Metallo-beta-lactamase inhibitors
View Patent ↗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.
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 -C 6 aminoalkyl, C 1 -C 6 haloalkyl, —CH 2 CH 2 N + (CH 3 ) 3 ; —(CH 2 ) 0-1 C 3 -C 6 cycloalkyl, —OH, C 1 -C 6 alkoxy, —C(O)OR a , —C(O)NH 2 , —CH(═NH), —C(═NH)NH 2 , —CN, —C(OH)(CH 3 ) 2 , —CH(OH)(CH 3 ), —(CH 2 ) 0-2 NR a R b , —CH 2 CHR f —(CH 2 ) 0-2 —NHR g , —CH 2 -AryD, —(CH 2 ) 0-2 -HetD, oxo, —SO 2 —C 1 -C 6 alkyl, wherein the cycloalkyl is optionally substituted with —(CH 2 ) 0-2 NHR a ; or
2) a 7-11-membered bicyclic ring with 1 or 2 N ring atoms optionally substituted with methyl, wherein the bicyclic ring is bridged, fused or spirocyclic;
HetC is a 5-6 membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 oxo substituents;
HetD is
1) a 4-6 membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, and O;
2) 7-9 membered bicyclic ring with 1 N heteroatom ring atom, wherein the bicyclic ring is bridged or spirocyclic;
R a is H or C 1 -C 6 alkyl;
R b is H, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 hydroxyalkyl, C 2 -C 6 aminoalkyl,
C 2 -C 6 dihydroxyalkyl, C 2 -C 6 diaminoalkyl, dimethylaminoC 2 -C 6 alkyl,
C 2 -C 6 hydroxyaminoalkyl, —(CH 2 ) 0-1 —C 3 -C 6 cycloalkyl, —C(O)C 1 -C 6 alkyl, or —CH 2 C(O)NHOH; or
R a and R b together with the atom(s) to which they are attached form a 3-7 membered cycloheteroalkyl ring with 0, 1 or 2 additional heteroatom ring atoms independently selected from N, O and S, wherein N is optionally substituted with R d ;
R d is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C(O)—C 1 -C 6 alkyl, —C(O)-AryC, —SO 2 —C 1 -C 6 alkyl, and —SO 2 -AryC; and
R e is C 1 -C 6 alkyl, —CF 3 or —CHF 2 ;
R f is C 1 -C 6 alkyl, —CH 2 OH, —(CH 2 ) 1-4 NH 2 , —(CH 2 ) 1-3 CONH 2 , —CH 2 -imidazole, benzyl; and
R g is H or C 1 -C 6 alkyl; or
R f and R g together with the atom(s) to which they are attached form a 4-6 membered cycloheteroalkyl ring with 0, 1 or 2 additional heteroatom ring atoms independently selected from N, O and S.
2. The compound of claim 1 , 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, —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 ) 1-2 —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 5 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 , —CONR a R b , —NHCONR a R b , —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, and HetB;
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 3 -C 6 cycloalkyl, —CF 3 , F, Cl, or Br, 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, —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 ;
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 1 -C 6 hydroxyalkyl,
c) —C 3 -C 6 cycloalkyl optionally substituted with —OH or —NR a R b ,
d) —C 3 -C 6 cycloalkenyl optionally substituted with —CN,
e) —(CH 2 ) 0-6 NR a R b ,
f) —CH(OH)R e ,
g) —CH 2 OR a ,
h) —(CH 2 ) 0-1 C(O)NR a R b ,
i) —CH 2 NR a —C 2 -C 4 alkyl-NR a R b ,
j) —CH 2 NHCH 2 C(O)NR a R b ,
k) —(CH 2 ) 0-2 C(O)OR a ,
l) —CH 2 NR a —C 1 -C 3 alkyl-C(O)OR a ,
m) —CH 2 NH—CH[C(OH)CH 3 ][C(O)OR a ],
n) —CH 2 NR a —C 1 -C 6 hydroxyalkyl,
o) —(CH 2 ) 0-2 SO 2 —C 1 -C 6 alkyl,
p) —NR a SO 2 —C 1 -C 6 alkyl,
q) —OR a ,
r) —O(CH 2 ) 0-6 NR a R b ;
s) —O—C 1 -C 6 hydroxyalkyl,
t) —SO 2 NR a R b ,
u) —CN,
v) halogen,
w) —CF 3 ,
x) —CH 2 NR a (CH 2 ) 0-1 —C 3 -C 6 cycloalkyl optionally substituted with —OH, NR a R b or 2 F,
y) —(CH 2 ) 0-1 -AryB,
z) —CH 2 NR a —C 1 -C 3 alkyl-AryB,
aa) —CH 2 NR a —CH(COOH)CH 2 -AryB,
bb) —C 0 -C 2 alkyl-HetB,
cc) —(CH 2 ) 0-1 NR a (CH 2 ) 0-2 -HetB,
dd) —O(CH 2 ) 0-2 -HetB,
ee) —C(O)-HetB, and
ff) —C(O)NR a (CH 2 ) 0-2 -HetB; or
2) a 9- or 10-membered bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from N, O and S, 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 , —COOR a , —(CH 2 ) 0-1 C(O)NR a R b , —CN, —(CH 2 ) 0-3 NR a R b , —OR a , —SO 2 —C 1 -C 6 alkyl, —SO 2 -phenyl, halogen, and oxo;
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 , —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;
HetA is
1) a 5-6-membered saturated or monounsaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 substituents independently selected from
a) C 1 -C 6 alkyl,
b) —C 1 -C 6 hydroxyalkyl,
c) —C(O)—C 3 -C 6 cycloalkyl optionally substituted with phenyl,
d) —(CH 2 ) 0-3 NR a R b ,
e) —(CH 2 ) 0-1 C(O)NR a R b ,
f) —(CH 2 ) 0-2 C(O)OR a ,
g) —(CH 2 ) 0-2 SO 2 —C 1 -C 6 alkyl,
h) —CN,
i) —OR a ,
j) F,
k) —CF 3 ,
l) —(CH 2 ) 0-1 -AryB,
m) —O-AryB,
n) —C 0 -C 2 alkyl-HetB, and
o) oxo; or
2) a 10-11-membered spirocyclic ring with 2 or 3 N ring atoms optionally substituted with oxo;
HetB 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, 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 3 -C 6 cycloalkyl, —OH, C 1 -C 6 alkoxy, —C(O)OR a , —C(O)NH 2 , —C(═NH 2 )NH 2 , —CN, —C(OH)(CH 3 ) 2 , —CH(OH)(CH 3 ), —(CH 2 ) 0-2 NR a R b , —CH 2 CHR f —(CH 2 ) 0-2 —NHR g , and oxo; or
2) 8-methyl-8-azabicyclo[3.2.1]octane with the point of attachment being the 3-position of the bridged bicyclic ring;
HetC is a 5-6 membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 oxo substituents;
R a is H or C 1 -C 6 alkyl;
R b is H, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 hydroxyalkyl, C 2 -C 6 aminoalkyl,
C 2 -C 6 dihydroxyalkyl, C 2 -C 6 diaminoalkyl, C 2 -C 6 hydroxyaminoalkyl, —(CH 2 ) 0-1 —C 3 -C 6 cycloalkyl, —C(O)C 1 -C 6 alkyl, or —CH 2 C(O)NHOH; or
R a and R b together with the atom(s) to which they are attached form a 3-7 membered cycloheteroalkyl ring with 0, 1 or 2 additional heteroatom ring atoms independently selected from N, O and S, wherein N is optionally substituted with R d ;
R d is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C(O)—C 1 -C 6 alkyl, —C(O)-AryC, —SO 2 —C 1 -C 6 alkyl, and —SO 2 -AryC; and
R e is C 1 -C 6 alkyl, —CF 3 or —CHF 2 ;
R f is C 1 -C 6 alkyl, —CH 2 OH, —(CH 2 ) 1-4 NH 2 , —(CH 2 ) 1-3 CONH 2 , —CH 2 -imidazole, benzyl; and
R g is H or C 1 -C 6 alkyl; or
R f and R g together with the atom(s) to which they are attached form a 4-6 membered cycloheteroalkyl ring with 0, 1 or 2 additional heteroatom ring atoms independently selected from N, O and S.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
R A is H, C 1 -C 6 alkyl, —(CH 2 ) 0-2 —C 3 -C 8 cycloalkyl, —CF 3 , C 1 -C 6 alkoxy, —COOR a , —CN, —NR a R b , HetA, —(CH 2 ) 0-2 -AryA, —(CH 2 ) 0-1 —O-AryA, —NR a (CH 2 ) 1-2 —C 3 -C 8 cycloalkyl, —NR a (CH 2 ) 1-2 -phenyl, —C≡C-pyridinyl, or —C≡C—CH 2 -HetC; wherein the R A C 1 -C 6 alkyl or any R A C 3 -C 8 cycloalkyl is optionally substituted with —OH, —(CH 2 ) 0-2 NR a R b , —NHSO 2 —C 1 -C 6 alkyl, AryB, or HetB;
R B is H, C 1 -C 6 alkyl, —OH, C 1 -C 6 alkoxy, —CN, F, or —NR a R b ;
or R A and R B together with the atom(s) to which they are attached form a 5-6 membered fused aromatic 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, —COOCH 3 , —C(O)NH 2 , or AryC;
R D is H, C 1 -C 6 alkyl, —(CH 2 ) 0-1 C 3 -C 6 cycloalkyl, —CH 2 -phenyl, —CH 2 -azetidinyl, —(CH 2 ) 1-2 -piperidinyl, or —CH 2 -pyrrolidinyl, —CF 3 , —CN, Cl, or Br, wherein the cycloalkyl is optionally substituted with —(CH 2 ) 0-1 NH 2 and the piperidinyl is optionally substituted with fluoro;
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 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 —OH,
d) —C 3 -C 6 cycloalkenyl optionally substituted with —CN,
e) —(CH 2 ) 0-6 NR a R b ,
f) —CH 2 NHCH═NH,
g) —CH(OH)R e ,
h) —CH 2 OR a ,
i) —(CH 2 ) 0-1 C(O)NR a R b ,
j) —CH 2 NR a —C 3 -C 4 alkyl-NR a R b ,
k) —CH 2 NHCH 2 C(O)NR a R b ,
l) —(CH 2 ) 0-2 C(O)OR a ,
m) —CH 2 NR a —C 1 -C 3 alkyl-C(O)OR a ,
n) —CH 2 NH—CH[C(OH)CH 3 ][C(O)OR a ],
o) —CH 2 NR a —C 1 -C 6 hydroxyalkyl,
p) —(CH 2 ) 0-2 SO 2 —C 1 -C 6 alkyl,
q) —NR a SO 2 —C 1 -C 6 alkyl,
r) —OR a ,
s) —O(CH 2 ) 0-6 NR a R b ;
t) —O—C 1 -C 6 hydroxyalkyl,
u) —SO 2 NR a R b ,
v) —CN,
w) halogen,
x) —CH 2 NR a (CH 2 ) 0-1 —C 3 -C 6 cycloalkyl optionally substituted with —OH, NR a R b or 2 F,
y) —(CH 2 ) 0-1 -AryB,
z) —CH 2 NR a —C 1 -C 3 alkyl-AryB,
aa) —CH 2 NR a —CH(COOH)CH 2 -AryB,
bb) —C 0 -C 2 alkyl-HetB,
cc) —(CH 2 ) 0-1 NR a (CH 2 ) 0-2 -HetB,
dd) —O(CH 2 ) 0-2 -HetB,
ee) —C(O)-HetB, and
ff) —C(O)NR a (CH 2 ) 0-2 -HetB; or
2) a 9- or 10-membered bicyclic ring with 1, 2 or 3 heteroatom ring atoms selected from N, O and S, optionally substituted with 1 or 2 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , C 1 -C 6 aminoalkyl, —CF 3 , —COOR a , —CONH 2 , —SO 2 —C 1 -C 6 alkyl, —SO 2 -phenyl, —CN, Cl, and oxo;
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 C 1 -C 6 alkyl, —CH 2 NH 2 , —NH 2 , —CH(OH)R e , or pyrrolindinyl; or
2) a 9-membered bicyclic ring with 2 or 3 N ring atoms optionally substituted with CH 3 ;
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;
HetA is
1) a 6-membered monounsaturated monocyclic ring with 1 heteroatom ring atom independently selected from N, O or S, optionally substituted with 1 or 2 substituents independently selected from C 1 -C 6 alkyl, —CN, and oxo;
2) a 6-membered saturated monocyclic ring with 1 N ring atom, optionally substituted with 1 substituent selected from
a) —C 1 -C 6 hydroxyalkyl,
b) —C(O)—C 3 -C 6 cycloalkyl,
c) —(CH 2 ) 1-2 NR a R a ,
d) —(CH 2 ) 0-1 C(O)NR a R a ,
e) —(CH 2 ) 0-2 C(O)OR a ,
f) —(CH 2 ) 0-2 SO 2 —C 1 -C 6 alkyl,
g) —OH,
h) —(CH 2 ) 0-1 -AryB,
i) —O-AryB, and
j) —C 0 -C 2 alkyl-HetB; or
3) a 10-11-membered spirocyclic ring with 2 or 3 N ring atoms optionally substituted with oxo;
HetB 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, 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 3 -C 6 cycloalkyl, —OH, C 1 -C 6 alkoxy, —C(O)OR a , —C(O)NH 2 , —C(═NH 2 )NH 2 , —CN, —C(OH)(CH 3 ) 2 , —CH(OH)(CH 3 ), —NH 2 , —N(CH 3 ) 2 , and oxo; or
2) 8-methyl-8-azabicyclo[3.2.1]octane with the point of attachment being the 3-position of the bridged bicycle;
HetC is a 5-6 membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 oxo substituents;
R a is H or C 1 -C 6 alkyl;
R b is H, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 dihydroxyalkyl, C 3 -C 6 cycloalkyl, —C(O)C 1 -C 6 alkyl, —CH 2 C(O)NHOH, or C 1 -C 6 aminoalkyl; or
R a and R b together with the atom(s) to which they are attached form a 3-7 membered cycloheteroalkyl ring with 0, 1 or 2 additional heteroatom ring atoms independently selected from N, O and S, wherein N is optionally substituted with R d ;
R e is —C 1 -C 6 alkyl, —CF 3 or —CHF 2 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is H, C 1 -C 6 alkyl, —(CH 2 ) 0-2 —C 3 -C 8 cycloalkyl, —CF 3 , C 1 -C 6 alkoxy, —COOR a , —CN, —NR a R b , HetA, —(CH 2 ) 0-2 -AryA, —CH 2 —O-AryA, —NR a (CH 2 ) 1-2 —C 3 -C 8 cycloalkyl, —NR a (CH 2 ) 1-2 -phenyl, —C≡C-pyridinyl, or —C≡C—CH 2 -HetC; wherein the R A cycloalkyl is optionally substituted with —OH, —(CH 2 ) 0-2 NH 2 , —NHSO 2 —C 1 -C 6 alkyl or HetB, 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 .
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein Formula I is
wherein
R A is C 1 -C 6 alkyl; —(CH 2 ) 0-2 —C 3 -C 8 cycloalkyl; —CF 3 ; C 1 -C 6 alkoxy; —COOR a ; —CN; —NR a R b ; HetA; —(CH 2 ) 0-2 -AryA; —CH 2 —O-AryA; —NR a (CH 2 ) 1-2 —C 3 -C 8 cycloalkyl; —NR a (CH 2 ) 1-2 -phenyl; —C≡C-pyridinyl; or —C≡C—CH 2 -HetC; wherein the R A cycloalkyl is optionally substituted with —(CH 2 ) 0-1 NR a R b , AryB, or —OH;
R B is C 1 -C 6 alkyl, —OH, C 1 -C 6 alkoxy, —CN, F, or —NR a R b ,
R C is C 1 -C 6 alkyl, Cl, —COOCH 3 , —C(O)NH 2 , or AryC; and
R D is C 1 -C 6 alkyl, —(CH 2 ) 0-1 C 3 -C 8 cycloalkyl, —CH 2 -phenyl, —CH 2 -azetidinyl, —(CH 2 ) 1-2 -piperidinyl, or —CH 2 -pyrrolidinyl, —CF 3 , Cl, or Br, wherein the cycloalkyl is optionally substituted with —(CH 2 ) 0-1 NH 2 and the piperidinyl is optionally substituted with fluoro.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein AryA is
1) phenyl optionally substituted with:
a) —C 1 -C 6 alkyl,
b) —C 1 -C 2 hydroxyalkyl,
c) —(CH 2 ) 1-3 NR a R b ,
d) —CH 2 NHCH═NH;
e) —CH 2 NHC(═NH)NH 2 ;
f) —CH(OH)R e ,
g) —CH 2 OR a ,
h) —CH 2 NR a —C 1 -C 6 hydroxyalkyl,
i) —(CH 2 ) 0-1 C(O)NR a R b ,
j) —C(O)OR a ,
k) —NHSO 2 —C 1 -C 6 alkyl,
l) —OR a ,
m) —OCH(CH 3 )CH 2 OH,
n) —SO 2 —C 1 -C 6 alkyl,
o) —SO 2 NR a R b ,
p) halogen,
q) —CN,
r) —CH 2 NR a (CH 2 ) 0-1 —C 3 -C 6 cycloalkyl optionally substituted with —OH, NR a R b or 2 F,
s) AryB,
t) —CH 2 NR a —C 3 -C 4 alkyl-NR a R b ,
u) —CH 2 NHCH 2 C(O)NR a R b ,
v) —CH 2 NR a —C 1 -C 3 alkyl-C(O)OR a ,
w) —CH 2 NH—CH[C(OH)CH 3 ][C(O)OR a ],
x) —CH 2 NR a —C 1 -C 3 alkyl-AryB,
y) —CH 2 NR a —CH(COOH)CH 2 -AryB,
z) —C 0 -C 2 alkyl-HetB,
aa) —C(O)-HetB,
bb) —(CH 2 ) 0-1 NR a (CH 2 ) 0-2 -HetB,
cc) —C(O)NR a (CH 2 ) 0-2 -HetB, or
dd) —O(CH2) 0-2 -HetB; or
2) dihydroindenyl substituted with —NH 2 or —NHC(═NH)NH 2 .
7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein AryA is an aromatic ring system selected from:
a) a 5-6 membered monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 substituents selected from C 1 -C 6 alkyl; C 1 -C 6 hydroxyalkyl; C 1 -C 6 alkoxy; C 1 -C 6 aminoalkyl; C 3 -C 6 hydroxycycloalkyl; —CH 2 CH 2 C(O)OCH 2 CH 3 ; —CN, —(CH 2 ) 0-2 SO 2 CH 3 ; —NR a R b , —N(R a )SO 2 CH 3 ; —OH; —O(CH 2 ) 0-6 NR a R b ; dioxolanyl substituted with —CF 3 ; halogen; —(CH 2 ) 0-1 -AryB; —C 0 -C 2 alkyl-HetB; and —(CH 2 ) 0-1 NR a (CH 2 ) 0-2 -HetB; or
b) a 9- or 10-membered bicyclic ring with 1, 2 or 3 heteroatom ring atoms selected from N, S and O, optionally substituted with 1 or 2 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NR a R b , C 1 -C 6 aminoalkyl, —CF 3 , —C(═NH)NH 2 , —COOR a , —CONH 2 , —SO 2 —C 1 -C 6 alkyl, —SO 2 -phenyl, —CN, Cl, and oxo.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein AryA is an aromatic ring system selected from:
a) a monocyclic ring selected from furanyl, imidazolyl, morpholinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl; pyrimidinyl, thiazolyl, and thiophenyl, wherein the monocyclic ring is optionally substituted with 1 or 2 substituents selected from C 1 -C 6 alkyl; C 1 -C 6 hydroxyalkyl; C 1 -C 6 alkoxy; C 1 -C 6 aminoalkyl; C 3 -C 6 hydroxycycloalkyl; —CH 2 CH 2 C(O)OCH 2 CH 3 ; —CN; —(CH 2 ) 0-2 SO 2 CH 3 ; —NR a R b ; —N(R a )SO 2 CH 3 ; —OH; —O(CH 2 ) 0-6 NR a R b ; dioxolanyl substituted with —CF 3 ; halogen; —(CH 2 ) 0-1 -AryB; —C 0 -C 2 alkyl-HetB; and —(CH 2 ) 0-1 NR a (CH 2 ) 0-2 -HetB; or
b) a bicyclic ring selected from 1H-benzo[d]imidazolyl, benzodiimidazolyl, benzooxadiazolyl, benzo[d]thiazolyl, benzothiophenyl, benzotriazolyl, dihydrobenzimidazol, dihydrobenzodioxinyl, dihydrobenzooxazinyl, dihydrochromenyl, dihydroisoindolyl, dihydroindolyl, dihydroquinazolinyl, furopyridinyl, imidazopyridinyl, indazolyl, indolinyl, indolyl, isoindolinyl, isoquinolinyl, naphthyridinyl, pyrazolopyrazinyl, pyrazolopyridinyl, pyrrolopyrazinyl, pyrroloppyridinyl, quinolinyl, tetrahydroimidazopyridinyl, tetrahydropyrazolopyridinyl, tetrahydroquinolinyl, and triazolopyridinyl; wherein the bicyclic ring is optionally substituted with 1 or 2 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NR a R b , C 1 -C 6 aminoalkyl, —CF 3 , —COOR a , —CONH 2 , —SO 2 —C 1 -C 6 alkyl, —SO 2 -phenyl, —CN, Cl, and oxo.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein
HetB is azabicyclo[3.2.1]octyl, azetidinyl, 1,1-dimethylazetidin-1-ium, 1,1-dimethylpiperidin-1-ium, dioxolanyl, morpholinyl, oxoimidazolidinyl, oxazolidinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, pyrazolyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, or thiazolidinyl; wherein HetB 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 3 -C 6 cycloalkyl, —OH, C 1 -C 6 alkoxy, —C(O)OR a , —C(O)NH 2 , —CH(═NH), —C(═NH 2 )NH 2 , —CN, —C(OH)(CH 3 ) 2 , —CH(OH)(CH 3 ), —NH 2 , —N(CH 3 ) 2 , —(CH 2 )-azetidinyl, and oxo; or
HetC is dioxidothiomorpholinyl, morpholinyl, piperidinyl, or pyrrolidin-1-yl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Formula I is
wherein
R A is 1) —(CH 2 ) 0-2 AryA optionally substituted with
a) —C 1 -C 6 alkyl,
b) —C 1 -C 2 hydroxyalkyl,
c) —(CH 2 ) 0-3 NR a R b ,
d) —C(═NH)NH 2
e) —CH 2 NHCH═NH;
f) —CH 2 NHC(═NH)NH 2 ;
g) —(CH 2 ) 0-1 C(O)NR a R b ,
h) —NHC(═NH)NH 2 ;
i) —NHSO 2 —C 1 -C 6 alkyl,
j) —OH,
k) —SO 2 NR a R b , or
l) HetB, or
2) —(CH 2 ) 0-2 C 3 -C 6 -cycloalkyl, wherein the C 3 -C 6 cycloalkyl optionally substituted with —OH or —(CH 2 ) 0-2 NR a R b ;
HetB is
1) a 4-6 membered saturated or monounsaturated monocyclic ring with 1 N ring atom, optionally substituted with 1 or 2 substituents selected from —CH(═NH), —C(═NH)NH 2 , —NH 2 , and —OH; or
2) a 4-6 membered saturated monocyclic ring with 1 N ring atom, in the form of a quarternary amine, wherein the N ring atom is substituted with 2 methyl;
R C is Cl;
R D is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CF 3 , Cl, Br, —CH 2 -cyclohexyl-(CH 2 ) 0-1 NH 2 , —CH 2 -azetidinyl, —(CH 2 ) 1-2 -piperidinyl, or —CH 2 -pyrrolidinyl, wherein the piperidinyl is optionally substituted with fluoro;
R a is H or CH 3 ; and
R b is H or CH 3 .
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein AryA is phenyl substituted with 1) —CH 3 , 2) —CH 2 CH 2 CH 3 , 3) —CH 2 OH, 4) —CH 2 NH 2 , 5) —CH 2 NHCH═NH, 6) —CH 2 NHC(═NH)NH 2 , 7) —CH 2 CH 2 NH 2 , 8) —CH 2 CH 2 CH 2 NH 2 , 9) —C(O)NH 2 , 10) —(CH 2 )C(O)NH 2 , 11) —NHSO 2 CH 3 , 12) —SO 2 NH 2 , 13) —SO 2 NHCH 3 , 14) dimethylazetidinium, 15) azetidinyl optionally substituted with —C(═NH)NH 2 or —OH, 16) piperidinyl optionally substituted with 1 or 2 substituents selected from —NH 2 , 17) —C(═NH)NH 2 , 18) —CH(═NH), 19) —CH-azetidinyl, or 20) pyrrolidinyl optionally substituted with —OH or 2,5-dihydro-1H-pyrrolyl.
12. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein AryA is pyridinyl substituted with —NH 2 .
13. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein AryA is benzodimidazolyl substituted with —NH 2 ; benzothiophenyl; benzothiazolyl substituted with —NH 2 or —C(═NH)NH 2 ; dihydrobenzimidazol; dihydroindenyl substituted with —NH 2 or —NHC(═NH)NH 2 ; dihydroisoindolyl substituted with oxo; imidazopyridinyl; indazolyl optionally substituted with —NH 2 ; isoindolinyl optionally substituted with —CH(═NH)NH 2 ; pyrazolopyridinyl; pyrrolopyrazinyl; pyrrolopyridinyl; quinolinyl optionally substituted with —CH 2 NH 2 ; or tetrahydroimidazopyridinyl.
14. The compound of claim 1 which is
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 which is
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 which is
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 which is
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition which comprises a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition according to claim 18 , which further comprises an effective amount of a beta-lactam antibiotic.
20. The pharmaceutical composition according to claim 19 , wherein the beta-lactam antibiotic is selected from the group consisting of imipenem, ertapenem, meropenem, doripenem, biapenem, panipenem, ticarcillin, ampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin, mezlocillin, ticarcillin, cefoperazone, cefotaxime, ceftriaxone, and ceftazidime.
21. The pharmaceutical composition according to claim 20 , wherein the beta-lactam antibiotic is imipenem.
22. The pharmaceutical composition according to claim 21 , further comprising cilastatin or a pharmaceutically acceptable salt thereof.
23. A method for inhibiting beta-lactamase in a subject which comprises administering to the subject an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, optionally in combination with a beta-lactam antibiotic.
24. A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic.
25. The method of claim 23 , wherein the beta-lactam antibiotic is selected from the group consisting of imipenem, ertapenem, meropenem, doripenem, biapenem, panipenem, ticarcillin, ampicillin, amoxicillin, carbenicillin, piperacillin, azlocillin, mezlocillin, ticarcillin, cefoperazone, cefotaxime, ceftriaxone, and ceftazidimem.
26. The method of claim 23 , wherein the beta-lactam antibiotic is imipenem.