# US 2017/0253603 A2 · Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment

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- Number: US 2017/0253603 A2
- Document ID: US20170253603A2
- Status: Published application
- Kind: A2
- Application number: 15/104,494
- Filed: 2014-12-19
- Published: 2017-09-07
- Earliest claimed: 2013-12-20
- Assignees: Agenebio, Inc.
- Inventors: Belew MEKONNEN; John A. BUTERA
- Web page: https://patentgrep.com/patent/US20170253603A2

## CPC

- C07D 487/14: Ortho-condensed systems
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 31/5517: condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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 GABAA receptor agonist (e.g., a α5-containing GABAA 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.

## Claims

### Claim 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, CR6, or N;
B and F are each independently selected from C, CR6, and N, wherein B and F cannot both be N;
D is selected from N, NR7, O, CR6 or C(R6)2;
E is N, NR7, CR6 or C(R6)2;
W is N, NR7, CR6 or C(R6)2;
X is N, NR7, O, CR6 or C(R6)2;
Y and Z are each independently selected from C, CR6, and N, wherein Y and Z cannot both be N;
V is C or CR6,
or when Z is C or CR6, V is C, CR6, or N;
wherein when the ring formed by X, Y, Z, V and W is
then R2 is —OR8, —SR8, —(CH2)nOR8, —(CH2)—O(CH2)nR8, —(CH2)pR8 and —(CH2)nN(R″)R10; and wherein R2 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 R1, R2, R4, and R5 are each independently selected from:
halogen, —R, —OR, —NO2, —NCS, —CN, —CF3, —OCF3, —SiR3, —N(R)2, —SR, —SOR, —SO2R, —SO2N(R)2, —SO3R, —(CR2)1-3R, —(CR2)1-3—OR, —(CR2)0-3—C(O)NR(CR2)0-3R, —(CR2)0-3—C(O)NR(CR2)0-3OR, —C(O)R, —C(O)C(O)R, —C(O)CH2C(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, —(CR2)0-3NHC(O)R, —N(R)N(R)COR, —N(R)N(R)C(O)OR, —N(R)N(R)CON(R)2, —N(R)SO2R, —N(R)SO2N(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);
R3 is absent or is selected from:
halogen, —R, —OR, —NO2, —NCS, —CN, —CF3, —OCF3, —SiR3, —N(R)2, —SR, —SOR, —SO2R, —SO2N(R)2, —SO3R, —(CR2)1-3R, —(CR2)1-3—OR, —(CR2)0-3—C(O)NR(CR2)0-3R, —(CR2)0-3—C(O)NR(CR2)0-3O R, —C(O)R, —C(O)C(O)R, —C(O)CH2C(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, —(CR2)0-3NHC(O)R, —N(R)N(R)COR, —N(R)N(R)C(O)OR, —N(R)N(R)CON(R)2, —N(R)SO2R, —N(R)SO2N(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 R6 is independently —H or —(C1-C6)alkyl;
each R7 is independently —H or —(C1-C6)alkyl;
each R8 is independently —(C1-C6)alkyl, —(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R8 is independently substituted with 0-5 R′;
each R10 is independently —(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R10 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 SO2, 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 SO2, 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, —CH2OR″, —CH2NR″2, —C(O)N(R″)2, —C(O)OR″, —NO2, —NCS, —CN, —CF3, —OCF3 and —NR2;
wherein each occurrence of R″ is independently selected from H, —(C1-C6)-alkyl, (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-.

### Claim 2

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 a and f3 together form a 5- or 6-membered aromatic ring having 0-2 nitrogen atoms;
A is C, CR6, or N;
B and F are each independently selected from C, CR6, and N, wherein B and F cannot both be N;
D is selected from N, NR7, O, CR6 or C(R6)2;
E is N, NR7, CR6 or C(R6)2;
W is N, NR7, CR6 or C(R6)2;
X is N, NR7, O, CR6 or C(R6)2;
Y and Z are each independently selected from C, CR6, and N, wherein Y and Z cannot both be N;
V is C or CR6,
or when Z is C or CR6, V is C, CR6, or N;
wherein when the ring formed by X, Y, Z, V and W is
then R2 is —OR8, —SR8, or —(CH2)nOR8;
m and n are independently integers selected from 0-4;
each occurrence of the bond “” is either a single bond or a double bond;
each occurrence of R1, R2, R4, and R5 are each independently selected from:
halogen, —R, —OR, —NO2, —NCS, —CN, —CF3, —OCF3, —SiR3, —N(R)2, —SR, —SOR, —SO2R, —SO2N(R)2, —SO3R, —(CR2)1-3R, —(CR2)1-3—OR, —(CR2)0-3—C(O)NR(CR2)0-3R, —(CR2)0-3—C(O)NR(CR2)0-3OR, —C(O)R, —C(O)C(O)R, —C(O)CH2C(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, —(CR2)0-3NHC(O)R, —N(R)N(R)COR, —N(R)N(R)C(O)OR, —N(R)N(R)CON(R)2, —N(R)SO2R, —N(R)SO2N(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);
R3 is absent or is selected from:
halogen, —R, —OR, —NO2, —NCS, —CN, —CF3, —OCF3, —SiR3, —N(R)2, —SR, —SOR, —SO2R, —SO2N(R)2, —SO3R, —(CR2)1-3R, —(CR2)1-3—OR, —(CR2)0-3—C(O)NR(CR2)0-3R, —(CR2)0-3—C(O)NR(CR2)0-3OR, —C(O)R, —C(O)C(O)R, —C(O)CH2C(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, —(CR2)0-3NHC(O)R, —N(R)N(R)COR, —N(R)N(R)C(O)OR, —N(R)N(R)CON(R)2, —N(R)SO2R, —N(R)SO2N(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 R6 is independently —H or —(C1-C6)alkyl;
each R7 is independently —H or —(C1-C6)alkyl;
each R8 is independently —(C1-C6)alkyl, —(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R8 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-,
3- to 10-membered heterocyclyl-,
(3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,
(3- to 10-membered heterocyclyl)-O—(C1-C12)aliphatic-,
5- to 10-membered heteroaryl-,
(5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, and
(5- to 10-membered heteroaryl)-O—(C1-C12)-aliphatic-;
wherein said heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, and SO2, 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 SO2, 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, —CH2OR″, —CH2NR″2, —C(O)N(R″)2, —C(O)OR″, —NO2, —NCS, —CN, —CF3, —OCF3 and —NR2;
wherein each occurrence of R″ is independently selected from H, —(C1-C6)-alkyl, (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-.

### Claim 3 (depends on 1, 2)

The compound according to claim 1 or 2, wherein U and the two carbon atoms designated by α and β together form a phenyl or pyridine ring.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein X, Y, Z, V and W together form a 5-membered aromatic or non-aromatic ring having 1-4 nitrogen atoms, wherein said ring is substituted with 0-3 R6 and 0-2 R7.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein X, Y, Z, V and W together form a 5-membered aromatic ring having 1-3 nitrogen atoms, wherein said ring is substituted with 0-2 R6 and 0-1 R7.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein X, Y, Z, V and W form a ring that is selected from:

### Claim 7 (depends on 5)

The compound according to claim 5, wherein X, Y, Z, V and W form a ring that is selected from:

### Claim 8 (depends on 1)

The compound according to claim 1, wherein W is N.

### Claim 9 (depends on 8)

The compound according to claim 8, wherein X, Y, Z, V and W form a ring that is selected from:

### Claim 10 (depends on 8)

The compound according to claim 8, wherein X, Y, Z, V and W form a ring that is selected from:

### Claim 11 (depends on 10)

The compound according to claim 10, wherein the ring formed by X, Y, Z, V and W is:

### Claim 12 (depends on 6)

The compound according to claim 6, wherein the ring formed by X, Y, Z, V and W is:

### Claim 13 (depends on 10)

The compound according to claim 10, wherein the ring formed by X, Y, Z, V and W is selected from:

### Claim 14 (depends on 10)

The compound according to claim 10, wherein the ring formed by X, Y, Z, V and W is selected from:

### Claim 15 (depends on 14)

The compound according to claim 14, wherein the ring formed by X, Y, Z, V and W is:

### Claim 16 (depends on 14)

The compound according to claim 14, wherein the ring formed by X, Y, Z, V and W is:

### Claim 17 (depends on 1)

The compound according to claim 1, wherein A, B, D, E and F together form a 5-membered aromatic or non-aromatic ring having 1-4 nitrogen atoms, wherein said ring is substituted with 0-3 R6 and 0-2 R7.

### Claim 18 (depends on 1)

The compound according to claim 1, wherein A, B, D, E and F together form a 5-membered aromatic ring having 1-3 nitrogen atoms, wherein said ring is substituted with 0-2 R6 and 0-1 R7.

### Claim 19 (depends on 18)

The compound according to claim 18, wherein A, B, D, E and F form a ring that is selected from:

### Claim 20 (depends on 19)

The compound according to claim 19, wherein the ring formed by A, B, D, F and E is:

### Claim 21 (depends on 1, 20)

The compound according to claim 20, wherein said compound has a structure of formula II:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein m, R1, R2, R3, R4, R5 and R6 are as defined in claim 1.

### Claim 22 (depends on 1, 20)

The compound according to claim 20, wherein said compound has a structure of formula III:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein m, R1, R2, R3, R4, R5 and R6 are as defined in claim 1.

### Claim 23 (depends on 1, 20)

The compound according to claim 20, wherein said compound has a structure of formula IV:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein R2 is —OR8, —SR8, or —(CH2)nOR8, wherein R2 is independently substituted with 0-5 R′ and wherein m, n, R′, R3, R4, R5, R6, and R8 are as defined in claim 1.

### Claim 24 (depends on 1, 20)

The compound according to claim 20, wherein said compound has a structure of formula IV:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein R2 is —(CH2)nO(CH2)nR8, —(CH2)pR8 or —(CH2)—N(R″)R10, wherein R2 is independently substituted with 0-5 R′ and wherein m, n, p, R′, R3, R4, R5, R6, R8, R10, and R″ are as defined in claim 1.

### Claim 25 (depends on 1)

The compound according to claim 1, wherein R2 is selected from: halogen, —R, —OR, —NO2, —(CR2)1-3R, —(CR2)1-3—OR, —CN, —CF3, —C(O)NR2, —C(O)OR, and —OCF3, wherein each occurrence of R is independently substituted with 0-5 R′.

### Claim 26 (depends on 25)

The compound according to claim 25, wherein R2 is selected from:
—H, —(C1-C6)alkyl, —CH2—O((C1-C6)alkyl), —(C((C1-C6)alkyl)2)1-3—O((C1-C6)alkyl), —OH, —O((C1-C6)alkyl), —NO2, —CN, —CF3, —OCF3, (C3-C10)-cycloalkyl-,
—C(O)N((C1-C6)alkyl)2, —C(O)O((C1-C6)alkyl), 3- to 10-membered heterocyclyl-,
(C6-C10)aryl-, 5- to 10-membered heteroaryl-,
(C6-C10)aryl-(C1-C12)aliphatic-,
(C6-C10)aryl-O—(C1-C12)aliphatic-,
(C6-C10)aryl-N(R″)—(C1-C12)aliphatic-(C6-C10)aryl-(C1-C12)aliphatic-O—,
(5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-,
(5- to 10-membered heteroaryl)-O—(C1-C12)-aliphatic-,
(5- to 10-membered heteroaryl)-N(R″)—(C1-C12)-aliphatic-,
(5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-O—,
(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-, and
(3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-O—, wherein said R2 is independently substituted with 0-5 R′.

### Claim 27 (depends on 26)

The compound according to claim 26, wherein R2 is selected from: —H, —Me, —Et, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CF3, —C(O)OMe, —C(O)OEt, —OMe, —CH2OMe, —CH2OEt, —CH2OPh, —CH2-pyrrolidine, —CH2-morpholine, —CH2-pyridine, —CH2Ph, wherein said R2 is substituted with 0-3 R′.

### Claim 28 (depends on 27)

The compound according to claim 27, wherein R2 is —Me substituted with 0-3 R′ independently selected from —R″, —OR″, oxo, —CH2OR″, —CH2NR″2, —C(O)N(R″)2, —C(O)OR″, —NO2, —NCS, —CN, —CF3, —OCF3 and —N(R″)2, wherein R″ is independently selected from H, —(C1-C6)-alkyl, (C6-C10)-aryl-, and (C6-C10)-aryl-(C1-C6)-alkyl-.

### Claim 29 (depends on 26)

The compound according to claim 26, wherein R2 is selected from: —CH2Ph, —CH2CH2Ph, -Ph, —OCH2Ph, —CH2OPh, —OCH2CH2Ph, —CH2CH2OPh, —CH2-pyrrolidine, —CH2-morpholine, —CH2-pyridine, and —CH2Ph, wherein said Ph, pyrrolidine, pyridine or morpholine is substituted with 0-5 R′.

### Claim 30 (depends on 29)

The compound according to claim 29, wherein said -Ph, pyrrolidine, pyridine or morpholine is substituted with 0-5 R′ independently selected from —F, —Cl, —CN, —Me, —Et, —OMe, and -OEt.

### Claim 31 (depends on 26)

The compound according to claim 26, wherein R2 is —Me, —C(O)OEt, —CH2Ph, —CH2OPh, —CH2-pyrrolidine, —CH2-pyridine or —CH2-morpholine wherein said -Ph, pyrrolidine, pyridine, or morpholine is substituted with 0-3 R′ independently selected from —F, —Me, and —OMe.

### Claim 32 (depends on 24)

The compound according to claim 24, wherein R2 is OR8, SR8, (CH2)nOR8, —(CH2)—O(CH2)nR8, —(CH2)pR8 or —(CH2)nN(R″)R10, wherein each R8 is independently —(C1-C6)alkyl, —(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R8 is independently substituted with 0-5 R′; n is an integer selected from 0-4; p is an integer selected from 2-4; and each R10 is independently —(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R10 is independently substituted with 0-5 R′.

### Claim 33 (depends on 32)

The compound according to claim 32, wherein R2 is OR8.

### Claim 34 (depends on 32)

The compound according to claim 32, wherein R2 is —(CH2)nOR8 or —(CH2)—O(CH2)nR8.

### Claim 35 (depends on 33)

The compound according to claim 33, wherein R8 is (C6-C10)-aryl, substituted with 0-5 R′.

### Claim 36 (depends on 34)

The compound according to claim 34, wherein R8 is —(C1-C6)alkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R8 is independently substituted with 0-5 R′.

### Claim 37 (depends on 1)

The compound according to claim 1, wherein each occurrence of R1 is selected from: halogen, —R, —OR, —NO2, —CN, —CF3, —OCF3, —N(R)2, —N(R)SO2R, wherein each occurrence of R is independently substituted with 0-5 R′.

### Claim 38 (depends on 37)

The compound according to claim 37, wherein each occurrence of R1 is independently selected from: halogen, —H, —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —NO2, —CN, —CF3, —OCF3, —NH2, —N((C1-C6)alkyl)2, —N((C1-C6)alkyl)SO2((C1-C6)alkyl), and NHSO2((C1-C6)alkyl), wherein said alkyl is independently substituted with 0-5 R′.

### Claim 39 (depends on 38)

The compound according to claim 38, wherein each occurrence of R1 is independently selected from: —H, —F, —Cl, —Br, —OH, —Me, —Et, —OMe, —OEt, —NO2, —CN, —CF3, —OCF3, —NH2, —NMe2, —NEt2, —NHSO2Me, and -NHSO2Et.

### Claim 40 (depends on 37)

The compound according to claim 37, wherein at least one R1 is —OR.

### Claim 41 (depends on 40)

The compound according to claim 40, wherein the at least one R1 is —O((C1-C6)alkyl).

### Claim 42 (depends on 41)

The compound according to claim 41, wherein the at least one R1 is —OMe.

### Claim 43 (depends on 1)

The compound according to claim 1, wherein R3 is selected from: halogen, —R, —CN, —CF3, —SO2R, —C(O)N(R)2, —C(O)R and —C(O)OR, wherein each occurrence of R is independently substituted with 0-5 R′.

### Claim 44 (depends on 43)

The compound according to claim 43, wherein R3 is selected from:
—H, —F, —Br, —Cl, —(C1-C6)alkyl, —CN, —CF3, —SO2((C1-C6)alkyl), —C(O)N((C1-C6)alkyl)2, —C(O)NH2, —C(O)((C1-C6)alkyl), —SO2((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′.

### Claim 45 (depends on 44)

The compound according to claim 44, wherein R3 is selected from:
—H, —C(O)OMe, —C(O)Et, —C(O)NMe2, —C(O)NH2, —C(O)OEt, —C(O)OCH2(tert-butyl), —C(O)OCH2CF3, —C(O)O(isopropyl), —C(O)NEt2, —CHF2, —CN, —SO2Me, —SO2Et, —SO2Ph(Me), —CF3, —CHF2, —Me, —Et, —Br, —Cl, —CH2Ph,
wherein R9 is selected from —H, —Me, —Et, —CF3, isopropyl, —OMe, —OEt, —O-isopropyl, —CH2NMe2, -tert-butyl and cyclopropyl.

### Claim 46 (depends on 45)

The compound according to claim 45, wherein R3 is —C(O)OMe or —C(O)OEt.

### Claim 47 (depends on 45)

The compound according to claim 45, wherein R3 is:
wherein R9 is selected from —H, —Me, —Et, —CF3, isopropyl, —OMe, —OEt, —O-isopropyl, —CH2NMe2, -tert-butyl and cyclopropyl.

### Claim 48 (depends on 1)

The compound according to claim 1, wherein R4 and R5 are each independently selected from —H, halogen and —R, wherein each occurrence of R is independently substituted with 0-5 R′, or
R4 and R5 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 SO2, wherein said ring is substituted with 0-5 R′.

### Claim 49 (depends on 48)

The compound according to claim 48, wherein R4 and R5 are each independently selected from —H, —Me, —Et, —F, or R4 and R5 are taken together with the carbon atom to which they are bound to form a 3- to 8-membered aliphatic ring.

### Claim 50 (depends on 49)

The compound according to claim 49, wherein both R4 and R5 are —H.

### Claim 51 (depends on 1)

The compound according to claim 1, wherein said compound has a structure of formula II:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:
m is 0-3;
each R1 is independently selected from: halogen, —H, —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —NO2, —CN, —CF3, —OCF3, wherein said alkyl is independently substituted with 0-5 R′;
R2 is selected from: —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —C(O)O((C1-C6)alkyl), (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O—(C1-C12)aliphatic-, (C6-C10)-aryl-(C1-C12)aliphatic-O—, (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, (5- to 10-membered heteroaryl)-O—(C1-C12)-aliphatic-, and (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-O—, wherein said alkyl, aryl or heteroaryl is independently substituted with 0-5 R′;
R3 is selected from: —(C1-C6)alkyl, —SO2((C1-C6)alkyl), —C(O)N((C1-C6)alkyl)2, and —C(O)O((C1-C6)alkyl), wherein said alkyl is independently substituted with 0-5 R′;
R4 and R5 are each independently selected from —H, halogen and —(CI1-C6)alkyl; and
R6 is selected from —H and —(C1-C6)alkyl.

### Claim 52 (depends on 51)

The compound according to claim 51, wherein:
m is 0, 1 or 2;
when m is 1 or 2, at least one occurrence of R1 is halogen or —O((C1-C6)alkyl);
R2 is selected from: —(C1-C6)alkyl, (C6-C10)-aryl-(C1-C12)aliphatic-, and (C6-C10)-aryl-O—(C1-C12)aliphatic-, wherein said aryl is independently substituted with 0-5 R′ independently selected from —F, —Me, and —OMe;
R3 is —C(O)O((C1-C6)alkyl);
R4 and R5 are both —H; and
R6 is —H.

### Claim 53 (depends on 1, 2)

The compound according to claim 1 or 2, wherein said compound has a structure of formula II:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:
m is 0-3;
each R1 is independently selected from: halogen, —H, —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —NO2, —CN, —CF3, —OCF3, wherein said R1 is independently substituted with 0-5 R′;
R2 is selected from:
—(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —C(O)O((C1-C6)alkyl),
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C6-C10)-aryl-O—(C1-C12)aliphatic-,
(C6-C10)-aryl-N(R″)—(C1-C12)aliphatic-,
(5- to 10-membered heteroaryl)-(C1-C12)aliphatic-,
(5- to 10-membered heteroaryl)-O—(C1-C12)aliphatic-,
(5- to 10-membered heteroaryl)-N(R″)—(C1-C12)aliphatic-,
(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-,
wherein R2 is independently substituted with 0-5 R′;
R3 is selected from:
—(C1-C6)alkyl, —CN, halogen, —SO2((C6-C10)-aryl), —SO2((C1-C6)alkyl), —C(O)N((C1-C6)alkyl)2, —C(O)NH2, —C(O)O((C1-C6)alkyl), —C(O)((C1-C6)alkyl),
—(C6-C10)aryl, 5- to 10-membered heteroaryl, wherein R3 is independently substituted with 0-5 R′;
R4 and R5 are each independently selected from —H, halogen and —(C1-C6)alkyl; and
R6 is selected from —H and —(C1-C6)alkyl.

### Claim 54

The compound according to 53, wherein:
m is 0, 1 or 2;
when m is 1 or 2, at least one occurrence of R1 is halogen or —O((C1-C6)alkyl);
R2 is selected from:
—(C1-C6)alkyl, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)aryl-O—(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-(C1-C12)aliphatic-, and (3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-, wherein R2 is independently substituted with 0-3 R′;
R3 is halogen, —CN, —C(O)NH2, —(C1-C6)alkyl, —C(O)((C1-C6)alkyl), —C(O)O((C1-C6)alkyl), —SO2(Ph(Me)),
wherein R3 is independently substituted with 0-3 R′, and wherein R9 is selected from —H, —Me, —Et, —CF3, isopropyl, —OMe, -tert-butyl and cyclopropyl;
R4 and R5 are both —H; and
R6 is —H.

### Claim 55

The compound according to 54, wherein R3 is:
wherein R9 is selected from —H, —Me, —Et, —CF3, isopropyl, —OMe, and -tert-butyl.

### Claim 56 (depends on 1, 2)

The compound according to claim 1 or 2, wherein said compound has a structure of formula III:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:
m is 0, 1, or 2, and when m is 1 or 2, at least one occurrence of R1 is —O((C1-C6)alkyl);
R2 is selected from: —(C1-C6)alkyl and (C6-C10)-aryl-(C1-C12)aliphatic-;
R3 is —C(O)O((C1-C6)alkyl);
R4 and R5 are both —H; and
R6 is —H.

### Claim 57 (depends on 1, 2)

The compound according to claim 1 or 2, wherein said compound has a structure of formula IV:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:
m is 0, 1, or 2, and when m is 1 or 2, at least one occurrence of R1 is —O((C1-C6)alkyl);
R2 is OR8, wherein R8 is (C6-C10)-aryl, substituted with 0-3 halogen;
R3 is —C(O)O((C1-C6)alkyl);
R4 and R5 are both —H; and
R6 is —H.

### Claim 58 (depends on 1, 2)

The compound according to claim 1 or 2, wherein said compound has a structure of formula IV:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:
m is 0-3;
when m is 1 or 2, at least one occurrence of R1 is -halogen or —O((C1-C6)alkyl);
each R1 is independently selected from: halogen, —H, —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —NO2, —CN, —CF3, —OCF3, wherein R1 is independently substituted with 0-5 R′;
R2 is selected from —OR8, —SR8, —(CH2)nOR8, —(CH2)—O(CH2)nR8, —(CH2)pR8 and —(CH2)nN(R″)R10, wherein n is an integer selected from 0-4; p is an integer selected from 2-4; each R8 is independently —(C1-C6)alkyl, —(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R8 is independently substituted with 0-5 R′; each R10 is independently —(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R10 is independently substituted with 0-5 R′; and wherein R2 is independently substituted with 0-5 R′;
R3 is selected from:
—H, —CN, halogen, —(C1-C6)alkyl, —SO2((C1-C6)alkyl), —C(O)N((C1-C6)alkyl)2, —C(O)((C1-C6)alkyl), —C(O)O((C1-C6)alkyl), and
wherein R9 is selected from —Me, —Et, isopropyl, —CF3, —OMe, —OEt, —O-isopropyl, —CH2NMe2, and cyclopropyl; wherein R3 is independently substituted with 0-5 R′;
R4 and R5 are each independently selected from —H, halogen and —(C1-C6)alkyl; and
R6 is selected from —H and —(C1-C6)alkyl.

### Claim 59 (depends on 58)

The compound according to claim 58, wherein:
m is 0, 1, or 2;
R2 is OR8, —(CH2)nOR8, —(CH2)—O(CH2)nR8, wherein n is 1, and wherein R8 is —(C1-C6)alkyl, (C6-C10)-aryl or 5- to 10-membered heteroaryl, wherein R8 is independently substituted with 0-3 R′;
R3 is halogen, —H, —CN, —(C1-C6)alkyl, —C(O)((C1-C6)alkyl), —C(O)O((C1-C6)alkyl),
wherein said alkyl is independently substituted with 0-3 R′; R9 is selected from —Me, —Et, isopropyl, and —CF3;
R4 and R5 are both —H; and
R6 is —H.

### Claim 60

A compound selected from:
Compound
Structure
1
2
3
4
5
6
7
8
9
10
11
12
44
45
46
47
48
49
50
51
52
53
54
55
56
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

### Claim 61 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, in a therapeutically effective amount; and an acceptable carrier, adjuvant or vehicle.

### Claim 62 (depends on 61)

The pharmaceutical composition according to claim 61, wherein said composition further comprises a second therapeutic agent.

### Claim 63 (depends on 62)

The pharmaceutical composition according to claim 62, wherein the second therapeutic agent is selected from an antipsychotic, memantine or an acetylcholine esterase inhibitor (AChE-I).

### Claim 64 (depends on 63)

The pharmaceutical composition according to claim 63, wherein the second therapeutic agent is an antipsychotic selected from aripiprazole, olanzapine and ziprasidone, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

### Claim 65 (depends on 63)

The pharmaceutical composition according to claim 63, wherein the second therapeutic agent is memantine, a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

### Claim 66 (depends on 63)

The pharmaceutical composition according to claim 63, 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.

### Claim 67 (depends on 61)

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 61.

### Claim 68 (depends on 67)

The method of claim 67, wherein the CNS disorder is age-related cognitive impairment.

### Claim 69

The method of embodiment 68, wherein the age-related cognitive impairment is Mild Cognitive Impairment (MCI).

### Claim 70

The method of embodiment 69, wherein the Mild Cognitive Impairment is amnestic Mild Cognitive Impairment (AMCI).

### Claim 71 (depends on 67)

The method according to claim 67, wherein the CNS disorder is dementia.

### Claim 72 (depends on 71)

The method of claim 71, wherein the dementia is Alzheimer's disease.

### Claim 73 (depends on 67)

The method of claim 67, wherein the CNS disorder is schizophrenia or bipolar disorder.

### Claim 74 (depends on 67)

The method of claim 67, wherein the CNS disorder is amyotrophic lateral sclerosis (ALS).

### Claim 75 (depends on 67)

The method of claim 67, wherein the CNS disorder is post traumatic stress disorder (PTSD).

### Claim 76 (depends on 67)

The method of claim 67, wherein the CNS disorder is associated with cancer therapy.

### Claim 77 (depends on 67)

The method of claim 67, wherein the CNS disorder is mental retardation.

### Claim 78 (depends on 67)

The method of claim 67, wherein the CNS disorder is Parkinson's disease (PD).

### Claim 79 (depends on 67)

The method of claim 67, wherein the CNS disorder is autism.

### Claim 80 (depends on 67)

The method of claim 67, wherein the CNS disorder is compulsive behavior.

### Claim 81 (depends on 67)

The method of claim 67, wherein the CNS disorder is substance addiction.