Inhibitors of histone deacetylase
View Patent ↗The present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , W 1 , W 2 , W 3 , and W 4 are as described. The present invention relates generally to inhibitors of histone deacetylase and to methods of making and using them. In one aspect, the invention relates to selective HDAC3 inhibitors useful for protecting β-cells and improving insulin resistance. The selective HDAC3 inhibitors are also useful for promoting cognitive function and enhancing learning and memory formation. Compounds of the invention are useful for treating, alleviating, and/or preventing various conditions, including for example, a metabolic disorder such as type 1 or type 2 diabetes, dyslipidemias, lipodystrophies, liver disease associated with metabolic syndrome, polycystic ovarian syndrome, or obesity; inflammatory disease; neurological disorder; a memory or cognitive function disorder/impairment; an extinction learning disorder; fungal disease or infection; viral disease or infection such as HIV; hematological disease; liver disease; lysosomal storage disease; or neoplastic disease in humans or animals.
1. A compound of formula I:
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:
X 3 is NR1C(O)R2, wherein R2 is unsubstituted C1-C8 alkyl, CF3, CH2F, or CF2H;
W 1 , W 2 , W 3 , and W 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, CF 3 , CH 3 , and deuterium, provided that at least one of W 1 , W 2 , W 3 , and W 4 is not hydrogen;
X 1 and X 5 are each independently selected from hydrogen, halogen, and C 1 -C 3 alkyl;
X 2 and X 4 are each independently selected from hydrogen, halogen, OR 5 , C(O)R 6 , OS(O) p R 7 , NR 3 R 4 , NR 1 C(O)R 2 , NR 1 S(O) p R 7 , S(O) q R 10 , C(O)OR 11 , C(O)NR 12 R 13 , OC(O)OR 14 , OC(O)NR 15 R 16 , NR 17 C(O)OR 18 , NR 19 C(O)NR 20 R 21 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R a , provided that one or two of X 2 and X 4 is hydrogen;
R a is selected from halogen, OR 25 , C 1 -C 8 alkyl, CF 3 , CHF 2 , CH 2 F, NR 26 C(O)R 27 , and NR 28 R 29 ; or
R 1 and R 26 are each independently selected from hydrogen and C 1 -C 8 alkyl;
R 2 is selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R b ;
R 27 is selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R b ;
R b is selected from halogen, C 1 -C 8 alkyl, CF 3 , CHF 2 , CH 2 F, OR 25 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R b1 ;
R b1 is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 3 and R 4 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloakenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R g ;
R 28 and R 29 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloakenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R g ;
R g is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R h ;
R h is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 5 and R 25 are each independently selected from hydrogen, C(O)R 6 , C 1 -C 8 alkyl, CF 3 , CHF 2 , CH 2 F, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R c ;
R c is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R d ;
R d is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 6 is selected from hydrogen, OR 25 , C 1 -C 8 alkyl, CF 3 , CHF 2 , CH 2 F, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R e ;
R e is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R f ;
R f is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 7 is selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring; wherein said alkyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R i ;
R i is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 10 is selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring; wherein said alkyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R j ;
R j is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 11 is selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R k ;
R k is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R k1 ;
R k1 is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , SO 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 12 and R 13 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R l ;
R l is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R m ;
R m is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 14 is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, and aromatic ring; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and aromatic ring are unsubstituted or substituted with one or more R n ;
R n is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R n1 ;
R n1 is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , SO 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 15 and R 16 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R o ;
R o is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R p ;
R p is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 17 and R 19 are each independently selected from hydrogen and C 1 -C 8 alkyl;
R 18 is selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered saturated heterocyclic ring; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroaromatic ring, heterocyclic ring, and aromatic ring are unsubstituted or substituted with one or more R q ;
R q is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R q1 ;
R q1 is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , SO 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 20 and R 21 are each independently selected from selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R r ;
R r is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more R s ;
R s is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , SO 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ; and
p and q are each independently selected from 0, 1, and 2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein X 1 , X 2 , X 4 , and X 5 are all hydrogen.
3. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvent, or prodrug thereof, wherein one of X 1 , X 2 , X 4 , and X 5 is halogen.
4. A kit containing one or more compounds of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
5. The compound of claim 1 , wherein the compound is of Formula (I), or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
7. The compound of claim 1 , wherein the compound is of the formula:
or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
8. The compound of claim 1 , wherein X 3 is NHC(O)CH 3 .
9. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
10. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
11. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutical carrier, diluent, or excipient.
12. A method of treating or alleviating an HDAC3 mediated disease in a subject comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein the HDAC3 mediated disease is cognitive function disorder, extinction learning disorder, memory loss or impairment, diabetes, obesity, Gaucher disease, Niemann-Pick type C disease, liver disease, post-traumatic stress disorder (PTSD), phobias, drugg addiction, anxiety disorder, obsessive compulsive disorder, bipolar disorder, major depressive disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington'disease, leukemia, lymphoma, melanoma, liver cancer, or lung cancer.
13. The method of claim 12 , wherein the HDAC3 mediated disease is lymphoma.
14. The method of claim 13 , wherein the lymphoma is cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T-cell leukemia/lymphoma (ATLL), Hodgkin's disease, non-Hodgkin's lymphoma, large-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, or primary central nervous system (CNS) lymphoma.
15. The method of claim 12 , wherein the HDAC3 mediated disease is melanoma.
16. The method of claim 12 , wherein the HDAC3 mediated disease is lung cancer.
17. The method of claim 12 , wherein the HDAC3 mediated disease is post-traumatic stress disorder (PTSD), phobias, or drug addiction.
18. The method of claim 12 , wherein the HDAC3 mediated disease is Alzheimer's disease, Parkinson's disease, or Huntington's disease.
19. The method of claim 12 , wherein the compound is of the formula:
20. A method of treating or alleviating an HDAC3 mediated disease in a subject comprising administering to a subject in need thereof an effective amount of: a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and an anti-cancer or chemotherapeutic agent, in combination or seperately, wherein the HDAC3 mediated disease is breast cancer.
21. The method of claim 20 , wherein the compound is of the formula:
22. A compund of the formula:
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
23. A pharmaceutical composition comprising an effective amount of a compound of claim 22 , or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutical carrier, diluent, or excipient.
24. A method of treating or alleviating an HDAC3 mediated disease in a subject comprising administering to a subject in need thereof an effective amount of a compound of claim 22 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein the HDAC3 mediated disease is cognitive function disorder, extinction learning disorder, memory loss or impairment, diabetes, obesity, Gaucher disease, Niemann-Pick type C disease, liver disease, post-traumatic stress disorder (PTSD), phobias, drug addiction, anxiety disorder, obsessive compulsive disorder, bipolar disorder, major depressive disorder, schizophrenia, ALzheimer's disease, Parkinson's disease, Huntington's disease, leukemia, lymphoma, melanoma, liver cancer, or lung cancer.
25. A method of treating or alleviating an HDAC3 mediated disease in a subject comprising administering to a subject in need thereof an effective amount of: a compound of claim 22 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and an anti-cancer or chemotherapeutic agent, in combination or separately, wherein the HDAC3 mediated disease is breast cancer.