Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
This invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those benzodiazepine derivatives and methods of using those derivatives or compositions in treating cognitive impairment associated with central nervous system (CNS) disorders. In particular, it relates to the use of a α5-containing GABA A receptor agonist (e.g., a α5-containing GABA A receptor positive allosteric modulator) as described herein in treating cognitive impairment associated with central nervous system (CNS) disorders in a subject in need or at risk thereof, including, without limitation, subjects having or at risk for age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI (aMCI), Age-Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD), dementia, Alzheimer's Disease (AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction.
1. A compound of formula IV:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer, or combination thereof, wherein:
wherein R 2 is —OR 8 ,
—SR 8 , —(CH 2 ) n OR 8 , —(CH 2 ) n O(CH 2 ) n R 8 , and —(CH 2 ) n N(R″)R 10 ; and wherein R 2 is independently substituted with 0-5 R′;
m and n are independently integers selected from 0-4;
each occurrence of R 1 , R 2 , R 4 , and R 5 are each independently selected from:
halogen, —R, —OR, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 , —SiR 3 , —N(R) 2 , —SR, —SOR, —SO 2 R, —SO 2 N(R) 2 , —SO 3 R, —(CR 2 ) 1-3 R, —(CR 2 ) 1-3 —OR, —(CR 2 ) 0-3 —C(O)NR(CR 2 ) 0-3 R, —(CR 2 ) 0-3 —C(O)NR(CR 2 ) 0-3 OR, —C(O)R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)R, —C(S)OR, —C(O)OR, —C(O)C(O)OR, —C(O)C(O)N(R) 2 , —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —C(S)N(R) 2 , —(CR 2 ) 0-3 NHC(O)R, —N(R)N(R)COR, —N(R)N(R)C(O)OR, —N(R)N(R)CON(R) 2 , —N(R)SO 2 R, —N(R)SO 2 N(R) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(S)R, —N(R)C(O)N(R) 2 , —N(R)C(S)N(R) 2 , —N(COR)COR, —N(OR)R, —C(═NH)N(R) 2 , —C(O)N(OR)R, —C(═NOR)R, —OP(O)(OR) 2 , —P(O)(R) 2 , —P(O)(OR) 2 , and —P(O)(H)(OR);
R 3 is absent or is selected from:
halogen, —R, —OR, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 , —SiR 3 , —N(R) 2 , —SR, —SOR, —SO 2 R, —SO 2 N(R) 2 , —SO 3 R, —(CR 2 ) 1-3 R, —(CR 2 ) 1-3 —OR, —(CR 2 ) 0-3 —C(O)NR(CR 2 ) 0-3 R, —(CR 2 ) 0-3 —C(O)NR(CR 2 ) 0-3 OR, —C(O)R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)R, —C(S)OR, —C(O)OR, —C(O)C(O)OR, —C(O)C(O)N(R) 2 , —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —C(S)N(R) 2 , —(CR 2 ) 0-3 NHC(O)R, —N(R)N(R)COR, —N(R)N(R)C(O)OR, —N(R)N(R)CON(R) 2 , —N(R)SO 2 R, —N(R)SO 2 N(R) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(S)R, —N(R)C(O)N(R) 2 , —N(R)C(S)N(R) 2 , —N(COR)COR, —N(OR)R, —C(═NH)N(R) 2 , —C(O)N(OR)R, —C(═NOR)R, —OP(O)(OR) 2 , —P(O)(R) 2 , —P(O)(OR) 2 , and —P(O)(H)(OR);
R 6 is —H or —(C1-C6)alkyl;
R 8 is —(C1-C6)alkyl, —(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R 8 is independently substituted with 0-5 R′;
R 10 is —(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R 10 is independently substituted with 0-5 R′;
each R is independently selected from:
H—,
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl-,
(C3-C10)-cycloalkenyl-,
[(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-,
[(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic-,
[(C3-C10)-cycloalkyl]-O—(C1-C12)-aliphatic-,
[(C3-C10)-cycloalkenyl]-O—(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C6-C10)-aryl-O—(C1-C12)aliphatic-,
(C6-C10)-aryl-N(R″)—(C1-C12)aliphatic-,
3- to 10-membered heterocyclyl-,
(3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,
(3- to 10-membered heterocyclyl)-O—(C1-C12)aliphatic-,
(3- to 10-membered heterocyclyl)-N(R″)—(C1-C12)aliphatic-,
5- to 10-membered heteroaryl-,
(5- to 10-membered heteroaryl)-O—(C1-C12)-aliphatic- and
(5- to 10-membered heteroaryl)-N(R″)—(C1-C12)-aliphatic-;
wherein said heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , and said heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, and S;
wherein each occurrence of R is independently substituted with 0-5 R′;
or when two R groups bound to the same atom, the two R groups may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally substituted with 0-5 R′, and wherein said ring is optionally fused to a (C6-C10)aryl, 5- to 10-membered heteroaryl, (C3-C10)cycloalkyl, or a 3- to 10-membered heterocyclyl;
wherein each occurrence of R′ is independently selected from halogen, —R″, —OR″, oxo, —CH 2 OR″, —CH 2 NR″ 2 , —C(O)N(R″) 2 , —C(O)OR″, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 and —N(R″) 2 ;
wherein each occurrence of R″ is independently selected from H, —(C1-C6)-alkyl, —(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O—(C1-C6)-alkyl-, and (C6-C10)-aryl-O—(C1-C6)-alkyl-, wherein each occurrence of R″ is independently substituted with 0-3 substituents selected from: halogen, —R o , —OR o , oxo, —CH 2 OR o , —CH 2 N(R o ) 2 , —C(O)N(R o ) 2 , —C(O)OR o , —NO 2 , —NCS, —CN,
—CF 3 , —OCF 3 and —N(R o ) 2 , wherein each occurrence of R o is independently selected from: —(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl-.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer, or combination thereof, wherein:
m is 0-3;
each R 1 is independently selected from: halogen, —H, —(C1-C6)alkyl, —C≡CH, —OH, —O((C1-C6)alkyl), —NO 2 , —CN, —CF 3 , —OCF 3 , wherein R 1 is independently substituted with 0-5 R′;
R 2 is selected from —OR 8 , —SR 8 , —(CH 2 ) n OR 8 , —(CH 2 ) n O(CH 2 ) n R 8 and
—(CH 2 ) n N(R″)R 10 , wherein n is an integer selected from 0-4; p is an integer selected from 2-4; each R 8 is independently —(C1-C6)alkyl, —(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R 8 is independently substituted with 0-5 R′; each R 10 is independently —(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R 10 is independently substituted with 0-5 R′; and wherein R 2 is independently substituted with 0-5 R′;
R 3 is selected from:
—H, —CN, halogen, —(C1-C6)alkyl, —C≡CH, —SO 2 ((C1-C6)alkyl), —C(O)N((C1-C6)alkyl) 2 , —C(O)NH((C1-C6)aliphatic) 2 , (C6-C10)-aryl-(C1-C12)aliphatic-, —C(O)((C1-C6)alkyl), —C(O)O((C1-C6)alkyl), 5- or 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; and wherein R 3 is independently substituted with 0-5 R′;
R 4 and R 5 are each independently selected from —H, halogen and —(C1-C6)alkyl;
R 6 is selected from —H and —(C1-C6)alkyl;
wherein each occurrence of R′ is independently selected from halogen, —R″, —OR″, oxo, —CH 2 OR″, —CH 2 NR″ 2 , —C(O)N(R″) 2 , —C(O)OR″, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 and —N(R″) 2 ;
wherein each occurrence of R″ is independently selected from H, —(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O—(C1-C6)-alkyl-, and (C6-C10)-aryl-O—(C1-C6)-alkyl-.
3. The compound of claim 1 , wherein the compound is selected from the group consisting of:
Cmp
No.
Structure
183
184
185
186
187
188
189
190
191
192
193
196
197
198
199
200
201
202
203
204
205
206
215
216
217
232
233
234
235
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237
238
239
240
241
242
243
244
245
246
249
254
255
256
259
260
261
263
264
265
266
267
268
270
271
274
275
276
278
280
281
282
283
284
285
286
287
288
293
294
295
296
297
301
302
303
304
305
306
307
308
309
310
311
312
313
or a pharmaceutically acceptable salt, tautomer, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer, or combination thereof.
4. The compound of claim 1 , wherein the compound is selected from the group consisting of:
Com-
pound
Structure
183
184
185
186
187
188
189
190
191
192
193
196
197
198
199
200
201
202
203
204
205
206
or a pharmaceutically acceptable salt, tautomer, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer, or combination thereof.
5. A pharmaceutical composition comprising a compound according to any one of claims 1 , or 2 - 4 , or a pharmaceutically acceptable salt, tautomer, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer, or combination thereof, in a therapeutically effective amount; and an acceptable carrier, adjuvant or vehicle.
6. The pharmaceutical composition according to claim 5 , wherein said composition further comprises a second therapeutic agent.
7. The pharmaceutical composition according to claim 6 , wherein the second therapeutic agent is selected from an antipsychotic, memantine and an acetylcholine esterase inhibitor (AChE-I).
8. The pharmaceutical composition according to claim 6 , wherein the second therapeutic agent is an antipsychotic selected from aripiprazole, olanzapine and ziprasidone, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphs thereof.
9. The pharmaceutical composition according to claim 6 , wherein the second therapeutic agent is memantine, a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
10. The pharmaceutical composition according to claim 6 , wherein the second therapeutic agent is an AChE-I selected from Donepezil, Galantamine, and Rivastigmine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.