Inhibitors of mycobacterium tuberculosis lipoamide dehydrogenase

Patent metadata

Field	Value
Publication number	US-2024132480-A1
Application number	US-202218270621-A
Country	US
Kind code	A1
Filing date	Jan 7, 2022
Priority date	Jan 8, 2021
Publication date	Apr 25, 2024
Grant date	—

Abstract

Disclosed are compounds for inhibiting lipoamide dehydrogenase (Lpd), and methods of treating tuberculosis.

First claim

We claim:

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 2 , R 3 , and R 4 independently are hydrogen, halogen, amino, hydroxyl, alkoxy, cyano, nitro, carbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 5 and R 10 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each R 6a and R 6b independently is hydrogen, halogen, amino, hydroxyl, alkoxy, cyano, nitro, alkyl, alkenyl, alkynl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 6a and R 6b complete a cycloalkyl, heterocyclyl, or an oxo group; or R 5 , R 6a , and the intervening carbon and nitrogen atoms complete a 3- to 6-membered heterocyclyl;
R 7 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
is a single bond or a double bond; wherein when is a double bond, X is N or CR 8 , and Y is N or CR 1 ; when is a single bond, X is NR 5 , C(R 8 ) 2 , or C(═O) and Y is NR 5 , C(R 1 ) 2 , or C(═O);
R 1 and R 8 independently are hydrogen, halogen, amino, hydroxyl, alkoxy, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
Z is —C(R 9 ) 2 — or a bond;
each R 9 is independently H or alkyl; and
m is an integer from 1 to 3.

2 . The compound of claim 1 , wherein the compound is of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 2 , R 3 , and R 4 independently are hydrogen, halogen, amino, hydroxyl, alkoxy, cyano, nitro, alkyl, alkenyl, alkynl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 5 and R 10 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each R 6a and R 6b independently is hydrogen, halogen, amino, hydroxyl, alkoxy, cyano, nitro, alkyl, alkenyl, alkynl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 6a and R 6b complete a cycloalkyl, heterocyclyl, or an oxo group; or R 5 , R 6a , and the intervening carbon and nitrogen atoms complete a 3- to 6-membered heterocyclyl;
R 7 is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
is a single bond or a double bond; wherein when is a double bond, X is N or CR 8 , and Y is N or CR 1 ; when is a single bond, X is NR 5 , C(R 8 ) 2 , or C(═O) and Y is NR 5 , C(R 1 ) 2 , or C(═O);
R 1 and R 8 independently are hydrogen, halogen, amino, hydroxyl, alkoxy, cyano, nitro, alkyl, alkenyl, alkynl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
Z is CH 2 or a bond; and
m is an integer from 1 to 3.

3 . The compound of claim 1 or 2 , wherein the compound is a compound of formula Ia

or a pharmaceutically acceptable salt thereof.

4 . The compound of any one of claims 1 - 3 , wherein X is CR 8 .

5 . The compound of claim 4 , wherein R 8 is hydrogen, halogen, amino, alkoxy, cyano, nitro, alkyl, cycloalkyl, or heterocyclyl.

6 . The compound of claim 4 , wherein R 8 is hydrogen, halogen, cyano, or C 1-6 alkyl.

7 . The compound of claim 4 , wherein R 8 is hydrogen, cyano, or methyl.

8 . The compound of any one of claims 1 - 3 , wherein X is N.

9 . The compound of any one of claims of 1 - 8 , wherein Y is CR 1 .

10 . The compound of claim 9 , wherein R 1 is hydrogen, halogen, alkyl, alkenyl, alkynl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

11 . The compound of claim 9 , wherein R 1 is hydrogen, halogen, or C 1-6 alkyl.

12 . The compound of claim 9 , wherein R 1 is hydrogen, methyl, halogen, cyano, methylamino methyl, or methoxy methyl.

13 . The compound of claim 9 , wherein R 1 is hydrogen.

14 . The compound of any one of claims 1 - 8 , wherein Y is N.

15 . The compound of any one of claims 1 - 9 , wherein the compound is a compound of formula IIa

or a pharmaceutically acceptable salt thereof.

16 . The compound of any one of claims 1 - 15 , wherein R 2 is hydrogen, halogen, alkyl, alkenyl, alkynl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

17 . The compound of any one of claims 1 - 15 , wherein R 2 is hydrogen, halogen, or C 1-6 alkyl.

18 . The compound of any one of claims 1 - 15 , wherein R 2 is hydrogen or fluoro.

19 . The compound of any one of claims 1 - 18 , wherein R 3 is halogen, cyano, alkyl, cycloalkyl, or heterocyclyl.

20 . The compound of any one of claims 1 - 18 , wherein R 3 is halogen, cyano, C 1-6 alkyl, C 3-10 cycloalkyl, or C 1-6 haloalkyl.

21 . The compound of any one of claims 1 - 18 , wherein R 3 is cyano, methyl, chloro, bromo, cyclopropyl, or difluoromethyl.

22 . The compound of any one of claims 1 - 21 , wherein R 4 is hydrogen, halogen, alkyl, cycloalkyl, or heterocyclyl.

23 . The compound of any one of claims 1 - 22 , wherein R 4 is hydrogen or halogen.

24 . The compound of any one of claims 1 - 23 , wherein R 4 is hydrogen or fluoro.

25 . The compound of any one of claims 1 - 24 , wherein the compound of formula I is a compound of formula I-1 or I-2

or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

26 . The compound of any one of claims 1 - 25 , wherein R 5 is hydrogen, alkyl, cycloalkyl, or heterocyclyl.

27 . The compound of any one of claims 1 - 26 , wherein R 5 is C 1-6 alkyl or 3- to 10-membered heterocyclyl.

28 . The compound of any one of claims 1 - 27 , wherein R 5 is methyl, ethyl, isopropyl, or oxetanyl.

29 . The compound of any one of claims 1 - 28 , wherein R 6a and R 6b independently are hydrogen or alkyl.

30 . The compound of any one of claims 1 - 28 , wherein R 6a and R 6b are taken together to form a C 3-10 carbocycle, a 3- to 10-membered heterocycle, or an oxo group.

31 . The compound of any one of claims 1 - 25 , wherein R 5 , R 6a , and the intervening carbon and nitrogen atoms are taken together to form a 3- to 6-membered heterocycle.

32 . The compound of any one of claims 1 - 31 , wherein m is 1 or 2, such as 1.

33 . The compound of any one of claims 1 - 32 , wherein the compound of formula I is a compound of formula I-1-a, I-1-b, I-1-c, I-2-a, I-2-b, or I-2-c:

or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

34 . The compound of any one of claims of 1 - 28 , wherein the compound of formula I is a compound of formula I-3

or a pharmaceutically acceptable salt thereof.

35 . The com

Assignees

• Univ Cornell
• Tri Inst Therapeutics Discovery Inst Inc

Inventors

• Ginn John
• Sun Shan
• Michino Mayako
• Liverton Nigel
• Liang Rui
• Meinke Peter T
• Huggins David
• Bryk Ruslana
• Nathan Carl F

Classifications

• C07D403/12 Primary

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

• A61P31/06

  for tuberculosis · CPC title

• C07D209/08

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07D209/34

  in position 2 · CPC title

• C07D209/42 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title