HDAC inhibitors and therapeutic methods using the same

A compound having a structural formula

• Cap-L-M
• wherein Cap is selected from the group consisting of
• wherein ring
• is an aliphatic or aromatic five or six membered ring,
• W, X, Y, and Z independently are selected from the group consisting of null, C(R1)2, O, S, and NR1,
• ring
• is an aliphatic or aromatic six membered ring,
• wherein D, E, F, and G independently are selected from the group consisting of C(R1)2, O, and S,
• or ring
• is an aliphatic or aromatic five membered ring, wherein D, E, F, and G are selected from the group consisting of null, C(R1)2, and NR1,
• R1, independently, is selected from the group consisting of null, hydrogen, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C1-6perfluoroalkyl, C1-6perfluoroalkoxy, aryl, heteroaryl, C3-10cycloalkyl, C3-10heterocycloalkyl, C1-6alkylenearyl, C1-6alkyleneheteroaryl, C1-6alkyleneheterocycloalkyl, C1-6alkylenecycloalkyl,
• ORa, halo, N(Ra)2, SRa, SORa, SO2Ra, CN, C(═O)Ra, CF3, OCF3, NO2, OC(═O)Ra, SO2N(Ra)2, OSO2CF3, C(═O)ORa, C(═O)N(Ra)2, C1-6alkyleneN(Ra)2, C1-6alkyleneC(═O)Ra, C1-6alkyleneORa, C1-6alkyleneSRa, C1-6alkyleneNRaSO2Ra, C1-6alkyleneSORa, C1-6alkyleneCN, C1-6heteroalkyleneCN, C1-6alkyleneC(═O)ORa, C1-6alkyleneOC(═O)N(Ra)2, C1-6alkyleneNRaC(═O)ORa, C1-6alkyleneNRaC(═O)Ra, C1-6alkylene C(═O)N(Ra)2, C1-6alkyleneOC1-6alkyleneC(═O)ORa, C(═O)NRaSO2Ra, C(═O)C1-6alkylenearyl, C(═O)NRaC1-6alkyleneORa, OC1-6alkyleneC(═O)ORa, OC1-6alkyleneN(Ra)2, OC1-6alkyleneORa, OC1-6alkyleneNRaC(═O)ORa, NRaC1-6alkyleneN(Ra)2, NRaC(═O)Ra, NRaC(═O)N(Ra)2, N(SO2C1-6alkyl)2, and NRa(SO2C1-6alkyl), and
• Ra, 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, C1-6alkyleneNHC(═O)(C1-6alkyl), C1-6alkyleneC(═O)NH2, C1-6alkyleneOH, C1-6alkyleneCN, C1-6heteroalkyleneCN, C1-6alkyleneOC1-6alkyl, C1-6alkyleneSH, C1-6alkyleneSC1-6alkyl, C1-6alkyleneNH(SO2C1-6alkyl), aryl, heteroaryl, C3-8cycloalkyl, and C3-10heterocycloalkyl,
• wherein linker L is attached to any atom D, E, F, or G,
• wherein ring
• is an aliphatic or aromatic five or six membered ring,
• E, F, W, X, Y, Z, R1, and Ra are as defined above, and
• wherein A is C, N, O, S, B, or P, and L is attached to A,
• R2, R3 and R4 independently are selected from the group consisting of null, hydrogen, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C1-6perfluoroalkyl, C1-6perfluoroalkoxy, aryl, heteroaryl, C3-10cycloalkyl, C3-8heterocycloalkyl, C1-6alkylenearyl, C1-6alkyleneheteroaryl, C1-6alkyleneheterocycloalkyl, C1-6alkylenecycloalkyl,
• ORa, halo, N(Ra)2, SRa, SORa, SO2Ra, CN, C(═O)Ra, OC(═O)Ra, C(═O)ORa, C1-6alkyleneN(Ra)2, C1-6alkyleneORa, C1-6alkyleneSRa, C1-6alkyleneC(═O)ORa, C(═O)N(Ra)2, C(═O)NRaC1-6alkyleneORa, OC1-6alkyleneC(═O)ORa, OC1-6alkyleneN(Ra)2, OC1-6alkyleneORa, OC1-6alkyleneNRaC(═O)ORa, NRaC1-6alkyleneN(Ra)2, NRaC(═O)Ra, NRaC(═O)N(Ra)2, N(SO2C1-6alkyl)2, NRa(SO2C1-6alkyl), nitro, and SO2N(Ra)2, and
• Ra is defined above;
• L is selected from the group consisting of null, C1-8alkylene, Ra substituted C1-8alkylene, NRa, C(═O), aryl, C(═O)aryl, C(═O)C1-6alkylene, C1-8alkyleneNRa, C1-6alkylenearyleneC1-6alkylene, C2-6alkenylene, C4-8alkdienylene, C1-6alkylenearylene, C1-6alkyleneheteroarylene, Ra substituted C1-6alkyleneheteroarylene, and C2-6alkenylenearyleneC1-6alkylene, and Ra is defined above;
• M is selected from the group consisting of —C(═O)N(Rb)OH,
• —O(CH2)1-6C(═O)N(Rb)ORb,
• —N(Rb)(CH2)1-6C(═O)N(Rb)ORb,
• —N(Rb)(CH2)1-6C(═O)N(Rb)ORb,
• arylC(═O)NHOH,
• —N(OH)C(═O)Rb,
• heteroarylC(═O)NHOH,
• —C3-6cycloalkylN—C(═O)CH2SH,
• —B(ORb)2,
• —SO2NHRb,
• —NHSO2NHRb,
• —NHSO2C1-6alkyl,
• —SO2C1-6alkyl,
• —SRc,
• —C(═O)Re,
• —P(═O)(ORf)2,
• —NH—P(═O)(ORf)2,
• —C(═O)(C(Rb)2)1-6SH,
• —C(═O)C(═O)NHRb,
• —C(═O)NHN(Rb)2,
• —C(═O)NH(CH2)1-3N(Rb)2,
• —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)Rd, —NH2, and —SH,
• heteroaryl optionally substituted with —NH2, —SH, or both,
• —N(H)C(═O)SH,
• —NHC(═O)NHRd,
• —NHC(═O)CH2Rd,
• —NHC(═O)(CH2)1-6SH,
• —NHC(═O)CH2Hal,
• —NHC(═S)NHRd,
• —NHC(═S)CH2Rd,
• —C(═S)NHRd,
• —C(═S)CH2Rd,
• —NHC(═S)CH2Rd,
• —NHC(═S)CH2Hal, and
• —(C═O)C1-6alkyl;
• Rb, independently, is selected from the group consisting of hydrogen, (C═O)CH3, C1-6alkyl, CF3, CH2F, and aryl, or two Rb groups are taken together with the carbon to which they attached to form a C3-8cycloalkyl group;
• Rc is selected from hydrogen or (C═O)CH3;
• Rd is NH2 or OH;
• Re is selected from the group consisting of OH, N(Rb)2, NH(OCH3), N(CH3)OH, C1-6alkyl, CF3, aryl, heteroaryl, C3-8cycloalkyl, NHSO2CH3, NHSO2CF3, and C1-6haloalkyl;
• Rf independently is hydrogen, methyl, or ethyl;
• and
• Hal is halo,
• or a pharmaceutically acceptable salt, hydrate, or prodrug thereof.