Azolopyrimidine for the treatment of cancer-related disorders

Patent metadata

Field	Value
Publication number	US-10399962-B2
Application number	US-201815875106-A
Country	US
Kind code	B2
Filing date	Jan 19, 2018
Priority date	Jan 20, 2017
Publication date	Sep 3, 2019
Grant date	Sep 3, 2019

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 and R 4 are each independently H, deuterium or C 1-3 alkyl;
Ar 1 a 5 to 6-membered heteroaryl, each of which is optionally substituted with 1-3 R 9 ;
Ar 2 is phenyl or a 5 to 6-membered heteroaryl, each of which is optionally substituted with 1-3 R 10 ;
wherein the 5 to 6-membered heteroaryl of Ar 1 and Ar 2 each independently have 1-3 heteroatom ring vertices selected from the group consisting of O, N, N + —O − and S;
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, —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, —X 1 —O—X 1 —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 1 —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, —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 ;
each R d and R e are independently selected from the group consisting of H, deuterium, C 1-8 alkyl, —S(O) 2 —C 1-6 alkyl; and

provided that when G 1 and G 2 are each N, G 3 is CH, R 2 is CH 3 , and R 1a and R 1b are each H or deuterium, then Ar 2 is other than 2-thienyl, phenyl, 2-, 3- or 4-methoxyphenyl, 3- or 4-halophenyl, 2,4-dimethoxyphenyl, 2,4-dichlorophenyl or 2- or 4-methylphenyl.

2. The compound of claim 1 , wherein Ar 1 is selected from the group consisting of pyridyl, pyridyl N-oxide, imidazolyl, pyrazolyl, and thiazolyl optionally substituted with 1-3 R 9 .

3. The compound of claim 2 , wherein Ar 1 is pyridyl optionally substituted with 1-3 R 9 .

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

5. The compound of claim 1 , wherein the compound of Formula (I) is represented by Formula (Ia)

wherein, n is an integer from 0 to 2.

6. The compound of claim 1 , wherein the compound of Formula (I) is represented by Formula (Ib)

7. The compound of claim 1 , wherein Ar 2 is substituted with from 1-3 R 10 is cyano.

8. The compound of claim 1 , wherein the compound of Formula (I) is represented by Formula (Ic)

wherein m is an integer from 0 to 2.

9. The compound of claim 1 , wherein the compound of Formula (I) is represented by Formula (Id)

10. 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, —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 .

11. 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 .

12. The compound of claim 1 , wherein the compound of Formula (I) is represented by Formula (Ie)

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

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

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

16. The compound of claim 1 , wherein R 2 is H.

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

18. The compound of claim 5 , wherein R 1b is H.

19. The compound of claim 5 , 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, —O—X 1 —O—C 1-8 alkyl, wherein each of said R 10 substituents is optionally substituted with 1-3 R 12 .

20. The compound of claim 18 , wherein each R 10 is independently selected from the group consisting of C 1-8 alkyl, halo, cyano, —O—C 1-8 alkyl.

21. The compound of claim 1 , selected from the group consisting of

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title