Histone deacetylase inhibitors and methods for use thereof
The present invention relates to methods of modulating (for example inhibiting) activity of histone deacetylases (HDACs) and/or treating HDACs-associated diseases including, for example, cancers, inflammatory disorders, neurodegenerative disorders, etc. The invention also provides novel compounds and compositions thereof, methods of preparation of the same, as well as methods of use of the same for inhibition of HDACs and/or treatment of HDAC-associated diseases.
1. A compound selected from the group consisting of Formulae VI-A, VII-A, VIII-A, IX-A, X-A, VI-B, VII-B, VIII-B, IX-B, and X-B, or a salt or solvate thereof:
wherein in Formulae VI-A to X-B:
R 11 , R 12 , R 13 , R 14 , R 14′ , R 15 , R 15′ , R 16 , R 16′ , R 17 and R 17′ 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 , 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 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 d′ , R e or R f can optionally be joined to form additional rings; and any of R 11 , R 12 , R 13 , R 14 , R 14′ , R 15 , R 15′ , R 16 , R 16′ , R 17 , and R 17′ can optionally be connected to each other to form various carbo- or heterocyclic rings;
m is an integer from 0 to 3, n is an integer from 0 to 7 and 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:
R 8 , R 8′ , R 9 , and R 10 are each independently 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, and R 10 can represent single, multiple, or no substitution.
2. The compound of claim 1 , wherein the compound has a chemical structure selected from the group consisting of N-(2-amino-4-(thiophen-2-yl)phenyl)-4-((3-oxoisothiazolo[5,4-b]pyridin-2(3H)-yl)methyl)benzamide, N-(2-amino-5-(thiophen-2-yl)phenyl)-4-((3-oxoisothiazolo[5,4-b]pyridin-2(3H)-yl)methyl)benzamide, N-hydroxy-4((3-oxoisothiazolo[5,4-b]pyridin-2(3H)-yl)methyl)benzamide, N-(7-(hydroxyamino)-7-oxoheptyl)-4-((3-oxoisothiazolo[5,4-b]pyridin-2(3H)-yl)methyl)benzamide, N-(2-aminophenyl)-4((3-oxoisothiazolo[5,4-b]pyridin-2(3H)-yl)methyl)benzamide, N-(4-((2-amino-4-(thiophen-2-yl)phenyl)carbamoyl)benzyl)-2-mercaptonicotinamide, N-(4-((2-amino-5-(thiophen-2-yl)phenyl)carbamoyl)benzyl)-2-mercaptonicotinamide, N-(4-(hydroxycarbamoyl)benzyl)-2-mercaptonicotinamide, N-(4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)benzyl)-2-mercaptonicotinamide, and N-(4-((2-aminophenyl)carbamoyl)benzyl)-2-mercaptonicotinamide, or a pharmaceutically acceptable salt thereof.
3. A composition comprising the compound of claim 1 , or a salt or solvate thereof, and at least one pharmaceutically acceptable carrier.
4. A method of inhibiting HDAC in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formulae VI-A, VII-A, VIII-A, IX-A, X-A, VI-B, VII-B, VIII-B, IX-B, and X-B, or a salt or solvate thereof:
wherein in Formulae VI-A to X-B:
R 11 , R 12 , R 13 , R 14 , R 14′ , R 15 , R 15′ , R 16 , R 16′ , R 17 and R 17′ 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 , 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 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 d′ , R e or R f can optionally be joined to form additional rings; and any of R 11 , R 12 , R 13 , R 14 , R 14′ , R 15 , R 15′ , R 16 , R 16′ , R 17 , and R 17′ can optionally be connected to each other to form various carbo- or heterocyclic rings;
m is an integer from 0 to 3, n is an integer from 0 to 7 and 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:
R 8 , R 8′ , R 9 , and R 10 are each independently 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, and R 10 can represent single, multiple, or no substitution.
5. The method of claim 4 wherein the compound has a chemical structure selected from the group consisting of N-(2-amino-4-(thiophen-2-yl)phenyl)-4-((3-oxoisothiazolo[5,4-b]pyridin-2(3H)-yl)methyl)benzamide, N-(2-amino-5-(thiophen-2-yl)phenyl)-4-((3-oxoisothiazolo[5,4-b]pyridin-2(3H)-yl)methyl)benzamide, N-hydroxy-4((3-oxoisothiazolo[5,4-b]pyridin-2(3H)-yl)methyl)benzamide, N-(7-(hydroxyamino)-7-oxoheptyl)-4-((3-oxoisothiazolo[5,4-b]pyridin-2(3H)-yl)methyl)benzamide, N-(2-aminophenyl)-4((3-oxoisothiazolo[5,4-b]pyridin-2(3H)-yl)methyl)benzamide, N-(4-((2-amino-4-(thiophen-2-yl)phenyl)carbamoyl)benzyl)-2-mercaptonicotinamide, N-(4-((2-amino-5-(thiophen-2-yl)phenyl)carbamoyl)benzyl)-2-mercaptonicotinamide, N-(4-(hydroxycarbamoyl)benzyl)-2-mercaptonicotinamide, N-(4-((7-(hydroxyamino)-7-oxoheptyl)carbamoyl)benzyl)-2-mercaptonicotinamide, and N-(4-((2-aminophenyl)carbamoyl)benzyl)-2-mercaptonicotinamide, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.
6. The method of claim 4 , wherein the compound selectively inhibits an HDAC selected from the group consisting of HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7.
7. The method of claim 4 , wherein the compound selectively inhibits HDAC6.
8. The method of claim 4 , wherein the compound selectively inhibits HDAC8.
9. The method of claim 4 , wherein the subject is a human.
10. The method of claim 4 , wherein the subject has cancer.
11. The method of claim 4 , wherein the subject has a disease or disorder is selected from the group consisting of a psychiatric disease or disorder, a neurologic disease or disorder, a neurodegenerative disease or disorder, and a neuroinflammation disease or disorder.
12. The method of claim 4 wherein the compound is administered to the subject orally, parenterally, intravascularly, intranasally, or intrabronchially.
13. The method of claim 4 , further comprising:
administering to the subject a therapeutically effective amount of an additional therapeutic agent for the treatment of a disease or disorder.
14. The method of claim 13 , wherein the additional therapeutic agent is selected from the group consisting of an immunomodulatory drug, an immunotherapeutic drug, a DNA-damaging chemotherapeutic, a proteasome inhibitor, an anti-androgen receptor, an antiretroviral drug, a reverse-transcriptase inhibitor, a chemotherapeutic drug, and an immunosuppressant.