Histone deacetylase inhibitors and methods of use thereof

1. A compound of Formula I, or a salt or solvate thereof:

wherein in Formula I:

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, SO 2 , or NR a , and wherein Ring B may optionally be substituted by one or more R b s;

L 1 is a bond or a C 1 -C 3 alkyl group optionally substituted by R b ;

L 2 is a bond, a C 1 -C 3 alkyl group optionally substituted by R b , an alkenyl, or an alkynyl;

X is CH 2 , O, or NR c ;

each R a is independently selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , OR d , OC(═O)R d , OC(═O)OR d , OC(═O)NR d R e , CR d R e R f , CR d R e OR f , C(═O)R d , C(═O)NR d R e , C(═O)OR d , NR d R e , NR d C(═O)R e , NR d C(═O)OR e , NR d C(═O)NR e R f , NR d S(═O) 2 R e , NR d S(═O) 2 NR e R f , SR d , S(═O)R d , S(═O) 2 R d , and S(═O) 2 NR d R e , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Cl, Br, I, CN, NO 2 , OR d , OC(═O)R d , OC(═O)OR d , OC(═O)NR d R e , CR d R e R f , CR d R e OR f , C(═O)R d , C(═O)NR d R e , C(═O)OR d , NR d R e , NR d C(═O)R e , NR d C(═O)OR e , NR d C(═O)NR e R f , NR d S(═O) 2 R e , NR d S(═O) 2 NR e R f , SR d , S(═O)R d , S(═O) 2 R d , and S(═O) 2 NR d R e , and wherein each R d , R e and R f is independently selected from the group consisting of H, and optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of R d , R e or R f may be optionally joined to form additional rings;

each R b is independently selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , OR d , OC(═O)R d , OC(═O)OR d , OC(═O)NR d R e , CR d R e R f , CR d R e OR f , C(═O)R d , C(═O)NR d R e , C(═O)OR d , NR d R e , NR d C(═O)R e , NR d C(═O)OR e , NR d C(═O)NR e R f , NR d S(═O) 2 R e , NR d S(═O) 2 NR e R f , SR d , S(═O)R d , S(═O) 2 R d , and S(═O) 2 NR d R e , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 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, NO 2 , OR d , OC(═O)R d , OC(═O)OR d , OC(═O)NR d R e , CR d R e R f , CR d R e OR f , C(═O)R d , C(═O)NR d R e , C(═O)OR d , NR d R e , NR d C(═O)R e , NR d C(═O)OR e , NR d C(═O)NR e R f , NR d S(═O) 2 R e , NR d S(═O) 2 NR e R f , SR d , S(═O)R d , S(═O) 2 R d , and S(═O) 2 NR d R e , and wherein each R d , R e and R f is independently selected from the group consisting of H, and optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of R d , R e or R f may be optionally joined to form additional rings;

wherein any R a and R b may be optionally joined to form additional rings;

R c is selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 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, NO 2 , OR d , OC(═O)R d , OC(═O)OR d , OC(═O)NR d R e , CR d R e R f , CR d R e OR f , C(═O)R d , C(═O)NR d R e , C(═O)OR d , NR d R e , NR d C(═O)R e , NR d C(═O)OR e , NR d C(═O)NR e R f , NR d S(═O) 2 R e , NR d S(═O) 2 NR e R f , SR d , S(═O)R d , S(═O) 2 R d , and S(═O) 2 NR d R e , and wherein R d , R e and R f are each independently selected from the group consisting of H, and optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of R d , R e or R f 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:

R 8 , R 8′ , and R 10 are each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl may optionally be substituted, and R 10 can represent single, multiple, or no substitution;

R 9 is selected from the group consisting of H, halogen, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein the C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl may optionally be substituted;

m is an integer from 0-3; and

n is an integer from 0-3.

2. The compound of claim 1 , wherein the compound is selected from the group consisting of

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

wherein in Formula I-A:

Ring A is an aromatic ring having 0-3 ring nitrogen atoms, and wherein Ring A may optionally be substituted by one or more R b s;

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, SO 2 , or NR b , and wherein Ring B may optionally be substituted by one or more R c s;

R a , R b and R c are each independently selected from the group consisting of H, F, Cl, Br, I, CN, NO 2 , OR d , OC(═O)R d , OC(═O)OR d , OC(═O)NR d R e , CR d R e R f , CR d R e OR f , C(═O)R d , C(═O)NR d R e , C(═O)OR d , NR d R e , NR d C(═O)R e , NR d C(═O)OR e , NR d C(═O)NR e R f , NR d S(═O) 2 R e , NR d S(═O) 2 NR e R f , SR d , S(═O)R d , S(═O) 2 R d , and S(═O) 2 NR d R e , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 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, NO 2 , OR d , OC(═O)R d , OC(═O)OR d , OC(═O)NR d R e , CR d R e R f , CR d R e OR f , C(═O)R d , C(═O)NR d R e , C(═O)OR d , NR d R e , NR d C(═O)R e , NR d C(═O)OR e , NR d C(═O)NR e R f , NRdS(═O) 2 R e , NR d S(═O) 2 NR e R f , SR d , S(═O)R d , S(═O) 2 R d , and S(═O) 2 NR d R e , and wherein R d , R e and R f are each independently selected from the group consisting of H, and optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of R d , R e or R f can optionally be joined to form additional rings; and R a , R b and R c 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, and wherein a null selection for any of the X 1 to X 7 nodes results in a null selection for the adjacent R groups;

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently selected from the group consisting of null, C, CH, CH 2 , C(═O), O, N, NH, S, S(═O) and S(═O) 2 ;

R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 7 and R 7′ are each independently selected from the group consisting of null, H, F, Cl, Br, I, CN, NO 2 , OR d , OC(═O)R d , OC(═O)OR d , OC(═O)NR d R e , CR d R e R f , CR d R e OR f , C(═O)R d , C(═O)NR d R e , C(═O)OR d , NR d R e , NR d C(═O)R e , NR d C(═O)OR e , NR d C(═O)NR e R f , NR d S(═O) 2 R e , NR d S(═O) 2 NR e R f , SR d , S(═O)R d , S(═O) 2 R d , and S(═O) 2 NR d R e , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 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, NO 2 , OR d , OC(═O)R d , OC(═O)OR d , OC(═O)NR d R e , CR d R e R f , CR d R e OR f , C(═O)R d , C(═O)NR d R e , C(═O)OR d , NR d R e , NR d C(═O)R e , NR d C(═O)OR e , NR d C(═O)NR e R f , NR d S(═O) 2 R e , NR d S(═O) 2 NR e R f , SR d , S(═O)R d , S(═O) 2 R d , and S(═O) 2 NR d R e , and wherein R d , R e and R f are each independently selected from the group consisting of H, and optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and wherein any of R d , R e or R f can optionally be joined to form additional rings; and any of R′, R 1′ , R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 5 , R 5′ , R 6 , R 6′ , R 7 and R 7′ 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:

R 8 , R 8′ , R 9 , and R 10 are each independently selected from the group consisting of null, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, and R 10 can represent single, multiple, or no substitution;

n is an integer of 0-3.

4. A kit for inhibiting an HDAC or for treating a disease or disorder associated with an HDAC in a subject, comprising an amount of a compound of claim 1 , or a salt or solvate thereof, and an instruction manual for the use thereof.

5. A probe for imaging, diagnosing, or theragnosting a disease or disorder associated with an HDAC in a subject, comprising a compound of claim 1 , or a salt or solvate thereof.

6. A kit for inhibiting an HDAC or for treating a disease or disorder associated with an HDAC in a subject, comprising an amount of a compound of claim 3 , or a salt or solvate thereof, and an instruction manual for the use thereof.

7. A probe for imaging, diagnosing, or theragnosting a disease or disorder associated with an HDAC in a subject, comprising a compound of claim 3 , or a salt or solvate thereof.