β-lactamase inhibitors

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is:

(1) CH 2 , or

(2) CH 2 CH 2 ;

R 1 is C(O)N(R 3 )R 4 ,

R 2 is SO 3 M, OSO 3 M, SO 2 NH 2 , PO 3 M, OPO 3 M, CH 2 CO 2 M, CF 2 CO 2 M, or CF 3 ;

M is H or a pharmaceutically acceptable cation;

R 3 is HetA;

R 4 is H;

or alternatively R 3 and R 4 together with the N atom to which they are both attached form heterocyclyl selected from the group consisting of:

HetA is a 4- to 9-membered saturated or mono-unsaturated heterocyclic ring containing 1 or 2 N atoms; wherein the ring is optionally fused with a C 3-7 cycloalkyl; and wherein the optionally fused, saturated or mono-unsaturated heterocyclic ring is optionally substituted with 1 to 2 substituents selected from N(R A )R B and (CH 2 ) n R C ;

each n is independently an integer which is 0, 1, 2, or 3;

each R A is independently H or C 1-8 alkyl;

each R B is independently H or C 1-8 alkyl;

each R C is independently C 1-6 alkyl, OH, O—C 1-8 alkyl, halogen pyridyl, pyrrolidinyl, or piperidinyl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is OSO 3 M.

3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is OSO 3 H.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein HetA is an optionally fused, saturated heterocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, and azabicyclo[3.1.0]cyclohexyl, wherein the heterocyclic ring is optionally substituted with N(R A )R B and optionally substituted with 1 or 2 (CH 2 ) n R C .

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound selected from the group consisting of:

wherein T is H, C 1-3 alkyl, pyrrolidin-3-yl, piperidin-4-yl, (CH 2 ) 2-3 —O—C 1-3 alkyl, (CH 2 ) 2-3 OH, (CH 2 ) 2-3 F, (CH 2 ) 2-3 -piperidinyl, (CH 2 ) 2-3 -pyrrolidinyl; and T′ is H, Cl, Br, F, C 1-3 alkyl, O—C 1-3 alkyl, OH, NH 2 , N(H)—C 1-3 alkyl, or N(—C 1-3 alkyl) 2 .

6. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein T is H, CH 3 , pyrrolidin-3-yl, piperidin-4-yl, (CH 2 ) 2-3 OCH 3 , (CH 2 ) 2-3 OH, (CH 2 ) 2-3 F, (CH 2 ) 2-3 -piperidinyl, (CH 2 ) 2-3 -pyrrolidinyl; and T′ is H, F, O—C 1-3 alkyl, OH, NH 2 , N(H)CH 3 , or N(CH 3 ) 2 .

7. A compound according to claim 1 , which is a compound selected from the group consisting of:

(2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-[(4S)-azepan-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-[(4R)-azepan-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2-carboxamide;

(2S,5R)—N-azocan-5-yl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-2-[(piperidin-4-ylamino)carbonyl]-1,6-diazabicyclo[3.2.1]octane-6-sulfonic acid;

(4R,6S)-2-oxo-N-piperidin-4-yl-3-(sulfooxy)-1,3-diazabicyclo[2.2.1]-heptane-6-carboxamide;

(4R,6S)-2-oxo-N-[(4S)-azepan-4-yl]-3-(sulfooxy)-1,3-diazabicyclo[2.2.1]-heptane-6-carboxamide;

and

pharmaceutically acceptable salts thereof.

8. A compound according to claim 1 , which is a compound selected from the group consisting of:

(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-[(3R,4S)-3-fluoropiperidin-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

Diastereomer 1 of (2S,5R)-7-oxo-N-[(3)-piperidin-3-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide;

Diastereomer 2 of (2S,5R)-7-oxo-N-[(3)-piperidin-3-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-azetidin-3-yl-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(4R)-azepan-4-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[1-methylpiperidin-4-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3S,4S)-3-fluoropiperidin-4-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide or its 3R,4R diastereomer or a mixture thereof;

(2S,5R)-7-oxo-N-[(3S,4R)-3-fluoropiperidin-4-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3S,4R)-3-methoxypiperidin-4-yl]-6-(sulfooxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-[(3R,4R)-4-aminopyrrolidin-3-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-[(3R,4S)-4-hydroxypyrrolidin-3-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-[(3R,4S)-4-fluoropyrrolidin-3-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-[(3S,4R)-3-fluoroazepan-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-[(3R,4S)-3-fluoroazepan-4-yl]-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)—N-3-azabicyclo[3.1.0]hex-6-yl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-2-{[2-(aminomethyl)piperidin-1-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one;

(2S,5R)-2-[(4-aminopiperidin-1-yl)carbonyl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one;

(2S,5R)-2-(piperazin-1-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one;

(2S,5R)-2-(2,7-diazaspiro[3.5]non-2-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one;

(2S,5R)-2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylcarbonyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one;

(2S,5R)-2-{[(3R)-3-aminopyrrolidin-1-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one;

(2S,5R)-2-{[(3S)-3-aminopyrrolidin-1-yl]carbonyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one;

(2S,5R)-2-{[3-(dimethylamino)pyrrolidin-1-yl]-carb-onyl}-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octan-7-one;

(2S,5R)—N-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

and

pharmaceutically acceptable salts thereof.

9. A compound according to claim 1 , which is a compound selected from the group consisting of:

(2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide;

(2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; and

pharmaceutically acceptable salts thereof.

10. A compound according to claim 9 , which is (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 , which is (2S,5R)-7-oxo-N-[(3S)-pyrrolidin-3-yl]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 , which is (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide in the form of a crystalline monohydrate.

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

14. A pharmaceutical composition according to claim 13 , which further comprises a beta-lactam antibiotic.

15. A method for treating a bacterial infection which comprises administering to a subject in need of such treatment (i) a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, optionally in combination with a beta-lactam antibiotic.

16. A compound which is (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide.

17. A pharmaceutical composition which comprises a compound according to claim 16 and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition according to claim 17 , which further comprises a beta-lactam antibiotic.

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

20. The pharmaceutical composition of claim 19 , which further comprises cilastatin.

21. A method for treating a bacterial infection which comprises administering to a subject in need of such treatment (i) a therapeutically effective amount of a compound according to claim 16 in combination with a beta-lactam antibiotic.

22. The method according to claim 21 , wherein the beta-lactam antibiotic is imipenem.

23. The method of claim 22 , which further comprises administering cilastatin.