Benzoylglycine derivatives and methods of making and using same

Patent metadata

Field	Value
Publication number	US-11034649-B2
Application number	US-201716096611-A
Country	US
Kind code	B2
Filing date	Apr 25, 2017
Priority date	Apr 25, 2016
Publication date	Jun 15, 2021
Grant date	Jun 15, 2021

Abstract

Disclosed are compounds of formulae: and pharmaceutically acceptable salts thereof, wherein the variables, R1, R2, R3, R4, R5, R6, R7, R11, R12, R13, R14, R15, R16, R17, n, and m are defined herein. These compounds are useful for treating Gram-negative bacteria infections. Also disclosed are methods of making these compounds.

First claim

What is claimed is:

1. A compound, which is:

or a pharmaceutically acceptable salt thereof.

2. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein
m is an integer 0, 1, 2, 3, or 4;
R 11 is —C≡C—R 10 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —CO(C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CO(C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CO 2 H, C 3 -C 8 cycloalkyl optionally substituted with R 18 , (C 3 -C 8 cycloalkyl)C 1 -C 6 alkyl- optionally substituted with R 18 , or heterocyclyl optionally substituted with R 18 ;
wherein R 10 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —CO(C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CO(C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CO 2 H, C 3 -C 8 cycloalkyl optionally substituted with R 19 , (C 3 -C 8 cycloalkyl)C 1 -C 6 alkyl- optionally substituted with R 19 , or heterocyclyl optionally substituted with R 19 ;

R 12 is selected from the group consisting of 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 13 is selected from the group consisting of 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 14 is C 1 -C 6 haloalkyl;
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, C 1 -C 6 haloalkoxy, —CONH 2 , —CON(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CONH—OH, —CONH—OCO(C 1 -C 6 alkyl), —CONH—NH 2 , —CO 2 H, and —CO 2 (C 1 -C 6 alkyl);
R 16 is hydrogen or C 1 -C 6 alkyl;
each R 17 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 18 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, —C 1 -C 6 alkyl-OH, —C 1 -C 6 alkyl-(C 1 -C 6 alkoxy), —C 1 -C 6 alkyl-NH 2 , —C 1 -C 6 alkyl-NH—C 1 -C 6 alkyl), —C 1 -C 6 alkyl-N(C 1 -C 6 alkyl) 2 , —C 1 -C 6 alkyl-NH(SO 2 C 1 -C 6 alkyl), —CONH 2 , —CON(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —NH(SO 2 C 1 -C 6 alkyl), —CONH—OH, —CONH—OCO(C 1 -C 6 alkyl), —C(NH)NH—OH, —CONH—NH 2 , —CO(C 1 -C 6 alkyl), —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CONH 2 , —C 1 -C 6 alkyl-CON(C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CON(C 1 -C 6 alkyl) 2 , —C 1 -C 6 alkyl-CONH—OH, —C 1 -C 6 alkyl-CO(C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CO 2 H, and —C 1 -C 6 alkyl-CO 2 (C 1 -C 6 alkyl); or two R 18 groups when attached to the same carbon atom form ═O; and
each R 19 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, —C 1 -C 6 alkyl-OH, —C 1 -C 6 alkyl-(C 1 -C 6 alkoxy), —C 1 -C 6 alkyl-NH 2 , —C 1 -C 6 alkyl-NH—C 1 -C 6 alkyl), —C 1 -C 6 alkyl-N(C 1 -C 6 alkyl) 2 , —C 1 -C 6 alkyl-NH(SO 2 C 1 -C 6 alkyl), —CONH 2 , —CON(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —NH(SO 2 C 1 -C 6 alkyl),—CONH—OH, —CONH—OCO(C 1 -C 6 alkyl), —C(NH)NH—OH, —CONH—NH 2 , —CO(C 1 -C 6 alkyl), —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CONH 2 , —C 1 -C 6 alkyl-CON(C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CON(C 1 -C 6 alkyl) 2 , —C 1 -C 6 alkyl-CONH—OH, —C 1 -C 6 alkyl-CO(C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CO 2 H, and —C 1 -C 6 alkyl-CO 2 (C 1 -C 6 alkyl); or two R 19 groups when attached to the same carbon atom form ═O.

3. A compound according to claim 2 , wherein R 14 is —CH 2 F, —CHF 2 , or —CF 3 .

4. A compound according to claim 2 , wherein R 12 is halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

5. A compound according to claim 2 , wherein R 13 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).

6. A compound according to claim 2 , wherein R 16 is hydrogen.

7. A compound according to claim 2 , wherein R 11 is —C≡C—R 10 , and R 10 is C 3 -C 8 cycloalkyl optionally substituted with R 19 .

8. A compound according to claim 2 , wherein Ru is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —CO(C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CO(C 1 -C 6 alkyl), —C 1 -C 6 alkyl-CO 2 H, C 3 -C 8 cycloalkyl optionally substituted with R 18 , or heterocyclyl optionally substituted with R 18 .

9. A compound according to claim 2 , which is:

or pharmaceutically acceptable salts thereof.

10. A compound, which is:

or pharmaceutically acceptable salts thereof.

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

12. A method of treating Gram-negative bacterial infections, the method comprising administering to a subject in need of such treatment an effective amount of one or more compounds of formula:

or a pharmaceutically acceptable salt thereof, wherein
Y represents aryl optionally substituted with R 8 , heteroaryl optionally substituted with R 8 , or heterocyclyl optionally substituted with R 8 ;
n is an integer 0, 1, 2, 3, or 4;
R 1 is hydrogen, C 1 -C 6 alkyl optionally substituted with R 9 , aryl optionally substituted with R 9 , heteroaryl optionally substituted with R 9 , or heterocyclyl optionally substituted with R 9 ;
R 2 is selected from the group consisting of 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 3 is selected from the group consisting of 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

Assignees

• Univ Duke
• Univ North Carolina Chapel Hill

Inventors

• Zhou Pei
• Toone Eric J
• Nicholas Robert A
• Gopalaswamy Ramesh
• Liang Xiaofei
• Navas Iii Frank

Classifications

• C07D295/10

  substituted by doubly bound oxygen or sulphur atoms · CPC title

• C07D277/40

  Unsubstituted amino or imino radicals · CPC title

• C07C2601/02

  with a three-membered ring · CPC title

• C07D309/10

  Oxygen atoms · CPC title

• C07C2601/14

  The ring being saturated · CPC title