Fused tricyclic dual inhibitors of CDK 4/6 and FLT3

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a mixture thereof, wherein:

R 1 is a group of Formula IA, Formula IB, Formula IC, or Formula ID

wherein the symbol indicates the point of attachment of the group of Formula IA, IB, IC, or ID to the rest of the molecule;

R 2 is a C 5 -C 7 cycloalkyl group, is a 5 to 7-membered heterocyclyl group that includes 1, 2, or 3 heteroatoms selected from N, O, and S, or is a C 7 -C 10 bicyclic group; wherein the C 5 -C 7 cycloalkyl group, the 5 to 7 membered heterocyclyl group, or the C 7 -C 10 bicyclic group is unsubstituted or is substituted with 1-3 substituents independently selected from unsubstituted —(C 1 -C 6 alkyl), —OH, halo, —O—(C 1 -C 6 alkyl), —CO 2 H, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)—NR′R″, —NR′R″, or a substituted —(C 1 -C 4 alkyl), wherein the substituted —(C 1 -C 4 alkyl) is substituted with 1-3 substituents independently selected from halo, —OH, —OCH 3 , —S(═O) 2 —CH 3 , or —C(═O)—CH 3 ;

R 3a is selected from —H, —F, or —Cl, —(C 1 -C 3 alkyl), or —O—(C 1 -C 3 alkyl);

R 3b is —H, halo, —OH, —O—(C 1 -C 6 alkyl), unsubstituted —(C 1 -C 6 alkyl), —NR′R″, —C(═O)—(C 1 -C 6 alkyl), —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)—NR′R″, or a substituted —(C 1 -C 6 alkyl), wherein the substituted —(C 1 -C 6 alkyl) is substituted with 1-3 substituents independently selected from halo, —OH, —OCH 3 , —CN, or —NO 2 ;

R 3c is —H, —(C 1 -C 3 alkyl), or halo;

R 4 is —H;

R 5 is —H;

R 6 is selected from —H, —(C 1 -C 6 alkyl), —C(═O)—(C 1 -C 6 alkyl), —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)—C(═O)—OH, —C(═O)—NR′R″, or —S(═O)—NR′R″, wherein the alkyl group of the —(C 1 -C 6 alkyl), —C(═O)—(C 1 -C 6 alkyl), and —C(═O)—O—(C 1 -C 6 alkyl) groups is unsubstituted or is substituted with 1-3 substituents independently selected from —OH, F, —S(═O) 2 —(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl), —NR′R″, or —CN;

R 7a is —H, —CH 3 , or halo;

R 7b is —H, —(C 1 -C 6 alkyl), or halo; or R 7b is absent if R 1 is a group of Formula IB or Formula ID;

R 7c is —H, unsubstituted —(C 1 -C 6 alkyl), halo, —O—(C 1 -C 6 alkyl), —NO 2 , —CN, —NR′R″, —CO 2 H, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)—NR′R″, or a substituted —(C 1 -C 6 alkyl), wherein the substituted —(C 1 -C 6 alkyl) is substituted with 1-3 substituents independently selected from —OH, halo, —O—(C 1 -C 6 alkyl), —CN, —NR′R″, or —S(═O) 2 —CH 3 ; or R 7c is absent if R 1 is a group of Formula IA or Formula IC;

R 8a is —H, unsubstituted —(C 1 -C 6 alkyl), or a substituted —(C 1 -C 6 alkyl), wherein the substituted —(C 1 -C 6 alkyl) is substituted with 1-3 substituents independently selected from —OH, halo, or —O—(C 1 -C 6 alkyl);

R 8b is —H, unsubstituted —(C 1 -C 6 alkyl), or a substituted —(C 1 -C 6 alkyl), wherein the substituted —(C 1 -C 6 alkyl) is substituted with 1-3 substituents independently selected from —OH, halo, or —O—(C 1 -C 6 alkyl); or R 8a and R 8b , when taken together, can represent ═O;

R 8c is selected from —H, —OH, unsubstituted —(C 1 -C 6 alkyl), or a substituted —(C 1 -C 6 alkyl), wherein the substituted —(C 1 -C 6 alkyl) is substituted with 1-3 substituents independently selected from —OH, halo, or —O—(C 1 -C 6 alkyl);

R 8d is —H, unsubstituted —(C 1 -C 6 alkyl), or a substituted —(C 1 -C 6 alkyl), wherein the substituted —(C 1 -C 6 alkyl) is substituted with 1-3 substituents independently selected from —OH, halo, or —O—(C 1 -C 6 alkyl);

R 8e is —H, unsubstituted —(C 1 -C 6 alkyl), or a substituted —(C 1 -C 6 alkyl), wherein the substituted —(C 1 -C 6 alkyl) is substituted with 1-3 substituents independently selected from —OH, halo, or —O—(C 1 -C 6 alkyl);

R 8f is —H, unsubstituted —(C 1 -C 6 alkyl), or a substituted —(C 1 -C 6 alkyl), wherein the substituted —(C 1 -C 6 alkyl) is substituted with 1-3 substituents independently selected from —OH, halo, or —O—(C 1 -C 6 alkyl); or R 8e and R 8f , when taken together, can represent ═O; and

R′ and R″ are independently selected from —H, unsubstituted —(C 1 -C 4 alkyl), or —(C 1 -C 4 alkyl) substituted with 1 to 3 substituents independently selected from —OH or —F.

2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein R 2 is a C 5 -C 7 cycloalkyl group that is unsubstituted or is substituted with 1-3 substituents independently selected from unsubstituted —(C 1 -C 6 alkyl), —OH, halo, —O—(C 1 -C 6 alkyl), —CO 2 H, —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)—NR′R″, —NR′R″, or a substituted —(C 1 -C 4 alkyl), wherein the substituted —(C 1 -C 4 alkyl) is substituted with 1-3 substituents independently selected from halo, —OH, —OCH 3 , —S(═O) 2 —CH 3 , or —C(═O)—CH 3 .

3. The compound of claim 2 or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein R 2 is a cyclohexyl group substituted with a —(C 1 -C 2 alkyl) group.

4. The compound of claim 3 or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein R 2 is a group of formula

wherein the symbol indicates the point of attachment to the rest of the molecule.

5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein R 1 is a group of Formula IA or IB.

6. The compound of claim 5 or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein R 1 is a group of Formula IA.

7. The compound of claim 1 , wherein:

R 2 is a C 5 -C 7 cycloalkyl group that is unsubstituted or is substituted with 1-3-(C 1 -C 6 alkyl) groups;

R 3a is selected from —H, —(C 1 -C 3 alkyl), or —O—(C 1 -C 3 alkyl);

R 3b is —H;

R 3c is —H;

R 4 is —H;

R 5 is —H;

R 6 is selected from —H, —(C 1 -C 6 alkyl), —C(═O)—(C 1 -C 6 alkyl), or —C(═O)—C(═O)—OH, wherein the alkyl group of the —(C 1 -C 6 alkyl) and —C(═O)—(C 1 -C 6 alkyl) groups is unsubstituted or is substituted with 1-3 substituents independently selected from —OH, F, —S(═O) 2 —(C 1 -C 6 alkyl), or —O—(C 1 -C 6 alkyl);

R 7a is —H;

R 7b is —H; or is absent if R 1 is a group of Formula IB or Formula ID;

R 7c is —H; or is absent if R 1 is a group of Formula IA or Formula IC;

R 8a is —H;

R 8b is —H;

R 8c is selected from —H, —OH, or unsubstituted —(C 1 -C 6 alkyl);

R 8d is —H;

R 8e is —H; and

R 8f is —H,

or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof.

8. The compound of claim 1 , wherein the compound has the Formula IIA

or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein:

R 3a is selected from —H, —F, or —Cl, —(C 1 -C 3 alkyl), or —O—(C 1 -C 3 alkyl);

R 3b is —H, halo, —OH, —O—(C 1 -C 6 alkyl), unsubstituted —(C 1 -C 6 alkyl), —NR′R″, —C(═O)—(C 1 -C 6 alkyl), —C(═O)—O—(C 1 -C 6 alkyl), —C(═O)—NR′R″, or a substituted —(C 1 -C 6 alkyl), wherein the substituted —(C 1 -C 6 alkyl) is substituted with 1-3 substituents independently selected from halo, —OH, —OCH 3 , —CN, or —NO 2 ;

R 6 is selected from —H, —(C 1 -C 6 alkyl), —C(═O)—(C 1 -C 6 alkyl), —C(═O)—C(═O)—OH, —C(═O)—NR′R″, or —S(═O)—NR′R″, wherein the alkyl group of the —(C 1 -C 6 alkyl) and —C(═O)—(C 1 -C 6 alkyl) groups is unsubstituted or is substituted with 1-3 substituents independently selected from —OH, F, —S(═O) 2 —(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl), —NR′R″, or —CN; and

R 8c is selected from —H, —OH, unsubstituted —(C 1 -C 6 alkyl), or a substituted —(C 1 -C 6 alkyl), wherein the substituted —(C 1 -C 6 alkyl) is substituted with 1-3 substituents independently selected from —OH, halo, or —O—(C 1 -C 6 alkyl).

9. The compound of claim 8 , wherein:

R 3a is selected from —H, —(C 1 -C 3 alkyl), or —O—(C 1 -C 3 alkyl);

R 3b is —H;

R 6 is selected from —H, —(C 1 -C 6 alkyl), —C(═O)—(C 1 -C 6 alkyl), or —C(═O)—C(═O)—OH, wherein the alkyl group of the —(C 1 -C 6 alkyl) and —C(═O)—(C 1 -C 6 alkyl) groups is unsubstituted or is substituted with 1-3 substituents independently selected from —OH, F, —S(═O) 2 —(C 1 -C 6 alkyl), or —O—(C 1 -C 6 alkyl); and

R 8c is selected from —H, unsubstituted —(C 1 -C 6 alkyl), or —OH,

or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof.

10. The compound of claim 9 or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein R 8c is selected from —H, —CH 3 , or —OH.

11. The compound of claim 10 or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein R 8c is —H.

12. The compound of claim 11 or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein R 3a is —H.

13. The compound of claim 12 or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein R 6 is selected from —H, —C(═O)—CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —C(═O)—CH 2 OH, —C(═O)—C(═O)—OH, —CH 2 CH 2 CF 3 , —CH 2 CH 2 F, —CH 2 CH 2 S(═O) 2 —CH 3 , or —CH 2 CH 2 OCH 3 .

14. The compound of claim 13 or the pharmaceutically acceptable salt thereof, the hydrate thereof, or the mixture thereof, wherein R 6 is selected from —C(═O)—CH 3 or —C(═O)—CH 2 OH.

15. A compound selected from

or a pharmaceutically acceptable salt or a hydrate thereof.

16. The compound of claim 15 , wherein the compound is

or the pharmaceutically acceptable salt or the hydrate thereof.

17. The compound of claim 15 , wherein the compound is

or the pharmaceutically acceptable salt or the hydrate thereof.

18. A compound or a pharmaceutically acceptable salt or a hydrate thereof, wherein the compound has the formula

.

19. A compound selected from

or a pharmaceutically acceptable salt or a hydrate thereof.

20. The compound of claim 1 in a neutral form.

21. The pharmaceutically acceptable salt or the hydrate thereof of claim 1 .

22. The pharmaceutically acceptable salt or the hydrate thereof of claim 21 , wherein the pharmaceutically acceptable salt or the hydrate thereof is selected from a chloride salt, a methanesulfonate salt, or a benzenesulfonate salt.

23. A pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of the compound, the pharmaceutically acceptable salt, the hydrate thereof, or the mixture thereof according to claim 1 and at least one pharmaceutically acceptable excipient, carrier, or diluent.

24. The compound of claim 15 in a neutral form.

25. The pharmaceutically acceptable salt or the hydrate thereof of claim 15 .

26. The pharmaceutically acceptable salt or the hydrate thereof of claim 25 , wherein the pharmaceutically acceptable salt or the hydrate thereof is selected from a chloride salt, a methanesulfonate salt, or a benzenesulfonate salt.

27. A pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of the compound, the pharmaceutically acceptable salt, or the hydrate thereof according to claim 15 and at least one pharmaceutically acceptable excipient, carrier, or diluent.

28. The compound of claim 19 in a neutral form.

29. The pharmaceutically acceptable salt or the hydrate thereof of claim 19 .

30. The pharmaceutically acceptable salt or the hydrate thereof of claim 29 , wherein the pharmaceutically acceptable salt or the hydrate thereof is selected from a chloride salt, a methanesulfonate salt, or a benzenesulfonate salt.

31. A pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of the compound, the pharmaceutically acceptable salt, or the hydrate thereof according to claim 19 and at least one pharmaceutically acceptable excipient, carrier, or diluent.

32. The compound of claim 18 in a neutral form.

33. The pharmaceutically acceptable salt or the hydrate thereof of claim 18 .

34. The pharmaceutically acceptable salt or the hydrate thereof of claim 33 , wherein the pharmaceutically acceptable salt or the hydrate thereof is selected from a chloride salt, a methanesulfonate salt, or a benzenesulfonate salt.

35. A pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of the compound, the pharmaceutically acceptable salt, or the hydrate thereof according to claim 18 and at least one pharmaceutically acceptable excipient, carrier, or diluent.