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 a5-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, isomer, or combination thereof, wherein:
R 2 is —OR 8 , —SR 8 , —(CH 2 ) n OR 8 , —(CH 2 ) n O(CH 2 ) n R 8 or —(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 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 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);
each R 6 is independently —H or —(C1-C6)alkyl;
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′;
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 are 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, (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-.
2. The compound according to claim 1 , wherein R 2 is OR 8 .
3. The compound according to claim 1 , wherein R 2 is —(CH 2 ) n OR 8 or —(CH 2 ) n O(CH 2 ) n R 8 .
4. The compound according to claim 2 , wherein R 8 is (C6-C10)-aryl, substituted with 0-5 R′.
5. The compound according to claim 3 , wherein R 8 is —(C1-C6)alkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R 8 is independently substituted with 0-5 R′.
6. The compound according to claim 1 , wherein each occurrence of R 1 is selected from: halogen, —R, —OR, —NO 2 , —CN, —CF 3 , —OCF 3 , —N(R) 2 , and —N(R)SO 2 R, wherein each occurrence of R is independently substituted with 0-5 R′.
7. The compound according to claim 6 , wherein each occurrence of R is independently selected from: halogen, —H, —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —NO 2 , —CN, —CF 3 , —OCF 3 , —NH 2 , —N((C1-C6)alkyl) 2 , —N((C1-C6)alkyl)SO 2 ((C1-C6)alkyl), and NHSO 2 ((C1-C6)alkyl), wherein said alkyl is independently substituted with 0-5 R′.
8. The compound according to claim 7 , wherein each occurrence of R 1 is independently selected from: —H, —F, —Cl, —Br, —OH, -Me, -Et, —OMe, —OEt, —NO 2 , —CN, —CF 3 , —OCF 3 , —NH 2 , —NMe 2 , —NEt 2 , —NHSO 2 Me, and —NHSO 2 Et.
9. The compound according to claim 6 , wherein at least one R 1 is —OR.
10. The compound according to claim 9 , wherein the at least one R 1 is —O((C1-C6)alkyl).
11. The compound according to claim 10 , wherein the at least one R 1 is —OMe.
12. The compound according to claim 1 , wherein R 3 is selected from: halogen, —R, —CN, —CF 3 , —SO 2 R, —C(O)N(R) 2 , —C(O)R and —C(O)OR, wherein each occurrence of R is independently substituted with 0-5 R′.
13. The compound according to claim 12 , wherein R 3 is selected from: —H, —F, —Br, —Cl, —(C1-C6)alkyl, —CN, —C≡CH, —CF 3 , —SO 2 ((C1-C6)alkyl), —C(O)N((C1-C6)alkyl) 2 , —C(O)NH 2 , —C(O)((C1-C6)alkyl), —SO 2 ((C6-C10)-aryl) —C(O)O((C1-C6)alkyl), —(C2-C6)-alkenyl, —(C2-C6)-alkynyl, —(C6-C10)-aryl, 5- to 10-membered heteroaryl-, and 3- to 10-membered heterocyclyl-, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl is independently substituted with 0-5 R′.
14. The compound according to claim 13 , wherein R 3 is selected from: —H, —C(O)OMe, —C(O)Et, —C(O)NMe 2 , —C(O)NH 2 , —C(O)OEt, —C(O)OCH 2 (tert-butyl), —C(O)OCH 2 CF 3 , —C(O)O(isopropyl), —C(O)NEt 2 , —CN, —SO 2 Me, —SO 2 Et, —SO 2 Ph(Me), —CF 3 , —CHF 2 , -Me, -Et, —Br, —Cl, —CH 2 Ph,
wherein R′ is selected from —H, -Me, -Et, —CF 3 , isopropyl, —OMe, —OEt, —O-isopropyl, —CH 2 NMe 2 , -tert-butyl and cyclopropyl.
15. The compound according to claim 14 , wherein R 3 is —C(O)OMe or —C(O)OEt.
16. The compound according to claim 14 , wherein R 3 is:
wherein R′ is selected from —H, -Me, -Et, —CF 3 , isopropyl, —OMe, —OEt, —O-isopropyl, —CH 2 NMe 2 , -tert-butyl and cyclopropyl.
17. The compound according to claim 1 , wherein R 4 and R 5 are each independently halogen or —R, wherein each occurrence of R is independently substituted with 0-5 R′, or
R 4 and R 5 may be taken together with the carbon atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-3 additional heteroatoms independently selected from N, O, S, SO, and SO 2 , wherein said ring is substituted with 0-5 R′.
18. The compound according to claim 17 , wherein R 4 and R 5 are each independently selected from —H, -Me, -Et, —F, or R 4 and R 5 are taken together with the carbon atom to which they are bound to form a 3- to 8-membered non-aromatic ring.
19. The compound according to claim 18 , wherein both R 4 and R 5 are —H.
20. The compound according to claim 1 , or a pharmaceutically acceptable salt, isomer, or combination thereof, wherein:
m is 0-3;
when m is 1 or 2, at least one occurrence of R 1 is -halogen or —O((C1-C6)alkyl);
each R 1 is independently selected from: halogen, —H, —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —NO 2 , —CN, —CF 3 , and —OCF 3 , wherein the (C1-C6)alkyl and —O((C1-C6)alkyl) are 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; 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, —SO 2 ((C1-C6)alkyl, —C(O)N((C1-C6)alkyl) 2 , —C(O)((C1-C6)alkyl), —C(O)O((C1-C6)alkyl),
wherein R′ is selected from -Me, -Et, isopropyl, —CF 3 , —OMe, —OEt, —O-isopropyl, —CH 2 NMe 2 , and cyclopropyl; wherein, with the exception of —H, —CN, and halogen, 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; and
R 6 is selected from —H and —(C1-C6)alkyl.
21. A compound selected from:
Com-
pound
Structure
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or a pharmaceutically acceptable salt, isomer, or combination thereof.
22. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, isomer, or combination thereof, in a therapeutically effective amount; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
23. The pharmaceutical composition according to claim 22 , wherein said composition further comprises a second agent selected from the group consisting of:
a) an antipsychotic, selected from aripiprazole, olanzapine, and ziprasidone, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof;
b) memantine or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and
c) an acetylcholine esterase inhibitor (AChE-I) selected from:
i) Donepezil, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof; and
ii) Galantamine and Rivastigmine, or a pharmaceutically acceptable salt thereof.
24. A method of treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising the step of administering a pharmaceutical composition according to claim 22 or 23 or a compound according to claim 1 or a pharmaceutically acceptable salt, isomer or combination thereof.
25. The method of claim 24 , wherein the CNS disorder is age-related cognitive impairment.
26. The method of claim 24 , wherein the CNS disorder is Mild Cognitive Impairment (MCI).
27. The method of claim 26 , wherein the Mild Cognitive Impairment is amnestic Mild Cognitive Impairment (aMCI).
28. The method of claim 24 , wherein the CNS disorder is dementia.
29. The method of claim 24 , wherein the CNS disorder is Alzheimer's disease.
30. The method of claim 24 , wherein the CNS disorder is schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder (PTSD), mental retardation, Parkinson's disease (PD), autism, compulsive behavior, substance addiction, or a disorder associated with cancer therapy.