2-Piperidinyl Substituted N,3-Dihydroxybutanamides

Patent metadata

Field	Value
Publication number	US-2016200682-A1
Application number	US-201414912137-A
Country	US
Kind code	A1
Filing date	Aug 18, 2014
Priority date	Aug 16, 2013
Publication date	Jul 14, 2016
Grant date	—

Abstract

Disclosed are compounds of formulae: (I) and pharmaceutically acceptable salts thereof, wherein the variables, R1, R2, Y, and Z are defined herein. These compounds are useful for treating Gram-negative bacteria infections.

First claim

What is claimed is:

1 . A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein
Y represents aryl optionally substituted with R 4 , heteroaryl optionally substituted with R 4 , or heterocyclyl optionally substituted with R 4 ;
Z represents aryl optionally substituted with R 5 , heteroaryl optionally substituted with R 5 , or heterocyclyl optionally substituted with R 5 ;
R 1 is hydrogen, aryl optionally substituted with R 6 , heteroaryl optionally substituted with R 6 , or heterocyclyl optionally substituted with R 6 ;
R 2 is

each R 4 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy, or two R 4 groups when attached to the same carbon atom form ═O;
each R 5 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy, or two R 5 groups when attached to the same carbon atom form ═O;
each R 6 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —SH, —S(C 1 -C 6 alkyl), oxo, hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), amino(C 1 -C 6 alkyl), —CONH 2 , —CON(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CONH—OH, —CONH—NH 2 , —COH, —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —OCO(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkoxy), —NHCO(C 1 -C 6 alkyl), —NHCONH 2 , —NHCONH(C 1 -C 6 alkyl), —NHC(═NH)NH 2 , —NH—S(O) 0-2 —(C 1 -C 6 alkyl), —NH—S(O) 0-2 -aryl, and —NH—S(O) 0-2 -heteroaryl;
R 7 is C 1 -C 6 alkyl optionally substituted with one or more R 9 ;
R 8 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, oxo, —CONH 2 , —CON(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CONH—OH, —CONH—NH 2 , —CO 2 H, and —CO(C 1 -C 6 alkyl);
R 3 is hydrogen or C 1 -C 6 alkyl;
each R 9 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —SH, —S(C 1 -C 6 alkyl), oxo, hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), amino(C 1 -C 6 alkyl), —CONH 2 , —CON(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CONH—OH, —CONH—NH 2 , —COH, —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —OCO(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkoxy), —NHCO(C 1 -C 6 alkyl), —NHCONH 2 , —NHCONH(C 1 -C 6 alkyl), —NHC(═NH)NH 2 , —NH—S(O) 0-2 —(C 1 -C 6 alkyl), —NH—S(O) 0-2 -aryl, and —NH—S(O) 0-2 -heteroaryl.

2 . A compound according to claim 1 , wherein R 2 is of formula:

R 24 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —SH, —S(C 1 -C 6 alkyl), hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), amino(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCONH 2 , —NHCONH(C 1 -C 6 alkyl), —OCO(C 1 -C 6 alkyl), and —NHCO(C 1 -C 6 alkoxy);
R 25 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —SH, —S(C 1 -C 6 alkyl), hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), and amino(C 1 -C 6 alkyl);
R 26 is C 1 -C 8 alkyl or C 1 -C 6 haloalkyl;
R 8 is —CONH 2 , —CON(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CONH—OH, —CONH—NH 2 , —CO 2 H, or —CO 2 (C 1 -C 6 alkyl); and
R 3 is hydrogen, C 1 -C 6 alkyl.

3 . A compound according to claim 2 , wherein R 26 is C 1 haloalkyl.

4 . A compound according to claim 3 , wherein R 26 is —CH 2 F, —CHF 2 , or —CF 3 .

5 . A compound according to claim 4 , wherein R 26 is —CHF 2 .

6 . A compound according to claim 2 , wherein R 26 is C 1 -C 6 alkyl.

7 . A compound according to claim 6 , wherein R 26 is methyl.

8 . A compound according to any one of claims 2 - 7 , wherein R 25 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

9 . A compound according to claim 8 , where R 25 is hydrogen or C 1 -C 6 alkyl.

10 . A compound according to claim 9 , where R 25 is hydrogen.

11 . A compound according to claim 8 , where R 25 is C 1 -C 6 alkyl.

12 . A compound according to claim 11 , where R 25 is methyl.

13 . A compound according to claim 2 , wherein R 25 is methyl, and R 26 is —CHF 2 .

14 . A compound according to claim 2 , wherein R 25 is hydrogen, and R 26 is —CHF 2 .

15 . A compound according to any one of claims 2 - 14 , wherein R 24 is selected from the group consisting of —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —SH, —S(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCONH 2 , —NHCONH(C 1 -C 6 alkyl), —OCO(C 1 -C 6 alkyl), and —NHCO(C 1 -C 6 alkoxy).

16 . A compound according to claim 15 , wherein R 24 is selected from the group consisting of —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHCO(C 1 -C 6 alkyl), —NHCONH 2 , —NHCONH(C 1 -C 6 alkyl), and —NHCO(C 1 -C 6 alkoxy).

17 . A compound according to claim 16 , wherein R 24 is —NH 2 .

18 . A compound according to claim 16 , wherein R 24 is —NHCO(C 1 -C 6 alkyl), —NHCONH 2 , —NHCONH(C 1 -C 6 alkyl), or —NHCO(C 1 -C 6 alkoxy).

19 . A compound according to claim 15 , wherein R 24 is —OH or C 1 -C 6 alkoxy.

20 . A compound according to claim 19 , wherein R 24 is —OH.

21 . A compound according to any one of claims 2 - 20 , wherein R 8 is —CONH—OH, —CONH—NH 2 , or —CO 2 H.

22 . A compound according to claim 21 , wherein R 8 is —CONH—OH.

23 . A compound according to any one of claims 2 - 22 , wherein R 3 is hydrogen.

24 . A compound according to any one of claims 2 - 22 , wherein R 3 is methyl.

25 . A compound according to claim 2 , where R 2 is of formula:

26 . A compound according to claim 1 , wherein
R 7 is C 1 -C 6 alkyl optionally substituted with one or more R 9 ; R 8 is —CONH 2 , —CON(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CONH—OH, —CONH—NH 2 , —CO 2 H, or —CO 2 (C 1 -C 6 alkyl); and R 3 is hydrogen C 1 -C 6 alkyl.

27 . A compound according to claim 26 , wherein R 3 is hydrogen.

28 . A compound according to claim 26 , wherein R 3 is methyl.

29 . A compound according to any one of claims 26 - 27 , wherein R 8 —CONH—OH or —CONH—NH 2 .

30 . A comp

Assignees

• Univ Duke

Inventors

• Zhou Pei
• Toone Eric J
• Nicholas Robert A

Classifications

• C07D211/06 Primary

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D211/14

  with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61K31/455

  Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides · CPC title