Compositions comprising thienopyrimidine and thienopyridine compounds and methods of use thereof
The present disclosure relates generally to thienopyrimidine and thienopyridine compounds and methods of use thereof. In particular embodiments, the present disclosure provides compositions comprising thienopyrimidine and thienopyridine compounds of Formula 2: and methods of use to inhibit the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins.
1. A compound of Formula 2:
or a pharmaceutically acceptable salt thereof, wherein:
each of R 1 and R 2 is independently H, alkyl, substituted alkyl, alcohol, ether, amine, thioalkyl, halogen, ketone, carbocyclic ring, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, thiol, disulfide, sulfoxide, or sulfone;
Y is N, C—H, or C—R a ;
R a is alkyl, heteroalkyl, alkyl-substituted aryl, substituted alkyl, alcohol, ether, amino, cyano, aldehyde, heterocycloalkyl, or aromatic group;
L is alkylene, oxalkylene, or absent;
wherein when L is absent the bonds attached to L do not exist;
Q is alkylene or heteroalkylene;
each R 3 is independently H, alkyl, substituted alkyl, alcohol, ether, amine, thioalkyl, halogen, ketone, carbocyclic ring, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;
n is 1, 2, 3, or 4; and
Z is CHR 4 SO 2 R 5 or —NR 4 SO 2 R 5 , wherein R 4 is H, alkyl, substituted alkyl, alcohol, ether, amine, or carbocyclic ring and R 5 is H, alkyl, substituted alkyl, alcohol, ether, amine, thioalkyl, ketone, carbocyclic ring, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is alkyl or substituted alkyl.
3. The compound or pharmaceutically acceptable salt of claim 2 , wherein R 1 is a halogen-substituted alkyl group.
4. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is H, alkyl, substituted alkyl, halogen, alcohol, ether, or amine.
5. The compound or pharmaceutically acceptable salt of claim 4 , wherein R 2 is H.
6. The compound or pharmaceutically acceptable salt of claim 1 , wherein Y is N.
7. The compound or pharmaceutically acceptable salt of claim 1 , wherein Y is C—R a .
8. The compound or pharmaceutically acceptable salt of claim 1 , wherein L is absent.
9. The compound or pharmaceutically acceptable salt of claim 1 , wherein Q is alkylene.
10. The compound or pharmaceutically acceptable salt of claim 9 , wherein Q is C 1 -C 5 alkylene.
11. The compound or pharmaceutically acceptable salt of claim 10 , wherein Q is C 1 alkylene.
12. The compound or pharmaceutically acceptable salt of claim 1 , wherein Q is heteroalkylene.
13. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 3 is H, alkyl, haloalkyl, alcohol, ether, amine, halogen, or methyl-sulfonyl-amine.
14. The compound or pharmaceutically acceptable salt of claim 13 , wherein R 3 is H, alcohol, ether, or halogen.
15. The compound or pharmaceutically acceptable salt of claim 1 , wherein n is 1.
16. The compound or pharmaceutically acceptable salt of claim 1 , wherein n is 2, 3, or 4.
17. The compound or pharmaceutically acceptable salt of claim 1 , comprising an R 3 at an ortho position of a benzene ring.
18. The compound or pharmaceutically acceptable salt of claim 1 , comprising an R 3 at a meta position of a benzene ring.
19. The compound or pharmaceutically acceptable salt of claim 1 , wherein Z is —CHR 4 SO 2 R 5 or —NR 4 SO 2 R 5 , wherein R 4 is H, alkyl, or substituted alkyl and R 5 is H, alkyl, or substituted alkyl.
20. The compound or pharmaceutically acceptable salt of claim 19 , wherein Y is N.
21. The compound or pharmaceutically acceptable salt of claim 20 , wherein R 1 is alkyl or substituted alkyl.
22. The compound or pharmaceutically acceptable salt of claim 21 , wherein R 2 is H, alkyl, substituted alkyl, halogen, alcohol, ether, or amine.
23. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is selected from:
24. A method for the treatment of leukemia comprising administering the compound or pharmaceutically acceptable salt of claim 1 to a subject suffering from leukemia.
25. The method of claim 24 , wherein said leukemia comprises AML or ALL.
26. A method of inhibiting the interaction of MLL and menin comprising administering the compound or pharmaceutically acceptable salt of claim 1 to a sample comprising MLL or MLL fusion protein and menin.