HDAC Inhibitors and Therapeutic Methods of Using Same

A compound having a structural formula

• wherein ring
• is an aliphatic or aromatic five- or six-membered ring;
• D, E, and F, independently, are selected from the group consisting of C(Ra)2, O, S, and NRa;
• G is selected from the group consisting of null, C(Ra)2, O, S, NRa, C(Ra)2—C(Ra)2, NRa—C(Ra)2, NRa—NRa, C(Ra)2—O, and C(Ra)2—S;
• R0, independently, is selected from the group consisting of C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C1-6 perfluoroalkyl, C1-6 perfluoroalkoxy, aryl, heteroaryl, C3-10cycloalkyl, C3-8heterocycloalkyl, C1-6alkylenearyl, C1-6alkyleneheteroaryl, C1-6alkyleneheterocycloalkyl, C1-6alkylenecycloalkyl,
• ORb, halo, N(Rb)2, SRb, SORb, SO2Rb, CN, C(═O)Rb, OC(═O)Rb, C(═O)ORb, C1-6alkyleneN(Rb)2, C1-6alkyleneORb, C1-6alkyleneSRb, C1-6alkyleneC(═O)ORb, C(═O)N(Rb)2, C(═O)NRbC1-6alkyleneORb, OC1-6alkyleneC(═O)ORb, OC1-6alkyleneN(Rb)2, OC1-6alkyleneORb, OC1-6alkyleneNRbC(═O)ORb, NRbC1-6alkyleneN(Rb)2, NRbC(═O)Rb, NRbC(═O)N(Rb)2, N(SO2C1-6alkyl)2, NRb(SO2C1-6alkyl), nitro, and SO2N(Rb)2;
• m is an integer 0, 1, 2, 3, or 4;
• Ra, independently, is selected from the group consisting of null, hydrogen, C1-6alkyl, C2-6alkenyl, C1-6heteroalkyl, aryl, heteroaryl, C3-8cycloalkyl, C3-10heterocycloalkyl, C1-6alkylenearyl, C1-6alkyleneheteroaryl, C1-6alkyleneC(═O)ORb, C1-6alkyleneC(═O)Rb, C1-6alkyleneC(═O)N(Rb)2, C(═O)Rb, C(═O)N(Rb)2, C(═O)ORb, CN, ORb, halo, N(Rb)2, SRb, SORb, SO2Rb, CF3, OCF3, NO2, OC(═O)Rb, OC1-6alkyleneC(═O)ORb, C1-6alkyleneOC1-6alkyleneC(═O)ORb, C(═O)NRbSO2Rb, C(═O)C1-6alkylenearyl, C1-6alkyleneN(Rb)2, C1-6alkyleneORb, C1-6alkyleneSRb, C(═O)NRbC1-6alkyleneORb, OC1-6alkyleneN(Rb)2, OC2-6alkyleneORb, OC2-6alkyleneNRbC(═O)ORb, NRbC1-6alkyleneN(Rb)2, NRbC(═O)Rb, NRbC(═O)N(Rb)2, N(SO2C1-6alkyl)2, NRb(SO2C1-6alkyl), SO2N(Rb)2, and OSO2CF3;
• Rb, independently, is selected from the group consisting of hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6alkyleneNH2, C1-6alkyleneNH(C1-6alkyl), C1-6alkyleneN(C1-6alkyl)2, C1-6alkyleneNH(C1-6alkyl)2, C1-6alkyleneOH, C1-6alkyleneOC1-6alkyl, C1-6alkyleneSH, C1-6alkyleneSC1-6alkyl, aryl, heteroaryl, C3-8cycloalkyl, and C3-10heterocycloalkyl;
• Y is selected from the group consisting of null, C1-8alkylene, Ra substituted C1-8alkylene, NRb, C(═O), aryl, C(═O)aryl, C(═O)C1-6alkylene, C1-8alkyleneNRb, C1-6alkylenearyleneC1-6alkylene, C2-6alkenylene, C4-8alkdienylene, C1-6alkylenearylene, C1-6alkyleneheteroarylene, Ra substituted C1-6alkyleneheteroarylene, and C2-6alkenylenearyleneC1-6alkylene;
• Z is selected from the group consisting of —C(═O)N(Rc)OH,
• —O(CH2)1-6C(═O)N(Rc)ORb,
• —N(Rc)(CH2)1-6C(═O)N(Rc)ORc,
• arylC(═O)NHOH,
• —N(OH)C(═O)Rc,
• heteroarylC(═O)NHOH,
• —B(ORc)2,
• —SO2NHRc,
• —NHSO2NHRc,
• —NHSO2C1-6alkyl,
• —SO2C1-6alkyl,
• —P(═O)(ORg)2, wherein Rg independently is hydrogen, methyl, or ethyl,
• —NH—P(═O)(ORg)2,
• —C(═O)Rf wherein Rf is selected from the group consisting of OH, N(Rc)2, NH(OCH3), N(CH3)OH, C1-6alkyl, CF3, aryl, heteroaryl, C3-8cycloalkyl, NHSO2CH3, NHSO2CF3, and C1-6haloalkyl,
• —C(═O)(C(Rc)2)1-6SH,
• —C(═O)C(═O)NHRc, —C(═O)NHN(Rc)2,
• —C(═O)NH(CH2)1-3N(Rc)2,
• —SR″ wherein Rd is hydrogen or (C═O)CH3,
• —S—(C═O)C1-6alkyl,
• C3-10heterocycloalkyl optionally substituted with oxo (═O), thioxo (═S), or both,
• aryl optionally substituted with one or more of C1-6alkyl, —C(═O)Re, —NH2, and —SH,
• heteroaryl optionally substituted with —NH2, —SH, or both,
• —N(H)C(═O)SH,
• —NHC(═O)NHRe,
• —NHC(═O)CH2Re,
• —NHC(═O)(CH2)1-6SH,
• —NHC(═O)CH2Hal,
• —NHC(═S)NHRe,
• —NHC(═S)CH2Re,
• —C(═S)NHRe,
• —C(═S)CH2Re,
• —NHC(═S)CH2Re,
• —NHC(═S)CH2Hal, and
• —(C═O)C1-6alkyl;
• Rc, independently, is selected from the group consisting of hydrogen, (C═O)CH3, C1-6alkyl, CF3, CH2F, and aryl, or two Rc groups are taken together with the carbon to which they attached to form a C3-8cycloalkyl group;
• and
• Re is NH2 or OH;
• or a pharmaceutically acceptable salt, hydrate, or prodrug thereof.