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. It also 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 brain cancers (including brain tumors, e.g., medulloblastomas), and cognitive impairment associated therewith.
1. A compound according to formula VII
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:
m is 0-3;
each R 1 is independently selected from: -halogen, —OMe, —C≡C—R 8 , —CN, —CHF 2 , —CH 2 CF 3 , —CF 3 , —OCF 3 , —(C1-C6) alkyl, —(C6-C10) aryl, —(C1-C6) alkyl-(C6-C10) aryl, -5-10 membered heteroaryl, —(C1-C6) alkyl-5-10 membered heteroaryl, and —(C3-C6) cycloalkyl;
wherein R 8 is —H, —(C1-C6) alkyl, —(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C6-C10) aryl, —(C6-C10) aryl, -5-10 membered heteroaryl, or —(C1-C6) alkyl-5-10 membered heteroaryl;
wherein each R 8 excluding —H and —(C1-C6) alkyl is independently substituted by 0-5 of -halogen, —(C1-C6) alkyl, —CF 3 , —OCF 3 , or —(C1-C6) alkyl;
R 2 is —(CH 2 ) n OR 8 , or —(CH 2 ) n O(CH 2 ) n R 8 , wherein each occurrence of R 8 is independently —H, —(C1-C6)alkyl, —(C6-C10)-aryl, 5- to 10-membered heteroaryl-, 5-10 membered heteroaryl-(C1-C6) alkyl-, —(C3-C6)cycloalkyl, —(C1-C6) alkyl-(C6-C10) aryl, or —(C1-C6) alkyl-(C3-C6) cycloalkyl;
wherein each R 8 excluding —H and —(C1-C6) alkyl is independently substituted by 0-5 of -halogen, —(C1-C6) alkyl, —CF 3 , —OCF 3 , or —O—(C1-C6) alkyl;
wherein n is an integer from 0-4;
wherein R 2 is independently substituted with 0-5 R′;
R 3 is selected from: —C≡CR 9 , —(C1-C6)alkyl-C≡C—R 10 , —CH 2 —O—R 10 , —CH 2 —O—CH 2 —R 10
wherein R 9 is selected from —H, —(C1-C6) alkyl, —(C6-C10) aryl, —(C1-C6) alkyl-(C6-C10) aryl, —(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C3-C6) cycloalkyl, and —C(O)—(C6-C10) aryl;
wherein each R 9 is independently substituted with 0-5 R 11 ;
wherein R 10 is selected from —H, —(C1-C6) alkyl, —(C6-C10) aryl, -5-10 membered heteroaryl, —(C3-C6) cycloalkyl, —CH 2 —(C3-C6) cycloalkyl, —CH 2 —(C6-C10) aryl, and —CH 2 -5-10-membered heteroaryl,
wherein each R 10 is independently substituted with 0-5 R′;
wherein each occurrence of R H is independently selected from -halogen, —CF 3 , —OCF 3 , —OMe, —(C6-C10) aryl, and —(C1-C6)alkyl,
wherein R 7 is selected from —(C1-C6)alkyl, —(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, —(C6-C10) aryl, —(C6-C10)aryl-(C1-C6)alkyl, and -5 to 10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl;
wherein each R 7 is independently substituted with 0-5 R′;
wherein R 3 is substituted with 0-5 R′;
each occurrence of R 4 and R 5 is independently —H or —(C1-C6)alkyl;
each R 6 is independently —H or —(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 , —OMe;
wherein each occurrence of R″ is independently selected from H, —(C1-C6)-alkyl, —(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (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 0-5 R t independently 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 according to claim 1 , wherein the compound has a structure according to formula IX:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:
m is 0-3;
each R 1 is independently selected from: —Cl, —OMe, —C≡C—R 8 , —CHF 2 , —CF 3 , and —OCF 3 ;
wherein R 8 is —H, —(C1-C6) alkyl, —(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C6-C10) aryl, —(C6-C10) aryl, -5-10 membered heteroaryl, or —(C1-C6) alkyl-5-10 membered heteroaryl;
wherein each R 8 excluding —H and —(C1-C6) alkyl is independently substituted by 0-5 of -halogen, —(C1-C6) alkyl, —CF 3 , —OCF 3 , or O—(C1-C6) alkyl;
R 2 is —CH 2 OR 8 , wherein each occurrence of R 8 is independently —H, —(C1-C6)alkyl, —(C6-C10)-aryl, 5- to 10-membered heteroaryl-, 5-10 membered heteroaryl-(C1-C6) alkyl-, —(C3-C6)cycloalkyl, —(C1-C6) alkyl-(C6-C10) aryl, or —(C1-C6) alkyl-(C3-C6) cycloalkyl;
wherein each R 8 excluding —H and —(C1-C6) alkyl is independently substituted by 0-5 of -halogen, —(C1-C6) alkyl, —CF 3 , —OCF 3 , or —O—(C1-C6) alkyl;
wherein R 2 is independently substituted with 0-5 R′,
R 3 is selected from: —C≡CR 9 , —(C1-C6)alkyl-C≡C—R 10 ,
wherein R 9 is selected from —H, —(C1-C6) alkyl, —(C6-C10) aryl, —(C1-C6) alkyl-(C6-C10) aryl, —(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C3-C6) cycloalkyl, and —C(O)—(C6-C10) aryl;
wherein each R 9 is independently substituted with 0-5 R 11 ;
wherein R 10 is selected from —H, —(C1-C6) alkyl, —(C6-C10) aryl, -5-10 membered heteroaryl, —(C3-C6) cycloalkyl, —CH 2 —(C3-C6) cycloalkyl, —CH 2 —(C6-C10) aryl, and —CH 2 -5-10-membered heteroaryl,
wherein each R 10 is independently substituted with 0-5 R′;
wherein each occurrence of R 11 is independently selected from -halogen, —CF 3 , —OCF 3 , —OMe, —(C6-C10) aryl, and —(C1-C6)alkyl,
wherein R 7 is selected from —(C1-C6)alkyl, —(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, —(C6-C10) aryl, —(C6-C10)aryl-(C1-C6)alkyl, and -5 to 10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl;
wherein each R 7 is independently substituted with 0-5 R′;
wherein R 3 is substituted with 0-5 R′;
each occurrence of R 4 and R 5 is independently —H or —(C1-C6)alkyl;
each R 6 is independently —H or —(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, —(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (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-;
wherein each said heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , and each said heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, and S.
3. A compound according to formula IV:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:
m is 0-3;
each R 1 is independently selected from: —Cl, —F, —OMe, and —C≡CH;
R 2 is —(CH 2 ) n OR 8 or —(CH 2 ) n O(CH 2 ) n R 8 , wherein each occurrence of R 8 is independently —(C1-C6)alkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl- and wherein R 2 is independently substituted with 0-5 R′;
wherein n is an integer from 0-4;
R 3 is selected from: —C≡CH,
wherein R 3 is substituted with 0-5 R′;
each occurrence of R 4 and R 5 is independently —H or —(C1-C6)alkyl;
each R 6 is independently —H or —(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, —(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 0-5 R o independently 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-.
4. A compound selected from:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
5. A compound selected from:
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or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 , 3 , 4 or 5 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, in a therapeutically effective amount; and an acceptable carrier, adjuvant or vehicle.
7. The pharmaceutical composition according to claim 6 , wherein said composition further comprises a second therapeutic agent.
8. The pharmaceutical composition according to claim 7 , wherein the second therapeutic agent is:
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; or
c) an acetylcholine esterase inhibitor (AChE-I) selected from Donepezil, Galantamine, and Rivastigmine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
9. A method of treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising administering a compound according to any one of claims 1 , 3 , 4 or 5 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
10. The method according to claim 9 , wherein the CNS disorder is:
a) age-related cognitive impairment, Mild Cognitive Impairment (MCI) or amnestic Mild Cognitive Impairment (aMCI); or
b) dementia, Alzheimer's disease, schizophrenia, bipolar disorder, Parkinson's disease (PD), or autism.
11. A method of treating a brain cancer in a subject in need thereof, comprising administering a compound according to claims 1 or 3 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
12. A method of treating cognitive impairment associated with a brain cancer in a subject in need thereof, comprising administering a compound according to claims 1 or 3 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
13. The method according to claim 11 , wherein said brain cancer is medulloblastoma.
14. A method of treating a brain cancer or cognitive impairment associated with a brain cancer in a subject in need thereof, optionally wherein said brain cancer is medulloblastoma, wherein the compound or the pharmaceutical composition comprising the compound is selected from:
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or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
15. A method of treating a brain cancer or cognitive impairment associated with a brain cancer in a subject in need thereof, optionally wherein said brain cancer is medulloblastoma, wherein the compound or the pharmaceutical composition comprising the compound is selected from:
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or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.
16. A method of treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising administering a pharmaceutical composition according to claim 6 .
17. The method according to claim 16 , wherein the CNS disorder is:
a) age-related cognitive impairment, Mild Cognitive Impairment (MCI) or amnestic Mild Cognitive Impairment (aMCI); or
b) dementia, Alzheimer's disease, schizophrenia, bipolar disorder, Parkinson's disease (PD), or autism.
18. A method of treating a brain cancer in a subject in need thereof, comprising administering a pharmaceutical composition according to claim 6 .
19. A method of treating cognitive impairment associated with a brain cancer in a subject in need thereof, comprising administering a or a pharmaceutical composition according to claim 6 .
20. The method according to claim 18 wherein said brain cancer is medulloblastoma.
21. The method according to claim 19 wherein said brain cancer is medulloblastoma.
22. The method according to claim 12 wherein said brain cancer is medulloblastoma.