Beta-lactamase inhibitors

1. A compound of Formula I or a pharmaceutically-acceptable salt thereof, wherein the compound of Formula I, when used in the Synergy MIC Assay of Example 23 with an antibiotic selected from ceftolozane or ceftazidime at a fixed concentration of 4 μg/mL, has an MIC of 8 μg/mL or less against one or more isogenic β-lactamase expressing bacterial strains from Table X, wherein the compound of Formula (I) is:

wherein

Z is selected from the group consisting of isoxazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole;

R is selected

from

and

R 1 is selected from:

a. hydrogen,

b. cyano,

c. (C 1 -C 3 )-unsubstituted alkyl,

d. (C 1 -C 3 )-alkyl substituted with at least one substituent selected from hydroxyl,

 wherein each of R 2 , R 3 and R 4 is independently selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, or hydroxyalkyl,

e.

 wherein R 5 is selected from H or aminoalkyl,

f.

g. amino,

h. (C 1 -C 3 )alkylamino, or

i. a 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from O and N, or NX, wherein X is H,

wherein

Table X is:

TABLE X

GenBank

Accession

Species

Number

β-

Origin

of β-

Lactamase

Name & SEQ. ID of

β-

of β-

Lactamase

Expressing

plasmids producing

Lactamase

Lactamase

Gene

Strain

β-Lactamase

Class

Gene

Sequence

KPC-2

pBR-CBST-KPC-2

A

K.

EU784136

SEQ ID 6

pneumoniae

CTX-M-15

pBR-CBST-CTX-M-15

A

K.

JF775516

SEQ ID 7

pneumoniae

SHV-12

pBR-CBST-SHV-12

A

K.

AY008838

SEQ ID 8

pneumoniae

P99 AmpC

pBR-CBST-P99 AMPC

C

E.

XO7274

SEQ ID 9

cloacea

OXA-15

pBR-CBST-OXA-15

D

P.

PAU63835

SEQ ID 10

aeruginosa .

2. The compound of claim 1 wherein the β-lactamase is selected from a KPC, CTX-M, SHV or AmpC β-lactamase.

3. The compound of claim 1 wherein the β-lactamase is an OXA β-lactamase.

4. The compound of claim 3 wherein the OXA β-lactamase is OXA-15.

5. A compound of Formula (I) or a pharmaceutically acceptable salt thereof that has inhibition kinetics of at least 250 mM −1 s −1 according to the assay described in Example 24:

wherein

Z is selected from the group consisting of isoxazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole;

R is selected

from

and

R 1 is selected from:

a. hydrogen,

b. cyano,

c. (C 1 -C 3 )-unsubstituted alkyl,

d. (C 1 -C 3 )-alkyl substituted with at least one substituent selected from hydroxyl,

 wherein each of R 2 , R 3 and R 4 is independently selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, or hydroxyalkyl,

e.

 wherein R 5 is selected from H or aminoalkyl,

f.

g. amino,

h. (C 1 -C 3 )alkylamino, or

i. a 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from O and N, or NX, wherein X is H,

6. A compound of Formula (A-I) or a pharmaceutically acceptable salt thereof:

wherein

Z is selected from the group consisting of 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-thiadiazole;

R* is selected from

and

R 1* is selected from:

a. hydrogen;

b.

wherein

R 2* is selected from

R 3* is selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, hydroxyalkyl,

each of R 4* , R 5* , R 6* and R 7* is independently selected from hydrogen or (C 1 -C 6 )-alkyl, aminoalkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 4* , R 5* , R 6* and R 7* is hydrogen,

n is selected from 1, 2, 3 and 4, and

m is selected from 1, 2 and 3;

c.

wherein R 8* is selected from NH 2 ,

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously and each of R 9 , R 10 , and R 11 is independently selected from hydrogen or (C 1 -C 6 )-alkyl, provided that at least one of R 9 , R 10 , and R 11 is hydrogen;

d. amino;

e.

wherein Z* is selected from CR 12 R 13 or NR 14 ,

each of R 12 and R 13 is independently selected from H, NH 2 and

 wherein each of R 4* , R 5* , R 6* and R 7* is as described previously, alternatively, R 12 and R 13 together with the carbon to which they are attached, form a cycloalkyl or heterocyclyl ring containing 4-6 ring members,

R 14 is selected from H and

 wherein each of R 15 , R 16 and R 17 is independently selected from hydrogen, (C 1 -C 6 )-alkyl, aminoalkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R 15 , R 16 and R 17 is hydrogen,

R 18 is selected from NH 2 and

 wherein each of R 4* , R 5* ,

R 6* and R 7* is as described previously,

each of p* and q* is independently selected from 0, 1, 2 and 3,

T is selected from NH and O

t is selected from 0, 1, 2, 3, and 4, and

each of r and y is independently selected from 0 and 1;

f.

wherein R 19 is selected from NH 2 and

 wherein each of R 4 *,

R 5* , R 6* and R 7* is as described previously,

R 20 is selected from amino and hydroxyl, and

w is selected from 0 and 1;

g.

h.

 wherein each of R 4* , R 6* and R 7* is as described previously;

i.

wherein R 21 is selected from NH 2 , —NH(C 1 -C 3 )-alkyl and

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously,

s is selected from 0 and 1, and

v is selected from 0, 1, 2, and 3;

j.

k.

wherein M is selected from NR 22 , CR 23 R 24 and O,

wherein R 22 is H or

 wherein each of R 15 , R 16 and R 17 is as described previously,

each of R 23 and R 24 is independently selected from H, NH 2 and

wherein each of R 4* , R 5* , R 6* and R 7* is as described previously, and

u is selected from 0, 1 and 2;

l.

m.

n.

o. (C 1 -C 3 )-unsubstituted alkyl; and

p.

7. The compound of claim 5 , wherein Z is isoxazole.

8. The compound of claim 5 , wherein Z is 1,3,4-oxadiazole.

9. The compound of claim 5 , wherein Z is 1,2,4-oxadiazole.

10. The compound of claim 5 , wherein Z is 1,3,4-thiadiazole.

11. The compound of claim 5 , wherein Z is 1,2,4-thiadiazole.

12. The compound of claim 6 , wherein Z is 1,3,4-oxadiazole.

13. The compound of claim 6 , wherein Z is 1,2,4-oxadiazole.

14. The compound of claim 6 , wherein Z is 1,3,4-thiadiazole.

15. The compound of claim 6 , wherein Z is 1,2,4-thiadiazole.