Acetylene derivatives as inhibitors of histone deacetylase

Abstract

The present invention is directed to certain hydroxamate derivatives that are inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.

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         18 . The pharmaceutical composition of  claim 23  wherein Ar 2  is thiophenyl, pyridinyl, quinolinyl, thiazolyl, benzthiazolyl, benzoxazolyl, furanyl, benzimidazolyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, or isoquinolinyl optionally substituted with one or two substituents independently selected from alkyl, alkoxy, alkoxyalkyl, halo, haloalkyl, haloalkoxy, alkylamino, dialkylamino, hydroxy, hydroxyalkyl, hydroxyalkyloxy, aminoalkyl, aminoalkoxy, alkoxyalkyloxy, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted phenyloxyalkyl, optionally substituted heteroaralkyloxy, optionally substituted heteroaryloxyalkyl, optionally substituted heterocycloalkylalkyloxy, or optionally substituted heterocycloalkylallyl. 
     
     
         19 . The pharmaceutical composition of  claim 23  wherein Ar 2  is thiazolyl, quinolinyl, oxazolyl, benzothiophenyl, indolyl, benzofuranyl, benzthiazolyl, or benzimidazolyl optionally substituted with a substitutent selected from halo, haloalkyl, alkoxy, haloalkoxyalkyl, aminoalkoxy, aminoalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, optionally substituted heterocycloalkyloxy, optionally substituted hetrocycloalkylalkyloxy, or phenyl optionally substituted with -(alkylene)NRR′ where R and R 1  are independently hydrogen or alkyl. 
     
     
         20 . A pharmaceutical composition comprising a compound selected from the group consisting of; 
       N-hydroxy-4-[3-(3-phenylacryloylamino)prop-1-ynyl]-benzamide, 
       N-hydroxy-4-[3-(4-phenylthiazol-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-S-(3-phenylacryloylamino)-but-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(4-methoxyquinolin-2-ylcarbonylamino)prop-ynyl]-benzamide; 
       N-hydroxy-4-{3-[2-(4-aminomethylphenyl)oxazol-5-ylcarbonylamino}prop-1ynyl]-benzamide hydrochloride; 
       N-hydroxy-4-[3S-(4-phenylthiazol-2-ylcarbonylamino)but-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(phenylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(benzothiophen-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(5-chlorobenzofuran-2-ylcarbonylamino)-prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(5-indol-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(benzofuran-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3S-(benzothiophen-2-ylcarbonylamino)but-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(indol-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-{3-[3-(2,2,2-trifluoroethyloxymethyl)benzofuran-2-yl-carbonyl-amino]prop-1-ynyl}-benzamide; 
       N-hydroxy-4-[3-(benzthiazol-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(4-trifluoromethylbenzothiophen-2-ylcarbonyl-amino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(benzimidazol-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(5-fluorobenzothiophen-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(3-N,N-dimethylaminomethylbenofuran-2-ylcarbonylamino)prop-1-ynyl]-benzamide hydrochloride; 
       N-hydroxy-4-{3-[1-(2-N,N-dimethylaminoethyl)benzimidazol-2-ylcarbonyl-amino]prop-1-ynyl}benzamide; 
       N-hydroxy-4-[3-(4-methoxybenzofuran-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(4-N,N-dimethylaiinoethoxybenzofuran-2-ylcarbonylamino-)prop-1-ynyl]-benzamide hydrochloride, 
       N-hydroxy-4-[3-(4-methoxyindol-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(4-N,N-dimethylaminoet-hoxyindol-2-yl-carbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(5-methoxyindol-2-ylcarbonylamino)prop-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-(5-N,N-dimethylaminoethoxyindol-2-ylcarbonyl-amino)prop-1-nynl]-benzamide hydrochloride; 
       N-hydroxy-4-{3-[3-(2-methoxyethyloxymethyl)-benzofuran-2-yl-carbonylamino]prop-1-ynyl}benzamide; 
       N-hydroxy-4-{3-[3-(2-methoxyethyloxy)indol-2-yl-carbonylamino]prop-1-ynyl}-benzamide; 
       N-hydroxy-4-[3-(5-tetrahydropyran-4-yloxybenzofuran-2-yl-carbonylamino)prop-1-ynyl]benzamide; 
       N-hydroxy-4-(3-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-yl-carbonylamino]prop-1-ynyl}benzamide hydrochloride; 
       N-hydroxy-4-{3-[5-(2-methoxyethyloxy)benzofuran-2-yl-carbonylamino]prop-1-ynyl}-benzamide; 
       N-hydroxy-4-{3-[4-(N,N-dimethylaminoethyloxy)quinolin-2-yl-carbonlyamino]prop-1-ynyl}benzamide hydrochloride; 
       N-hydroxy-4-{3-[5-(1-(2,2,2-trifluoroethyl)piperidin-4-yloxy)benzofuran-2-ylcarbonyl-amino]prop-1-ynyl}benzamide; 
       N-hydroxy-4-{3-[5-(1-cyclopropypiperidin-4-yloxy)benzofuran-2-yl-carbonylamino]-prop-1-ynyl}benzamide hydrochloride; 
       N-hydroxy-4-{3-[5-(tetrahydropyran-4-ylmethyloxy)benzofuran-2-ylcarbonylamino]-prop-1-ynyl}benzamide; 
       N-hydroxy-4-{3-[5-(2-morpholin-4-ylethyloxy)benzofuran-2-yl-carbonylamino]prop-1-ynyl}benzamide hydrochloride; 
       N-hydroxy-4-{3-[3-(4-chlorophenyl)ureido]prop-1-ynyl}benzamide; 
       N-hydroxy-4-{3-[3-(4-trifluoromethylphenyl)ureido]prop-1-ynyl}benzamide; 
       N-hydroxy-4-{3-[3-(phenyl)ureido]prop-1-ynyl}benzamide; 
       N-hydroxy-4-{3-[3-(2-trifluoromethyoxyphenyl)ureido]prop-1-ynyl}benzamide; 
       N-hydroxy-4-[3-methyl-3-(3-phenylacryloylamino)but-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-methyl-3-(4-phenylthiazol-2-ylcarbonylamino)but-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-methyl-3-(benzithiazol-2-ylcarbonylamino)but-1-ynyl]-benzamide; 
       N-hydroxy-4-[3-methyl-3-(benzofuran-2-ylcarbonylamino)but-1-ynyl]-benzamide; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. 
     
     
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         23 . A pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R is hydrogen; 
 Ar 1  is phenylene and the triple bond attached to Ar 1  is in the para position relative to the —CONHOH group, wherein said Ar 1  is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy. Haloalkoxy or haloalkyl; 
 X and Y are a bond, 
 R 1  and R 2  are hydrogen or alkyl; 
 Z is —CONH—; 
 Ar 2  is heteroaryl: 
 
       and individual stereoisomers, individual geometric isomers, or mixtures thereof; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
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         25 . A pharmaceutical composition comprising a therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient. 
     
     
         26 . A pharmaceutical composition comprising a therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient. 
     
     
         27 . A method for treating a disease in an animal mediated by HDAC which method comprises administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R is hydrogen: 
 Ar 1  is phenylene and the triple bond attached to Ar 1  is in the para position relative to the —CONHOH group. Wherein said Ar 1  is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkoxy, or haloalkyl; 
 X and Y are a bond; 
 R 1  and R 2  are hydrogen or alkyl; 
 Z is —CONH—; 
 Ar 2  is heteroaryl; 
 
       and individual stereoisomers. Individual geometric isomers, or mixtures thereof; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
         28 . The method of  claim 27  wherein the disease is cancer and the animal is a human. 
     
     
         29 . A method for treating cancer which method comprises administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of having the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R is hydrogen, 
 Ar 1  is phenylene and the triple bond attached to Ar 1  is in the para position relative to the —CONHOH groups wherein said Ar 1  is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkoxy, or haloalkyl; 
 X and Y are a bond; 
 R 1  and R 2  are hydrogen or alkyl; 
 Z is —CONH—: 
 Ar 2  is heteroaryl; 
 
       and individual stereoisomers, individual geometric isomers, or mixtures thereof; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination will one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an IIIV protease inhibitor, a reverse transcriptase inhibitor, or angiogenesis inhibitor. 
     
     
         30 . A method for treating cancer which method comprises administering to the animal a pharmaceutical composition comprising a therapeutically effective amount of having the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R is hydrogen: 
 Ar 1  is phenylene and the triple bond attached to Ar 1  is in the para position relative to the —CONHOH group. Wherein said Ar 1  is optionally substituted with one or two substituents independently selected from alkyl halo, alkoxy. Haloalkoxy. Or haloalkyl: 
 X and Y are a bond; 
 R 1  and R 2  are hydrogen or alkyl; 
 Z is —CONH—; 
 Ar 2  is heteroaryl; 
 
       and individual stereoisomers, individual geometric isomers, or mixtures thereof; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with radiation therapy and one or more compound(s) independently selected from an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic agent, another antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-COA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, or an angiogenesis inhibitor.