Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors

Abstract

This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the following formula: (I) A is an aryl group; Q 1 is a covalent bond or an aryl leader group; J is a sulfonamide linkage selected from: —S(═O) 2 NR 1 — and —NR 1 S(═O) 2 —; R 1 is a sulfonamido substituent; and, Q 2 is an acid leader group; with the proviso that if J is —S(═O) 2 NR 1 —, then Q 1 is an aryl leader group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and, e.g., to inhibit proliferative conditions, such as cancer and psoriasis.

1 - 219 . (canceled)  
     
     
         220 . An inhibitor of histone deacetylase represented by the formula  
         Cy-L 1 -Ar—Y 1 —C(O)—NH-Z  wherein    Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted;    L 1  is —(CH 2 ) m —W—, where m is 0, 1, 2, 3, or 4, and W is selected from the group consisting of —C(O)NH—, —S(O) 2 NH—, —NHS(O) 2 —, and —NH—C(O)—NH—;    Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;    Y 1  is a chemical bond or a straight- or branched-chain saturated alkylene, wherein said alkylene may be optionally substituted; and    Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O-M, M being H or a pharmaceutically acceptable cation;    provided that when L 1  is —C(O)NH—, Y 1  is an alklene of formula —(CH 2 ) n —, n being 1, 2 or 3, and Z is —O-M, then Cy is not aminophenyl, dimethylaminophenyl, or hydroxyphenyl; and further provided that when L 1  is —C(O)NH— and Z is pyridyl, then Cy is not substituted indolinyl.    
     
     
         221 . The inhibitor of  claim 220 , wherein Z is selected from the group consisting of 2-anilinyl, 2-pyridyl, 1,3,4-thiadiazol-2-yl, and —O-M, M being H or a pharmaceutically acceptable cation.  
     
     
         222 . The inhibitor of  claim 221 , wherein Z is 1,3,4-thiadiazol-2-yl which is substituted at the 5-position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.  
     
     
         223 . The inhibitor of  claim 220 , wherein Y 1  is C 1 -C 6  alkylene.  
     
     
         224 . The inhibitor of  claim 220 , wherein Y 1  is C 1 -C 3  alkylene.  
     
     
         225 . The inhibitor of  claim 220 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.  
     
     
         226 . The inhibitor of  claim 225 , wherein the phenylene is 4-phenylene.  
     
     
         227 . The inhibitor of  claim 220 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.  
     
     
         228 . The inhibitor of  claim 227 , herein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 6 -C 10  aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, halo, nitro, hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkoxycarbonyl, carboxy, and amino.  
     
     
         229 . The inhibitor of  claim 220 , wherein m is zero.  
     
     
         230 . An inhibitor of histone deacetylase represented by the formula  
         Cy-L 2 -Ar—Y 2 —C(O)NH-Z  wherein    Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;    L 2  is C 1 -C 6  saturated alkylene or C 2 -C 6  alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 2  is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by a heteroatom moiety selected from the group consisting of O; NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;    Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and    Y 2  is a chemical bond or a straight- or branched-chain saturated alkylene, which may be optionally substituted, provided that the alkylene is not substituted with a substituent of the formula —C(O)R wherein R comprises an α-amino acyl moiety; and    Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O-M, M being H or a pharmaceutically acceptable cation;    provided that when the carbon atom to which Cy is attached is oxo substituted, then Cy and Z are not both pyridyl.    
     
     
         231 . The inhibitor of  claim 230 , wherein Z is selected from the group consisting of 2-nilinyl, 2-pyridyl, 1,3,4-thiadiazol-2-yl, and —O-M, M being H or a pharmaceutically acceptable cation.  
     
     
         232 . The inhibitor of  claim 231 , wherein Z is 1,3,4-thiadiazol-2-yl which is substituted at the 5-position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.  
     
     
         233 . The inhibitor of  claim 230 , wherein Y 2  is a chemical bond.  
     
     
         234 . The inhibitor of  claim 230 , wherein Y 2  is C 1 -C 3  alkylene.  
     
     
         235 . The inhibitor of  claim 230 , wherein Y 2  is C 1 -C 2  alkylene.  
     
     
         236 . The inhibitor of  claim 230 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.  
     
     
         237 . The inhibitor of  claim 236 , wherein the phenylene is 4-phenylene.  
     
     
         238 . The inhibitor of  claim 230 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.  
     
     
         239 . The inhibitor of  claim 238 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 6 -C 10  aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, halo, nitro, hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkoxycarbonyl, carboxy, and amino.  
     
     
         240 . The inhibitor of  claim 230 , wherein one or two saturated carbons in L 2  are substituted with a substituent independently selected from the group consisting of C 1 -C 6  alkyl, C 6 -C 10  aryl, amino, oxo, hydroxy, C 1 -C 4  alkoxy, and C 6 -C 10  aryloxy.  
     
     
         241 . The inhibitor of  claim 240 , wherein the substituent is oxo or hydroxy.  
     
     
         242 . The inhibitor of  claim 230 , wherein L 2  is C 1 -C 6  saturated alkylene, and no carbon atom of the alkylene is replaced by a heteroatom moiety.  
     
     
         243 . The inhibitor of  claim 230 , wherein one carbon atom of the Y 2  alkylene is replaced by a heteroatom moiety selected from the group consisting of O; 
 NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 .    
     
     
         244 . The inhibitor of  claim 243 , wherein L 2  is selected from the group consisting of —S—(CH 2 ) n , —S(O)—(CH 2 ) n —, and —S(O) 2 —(CH 2 ) n —, wherein n is 0, 1, 2, 3, or 4.  
     
     
         245 . An inhibitor of histone deacetylase represented by the formula  
         Cy-L 3 -Ar—Y 3 —C(O)NH-Z  wherein    Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;    L 3  is selected from the group consisting of    (a) —(CH 2 ) m —W—, where m is 0, 1, 2, 3, or 4, and W is selected from the group consisting of —C(O)NH—, —S(O) 2 NH—, —NHC(O)—, —NHS(O) 2 —, and —NH—C(O)—NH—; and    (b) C 1 -C 6  alkylene or C 2 -C 6  alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3  is not —C(O)—, and wherein one of the carbon atoms of the alkylene optionally may be replaced by O; NR′, R′ being alkyl, acyl, or hydrogen; S; S(O); or S(O) 2 ;    Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and    Y 3  is C 2  alkenylene or C 2  alkynylene, wherein one or both carbon atoms of the alkenylene optionally may be substituted with alkyl, aryl, alkaryl, or aralkyl; and    Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O-M, M being H or a pharmaceutically acceptable cation;    provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L 3  and Y 3  are oriented ortho or meta to each other.    
     
     
         246 . The inhibitor of  claim 245 , wherein Z is selected from the group consisting of 2-anilinyl, 2-pyridyl, 1,3,4-thiadiazol-2-yl, and —O-M, M being H or a pharmaceutically acceptable cation.  
     
     
         247 . The inhibitor of  claim 246 , wherein Z is 1,3,4-thiadiazol-2-yl which is substituted at the 5-position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.  
     
     
         248 . The inhibitor of  claim 245 , wherein Y 3  is selected from the group consisting of —CH═CH—, —C(CH 3 )═CH—, and —CH═C(CH 3 )—.  
     
     
         249 . The inhibitor of  claim 245 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.  
     
     
         250 . The inhibitor of  claim 249 , wherein the phenylene is 4-phenylene.  
     
     
         251 . The inhibitor of  claim 245 , wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.  
     
     
         252 . The inhibitor of  claim 251 , wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 6 -C 10  aryl, (C 6 -C 10 )ar(C 1 -C 6 )alkyl, halo, nitro, hydroxy, C 1 -C 6  alkoxy, C 1 -C 6  alkoxycarbonyl, carboxy, and amino.  
     
     
         253 . An inhibitor of histone deacetylase selected from the group consisting of  
       
         
           
           
               
               
           
         
       
     
     
         254 . An inhibitor of histone deacetylase represented by the formula  
         Cy-L 1 -Ar—Y 1 —C(O)—N H-Z  wherein    Cy is aryl or heteroaryl, any of which may be optionally substituted;    L 1  is —(CH 2 ) m —W—, where m is 0, 1, 2, 3, or 4, and W is selected from the group consisting of —S(O) 2 NH— and —NHS(O) 2 —   Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted;    Y 1  is a chemical bond or a straight- or branched-chain saturated alkylene, wherein said alkylene may be optionally substituted; and    Z is —O-M, M being H or a pharmaceutically acceptable cation.    
     
     
         255 . The inhibitor of  claim 254 , wherein Y 1  is C 1 -C 7  alkylene.  
     
     
         256 . The inhibitor of  claim 254 , wherein Y 1  is —CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 —, —CH═CH—, —C≡C—, —CH(CH 2 CH 3 )—, —CH(CH 3 )CH 2 —, —CH 2 CH(CH 3 )—, —CH═C(CH 3 )—, —C(CH 3 )═CH 2 —, —CH 2 CH 2 CH 2 —, —CH═CHCH 2 —, —CH 2 CH═CH—, —C═CCH 2 —, or —CH 2    
     
     
         257 . The inhibitor of  claim 254 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.  
     
     
         258 . The inhibitor of  claim 257 , wherein the phenylene is 4-phenylene.  
     
     
         259 . The inhibitor of  claim 254 , wherein Cy is selected from the group consisting of phenyl, naphthyl, benzothienyl, and quinolyl, any of which may be optionally substituted.  
     
     
         260 . The inhibitor of  claim 259 , herein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 -C 7  alkyl, C 1 -C 7  haloalkyl, C 5 -C 20  aryl, (C 5 -C 20 )ar(C 1 -C 7 )alkyl, halo, nitro, hydroxy, C 1 -C 7  alkoxy, C 1 -C 7  alkoxycarbonyl, carboxy, and amino.  
     
     
         261 . The inhibitor of  claim 254 , wherein m is zero.  
     
     
         262 . An inhibitor of histone deacetylase represented by the formula  
         Cy-L 2 -Ar—Y 2 —C(O)NH-Z  wherein    Cy is aryl orheteroaryl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;    L 2  is C 1 -C 7  saturated alkylene or C 2 -C 7  alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 2  is not —C(O)—;    Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and    Y 2  is a chemical bond or a straight- or branched-chain saturated alkylene, which may be optionally substituted, provided that the alkylene is not substituted with a substituent of the formula —C(O)R wherein R comprises an α-amino acyl moiety; and    Z is —O-M, M being H or a pharmaceutically acceptable cation;    provided that when the carbon atom to which Cy is attached is oxo substituted, then Cy and Z are not both pyridyl.    
     
     
         263 . The inhibitor of  claim 262 , wherein Y 2  is a chemical bond.  
     
     
         264 . The inhibitor of  claim 262 , wherein Y 2  is C 1 -C 3  —CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 —, —CH═CH—, —C≡C—, —CH(CH 2 CH 3 )—, —CH(CH 3 )CH 2 —, —CH 2 CH(CH 3 )—, —CH═C(CH 3 )—, —C(CH 3 )═CH 2 —, —CH 2 CH 2 CH 2 —, —CH═CHCH 2 —, —CH 2 CH═CH—, —C≡CCH 2 —, or —CH 2 C≡C—.  
     
     
         265 . The inhibitor of  claim 262 , wherein Y 2  is —CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 —, —CH═CH—, or —C≡C—.  
     
     
         266 . The inhibitor of  claim 262 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.  
     
     
         267 . The inhibitor of  claim 266 , wherein the phenylene is 4-phenylene.  
     
     
         268 . The inhibitor of  claim 262 , wherein Cy is selected from the group consisting of phenyl, naphthyl, benzothienyl, and quinolyl, any of which may be optionally substituted.  
     
     
         269 . The inhibitor of  claim 268 , wherein the phenyl, naphthyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 -C 7  alkyl, C 1 -C 7  haloalkyl, C 5 -C 20  aryl, (C 5 -C 20 )ar(C 1 -C 7 )alkyl, halo, nitro, hydroxy, C 1 -C 7  alkoxy, C 1 -C 7  alkoxycarbonyl, carboxy, and amino.  
     
     
         270 . The inhibitor of  claim 262 , wherein one or more carbons in L 2  are substituted with a substituent independently selected from the group consisting of C 1 -C 7  alkyl, C 5 -C 20  aryl, amino, oxo, hydroxy, C 1 -C 7  alkoxy, and C 5 -C 20  aryloxy.  
     
     
         271 . The inhibitor of  claim 270 , wherein the substituent is oxo or hydroxy.  
     
     
         272 . The inhibitor of  claim 264 , wherein L 2  is C 1 -C 7  saturated alkylene, and no carbon atom of the alkylene is replaced by a heteroatom moiety.  
     
     
         273 . An inhibitor of histone deacetylase represented by the formula  
         Cy-L 3 -Ar—Y 3 —C(O)NH-Z  wherein    Cy is arylor heteroaryl, any of which may be optionally substituted, provided that Cy is not a (spirocycloalkyl)heterocyclyl;    L 3  is selected from the group consisting of    (a) —(CH 2 ) m —W—, where m is 0, 1, 2, 3, or 4, and W is selected from the group consisting of —S(O) 2 NH— and —NHS(O) 2 —; and    (b) C 1 -C 7  alkylene or C 2 -C 7  alkenylene, wherein the alkylene or alkenylene optionally may be substituted, provided that L 3  is not —C(O)—;    Ar is arylene, wherein said arylene optionally may be additionally substituted and optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted; and    Y 3  is —CH═CH— or —C≡C—, wherein one or both carbon atoms of —CH═CH— optionally may be substituted with C 1-7 alkyl, C 5-20 aryl, C 1-7 alkyl-C 5-20 aryl, or C 1-7 alkyl; and    Z is —O-M, M being H or a pharmaceutically acceptable cation;    provided that when Cy is unsubstituted phenyl, Ar is not phenyl wherein L 3  and Y 3  are oriented ortho or meta to each other.    
     
     
         274 . The inhibitor of  claim 273 , wherein Y 3  is selected from the group consisting of —CH═CH—, —C(CH 3 )═CH—, and —CH═C(CH 3 )—.  
     
     
         275 . The inhibitor of  claim 273 , wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.  
     
     
         276 . The inhibitor of  claim 275 , wherein the phenylene is 4-phenylene.  
     
     
         277 . The inhibitor of  claim 273 , wherein Cy is selected from the group consisting of phenyl, naphthyl, benzothienyl, and quinolyl, any of which may be optionally substituted.  
     
     
         278 . The inhibitor of  claim 277 , wherein the phenyl, naphthyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C 1 -C 7  alkyl, C 1 -C 7  haloalkyl, C 5 -C 20  aryl, (C 5 -C 20 )ar(C 1 -C 7 )alkyl, halo, nitro, hydroxy, C 1 -C 7  alkoxy, C 1 -C 7  alkoxycarbonyl, carboxy, and amino.