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 3: and methods of use to inhibit the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins.
1. A compound of Formula 3:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —CH 2 CF 3 , alcohol, ether, amine, thioalkyl, ketone, carbocyclic ring, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;
each of R 2 , R 3 , and R 4 is independently H, alkyl, substituted alkyl, alcohol, ether, amine, thioalkyl, halogen, ketone, carbocyclic ring, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;
Y is N, C—H, or C—R a ;
R a is alkyl, heteroalkyl, alkyl-substituted aryl, substituted alkyl, alcohol, ether, amino, cyano, sulfonyl, aldehyde, heterocycloalkyl, or aromatic group;
L is alkylene, oxalkylene, or absent, wherein when L is absent the bonds attached to L do not exist;
each R 5 is independently alkyl, substituted alkyl, alcohol, ether, amine, thioalkyl, amide, alkylamide, halogen, ketone, carbocyclic ring, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl; and
n is an integer from 0 to 5;
wherein R 3 is optionally fused in a ring with R 2 , and
wherein an R 5 optionally bridges two positions of a benzene ring.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 1 is a halogen-substituted alkyl group.
3. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 2 is H, alkyl, substituted alkyl, halogen, alcohol, ether, or amine.
4. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 2 is H.
5. The compound or pharmaceutically acceptable salt of claim 1 , wherein Y is N.
6. The compound or pharmaceutically acceptable salt of claim 1 , wherein Y is C-R a .
7. The compound or pharmaceutically acceptable salt of claim 1 , wherein L is absent.
8. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 3 is H, alkyl, amine, NH-alcohol, alcohol, or haloalkyl.
9. The compound or pharmaceutically acceptable salt of claim 8 , wherein R 3 is H.
10. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 3 is fused in a ring with R 2 .
11. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 3 is not fused in a ring with R 2 .
12. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 4 is H, alkyl, substituted alkyl, alcohol, or amine.
13. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 5 is alkyl, substituted alkyl, alcohol, amine, halogen, or heterocycloalkyl.
14. The compound or pharmaceutically acceptable salt of claim 1 , wherein an R 5 bridges two positions of the benzene ring.
15. The compound or pharmaceutically acceptable salt of claim 1 , wherein an R 5 does not bridge two positions of the benzene ring.
16. The compound or pharmaceutically acceptable salt of claim 1 , comprising an R 5 at an ortho position of the benzene ring.
17. The compound or pharmaceutically acceptable salt of claim 1 , comprising an R 5 at a meta position of the benzene ring.
18. The compound or pharmaceutically acceptable salt of claim 1 , comprising an R 5 at a para position of the benzene ring.
19. The compound or pharmaceutically acceptable salt of claim 1 , wherein n is 0.
20. The compound or pharmaceutically acceptable salt of claim 1 , wherein n is 1.
21. The compound or pharmaceutically acceptable salt of claim 1 , wherein n is 2, 3, 4 , or 5.
22. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is selected from:
23. A method for the treatment of leukemia comprising administering the compound or pharmaceutically acceptable salt of claim 1 to a subject suffering from leukemia.
24. The method of claim 23 , wherein said leukemia comprises AML or ALL.
25. 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.