Quinazolinone-based oncogenic-RAS-selective lethal compounds and their use

1. A compound having the structure (1):

wherein

R 1 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, and halogen;

R 2 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl, heteroaryl, C 1-4 aralkyl;

R 3 is selected from the group consisting of nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

with the proviso that when X is C, n=0, and R 3 is nothing, R 1 cannot be H when R 2 is CH 3 ,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 having the structure (10):

wherein

R 1 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, and halogen;

R 3 is selected from the group consisting of nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 having the structure (20):

wherein

R 3 is selected from the group consisting of nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , which is selected from the group consisting of:

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

5. A compound having the structure (30):

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

6. A composition comprising a pharmaceutically acceptable carrier and a compound having the structure (1):

wherein

R 1 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, and halogen;

R 2 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl, heteroaryl, C 1-4 aralkyl;

R 3 is selected from the group consisting of nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

with the proviso that when X is C, n=0, and R 3 is nothing, R 1 cannot be H when R 2 is CH 3 ,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

7. A composition according to claim 6 , wherein the compound has the structure (10):

wherein

R 1 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, and halogen

R 3 is selected from the group consisting of nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

8. A composition according to claim 6 , wherein the compound has the structure (20):

wherein

R 3 is selected from the group consisting nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

9. A composition according to claim 6 , wherein the compound is selected from the group consisting of:

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

10. A composition comprising a pharmaceutically acceptable carrier and a compound having the structure (30):

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

11. A method for modulating a lipoxygenase in a ferroptosis cell death pathway comprising administering to a cell an effective amount of a compound having the structure (1):

wherein

R 1 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, and halogen;

R 2 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl, heteroaryl, C 1-4 aralkyl;

R 3 is selected from the group consisting of nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

with the proviso that when X is C, n=0, and R 3 is nothing, R 1 cannot be H when R 2 is CH 3 ,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

12. The method according to claim 11 , wherein the compound has the structure (10):

wherein

R 1 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, and halogen

R 3 is selected from the group consisting of nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

13. The method according to claim 11 , wherein the compound has the structure (20):

wherein

R 3 is selected from the group consisting nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

14. The method according to claim 11 , wherein the compound is selected from the group consisting of:

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

15. The method according to claim 11 , wherein the compound has the structure (30):

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

16. The method according to claim 11 , wherein the modulation comprises activation of one or more polypeptides encoded by ALOX genes.

17. A method for depleting reduced glutathione (GSH) in a cell harboring an oncogenic RAS mutation comprising administering to the cell an effective amount of a compound having the structure (1):

wherein

R 1 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, and halogen;

R 2 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl, heteroaryl, C 1-4 aralkyl;

R 3 is selected from the group consisting of nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

with the proviso that when X is C, n=0, and R 3 is nothing, R 1 cannot be H when R 2 is CH 3 ,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

18. A compound having the structure (100):

wherein

R 1 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, and halogen;

R 2 is selected from the group consisting of H, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, aryl, heteroaryl, C 1-4 aralkyl;

R 3 is selected from the group consisting of nothing, H, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

R 4 and R 5 are independently selected from the group consisting of H, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

R 6 is selected from the group consisting of H, —NH 2 , C 1-4 alkyl, C 1-4 alkoxy, carbonyl, aryl, heteraryl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

with the proviso that when X is C, n=0, and R 3 is nothing, R 1 cannot be H when R 2 is CH 3 ,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

19. The compound according to claim 18 having the structure (200):

wherein

R 3 is selected from the group consisting of nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

R 6 is selected from the group consisting of H, —NH 2 , C 1-4 alkyl, C 1-4 alkoxy, carbonyl, aryl, heteraryl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

X is selected from the group consisting of C, N, and O; and

n is an integer from 0-6,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

20. The compound according to claim 18 having the structure (300):

wherein

R 3 is selected from the group consisting of nothing, C 1-4 alkyl, C 1-4 alkoxy, carbonyl, C 3-8 cycloalkyl, and C 3-8 heterocycloalkyl;

n is an integer from 0-6,

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

21. The compound according to claim 18 , which is selected from the group consisting of:

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

22. A composition comprising a pharmaceutically acceptable carrier and a compound according to claim 18 .

23. A method for modulating a lipoxygenase in a ferroptosis cell death pathway comprising administering to a cell an effective amount of a compound according to claim 18 .

24. The method according to claim 23 , wherein the modulation comprises activation of one or more polypeptides encoded by ALOX genes.

25. A method for modulating a lipoxygenase in a ferroptosis cell death pathway comprising administering to a cell an effective amount of a compound selected from the group consisting of:

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

26. The method according to claim 25 , wherein the modulation comprises activation of one or more polypeptides encoded by ALOX genes.

27. A method for depleting reduced glutathione (GSH) in a cell harboring an oncogenic RAS mutation comprising administering to the cell an effective amount of a compound according to claim 18 .

28. A method for depleting reduced glutathione (GSH) in a cell harboring an oncogenic RAS mutation comprising administering to the cell an effective amount of a compound selected from the group consisting of:

or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.