Tricyclic gyrase inhibitors

Patent metadata

Field	Value
Publication number	US-10858360-B2
Application number	US-201715643760-A
Country	US
Kind code	B2
Filing date	Jul 7, 2017
Priority date	Mar 15, 2011
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

Related pharmaceutical compositions, uses and methods of making the compounds are also contemplated.

First claim

What is claimed is:

1. A compound having the structure of Formula I

or a pharmaceutically suitable salt, or an ester thereof,
wherein
L is O or S;
wherein when L is O, R 8 is H or an interacting substituent, and when L is S, R 8 is an interacting substituent,
wherein the interacting substituent is selected from the group consisting of Cl, F, Br, OH, 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 , CCl 3 , CH 2 CH 2 Cl, CH 2 Br, CHBr 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;
X, Y and Z are CR X , CR Y , and CR Z , respectively,
wherein R X is H, CH 3 , Cl, Br, or F;
wherein R Y is H, CH 3 , CHF 2 , CF 3 , CN, CH 2 CH 3 , Cl, Br, or F;
wherein R Z is H, CH 3 , Cl, Br, or F;

R 2 is a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents, wherein 2 adjacent noninterfering substituents on R 2 may form one or more fused rings with the 6-membered aryl or heteroaryl ring;
wherein the noninterfering substituents for R 2 are selected from the group consisting of OH, CO 2 H, CN, NH 2 , Br, Cl, F, SO 3 H, SO 2 NH 2 , SO 2 CH 3 , SOCH 3 , NHOH, NHOCH 3 , NO 2 and an optionally substituted C1-15 hydrocarbyl residue containing 0-5 O, S, or N heteroatoms, wherein the C1-15 hydrocarbyl residue is optionally substituted with OH, CN, ═O, NH 2 , NHOH, ═NOH, ═NNH 2 , ═NOCH 3 , Br, F, Cl, SO 3 H, or NO 2 ;
wherein the 6-membered aryl or heteroaryl ring of R 2 has a CH at the positions immediately adjacent the position where R 2 attaches to L;

R 4 is:
H;
an optionally substituted OR a ;
an optionally substituted secondary or tertiary amine attached to the C Ring through the secondary or tertiary amine N; or
an optionally substituted 5-10 membered unsaturated cyclic or heterocyclic residue containing 0-3 N, O or S heteroatoms;
wherein the optional substituent is 0-3 noninterfering substituents;
wherein R a is a 5-6 membered aryl or heteroaryl containing 0-3 O, S, or N heteroatoms optionally substituted with 0-3 noninterfering substituents;
wherein the noninterfering substituents for R 4 are selected from the group consisting of OH, NO, CO 2 H, CN, NH 2 , Br, Cl, F, SO 3 H, NO 2 , and C1-15 hydrocarbyl residue containing 0-5 O, S, or N heteroatoms, wherein the C1-15 hydrocarbyl residue is optionally substituted with OH, CN, ═O, NH 2 , ═NOH, ═NNH 2 , ═NOCH 3 , Br, F, Cl, SO 3 H, or NO 2 ;
wherein the R 4 substituent does not project greater than about 3 Å below the plane of the A, B and C Rings toward the GyrB/ParE binding pocket floor in the bound conformation; and
wherein R 4 does not sterically interfere with R 2 or Z when the compound is in the bound conformation.

2. The compound of claim 1 wherein L is O.

3. The compound of claim 1 wherein L is S.

4. The compound of claim 1 wherein R 8 is H, CH 3 , CH 2 CH 3 , Cl, OCH 3 , NHCD 3 , NHCH 3 , NHCH 2 CH 3 , or NH 2 .

5. The compound of claim 4 wherein R 8 is NHCH 3 .

6. The compound of claim 1 wherein R 2 is a 6-membered heteroaryl ring substituted with C1-15 hydrocarbyl residue, wherein the C1-15 hydrocarbyl residue contains 0-5 O, S, or N heteroatoms and is optionally substituted with OH, CN, ═O, NH 2 , ═NOH, ═NNH 2 , ═NOCH 3 , Br, F, Cl, SO 3 H, or NO 2 .

7. The compound of claim 1 wherein 2 adjacent noninterfering substituents on R 2 form one or more fused rings, and
wherein the combination of the one or more fused rings with the 6-membered aryl or heteroaryl ring of R 2 contains 5-15 members, and 0-5 O, S, or N heteroatoms, optionally substituted with OH, ═O, CN, NH 2 , Br, F, or Cl.

8. The compound of claim 1 wherein R 2 is selected from the group consisting of an optionally substituted pyrimidinyl, phenyl, and pyridyl; or
wherein the optionally substituted 6-membered aryl or heteroaryl ring of R 2 in combination with the one or more fused rings is present and is selected from the group consisting of optionally substituted indolyl, azaindolyl, pyrimidopyridyl, quinazolinyl, quinoxalinyl, naphthyridinyl, purinyl, imidizopyridinyl, furopyridinyl, isoindolylinyl, benzodioxinyl, dihydrobenzodioxinyl, benzothiazolyl, pyrrolopyridinyl, dihydropyrrolopyridinyl, benzoimidazolyl, imidazopyridinyl, dihydroimidazopyridinyl, tetrahydroisoindolyl, chromenyl, benzthiophene, benztriazolyl, benzfuranyl, benzoxadiazolyl, indazolyl, quinolinyl, isoquinolinyl, indoline, azaindolinyl, and

9. The compound of claim 8 wherein R 2 is pyrimidinyl or pyridinyl optionally substituted with CH(OH)CH 3 , C(OH)(CH 3 ) 2 , OCH 3 , CN, CH 3 , CH 2 CH 3 , O-cyclopropyl, SCH 3 , Br, Cl, F, or NH 2 .

10. The compound of claim 1 wherein R 2 is selected from the group consisting of:

11. The compound of claim 1 wherein R 4 is the optionally substituted OR a and R a is an optionally substituted pyrimidinyl or pyridinyl.

12. The compound of claim 11 wherein R a is unsubstituted pyrimidinyl or pyrimidinyl substituted with CH 3 or NH 2 .

13. The compound of claim 1 wherein R 4 is the optionally substituted secondary or tertiary amine attached to the C Ring through the secondary or tertiary amine N, further comprising a primary or secondary amine, wherein the primary or secondary amine is not directly attached to the C Ring;
wherein the primary or secondary amine not directly attached to the C Ring is positioned in the compound in the bound conformation wherein:
the distance between the C or N atom of Y and the primary or secondary amine N is about 7 Å to about 10.5 Å;
the distance between the C atom to which R 8 is attached and the primary or secondary amine N is about 6 Å to about 9 Å;
the distance between the C atom to which R 4 is attached and the primary or secondary amine N is about 3.5 Å to about 6 Å; and
the distance between the C atom to which R 2 is attached and the primary or secondary amine N is about 5 Å to about 7.5 Å.

14. The compound of claim 1
wherein R 4 is an optionally substituted 4-14 membered saturated cycloheteroaliphatic tertiary amine ring system containing 1-3 N atoms, 0-3 O atoms and 0-1 S atoms; and
wherein the optionally substituted 4-14 membered saturated cycloheteroaliphatic ring system is an optionally substituted single ring, a fused ring system, a bridge ring system, or a spiro ring system.

15. The compound of claim 1 wherein R 4 is the optionally substituted tertiary amine attached to the C ring through the

Assignees

• Merck Sharp & Dohme
• L Livermore Nat Security Llc

Inventors

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

Classifications

• C07D487/14

  Ortho-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P37/08

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

• A61P31/04

  Antibacterial agents · CPC title