Gyrase inhibitors

Patent metadata

Field	Value
Publication number	US-9481675-B2
Application number	US-201013394985-A
Country	US
Kind code	B2
Filing date	Sep 10, 2010
Priority date	Sep 11, 2009
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

Abstract

Novel gyrase inhibitors and related compositions and methods are useful for impeding bacterial growth. Compounds of Formula I are disclosed:

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 ;
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, Cl, 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 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, optionally wherein R 5 and R 4 together join to form a fused ring;
R 6 is CH 3 or —CH 2 CH 3 ; and
R 5 is methyl, C(O)CH 3 , C(O)NH 2 , CH 2 OH, CF 3 , CN, CHF 2 , CHO, halogen;
or a pharmaceutically-acceptable salt, or ester thereof.

2. A compound having the structure of Formula I,

Y is N;
Z is 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 , 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, Cl, 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 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, optionally wherein R 5 and R 4 together join to form a fused ring; and
R 6 is —CH 3 or —CH 2 CH 3 ;
or a pharmaceutically-acceptable salt, or ester thereof,
wherein the at least one aryl or a heteraryl moiety of R 2 is directly linked to L.

3. The compound of claim 1 , wherein R 6 is ethyl.

4. The compound of claim 1 , having the structure of Formula II

wherein X is halogen;
R 4 is an amine-substituted heteroalicyclic ring; and
Q is N or N + —O − .

5. The compound of claim 4 ,
wherein X is Cl or Br;
wherein R 4 is a 4-7 membered heteroalicyclic ring containing an N heteroatom; and
wherein the 4-7 membered heteroalicyclic ring is substituted with NH 2 .

6. The compound of claim 4 ,
wherein X is Cl;
wherein R 4 is a 5-6 membered heteroalicyclic ring having one N heteroatom in the backbone of the ring;
wherein the N heteroatom is directly linked to the remainder of the compound; and
wherein the 5-6 membered heteroalicyclic ring is substituted with one NH 2 substituent.

7. The compound of claim 1 , wherein
R 4 is

8. The compound of claim 1 which is

9. The compound of claim 1 which is

10. The compound of claim 1 which is

Assignees

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

• C07D491/048

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D513/04

  Ortho-condensed systems · 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

• C07D471/16

  Peri-condensed systems · CPC title