WDR5 inhibitors and modulators
Described are compounds that disrupt the WDR5-MLL1 protein-protein interaction, pharmaceutical compositions including the compounds, and methods of using the compounds and compositions for treating disorders and conditions in a subject.
1. A compound of formula (I),
or a pharmaceutically acceptable salt thereof, wherein:
Q 1 is N or CR Q1 ;
Q 2 is N or CR Q2 ;
Q 3 is N or CR Q3 ;
R Q1 , R Q2 , and R Q3 are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, and haloalkoxycarbonyl;
R 1 is hydrogen, halogen, amino, alkyl, alkylamino, dialkylamino, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, arylalkenyl, heteroarylalkyl, cycloalkyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy, or heterocyclylalkyloxy;
R 2 is hydrogen, alkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, di(cycloalkyl)alkyl, heterocyclyl, or heterocyclylalkyl;
X 1 is selected from the group consisting of a bond and —N(R a )—, wherein R a is selected from the group consisting of hydrogen, alkyl, and haloalkyl;
R 3 is alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, arylalkenyl, or heteroarylalkyl;
R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, alkoxyalkyl, alkylamino, haloalkoxyalkyl, and dialkylamino, or optionally R 4 and R 5 together with the carbon atom to which they are attached may form a spirocycle C 3 -C 6 cycloalkyl or C 4 -C 6 heterocyclic ring; and
R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b are each independently selected from the group consisting of hydrogen, alkyl, and haloalkyl;
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are each optionally substituted with one or more substituents.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q 1 is CR Q1 ; Q 2 is CR Q2 ; and Q 3 is CR Q3 .
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q 1 is N; Q 2 is CR Q2 ; and Q 3 is CR Q3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Q1 , R Q2 , and R Q3 , when present, are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkoxycarbonyl, and C 1 -C 6 -haloalkoxycarbonyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Q1 , R Q2 , and R Q3 , when present, are each independently selected from the group consisting of:
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Q1 , R Q2 , and R Q3 , when present, are each independently hydrogen.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, di-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-haloalkylamino, monocyclic aryl, monocyclic heteroaryl, C 3 -C 8 -cycloalkyl, monocyclic heterocyclyl, monocyclic aryloxy, monocyclic heteroaryloxy, C 3 -C 8 -cycloalkyloxy, monocyclic heterocyclyloxy, monocyclic aryl-C 1 -C 6 -alkyloxy, monocyclic heteroaryl-C 1 -C 6 -alkyloxy, monocyclic cycloalkyl-C 1 -C 6 -alkyloxy, or monocyclic heterocyclyl-C 1 -C 6 -alkyloxy, wherein the aryl, heteroaryl, cycloalkyl, and heterocyclyl, whether alone or part of another group, are substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -haloalkoxy.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of: hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, monocyclic aryl, monocyclic aryl-C 1 -C 6 -alkyl, monocyclic heteroaryl, monocyclic heteroaryl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, di(C 3 -C 8 -cycloalkyl)-C 1 -C 6 -alkyl, monocyclic heterocyclyl, and monocyclic heterocyclyl-C 1 -C 6 -alkyl, wherein the alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, whether alone or part of another group, are substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, and C 1 -C 6 -haloalkoxy.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of:
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is a bond or —N(H)—.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of: alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, arylalkenyl, and heteroarylalkyl, wherein the alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, whether alone or part of another group, are substituted with 0, 1, 2, 3, 4, or 5 substituents, each independently selected from the group consisting of halogen, ═O, ═S, cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, silyl, substituted silyl, t-butyldimethylsilyl, alkylsulfanyl, sulfanyl, and acyl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently selected from the group consisting of: hydrogen and C 1 -C 6 -alkyl.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are each independently selected from the group consisting of:
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having formula (I-a):
17. The compound of claim 1 , selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is isotopically labeled.
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. A method for treating leukemia in a mammal, comprising a step of administering to the mammal a therapeutically effective amount a compound of claim 1 , or pharmaceutically acceptable salt thereof.
21. A method of disrupting the protein-protein interaction between MLL1 and WDR5, comprising administration to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.