Claims for Patent: 8,487,093

Summary for Patent: 8,487,093

Title:	β-lactamase inhibitors
Abstract:	Substituted bicyclic beta-lactams of Formula I: (I), are β-lactamase inhibitors, wherein a, X, R1 and R2 are defined herein. The compounds and pharmaceutically acceptable salts thereof are useful in the treatment of bacterial infections in combination with β-lactam antibiotics. In particular, the compounds can be employed with a β-lactam antibiotics (e.g., imipenem, piperacillin, or ceftazidime) against microorganisms resistant to β-lactam antibiotics due to the presence of the β-lactamases.
Inventor(s):	Timothy A. Blizzard, Helen Chen, Candido Gude, Jeffrey D. Hermes, Jason Imbriglio, Seongkon Kim, Jane Y. Wu, Christopher J. Mortko, Ian Mangion, Nelo Rivera, Rebecca T. Ruck, Michael Shevlin
Assignee:	Merck Sharp and Dohme LLC
Application Number:	US12/812,763
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,487,093
Patent Claims:	1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: X is: (1) CH2, or (2) CH2CH2; R1 is C(O)N(R3)R4, R2 is SO3M, OSO3M, SO2NH2, PO3M, OPO3M, CH2CO2M, CF2CO2M, or CF3; M is H or a pharmaceutically acceptable cation; R3 is HetA; R4 is H; or alternatively R3 and R4 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 C3-7 cycloalkyl; and wherein the optionally fused, saturated or mono-unsaturated heterocyclic ring is optionally substituted with 1 to 2 substituents selected from N(RA)RB and (CH2)nRC; each n is independently an integer which is 0, 1, 2, or 3; each RA is independently H or C1-8 alkyl; each RB is independently H or C1-8 alkyl; each RC is independently C1-6 alkyl, OH, O—C1-8 alkyl, halogen pyridyl, pyrrolidinyl, or piperidinyl. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is OSO3M. 3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is OSO3H. 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(RA)RB and optionally substituted with 1 or 2 (CH2)nRC. 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, C1-3 alkyl, pyrrolidin-3-yl, piperidin-4-yl, (CH2)2-3—O—C1-3 alkyl, (CH2)2-3OH, (CH2)2-3F, (CH2)2-3-piperidinyl, (CH2)2-3-pyrrolidinyl; and T′ is H, Cl, Br, F, C1-3 alkyl, O—C1-3 alkyl, OH, NH2, N(H)—C1-3 alkyl, or N(—C1-3 alkyl)2. 6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein T is H, CH3, pyrrolidin-3-yl, piperidin-4-yl, (CH2)2-3OCH3, (CH2)2-3OH, (CH2)2-3F, (CH2)2-3-piperidinyl, (CH2)2-3-pyrrolidinyl; and T′ is H, F, O—C1-3 alkyl, OH, NH2, N(H)CH3, or N(CH3)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.