Beta-tetrazolyl-propionic acids as metallo-beta-lactamase inhibitors

1. A compound of formula Ia or Ib

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is:

a) —C 2-8 alkyl,

b) —C 1-4 alkyl substituted with 1, 2, or 3 halo substituents or 1 substituent selected from —C 3-6 cycloalkyl, —CN, —C(═O)NH 2 , —OH, —C 1-3 alkoxy, phenyl, and HetY,

c) —C 2-6 alkenyl,

d) —C 3-6 cycloalkyl, or

e) HetY,

R 2 is hydrogen, C 1-4 alkyl, or C 1-4 alkoxy;

HetY is a 4- to 6-membered saturated monocyclic ring with 1 heteroatom ring atom selected from N and O;

W is AryA; HetA; —(CH 2 ) 1-2 -AryA; —CH(CH 3 )-phenyl; or cyclohexyl substituted with —COOH or —NH 2 ;

AryA is an aromatic ring system selected from:

a) 5- to 6-membered monocyclic aromatic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from N and S, optionally substituted with 1 or 2 substituents R; or

b) 9- to 11-membered bicyclic aromatic ring system with 1, 2 or 3 heteroatom ring atoms selected from N, O, and S, optionally substituted with 1 substituent R′ selected from Br, C 1-6 alkyl, —NH 2 , and —NHCH 2 CH 2 OH;

HetA is a piperidinyl ring optionally substituted with 1 substituent selected from —C(═O)CH 3 ;

each R is independently

halo;

—CF 3 ;

C 1-6 alkyl optionally substituted with —NR x R y or 1 or 2 —OH;

C 3-6 cycloalkenyl optionally substituted with —NR x R y ;

—(CH 2 ) 0-1 NHR z ;

—CN;

—C(NH 2 )═NOH;

—C(═O)NR x R y ;

—C(═O)NHR z ;

—C(═O)OH;

—NR x R y ;

—N + (CH 3 ) 3 ;

—NHCH 2 CH 2 CH(CF 3 )NH 2 ;

—NHCH 2 C(═O)N(CH 3 ) 2 ;

—NHCH 2 CH 2 SO 2 NH 2 ;

—NHC(═NH)NH 2 ;

—OH;

—OR z ;

—OCH 2 CH(NH 2 )CH 2 OH;

—SCH 3 ;

—SO 2 R w ;

AryB;

—NH(CH 2 ) 0-2 -AryB;

—O-AryB;

—(CH 2 ) 0-2 -HetB;

—CH 2 O(CH 2 ) 0-2 -HetB;

—C(═O)-HetB;

—NH(CH 2 ) 0-2 -HetB; or

—O-HetB;

AryB is

a) a 5- to 6-membered monocyclic aromatic ring with 0, 1, or 2 heteroatom ring atoms independently selected from N and S, optionally substituted with 1, 2 or 3 substituents independently selected from

F;

—CH 3 ;

—CH 2 NH 2 ;

—CH 2 N(CH 3 ) 2 ;

—CH 2 CH 2 NH 2 ,

—CH 2 C(CH 3 ) 2 NH 2 ;

—CH 2 OH;

—C(CH 3 ) 2 OH;

—C(═O)NR x R y ;

—NR x R y ;

—NHC(═O)CH 3 ;

—NHSO 2 CH 3 ;

—N(CH 3 )SO 2 CH 3 ;

—OH;

—OCH 3 ;

—SO 2 CH 3 ;

—SO 2 NH 2 ;

—(CH 2 ) 0-1 -AryC;

—C 0 -C 2 alkyl-HetC; and

—O-HetC;

b) triazolyl;

c) tetrazolyl;

d) 1,3-dimethylpyrimidine-2,4(1H,3H)-dione; or

e) a 9- to 10-membered bicyclic aromatic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from N or O, optionally substituted with Br, —CH 3 , —CN, —NH 2 , or oxo;

HetB is

a) a 4- to 6-membered saturated or monosaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O, optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo; —CF 3 ; C 1-6 alkyl, C 1-6 aminoalkyl; C 1-6 hydroxyalkyl; —CH(═NH);

—C(═NH)NH 2 ; —C(═O)CH 3 ; —C(═O)NHCH 3 ; —C(═O)NHSO 2 CH 3 ; —NH 2 ;

—NHSO 2 CH 3 , —OH; oxo; —SO 2 CH 3 ; AryC; or HetC; or

b) a 8- to 10-membered bicyclic saturated ring system with 1, 2 or 3 ring atoms independently selected from N or O, optionally substituted with 1 or 2 substituents independently selected from —CH 3 and oxo; wherein the rings in the bicyclic ring system are fused or spirocyclic;

AryC is phenyl, pyridinyl, or tetrazolyl;

HetC is a 4- to 6-membered saturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N and O, optionally substituted with 1 or 2 substituents selected from —CH 3 , —OH and oxo;

each R x and R y is independently hydrogen or C 1-6 alkyl;

each R z is independently —(CH 2 ) 0-1 -C 3-6 cycloalkyl optionally substituted with —NH 2 ;

C 1-6 aminoalkyl; or C 1-6 hydroxyalkyl; and

R w is selected from C 1-8 alkyl and C 3-6 cycloalkyl.

2. The compound of claim 1 , which has the formula Ic or Id

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 )CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 CH 2 CF 3 , —CH 2 -cyclopropyl, —CH 2 -cyclopentyl, —CH 2 CH 2 -cyclohexyl, —CH 2 CH 2 CH 2 CH 2 CN, —CH 2 CH 2 CH 2 CH 2 C(═O)NH 2 , —CH 2 CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OCH 3 , —CH 2 -phenyl, —CH 2 CH 2 CH 2 CH 2 -phenyl, CH 2 —CH(CH 3 )-phenyl, —CH 2 CH 2 CH 2 -piperidinyl, —CH 2 -oxetanyl, —CH 2 CH═CH 2 , —CH 2 CH 2 CH═C(CH 3 ) 2 , cyclopentyl, tetrahydrofuranyl, or tetrahydropyranyl.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein W is

5. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein W is

wherein

R A and R B are independently Br; F; Cl; —CF 3 ; —CH 3 ; —CH 2 NH 2 ; —CH 2 CH 2 NH 2 ; —CN; —CH 2 OH; —CONH 2 ; —CONCH 3 ; —CON(CH 3 ) 2 ; —CONH-cyclopropyl; —CONHCH 2 -cyclopropyl; —CONHCH 2 CH 2 NH 2 ; —CONHCH 2 CH 2 OH; —COOH; —NH 2 ; —NHCH 3 ; —NHCH 2 CH 2 OH; —NHC(═NH)NH 2 ; —OH; —OCH 2 CH 2 NH 2 ; —NH-cyclopentyl-NH 2 ;—SO 2 CH 3 ; —SO 2 -cyclopropyl; AryB; HetB; —CO-piperazinyl; —CH 2 -tetrahydropyranyl;—CH 2 -piperidinyl optionally substituted with —NH 2 ; —NH-pyrrolidinyl; —NHCH 2 -piperidinyl with —OH; —NH-tetrahydroisoquinolinyl; —O-phenyl substituted with —CONH 2 , —CH 2 OH, —CH 2 NH 2 , —CH 2 C(CH 3 ) 2 NH 2 , —CH(CH 3 )NH 2 , —CH 2 CH 2 NH 2 , piperidinyl, pyrrolidinyl, or piperazinyl; —O-tetrahydroisoquinolinyl; —O-tetrahydroquinolinyl; or —O-pyridinyl optionally substituted with piperazinyl;

AryB is

1) phenyl substituted with —CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —CH 2 OH, —CONH 2 , —CONHCH 3 , —NHSO 2 CH 3 , —SO 2 CH 3 , —SO 2 NH 2 , AryC, HetC, —CH 2 -HetC, or tetrazolyl;

2) pyridinyl optionally substituted with —C(CH 3 ) 2 OH, —NH 2 , —N(CH 3 ) 2 , —NH 2 or F;

3) piperazinyl optionally substituted with —CH 3 , —CH 2 -piperidinyl, —O-piperidinyl, or morpholinyl;

4) pyrimidinyl substituted with —NH 2 , —N(CH 3 ) 2 , —NHCH 2 CH 2 OH, —NHCOCH 3 , —NCH 3 SO 2 CH 3 , or HetC;

5) pyrazinyl substituted with two —CH 3 ;

6) pyrazolyl optionally substituted with 1 to 3 substitutents selected from —CH 3 , phenyl, and —CH 2 -pyridinyl;

7) dimethylpyrimidinedione;

8) tetrazolyl;

9) thiazolyl substituted with —CH 2 OH;

10) 1,2,3,4-tetrahydroquinoline;

11) imidazopyridinone;

12) indazolyl;

13) isoindolinone;

14) isoindolinyl;

15) isoquinolinyl optionally substituted with —CN;

16) methylbenzotriazolyl;

17) benzooxazinone;

18) triazolopyridinyl; or

19) 1,2,3,4-tetrahydronaphthalen-2-amine;

HetB is

1) azetidinyl substituted with —NH 2 ; —CH 2 NH 2 ; —CH 2 CH 2 NH 2 ; —C(CH 3 ) 2 NH 2 ; —CH 2 CH 2 OH; —SO 2 CH 3 ; morpholinyl; piperazinyl; (CH 2 OH) 2 ; —CH 2 NH 2 and —CH 3 ; or —OH and —CF 3 ;

2) pyrrolidinyl optionally substituted with —CH 2 NH 2 , —CH 2 OH, —CONHCH 3 , —NH 2 , —OH, or AryC;

3) piperidinyl optionally substituted with —CH 3 , —CH 2 NH 2 , —C(CH 3 ) 2 NH 2 , —CH 2 OH, —CONHCH 3 , —CH 2 NHSO 2 CH 3 , —NH 2 , —OH, —C(═NH)NH; —C(═NH 2 )NH 2 , or —CH═NH;

4) piperazinyl substituted with —CH 3 , —CH 2 OH, —CH 2 CH 2 OH, —COCH 3 , ═O, or AryC;

5) morpholinyl;

6) dihydropyrrolyl;

7) tetrahydropyridinyl optionally substituted with —CH 3 ;

8) octahydropyrrolo[1,2-a]pyrazine;

9) diazaspirononanyl;

10) diazaspirooctanyl;

11) 2,6-diazaspiro[3.4]octan-7-one; or

12) 7-methyl-5-oxa-2,7-diazaspiro[3.4]octan-6-one;

wherein

R C is F; Br; —CF 3 ; —CH 2 NH 2 ; pyrrolidinyl; 2,5-dihydro-1H-pyrrole; pyridinyl substituted with —NH 2 ; or piperazinyl;

R D is F, Br, —CH 3 , or —CF 3 ;

wherein

R E is Cl, —NH 2 or —NHCH 2 CH 2 OH;

R F is Cl;

wherein R G is —NH 2 , —N(CH 3 ) 2 , —NHCH 2 CH 2 OH, —SCH 3 , —SO 2 CH 3 , morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,5-dihydro-1H-pyrrole, or —O-piperidinyl; or

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from the group consisting of:

a) —C 2-4 alkyl,

b) ethyl substituted with three halo substituents, or

c) —C 3-6 cycloalkyl,

R 2 is hydrogen;

W is AryA; —CH 2 -phenyl; or —CH(CH 3 )-phenyl;

AryA is an aromatic ring system selected from:

a) 5- to 6-membered monocyclic aromatic ring with 0, 1, or 2 heteroatom ring atoms independently selected from N and S. optionally substituted with 1 or 2 substituents R; or

b) 9- to 10-membered bicyclic aromatic ring system with 1, 2 or 3 heteroatom ring atoms selected from N and S, substituted with 1 substituent selected from C 1-6 alkyl and —NH 2 ;

each R is independently fluoro NHR z , —NR x R y , —NHC(═NH)NH 2 ; —OR z , AryB, —O-AryB, or —(CH 2 ) 0-1 -HetB;

AryB is a 5- to 6-membered monocyclic aromatic ring with 0, 1, or 2 N ring atoms, optionally substituted with 1 substituent selected from —CH 2 NH 2 , —CH 2 OH, —C(═O)NR x R Y , —NR x R y , —NHSO 2 CH 3 , and HetC;

HetB is a) a 5- to 6-membered saturated or monosaturated monocyclic ring with 1 or 2 N ring atoms, optionally substituted with 1 substituent selected from C 1-6 hydroxyalkyl, —CH(═NH), —C(═NH)NH 2 , and —OH; or

b) a 9-membered saturated spirocyclic ring system with 2 N ring atoms;

HetC is a 6-membered saturated monocyclic ring with 1 N ring atom,

each R x and R y is independently hydrogen or methyl; and

each R z is independently C 1-6 aminoalkyl or C 1-6 hydroxyalkyl.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein

AryA is a monocyclic ring selected from thiazolyl, phenyl, and pyridinyl, wherein the monocyclic ring optionally substituted with 1 or 2 R substituents; or a bicyclic ring selected from quinolinyl, benzo[d]thiazolyl, and 1H-benzo [d][1,2,3]triazole, wherein the bicyclic is optionally substituted with 1 substituent selected from C 1-6 alkyl and —NH 2 ;

AryB is a monocyclic ring selected from pyrazolyl, phenyl or pyridyl, wherein the monocyclic is optionally substituted with 1 substituent selected from —CH 2 NH 2 , —CH 2 OH, —C(═O)NR x R y , —NR x R y , —NHSO 2 CH 3 , and HetC; and

HetB is a monocyclic ring selected from pyrrolidinyl, dihydropyrrolyl, piperidinyl, or piperazinyl, wherein the monocyclic is optionally substituted with 1 substituent selected from C 1-6 hydroxyalkyl, —CH(═NH), —C(═NH)NH 2 , and —OH; or diazaspirononanyl.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein W is

1) phenyl optionally substituted with

a) phenyl substituted with —CONH 2 , —NHSO 2 CH 3 , or piperidinyl,

b) pyridinyl substituted with —NH 2 ,

c) pyrrolidinyl,

d) pyrrolidinyl and fluoro,

e) piperidinyl substituted with —CH═NH,

f) piperidinyl substituted with —CH(═NH)NH 2 ,

g) piperizinyl and fluoro,

h) dihydropyrrolyl,

i) pyrazolyl, or

j) —CH 2 -piperazinyl;

2) —CH 2 -phenyl;

3) —CH(CH 3 )-phenyl;

4) pyridinyl optionally substituted with

a) —NH 2 ,

b) —NHCH 3 ,

c) —NHCH 2 CH 2 NH 2 ,

d) —NHCH 2 CH 2 OH,

e) —NHC(═NH)NH 2 ,

f) pyrrolidinyl optionally substituted with —OH,

g) piperidinyl optionally substituted with —CH 2 OH,

h) phenyl substituted with —CH 2 NH 2 or —CH 2 OH,

i) —O-phenyl substituted with —CH 2 NH 2 ,

j) pyridinyl substituted with —NH 2 , or

k) diazaspirononanyl,

5) thiazolyl substituted with —NH 2 ,

6) quinolinyl substituted with —NH 2 ,

7) benzo[d]thiazolyl substituted with —NH 2 , or

8) 1H-benzo[d][1,2,3]triazole] substituted with —CH 3 .

9. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 6 having the structure:

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition which comprises a compound acccording 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 , 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.

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

15. The pharmaceutical composition according to claim 14 , further comprising cilastatin or a pharmaceutically acceptable salt thereof.

16. 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.

17. 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.

18. The method of claim 17 , 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.

19. The method of claim 17 , wherein the beta-lactam antibiotic is imipenem.