Antibacterial Compounds

Patent metadata

Field	Value
Publication number	US-2016200673-A1
Application number	US-201414912136-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 (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

1 . A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein
X represents CH or N;
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, C 1 -C 6 alkyl optionally substituted with R 6 , aryl optionally substituted with R 6 , heteroaryl optionally substituted with R 6 , or heterocyclyl optionally substituted with R 6 ;
R 2 is

R 3 is hydrogen or C 1 -C 6 alkyl;
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, and wherein each C 1 -C 6 alkyl, C 1 -C 6 alkylamino, and C 1 -C 6 alkoxy within R 14 is optionally substituted with aryl, heteroaryl, or heterocyclyl, wherein each aryl, heteroaryl, and heterocyclyl moiety is optionally substituted with one or more R 10 ;
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, —S(O) 2 —(C 1 -C 6 alkyl), aryl, aryl(C 1 -C 6 alkyl), heteroaryl, heteroaryl(C 1 -C 6 alkyl), heterocyclyl, or heterocyclyl(C 1 -C 6 alkyl), wherein each alkyl, aryl, heteroaryl, or heterocyclyl moiety is optionally substituted with one or more R 10 ;
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 2 (C 1 -C 6 alkyl);
R 9 is hydrogen or C 1 -C 6 alkyl;
each R 10 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.

2 . A compound according to claim 1 , wherein X represents C and R 3 is hydrogen of formula:

3 . A compound according to claim 1 , wherein X represents N formula:

4 . A compound according to claim 3 , 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 6 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(C 1 -C 6 alkyl); and
R 9 is hydrogen, C 1 -C 6 alkyl; and

R 3 is hydrogen or methyl.

5 . (canceled)

6 . A compound according to claim 2 , 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 6 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 9 is hydrogen, C 1 -C 6 alkyl.

7 . A compound according to claim 6 , wherein R 26 is C 1 haloalkyl.

8 . A compound according to claim 7 , wherein R 26 is —CH 2 F, —CHF 2 , or —CF 3 .

9 . A compound according to claim 8 , wherein R 26 is —CHF 2 .

10 - 16 . (canceled)

17 . A compound according to claim 6 , wherein R 25 is methyl or hydrogen, and R 26 is —CHF 2 .

18 - 26 . (canceled)

27 . A compound according to claim 7 , wherein R 8 is —CONH—OH, —CONH—NH 2 , or —CO 2 H.

28 - 58 . (canceled)

59 . A compound according to claim 1 that is:

Assignees

• Univ Duke

Inventors

• Zhou Pei
• Toone Eric J
• Nicholas Robert A

Classifications

• C07D409/04

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

• C07D405/04

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

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• 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

• C07D333/28

  Halogen atoms · CPC title