Azolopyrimidine for the treatment of cancer-related disorders
Compound that is an inhibitor of 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. 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 A 2A receptor and/or the adenosine A 2B receptor.
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.