Compositions comprising thienopyrimidine and thienopyridine compounds and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016137665-A1
Application number	US-201514937421-A
Country	US
Kind code	A1
Filing date	Nov 10, 2015
Priority date	Mar 13, 2013
Publication date	May 19, 2016
Grant date	—

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 2:

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

First claim

1 .- 6 . (canceled)

7 . 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 H, alkyl, substituted alkyl, alcohol, ether, amine, thioalkyl, halogen, ketone, carbocyclic ring, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, thiol, disulfide, sulfoxide, sulfone, sulfinic acid, or thiocyanate;
wherein an R 3 and Z optionally bridge two positions of a benzene ring.

8 . The compound or pharmaceutically acceptable salt of claim 7 , wherein R 1 is alkyl or substituted alkyl.

9 . The compound or pharmaceutically acceptable salt of claim 8 , wherein R 1 is a halogen-substituted alkyl group.

10 . The compound or pharmaceutically acceptable salt of claim 7 , wherein R 2 is H, alkyl, substituted alkyl, halogen, alcohol, ether, or amine.

11 . The compound or pharmaceutically acceptable salt of claim 10 , wherein R 2 is H.

12 . The compound or pharmaceutically acceptable salt of claim 7 , wherein Y is N.

13 . The compound or pharmaceutically acceptable salt of claim 7 , wherein Y is C—R a .

14 . The compound or pharmaceutically acceptable salt of claim 7 , wherein L is absent.

15 . The compound or pharmaceutically acceptable salt of claim 7 , wherein Q is alkylene.

16 . The compound or pharmaceutically acceptable salt of claim 15 , wherein Q is C 1 -C 5 alkylene.

17 . The compound or pharmaceutically acceptable salt of claim 16 , wherein Q is C 1 alkylene.

18 . The compound or pharmaceutically acceptable salt of claim 7 , wherein Q is heteroalkylene.

19 . The compound or pharmaceutically acceptable salt of claim 7 , wherein R 3 is H, alkyl, haloalkyl, alcohol, ether, amine, halogen, or methyl-sulfonyl-amine.

20 . The compound or pharmaceutically acceptable salt of claim 19 , wherein R 3 is H, alcohol, ether, or halogen.

21 . The compound or pharmaceutically acceptable salt of claim 7 , wherein n is 1.

22 . The compound or pharmaceutically acceptable salt of claim 7 , wherein n is 2, 3, or 4.

23 . The compound or pharmaceutically acceptable salt of claim 7 , comprising an R 3 at an ortho position of a benzene ring.

24 . The compound or pharmaceutically acceptable salt of claim 7 , comprising an R 3 at a meta position of a benzene ring.

25 . The compound or pharmaceutically acceptable salt of claim 7 , wherein Z is selected from dimethyl sulfone, amino-sulfonyl-methane, amino-sulfonyl-amine, methyl-sulfonyl-amino, methylamino-sulfonyl-methane, amino-sulfonyl-amino-methane, amino-sulfonyl-ethane-2-amine, amino-sulfonyl-ethane, amino-sulfonyl-dimethylamine, amino-sulfonyl-isopropane, amino-sulfonyl-heterocycloalkyl, amino-sulfonyl-alkyl, sulfinic acid, thiocyanate, and any combination thereof.

26 . The compound or pharmaceutically acceptable salt of claim 7 , wherein 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.

27 . The compound or pharmaceutically acceptable salt of claim 7 , 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.

28 . The compound or pharmaceutically acceptable salt of claim 27 , wherein Y is N.

29 . The compound or pharmaceutically acceptable salt of claim 28 , wherein R 1 is alkyl or substituted alkyl.

30 . The compound or pharmaceutically acceptable salt of claim 29 , wherein R 2 is H, alkyl, substituted alkyl, halogen, alcohol, ether, or amine.

31 . The compound or pharmaceutically acceptable salt of claim 7 , wherein the compound is selected from:

32 . A method for the treatment of leukemia comprising administering the compound or pharmaceutically acceptable salt of claim 7 to a subject suffering from leukemia.

33 . The method of claim 32 , wherein said leukemia comprises AML or ALL.

34 . A method of inhibiting the interaction of MLL and menin comprising administering the compound or pharmaceutically acceptable salt of claim 7 to a sample comprising MLL or MLL fusion protein and menin.

Assignees

• Univ Michigan

Inventors

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

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D495/16

  Peri-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title