Azolopyrimidine for the treatment of cancer-related disorders

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

22. The compound of claim 1 , having the Formula

23. The compound of claim 1 , having the Formula

24. A compound selected from the compounds of Table 1.

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