WDR5 inhibitors and modulators

Patent metadata

Field	Value
Publication number	US-10160763-B2
Application number	US-201715703289-A
Country	US
Kind code	B2
Filing date	Sep 13, 2017
Priority date	Sep 13, 2016
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

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.

First claim

What is claimed is:

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 , sele

Assignees

• Univ Vanderbilt

Inventors

• Fesik Stephen W
• Stauffer Shaun R
• Tansey William P
• Olejniczak Edward T
• Phan Jason
• Wang Feng
• Jeon Kyuok
• Gogliotti Rocco D

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title