# US 11,993,587 B2 · Substituted pyrazolo-pyrazines and their use as GluN2B receptor modulators

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- Number: US 11,993,587 B2
- Document ID: US11993587B2
- Status: Granted
- Kind: B2
- Application number: 17/618,068
- Filed: 2020-06-12
- Published: 2022-10-06
- Granted: 2024-05-28
- Earliest claimed: 2019-06-14
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: Curt Dvorak; Heather Coate
- Web page: https://patentgrep.com/patent/US11993587B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Substituted PYRAZOLO-PYRAZINES as GluN2B receptor ligands. Such compounds may be used in GluN2B receptor modulation and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by GluN2B receptor activity.

## Claims

### Claim 1

A compound having the structure of Formula (I):
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,
wherein
R1 is H;
Ar1 is phenyl substituted with one, two or three members each independently selected from the group consisting of: halo, C1-6alkyl, C1-6perhaloalkyl, OC1-6alkyl, and OC1-6perhaloalkyl;
R2 is selected from the group consisting of:
wherein Ra is selected from the group consisting of: H, halo, and C1-6alkyl;
wherein Rb is C1-6alkyl and Rc is C1-6alkyl.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein Ar1 is phenyl substituted with two members each independently selected from the group consisting of: Cl, F, CH3, CHF2, CF3, CHF2CH3, OCH3, and OCHF2.

### Claim 3 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein Ar1 is

### Claim 4 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein R2 is
wherein Ra is selected from the group consisting of: H, F, and CH3.

### Claim 5 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein R2 is

### Claim 6 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof, wherein R2 is

### Claim 7 (depends on 1)

The compound of claim 1 having the structure of Formula (IA):
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,
wherein
R1 is H;
Ar1 is phenyl substituted with two members each independently selected from the group consisting of: halo, C1-6alkyl, C1-6perhaloalkyl, and OC1-6perhaloalkyl; and
Ra is H, halo, or C1-6alkyl.

### Claim 8 (depends on 1)

The compound of claim 1 having the structure of Formula (IB):
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,
wherein
R1 is H; and
Ar1 is phenyl substituted with two members each independently selected from the group consisting of: halo, C1-6alkyl, C1-6perhaloalkyl, and OC1-6perhaloalkyl.

### Claim 9

A pharmaceutical composition comprising (A) a compound selected from the group consisting of:
1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]butan-2-one;
2-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-cyclopropyl-ethanone;
N, N-Dimethyl-2-[6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[3,4-b]pyrazin-1-yl]acetamide;
N,N-Dimethyl-2-[6-(m-tolyl)pyrazolo[3,4-b]pyrazin-1-yl]acetamide;
2-[6-(4-Chloro-3-fluoro-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-(3-Fluoro-4-methyl-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-(4-Chloro-3-methyl-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-(3-Chloro-4-methoxy-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-[4-Chloro-3-(difluoromethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-[3-(1, 1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-[4-Chloro-3-(1, 1-difluoroethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-[4-Chloro-3-(trifluoromethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-[4-(Difluoromethoxy)-3-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-[3-Chloro-4-(trifluoromethoxy)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-(3,5-Difluoro-4-methyl-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
2-[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
N, N-Dimethyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[3,4-b]pyrazin-1-yl]acetamide;
N, N-Dimethyl-2-[6-(2,3,4-trifluorophenyl)pyrazolo[3,4-b]pyrazin-1-yl]acetamide;
1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
1-(Azetidin-1-yl)-2-[6-[4-chloro-3-(1, 1-difluoroethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
1-(Azetidin-1-yl)-2-[6-[3-(1, 1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
1-(Azetidin-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
1-(Azetidin-1-yl)-2-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-methylazetidin-1-yl]ethanone;
2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-methylazetidin-1-yl)ethanone;
2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone;
2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone;
2-[6-[4-Chloro-3-(1, 1-difluoroethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-methylazetidin-1-yl)ethanone;
2-[6-[4-Chloro-3-(1, 1-difluoroethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone;
2-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-methylazetidin-1-yl)ethanone;
2-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone;
2-[6-[4-Chloro-3-(1, 1-difluoroethyl)phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-morpholino-ethanone;
2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;
2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;
5-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]methyl]-3-methyl-isoxazole;
6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[3,4-b]pyrazine;
1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazine;
6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[3,4-b]pyrazine;
5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]methyl]pyridine-3-carbonitrile;
5-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[3,4-b]pyrazin-1-yl]methyl]pyridine-3-carbonitrile; and
1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazine;
2-(6-(4-Chloro-2-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-N, N-dimethylacetamide;
N, N-Dimethyl-2-(6-(4-(trifluoromethoxy)phenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)acetamide;
2-(6-(2,5-Difluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-N, N-dimethylacetamide;
5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)oxazolidin-2-one;
6-(3-(Difluoromethoxy)-4-fluorophenyl)-1-((5-methoxypyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine;
2-(6-(4-(1, 1-Difluoroethyl)phenyl)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-N, N-dimethylacetamide;
and pharmaceutically acceptable salts thereof;
and (B) at least one pharmaceutically acceptable excipient.

### Claim 10

A pharmaceutical composition comprising (A) a compound selected from the group consisting of:
2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-N, N-dimethyl-acetamide;
1-(Azetidin-1-yl)-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]ethanone;
1-(Azetidin-1-yl)-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl)ethanone;
2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[3,4-b]pyrazin-1-yl]-1-(3-fluoroazetidin-1-yl)ethanone;
and pharmaceutically acceptable salts thereof;
and (B) at least one pharmaceutically acceptable excipient.

### Claim 11

A pharmaceutical composition comprising: (A) at least one compound selected from compounds of Formula (I):
and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof,
wherein
R1 is H;
Ar1 is phenyl substituted with one, two or three members each independently selected from the group consisting of: halo, C1-6alkyl, C1-6perhaloalkyl, OC1-6alkyl, and OC1-6perhaloalkyl; and
R2 is selected from the group consisting of:
wherein Ra is selected from the group consisting of: H, halo, and C1-6alkyl;
wherein Rb is C1-6alkyl and Rc is C1-6alkyl; and
(B) at least one pharmaceutically acceptable excipient.

### Claim 12

A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by GluN2B receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from compounds of Formula (I):
and pharmaceutically acceptable salts, solvates, stereoisomers, isotopic variants, and N-oxides thereof,
wherein
R1 is H;
Ar1 is phenyl substituted with one, two or three members each independently selected from the group consisting of: halo, C1-6alkyl, C1-6perhaloalkyl, OC1-6alkyl, and OC1-6perhaloalkyl; and
R2 is selected from the group consisting of:
wherein Ra is selected from the group consisting of: H, halo, and C1-6alkyl;
wherein Rb is C1-6alkyl and Rc is C1-6alkyl;
wherein the disorder, disease or medical condition mediated by GluN2B receptor activity is selected from the group consisting of: bipolar disorder, major depressive disorder, treatment-resistant depression, post-partum depression, seasonal affective disorder, Alzheimer's disease, Parkinson's disease, Huntington's chorea, multiple sclerosis, cognitive impairment, head injury, spinal cord injury, stroke, epilepsy, dyskinesias, amyotrophic lateral sclerosis, neurodegeneration associated with bacterial or chronic infections, pain, diabetic neuropathy, migraine, cerebral ischemia, schizophrenia, encephalitis, autism and autism spectrum disorders, memory and learning disorders, obsessive compulsive disorder, attention deficit hyperactivity disorder (ADHD) and an addictive illness.

### Claim 13 (depends on 12)

The method of claim 12, wherein the disorder, disease or medical condition is selected from the group consisting of treatment-resistant depression, major depressive disorder and bipolar disorder.

### Claim 14 (depends on 1)

A method of treating a subject suffering from or diagnosed with treatment-resistant depression, comprising administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 15 (depends on 1)

A method of treating a subject suffering from or diagnosed with major depressive disorder, comprising administering to the subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 16 (depends on 9)

A method of treating a subject suffering from or diagnosed with treatment-resistant depression, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 9.

### Claim 17 (depends on 9)

A method of treating a subject suffering from or diagnosed with major depressive disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 9.

### Claim 18 (depends on 10)

A method of treating a subject suffering from or diagnosed with treatment-resistant depression, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 10.

### Claim 19 (depends on 10)

A method of treating a subject suffering from or diagnosed with major depressive disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 10.