Histone Deacetylase Inhibitors and Methods of Use Thereof

A compound of Formula I-B, or a salt or solvate thereof:

• wherein in Formula I-B:
• Ring A is an aromatic ring having 0-3 ring nitrogen atoms, and wherein Ring A may optionally be substituted by one or more Rbs;
• Ring B is a saturated or unsaturated 3-7 membered carbocyclic ring or a saturated or unsaturated 3-7 membered heterocyclic ring having 1-3 ring atoms of O, S, SO, SO2, or NRb, and wherein Ring B may optionally be substituted by one or more Rcs;
• Ra, Rb and Rc are each independently selected from the group consisting of H, F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, and wherein Rd, Re and Rf are each independently selected from the group consisting of H, and optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of Rd, Re or Rf can optionally be joined to form additional rings;
• and Ra, Rb and Rc can optionally be joined to form additional
• chain
• is an uninterrupted chain, wherein any bond can be a single, double or triple bond, consistent with the hybridization state of the connected atoms, and wherein a null selection for any of the X1 to X7 nodes results in a null selection for the adjacent R groups;
• X1, X2, X3, X4, X5, X6, and X7 are each independently selected from the group consisting of null, C, CH, CH2, C(═O), O, N, NH, S, S(═O) and S(═O)2;
• R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5, R5′, R6, R6′, R7 and R7′ are each independently selected from the group consisting of null, H, F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, and wherein Rd, Re and Rf are each independently selected from the group consisting of H, and optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of Rd, Re or Rf can optionally be joined to form additional rings;
• and any of R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5, R5′, R6, R6′, R7 and R7′ can optionally be connected to each other to form various carbocyclic or heterocyclic systems;
• and
• Fn is selected from the group consisting of Formulae II, III, IV and V:
• wherein in Formulae II, III, IV and V:
• R8, R8′, R9, and R10 are each independently selected from the group consisting of null, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and R10 can represent single, multiple, or no substitution;
• n is an integer of 0-3.

A compound having a structure selected from the group consisting of Formulae VI-A, VII-A, VIII-A, IX-A, X-A, VI-B, VII-B, VIII-B, IX-R, and X-B, or a salt or solvate thereof:

• wherein in Formulae VI-A to X-B:
• R11, R12, R13, R14, and R14 are each independently selected from the group consisting of H, F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, and wherein each Rd, Re and Rf is independently selected from the group consisting of H, and optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of Rd, Re or Rf can optionally be joined to form additional rings;
• and any of R11, R12, R13, R14, and R14 can optionally be joined to each other to form various carbocyclic or heterocyclic rings;
• m is an integer from 0 to 3;
• q is an integer from 0 to 7;
• p is an integer from 0 to 2;
• J is selected from the group consisting of CH and N;
• and
• Fn is selected from the group consisting of Formulae II, III, IV and V:
• wherein in Formulae II, III, IV and V:
• R8, R8′, R9, and R10 are each independently selected from the group consisting of null, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and R10 can represent single, multiple, or no substitution.

A method of treating a disease or disorder associated with HDACs in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula I-A or Formula I-B, or a salt or solvate thereof:

• wherein in Formula F
• Ring A is an aromatic ring having 0-2 ring nitrogen atoms;
• Ring B is a 3-7 membered saturated or unsaturated carbocyclic ring, or a 3-7 membered saturated or unsaturated heterocyclic ring having 1-3 ring atoms of O, S, SO, SO2, or NR3, and wherein Ring B may optionally be substituted by one or more Rbs;
• L1 is a bond or a C1-C3 alkyl group optionally substituted by Rb;
• L2 is a bond, a C1-C3 alkyl group optionally substituted by Rb, an alkenyl, or an alkynyl;
• X is CH2, O, or NRc;
• each Ra and Rb is independently selected from the group consisting of H, F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, and wherein each Rd, Re and Rf is independently selected from the group consisting of H, and optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of Rd, Re or Rf may be optionally joined to form additional rings;
• and any Ra and Rb may be optionally joined to form additional rings;
• Rc is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, and wherein Rd, Re and Rf are each independently selected from the group consisting of H, and optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of Rd, Re or Rf may be optionally joined to form additional rings;
• Fn is selected from the group consisting of Formulae II, III, IV and V:
• wherein in Formulae II, III, IV and V:
• R8, R8′, R9, and R10 are each independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl may optionally be substituted, and R10 can represent single, multiple, or no substitution;
• m is an integer from 0-3;
• and
• n is an integer from 0-3;
• wherein in Formula I-A and Formula I-B:
• Ring A is an aromatic ring having 0-3 ring nitrogen atoms, and wherein Ring A may optionally be substituted by one or more Rbs;
• Ring B is a saturated or unsaturated 3-7 membered carbocyclic ring or a saturated or unsaturated 3-7 membered heterocyclic ring having 1-3 ring atoms of O, S, SO, SO2, or NRb, and wherein Ring B may optionally be substituted by one or more Rcs;
• Ra, Rb and Rc are each independently selected from the group consisting of H, F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, and wherein Rd, Re and Rf are each independently selected from the group consisting of H, and optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of Rd, Re or Rf can optionally be joined to form additional rings;
• and Ra, Rb and Rc can optionally be joined to form additional rings;
• chain
• is an uninterrupted chain, wherein any bond can be a single, double or triple bond, consistent with the hybridization state of the connected atoms, e.g. if X2 is an sp hybridized carbon atom and X3 is also an sp hybridized carbon atom, then the X2—X3 bond is a triple C—C bond, etc., wherein a null selection for any of the X1 to X7 nodes will result in connecting the adjacent nodes, e.g. if X5 is null, then X4 connects to X6, or if X4 and X5 are both null, then X3 connects with X6, etc., and wherein a null selection for any of the X1 to X7 nodes will result in an automatic null selection for the adjacent R groups, e.g. if X3 is null, then R3 and R3′ are both automatically null, etc.;
• X1, X2, X3, X4, X5, X6, and X7 are each independently selected from the group consisting of null, C, CH, CH2, C(═O), O, N, NH, S, S(═O) and S(═O)2;
• R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5, R5′, R6, R6′, R7 and R7′ are each independently selected from the group consisting of null, H, F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from F, Cl, Br, I, CN, NO2, ORd, OC(═O)Rd, OC(═O)ORd, OC(═O)NRdRe, CRdReRf, CRdReORf, C(═O)Rd, C(═O)NRdRe, C(═O)ORd, NRdRe, NRdC(═O)Re, NRdC(═O)ORe, NRdC(═O)NReRf, NRdS(═O)2Re, NRdS(═O)2NReRf, SRd, S(═O)Rd, S(═O)2Rd, and S(═O)2NRdRe, and wherein Rd, Re and Rf are each independently selected from the group consisting of H, and optionally substituted C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of Rd, Re or Rf can optionally be joined to form additional rings;
• and any of R1, R1′, R2, R2′, R3, R3′, R4, R4′, R5, R5′, R6, R6′, R7 and R7′ can optionally be connected to each other to form various carbocyclic or heterocyclic systems;
• and
• Fn is selected from the group consisting of Formulae II, III, IV and V:
• wherein in Formulae II, III, IV and V:
• R8, R8′, R9, and R10 are each independently selected from the group consisting of null, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and R10 can represent single, multiple, or no substitution;
• and
• n is an integer of 0-3.