Quinolone derivatives as antibacterials

Patent metadata

Field	Value
Publication number	US-10160726-B2
Application number	US-201515500870-A
Country	US
Kind code	B2
Filing date	Aug 3, 2015
Priority date	Aug 6, 2014
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

This invention is in the field of medicinal chemistry and relates to compounds, and pharmaceutical compositions thereof, that inhibit bacterial gyrase. The compounds are useful as inhibitors of bacterial gyrase activity and bacterial infections, and have the structure of Formula (I)

as further described herein. The invention further provides pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds and compositions to treat bacterial infections.

First claim

We claim:

1. A compound of formula (I):

wherein:
R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkynyl, and C 3 -C 7 cycloalkyl, each of which is optionally substituted with up to three groups selected from halogen, —OR 2 , CN, —N(R 2 ) 2 , and oxo;
R 3 is selected from the group consisting of -L 1 -OR 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, -L 1 -CN, -L 1 -N(R 2 ) 2 , -L 1 -COOR 2 ; -L 1 -CON(R 2 ) 2 , -L 1 -N(R 2 )C(O)R 2 , -L 1 -N(R 2 )C(O)OR, -L 1 -SO 2 R, -L 1 -N(R 2 )—SO 2 —R, and -L 1 -SO 2 —N(R 2 ) 2 ;
L 1 is a bond or a C 1 -C 4 straight or branched chain alkylene linker;

each R is independently C 1 -C 4 alkyl optionally substituted with one to three groups selected from halogen, —OH, C 1 -C 4 alkoxy, CN, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —SO 2 (C 1 -C 4 alkyl), and oxo;
each R 2 is independently H or C 1 -C 4 alkyl optionally substituted with up to three groups selected from halogen, —OH, C 1 -C 4 alkoxy, CN, —NR 12 R 13 , —SO 2 R and oxo;
or two R 2 on the same nitrogen can be taken together to form a 4-6 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S as a ring member and optionally substituted with up to three groups selected from halogen, —OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CN, —NR 12 R 13 , and oxo;
R 4 is selected from the group consisting of H, halo, C 1 -C 4 haloalkyl, —NH 2 , —CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -L 2 -C 3 -C 7 cycloalkyl, -L 2 -CN, -L 2 -N(R 2 ) 2 , -L 2 -NR 2 C(O)—R 2 , -L 2 -NR 2 C(O)—OR 2 , -L 2 -NR 2 C(O)—N(R 2 ) 2 , -L 2 -NR 2 C(═NR 2 )—N(R 2 ) 2 , -L 2 -C(O)—NR 2 —OR 2 , -L 2 -COOR 2 , -L 2 -CON(R 2 ) 2 , -L 2 -C(═NR 2 )—N(R 2 ) 2 , -L 2 -C(═NR 2 )—NR 2 —OR 2 , -L 2 -SO 2 R, -L 2 -SO 2 —N(R 2 ) 2 , -L 2 -Q, and -L 2 -O—(C 1 -C 4 alkyl), wherein the C 1 -C 4 alkyl is optionally substituted with one or two groups selected from —OR 2 , —CN, oxo, ═N—OR 2 , —N(R 2 ) 2 , —COOR 2 , —C(═X)—NR 2 —OR 2 , —C(═X)—N(R 2 ) 2 , —NR 2 C(═X)R 2 , —NR 2 C(═X)OR, —NR 2 C(═X)N(R 2 ) 2 , —NR 2 C(O)—O-L 2 -Q, —CON(R 2 ) 2 , —SO 2 R, —SO 2 —N(R 2 ) 2 , —NR 2 —SO 2 R, and Q;
wherein each Q is an optionally substituted ring selected from phenyl and a 5-6 membered heteroaryl or heterocyclyl ring containing up to four heteroatoms selected from N, O and S as ring members, wherein the optional substituents for the optionally substituted ring are up to three groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, oxo, ═N—OR 2 , —COOR 2 , —CON(R 2 ) 2 , —NR 2 C(O)R 2 , —NR 2 C(O)OR, —C(O)NR 2 —OR 2 , —SO 2 R, and —SO 2 —N(R 2 ) 2 , and
each L 2 is independently selected from a bond and a divalent straight chain or branched C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl linking group;
and each X is independently O or ═NR 11 ;
R 5 is selected from the group consisting of H, halo, amino, CN, C 1 -C 4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkyl;
R 6 is selected from the group consisting of H, halo, CN, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkyl;
Y is pyridinyl optionally substituted with one to three groups selected from halo, CN, amino, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and —(CH 2 ) 1-4 —X, where X is selected from —OH, —CN, —N(R 2 ) 2 , —COOR 2 , —C(O)N(R 2 ) 2 , —NR 2 C(O)R 2 , —NR 2 C(O)OR, —SO 2 R, and —SO 2 N(R 2 ) 2 ;
or Y is a group of the formula —NR 7A R 7B , wherein R 7A is selected from the group consisting of H, —C(O)R 2 , —C(O)OR 2 , and C 1 -C 6 alkyl optionally substituted with up to two groups independently selected from halogen, —OH, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, oxo, ═N—OR 2 , —N(R 2 ) 2 , C 3 -C 7 cycloalkyl, —COOR 2 , —C(O)N(R 2 ) 2 , —NR 2 C(O)R 2 , —NR 2 C(O)OR, and a 4-6 membered heteroaryl or heterocyclyl group that contains up to two heteroatoms selected from N, O and S as ring members and is optionally substituted with up to two groups selected from hydroxy, amino, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
R 7B is -L 3 -Q 3 ;
wherein L 3 is a bond or a straight or branched chain C 1 -C 6 alkyl linker, and Q 3 is selected from pyridinyl and a 4-7 membered heterocyclyl containing one or two heteroatoms selected from N, O and S as ring members, and wherein Q 3 is optionally substituted with up to three groups selected from halogen, CN, —OH, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, oxo, ═N—OR 2 , —N(R 2 ) 2 , —COOR 2 , —C(O)N(R 2 ) 2 , —NR 2 C(O)R 2 , —NR 2 C(O)OR;
or R 7A and R 7B together with the nitrogen atom to which they are attached form a 4- to 7-membered monocyclic heterocyclic group optionally including one additional heteroatom selected from N, O and S as a ring member, or a 6-10 membered bicyclic heterocyclic group optionally including one or two additional heteroatoms selected from N, O and S as ring members, wherein the monocyclic or bicyclic heterocyclic group formed by R 7A and R 7B together with the nitrogen atom to which they are attached is optionally substituted by up to four groups selected from halogen, —CN, hydroxy, phenyl, oxo, —OR 9 , —N(R 9 ) 2 , —COOR 9 , —C(O)N(R 9 ) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, oxo, C 3 -C 6 cycloalkyl, and a 4-6 membered heteroaryl or heterocyclyl group that contains up to two heteroatoms selected from N, O and S as ring members,
wherein the C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, phenyl, and 4-6 membered heteroaryl or heterocyclyl are each optionally substituted by up to three groups independently selected from halogen, —CN, hydroxy, oxo, —OR 10 , ═N—OR 10 , —N(R 10 ) 2 , —COOR 10 , —N(R 10 )—C(O)—O—(C 1 -C 4 alkyl), —C(O)N(R 10 ) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
R 8 is selected from the group consisting of H, halo, CN, C 1 -C 4 alkyl optionally substituted with hydroxy or amino, C 2-4 alkenyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkyl;
R 9 and R 10 are each independently selected from H and C 1 -C 4 alkyl optionally substituted with up to three groups selected from halogen, —OH, C 1 -C 4 alkoxy, CN, —NR 12 R 13 , —SO 2 R and oxo;
or two R 9 or two R 10 on the same nitrogen can be taken together to form a 4-6 membered heterocyclic ring optionally containing an additional heteroatom selected from N, O and S as a ring member and optionally substituted with up to three groups selected from halogen, —OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CN, —NR 12 R 13 , and oxo;
each R 11 is independently hydrogen or C 1 -C 4 alkyl optionally substituted with one or two groups selected from halogen, —OH, C 1 -C 4 alkoxy, CN, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —SO 2 (C 1 -C 4 alkyl), and oxo;
each R 12 and R 13 is independently hydrogen or C 1 -C 4 alkyl optionally substituted with one or two groups selected from halogen, —OH, C 1 -C 4 alkoxy, CN, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —SO 2 (C 1 -C 4 alkyl), and oxo;
or R 12 and R 13 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally including an additional heteroatom selected from N, O and S as a ring member and optionally substituted by one to three substituents selected from OH, halogen, oxo, ═N—OR 11 , C 1 -C 6 alkyl optionally substituted by one to three halogen atoms or NH 2 , C 1 -C 6 alkoxy optionally substituted by one or more OH groups or C 1 -C 6 alkoxy; and —C(O)OC 1 -C 6 alkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 is C 3 -C 6 cycloalkyl or C 2 -C 4 a

Assignees

• Novartis Ag

Inventors

• Fidalgo Javier De Vicente
• He Haiying
• Hu Cheng
• Jiang Zhigan
• Li Xiaolin
• Lu Peichao
• Mergo Wosenu
• Mutnick Daniel
• Reck Folkert
• Rivkin Alexey
• SKEPPER Colin Keith
• Wang Xiaojing Michael
• Xia Jianhua
• Xu Yongjin

Classifications

• C07D215/38 Primary

  Nitrogen atoms (nitro radicals C07D215/18) · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D401/04 Primary

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

• C07D498/10

  Spiro-condensed systems · CPC title