IP Library › Patent Application 15847906

Patent Application

App. No. 15/847,906

BENZODIAZEPINE DERIVATIVES, COMPOSITIONS, AND METHODS FOR TREATING COGNITIVE IMPAIRMENT

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App. No.: 15/847,906

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Abstract

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.

Claims (553)

1 . A compound of formula I:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:

U and the two carbon atoms designated by α and β together form a 5- or 6-membered aromatic ring having 0-2 nitrogen atoms;

A is C, CR 6 , or N;

B and F are each independently selected from C, CR 6 , and N, wherein B and F cannot both be N;

D is N, NR 7 , O, CR 6 or C(R 6 ) 2 ;

E is N, NR 7 , CR 6 or C(R 6 ) 2 ;

W is N, NR 7 , CR 6 or C(R 6 ) 2 ;

X is N, NR 7 , O, CR 6 or C(R 6 ) 2 ;

Y and Z are each independently selected from C, CR 6 , and N, wherein Y and Z cannot both be N;

V is C or CR 6 ,

or when Z is C or CR 6 , V is C, CR 6 , or N;

wherein when the ring formed by X, Y, Z, V and W is then R 2 is —OR 8 , —SR 8 , —(CH 2 ) n OR 8 , —(CH 2 ) n O(CH 2 ) n R 8 , —(CH 2 ) p 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;

p is an integer selected from 2-4;

each occurrence of the bond “ ” is either a single bond or a double bond;

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, —(O)C(O)OR, —(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:

each R 6 is independently —H or —(C1-C6)alkyl;

each R 7 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)-(C1-C12)-aliphatic-,

(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, 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-.

2 . A compound of formula II:

m is 0-3;

each R 1 is independently selected from: —Cl, —F, —OMe, and —C ≡CH;

R 2 is halogen, —(CR 2 ) 1-3 OR, or —(CR 2 ) 1-3 —O(CR 2 ) 1-3 —R, wherein each occurrence of R is independently selected from —H, —(C1-C6)alkyl, (C6-C10)-aryl-, or 5- to 10-membered heteroaryl- and (C6-C10)-aryl-(C1-C12)aliphatic-, and wherein each occurrence of R is independently substituted with 0-5 R′;

R 3 is selected from: CN, —C≡CH, —C≡C—(C1-C6)alkyl, —C≡C-phenyl, —COOMe, —COOEt, —(C1-C6)alkyl,

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 —NR 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-, or (C6-C10)-aryl-O—(C1-C6)-alkyl-, wherein each occurrence of R″ is independently substituted with 0-5 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-.

3 . A compound of formula IV:

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:

Compound

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or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

5 . A pharmaceutical composition comprising a compound according to any one of claims 1 - 4 , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, 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, and the pharmaceutically acceptable salts, hydrates, solvates, and 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, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

11 . 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 compound according to any one of claims 1 - 4 or a pharmaceutical composition according to any one of claims 5 - 10 .

12 . The method of claim 11 , wherein the CNS disorder is age-related cognitive impairment.

13 . The method of claim 12 , wherein the age-related cognitive impairment is Mild Cognitive Impairment (MCI).

14 . The method of claim 13 , wherein the Mild Cognitive Impairment is amnestic Mild Cognitive Impairment (AMCI).

15 . The method according to claim 11 , wherein the CNS disorder is dementia.

16 . The method of claim 15 , wherein the dementia is Alzheimer's disease.

17 . The method of claim 11 , wherein the CNS disorder is schizophrenia or bipolar disorder.

18 . The method of claim 11 , wherein the CNS disorder is amyotrophic lateral sclerosis (ALS).

19 . The method of claim 11 , wherein the CNS disorder is post traumatic stress disorder (PTSD).

20 . The method of claim 11 , wherein the CNS disorder is associated with cancer therapy.

21 . The method of claim 11 , wherein the CNS disorder is mental retardation.

22 . The method of claim 11 , wherein the CNS disorder is Parkinson's disease (PD).

23 . The method of claim 11 , wherein the CNS disorder is autism.

24 . The method of claim 11 , wherein the CNS disorder is compulsive behavior.

25 . The method of claim 11 , wherein the CNS disorder is substance addiction.

26 . A method of treating a brain cancer in a subject in need thereof, comprising the step of administering a compound according to any one of claims 1 - 4 or a pharmaceutical composition according to any one of claims 5 - 10 .

27 . A method of treating cognitive impairment associated with a brain cancer in a subject in need thereof, comprising the step of administering a compound according to any one of claims 1 - 4 or a pharmaceutical composition according to any one of claims 5 - 10 .

28 . The method of claim 26 or 27 , wherein the compound is selected from:

Compound

Structure

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or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

29 . The method of claim 26 or 27 , wherein said brain cancer is medulloblastoma.

30 . The method of claim 28 , wherein said brain cancer is medulloblastoma.

31 . A compound of formula V:

—SO 2 R, —SO 2 N(R) 2 , —SO 3 R, —(CR 2 ) 1-3 R, —(CR 2 ) 1-3 —OR, —(CR 2 ) 1-3 —R, (CR 2 ) 1-3 —R, —(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, —(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)R, —C(S)OR, —C(O)OR, —(O)C(O)OR, —(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 , —P(O)(H)(OR), C≡C—R 8 , CH 2 CF 3 , and CHF 3 ;

each occurrence of 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 3 is absent or is selected from:

wherein each of R 9 is selected from —H, —(C1-C6) alkyl, —(C6-C10) aryl, -5-10 membered heteroaryl, —(C1 -C6) alkyl-(C6-C10) aryl, —(C1-C6) alkyl-5-10 membered heteroaryl, —(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C3-C6) cycloalkyl, —C(O)—(C6-C10) aryl,

wherein each R 9 is independently substituted with 0-5 R 11 ;

wherein each occurrence of R 11 is independently selected from -halogen, —CF 3 , —OCF 3 , —Ome, —(C6-C10) aryl, —(C1-C6)alkyl, and -5 to 10 membered heteroaryl,

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 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 R7 is independently substituted with 0-5 R′;

each R 6 is independently —H or —(C1-C6)alkyl;

each R 7 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 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)-(C1-C12)-aliphatic-,

(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′;

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-.

32 . A compound of formula VI:

-halogen, —(C1-C6) alkyl, —CF 3 , —OCF 3 , or —O—(C1-C6) alkyl,

wherein R 9 is selected from —H, —(C1-C6) alkyl, —(C6-C10) aryl, -5-10 membered heteroaryl, —(C1 -C6) alkyl-(C6-C10) aryl, —(C1-C6) alkyl-5-10 membered heteroaryl, —(C3-C6) cycloalkyl, and —(C1-C6) alkyl-(C3-C6) cycloalkyl;

wherein each R 9 is independently substituted with 0-5 R 11 ;

wherein each occurrence of RH is independently selected from -halogen, —CF 3 , —OCF 3 , —OMe, —(C6-C10) aryl, —(C1-C6)alkyl, and -5 to 10 membered heteroaryl,

R 3 is selected from: -halogen, —CN, —C≡CR

wherein R 3 is substituted with 0-5 R′;

each occurrence of R 4 and R 5 is independently —H, —(C1-C6)alkyl, or —(C1-C6) alkyl-(C6-C10) aryl; the (C6-C10) aryl being independently substituted with 0-5 -halogen;

each R 6 is independently —H or —(C1-C6)alkyl;

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-, or (C6-C10)-aryl-O—(C1-C6)-alkyl-, wherein each occurrence of R″ is independently substituted with 0-5 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.

33 . A compound of 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 9 , —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 9 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 9 excluding —H and —(C1-C6) alkyl is independently substituted by 0-5 of -halogen, —(C1-C6) alkyl, —CF 3 , —OCF 3 , or 0—(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: -halogen, —CN, —C≡CR 9 , COOMe, —COOEt, —(C1-C6)alkyl-C≡C—-R 10 , —CH 2 —O—R 10 , —CH 2 —O—CH 2 —R 10

wherein each R 9 is independently substituted with 0-5 R 11 ;

wherein each R 10 is independently substituted with 0-5 R′;

wherein each occurrence of R″ is independently selected from -halogen, —CF 3 , —OCF 3 , —Ome, —(C6-C10) aryl, —(C1-C6)alkyl, and -5 to 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;

—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-.

34 . A compound of formula VIII:

wherein R 9 is selected from —H, —(C1-C6) alkyl, —(C6-C10) aryl, -5-10 membered heteroaryl, —(C1-C6) alkyl-(C6-C10) aryl, —(C1-C6) alkyl-5-10 membered heteroaryl, —(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 each occurrence of R 11 is independently selected from -halogen, —CF 3 , —OCF 3 , —Ome, —(C6-C10) aryl, —(C1-C6)alkyl, and -5 to 10 membered heteroaryl,

wherein each R 10 is independently substituted with 0-5 R′;

each occurrence of R 4 and R 5 is independently —H, —(C1-C6)alkyl, or —(C1-C6) alkyl-(C6-C10) aryl; the (C6-C10) aryl being independently substituted with 0-5 -halogen;

each R 6 is independently —H or —(C1-C6)alkyl.

35 . A compound of formula IX:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:

each R 1 is independently selected from: —Cl, —OMe, —CF 3 , and —OCF 3 ;

wherein each R 9 excluding —H and —(C1-C6) alkyl is independently substituted by 0-5 of -halogen, —(C1-C6) alkyl, —CF 3 , —OCF 3 , or 0—(C1-C6) alkyl;

R 2 is —H, CH 2 OR 8 , CH 3 , CH 2 -phenyl, 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;

R 3 is selected from: —C≡CR 9 , —(C1-C6)alkyl-C≡C—R 10 ,

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 Rim 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, —(C1-C6)alkyl, and -5 to 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)allcyl;

each R 6 is independently —H or —(C1-C6)alkyl.

36 . A compound selected from:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

37 . A pharmaceutical composition comprising a compound according to any one of claims 31 - 36 , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, in a therapeutically effective amount; and an acceptable carrier, adjuvant or vehicle.

38 . The pharmaceutical composition according to claim 37 , wherein said composition further comprises a second therapeutic agent.

39 . The pharmaceutical composition according to claim 38 , wherein the second therapeutic agent is selected from an antipsychotic, memantine and an acetylcholine esterase inhibitor (AChE-I).

40 . The pharmaceutical composition according to claim 38 , wherein the second therapeutic agent is an antipsychotic selected from aripiprazole, olanzapine and ziprasidone, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

41 . The pharmaceutical composition according to claim 38 , wherein the second therapeutic agent is memantine, a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

42 . The pharmaceutical composition according to claim 38 , wherein the second therapeutic agent is an AChE-I selected from Donepezil, Galantamine, and Rivastigmine, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

43 . 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 compound according to any one of claims 31 - 36 or a pharmaceutical composition according to any one of claims 37 - 42 .

44 . The method of claim 43 , wherein the CNS disorder is age-related cognitive impairment.

45 . The method of claim 44 , wherein the age-related cognitive impairment is Mild Cognitive Impairment (MCI).

46 . The method of claim 45 , wherein the Mild Cognitive Impairment is amnestic Mild Cognitive Impairment (AMCI).

47 . The method according to claim 43 , wherein the CNS disorder is dementia.

48 . The method of claim 47 , wherein the dementia is Alzheimer's disease.

49 . The method of claim 43 , wherein the CNS disorder is schizophrenia or bipolar disorder.

50 . The method of claim 43 , wherein the CNS disorder is amyotrophic lateral sclerosis (ALS).

51 . The method of claim 43 , wherein the CNS disorder is post traumatic stress disorder (PTSD).

52 . The method of claim 43 , wherein the CNS disorder is associated with cancer therapy.

53 . The method of claim 43 , wherein the CNS disorder is mental retardation.

54 . The method of claim 43 , wherein the CNS disorder is Parkinson's disease (PD).

55 . The method of claim 43 , wherein the CNS disorder is autism.

56 . The method of claim 43 , wherein the CNS disorder is compulsive behavior.

57 . The method of claim 43 , wherein the CNS disorder is substance addiction.

58 . A method of treating a brain cancer in a subject in need thereof, comprising the step of administering a compound according to any one of claims 31 - 36 , or a pharmaceutical composition according to any one of claims 37 - 42 .

59 . A method of treating cognitive impairment associated with a brain cancer in a subject in need thereof, comprising the step of administering a compound according to any one of claims 31 - 36 , or a pharmaceutical composition according to any one of claims 34 - 39 .

60 . The method of claim 58 or 59 , wherein the compound is selected from:

or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

61 . The method of claim 58 or 59 , wherein said brain cancer is medulloblastoma.

62 . The method of claim 60 , wherein said brain cancer is medulloblastoma.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 24, 2018

From: MEKONNEN, BELEW; BUTERA, JOHN A.; HUANG, JIANXING

To: HAGER BIOSCIENCES

Reel/Frame 044716/0197 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 24, 2018

From: HAGER BIOSCIENCES

To: AGENEBIO, INC.

Reel/Frame 044716/0206 →