Substituted dihydropyrazino[1 ′,2′:1,5]pyrrolo[2,3-d]pyrimidine-based antiproliferative agents

1. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof,

wherein:

y is 1 or 2;

Q is —C(O)—;

R is hydrogen, C 1 -C 6 alkyl, —(C 0 -C 2 alkyl)(C 3 -C 8 carbocyclyl), —(C 0 -C 2 alkyl)(C 3 -C 8 heterocyclyl), —C(O)—O—H, —(C 0 -C 2 alkyl)(aryl), —(C 0 -C 2 alkyl)(heteroaryl), —C(O)—O-alkyl, or —C(O)—O-arylalkyl;

each R 1 is independently alkyl, haloalkyl, cycloalkyl, or aryl, wherein each alkyl, haloalkyl, and cycloalkyl optionally includes in place of a chain carbon atom a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur; or

two geminal R 1 groups, together with the carbon atom to which they are attached, form a 3-8-membered ring; or

two vicinal R 1 groups, together with the carbon atoms to which they are attached, form a 3-8-membered ring;

R 7 is:

wherein:

X 1 is CR 8 or N;

X 2 is CR 8 or N;

X 3 is CR 8 or N;

X 4 is CR 8 or N; and

each R 8 is independently R 2 or R 6 ; or

R 7 is alkyl, cycloalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of —NR 14 R 15 , —OR 14 , R 2 , and R 6 ;

each R 14 is independently hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, —C(O)H, —C(O)-alkyl, —C(S)-alkyl, —S(O) 2 -alkyl, aryl, or heteroaryl;

each R 15 is independently hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, —C(O)H, —C(O)-alkyl, —C(S)-alkyl, —S(O) 2 -alkyl, aryl, or heteroaryl;

R 16 is cycloalkyl, wherein the cycloalkyl is substituted with one R 2 ;

each R 2 is independently -(alkylene) m -heterocyclyl, wherein each -(alkylene)m-heterocyclyl is independently substituted with one or more independently selected R x substituents;

each R x is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—S(O) 2 —R 5 , -(alkylene) m -OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -N(R 3 )—C(S)—OR 5 , -(alkylene) m -N(R 3 )—S(O) 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O)—R 5 , -(alkylene) m -S(O) 2 —NR 3 R 4 , cycloalkylalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

two geminal R x groups, together with the atom to which they are attached, form a ring; or

two vicinal R x groups, together with the atoms to which they are attached, form a ring;

each R 3 is independently hydrogen, alkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

each R 4 is independently hydrogen, alkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

R 3 and R 4 , together with the nitrogen atom to which they are attached, form a heterocyclyl ring;

each R 5 is independently hydrogen, alkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

each R 6 is independently hydrogen, halogen, alkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

each m is independently 0, 1, or 2; and

each n is independently 0, 1, or 2;

with the provisos that:

(1) at least one of X 1 , X 2 , X 3 , or X 4 is CR 8 ; and

(2) one R 8 is R 2 .

2. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

4. The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

6. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein each IV is independently heterocyclyl, wherein each heterocyclyl is independently substituted with one or more independently selected R x substituents.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein at least one R x substituent is cycloalkylalkyl, heterocycloalkyl, or heteroarylalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein y is 1.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein y is 2.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:

two geminal R 1 groups, together with the carbon atom to which they are attached, form a 3-8-membered ring; or

two vicinal R 1 groups, together with the carbon atoms to which they are attached, form a 3-8-membered ring.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein the 3-8-membered ring is a 6-membered ring.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein at least one R 2 is 4-(morpholino)piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-isopropylpiperazin-1-yl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is:

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is:

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein:

R 8 is R 2 ; and

R 2 is heterocyclyl, wherein the heterocyclyl is substituted with one or more independently selected R x substituents.

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein each R x is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently heterocyclyl, wherein each heterocyclyl is independently substituted with one or more independently selected R x substituents.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein each R x is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein y is 2.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently 4-(morpholino)piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, or 4-isopropylpiperazin-1-yl.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

each R 3 is independently hydrogen; and

each R 4 is independently hydrogen.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently alkyl.

23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each m is independently 0.

24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each n is independently 0.

25. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.