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 of formula I:
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:
U is selected from single bond, CR 2e R 2f -CR 2g R 2h , NR 2d , NR 2d -NR 2d′ , and O;
J′ is selected from NH 2 and SH;
each X is independently selected from hydrogen, deuterium, methyl, CF 3 , and halogen;
R 2d is selected from NH 2 , hydrogen, and C 1 -C 8 alkyl;
R 2d′ is selected from NH 2 , hydrogen, and C 1 -C 8 alkyl;
R 2e , R 2f , R 2g , and R 2h are each independently selected from hydrogen, halogen, and C 1 -C 4 alkyl;
or taken together R 2e and R 2f , or R 2g and R 2h taken together form ═O;
or taken together two of R 2e , R 2f , R 2g , and R 2h on two adjacent carbon atoms together with the bond between said adjacent carbon atoms form a carbon-carbon double bond;
R 2a R 2b R 2c V- is of the formula:
J is selected from O, C, and S; provided that:
when J is 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 , wherein R 3a is C 1 -C 8 alkyl; and
when J is O or S, R u is absent;
v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8;
d and d′ are each independently selected from 0, 1, 2, and 3;
R 2c is selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl;
each R x is independently selected from hydrogen, (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 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 each independently 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 fused with
and are each independently substituted with one or more R z ;
each R z is independently selected from hydrogen, 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 R 3 is independently selected from C 1 -C 8 alkyl and O(C 1 -C 8 alkyl);
each R 4 is independently selected from C 1 -C 8 alkyl and CF 3 ;
R 5 is selected from O(C 2 -C 8 alkyl), C 2 -C 8 alkyl, C 2 -C 8 alkenyl, (CH 2 ) u -5-6 membered, saturated, unsaturated, or partially unsaturated, heterocyclic ring, (CH 2 ) v″ -C 4 -C 8 cycloalkyl ring, (C 1 -C 8 -alkyl) w -C 4 -C 8 cycloalkenyl ring, (CH 2 ) s -aromatic ring, and (CH 2 ) s -heteroaromatic ring, and wherein said heterocyclic ring, cycloalkyl ring, cycloalkenyl ring, heteroaromatic ring, and aromatic ring are each independently substituted with one or more R y , and said alkenyl is substituted with one or more R T ;
each R y is independently selected from hydrogen, halogen, OR 6 , NH 2 , NHR 6 , NR 6 R 6 , OH, CF 3 , phenyl, C(O)R 6 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl;
each R 6 is independently C 1 -C 8 alkyl;
each R T is independently selected from hydrogen, halogen, Si(R 3 ) 3 , phenyl, and C 1 -C 8 alkyl;
u is selected from 0, 1, and 2;
v″ is selected from 0, 1, and 2;
w is selected from 0, 1, and 2;
s is selected from 0, 1, and 2;
t is selected from 0, 1, and 2; and
each z is independently selected from 0, 1, 2, and 3.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein the moiety:
3. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is selected from:
wherein m is selected from 2, 3, and 4; and
wherein n is selected from 1, 2, 3, and 4.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is selected from phenyl, 4-fluorophenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, oxazolyl, thiazolyl, and isoxazolyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 2a R 2b R 2c V- is of the formula:
6. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 2a R 2b R 2c V- is
wherein x is selected from 1, 2, 3, and 4.
7. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 2a R 2b R 2c V- is of any one of the formulae:
wherein:
n is 1, 2, or 3; and
v is selected from 2, 3, 4, 5, 6, 7, and 8.
8. A compound of the formula:
No.
Formula
8
11
12
13
14
15
16
17
18
19
20
22
23
24
25
26
27
30
31
32
33
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
83
91
95
98
100
104
163
166
167
169
170
171
179
180
182
183
188
189
191
192
198
204
208
211
214
221
225
or
239
;
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
9. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof and a pharmaceutical carrier, diluent, or excipient.
10. A kit containing one or more compounds of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
11. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is
12. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is
wherein each Y is independently selected from CRY and N; and j is 0.
13. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is
wherein each Y is independently selected from CRY and N; and j is selected from 0 and 1.
14. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is
wherein k is selected from 0, 1, 2, and 3.
15. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is
wherein each Z is independently selected from CR y R y , O, NR y , and S; and m is selected from 0, 1, and 2.
16. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 2a R 2b R 2c V- is of the formula:
wherein:
o and o′ are each independently selected from 0, 1, and 2; and
q is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8.
17. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:
each RX is independently selected from hydrogen, (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 form ═O.
18. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein taken together two RX 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 each independently substituted with one or more R z .
19. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein taken together two RX form an aromatic ring or heteroaromatic ring, wherein said aromatic ring and heteroaromatic ring are each independently substituted with one or more R z .
20. The compound of claim 8 , or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
22. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein t is 0, and U is a single bond.
24. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein J′ is NH 2 .
25. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein each X is hydrogen.
26. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 2a R 2b R 2c V- is of the formula:
27. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 2a R 2b R 2c V- is of the formula:
28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition comprising an effective amount of a compound of claim 8 or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof and a pharmaceutical carrier, diluent, or excipient.
30. A kit containing a compound of claim 8 or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
31. The compound of claim 17 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein J is O.
32. The compound of claim 17 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein J is C.
33. The compound of claim 18 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein J is 0.
34. The compound of claim 18 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein J is C.
35. The compound of claim 19 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein J is 0.
36. The compound of claim 19 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein J is C.
37. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is phenyl substituted with one or more R.
38. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 2a R 2b R 2c V- is of the formula:
wherein:
V is CH;
each 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 ; and
b is 0.