Tryptoline derivatives having kinase inhibitory activity and uses thereof

1. A compound having the formula:

or a stereoisomer, pharmaceutically acceptable salt,

wherein

each R 1 , R 2 , R 3 , and R 4 is, independently, CR 5 , wherein each R 5 is, independently, H or halo;

A is H, optionally substituted C 1-12 heterocyclyl, or —C(O)—NR A1 R A2 , wherein each R A1 and R A2 is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, or optionally substituted C 1-6 alkoxy-C 1-6 alkyl, or wherein the combination of R A1 and R A2 can together form optionally substituted C 1-12 heterocyclyl;

X has the formula:

wherein each of X a , X b , and X c is, independently, selected from O, S, NR x1 , N, or CR x2 ;

R x1 is H or optionally substituted C 1-6 alkyl; and

R X2 is H, halo, or optionally substituted C 1-6 alkyl;

L is —CH 2 —NZ N1 —or —CH 2 —O—, wherein each Z N1 is, independently, H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, or an N-protecting group;

each Z 3a , and Z 3b is, independently, H or C 1-6 alkyl;

Z 4 is H, optionally substituted C 1-6 alkyl, optionally substituted halo-C 1-6 alkyl, optionally substituted C 1-7 acyl, or an N-protecting group;

each Z 5a and Z 5b is, independently, H or C 1-6 alkyl; and

Y is optionally substituted bicyclic C 1-12 heterocyclyl.

2. The compound of claim 1 , wherein

each R 1 , R 2 , R 3 , and R 4 is, independently, CR 5 , wherein each R 5 is H;

A is H, or —C(O)—NR A1 R A2 , wherein each R A1 and R A2 is, independently, H, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy-C 1-6 alkyl; and

each Z 3a , Z 3b , and Z 4 is, independently, H or C 1-6 alkyl.

3. The compound of claim 1 , wherein said compound has the formula:

or a pharmaceutically acceptable salt, wherein Z 3a is H or C 1-6 alkyl.

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

or a pharmaceutically acceptable salt, wherein Z 3a is H or C 1-6 alkyl.

5. The compound of claim 1 , wherein said compound has the formula:

or a stereoisomer, pharmaceutically acceptable salt, wherein Z 3a is H or optionally substituted C 1-6 alkyl.

6. The compound of claim 1 , wherein said compound has the formula:

or a stereoisomer, pharmaceutically acceptable salt, wherein Z 3a is H or C 1-6 alkyl.

7. The compound of claim 1 , wherein Y has the formula:

and wherein the combination of Y a and Y b or the combination of Y b and Y c can together form optionally substituted C 1-12 heterocyclyl.

8. The compound of claim 7 , wherein Y is optionally substituted C 1-12 heteroaryl.

9. The compound of claim 8 , wherein Y is selected from the group consisting of optionally substituted quinoxalinyl, optionally substituted dihydroquinoxalinyl, optionally substituted quinazolinyl, optionally substituted cinnolinyl, optionally substituted phthalazinyl, optionally substituted quinolyl, optionally substituted isoquinolyl, optionally substituted dihydroquinolyl, optionally substituted tetrahydroquinolyl, optionally substituted dihydroisoquinolyl, optionally substituted tetrahydroisoquinolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted indolyl, optionally substituted dihydroindolyl, optionally substituted indazolyl, optionally substituted benzofuranyl, optionally substituted isobenzofuranyl, and optionally substituted benzothienyl.

10. The compound of claim 9 , wherein Y is optionally substituted optionally substituted dihydroquinoxalinyl, optionally substituted dihydroquinolyl, optionally substituted tetrahydroquinolyl, optionally substituted dihydroisoquinolyl, optionally substituted tetrahydroisoquinolyl, or optionally substituted dihydroindolyl comprising oxo.

11. The compound of claim 1 , wherein X is selected from the group consisting of optionally substituted furyl, optionally substituted pyrazolyl, optionally substituted thiazolyl, optionally substituted pyrrolyl, optionally substituted oxadiazolyl, optionally substituted isoxazolyl, optionally substituted oxazolyl, optionally substituted imidazolyl, optionally substituted thienyl, optionally substituted isothiazolyl, and optionally substituted thiadiazolyl.

12. The compound of claim 1 , wherein A is H, optionally substituted C 1-12 heteroaryl, or —C(O)—NR A1 R A2 , wherein each R A1 and R A2 is, independently, H, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy-C 1-6 alkyl.

13. The compound of claim 1 , wherein each of Z 1 , Z 2 , Z 3a , and Z 3b , if present, is, independently, H or methyl.

14. The compound of claim 1 , wherein both R 1 and R 4 are CH.

15. The compound of claim 1 , wherein said compound has the formula:

or a stereoisomer, pharmaceutically acceptable salt,

wherein

each R 2′ , R 3′ , and R 4′ is, independently, H or halo;

each of X a , X b , and X c is, independently, selected from O, S, NR x1 , N, or CR X2 , wherein R X1 is H or optionally substituted C 1-6 alkyl, and R X2 is H, halo, or optionally substituted C 1-6 alkyl; and

the combination of Y a and Y b or the combination of Y b and Y c together form optionally substituted C 1-12 heterocyclyl.

16. The compound of claim 1 , wherein said compound has the formula:

or a stereoisomer, pharmaceutically acceptable salt,

wherein

each R 2′ , R 3′ , and R 4′ is, independently, H or halo;

each of X a , X b , and X c is, independently, selected from O, S, NR x1 , N, or CR X2 , wherein R X1 is H or optionally substituted C 1-6 alkyl, and R X2 is H, halo, or optionally substituted C 1-6 alkyl; and

the combination of Y a and Y b or the combination of Y b and Y c together form optionally substituted C 1-12 heterocyclyl.

17. A compound having the formula:

or a stereoisomer, pharmaceutically acceptable salt.

18. A pharmaceutical composition comprising the compound of claim 1 , or a stereoisomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.