7-, 8-, and 10-substituted amino triazolo quinazoline derivatives as adenosine receptor antagonists, pharmaceutical compositions and their use

Patent metadata

Field	Value
Publication number	US-12263171-B2
Application number	US-201917294836-A
Country	US
Kind code	B2
Filing date	Nov 26, 2019
Priority date	Nov 30, 2018
Publication date	Apr 1, 2025
Grant date	Apr 1, 2025

Abstract

In its many embodiments, the present invention provides certain 7-, 8-, and 10-substituted amino triazolo quinazoline derivatives of Formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A, R1, R2, and R4 are as defined herein, pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other therapeutic 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:

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

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from H, F, Cl, Br, CN, OH, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, and O(C 1 -C 6 )haloalkyl;
R 2 is selected from H, F, Cl, Br, CN, OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, O(C 1 -C 6 )alkyl, O(C 1 -C 6 )haloalkyl, (C 3 -C 4 )cycloalkyl, S(O) 2 (C 1 -C 6 )alkyl, S(O) 2 (C 1 -C 6 )haloalkyl, and 4-5 membered monocyclic heterocycloalkyl comprising 1 or 2 ring nitrogen atoms;
R 4 is selected form H, F, Cl, Br, (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl,
with the proviso that at least one of R 1 , R 2 , or R 4 is not H; and
ring A is a moiety selected from:

wherein:
R 3 is selected from:

each R 3A is independently selected from H, F, Cl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-OH, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkylNH 2 , O(C 1 -C 6 )alkyl, O(C 1 -C 6 )haloalkyl, C(O)(C 1 -C 3 )alkyl, (C 1 -C 4 )alkylC(O)(C 1 -C 3 )alkyl, (C 1 -C 4 )alkylO(C 1 -C 3 )alkyl, (C 1 -C 4 )alkylCH(OH)(C 1 -C 3 )alkyl, (C 1 -C 4 )alkylS(O) 2 (C 1 -C 3 )alkyl, (C 1 -C 6 )alkylC(O)NH(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylC(O)OH, (C 1 -C 6 )alkylC(O)NH(C 3 -C 6 )cycloalkyl,

—(CH 2 ) n (C 3 -C 7 )cycloalkyl, and —(CH 2 ) n 4-7 membered monocyclic heterocycloalkyl comprising 1 or 2 ring heteroatoms selected from O, N, S, and S(O) 2 ,
wherein said (C 3 -C 7 )cycloalkyl, and said 4-7 membered monocyclic heterocycloalkyl are each unsubstituted or substituted with 1, 2, or 3 groups independently selected from F, Cl, OH, oxo, (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and O(C 1 -C 6 )haloalkyl;
n is 0, 1, or 2;
each R 3Aa is independently selected from H, (C 1 -C 4 )alkyl, O(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, O(C 1 -C 4 )haloalkyl, and (C 3 -C 4 )cycloalkyl;
R A1 is selected from H, and (C 1 -C 4 )alkyl;
each RA 2 is independently selected from H, F, and (C 1 -C 4 )alkyl;
R A3 is selected from H, F, and (C 1 -C 4 )alkyl;
R A4 is selected from H and OH; and
R A5 is selected from H, F, and (C 1 -C 4 )alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.1):

wherein R 1 is selected from F, Cl, Br, CN, OH, CH 3 , CH 2 CH 3 , OCH 3 OCH 2 CH 3 and O(C 1 -C 6 )haloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.2):

wherein R 2 is selected from F, Cl, Br, CN, OH, CH 3 , CHF 2 , CF 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , OCHF, S(O) 2 CH 3

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.3):

wherein R 4 is selected from F, Cl, Br, (C 1 -C 6 )alkyl, and (C 1 -C 6 )haloalkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.4):

wherein R 1 is selected from F, Cl, Br, CN, OH, CH 3 , OCH 3 , and CF 3 ; and
R 2 is selected from F, Cl, Br, CN, OH, CH 3 , OCH 3 , and CF 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compounds have the structural Formula (I.5):

wherein R 1 is selected from F, Cl, Br, CN, OH, CH 3 , OCH 3 , and CF 3 ; and
R 4 is selected from F, Cl, Br, CN, OH, CH 3 , OCH 3 , and CF 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is:

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is:

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is:

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is a moiety selected from:

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
ring A is:

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

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Zhang Yonglian
• Ali Amjad
• Cumming Jared
• Demong Duane
• Deng Qiaolin
• Graham Thomas H
• Hennessy Elisabeth
• Larsen Matthew A
• Liu Kun
• Liu Ping
• Mansoor Umar Faruk
• Pan Jianping
• Plummer Christopher W
• Sather Aaron
• Swaminathan Uma
• Wang Huijun

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

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K39/3955

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

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61P35/00

  Antineoplastic agents · CPC title