# US 2019/0169137 A1 · Substituted triazoles and methods relating thereto

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- Number: US 2019/0169137 A1
- Document ID: US20190169137A1
- Status: Published application
- Kind: A1
- Application number: 16/173,025
- Filed: 2018-10-29
- Published: 2019-06-06
- Earliest claimed: 2015-01-30
- Assignees: Neurocrine Biosciences, Inc.
- Applicants: Neurocrine Biosciences, Inc.
- Inventors: Neil J. Ashweek; John P. Williams; Deborah Slee; Manisha Moorjani
- Web page: https://patentgrep.com/patent/US20190169137A1

## CPC

- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 39/02: Antidotes
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Substituted 1,2,3-triazole compounds are disclosed which have utility in the treatment of a variety of neurological disorders. The compounds provided herein have the general structure: wherein R1, R2, R3 and n are as defined herein, including stereoisomers, esters, solvates and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound provided herein in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for treating neurological disorders in a subject in need thereof.

## Claims

### Claim 1

A compound having the following structure (A):
or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof,
wherein:
R1 is H or C1-4alkyl;
R2 is C1-4alkyl, —C(═O)OR4, —C(═O)—C1-6alkanediyl-NH2, —C(═O)NR5R5, or —C(═O)R6, wherein said C1-6alkanediyl is optionally substituted with a group selected from —NH—C(═NH)NH2, —CO2H, —CO2CH3, —SH, —C(═O)NH2, —NH2, —SCH3, phenyl, —OH, —OC1-4alkyl, 4-hydroxy-phenyl, imidazolyl, cyclohexyl, and indolyl;
R3 at each occurrence is Cl, F, C1-4alkyl, —OC1-4alkyl or trifluoromethyl;
R4 at each occurrence is C1-4alkyl;
R5 at each occurrence is independently H or C1-4alkyl;
R6 is C1-4alkyl, 5-6 member nonaromatic heterocycle, or 5-6 member heterocycleC1-4alkyl wherein 5-6 member heterocycleC1-4alkyl is optionally substituted with OH, Cl, F, C1-4alkyl, —OC1-4alkyl or trifluoromethyl; and
n is 0-3.

### Claim 2 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein n is 1.

### Claim 3 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein n is 2.

### Claim 4 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R1 is H.

### Claim 5 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R1 is C1-4alkyl.

### Claim 6 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R2 is C1-4alkyl, —C(═O)OR4, —C(═O)NR5R5, or —C(═O)R6.

### Claim 7 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R2 is —C(═O)—C1-6alkanediyl-NH2, optionally substituted with a group selected from —NH—C(═NH)NH2, —CO2H, —CO2CH3, —SH, —C(═O)NH2, —NH2, —SCH3, phenyl, —OH, —OC1-4alkyl, 4-hydroxy-phenyl, cyclohexyl, imidazolyl, and indolyl.

### Claim 8 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R1 and R2 are both C1-4alkyl.

### Claim 9 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R3 is Cl, F, or trifluoromethyl.

### Claim 10 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R3 is C1-4alkyl or —OC1-4alkyl.

### Claim 11 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein n=1 or 2 and R3 is F.

### Claim 12 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R6 is C1-4alkyl.

### Claim 13 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R6 is a 5-6 member nonaromatic heterocycle.

### Claim 14 (depends on 1)

The compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein R6 is a 5-6 member heterocycleC1-4alkyl wherein 5-6 member heterocycleC1-4alkyl is optionally substituted with OH, Cl, F, C1-4alkyl, —OC1-4alkyl or trifluoromethyl.

### Claim at position 15

15-24. (canceled)

### Claim 25 (depends on 1)

The compound of claim 1, wherein the compound is one of the following compounds, or a solvate, or pharmaceutically acceptable salt thereof:
(2S)-2-amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-3-phenylpropanamide;
(2R)-2-amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-3-phenylpropanamide;
(3S)—N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}morpholine-3-carboxamide;
(3R)—N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}morpholine-3-carboxamide;
(2R)-2-amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-3-methoxypropanamide;
(2R)-2-amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-3-hydroxypropanamide;
N-[1-(2,6-difluoro-benzyl)-1H-[1,2,3 ]triazol-4-yl]-3-pyridin-3-yl-propionamide;
3-(3-chlorophenyl)-N-{1-[(4-fluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}propanamide;
(2S)—N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-2-(2-oxopyrrolidin-1-yl)butanamide;
[1-(2,6-difluoro-benzyl)-1H-[1,2,3]triazol-4-yl]-dimethyl-amine;
[1-benzyl-1H-[1,2,3]triazol-4-yl]-dimethyl-amine;
1-[(2,6-difluorophenyl)methyl]-N-methyl-1H-1,2,3-triazol-4-amine;
1-[(2,6-difluorophenyl)methyl]-N-ethyl-1H-1,2,3-triazol-4-amine; or
2-({1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}amino)ethan-1-ol.

### Claim 26 (depends on 1)

The compound of claim 1, wherein the compound is (2S)-2-amino-N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}-3-phenylpropanamide, or a solvate, or pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 1)

The compound of claim 1, wherein the compound is (3R)—N-{1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazol-4-yl}morpholine-3-carboxamide, or a solvate, or pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 1)

The compound of claim 1, wherein the compound is [1-(2,6-difluoro-benzyl)-1H-[1,2,3]triazol-4-yl]-dimethyl-amine, or a solvate, or pharmaceutically acceptable salt thereof.

### Claim at position 20

-30. (canceled)

### Claim 31 (depends on 1)

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

### Claim 32 (depends on 1)

A method for treating a neurological condition of a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

### Claim 33 (depends on 31)

A method for treating a neurological condition of a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition of claim 31.

### Claim 34 (depends on 33)

The method of claim 33, wherein the condition is essential tremor, epilepsy, status epilepticus, or nerve agent exposure.

### Claim 35 (depends on 34)

The method of claim 34, wherein the condition is essential tremor.

### Claim 36 (depends on 1)

The compound of claim 1, wherein the compound is 1-[(2,6-difluorophenyl)methyl]-N-methyl-1H-1,2,3-triazol-4-amine, or a solvate, or pharmaceutically acceptable salt thereof.