -alkylene) p  where R 1  is hydrogen or alkyl and p is zero or one, provided that when Q is one of —NR 1 C(O)NR 1 —, —NR 1 C(O)—, —C(O)NR 1 —, —(C 1 -C 3 -alkylene) p NR 1 , or —NR 1 —(C 1 -C 3 -alkylene) p  and p is not zero Q is not attached to a nitrogen atom; 
 L is selected from the group consisting of a covalent bond, (C 1 -C 4 )alkylene, substituted (C 1 -C 4 )alkylene, (C 2 -C 4 )alkenylene, and substituted (C 2 -C 4 )alkenylene, (C 3 -C 8 )cycloalkylene, and substituted (C 3 -C 8 )cycloalkylene; 
 and tautomers, isomers, prodrugs and pharmaceutically acceptable salts thereof. 
 
     
     
         2 . A compound according to  claim 1 , wherein said compound is represented by formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein:
 W is selected from the group consisting of —O—, —S—, —S(O)—, —S(O) 2 — and —NR 1 —, and tautomers, isomers, prodrugs and pharmaceutically acceptable salts thereof. 
 
     
     
         3 . The compound according to  claim 2 , wherein said compound is represented by formula Ib: 
       
         
           
           
               
               
           
         
         and tautomers, isomers, prodrugs and pharmaceutically acceptable salts thereof. 
       
     
     
         4 . The compound according to  claim 3 , wherein said compound is represented by formula II: 
       
         
           
           
               
               
           
         
       
       where
 each R 3  is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
 n and z, and z′ are independently integers equal to zero, one or two; with the proviso that both z and z′ are not zero; and 
 tautomers, isomers, prodrugs, and pharmaceutically acceptable salts thereof. 
 
     
     
         5 . The compound according to  claim 3 , wherein said compound is represented by formula III: 
       
         
           
           
               
               
           
         
       
       where
 each R 3  is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
 n and z, are independently integers equal to zero, one or two; and 
 tautomers, isomers, prodrugs, and pharmaceutically acceptable salts thereof. 
 
     
     
         6 . The compound according to  claim 3 , wherein said compound is represented by formula IV: 
       
         
           
           
               
               
           
         
       
       where
 each R 3  is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
 n and z, are independently integers equal to zero, one or two; and 
 tautomers, isomers, prodrugs, and pharmaceutically acceptable salts thereof. 
 
     
     
         7 . The compound of  claim 3  wherein the fragment “ring A” is selected from the group consisting of optionally substituted piperidine, piperazine, morpholine, piperazinone, piperazindione, azetidine, hydantoin, oxazolidine, octahydro-pyrrolo[3,4-c]pyrrole, tetrahydropyridine, hexene, pyrrolidine 
     
     
         8 . The compound of  claim 7  wherein the fragment “R-T-ring A-Q” is selected from 
       
         
           
           
               
               
           
         
         where each b is independently 0 or 1 and each “A ring” is optionally substituted with from 0 to 2 substituents independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )substituted alkyl, aryl, substituted aryl. 
       
     
     
         9 . The compound of  claim 3  wherein “ring A” is a cycloalkylene or substituted heterocycloalkylene, which is an optionally substituted bicyclic or spirocyclic group. 
     
     
         10 . The compound of  claim 9  wherein “R-T-ring A-Q” is selected from 
       
         
           
           
               
               
           
         
         where each b is independently 0 or 1 and each “A ring” is optionally substituted with from 0 to 2 substituents independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )substituted alkyl, aryl, substituted aryl. 
       
     
     
         11 . The compound according to  claim 3 , wherein R is aryl or substituted aryl. 
     
     
         12 . The compound according to  claim 3 , wherein t is selected from the group consisting of phenyl, naphthyl, 3,4-dimethoxyphenyl, 4-trifluoromethoxyphenyl, 4 methylphenyl, 4-trifluororomethylphenyl, 4-nitrophenyl, 4-acetylphenyl, thiophen-2-yl, biphenyl, 5-(N,N-dimethylamino)-naphthalenyl, 4-fluorophenyl, methyl, benzyl, 2-hydroxyethyl, 2-aminoethyl, and 2-phenylethyl. 
     
     
         13 . The compound of  claim 3 , wherein Q is a covalent bond and the ring defined by A above is piperidinyl or piperazinyl. 
     
     
         14 . The compound according to  claim 3 , wherein X is —N═ and Y is ═CH—. 
     
     
         15 . The compound according to  claim 14 , wherein L is alkenylene. 
     
     
         16 . The compound according to  claim 15 , wherein L is a (E)-ethylenylene. 
     
     
         17 . The compound of  claim 3  wherein T is selected from the group consisting of a bond, —SO 2 —, —SO 2 NH—, and —CH 2 NR 16 —. 
     
     
         18 . A compound according to  claim 1 , which compound is selected from the group consisting of: 
       1-(2-naphthylsulfonyl)-4-(5-hydroxyaminocarbonylthiazol-2-yl)piperazine; 
       1-(2-naphthylsulfonyl)-4-(5-hydroxyaminocarbonylthiazol-2-yl)-1,4-diazepane; 
       1-(2-naphthylsulfonyl)-4-(4-hydroxyaminocarbonylthiazol-2-yl)piperazine; 
       1-(2-naphthylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(phenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(3,4-dimethoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(4-methoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(4-trifluoromethoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(4-methylphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(4-trifluoromethylphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(4-nitrophenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(thien-2-ylsulfonyl-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(1,1′biphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(5-dimethylamino-naphthalene-1-sulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       1-(4-fluorophenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine; 
       4-(2-naphthylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine; 
       4-(1,1′-biphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine; 
       4-(3,4-dimethoxyphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine; 
       4-(4-methylphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine; 
       2-(4-{[(1,1′-biphenylsulfonyl)amino]methyl}piperidin 1-yl)-1,3-thiazole-5-carboxylic acid hydroxyamide; 
       2-{[1-(2-naphthylsulfonyl)piperidin-4-yl]amino}-1,3-thiazole-5-carboxylic acid hydroxyamide; 
       2-(6-{[(4-methylphenyl)sulfonyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)-1,3-thiazole-5-carboxylic acid hydroxyamide; 
       2-[3-[(4-methylphenyl)sulfonyl]tetrahydropyrimidin-1(2H)-yl]-1,3-thiazole-5-carboxylic acid hydroxylamide; 
       2-[4-(3,4-dimethoxy-benzene sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide; 
       2-[4-(4-trifluoromethoxy-benzene sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide; 
       2-[4-(4 toluene-4-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide; 
       2-[4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide; 
       2-[4-(4-nitro-benzene sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide; 
       2-[4-(4-acetyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide; 
       2-[4-(thiophene-2-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide; 
       2-[4-(biphenyl-4-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide; 
       2-[4-(5-dimethylamino-naphthalene-1-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide; 
       2-[4-(4-fluoro-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide; 
       2-(4-methyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxyamide; 
       2-(4-Benzyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxyamide (16b-hydroxamate); 
       2-(4-(2-hydroxyethyl)-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxyamide; 
       2-(4-(2-aminoethyl)-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxyamide; 
       2-(4-phenylethyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxyamide; 
       2-(4-(2-oxo-2-phenylethyl % piperazin-1-yl)-1,3-thiazole-5-carboxylic acid hydroxyamide; 
       2-(4-acetyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxamide; 
       2-(4-benzoyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxamide; 
       2-(4-phenylacetyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxamide; 
       2-[4-(3-{1H-indol-3-yl}propanoyl)-piperazin-1-yl]-1,3-thiazole-5-carboxylic acid hydroxyamide; 
       N-(2-naphthylsulfonyl)-N′-{2-[5-(N-hydroxycarboxamido)]thiazolyl}-piperazine; 
       2-[1-(1,1′-biphenyl-4-ylsulfonyl)piperidin-4-yl]-1,3-thiazole-5-carboxylic acid hydroxyamide;
 and pharmaceutically acceptable salts, isomers, tautomers, and prodrugs thereof 
 
     
     
         19 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1 , a pharmaceutically inert carrier, and, optionally, at least one other anti-cancer agent selected from the group consisting of platinum coordination compounds, taxane compounds, topoisomerase I inhibitors, topoisomerase II inhibitors, anti-tumour vinca alkaloids, anti-tumour nucleoside derivatives, alkylating agents, anti-tumour anthracycline derivatives, HER2 antibodies, estrogen receptor antagonists, selective estrogen receptor modulators, aromatase inhibitors, retinoids, retinoic acid metabolism blocking agents (RAMBA), DNA methyl transferase inhibitors, kinase inhibitors, farnesyltransferase inhibitors, other HDAC inhibitors, carboplatin, oxalyplatin, paclitaxel, docetaxel, irinotecan, topotecan, etoposide, teniposide, vinblastine, vincristine, vinorelbine, 5-fluorouracil, gemcitabine, capecitabine, cyclophosphamide, chlorambucil, carmustine, lomustine, daunorubicin, doxorubicin, darubicin, mitoxantrone, trastuzuma, tamoxifen, toremifene, droloxifene, faslodex, raloxifene, exemestane, anastrozole, letrazole, vorozole, vitamin D, accutane, azacytidine, flavoperidol, imatinib mesylate, and gefitinib. 
     
     
         20 . A method for inhibiting a proliferative disorder in a mammalian patient which method comprises administering to said patient a pharmaceutical composition according to  claim 19 .