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

Patent metadata

Field	Value
Publication number	US-12466831-B2
Application number	US-201917292511-A
Country	US
Kind code	B2
Filing date	Nov 15, 2019
Priority date	Nov 20, 2018
Publication date	Nov 11, 2025
Grant date	Nov 11, 2025

Abstract

In its many embodiments, the present invention provides certain substituted amino triazolopyrimidine and amino triazolopyrazine compounds of Formula (IA) and Formula (IB): or and pharmaceutically acceptable salts thereof, wherein, R 1 , 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 Formula (IB):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a moiety selected from (C 3 -C 7 )cycloalkyl and C-linked 4-7 membered monocyclic heterocycloalkyl comprising 1 or 2 ring nitrogen atoms,
wherein said (C 3 -C 7 )cycloalkyl, said C-linked 4-7 membered monocyclic heterocycloalkyl comprising 1 or 2 ring nitrogen atoms,
wherein each R 1A 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, (C 1 -C 6 )haloalkyl, —O(C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, C(O)(C 3 -C 6 )cycloalkyl, phenyl, and heteroaryl,
wherein said heteroaryl of R 1A is unsubstituted or substituted with 1, 2, or 3 R 1A1 groups,
wherein each R 1A1 group is independently selected from:
F, Cl, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl-OH, O(C 1 -C 6 )alkyl, O(C 1 -C 6 )haloalkyl, (C1-C6)alkyl-CH((C 3 -C 6 )cycloalkyl)OH, (C 1 -C 6 )alkyl-C(O)N(R 1N ) 2 , and (C 4 -C 6 )heterocycloalkyl,
wherein said (C 1 -C 6 )alkyl and the (C 1 -C 6 )alkyl portions of each of said O—(C 1 -C 6 )alkyl and said (C 1 -C 6 )alkyl-C(O)N(R 1N ) 2 are optionally further substituted with from 1 to 3 R 1A2 groups,
wherein each R 1A2 group is independently selected from OH, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl-OH, heterocycloalkyl, heteroaryl, N(R 1N ) 2 ; and
each R 1N is independently selected from H and (C 1 -C 6 )alkyl;
R 2 is selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, and (C 3 -C 4 )cycloalkyl,
wherein each said (C 1 -C 6 )alkyl and (C 3 -C 4 )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 phenyl and said heteroaryl are unsubstituted or substituted with 1, 2, or 3 R 3A groups,
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 cyclopropyl which is substituted with phenyl, 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, and
further provided that, in Formula (IA), R 2 is selected from H, (C 1 -C 6 )alkyl, and (C 2 -C 6 )alkenyl,
wherein each said (C 1 -C 6 )alkyl and cyclobutyl of R 2 is unsubstituted or substituted with 1, 2, or 3 R 2A groups.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from pyrrolidinyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein each said group is unsubstituted or substituted with 1, 2, or 3 R 1A groups.

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof,
wherein each R 1A (when present) is independently selected from: F, OH, oxo, CH 3 , CF 3 , CHF 2 , CH 2 CHF 2 , CH 2 CF 3 , C(CH 3 ) 2 OH, OCHF 2 , C(O)cyclopropyl, pyrazolyl, pyrazolyl substituted with 1, 2, or 3 substituents independently selected from CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CF 3 , CH(CH 3 )C(CH 3 ) 2 OH, CH 2 C(CH 3 ) 2 OH, CH 2 (cyclobutyl)OH, C(CH 3 ) 2 C(O)NHCH 3 , tetrahydropyranyl, pyridinyl, and pyridinyl substituted with 1, 2, or 3 substituents independently selected from F, Cl, CH 3 , OCHF 2 , oxo, and CHF 2 .

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from: pyrrolidinyl which is unsubstituted or substituted with 1, 2, or 3 R 1A groups, wherein each R 1A group is independently selected from F, CH 2 CF 3 , —C(O)cyclopropyl, pyrazolyl, and pyrazolyl substituted with CH 2 C(CH 3 )OH, piperidinyl which is unsubstituted or substituted with 1, 2, or 3 R 1A groups, wherein each R 1A group is independently selected from CH 3 , CH 2 CF 3 , pyrazolyl, and pyrazolyl substituted with 1, 2, or 3 substituents independently selected from —CH 3 ,—CH 2 CH 3 , —CH(CH 3 ) 2 , tetrahydropyranyl, CH 2 CF 3 , CH 2 (cyclobutyl)OH, CH 2 C(CH 3 ) 2 OH, CH(CH 3 )C(CH 3 ) 2 OH, and C(CH 3 ) 2 C(O)NHCH 3 , cyclopropyl which is unsubstituted or substituted with 1 or 2 R 1A groups, wherein each R 1A group is independently selected from —C(CH 3 ) 2 OH, pyridinyl, and pyridinyl substituted with 1, 2, or 3 substituents independently selected from F, Cl, and CH 3 , cyclobutyl which is unsubstituted or substituted with 1, 2, or 3 R 1A groups, wherein each R 1A group is independently selected from OH, CH 3 , and pyridyl, wherein said pyridyl is optionally substituted with R 1A1 , wherein said R 1A 1 is selected from (C 1 -C 6 )alkyl-OH and (C 1 -C 6 )alkyl-NH 2 , cyclopentyl which is unsubstituted or substituted with 1, 2, or 3 R 1A groups, wherein each R 1A group is independently selected from OH, and CH 3 , and cyclohexyl which is unsubstituted or substituted with 1, 2, or 3 R 1A groups, wherein each R 1A group is independently selected from OH, and CH 3 .

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

6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof,
wherein: each R 2A is selected from H, F, Cl, OH, oxo, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, O(C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkyl-OH.

7 . The compound of claim 1 , or a pharmaceutically acceptable
salt thereof, wherein: in Formula (IA), R 2 is selected from H, methyl, C(CH 3 ) 2 OH, and propenyl, and in Formula (IB), R 2 is selected from H, methyl, C(CH 3 ) 2 OH, propenyl, and cyclopropyl.

8 . The compound of claim 1 , or a pharmaceutically acceptable
salt thereof, wherein: R 3 is selected from phenyl, oxazolyl, pyrazolyl, pyridinyl, and thiazoyl, wherein said phenyl, oxazolyl, pyrazolyl, pyridinyl, and thiazoyl are unsubstituted or substituted with 1, 2, or 3 R 3A groups.

9 . The compound of claim 8 , or a pharmaceutically acceptable
salt thereof, wherein: in Formula (IA), each R 3A group is independently selected from F, Cl, OH, CH 3 , CF 3 , OCH 3 , and OCHF 2 ; and in Formula (IB), each R 3A group is independently selected from F, Cl, OH, CN, CH 3 , CF 3 , OCH 3 , and OCHF 2 .

10 . The compound of claim 1 , or a pharmaceutically acceptable
salt thereof, wherein R 1 is selected from: pyrrolidinyl which is unsubstituted or substituted with 1, 2 or 3 R 1A groups, wherein each R 1A group is independently selected from F, CH 2 CF 3 , C(O)cyclopropyl, pyrazolyl, and pyrazolyl substituted with —CH 2 C(CH 2 )OH, piperidinyl which is unsubstituted or substituted with 1, 2, or 3 R 1A groups, wherein each R 1A group is independently selected from CH 3 , CH 2 CF 3 , pyrazolyl, pyrazolyl substituted with 1, 2, or 3 substituents independently selected from CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , tetrahydro

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Brill Zachary G
• Ali Amjad
• Cumming Jared
• Demong Duane
• Deng Qiaolin
• Graham Thomas H
• Kuang Rongze
• Lim Yeon-Hee
• Plummer Christopher W
• Rico Duque Jenny Lorena
• Wang Huijun
• Zhang Yonglian
• Zhao Kake

Classifications

• C07K16/2818

  against CD28 or CD152 · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title