Substituted amino triazolopyrimidine and amino triazolopyrazine adenosine receptor antagonists, pharmaceutical compositions and their use

Patent metadata

Field	Value
Publication number	US-12414952-B2
Application number	US-201917292571-A
Country	US
Kind code	B2
Filing date	Nov 15, 2019
Priority date	Nov 20, 2018
Publication date	Sep 16, 2025
Grant date	Sep 16, 2025

Abstract

In its many embodiments, the present invention provides certain substituted amino triazolopyrimidine and amino triazolopyrazine compounds of Formula (IA) and Formula (IB): and, and pharmaceutically acceptable salts thereof, wherein, R 1 , n, R 2 , and R 3 are as defined herein, pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other therapeutically active agents), and methods for their preparation and use, alone and in combination with other therapeutic agents, as antagonists of A2a and/or A2b receptors, and their use in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor.

First claim

What is claimed is:

1. A compound having a structural Formula (IA):

or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
R 1 is selected from:
H,
OH,
S(O) 2 R 1C , wherein R 1C is selected from (C 1 -C 6 )alkyl and (C 3 -C 5 )cycloalkyl;
phenyl fused to a 5 or 6 membered partially or fully unsaturated ring comprising 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, wherein said fused phenyl is unsubstituted or substituted with 1, 2, or 3 R 1AB groups,
N(R 1A )(R 1B ), and
C(O)N(R 1A )(R 1B ), wherein:
R 1A is selected from H, (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl;
R 1B is selected from —CH 2 phenyl and —CH 2 heteroaryl, wherein said —CH 2 phenyl, and said —CH 2 heteroaryl are unsubstituted or substituted with 1, 2 or 3 groups independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH;
or, alternatively, R 1A and R 1B in each of said N(R 1A )(R 1B ) and said C(O)N(R 1A )(R 1B ) of R 1 are taken together with the nitrogen atom to which they are shown attached to form a 4, 5, or 6 membered monocyclic heterocycloalkyl ring comprising 1 or 2 ring nitrogen atoms (including the nitrogen atom of N(R 1A )(R 1B ) and of C(O)N(R 1A )(R 1B )), wherein said monocyclic heterocycloalkyl ring is optionally fused to a 5 or 6 membered ring, which fused ring is partially or fully unsaturated and comprises 1, 2, or 3 additional ring heteroatoms independently selected from N, O, and S, and wherein said optionally fused heterocycloalkyl ring is unsubstituted or substituted with 1, 2, or 3 R 1AB groups,
each R 1AB group is independently selected from:
F, Cl, OH, CN, oxo, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-OH, (C 1 -C 6 )haloalkyl, O(C 1 -C 6 )haloalkyl, C(O)O(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, C(O)(C 3 -C 6 )cycloalkyl, and heteroaryl,
wherein said cycloalkyl and said heteroaryl portions of R 1AB are unsubstituted or further substituted with 1, 2, or 3 R ab groups independently selected from F, OH, (C 1 -C 4 )alkyl, and O(C 1 -C 6 )alkyl;
R 2 is selected from H, (C 1 -C 6 )alkyl, and (C 3 -C 4 )cycloalkyl,
wherein each said (C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkyl of R 2 is unsubstituted or substituted with 1, 2, or 3 R 2A groups,
wherein each R 2A group is independently selected from F, Cl, OH, oxo, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-OH, and (C 1 -C 6 )haloalkyl, and
R 3 is selected from phenyl and heteroaryl, wherein said heteroaryl is a 4, 5 or 6 membered monocyclic ring comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S,
wherein said phenyl and said heteroaryl of R 3 are each unsubstituted or substituted with 1, 2, or 3 R 3A groups, and
wherein each R 3A group is independently selected from the group consisting of F, Cl, OH, CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, O(C 1 -C 6 )alkyl, and O(C 1 -C 6 )haloalkyl;
provided that, in Formula (IA), when R 1 is:
OH,
then each R 3A group is independently selected from the group consisting of F, Cl, OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, O(C 1 -C 6 )alkyl, and O(C 1 -C 6 )haloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
n is 2; and
R 1 is S(O) 2 R 1C , wherein R 1C is selected from (C 1 -C 6 )alkyl and (C 3 C 5 )cycloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
n is 1; and
R 1 is phenyl fused to a 5 or 6 membered partially or fully unsaturated ring comprising 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, wherein said fused phenyl is unsubstituted or substituted with 1, 2, or 3 R 1AB groups.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
n is 1;
R 1 is selected from N(R 1A )(R 1B ) and C(O)N(R 1A )(R 1B ), wherein:
R 1A is selected from H, (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl;
R 1B is selected from —CH 2 -phenyl and —CH 2 -heteroaryl, wherein said —CH 2 -phenyl, and said —CH 2 -heteroaryl are unsubstituted or substituted with 1 or 2 groups independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
n is 1 or 2;
R 1 is selected from N(R 1A )(R 1B ) and C(O)N(R 1A )(R 1B ), wherein:
R 1A and R 1B in each of said N(R 1A )(R 1B ) and said C(O)N(R 1A )(R 1B ) of R 1 are taken together with the nitrogen atom to which they are shown attached to form a 4, 5, or 6 membered monocyclic heterocycloalkyl ring comprising 1 or 2 ring nitrogen atoms (including the nitrogen atom of N(R 1A )(R 1B ) and of C(O)N(R 1A )(R 1B )), wherein said monocyclic heterocycloalkyl ring is optionally fused to a 5 or 6 membered ring, which fused ring is partially or fully unsaturated and comprises 1, 2, or 3 additional ring heteroatoms independently selected from N, O, and S, and wherein said optionally fused heterocycloalkyl ring is unsubstituted or substituted with 1, 2, or 3 R 1AB groups.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from H and OH.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
in Formula (IA): R 2 is selected from H, methyl, and propyl, wherein said methyl, and propyl are unsubstituted or substituted with 1, 2, or 3 R 2A groups.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is selected from phenyl, oxazolyl, pyrimidinyl, pyrazolyl, pyridinyl, and thiazoyl, wherein said phenyl, oxazolyl, pyrazolyl, pyridinyl, and thiazoyl are unsubstituted or substituted with 1, 2, or 3 R 3A groups,
provided that, in Formula (IA), when R 1 is:
OH,
each R 3A group is independently selected from the group consisting of F, Cl, OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, O(C 1 -C 6 )alkyl, and O(C 1 -C 6 )haloalkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:

10. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Brill Zachary G
• Ali Amjad
• Cumming Jared
• Demong Duane
• Deng Qiaolin
• Gallo-Etienne Gioconda V
• Graham Thomas H
• Kuang Rongze
• Larsen Matthew A
• Lim Yeon-Hee
• Liu Kun
• Mansoor Umar Faruk
• Moreno Jesus
• Vara Brandon A
• Wang Huijun
• Zhang Yonglian

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title