Gyrase inhibitors

Patent metadata

Field	Value
Publication number	US-10047105-B2
Application number	US-201615267978-A
Country	US
Kind code	B2
Filing date	Sep 16, 2016
Priority date	Sep 11, 2009
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

Novel gyrase inhibitors and related compositions and methods are useful for impeding bacterial growth. Compounds of Formula (I), are disclosed: Formula (I), wherein Y is N or CH; Z is N or CR 5 ; R 5 is H, a substituted or unsubstituted hydrocarbyl residue (1-3C) containing 0-2 heteroatoms selected from O, S and N, or is an inorganic residue; L is O, S, NR 7 , or CR 8 R 9 ; R 7 is H or C 1-3 alkyl; R 8 and R 9 are each independently H or C 1-3 alkyl; R 2 is H, a hydrocarbyl residue (1-40C) containing 0-10 heteroatoms selected from O, S and N optionally substituted with an inorganic residue; R 4 is H, an inorganic residue, or a hydrocarbyl residue (1-30C) containing 0-12 heteroatoms selected from O, S and N and containing 0-10 inorganic residues, wherein R 5 and R 4 together may join to form a fused ring; and R 6 is selected from the group consisting of H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, halo C 1-5 alkyl, halo C 2-5 alkenyl, halo C 2-5 alkynyl, C 1-5 hydroxyalkyl, C 1-5 alkyl chloride, C 2-5 alkenyl chloride, and C 2-5 alkynyl chloride; or a pharmaceutically-acceptable salt, ester, or prodrug thereof.

First claim

What is claimed is:

1. A compound having the structure of Formula I

wherein
Y is N;
Z is CR 5 ;
R 5 is methyl, C(O)CH 3 , C(O)NH 2 , CH 2 OH, CF 3 , CN, CHF 2 , CHO, Cl or Br;
L is O, S, NR 7 , SO 2 , or CR 8 R 9 ;
R 7 is H or C 1-3 alkyl;
R 8 and R 9 are each independently H or C 1-3 alkyl;
R 2 is H, COOCH 2 CH 3 , CH 3 , CH 2 CH 3 or a hydrocarbyl residue (1-40C) containing 0-10 heteroatoms selected from O, S and N optionally substituted with an inorganic residue wherein the hydrocarbyl residue comprises at least one aryl or heteroaryl moiety;
R 4 is
a) an inorganic residue selected from the group consisting of H, halo, NH 2 , SH, SO 2 H, NHOH, SO 3 H, SO 2 NH 2 , and NHSO 2 NH 2 ,
b) an aryl C5-14 or heteroaryl C1-14 moiety substituted with 0-10 substituents selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkylaryl, NH-aroyl, arylacyl, heteroarylacyl, halo, —O, OR′, NR′ 2 , SR′, SOR′, SO 2 R′, OCOR′, N-alkyl-OR′, CONR′OR′, NR′COR′, NR′CONR′ 2 , NR′COOR′, OCONR′ 2 , OR′, NR′ 2 , COOR′, alkyl-OOR′, SO 3 R′, CONR′ 2 , CONR′ 2 OH, SO 2 NR′ 2 , NR′SO 2 NR′ 2 , CN, CF 3 , or NO 2 , wherein each R′ is independently H, alkyl, alkenyl or aryl or heteroforms thereof, and wherein two of said substituents on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-14 members, and said substituents can only be —O if R 4 contains N,
c) alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkylaryl, alkenylaryl, alkynylaryl, heteroalkylaryl, heteroalkenylaryl, or heteroalkynylaryl moiety substituted with 0-10 substituents selected from the group consisting of aryl, haloaryl, arylalkyl, arylalkenyl, arylalkynyl, haloaryl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, acyl, aroyl, NH-aroyl, arylacyl, heteroarylacyl, halo, —O, ═O, ═NH, OR″, NR″ 2 , SR″, SOR″, SO 2 R″, OCOR″, CONR″OR″, NR″COR″, NR″CONR″ 2 , NR″COOR″, NR″COCOOR″, OCONR″ 2 , COOR″, SO 3 R″, CONR″ 2 , CONR″ 2 OH, SO 2 NR″ 2 , NR″SO 2 R″, NR″SO 2 NR″ 2 , CN, CF 3 , or NO 2 , wherein each R″ is independently H, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, or halo forms thereof, and wherein two of said substituents on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-14 members, and said substituents can only be —O if R 4 contains N, or
d) OR″′, NR″′ 2 , or OSO 2 R″′, wherein R″′ is an aryl C5-14 or heteroaryl C1-14, moiety substituted with 0-10 substituents selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, acyl, aroyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkylaryl, NH-aroyl, arylacyl, heteroarylacyl, halo, —O, OR′, NR′ 2 , SR′, SOR′, SO 2 R′, OCOR′, N-alkyl-OR′, CONR′OR′, NR′COR′, NR′CONR′ 2 , NR′COOR′, OCONR′ 2 , COOR′, alkyl-OOR′, SO 3 R′, CONR′ 2 , CONR′ 2 OH, SO 2 NR′ 2 , NR′SO 2 NR′ 2 , CN, CF 3 , or NO 2 , wherein each R′ is independently H, alkyl, alkenyl or aryl or heteroforms thereof, and wherein two of said substituents on adjacent positions can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-14 members, and said substituents can only be —O if R 4 contains N,

optionally wherein R 5 and R 4 together join to form a fused ring; and
R 6 is ethyl;

or a pharmaceutically-acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
Y is N; and
L is O, S, NH, SO 2 or CH 2 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is CR 5 , wherein R 5 is selected from the group consisting of Cl, Br, and methyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 comprises at least one aryl or heteroaryl moiety.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the at least one aryl or a heteroaryl moiety of R 2 is directly linked to L.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the aryl or heteroaryl moiety of R 2 comprises at least one moiety selected from the group consisting of phenyl, pyrido[2,3-b]pyrazine, pyridyl, thiazole, quinoline, pyridazine, pyrimidinedione, pyrido[2,3-d]pyrimidinedione, pyrimidine, [1,2,3]triazolo[4,5-b]pyridine, oxazole, benzotriazine, furo[3,2-b]pyridine, thiazolo[5,4-b]pyridine, pyrazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, pyrido[3,2-d]pyrimidine, 1,5-naphthyridine, quinolone, quinazoline, and quinoxoline.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L-R 2 is selected from the group consisting of

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of

Assignees

• Merck Sharp & Dohme

Inventors

• Creighton Christopher J
• Tari Leslie William
• Chen Zhiyong
• Hilgers Mark
• Lam Thanh To
• Li Xiaoming
• Trzoss Michael
• Zhang Junhu
• Finn John
• Bensen Daniel

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title