IP Library Granted Patent US 12,559,465
Granted Patent B2
US 12,559,465 · App. 17/998,131 · Granted Feb 24, 2026

Substituted benzotriazinone metabolites of a GPR139 agonist

Inventors: Stephen Uriah Bowlin (San Diego, CA); Amin Mohamed Kamel (San Diego, CA)
Assignee: Takeda Pharmaceutical Company Limited
C07D253/08C07H17/02
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Quick Facts
Patent No.
US 12,559,465
App. No.
17/998,131
Granted
Feb 24, 2026
Kind
B2
Abstract

Compounds that are mammalian metabolites of an agonist of G-protein-coupled receptor 1.39 (GPR139), intermediates used in the synthesis of such metabolites, pharmaceutical compositions comprising such metabolites, and the use of such metabolites as biomarkers and agents in the treatment of schizophrenia, for example, negative and/or cognitive symptoms of schizophrenia, disorders associated with social and cognitive dysfunction, as well as several other disorders related to modulated of GPR139.

Claims (62)

1 . A compound selected from:

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

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

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

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

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid;

(2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid;

(2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo [d][1,2,3]triazin-7-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid;

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid;

(S)-4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl hydrogen sulfate;

(S)-4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl hydrogen sulfate;

(S)-4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl hydrogen sulfate;

(S)-4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl hydrogen sulfate;

N5-(1-((carboxymethyl)amino)-1-oxo-3-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)thio)propan-2-yl)glutamine;

N5-(1-((carboxymethyl)amino)-1-oxo-3-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)thio)propan-2-yl)glutamine;

N5-(1-((carboxymethyl)amino)-1-oxo-3-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)thio)propan-2-yl)glutamine;

N5-(1-((carboxymethyl)amino)-1-oxo-3-((4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)thio)propan-2-yl)glutamine;

S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)cysteinylglycine;

S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)cysteinylglycine;

S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)cysteinylglycine;

S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)cysteinylglycine;

S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4 dihydrobenzo[d][1,2,3]triazin-6-yl)cysteine;

S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)cysteine;

S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)cysteine;

S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)cysteine;

N-acetyl-S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)cysteine;

N-acetyl-S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)cysteine;

N-acetyl-S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)cysteine;

N-acetyl-S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)-3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)cysteine;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(S)-2-oxo-3-((4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl) -3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)thio)propanoic acid;

(S)-2-oxo-3-((4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl) -3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)thio)propanoic acid;

(S)-2-oxo-3-((4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl) -3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)thio)propanoic acid;

(S)-2-oxo-3-((4-oxo-3-(2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl) -3,4-dihydrobenzo[d][1,2,3]triazin-8-yl)thio)propanoic acid;

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

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

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

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

(2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(5-((S)-1-(2-(4-oxobenzo[d][1,2,3]triazin -3 (4H)-yl)acetamido)ethyl)-2-(trifluoromethoxy)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid;

(2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-(2-((S)-1-(2-(4-oxobenzo[d][1,2,3]triazin -3 (4H)-yl)acetamido)ethyl)-5-(trifluoromethoxy)phenoxy)tetrahydro-2H-pyran-2-carboxylic acid;

(2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-((S)-1-(2-(4-oxobenzo[d][1,2,3]triazin-3(4H) -yl) acetamido)-1-(4-(trifluoromethoxy)phenyl)ethoxy)tetrahydro-2H-pyran-2-carboxylic acid;

(2R,3R,4R,5S,6S)-3,4,5-trihydroxy-6-((R)-2-(2-(4-oxobenzo[d][1,2,3]triazin-3(4H) -yl) acetamido)-2-(4-(trifluoromethoxy)phenyl)ethoxy)tetrahydro-2H-pyran-2-carboxylic acid;

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

2-(4-oxobenzo[d][1,2,3]triazin-3 (4H)-yl)acetic acid;

(S)-2-hydroxy-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide;

(S)-2-oxo-2-((1-(4-(trifluoromethoxy)phenyl)ethyl)amino)acetic acid;

(S)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-1,2,3-oxadiazol-5-amine, and pharmaceutically acceptable salts of any of the foregoing.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 26, 2025
From: BOWLIN, STEPHEN URIAH; KAMEL, AMIN MOHAMED
To: TAKEDA DEVELOPMENT CENTER AMERICAS, INC.
Reel/Frame 072123/0344 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 26, 2025
From: TAKEDA DEVELOPMENT CENTER AMERICAS, INC.
To: TAKEDA PHARMACEUTICAL COMPANY LIMITED
Reel/Frame 072123/0418 →
Continuity (2)
Provisional Application 63021895 · May 8, 2020
Related Publication 20230227416A1 · Jul 20, 2023
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