Compositions comprising thienopyrimidine and thienopyridine compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9505781-B2
Application number	US-201414773686-A
Country	US
Kind code	B2
Filing date	Mar 10, 2014
Priority date	Mar 13, 2013
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

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 4b:

and methods of use to inhibit the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins.

First claim

The invention claimed is:

1. A compound of Formula 4b:

or a pharmaceutically acceptable salt thereof, wherein
each of R 1 , R7, R 3 , R 4 , R 5 , R 6 , R 7 , and R is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkene, alkyne, heteroalkyl, alcohol, diol, substituted diol, ether, amine, alkylamine, thiol, thioalkyl, halogen, carbocyclic ring, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, aldehyde; ketone, CO—(CH 2 ) 1-6 —H, CO-ethenyl, CO-propenyl, CO-ethynyl, CO-propynyl, CO—(CH 2 ) 1-6 -aryl, CO—(CH 2 ) 1-6 -heteroaryl, CO—(CH 2 ) 1-3 -trifluoromethane, CO—(CH 2 ) 1-6 -cycloalkane, carboxylic acid, alkylcarboxylic acid, ester, alkylester, amide, CO-amino-dialkyl, alkylamide; sulfoxide, sulfone, SO 2 —(CH 2 ) 1-6 —H, SO 2 -alkenyl, SO 2 -alkynyl, SO 2 NH 2 , SO 2 —NH-alkyl, SO 2 -amino-dialkyl, sulfinic acid, cyano, alkylcyano, methylcarbonitrile, cyanate, thiocyanate, azide, or phosphate;
wherein R 6 is present at one or more positions of the indole;
Y is N, C—H, or
R a is alkyl, substituted alkyl, Amy, cycloalkyl, heteroalkyl, alkyl-substituted aryl, substituted aryl, aromatic heterocycle, non-aromatic heterocycle, alcohol, ether, amine, cyano, sulfonyl, aldehyde, or aromatic group;
L is alkylene, oxalkylene, or absent; wherein when L is absent the bonds attached to L do not exist; and
each of E and G is independently N or C, wherein each of E and G is independently optionally substituted with R 6 .

2. The compound or pharmaceutically acceptable salt of claim 1 , represented by the structure of Formula 4:

3. The compound or pharmaceutically acceptable salt of claim 1 , represented by the structure of Formula 4c:

wherein X is a bond, alkylene, substituted alkylene, heteroalkylene, or substituted heteroalkylene;
J is N, C—H, or C—R 12 ;
M is N—R 9 , O, S, SO 2 , or C—(R 9 ) 2 ;
each R 9 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkene, alkyne, heteroalkyl, alcohol, diol, substituted diol, ether, amine, alkylamine, thiol, thioalkyl, halogen, carbocyclic ring, aryl, substituted aryl, heteroaryl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, aldehyde, ketone, CO-alkyl, CO-alkenyl, CO-alkynyl, CO—(CH 2 ) 1-6 -aryl, CO—(CH 2 ) 1-6 -heteroaryl, CO—(CH 2 ) 1-3 -trifluoromethane, CO—(CH 2 ) 1-6 -cycloalkane, carboxylic acid, alkylcarboxylic acid, ester, alkylester, amide, CO-amino-dialkyl, alkylamide, sulfoxide, sulfone, SO 2 —(CH 2 ) 1-6 —H, SO 2 -alkenyl, SO 2 -alkynyl, SO 2 NH 2 , SO 2 —NH— alkyl, SO 2 -amino-dialkyl, sulfinic acid, cyano, alkylcyano, methylcarbonitrile, cyanate, thiocyanate, azide, or phosphate;
R 10 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkene, alkyne, heteroalkyl, alcohol, diol, substituted diol, ether, amine, alkylamine, thiol, thioalkyl, halogen, carbocyclic ring, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, aldehyde, ketone, CO—(CH 2 ) 1-6 —H, CO-ethenyl, CO-propenyl, CO-ethynyl, CO-propynyl, CO—(CH 2 ) 1-6 -aryl, CO—(CH 2 ) 1-6 -heteroaryl, CO—(CH 2 ) 1-3 -trifluoromethane, CO—(CH 2 ) 1-6 -cycloalkane, carboxylic acid, alkylcarboxylic acid, ester, alkylester, amide, CO-amino-dialkyl, alkylamide, sulfoxide, sulfone, SO 2 —(CH 2 ) 1-6 —H, SO 2 -alkenyl, SO 2 -alkynyl, SO 2 NH 2 , SO 2 —NH-alkyl, SO 2 -amino-dialkyl, sulfinic acid, ═O, cyano, alkylcyano, methylcarbonitrile, cyanate, thiocyanate, azide, or phosphate; and
R 12 is alkyl, substituted alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, alcohol, amino, alkoxy, alkylamine, halogen, ketone, CO-alkyl, CO-alkenyl, CO-alkynyl, CO—(CH 2 ) 1-6 -aryl, CO—(CH 2 ) 1-6 -heteroaryl, CO—(CH 2 ) 1-3 -trifluoromethane, CO—(CH 2 ) 1-6 -cycloalkane, carboxylic acid, alkylcarboxylic acid, ester, alkylester, amide, alkylamide, cyano, alkylcyano, CONH 2 , SO 2 NH 2 , SO 2 -amino-dialkyl, SO 2 —NH-alkyl, CO-amino-dialkyl, SO 2 —(CH 2 ) 1-6 —H, SO 2 -alkenyl, SO 2 -alkynyl, carbocyclic ring, aryl, substituted aryl, heteroaryl, or heterocycloalkyl.

4. The compound or pharmaceutically acceptable salt of claim 3 , wherein X is (CH 2 ) 0-6 .

5. The compound or pharmaceutically acceptable salt of claim 3 , wherein X is alkylene or substituted alkylene.

6. The compound or pharmaceutically acceptable salt of claim 3 , wherein X is heteroalkylene or substituted heteroalkylene.

7. The compound or pharmaceutically acceptable salt of claim 3 , wherein J is N.

8. The compound or pharmaceutically acceptable salt of claim 3 , wherein M is N—R 9 .

9. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 9 is H, alkyl, substituted alkyl, alcohol, formyl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO—(CH 2 ) 1-6 -aryl, CO—(CH 2 ) 1-6 -heteroaryl, CO—(CH 2 ) 1-3 -trifluoromethane, CO—(CH 2 ) 1-6 -cycloalkane, CONH 2 , SO 2 NH 2 , SO 2 -amino-dialkyl, SO 2 —NH-alkyl, CO-amino-dialkyl, SO 2 —(CH 2 ) 1-6 —H, SO 2 -alkenyl, or SO 2 -alkynyl.

10. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 10 is H, alkyl, ═O, trifluoromethane, or alcohol.

11. The compound or pharmaceutically acceptable salt of claim 1 , represented by the structure of Formula 4d:

wherein T is heteroaryl, cycloalkane, 5-membered ring comprising carbon atoms and one or more of N, S, and/or O; or 6-membered ring comprising carbon atoms and one or more of N, S, and/or O; wherein T is optionally substituted with R 11 at any position; and
R 11 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkene, alkyne, heteroalkyl, alcohol, diol, substituted diol, ether, amine, alkylarnine, thiol, thioalkyl, halogen, carbocyclic ring, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, aldehyde, ketone, CO—(CH 2 ) 1-6 —H, CO-ethenyl, CO-propenyl, CO-ethynyl, CO-propynyl, CO—(CH 2 ) 1-6 -aryl, CO—(CH 2 ) 1-6 -heteroaryl, CO—(CH 2 ) 1-3 -trifluoromethane, CO—(CH 2 ) 1-6 -cycloalkane, carboxylic add, alkylcarboxylic add, ester, alkylester, amide, CO-amino-dialkyl, alkylamide, sulfoxide, sulfone, SO 2 —(CH 2 ) 1-6 —H, SO 2 -alkenyl, SO 2 -alkynyl, SO 2 NH 2 , SO 2 —NH-alkyl, SO 2 -amino-dialkyl, sulfinic acid, cyano, alkylcyano, methylcarbonitrile, cyanate, thiocyanate, azide, or phosphate.

12. The compound or pharmaceutically acceptable salt of claim 11 , wherein T is cycloalkane.

13. The compound or pharmaceutically acceptable salt of claim 12 , wherein T comprises two or more rings that are fused, bridged, or spiro-connected.

14. The compound or pharmaceutically acceptable salt of claim 11 , wherein T is 5-membered ring comprising carbon atoms and one or more of N, S, and/or O or 6-membered ring comprising carbon atoms and one or more of N, S, and/or 0.

15. The compound or pharmaceutically acceptable salt of claim 11 , wherein R 11 is H, alkyl, substituted alkyl, alcohol, ether, amine, halogen, ketone, or amide.

16. The compound or pharmaceutically acceptable salt of claim 11 , wherein R 11 is H, a

Assignees

• Univ Michigan Regents

Inventors

• Grembecka Jolanta
• Cierpicki Tomasz
• Borkin Dmitry
• Hess Jay
• Sun Duxin
• Li Xiaoqin

Classifications

• C07D495/16

  Peri-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title