Metallo-β-lactamase inhibitors

Patent metadata

Field	Value
Publication number	US-10227331-B2
Application number	US-201615737334-A
Country	US
Kind code	B2
Filing date	Jun 24, 2016
Priority date	Jun 26, 2015
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

Abstract

The present invention relates to metallo-β-lactamase inhibitor compounds of Formula I: (I) and pharmaceutically acceptable salts thereof, wherein Z, R A , X 1 , X 2 and R B are as defined herein. The present invention also relates to compositions which comprise a metallo-β-lactamase inhibitor compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, optionally in combination with a beta lactam antibiotic and/or a beta-lactamase inhibitor. The invention further relates to methods for treating a bacterial infection comprising administering to a patient a therapeutically effective amount of a compound of the invention, in combination with a therapeutically effective amount of one or more β-lactam antibiotics and optionally in combination with one or more beta-lactamase inhibitor compounds. The compounds of the invention are useful in the methods described herein for overcoming antibiotic resistance.

First claim

What is claimed is:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is N or CH;
X 2 is N or CH;
Z is tetrazolyl, wherein Z is linked through a carbon to carbon bond to the six-membered core ring having X 1 and X 2 ;
R A is —(CH 2 ) n -AryA1, —(CH 2 ) n -HetA1, —(CH 2 ) n —C 4 -C 6 cycloalkyl, or —(CH 2 ) n —C 4 -C 6 cycloalkenyl, wherein said —(CH 2 ) n —C 4 -C 6 cycloalkyl and —(CH 2 ) n —C 4 -C 6 cycloalkenyl are optionally substituted with 1, 2, or 3 substituents independently selected from —NH 2 , —OH, —F, and —NR a C(O)C 1 -C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from —F, —CF 3 , —NR a R b , and —OR a ;
R B is —SR 1 , —SOR 2 or —SO 2 R 3 ;
R 1 is HetB1, AryB1, or —CH 3 ;
R 2 is HetB1 or —CH 3 ;
R 3 is
1) C 1 -C 6 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, —NR a R b , —N + R a R b H, —N + R a R b CH 3 , —OH, and cyclopropyl;
2) C 4 -C 6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from F, —NR a R b , and —OH;
3) —OH;
4) —(CH 2 ) k AryB1;
5) —(CH 2 ) k HetB1;

AryA1 is an aromatic ring system selected from:
1) a 5-6 membered monocyclic ring with 0, 1, 2, or 3 heteroatom ring atoms independently selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from:
a) halogen,
b) —C 1 -C 6 alkyl,
c) —CN,
d) —CH 2 OH,
e) —C(O)NR a R b ,
f) —C(O)NH(CH 2 ) 2-4 NH 2 optionally substituted with one or two substituents independently selected from —NR a R b and —(CH 2 ) n OR a ,
g) —C(O)OR a ,
h) —(CH 2 ) p NHR a optionally substituted with one or two substituents independently selected from —NR a R b or —OR a ,
i) —(CH 2 ) p NR a C(═NH)NH 2 ,
j) —NR a C(O)C 1 -C 6 alkyl optionally substituted with one or two substituents independently selected from —NR a R b or —OR a ,
k) —NR a SO 2 —C 1 -C 6 alkyl,
l) —NR a SO 2 -cyclopropyl,
m) —OR a ,
n) oxo,
o) —SC 1 -C 6 alkyl optionally substituted with one or two substituents independently selected from —NR a R b or —OR a ;
p) —SO 2 R a ,
q) —SO 2 NR a R b ,
r) —SO 2 NH-cyclopropyl,
s) -AryA2,
t) —(CH 2 ) n NR a AryA2,
u) —C(O)NR a HetA2 and
v) -HetA2, and

2) an 8- to 10-membered bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from N, O and S, wherein an S atom optionally has one or two oxo substituents and a N atom is optionally in the form of an N-oxide, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from
a) halogen;
b) C 1 -C 6 alkyl optionally substituted with one to three substituents independently selected from —NR a R b , —C(O)OR a , —NR a C(O)CF 3 , —F and —OR a ;
c) —(CH 2 ) n CF 3 ;
d) —C(═NH)NH 2 ;
e) —CN;
f) —C(O)CF 3 ;
g) —C(O)NR a R b ;
h) —C(O)NHCH 2 C(O)OR a ;
i) —C(O)NH—C 2 -C 4 alkyl-NH 2 ,
j) —C(O)OR a ;
k) —NR a R b ;
l) —NHCH 2 SO 3 H;
m) —(CH 2 ) n NHC(═NH)NH 2 ;
n) —NHC(O)C 1 -C 6 alkyl;
o) —NHC(O)NH 2 ;
p) —NHC(O)OR a ;
q) —NHSO 2 CH 3 ;
r) —OR a ;
s) oxo;
t) —SO 2 R a ,
u) —CH 2 -phenyl-OCH 3 ; and
v) -HetA2;

HetA1 is dihydrothiopyranyl, wherein the S atom is optionally substituted with 2 oxo, or tetrahydropyranyl;
AryA2 is a 5-6-membered aromatic monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms independently selected from N, N as a quaternary salt, and S, or 4 N ring atoms, optionally substituted with one or two substituents independently selected from: —CH 2 OH, —COOH, —CONH 2 , —C(O)OC 1 -C 6 alkyl, and —(CH 2 ) p NHR a optionally substituted with one or two substituents independently selected from —NR a R b and —OR a ;
HetA2 is a 4-6-membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein the S is optionally substituted with two oxo groups, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from C 1 -C 6 alkyl, —CN, —OH, and oxo;
AryB1 is an aromatic ring selected from:
1) a 5-6 membered monocyclic aromatic ring with 0, 1, 2, or 3 N ring atoms, optionally substituted with 1 substituent selected from —CF 3 , C 1 -C 6 alkyl, —(CH 2 ) n NH 2 and —OCH 3 ; and
2) a 9-membered bicyclic ring with 2 N ring atoms;

HetB1 is a saturated ring selected from:
1) a carbon-linked 4-6-membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein the S is optionally substituted with one or two oxo groups, and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from F, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, —CN, —C(O)C 1 -C 6 alkyl, —(C 1 -C 4 alkyl) n -NR a R b , —(CH 2 ) n C(O)NR a R b , —C(O)NH-cyclopropyl, —C(O)OR a , —OH, oxo, and —SO 2 —C 1 -C 6 alkyl; and
2) a carbon-linked 6-10-membered bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from N, O and S, optionally substituted with one to three substituents, independently selected from: —F, —C 1 -C 6 alkyl, —NR a R b , oxo, —(CH 2 ) 1-2 OH, —CH 2 NH 2 , —SO 2 CH 3 , —CH 2 C 3 -C 6 cycloalkyl or —NH 2 , wherein a ring sulfur atom is optionally substituted with one or two oxo groups, wherein the bicyclic ring may be bridged, fused or spirocyclic, and wherein the C 3 -C 6 cycloalkyl is optionally substituted with —CH 2 OH;

R a and R b are independently H or C 1 -C 6 alkyl;
k is 0, 1, 2, 3, or 4;
each n is independently 0 or 1; and
each p is independently 0, 1, 2, or 3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are CH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the Formula IA:

wherein:
R A is AryA1; HetA1; C 4 -C 6 cycloalkyl; or C 4 -C 6 cycloalkenyl wherein said C 4 -C 6 cycloalkyl and C 4 -C 6 cycloalkenyl are optionally substituted with —NH 2 or NHC(O)(CH 2 ) 1-3 NH 2 ;
R 3 is
1) —(CH 2 ) k HetB1;
2) C 1 -C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from —NR a R b , —OH, and cyclopropyl;
3) C 4 -C 6 cycloalkyl optionally substituted with —NH 2 ;
4) —OH; or
5) -AryB1;

AryA1 is an aromatic ring system selected from:
1) a 5-6 membered monocyclic ring with 0, 1, or 2 heteroatom ring atoms independently selected from N and S, substituted with 1 or 2 substituents independently selected from:
a) —F,
b) —C 1 -C 6 alkyl,
c) —CN,
d) —CH 2 OH,
e) —C(O)NR a R b ,
f) —C(O)NH(CH 2 ) 2-4 NH 2 ,
g) —C(O)OR a ,
h) —(CH 2 )NHR a ,
i) —NHC(═NH)NH 2 ,
j) —NHC(O)CH 3 ;
k) —NR a SO 2 —C 1 -C 6 alkyl,
I) —NHSO 2 -cyclopropyl,
m) —OR a ,
n) —SO 2 NR a R b ,
o) —SO 2 NH-cyclopropyl,
p) -AryA2, and
q) -HetA2, and

2) an 8- to 10-membered bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from N, O and S, wherein an S atom optionally has one or two oxo substituents and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from —F, —C 1 -C 6 alkyl, —CH 2 CF 3 , —CF 2 CH 2 NH 2 , —CF 3 , —C(═NH)NH 2 , —CN, —C(O)CF 3 , —C(O)NR a R b , —C(O)NHCH 2 C(O)OR a , —C(O)OR a , —(CH 2 ) 0-2 NR a R b , —NHC(O)CH 3 , —NHC(O)NH 2 , —NHC(O)OR a , —NHCH 2 SO 3 H, —NHSO 2 CH 3 , —OR a , oxo, —CH 2 -phenyl-OCH 3 , and -HetA2;

AryB1 is an aromatic ring system selected from:
1) a 5-6 membered monocyclic aromatic ring with 0, 1, 2, or 3 N ring atoms, optionally substituted with 1 substitu

Assignees

• Merck Sharp & Dohme

Inventors

• Bennett Frank
• Jiang Jinlong
• Pasternak Alexander
• Dong Shuzhi
• Gu Xin
• Scott Jack D
• Tang Haiqun
• Zhao Zhiqiang
• Huang Yuhua
• Hunter David
• Yang Dexi
• Young Katherine
• Xiao Li
• Zhang Zhibo
• Fu Jianmin
• Bai Yunfeng
• Zheng Zhixiang
• Zhang Xu

Classifications

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D417/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title

• C07D493/08

  Bridged systems · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title