O-glcnac transferase (ogt) inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2017166558-A1
Application number	US-201515323206-A
Country	US
Kind code	A1
Filing date	Jul 1, 2015
Priority date	Jul 1, 2014
Publication date	Jun 15, 2017
Grant date	—

Abstract

The present invention provides inhibitors of O-GlcNAc transferase. Typically, the inhibitors are quinolinone-6-sulfonamides. The invention also provides pharmaceutical compositions thereof and methods for using the same in diabetes and complications thereof, metabolic diseases, neurodegenerative diseases, proliferative diseases (e.g., cancers), autoimmune diseases, and inflammatory diseases.

First claim

What is claimed is:

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein
Ring A is of the formula

wherein a and b indicate the points of attachment to the phenyl ring;
R 1 is n-butyl, thiophene, —CH 2 -Ph, cyclohexyl, or of the formula:

R 1a is hydrogen, halogen, —OR 0 , or optionally substituted C 1-4 alkyl;
R 0 is hydrogen or C 1-4 alkyl;
each of R 2 and R 3 is independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted thiophenyl-C 1-4 alkylene, optionally substituted phenyl-C 1-4 alkylene, or optionally substituted furanyl-C 1-4 alkylene;
R 4 is hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group;
each of R 5a , R 5b , and R 5c is independently hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group;
R 1 and R 4 may optionally be taken together with the intervening nitrogen to form optionally substituted heteroaryl or optionally substituted heterocycle; and
R 2 and R 3 may optionally be taken together with the intervening nitrogen to form optionally substituted six-membered heterocycle.

2 . The compound of claim 1 of Formula (II):

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 2 of Formula (II-a):

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 2 of Formula (II-b):

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 of Formula (III):

or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 5 of Formula (III-a):

or a pharmaceutically acceptable salt thereof.

7 . The compound of claim 6 of Formula (III-a1):

or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 7 of Formula (III-a1-i):

or a pharmaceutically acceptable salt thereof.

9 . A compound of claim 7 of Formula (III-a1-ii):

or a pharmaceutically acceptable salt thereof.

10 . The compound of claim 6 of Formula (III-a2):

or a pharmaceutically acceptable salt thereof.

11 . The compound of claim 10 of Formula (III-a2-i):

or a pharmaceutically acceptable salt thereof.

12 . The compound of claim 10 of Formula (III-a2-ii):

or a pharmaceutically acceptable salt thereof.

13 . The compound of claim 1 , wherein R 1 is n-butyl.

14 . The compound of claim 1 , wherein R 1 is —CH 2 -Ph.

15 . The compound of claim 1 , wherein each of R 2 and R 3 is independently optionally substituted thiophenyl-C 1-4 alkylene, optionally substituted phenyl-C 1-4 alkylene, or optionally substituted furanyl-C 1-4 alkylene.

16 . The compound of claim 1 , wherein each of R 2 and R 3 is independently optionally substituted thiophenyl-C 1-4 alkylene or optionally substituted furanyl-C 1-4 alkylene.

17 . The compound of claim 1 , wherein each of R 2 and R 3 is independently optionally substituted thiophenyl-CH 2 —, optionally substituted phenyl-CH 2 —, or optionally substituted furanyl-CH 2 —.

18 . is The compound of claim 1 , wherein each of R 2 and R 3 independently optionally substituted thiophenyl-CH 2 — or optionally substituted furanyl-CH 2 —.

19 . The compound of claim 1 , wherein R 2 is hydrogen; and R 3 is C 1-4 alkyl.

20 . The compound of claim 1 , wherein R 2 is hydrogen; and R 3 is methyl or ethyl.

21 . The compound of claim 1 , wherein R 2 is C 1-4 alkyl; and R 3 is optionally substituted thiophenyl-C 1-4 alkylene, optionally substituted phenyl-C 1-4 alkylene, or optionally substituted furanyl-C 1-4 alkylene.

22 . R 3 The compound of claim 1 , wherein R 2 is C 1-4 alkyl; and is optionally substituted thiophenyl-C 1-4 alkylene or optionally substituted furanyl-C 1-4 alkylene.

23 . The compound of claim 1 , wherein R 2 is methyl; and R 3 is optionally substituted thiophenyl-CH 2 —, optionally substituted phenyl-CH 2 —, or optionally substituted furanyl-CH 2 —.

24 . The compound of claim 1 , wherein R 2 is methyl; and R 3 is optionally substituted thiophenyl-CH 2 — or optionally substituted furanyl-CH 2 —.

25 . The compound of claim 1 , wherein R 2 and R 3 are taken together with the intervening nitrogen to form optionally substituted six-membered heterocycle.

26 . The compound of claim 1 , wherein R 2 and R 3 are taken together with the intervening nitrogen to form optionally substituted piperidinyl, piperazinyl, or morpholinyl ring.

27 . The compound of claim 1 , wherein R 1a is halogen.

28 . The compound of claim 1 , wherein R 1a is optionally substituted C 1-4 alkyl.

29 . The compound of claim 1 , wherein R 1a is substituted C 1-4 alkyl.

30 . The compound of claim 1 , wherein R 1a is —CF 3 .

31 . The compound of claim 1 , wherein R 1a is unsubstituted C 1-4 alkyl.

32 . The compound of claim 1 , wherein R 1a is —CH 3 .

33 . The compound of claim 1 , wherein R 1a is —OR 0 .

34 . The compound of claim 1 , wherein R 1a is —OH or —OCH 3 .

35 . The compound of claim 1 , wherein R 4 is hydrogen.

36 . The compound of claim 1 , wherein R 4 is optionally substituted C 1-6 alkyl.

37 . The compound of claim 1 , wherein R 1 and R 4 are taken together with the intervening nitrogen to form optionally substituted heteroaryl or optionally substituted heterocycle.

38 . The compound of claim 37 , wherein R 1 and R 4 are taken together with the intervening nitrogen to form optionally substituted 5,6-membered heterocycle.

39 . The compound of claim 37 , wherein R 1 and R 4 are taken together with the intervening nitrogen to f

Assignees

• Harvard College
• The Us Secretary Dept Of Health And Human

Inventors

• Kahne Suzanne Walker
• Ortiz Meoz Rodrigo Fermin
• Thomas Craig Joseph
• Duveau Damien Yves

Classifications

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D215/227

  only one oxygen atom which is attached in position 2 · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/14 Primary

  containing three or more hetero rings · CPC title