Metallo-beta-lactamase inhibitors

Patent metadata

Field	Value
Publication number	US-9708336-B2
Application number	US-201515110431-A
Country	US
Kind code	B2
Filing date	Jan 16, 2015
Priority date	Jan 22, 2014
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

The present invention relates to compounds of formula (I) that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.

First claim

What is claimed:

1. A compound of formula I

or a pharmaceutically acceptable salt thereof,
wherein:
X 2 is N or CR B ;
X 3 is N or CR C ;
X 4 is N or CR D ;
wherein no more than 2 of X 2 , X 3 , and X 4 are N;
Z is tetrazolyl, wherein Z is linked to the six membered ring through a carbon to carbon bond;
R A is H, C 1 -C 6 alkyl, —(CH 2 ) 0-3 —C 3 -C 8 cycloalkyl, —C 3 -C 6 cycloalkenyl, —CF 3 , C 1 -C 6 alkoxy, —COOR a , —CN, —NR a R b , —(CH 2 ) 0-3 HetA, —(CH 2 ) 0-3 -AryA, —(CH 2 ) 0-1 —O-AryA, —NR a (CH 2 ) 0-2 —C 3 -C 8 cycloalkyl, —NR a (CH 2 ) 1-2 -phenyl, —C≡C-pyridinyl, —C≡C—CH 2 -HetC, or —C≡C—CH 2 —O-HetC; wherein the R A C 1 -C 6 alkyl or any R A C 3 -C 8 cycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, —OH, F, —CF 3 , —CN, —(CH 2 ) 0-3 NR a R b , —C(═NH)NH 2 ; —CONR a R b , —(CH 2 ) 0-1 NHC(═NH)NH 2 ; —NHCONR a R b , —NHCO-diaminoC 2 alkyl, —NH(CH 2 ) 0-1 —C 3 -C 6 cycloalkyl; —NHSO 2 —C 1 -C 6 alkyl, —SO 2 —C 1 -C 6 alkyl, —SO 2 —C 3 -C 6 cycloalkyl, —SO 2 NR a R b , AryB, —NH(CH 2 ) 0-1 -AryB, HetB, and —NH(CHR a ) 0-1 -HetB, and wherein any C 3 -C 6 cycloalkyl is optionally substituted with —(CH 2 ) 0-2 NH 2 , wherein —C 3 -C 6 cycloalkenyl is optionally substituted with cyano; and the pyridinyl is optionally substituted with 1 or 2 substituents independently selected from —CH 2 OH and —NH 2 ;
R B is H, C 1 -C 6 alkyl, —OH, C 1 -C 6 alkoxy, —CN, F, Cl, Br, or —NR a R b , wherein the R B C 1 -C 6 alkyl is optionally be substituted with 1, 2 or 3 substituents selected from —OH, —F, —NR a R b , —CF 3 , C 1 -C 6 alkoxy, and —CONR a R b ;
or R A and R B together with the atom(s) to which they are attached form a 5-7 membered fused ring containing 0, 1, or 2 heteroatoms independently selected from N, O and S, wherein N is optionally substituted with R d ;
R C is H, C 1 -C 6 alkyl, F, Cl, —CF 3 , —COOCH 3 , —C(O)NH 2 , or AryC;
R D is H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, —(CH 2 ) 0-2 C 3 -C 6 cycloalkyl, —C 3 -C 6 cycloalkenyl, —(CH 2 ) 2 C(O)OH, —CF 3 , F, Cl, Br, —(CH 2 ) 0-1 AryA, or —(CH 2 ) 0-2 HetA, wherein the R D C 1 -C 6 alkyl or
R D C 3 -C 6 cycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from C 3 -C 6 cycloalkyl, —OH, F, —CN, —(CH 2 ) 0-3 NR a R b , —CF 3 , —(CH 2 ) 0-2 HetB, —(CH 2 ) 0-2 AryB, —(CH 2 ) 0-1 NHC(═NH)NH 2 ; —SO 2 —C 1 -C 6 alkyl, —SO 2 —C 3 -C 6 cycloalkyl, —SO 2 NR a R b , C 1 -C 6 alkoxy, and —(CH 2 ) 0-4 CONR a R b , and wherein the —C 3 -C 6 cycloalkenyl is optionally substituted with cyano;
wherein when R A , R B , R C and R D are all present, then 1, 2 or 3 of R A , R B , R C and R D are H;
wherein when 1 or 2 of X 2 , X 3 , X 4 are N, then at least one of R A , R B , R C , and R D , if present, is not H;
AryA 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) —C 1 -C 6 alkyl,
b) —C 2 -C 6 diaminoalkyl;
c) —C 1 -C 6 hydroxyalkyl,
d) —C 1 -C 6 dihydroxyalkyl,
e) —C 3 -C 6 cycloalkyl optionally substituted with 1 or 2 substituents selected from —OH and —NR a R b ,
f) —C 3 -C 6 cycloalkenyl optionally substituted with —CN,
g) —(CH 2 ) 0-6 NR a R b ,
h) —CH(OH)R e ,
i) —CH 2 OR a ,
j) —(CH 2 ) 0-2 C(O)NR a R b ,
k) —CH 2 NR a —C 2 -C 4 alkyl-NR a R b ,
l) —C(═NH)NHR b ;
m) —CH 2 NHCH(═NH);
n) —CH 2 NHCH 2 C(O)NR a R b ,
o) —(CH 2 ) 0-2 C(O)OR a ,
p) —CH 2 NR a —C 1 -C 3 alkyl-C(O)OR a ,
q) —CH 2 NH—CH[C(OH)CH 3 ][C(O)OR a ],
r) —CH 2 NR a —C 1 -C 6 hydroxyalkyl,
s) —(CH 2 ) 0-2 SO 2 —C 1 -C 6 alkyl,
t) —NR a SO 2 —C 3 -C 6 cycloalkyl,
u) —NR a SO 2 —C 1 -C 6 alkyl,
v) —NR a SO 2 —NR a R b ,
w) —CH 2 NHC(═NH)NHR b ;
x) —NHC(═NH)NH 2 ;
y) —OR a ,
z) —O(CH 2 ) 0-6 NR a R b ;
aa) —O—C 1 -C 6 hydroxyalkyl,
bb) —(CH 2 ) 0-1 SO 2 (CH 2 ) 0-2 NR a R b ,
cc) —SO 2 (CH 2 ) 0-2 OH,
dd) —CN,
ee) halogen,
ff) —CF 3 ,
gg) —CH 2 NR a (CH 2 ) 0-1 —C 3 -C 6 cycloalkyl optionally substituted with —OH, NR a R b or 2 F,
hh) —(CH 2 ) 0-1 -AryB,
ii) —CH 2 NR a —C 1 -C 3 alkyl-AryB,
jj) —CH 2 NR a —CH(COOH)CH 2 -AryB,
kk) —C 0 -C 2 alkyl-HetB,
ll) —CH(OH)-HetB,
mm) —(CH 2 ) 0-1 NR a (CH 2 ) 0-2 -HetB,
nn) —C(═NH)NH-HetB;
oo) —O(CH 2 ) 0-2 -HetB,
pp) —C(O)-HetB, and
qq) —C(O)NR a (CH 2 ) 0-2 -HetB; or

2) a 9- or 10-membered bicyclic ring with 0, 1, 2, 3 or 4 heteroatom ring atoms selected from N, O and S, wherein an N atom is optionally in the form of a quaternary amine and wherein the ring is optionally substituted with 1, 2 or 3 substituents independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, —CF 3 , —C(═NH)NH 2 , —COOR a , —(CH 2 ) 0-1 C(O)NR a R b , —CN, —(CH 2 ) 0-3 NR a R b , —NHCH 2 CH 2 N(CH 3 ) 2 , —NH—C 3 -C 6 cycloalkyl, —NHC(═NH)NH 2 , —NH-HetB, —OR a , —SO 2 —C 1 -C 6 alkyl, —SO 2 -phenyl, halogen, and oxo, wherein the C 3 -C 6 cycloalkyl is optionally substituted with —NH 2 ;

AryB is
1) a 5-6 membered monocyclic aromatic ring with 0, 1, 2, 3, or 4 ring atoms selected from N, O and S, optionally substituted with 1 or 2 substituents selected from C 1 -C 6 alkyl, —CH 2 NH 2 , —CH 2 OH, —CONH 2 , —NH 2 , —OH, —CH(OH)R e , halogen, —CF 3 , and pyrrolidinyl; or
2) a 9- or 10-membered bicyclic ring with 1, 2 or 3 N ring atoms optionally substituted with 1 or 2 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, —CONH 2 , —NH 2 , —OH, —CH(OH)R e , halogen, —CF 3 , piperidinyl, pyrrolidinyl, and oxo;

AryC is
1) phenyl optionally substituted with —CONH 2 ;
2) a 5-6 membered monocyclic aromatic ring with 1 or 2 N ring atoms, optionally substituted with —CH 3 or —OH; or
3) a 9-membered bicyclic ring with 1 N ring atom optionally substituted with oxo;

AryD is a 5-membered monocyclic aromatic ring with 2 N ring atoms, optionally substituted with —CH 3 ;
HetA is
1) a 4-6-membered saturated or monounsaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein an N atom is optionally in the form of a quaternary amine and wherein the ring is optionally substituted with 1 or 2 substituents independently selected from
a) C 1 -C 6 alkyl,
b) —C 1 -C 6 hydroxyalkyl,
c) C 3 -C 6 cycloalkyl optionally substituted with —NH 2 ,
d) —C(O)—C 3 -C 6 cycloalkyl optionally substituted with phenyl,
e) —(CH 2 ) 0-4 NR a R b ,
f) —C(═NH)NH 2 ;
g) —(CH 2 ) 0-1 C(O)NR a R b ,
h) —(CH 2 ) 0-2 C(O)OR a ,
i) —(CH 2 ) 0-2 SO 2 —C 1 -C 6 alkyl,
j) —CN,
k) —NHC(═NH)NH 2 ;
l) —OR a ,
m) F,
n) —CF 3 ,
o) —(CH 2 ) 0-1 -AryB,
p) —O-AryB,
q) —C 0 -C 2 alkyl-HetB, and
r) oxo; or

2) a 6-11-membered bicyclic ring with 1 to 3 heteroatom ring atoms selected from N and O, optionally substituted with —CH 2 OH, —C(═NH)NH 2 ; —CH 2 C 3 -C 6 cycloalkyl, —C(═O), —NH 2 , or oxo, wherein the rings in the bicyclic ring are bridged, fused or spirocyclic, and wherein the C 3 -C 6 cycloalkyl is optionally substituted with —NH 2 ;

HetB is
1) a 4-7 membered saturated or monounsaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein an N atom is optionally in the form of a quaternary amine and wherein the ring is optionally substituted with 1, 2 or 3 substituents independently selected from —CF 3 , F, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 2

Assignees

• Merck Sharp & Dohme

Inventors

• Mandal Mihir
• Tang Haifeng
• Xiao Li
• Su Jing
• Li Guoqing
• Yang Shu-Wei
• Pan Weidong
• Tang Haiqun
• Dejesus Reynalda
• Hicks Jacqueline
• Lombardo Matthew
• Chu Hong
• Hagmann William
• Pasternak Alex
• Gu Xin
• Jiang Jinlong
• Dong Shuzhi
• Ding Fa-Xiang
• London Clare
• Biswas Dipshikha
• Young Katherine
• Hunter David N
• Zhao Zhiqiang
• Yang Dexi

Classifications

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title