Metallo-beta-lactamase inhibitors

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 1 is

1) —NH 2 ;

2) —NR a —C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from: —F, —CF 3 , C 1 -C 6 alkyl, —CH(NH 2 )C(O)NH 2 , —C(O)NR a R b , —C(O)OH, —(CH 2 ) 1-2 NH 2 , —NR a (CH 2 ) 2-3 NH 2 , —NR a R b , —N + R a R b CH 3 , —NHCH 2 CH 2 OCH 3 , —OR a , and —O(CH 2 ) 2-3 NH 2 ;

3) —NR a C(O)C 1 -C 6 alkyl optionally substituted with 1 or 2 substituents independently selected from: —F, —CF 3 , —C(O)NR a R b , —C(O)OH, —NR a R b , —N + R a R b CH 3 , —NHCH 2 CH 2 OCH 3 , —OR a , and —O(CH 2 ) 2-3 NH 2 ;

4) —NR a (CH 2 ) n —C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with —CH 2 OH or —NH 2 ;

5) a nitrogen-linked 4-6 membered monocyclic heterocycloalkyl with 0, 1, or 2, additional heteroatom ring atoms independently selected from N, O and S, or a nitrogen-linked 6- to 10-membered bicyclic heterocycloalkyl with 0, 1, 2, or 3 additional heteroatom ring atoms selected from N, O and S wherein the bicyclic ring may be bridged, fused or spirocyclic, wherein the 4-6 membered monocyclic heterocycloalkyl and the 6- to 10-membered bicyclic heterocycloalkyl are optionally substituted with one to three substituents, independently selected from: —F, —NR a R b , oxo, —(CH 2 ) 1-2 OH, —CH 2 NH 2 , —SO 2 CH 3 , and C 1 -C 6 alkyl and wherein a ring sulfur atom is optionally substituted with one or two oxo;

6) —NR a —(C 1 -C 3 alkyl) n -AryB1, wherein the C 1 -C 3 alkyl is optionally substituted with —NH 2 ; and

7) —NR a —(C 1 -C 3 alkyl) n -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 , —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 or tetrahydropyranyl;

AryA2 is a 5-6-membered aromatic monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, and S, or 4 N ring atoms, optionally substituted with —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 ; or

2) a 9-membered bicyclic ring with 2 N ring atoms;

HetB1 is a saturated ring selected from:

1) a 4-6 membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, wherein a N ring atom is optionally in the form of a quaternary amine, wherein the S is substituted with 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, —C(O)OR a , —(CH 2 ) k NR a R b , —OR a , and oxo; or

2) a 6-10-membered bicyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O, optionally substituted with —OH or —NH 2 , wherein the bicyclic ring is bridged or fused;

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, 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 ;

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, optionally 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 ) p NHR a ,

i) —NHC(═NH)NH 2 ;

j) —NHC(O)CH 3 ;

k) —NR a SO 2 —C 1 -C 6 alkyl,

l) —NHSO 2 -cyclopropyl,

m) —OR a ,

n) —SO 2 NR a R b ,

o) —SC 1 -C 6 alkyl,

p) —SO 2 NH-cyclopropyl,

q) -AryA2,

r) —(CH 2 ) n NR a AryA2,

s) —C(O)NR a HetA2 and

t) -HetA2, and

2) a 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 is optionally substituted with 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 F, C 1 -C 6 alkyl, —CH 2 CF 3 , —CF 2 CH 2 NH 2 , —CF 3 , —C(═NH)NH 2 , —CH(NH 2 )CH 3 , —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; and

all other variables are defined in claim 1 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is AryA1.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein AryA1 is 1) pyridyl optionally substituted with —NH 2 , 2) benzoimidazolyl substituted with 1 or 2 substituents independently selected from F, —CH 3 and —(CH 2 )NH 2 ; or 3) benzothiazolyl substituted with 1 or 2 substituents independently selected from —CH 3 and —(CH 2 ) n NH 2 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:

1) —NH 2 ;

2) —NR a —C 1 -C 6 alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from —F, —CF 3 , C 1 -C 6 alkyl, —CH(NH 2 )C(O)NH 2 , —C(O)NR a R b , —C(O)OH, —(CH 2 ) 1-2 NH 2 , —NR a R b , —N + R a R b CH 3 , —NHCH 2 CH 2 OCH 3 , —OR a , —NR a (CH 2 ) 2-3 NH 2 , and —O(CH 2 ) 2-3 NH 2 ;

3) —NR a (CH 2 ) n —C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with —CH 2 OH or —NH 2 ,

4) —NR a —(C 1 -C 3 alkyl) n -AryB1, wherein the C 1 -C 3 alkyl is optionally substituted with —NH 2 ; and

5) —NR a —(C 1 -C 3 alkyl) n -HetB1.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is: —NH 2 , —NH-HetB1 optionally substituted with —NH 2 , or —NH—C 2 -C 3 alkylNH 2 , optionally substituted with —CH 3 , —OH or —NH 2 .

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

wherein:

AryA1 is an aromatic ring system selected from:

1) a 5-6 membered monocyclic ring with 0 or 1 N ring atoms substituted with 1 or 2 substituents independently selected from F, —C 1 -C 6 alkyl, —CONH—C 2-4 alkyl-NH 2 , or —NHR a ; or

2) a 9-membered bicyclic ring with 2 heteroatom ring atoms selected from N and S, wherein the ring is optionally substituted with 1 or 2 substituents independently selected from F, C 1 -C 6 alkyl, and —(CH 2 ) x NR a R b

R 1 is

1) —NH 2 ,

2) —NR a —C 1-6 alkyl optionally substituted with 1 or 2 F substituents and optionally substituted with 1 or 2 substituents independently selected from —CF 3 , —CH(NH 2 )C(O)NH 2 ; —C(O)NR a R b ; —C(O)OH; —NR a (CH 2 ) 2-3 NH 2 , —NR a R b , —N + R a R b CH 3 , —NHCH 2 CH 2 OCH 3 , —OR a , and —O(CH 2 ) 2-3 NH 2 ;

3) —NR a (CH 2 ) n —C 3 -C 6 cycloalkyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with —CH 2 OH or —NH 2 ;

4) —NR a —(C 1 -C 3 alkyl) n -AryB1; and

5) —NR a —(C 1 -C 3 alkyl) n -HetB1;

R a and R b are H or —CH 3 ; and

x is 0, 1 or 2.

9. A compound of claim 1 having the structure

or a pharmaceutically acceptable salt thereof.

10. A zwitterion of the compound of claim 9 .

11. A pharmaceutical composition which comprises a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition according to claim 11 , which further comprises an effective amount of a beta-lactam antibiotic.

13. The pharmaceutical composition according to claim 12 , which further comprises an effective amount of one or more beta-lactamase inhibitor compounds.

14. The pharmaceutical composition according to claim 13 , wherein the composition comprises a beta-lactamase inhibitor compound selected from the group consisting of: relebactam, avibactam, vaborbactam, tazobactam, sulbactam, and clavulanic acid.

15. The pharmaceutical composition according to claim 14 , wherein the beta-lactamase inhibitor compound is tazobactam and the beta-lactam antibiotic is ceftolozane.

16. The pharmaceutical composition according to claim 14 , wherein the beta-lactamase inhibitor compound is relebactam.

17. The pharmaceutical composition according to claim 12 , 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, cefoperazone, cefotaxime, ceftriaxone, cefipime, ceftolozane, and ceftazidime.

18. The pharmaceutical composition according to claim 12 , wherein the beta-lactam antibiotic is imipenem.

19. The pharmaceutical composition according to claim 18 , further comprising cilastatin or a pharmaceutically acceptable salt thereof.

20. A method for inhibiting a bacterial 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.

21. 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.

22. The method of claim 21 , 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, cefoperazone, cefotaxime, ceftriaxone, cefipime, ceftolozane, and ceftazidime.

23. The method of claim 21 , wherein the beta-lactam antibiotic is imipenem.

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, and a therapeutically effective amount of imipenem, cilastatin, and relebactam.

25. The method of claim 21 , wherein the bacterial infection is due to Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichi spp., Morganella spp., Citrobacter spp., Serratia , spp. or Acintetobacter spp.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X 1 and X 2 are CH; and

R A is:

27. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —NR a —(C 1 -C 3 alkyl) n -HetB1.

28. The compound of claim 27 , or a pharmaceutically acceptable salt thereof, wherein R a is H and HetB1 is:

29. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —NHCH(CH 2 NH 2 )CH 2 NH 2 .

30. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —NHCH 2 CH(OH)CH 2 NH 2 .

31. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —NHCH 2 CH(NH 2 )CH 2 NH 2 .

32. A compound having the structure

or a pharmaceutically acceptable salt thereof.

33. A pharmaceutically acceptable salt of the compound of claim 32 .

34. A pharmaceutical composition comprising the compound of claim 32 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

35. The pharmaceutical composition of claim 34 further comprising relebactam.

36. 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 32 , or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic.

37. A compound having the structure

or a pharmaceutically acceptable salt thereof.

38. A pharmaceutically acceptable salt of the compound of claim 37 .

39. A pharmaceutical composition comprising the compound of claim 37 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

40. The pharmaceutical composition of claim 39 further comprising relebactam.

41. 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 37 , or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic.

42. A compound having the structure

or a pharmaceutically acceptable salt thereof.

43. A pharmaceutically acceptable salt of the compound of claim 42 .

44. A pharmaceutical composition comprising the compound of claim 42 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

45. The pharmaceutical composition of claim 44 further comprising relebactam.

46. 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 42 , or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic.

47. A compound having the structure

or a pharmaceutically acceptable salt thereof.

48. A pharmaceutically acceptable salt of the compound of claim 47 .

49. A pharmaceutical composition comprising the compound of claim 47 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

50. The pharmaceutical composition of claim 49 further comprising relebactam.

51. 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 47 , or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic.

52. A compound having the structure

or a pharmaceutically acceptable salt thereof.

53. A pharmaceutically acceptable salt of the compound of claim 52 .

54. A pharmaceutical composition comprising the compound of claim 52 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

55. The pharmaceutical composition of claim 54 further comprising relebactam.

56. 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 52 , or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic.

57. A compound having the structure

or a pharmaceutically acceptable salt thereof.

58. A pharmaceutically acceptable salt of the compound of claim 57 .

59. A pharmaceutical composition comprising the compound of claim 57 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

60. The pharmaceutical composition of claim 59 further comprising relebactam.

61. 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 57 , or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic.

62. A compound having the structure

63. A compound having the structure

64. A compound having the structure

65. A compound having the structure

66. A compound having the structure

67. A compound having the structure