# US 10,501,451 B2 · Selective NR2B antagonists

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- Number: US 10,501,451 B2
- Document ID: US10501451B2
- Status: Granted
- Kind: B2
- Application number: 15/767,385
- Filed: 2016-10-13
- Published: 2018-11-01
- Granted: 2019-12-10
- Earliest claimed: 2015-10-14
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Imadul Islam; Srinivasan Thangathirupathy; Jayakumar Sankara Warrier; Srinivas Cheruku; Poornima Shetty; John E. Macor
- Web page: https://patentgrep.com/patent/US10501451B2

## CPC

- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- A61K 31/4523: containing further heterocyclic ring systems
- A61K 31/497: containing further heterocyclic rings
- A61P 25/24: Antidepressants
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07B 2200/09: Geometrical isomers
- 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
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof. The Formula (I) compounds are ligands for NR2B N-Methyl-D-aspartate (NMD A) receptor and thereby making them useful for the treatment of various disorders of the central nervous system.

## Claims

### Claim 1

A compound of the formula I
where:
Ar1 is phenyl and is substituted with 0-3 substituent selected from cyano, halo, alkyl, haloalkyl and haloalkoxy;
Ar2 is phenyl, pyridinyl or pyrimidinyl, and is substituted with 1 OR substituent and with 0-2 halo or alkyl substituents;
R is hydrogen or a prodrug moiety selected from the group consisting of alkyl esters, amino acid esters, alkoxy esters, phosphonic acids, phosphonic alkyl esters, alkoxyphosphononate acid, alkoxyphosphonate alkyl esters, alkyl carabamates, amino acid carbamates, alkyl phosporamidates, aryl phosphoramidates, and sulfamates;
X is a bond or C1-C3 alkylene;
n is 1 or 2;
ring A is piperidine or piperazine and is substituted with 0-1 halo substituents;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound of claim 1 where Ar1 is phenyl and is substituted with 0-1 substituent selected from halo and alkyl; Ar2 is phenyl, pyridinyl or pyrimidinyl, and is substituted with 1 OR substituent and with 0-2 halo or alkyl substituents; R is hydrogen; X is a bond or C1-C3 alkylene; n is 1 or 2; ring A is piperidine or piperazine and is substituted with 0-1 halo substituents; or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

A compound of claim 2 where Ar1 is phenyl and is substituted with 0-1 substituent selected from halo and alkyl; Ar2 is phenyl or pyridinyl, and is substituted with 1 OR substituent and with 0-1 halo substituents; R is hydrogen; X is a methylene; n is 1 or 2; ring A is piperidine or piperazine and is substituted with 0-1 halo substituents; or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

A compound of claim 1 where n is 1 and ring A is piperazine or piperidine substituted with 0-1 fluoro.

### Claim 5 (depends on 1)

A compound of claim 1 where Ar1 is phenyl substituted with 0-1 substituents selected from chloro, fluoro and methyl.

### Claim 6 (depends on 1)

A compound of claim 1 where Ar2 is selected from

### Claim 7 (depends on 1)

A compound of claim 1 where X is methylene.

### Claim 8 (depends on 1)

A compound of claim 1 selected from the group consisting of
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 1)

A method for the treatment of depression, Alzheimer's disease, neuropathic pain, or Parkinson's disease, which comprises administering to a patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

The method of claim 10 directed to the treatment of depression.

### Claim 12 (depends on 10)

The method of claim 10 directed to the treatment of Alzheimer's disease.

### Claim 13 (depends on 10)

The method of claim 10 directed to the treatment of neuropathic pain.

### Claim 14

A compound:
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

A pharmaceutical composition comprising a compound of claim 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 14)

A method for the treatment of depression, Alzheimer's disease, neuropathic pain, or Parkinson's disease, which comprises administering to a patient a therapeutically effective amount of a compound of claim 14.

### Claim 17

A compound:
or a pharmaceutically acceptable salt thereof

### Claim 18 (depends on 17)

A pharmaceutical composition comprising a compound of claim 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 17)

A method for the treatment of depression, Alzheimer's disease, neuropathic pain, or Parkinson's disease, which comprises administering to a patient a therapeutically effective amount of a compound of claim 17.