Tricyclic gyrase inhibitors

Patent metadata

Field	Value
Publication number	US-9732083-B2
Application number	US-201213496188-A
Country	US
Kind code	B2
Filing date	Mar 14, 2012
Priority date	Mar 15, 2011
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

Disclosed herein are compounds having the structure of Formula I and pharmaceutically suitable salts, esters, and prodrugs thereof that are useful as antibacterially effective tricyclic gyrase inhibitors.
Related pharmaceutical compositions, uses and methods of making the compounds are also contemplated.

First claim

What is claimed is:

1. An intermediate compound having the structure:

wherein
G 1 and G 2 are leaving groups independently selected from the group consisting of SH, OH, Cl, Br, F, I, SR, SOR, SO 2 R, OSO 2 R, tosylate, triflate and OAr;
R is C1-8 alkyl, aryl, or heteroaryl;
Ar is aryl or heteroaryl containing 0-5 O, S, or N atoms optionally substituted with C1-C4 alkyl, C1-C4 alkoxy, halo or NO 2 ;
R 8 is
(a) an interacting substituent selected from the group consisting of Cl, F, Br, NH 2 , 1-3C alkyl, amino-1-3C alkyl, aminocyclopropyl, OCH 3 , OCH 2 CH 3 , cyclopropyl, CH 2 cyclopropyl, CH 2 Cl, CHCl 2 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , NHNH 2 , NHOH, NHNHCH 3 , NHOCH 3 , NHCD 3 , SCH 3 , and NHCOH; or
(b) an amine protected with a protecting group, wherein the protecting group is selected from the group consisting of carbobenzyloxy (Cbz) and BOC; and
X, Y and Z are independently selected from the group consisting of N, CR X , CR Y , and CR Z respectively, provided that no more than two of X, Y and Z are N,
wherein R X is H or an interacting substituent selected from the group consisting of CH 3 , Cl, Br, and F;
wherein R Y is H or an interacting substituent selected from the group consisting of CH 3 , CHF 2 , CF 3 CN, CH 2 CH 3 , Cl, Br, and F;
wherein R Z is H or an interacting substituent selected from the group consisting of CH 3 , Cl, Br, and F;

with a proviso wherein R 8 is not CH 3 .

2. The intermediate compound of claim 1 wherein R 8 is an amine protected with carbobenzyloxy (Cbz) or BOC.

3. The intermediate compound of claim 2 , wherein the G 1 and G 2 are leaving groups independently selected from the group consisting of mesylate, triflate, O-pyrimidine, O-phenyl and O-pyridine.

4. The intermediate compound of claim 1 , wherein the OAr for G 1 and G 2 is OBt, wherein Bt is benzotriazole.

5. The intermediate compound of claim 2 , wherein the amine is selected from the group consisting of NHCD 3 , NHCH 3 , NHCH 2 CH 3 , and NH 2 and is protected with Cbz or BOC.

Assignees

• Bensen Daniel
• Chen Zhiyong
• Finn John
• Lam Thanh To
• Lee Suk Joong
• Li Xiaoming
• Phillipson Douglas W
• Tari Leslie William
• Trzoss Michael
• Zhang Junhu
• Lightstone Felice C
• Nguyen Toan B
• Wong Sergio E
• Aristoff Paul
• Jung Michael
• Merck Sharp & Dohme
• L Livermore Nat Security Llc

Inventors

• Bensen Daniel
• Chen Zhiyong
• Finn John
• Lam Thanh To
• Lee Suk Joong
• Li Xiaoming
• Phillipson Douglas W
• Tari Leslie William
• Trzoss Michael
• Zhang Junhu
• Lightstone Felice C
• Nguyen Toan B
• Wong Sergio E
• Aristoff Paul
• Jung Michael

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title