Inhibitors of histone deacetylase
The present invention relates to compounds of formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein U, J, V, X, R 2a , R 2b , R 2c , R 5 and t are as described herein. The present invention relates generally to inhibitors of histone deacetylase and to methods of making and using them. These compounds are useful for promoting cognitive function and enhancing learning and memory formation. In addition, these compounds are useful for treating, alleviating, and/or preventing various conditions, including for example, neurological disorders, memory and cognitive function disorders/impairments, extinction learning disorders, fungal diseases and infections, inflammatory diseases, hematological diseases, and neoplastic diseases in humans and animals.
1. A compound having formula I:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
U is a single bond;
J′ is NH 2 ;
V is C;
X is hydrogen;
taken together two of R 2a , R 2b , and R 2c form a C 4 -C 5 cycloalkyl ring or C 4 -C 5 cycloalkenyl ring, and the remaining R 2a , R 2b , or R 2c is absent or selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl, wherein said cycloalkyl ring formed by taking together two of R 2a , R 2b , and R 2c is substituted with one or more R x , and said cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c is unsubstituted or substituted with one or more R x ;
each R x is independently selected from (CH 2 ) z NH 2 , (CH 2 ) z NHR 3 , (CH 2 ) z NR 3 R 3 , OR 3 , OCF 3 , OCH 2 F, OCHF 2 , (CH 2 ) z -heterocyclic ring, hydroxyl, halogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3 , (CH 2 ) z C(O)NH 2 , (CH 2 ) z C(O)NHR 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z NHC(O)R 4 , and (CH 2 ) z NR 4 C(O)R 4 ;
or:
taken together only two R x form: i) a C 3 -C 4 or C 7 -C 8 , cycloalkyl ring, or 3 to 8 membered, saturated or partially unsaturated, heterocyclic ring, wherein said cycloalkyl ring and heterocyclic ring are unsubstituted or substituted with one or more R z ; or ii) an aromatic ring or heteroaromatic ring, wherein said aromatic ring and heteroaromatic ring are unsubstituted or substituted with one or more R z ; and
optionally each remaining R x is independently selected from (CH 2 ) z NH 2 , (CH 2 ) z NHR 3 , (CH 2 ) z NR 3 R 3 , OR 3 , OCF 3 , OCH 2 F, OCHF 2 , (CH 2 ) z -heterocyclic ring, hydroxyl, halogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3 , (CH 2 ) z C(O)NH 2 , (CH 2 ) z C(O)NHR 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z NHC(O)R 4 , and (CH 2 ) z NR 4 C(O)R 4 ;
each R z is independently selected from halogen, C 1 -C 4 alkyl, OH, OR 3 , CF 3 , OCF 3 , OCH 2 F, OCHF 2 , NH 2 , NHR 3 , NR 3 R 3 , and C(O)CH 3 ;
each instance of R 3 is C 1 -C 8 alkyl;
each instance of R 4 is independently selected from C 1 -C 8 alkyl and CF 3;
R 5 is hydrogen;
t is 0; and
z is selected from 0, 1, 2, and 3.
2. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2a R 2b R 2c V— is
wherein w is selected from 1 and 2.
3. The compound of claim 1 , wherein the compound is of the formula:
No.
Formula
219
223
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c is unsubstituted.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
the cycloalkyl ring and cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c are substituted with one or more R x ; and
each R x is independently selected from (CH 2 ) z NH 2 , (CH 2 ) z NHR 3 , (CH 2 ) z NR 3 R 3 , OR 3 , OCF 3 , OCH 2 F, OCHF 2 , (CH 2 ) z -heterocyclic ring, hydroxyl, halogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3 , (CH 2 ) z C(O)NH 2 , (CH 2 ) z C(O)NHR 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z NHC(O)R 4 , and (CH 2 ) z NR 4 C(O)R 4 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
the cycloalkyl ring and cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c are substituted with two or more R x ;
taken together only two R x form a C 3 -C 4 or C 7 -C 8 , cycloalkyl ring, or 3 to 8 membered, saturated or partially unsaturated, heterocyclic ring, wherein said cycloalkyl ring and heterocyclic ring are unsubstituted or substituted with one or more R z ; and optionally:
each remaining R x is independently selected from (CH 2 ) z NH 2 , (CH 2 ) z NHR 3 , (CH 2 ) z NR 3 R 3 , OR 3 , OCF 3 , OCH 2 F, OCHF 2 , (CH 2 ) z -heterocyclic ring, hydroxyl, halogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3 , (CH 2 ) z C(O)NH 2 , (CH 2 ) z C(O)NHR 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z NHC(O)R 4 , and (CH 2 ) z NR 4 C(O)R 4 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2a R 2b R 2c V— is:
wherein:
J is selected from N, O, CH, C, and S;
when J is N, CH, or C, R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ; and when J is O or S, R u is absent;
R 3a is C 1 -C 8 alkyl;
n is 0; and
is selected from 0, 1, 2, 3, 4, 5, 6, and 7.
8. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2a R 2b R 2c V— is:
wherein:
J is selected from CH and C;
R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ; R 3a is C 1 -C 8 alkyl;
n is 0; and
is selected from 0, 1, 2, 3, 4, 5, 6, and 7.
9. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
the cycloalkyl ring and cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c are substituted with two or more R x ;
taken together only two R x form an aromatic ring, wherein said aromatic ring is unsubstituted or substituted with one or more R z ; and optionally:
each remaining R x is independently selected from (CH 2 ) z NH 2 , (CH 2 ) z NHR 3 , (CH 2 ) z NR 3 R 3 , OR 3 , OCF 3 , OCH 2 F, OCHF 2 , (CH 2 ) z -heterocyclic ring, hydroxyl, halogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3 , (CH 2 ) z C(O)NH 2 , (CH 2 ) z C(O)N H R 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z N HC(O) R 4 , and (CH 2 ) z NR 4 C(O)R 4 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2a R 2b R 2c V(CH 2 ) t U— is:
wherein:
V is CH;
each instance of T is independently CH, CR z , or N;
each R z is independently selected from halogen, C 1 -C 4 alkyl, OH, OR 3 , CF 3 , OCF 3 , OCH 2 F, OCHF 2 , NH 2 , NHR 3 , NR 3 R 3 , and C(O)CH 3 ;
b is 0; and
each instance of R 3 is C 1 -C 8 alkyl.
11. The compound of claim 10 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each instance of T is independently CH or CR z .
12. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the remaining R 2a , R 2b , or R 2c is absent or hydrogen.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
15. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
the cycloalkyl ring and cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c are substituted with two or more R x ;
taken together only two R x form a heteroaromatic ring, wherein said heteroaromatic ring is unsubstituted or substituted with one or more R z ; and optionally:
each remaining R x is independently selected from (CH 2 ) z NH 2 , (CH 2 ) z NHR 3 , (CH 2 ) z NR 3 R 3 , OR 3 , OCF 3 , OCH 2 F, OCHF 2 , (CH 2 ) z -heterocyclic ring, hydroxyl, halogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3 , (CH 2 ) z C(O)NH 2 , (CH 2 ) z C(O)NH R 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z NHC(O) R 4 , and (CH 2 ) z NR 4 C(O)R 4 .
16. A pharmaceutical composition comprising:
an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof; and
a pharmaceutical carrier, diluent, or excipient.
17. A kit containing one or more of: the compounds of claim 1 , and pharmaceutically acceptable salts, hydrates, and solvates thereof.
18. A compound of formula I:
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:
J′ is NH 2 ;
X is hydrogen;
R 5 is hydrogen;
U is a single bond;
t is selected from 0, 1, and 2;
R 2a R 2b R 2c V— is selected from:
J is selected from N, O, CH, C, and S;
when J is N, CH, or C, R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ; and when J is O or S, R u is absent;
R 3a is C 1 -C 8 alkyl;
n is 0, 1, or 2;
v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8;
R 2c is selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl;
or R 2a R 2b R 2c V(CH 2 ) t U— is
each R x is independently selected from (CH 2 ) z NH 2 , (CH 2 ) z NHR 3 , (CH 2 ) z NR 3 R 3 , OR 3 , OCF 3 , OCH 2 F, OCHF 2 , (CH 2 ) z -aromatic ring, (CH 2 ) z -heterocyclic ring, hydroxyl, halogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3 , (CH 2 ) z C(O)NH 2 , (CH 2 ) z C(O)NHR 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z NHC(O)R 4 , and (CH 2 ) z NR 4 C(O)R 4 ;
or taken together two R x attached to the same carbon atom of a cycloalkyl, cycloalkenyl, or heterocyclic ring form ═O;
or taken together two R x form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 cycloalkenyl ring, or 3 to 8 membered, saturated or partially unsaturated, heterocyclic ring, wherein said cycloalkyl ring, cycloalkenyl ring, and heterocyclic ring are unsubstituted or substituted with one or more R z ;
or taken together two R x form an aromatic ring or heteroaromatic ring, wherein said aromatic ring and heteroaromatic ring are unsubstituted or substituted with one or more R z ;
each R z is independently selected from halogen, C 1 -C 4 alkyl, OH, OR 3 , CF 3 , OCF 3 , OCH 2 F, OCHF 2 , NH 2 , NHR 3 , NR 3 R 3 , and C(O)CH 3 ;
each instance of R 3 is independently selected from C 1 -C 8 alkyl and O(C 1 -C 8 alkyl);
each instance of R 4 is independently selected from C 1 -C 8 alkyl and CF 3 ; and
z is selected from 0, 1, 2, and 3.
19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising:
an effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; and
a pharmaceutical carrier, diluent, or excipient.
21. A kit containing one or more of: the compounds of claim 18 , and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof.
22. A method of treating a condition in a subject in need thereof comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the condition is a disease.
23. The method of claim 22 , wherein the condition is a cancer.
24. The method of claim 22 , wherein the compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof is administered by a route selected from oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, rectal, and intracerebroventricular.
25. The method of claim 22 , wherein the condition is hematologic cancer.
26. The method of claim 25 , wherein the hematologic cancer is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndromes.
27. The method of claim 22 , wherein the condition is lymphoma.
28. The method of claim 22 , wherein the condition is non-Hodgkin's lymphoma.
29. The method of claim 22 , wherein the condition is diffuse large B-cell lymphoma.
30. A method of improving memory in a normal subject comprising administering to the normal subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
31. A method of increasing synaptic density, synaptic plasticity, or dendritic density in neurons in a subject in need of such increase comprising administering to the subject in need of such increase an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
32. A method of treating a condition in a subject in need thereof comprising administering to the subject in need thereof an effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein the condition is a neoplastic disease.
33. The method of claim 32 , wherein the condition is hematologic cancer.
34. The method of claim 32 , wherein the condition is lymphoma.
35. The method of claim 32 , wherein the condition is non-Hodgkin's lymphoma.
36. The method of claim 32 , wherein the condition is diffuse large B-cell lymphoma.
37. The method of claim 33 , wherein the hematologic cancer is selected from the group consisting of acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndromes.
38. A method of improving memory in a normal subject comprising administering to the normal subject an effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
39. A method of increasing synaptic density, synaptic plasticity, or dendritic density in neurons in a subject in need of such increase comprising administering to the subject in need of such increase an effective amount of a compound of claim 18 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.