Antibacterial compounds

Patent metadata

Field	Value
Publication number	US-10189786-B2
Application number	US-201414912136-A
Country	US
Kind code	B2
Filing date	Aug 18, 2014
Priority date	Aug 16, 2013
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

Disclosed are compounds of formulae (I) and (II) and pharmaceutically acceptable salts thereof, wherein the variables, R, R 1 , R 2 , R 3 , Y, Z, X, R 12 , R 17 , R 18 , R 19 , Y 1 , Z 1 , X 1 , and X 2 are defined herein. These compounds are useful for treating Gram-negative bacteria infections, such as Neisseria gonorrhoeae bacterial infections.

First claim

What is claimed is:

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein
X 1 represents —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH═CH—, —CH═CHCH 2 —, —CH 2 CH═CH—, —C(O)NH—, or —C(O)NH—CH 2 —;
X 2 represents CH 2 or NR 13 ;
Y 1 represents phenyl optionally substituted with R 14 , or thiophenyl optionally substituted with R 14 ;
Z 1 represents phenyl optionally substituted with R 15 , or thiophenyl optionally substituted with R 15 ;
R 12 is hydrogen, C 1 -C 6 alkyl optionally substituted with R 16 , or thiophenyl optionally substituted with R 16 ;
and

 moiety is of formula:

wherein
R 13 is hydrogen or C 1 -C 6 alkyl;
each R 14 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;
each R 15 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;
each R 16 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, aryl, aryl(C 1 -C 6 alkyl), heteroaryl, heteroaryl(C 1 -C 6 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 6 alkyl), wherein each alkyl, aryl, heteroaryl, or heterocyclyl moiety is optionally substituted with one or more R 11 ;
R 18 is independently selected from the group consisting of —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 2 (C 1 -C 6 alkyl);
R 19 is hydrogen or C 1 -C 6 alkyl;
R 27 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 28 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 29 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; and
each R 11 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.

2. A compound according to claim 1 , wherein R 28 is methyl.

3. A compound according to claim 1 , wherein
R 27 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).

4. A compound that is:

or pharmaceutically acceptable salts thereof.

5. A pharmaceutical composition comprising a compound according claim 1 and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

6. A compound according to claim 1 , wherein R 29 is methyl, —CH 2 F, —CHF 2 , or —CF 3 .

7. A compound according to claim 1 , where R 28 is hydrogen.

8. A compound according to claim 1 , wherein R 27 is —NH 2 , —NHCO(C 1 -C 6 alkyl), —NHCONH 2 , —NHCONH(C 1 -C 6 alkyl), or —NHCO(C 1 -C 6 alkoxy).

9. A compound according to claim 1 , wherein R 27 is —OH or C 1 -C 6 alkoxy.

10. A compound according to claim 1 , wherein R 18 is —CONH—OH, —CONH—NH 2 , or —CO 2 H.

11. A compound according to claim 1 , wherein R 19 is hydrogen or methyl.

12. A compound according to claim 1 , where

is of formula:

13. A compound according to claim 1 , wherein —X 1 —CH 2 —X 2 —moiety is: —(CH 2 ) 3 —, —(CH 2 ) 4 —, or —(CH 2 ) 5 —.

14. A compound according to claim 1 , wherein —X 1 —CH 2 —X 2 — moiety is: —(CH 2 ) 2 NH—, —(CH 2 ) 3 NH—, or —(CH 2 ) 4 NH—.

15. A compound according to claim 1 , wherein —X 1 —CH 2 —X 2 — moiety is: —C(O)NH 2 —(CH 2 ) 2 —,—C(O)NH 2 —CH 2 —NH—, or —C(O)NH 2 —(CH 2 ) 2 —NH—.

16. A compound according to claim 1 , wherein the compound is of formula:

17. A compound according to claim 1 , wherein the compound is of formula:

18. A compound according to claim 1 , wherein the compound is of formula:

19. A compound of claim 1 , that is:

or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Duke
• Univ Of North Carolina

Inventors

• Zhou Pei
• Toone Eric J
• Nicholas Robert A

Classifications

• C07D333/38

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

• C07D333/20

  by nitrogen atoms (nitro, nitroso radicals C07D333/12) · CPC title

• C07D249/06

  with aryl radicals directly attached to ring atoms · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title