Azolopyrimidine for the treatment of cancer-related disorders

Patent metadata

Field	Value
Publication number	US-11072597-B2
Application number	US-201916460263-A
Country	US
Kind code	B2
Filing date	Jul 2, 2019
Priority date	Jan 20, 2017
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

Compound that is an inhibitor of at least one of the A2A and A2B adenosine receptors, and compositions containing the compound and methods for synthesizing the compound, are described herein. The use of such compound and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer- and immune-related 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 the Formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein,
G 1 is N or CR 3a ;
G 2 is N or CR 3b ;
G 3 is N or CR 3c ;
R 3a , R 3b , and R 3c are each independently H, deuterium or C 1-3 alkyl;
R 1a and R 1b are each independently selected from the group consisting of
i) H or deuterium,
ii) C 1-8 alkyl optionally substituted with from 1-3 R 5 substituents,
iii) —X 1 —O—C 1-8 alkyl optionally substituted with from 1-3 R 5 substituents,
iv) —C(O)—R 6 ,
v) Y optionally substituted with 1-3 R 7 substituents, and
vi) —X 1 —Y optionally substituted with 1-3 R 7 substituents; or
vii) R 1a and R 1b together with the nitrogen to which they are attached form a 5-6 membered heterocycloalkyl ring optionally substituted with from 1-3 R 8 substituents, wherein the heterocycloalkyl has 0-2 additional heteroatom ring vertices selected from the group consisting of O, N, and S;

each Y is C 3-8 cycloalkyl or 4 to 6-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S;
R 2 is H or deuterium;
R 4 is H, deuterium or C 1-3 alkyl;
Ar 1 is phenyl, which is substituted with 1-3 R 9 ;
Ar 2 is phenyl, which is substituted with 1-3 R 10 ;
each X 1 is C 1-6 alkylene;
each R 5 is independently selected from the group consisting of hydroxyl, C 3-8 cycloalkyl, phenyl, —O-phenyl, —C(O)OR a and oxo;
each R 6 is C 1-8 alkyl or Y, each of which is optionally substituted with 1-3 substituents selected from the group consisting of hydroxyl, —O-phenyl, phenyl, and —O—C 1-8 alkyl;
each R 7 is independently selected from the group consisting of C 1-8 alkyl, hydroxyl,
—O—C 1-8 alkyl, oxo, and C(O)OR a ;
each R 8 is independently selected from the group consisting of C 1-8 alkyl, hydroxyl, and oxo;
each R 9 is independently selected from the group consisting of C 1-8 alkyl, C 1-8 deuteroalkyl, —C 1-8 alkyl, —C 1-8 deuteroalkyl, —X 1 —O—C 1-8 alkyl, —O—X—O—C 1-8 alkyl, —X 1 —O—X—O—C 1-8 alkyl, —C(O)OR a , halogen, cyano, —NR b R c , Y, —X 1 —C 3-8 cycloalkyl, and —X 2 —Z, wherein X 2 is selected from the group consisting of C 1-6 alkylene, —C 1-6 alkylene-O—, —C(O)—, and —S(O) 2 —, Z is 4 to 6-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each of said R 9 substituents is optionally substituted with 1-3 R 11 ;
each R 10 is independently selected from the group consisting of C 1-8 alkyl, C 1-8 deuteroalkyl, halo, cyano, —O—C 1-8 alkyl, —O—C 1-8 deuteroalkyl, —X 1 —O—C 1-8 alkyl, —O—X—O—C 1-8 alkyl, —S(O) 2 —C 1-6 alkyl, —C(O)NR d R e , and 4-6-membered heteroaryl having from 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, wherein each of said R 10 substituents is optionally substituted with 1-3 R 12 , or two R 10 on adjacent ring vertices of Ar 2 are optionally combined to form a 5-membered heterocyclic ring optionally substituted with 1-2 halogens;
each R 11 is independently selected from the group consisting of hydroxyl, halo, cyano, —NR d R e , —C(O)OR a , phenyl, C 3-8 cycloalkyl, and C 1-4 alkyl optionally substituted with C(O)OR a ;
each R 12 is independently selected from the group consisting of halo, cyano, hydroxy, and —C(O)OR a ; and
each R a is H, deuterium, or C 1-6 alkyl;
each R b and R c are independently selected from the group consisting of H, deuterium, C 1-8 alkyl, —S(O) 2 —C 1-6 alkyl, —C(O)OR a , and —X 1 —C(O)OR a ; and
each R d and R e are independently selected from the group consisting of H, deuterium, C 1-8 alkyl, and —S(O) 2 —C 1-6 alkyl.

2. The compound of claim 1 , wherein G 3 is CR 3c .

3. The compound of claim 1 , wherein at least one R 10 is cyano.

4. The compound of claim 1 , wherein each R 9 is independently selected from the group consisting of C 1-8 alkyl, C 1-8 deuteroalkyl, —O—C 1-8 alkyl, —O—C 1-8 deuteroalkyl, —X 1 —O—C 1-8 alkyl, —O—X 1 —O—C 1-8 alkyl, and —X 1 —O—X 1 —O—C 1-8 alkyl, wherein each of said R 9 substituents is optionally substituted with 1-3 R 11 .

5. The compound of claim 1 , wherein each R 9 is independently selected from the group consisting of —C(O)OR a , —NR b R c , Y, —X 1 —C 3-8 cycloalkyl, and —X 2 —Z, wherein X 2 is selected from the group consisting of C 1-6 alkylene, —C 1-6 alkylene-O—, —C(O)—, and —S(O) 2 —, Z is 4 to 6-membered heterocycloalkyl having 1-3 heteroatom ring vertices selected from the group consisting of O, N, and S, and wherein each of said R 9 substituents is optionally substituted with 1-3 R 11 .

6. The compound of claim 1 , wherein G 2 is N.

7. The compound of claim 1 , wherein G 1 is N.

8. The compound of claim 1 , wherein G 1 is CR 3 .

9. The compound of claim 1 , wherein R 4 is H.

10. The compound of claim 1 , wherein R 1b is H.

11. The compound of claim 1 , wherein each R 10 is independently selected from the group consisting of C 1-8 alkyl, halo, cyano, —O—C 1-8 alkyl, —X 1 —O—C 1-8 alkyl, and —O—X 1 —O—C 1-8 alkyl, wherein each of said R 10 substituents is optionally substituted with 1-3 R 12 .

12. The compound of claim 10 , wherein each R 10 is independently selected from the group consisting of C 1-8 alkyl, halo, cyano, and —O—C 1-8 alkyl.

13. A compound of claim 1 , selected from the group consisting of

14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

Assignees

• Arcus Biosciences Inc

Inventors

• Beatty Joel
• Debien Laurent
• Jeffrey Jenna
• Leleti Manmohan Reddy
• Mandal Debashis
• Miles Dillon
• Powers Jay
• Rosen Brandon
• Sharif Ehesan
• Thomas-Tran Rhiannon

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title