Pyridone A2R antagonists

Patent metadata

Field	Value
Publication number	US-12064433-B2
Application number	US-201917263016-A
Country	US
Kind code	B2
Filing date	Jul 26, 2019
Priority date	Jul 27, 2018
Publication date	Aug 20, 2024
Grant date	Aug 20, 2024

Abstract

Compound that inhibit at least one of the A 2A and A 2B adenosine receptors, and compositions containing the compound and methods for synthesizing the compound, are described herein. Also described are the use of such compounds 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 A 2A receptor and/or the adenosine A 2B receptor.

First claim

What is claimed is:

1. A compound represented by 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 ;
R 3a and R 3b are each independently H or C 1-3 alkyl;
R 1a and R 1b are each independently selected from the group consisting of
i) H,
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,
vi) —X 1 —Y optionally substituted with 1-3 R 7 substituents; and
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 or C 1-3 alkyl;
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;
the subscript n is 0, 1, 2 or 3;
each R 9 is independently selected from the group consisting of C 1-8 alkyl, —O—C 1-8 alkyl, —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 1-4 alkylene-O—C 1-4 alkylene-, —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 of R 10a , R 10b , R 10c , and R 10d is independently selected from the group consisting of H, 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, —S(O) 2 —C 1-6 alkyl, —C(O)NR d R c , 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 10a-d substituents is optionally substituted with 1-3 R 12 , or two of R 10a , R 10b , R 10c and R 10d on adjacent ring vertices 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, oxo, 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 ;
each R a is H or C 1-6 alkyl;
each R b and R c are independently selected from the group consisting of H, 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, C 1-8 alkyl, and —S(O) 2 —C 1-6 alkyl.

2. The compound of claim 1 , having Formula (Ia):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

3. The compound of claim 1 , having Formula (Ib):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

4. The compound of claim 1 , wherein at least one of R 10a , R 10b and R 1c is methoxy.

5. The compound claim 1 , having Formula (Ic):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

6. The compound of claim 1 , having Formula (Id):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein each R 9 is independently selected from the group consisting of C 1-8 alkyl, —O—C 1-8 alkyl, —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 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, 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 .

9. The compound of claim 1 , having Formula (Ie):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

10. The compound of claim 1 , having Formula (If):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

11. The compound of claim 1 , having Formula (Ig):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

12. The compound of claim 1 , having Formula (Ih):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

13. The compound of claim 1 , having Formula (Ii):

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

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

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

15. A compound selected from the group consisting of:

Assignees

• Arcus Biosciences Inc

Inventors

• Leleti Manmohan Reddy
• Mandal Debashis
• Miles Dillon Harding
• Powers Jay Patrick
• Rosen Brandon Reid
• Sharif Ehesan U I

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K45/06 Primary

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

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title