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:
J′ is selected from NH 2 , OH, and SH;
each X is independently selected from hydrogen, deuterium, methyl, CF 3 , and halogen;
R 5 is selected from 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; wherein said heterocyclic ring, cycloalkyl ring, cycloalkenyl ring, heteroaromatic ring, and aromatic ring are unsubstituted or substituted with one or more R y , and said alkenyl is substituted with one or more R T ;
R 2a R 2b R 2c V(CH 2 ) t U— is
b is selected from 0, 1, 2, and 3;
a is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
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 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 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 ;
each R y is independently selected from halogen, OR 6 , NH 2 , NHR 6 , NR 6 R 6 , OH, CF 3 , aromatic ring, C(O)R 6 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl, wherein 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; 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 J′ is NH 2 .
3. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein each X is hydrogen.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is of the formula:
wherein m is selected from 2, 3, and 4; or
wherein n is selected from 1, 2, 3, and 4.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is of the formula:
6. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is of the formula:
wherein each Y is independently selected from CH, CR y , and N; and j is 0 or 1; or
wherein each Z is independently selected from CH 2 , CHR y , CR y R y , O, NH, NR y , and S; and m is selected from 0, 1, and 2.
7. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is of the formula:
wherein k is selected from 0, 1, 2, or 3.
8. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is of the formula:
wherein each Y is independently selected from CH, CR y , and N; and j 0.
9. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is phenyl or 4-fluorophenyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is selected from 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 5 is selected from 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, oxazolyl, thiazolyl, and isoxazolyl.
12. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:
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 form ═O.
13. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein 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 .
14. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein 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 .
15. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 2a R 2b R 2c V(CH 2 ) t U— is of the formula:
wherein:
V is N;
T is CH, CR z , or N; and
b′ is 0.
16. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 2a R 2b R 2c V(CH 2 ) t U— is of the formula:
wherein b′ is 0, 1, 2, 3, or 4.
17. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein R 2a R 2b R 2c V(CH 2 ) t U— is of the formula:
wherein:
V is N; and
b′ is 0, 1, 2, or 3.
18. The compound of claim 1 , wherein the compound is of the formula:
No.
Formula
103
106
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
133
134
135
136
137
138
139
140
141
142
157
168
177
178
181
186
187
190
202
203
209
210
212
213
215
216
217
226
232
233
236
238
245
247
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
19. 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.
20. A kit containing one or more compounds of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.
21. The compound of claim 18 , or a hydrochloric acid salt thereof.
22. The compound of claim 1 , wherein the compound is of the formula:
No.
Formula
103
210
212
215
216
217
232
233
245
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.