Tricyclic gyrase inhibitors

Patent metadata

Field	Value
Publication number	US-2016222015-A1
Application number	US-201415021314-A
Country	US
Kind code	A1
Filing date	Sep 10, 2014
Priority date	Sep 11, 2013
Publication date	Aug 4, 2016
Grant date	—

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 . A compound having the structure of Formula I

or pharmaceutically suitable salts, esters, and prodrugs thereof,
wherein
L is O, S, NH or CH 2 ,
R 8 is:
a) NHCH 3 ;
b) a prodrug-containing substituent, wherein the compound has the structure of Formula II:

wherein R 8b and R 8c are independently H or C1-C6 alkyl;
wherein R 8d is

 or a pharmaceutically acceptable salt thereof;
wherein Q is CH or N;
wherein R 8e is (CR 8g 2 ) n -basic amine, wherein each R 8g may be independently be H or C1-C3 alkyl;
wherein n is 0-2;
wherein R 8f is hydrogen or an optionally substituted C1-C6 alkyl with OH or NH 2 ;
wherein R 8e and R 8f may join to form a ring;

wherein R 8j and R 8k are independently H or C1-C8 hydrocarbyl residue; or
c) a prodrug-containing substituent, wherein the compound has the structure of Formula II′:

R 2 is:
a) phenyl, thiadiazolyl, pyridinyl or pyrimidinyl optionally substituted with a noninterfering substituent wherein 2 optional noninterfering substituents may join to form a fused ring; or
b) a prodrug-containing substituent, wherein the compound has the structure of Formula IV:

or a pharmaceutically acceptable salt thereof;
wherein R 2a contains an oxygen residue derived from an R 2 as in a) wherein R 2 has an OH group, wherein the R 2 OH is replaced with an oxygen residue in R 2a , and wherein the oxygen residue is linked to P;

Z and R 4 are joined to form a fused ring, or are not joined,
when R 4 is not joined to Z to form a fused ring R 4 is:
a C3-C20 aliphatic hydrocarbyl residue containing 1-6 heteroatoms selected from O, S, and N wherein one heteroatoms of the 1-6 heteroatoms is an N in the backbone of the hydrocarbyl residue and wherein the N is attached to the C Ring, wherein the C3-C20 aliphatic hydrocarbyl residue is substituted with at least one hydroxyl substituent and 0-3 noninterfering substituents;
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;
c) a prodrug-containing substituent, wherein the compound has the structure of Formula V:

or a pharmaceutically acceptable salt thereof;
wherein R 4a contains an oxygen residue derived from an R 4 as in a), wherein hydroxyl substituent of R 4 is replaced with an oxygen residue in R 4a , and wherein the oxygen residue is linked to P;
when R 4 is joined to Z to form a fused ring, the compound has the structure of Formula VI

wherein R 4l is CR 10 , CR 10 CR 11 , NR 12 , O or S;
wherein R 4m is CR 10 , CR 10 CR 11 , or NR 12 ;
wherein R 4n is CR 10 , CR 10 CR 11 , NR 12 , O or S
wherein each of R 10 , R 11 and R 12 are independently H, an OH-containing substituent, or a noninterfering substituent, wherein at least one of R 10 , R 11 and R 12 is the OH-containing substituent, wherein R 10 , R 11 and R 12 on two adjacent C or N may form a fused ring;
wherein R 10 , R 11 and R 12 does not contain an N directly attached to the D Ring;
wherein none of R 4l , R 4m , R 4n and R 4o contain a basic amine;

the dashed lines indicate an optional double bond when two of R 4l , R 4m , and R 4n are CR 10 and R 4o is CH or N;
wherein R 4o is:
a) a bond, wherein a 7-membered D ring is formed, wherein R 4n may be CH, CH 2 , S, NH, O, CHF, or CF 2 ;
b) a 1 member link in the backbone of the D ring wherein an 8-membered D Ring is formed, wherein the 1 member link may be CH, CH 2 , S, NH, O, CHF, or CF 2 ;

wherein the D ring 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 the D ring does not sterically interfere with R 2 when the compound is in the bound conformation;
when Z is not joined with R 4 to form a fused ring,
X is CH;
each of Y and Z may be independently CR Y or CR Z respectively, or N,

wherein each of R Y and R Z is independently H, halo, such as F, Cl, or Br, CH 3 , CF 3 , CHF 2 , CH 2 F, or CN;
when Z is joined with R 4 to form a fused ring,

X is CH;
Y is N or CR Y , wherein R Y is H, halo, CH 3 , CF 3 , CHF 2 , CH 2 F, or CN.

2 . The compound of claim 1 wherein each of Y or Z are independently CH or CF.

3 . The compound of claim 2 wherein at least one of Y and Z is CF.

4 . The compound of claim 1 wherein R 2 is 1,3,4-thiadiazolyl.

5 . The compound of claim 1 wherein R 4 is selected from the group consisting of

6 . The compound of claim 1 wherein R 4 is selected from the group consisting of

7 . The compound of claim 1 wherein the compound is selected from the group consisting of

EC +

R4
L
R2
R5
SA
EC8
serum

O

Assignees

• Merck Sharp & Dohme
• L Livermore Nat Security Llc

Inventors

• Finn John
• Tari Leslie William
• Chen Zhiyong
• Zhang Junhu
• Phillipson Douglas
• Lee Suk Joong
• Trzoss Michael
• Bensen Daniel
• Li Xiaoming
• Teng Min
• Ong Voon
• Borchardt Allen John
• Lam Thanh To
• Lightstone Felice C
• Wong Sergio E
• Nguyen Toan B

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07D491/16

  Peri-condensed systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

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