IP Library › Granted Patent US 10,159,677

Granted Patent B2

US 10,159,677 · App. 15/683,589 · Granted Dec 25, 2018

4-OXO-3,4-dihydro-1,2,3-benzotriazine modulators of GPR139

Inventors: Stephen Hitchcock (San Diego, CA); Betty Lam (San Diego, CA); Holger Monenschein (San Diego, CA); Holly Reichard (San Diego, CA)

Assignee: Takeda Pharmaceutical Company Limited

A61K31/53 C07D253/08

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Patent No.: US 10,159,677
App. No.: 15/683,589
Granted: Dec 25, 2018
Kind: B2

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Abstract

The present invention provides a method for treating a disease, disorder or condition associated with GPR139 using compounds of formula 1: which are agonists of GPR139, certain compounds encompassed by formula 1, pharmaceutical compositions thereof, processes for making the compounds, and intermediates thereof.

Claims (341)

1. A method for agonizing GPR139 in a subject, the method comprising administering to the subject a compound of formula 2:

or a pharmaceutically acceptable salt thereof, wherein

m is selected from 0, 1, and 2;

n is selected from 0, 1, and 2;

each R 1 is independently selected from the group consisting of cyano, halo, hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, and trifluoromethoxy;

each R 4 is independently selected from the group consisting of cyano, halo, hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, fluoromethoxy, difluoromethoxy, and trifluoromethoxy; and

R 5 is selected from the group consisting of hydrogen, trifluoromethyl, and C 1-4 alkyl, provided:

(a) if R 5 is hydrogen, methyl, n-propyl, i-propyl, or i-butyl, then m and n are not both 0;

(b) if R 5 is hydrogen, m is 0, and n is 1, then R 4 is not chloro, methoxy, 3-trifluoromethyl, 4-trifluoromethyl, 4-methyl, 4-fluoro, 2-difluoromethoxy, 3-difluoromethoxy, 2-trifluoromethoxy, 4-trifluoromethoxy, or 2-(i-butoxy);

(c) if R 5 is methyl, m is 0, and n is 1, then R 4 is not chloro, 2-fluoro, 4-fluoro, 2-bromo, 4-ethyl, 2-methyl, 4-(i-propyl), 4-(i-butyl), or 3-trifluoromethyl;

(d) if R 5 is ethyl, m is 0, and n is 1, then R 4 is not 3-chloro, 4-chloro, 4-bromo, 4-methyl, 4-methoxy, or 2-difluoromethoxy;

(e) if R 5 is n-propyl, m is 0, and n is 1, then R 4 is not 3-trifluoromethyl;

(f) if R 5 is i-propyl, m is 0, and n is 1, then R 4 is not 4-fluoro or 4-methoxy;

(g) if R 5 is i-butyl, m is 0, and n is 1, then R 4 is not 3-trifluoromethyl;

(h) if R 5 is hydrogen, m is 0, and n is 2, then R 4 is not 2,6-difluoro, 2,4-dichloro, 3,5-dimethoxy, 3,4-dimethoxy, 4-methoxy-3-difluoromethoxy, 4-fluoro-2-trifluoromethyl, or 5-bromo-2-difluormethoxy; and

(i) if R 5 is methyl, m is 0, and n is 2, then R 4 is not 3,4-dimethyl, 3,4-dichloro, 2,4-dichloro, 3-fluoro-4-methoxy, 3-bromo-4-methoxy, 3-methoxy-4-isopropyloxy, or 3-methoxy-4-isobutyloxy.

2. The method according to claim 1 , wherein the compound is substantially enantiomerically pure and has a structure represented by formula 2A,

wherein R 5 is selected from the group consisting of trifluoromethyl and C 1-4 alkyl.

3. The method according to claim 1 , wherein m is 0.

4. The method according to claim 1 , wherein R 5 is C 1-4 alkyl.

5. The method according to claim 1 , wherein R 5 is selected from the group consisting of methyl, ethyl, and isopropyl.

6. The method according to claim 1 , wherein R 5 is methyl.

7. The method according to claim 1 , wherein n is 1 and R 4 is trifluoromethoxy.

8. The method according to claim 1 , wherein m is 1.

9. The method according to claim 1 , wherein m is 2.

10. The method according to claim 1 , wherein the compound is selected from the group of compounds consisting of:

2-(5 -methoxy-4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)-N-(1 -p-tolylethyl)acetamide;

N-(1 -(4-bromophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

2-(4-oxobenzo[d] [1,2,3 ]triazin-3 (4H)-yl)-N-(1-p-tolylethyl)acetamide;

N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(2,4-dimethylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(4-ethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(2,4-dimethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;

2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

N-(1-(4-methoxyphenyl)ethyl)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

N-(1-(4-methoxyphenyl)ethyl)-2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

2-(8-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(4-methoxyphenyl)ethyl)acetamide;

2-(5 -fluoro-4-oxobenzo[d][1,2,3 ]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

2-(5 -fluoro-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(4-methoxyphenyl)ethyl)acetamide;

2-(7-methyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-p-tolylethyl)acetamide;

N-(1 -(4-methoxyphenyl)ethyl)-2-(7-methyl-4-oxobenzo[d] [1,2,3 ]triazin-3 (4H)-yl)acetamide;

2-(7-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -p-tolylethyl)acetamide;

2-(7-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(4-methoxyphenyl)ethyl)acetamide;

2-(5 -methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(4-methoxyphenyl)ethyl)acetamide;

N-(1 -(4-methoxyphenyl)ethyl)-2-(5 -methyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

2-(6, 8-dimethyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(4-methoxyphenyl)ethyl)acetamide;

2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-p-tolylethyl)acetamide;

N-(1 -(4-methoxyphenyl)ethyl)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

2-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(p-tolyl)ethyl)acetami de;

N-(1 -(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

N-(1 -(2-bromo-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

N-(1 -(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)propanamide;

N-(1 -(2,4-dimethylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;

2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;

2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;

2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;

2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;

N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide; and

a pharmaceutically acceptable salt of any one of the above-mentioned compounds.

11. The method according to claim 1 , wherein the compound is selected from the group of compounds consisting of:

(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-N-(1-(4-bromophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(R)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-N-(1-(2,4-dimethylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-l)acetamide;

(S)-N-(1-(4-ethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-N-(1-(2,4-dimethoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

(S)-2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-2-(8-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-2-(6-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

(S)-2-(7-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-2-(8-chloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

(S)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(8-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-2-(6,8-dichloro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

(S)-2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(6-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

(S)-2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

(S)-2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(7-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-methoxyphenyl)ethyl)acetamide;

(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(5-methyl-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-2-(6, 8-dimethyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(4-methoxyphenyl)ethyl)acetamide;

(S)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1-p-tolylethyl)acetamide;

(S)-N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxo-6-(trifluoromethyl)benzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

(S)-2-(8-fluoro-6-methyl-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(p-tolyl)ethyl)acetami de;

(S)-N-(1 -(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

(S)-N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

(S)-N-(1-(2-bromo-4-fluorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

(S)-N-((S)-1 -(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)propanamide;

(R)-N-((S)- 1 -(2-methoxy-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)propanamide;

(S)-N-(1 -(2,4-dimethylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

(S)-N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

(S)-N-(1-(2-fluoro-4-methylphenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)acetamide;

(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

(S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

(S)-2-(7-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;

(S)-2-(6-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;

(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

(S)-2-(8-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;

(S)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide;

(S)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-N-(1-(4-(difluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

(S)-N-(1-(2-fluoro-4-(trifluoromethoxy)phenyl)ethyl)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide; and

a pharmaceutically acceptable salt of any one of the above-mentioned compounds.

12. The method according to claim 1 , wherein the compound is selected from the group of compounds consisting of:

(S)-2-(4-oxob enzo [d][1,2,3 ]tri azin-3 (4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)propyl)acetamide;

(S)-2-(4-oxobenzo [d][1,2,3 ]tri azin-3 (4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)propyl)acetamide; and

a pharmaceutically acceptable salt of any one of the above-mentioned compounds.

13. The method according to claim 1 , wherein the compound is (S)-2-(4-oxobenzo[d][1,2,3 ]triazin-3 (4H)-yl)-N-(1 -(4-(trifluoromethoxy)phenyl)ethyl)acetamide or a pharmaceutically acceptable salt thereof.

14. The method according to claim 1 , wherein the compound is (S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide or a pharmaceutically acceptable salt thereof.

15. The method according to claim 1 , wherein the compound is (S)-2-(5-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide or a pharmaceutically acceptable salt thereof.

16. The method according to claim 1 , wherein the compound is (S)-2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)acetamide or a pharmaceutically acceptable salt thereof.

17. A method for agonizing GPR139 in a subject, the method comprising administering to the subject a compound of formula 1,

or a pharmaceutically acceptable salt thereof, wherein:

m is selected from 0, 1, and 2;

n is selected from 0, 1, and 2;

each R 1 is independently selected from the group consisting of cyano, halo, hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, and trifluoromethoxy;

R 2 is selected from the group consisting of hydrogen and C 1-4 alkyl;

R 3 is selected from the group consisting of hydrogen and methyl;

each R 4 is independently selected from the group consisting of cyano, halo, hydroxy, amino, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, fluoromethoxy, difluoromethoxy, and trifluoromethoxy;

G is selected from the group consisting of —CHR 5 —, —CHR 5 —CH 2 —, and —CH 2 —CHR 5 —; and

R 5 is selected from the group consisting of hydrogen, trifluoromethyl, and C 1-4 alkyl.

18. The method according to claim 17 , wherein G is —CHR 5 —.

19. The method according to claim 17 , wherein R 5 is selected from the group consisting of methyl, ethyl, and isopropyl.

20. The method according to claim 17 , wherein R 5 is methyl.

21. The method according to claim 17 , wherein the compound is substantially enantiomerically pure and has a structure represented by formula 1A,

wherein R 5 is selected from the group consisting of trifluoromethyl and C 1-4 alkyl.

22. The method according to claim 17 , wherein R 2 is hydrogen.

23. The method according to claim 17 , wherein R 3 is hydrogen.

24. The method according to claim 17 , wherein m is 0.

25. The method according to claim 17 , wherein m is 1.

26. The method according to claim 25 , wherein R 1 is selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, and trifluoromethoxy.

27. The method according to claim 25 , wherein R 1 is C 1-4 alkoxy.

28. The method according to claim 17 , wherein m is 2.

29. The method according to claim 17 , wherein n is 1 and R 4 is selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

30. The method according to claim 17 , wherein n is 1 and R 4 is selected from the group consisting of C 1-4 alkyl and trifluoromethoxy.

31. The method according to claim 17 , wherein the compound is selected from the group of compounds consisting of:

2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-phenylethyl)acetamide;

2-(5-methoxy-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

N-(1-(4-bromophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-p-tolylethyl)acetamide;

N-(1-(4-methoxyphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(4-chlorophenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

N-(1-(2,4-dimethylphenyl)ethyl)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetamide;

2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-o-tolylethyl)acetamide;