Biaryl monobactam compounds and methods of use thereof for the treatment of bacterial infections

Patent metadata

Field	Value
Publication number	US-11230543-B2
Application number	US-202016912146-A
Country	US
Kind code	B2
Filing date	Jun 25, 2020
Priority date	Dec 15, 2015
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

Abstract

The present invention relates to biaryl monobactam compounds of Formula I:

and pharmaceutically acceptable salts thereof, wherein X, Y, Z, A 1 , Q, A 2 , M, W, R X and R z are as defined herein. The present invention also relates to compositions which comprise a biaryl monobactam compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic.

First claim

What is claimed:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
W is a bond or O;
R X and R Z are independently hydrogen, —SC 1 -C 3 alkyl, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl, or —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl, wherein the —SC 1 -C 3 alkyl, the C 1 -C 3 alkyl, the —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl and the —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl are optionally substituted with one to seven fluorines;
or, alternatively, R X and R Z , together with the carbon to which they are attached, form a monocyclic C 4 -C 7 cycloalkyl or a monocyclic C 4 -C 7 heterocycloalkyl with 1, 2, or 3 heteroatom ring atoms independently selected from N, O and S, wherein said C 4 -C 7 cycloalkyl and said C 4 -C 7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from —F, —OH and —OC 1 -C 3 alkyl;
X is N or CR 1 ;
R 1 is hydrogen, C 1 -C 3 alkyl, or halogen; wherein said C 1 -C 3 alkyl is optionally substituted with one to three R a ;
each occurrence of R a is independently hydrogen, halogen, C 1 -C 3 alkyl, —NR c R d or —OR e ;
Z is C 1 -C 3 alkylene, optionally substituted with one to three R b ;
each occurrence of R b is independently —C 1 -C 8 alkyl, —C 3 -C 7 cycloalkyl, —C(O)OR e , —C(O)NR c R d , tetrazolyl, oxadiazolonyl, HetA, AryA, —S(O) m R e , —S(O) m NR c R d , or —P(O)(R e ) p wherein said —C 1 -C 8 alkyl and said —C 3 -C 7 cycloalkyl are optionally substituted with one to three R a ;
HetA is a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;
AryA is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R 4 ;
Y is a bond, O, NR 2 , S, or CH 2 ;
R 2 is hydrogen, —C 1 -C 3 alkyl, —C(O)R e , —C(O)NR c R d , —S(O) m R e , or —S(O) m NR c R d , wherein said —C 1 -C 3 alkyl is optionally substituted with one to three R a ;
A 1 is AryA;
A 2 is:

wherein * indicates attachment to Q and ** indicates attachment to M;
each occurrence of R 4 is independently: —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl, halogen, —OR e , —S(O) m R e , —S(O) m NR c R d , —C(O)R e , —OC(O)R e , —C(O)OR e , —CN, —C(O)NR c R d , —NR c R d , —(CH 2 ) n NR c R d ; —NR c C(O)R e , —NR c C(O)OR e , —NR c C(O)NR c R d , —NR c S(O) m R e , ═NH, —CF 3 , —OCF 3 , —OCHF 2 , —C 3 -C 6 cycloalkyl, —O—C 3 -C 6 cycloalkyl, —C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl, —O—C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl, HetB, —O-HetB, —C 1 -C 10 alkylene-HetB, —O—C 1 -C 10 alkylene-HetB, AryA, —O-AryA, —C 1 -C 10 alkylene-AryA, or —O—C 1 -C 10 alkylene-AryA, wherein each R 4 is unsubstituted or substituted with one to four substituents selected from halogen, —C 1 -C 6 alkyl and —(CH 2 ) n NR c R d , or wherein R 4 and M, together with the atoms to which they are attached, form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S and —NR g ;
HetB is a 3- to 6-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to three R a ;
Q is a bond, CH 2 , O, S, —(CH 2 ) n NR 3 —, or —NR 3 (CH 2 ) n —, wherein each CH 2 is unsubstituted or substituted with one to two substituents selected from halogen, —C 1 -C 6 alkyl, OR e and —(CH 2 ) n NR c R d ;
R 3 is hydrogen or —C 1 -C 3 alkyl, wherein said —C 1 -C 3 alkyl is optionally substituted with one to three R a ;
M is R 5 , —NHR 5 , —N(R 5 ) 2 , —OR 5 , —(CH 2 ) n R 5 , —C(O)R 5 , —CH(NH)R 5 , or —S(O) m R 5 ;
R 5 is H, C 2 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl, HetB, AryB, or —NH(C 1 -C 6 alkyl), wherein said C 1 -C 6 alkyl, said C 2 -C 10 alkyl and said C 3 -C 7 cycloalkyl are optionally substituted with one to four R 6 ;
AryB is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, O and S, optionally substituted with one to four R 4 ;
each occurrence of R 6 is independently selected from the group consisting of: halogen, —OR e , —S(O) m R e , —S(O) m NR c R d , —C(O)R e , —OC(O)R e , —C(O)OR e , —CN, —C(O)NR c R d , —C(NH)NR c R d , —NR c R d , —(CH 2 ) n NR c R d , —N(R c )(C(O)R e ), —N(R c )(C(O)OR e ), —N(R c )(C(O)NR c R d ), —N(R c )(S(O) m R e ), and HetB;
each occurrence of R c and R d is independently: hydrogen, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —C 3 -C 6 cycloalkyl, —C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl, HetA, —C 1 -C 10 alkylene-HetB, AryB, —C 1 -C 10 alkylene-AryB, and —C 1 -C 10 alkylene-HetB, or, alternatively, R c and R d together with the nitrogen atom to which they are attached, form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S and —NR g , and wherein each R c and R d is optionally substituted with one to three R f ;
each occurrence of R e is independently: hydrogen, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —OH, —OC 1 -C 4 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl, HetB, —C 1 -C 10 alkylene-HetB, AryB, —C 1 -C 10 alkylene-AryB, or —C 1 -C 10 alkylene-HetB; wherein each R e is optionally substituted with one to three R h ;
each occurrence of R f is independently: halogen, —C 1 -C 10 alkyl, —OH, —OC 1 -C 4 alkyl, —S(O) m C 1 -C 4 alkyl, —CN, —CF 3 , —OCHF 2 , —OCF 3 , or NH 2 , wherein said —C 1 -C 10 alkyl is optionally substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;
each occurrence of R g is independently: hydrogen, —C(O)R e , and or —C 1 -C 10 alkyl, wherein said —C 1 -C 10 alkyl is optionally substituted with one to five fluorines;
each occurrence of R h is independently: halogen, —C 1 -C 10 alkyl, —OH, —OC 1 -C 4 alkyl, —S(O) m C 1 -C 4 alkyl, —CN, —CF 3 , —OCHF 2 , or —OCF 3 ; wherein said —C 1 -C 10 alkyl is optionally substituted with one to three substituents independently selected from: —OH, halogen, cyano, or —S(O) 2 CH 3 ;
each n is independently 0, 1, 2, 3 or 4;
each m is independently 0, 1 or 2, and
each p is independently 1 or 2.

2. The compound of formula (I) of claim 1

or a pharmaceutically acceptable salt thereof,
wherein:
W is a bond or O;
R X and R Z are independently hydrogen, —SC 1 -C 3 alkyl, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl, or —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl, wherein the —SC 1 -C 3 alkyl, the C 1 -C 3 alkyl, the —(C 1 -C 3 alkylene) n OC 1 -C 3 alkyl and the —(C 1 -C 3 alkylene) n NC 1 -C 3 alkyl are optionally substituted with one to seven fluorines;
or, alternatively, R X and R Z , together with the carbon to which they are attached, form a monocyclic C 4 -C 7 cycloalkyl or a monocyclic C 4 -C 7 heterocycloalkyl with 1, 2, or 3 heteroatom ring atoms independently selected from N, O and S, wherein said C 4 -C 7 cycloalkyl and said C 4 -C 7 heterocycloalkyl are opt

Assignees

• Merck Sharp & Dohme

Inventors

• Tang Haifeng
• Liu Weiguo
• Ding Fa-Xiang
• Sun Wanying
• Zang Yi
• Pan Weidong
• Ogawa Anthony
• Brockunier Linda
• Huang Xianhai
• Wang Hongwu
• Mal Rudrajit
• Biftu Tesfaye
• Park Min
• Guo Yan
• Jiang Jinlong
• Chen Helen Y
• Plummer Christopher W

Classifications

• A61K31/397 Primary

  having four-membered rings, e.g. azetidine · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/431

  containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin · CPC title