Claims for Patent: 9,309,245

Summary for Patent: 9,309,245

Title:	Beta-lactamase inhibitor compounds
Abstract:	The present invention is directed to compounds which are beta-lacatamase inhibitors. The compounds and their pharmaceutically acceptable salts, are useful in combination with beta-lactam antibiotics, or alone, for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant organisms. The present invention includes compounds according to formula (Ia): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R2, R3 and R4 are described herein.
Inventor(s):	Helen McGuire, Shanta Bist, Neil Bifulco, Liang Zhao, Ye Wu, Hoan Huynh, Hui Xiong, Janelle Comita-Prevoir, Daemian Dussault, Bolin Geng, Brendan Chen, Thomas Durand-Reville, Satenig Guler
Assignee:	AstraZeneca UK Ltd, Entasis Therapeutics Ltd, AstraZeneca Pharmaceuticals LP
Application Number:	US14/389,854
Patent Claims:	1. A compound according to formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: R1 is —CONR′R″, —CN, or an C1-C3 alkyl substituted with C1-C3 alkoxy, —OH, —CN, —NR′R″, or —CONR′R″; R2 and R3 are independently selected from H, halo, —CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, —CONR′R″, or C(O)2R′; wherein the alkyl, alkenyl, cycloalkyl, and alkoxy represented by R2 or R3 are independently and optionally substituted by one or more halo, —CN, —OH, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR′R″, 5-7 membered heterocycle, —C(O)NR′R″ or —NR′C(O)R″; and each R′ and R″ are independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 5 to 6 membered heterocyclyl or a 5 to 6 membered heteroaryl; wherein each alkyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl is optionally and independently substituted with one or more halo, —CN, —OH, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —C(O)(C1-C6 alkyl), —C(O)(C1-C6 alkoxy), —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, a 5-7 membered heterocyclyl or a 5-7 membered heteroaryl; provided that R2 and R3 are not both hydrogen; and when R1 is —C(O)NR′R″, then neither of R2 or R3 is —C(O)NR′R″. 2. The compound of claim 1, according to formula (III): or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are independently selected from the group consisting of H, C1-C3 alkyl, C3-C6 cycloalkyl, and —CONR′R″, wherein the alkyl and cycloalkyl represented by R2 and/or R3 are independently and optionally substituted by one or more group selected from halo, —CN, —OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR′R″, a siderophore, —C(O)NR′R″ and —NR′C(O)R″. 4. The compound of claim 2, according to formula (V): or a pharmaceutically acceptable salt thereof. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl, ethyl, isopropyl, or cyclopropyl, wherein each R2 is optionally and independently substituted with one or more group selected from —OH and C1-C3 alkoxy. 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl. 7. The compound of claim 2, according to formula (IV): or a pharmaceutically acceptable salt thereof. 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R3 is C1-C3 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, or —CONR′R″, each of which is optionally and independently substituted with one or more substituent selected from the group consisting of halo, —CN, —OH, C1-C3 alkyl, cyclopropyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, —NR′R″, a siderophore, —C(O)NR′R″ and —NR′C(O)R″; and each R′ and R″ is independently selected from H and C1-C3 alkyl. 9. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R3 is methyl, ethyl, isopropyl, cyclopropyl, —CONH2, —CONH(C1-C3 alkyl), or —CON(C1-C3 alkyl)2, each of which is optionally and independently substituted with one or more group selected from —OH, C1-C3 alkyl, C1-C3 alkoxy, —NR′R″, C(O)NR′R″ and —NR′C(O)R″; and each R′ and R″ is independently selected from H and C1-C3 alkyl. 10. The compound of claim 7, or pharmaceutically acceptable salt thereof, wherein R3 is C1-C3 alkyl, cyclopropyl, —CONR′R″, wherein each alkyl, and cyclopropyl is optionally and independently substituted with one or more —OH, C1-C3 alkoxy, —NH2, or —NHC(O)(C1-C3 alkyl); and each R′ and R″ are independently selected from H, C1-C3 alkyl, and 5-6 membered heterocyclyl, wherein each alkyl and heterocyclyl represented by R′ or R″ is optionally and independently substituted with one or more —OH, C1-C3 alkyl, or C1-C3 alkoxy. 11. The compound of claim 7, or pharmaceutically acceptable salt thereof, wherein R3 is methyl, —CH2OCH3, or —CONH2. 12. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 is —CONR′R″, —CN, or an C1-C3 alkyl substituted with C1-C3 alkoxy or —OH; and the R′ and R″ of R1 are independently selected from the group consisting of H, C1-C3 alkyl, or a 5-7 membered heterocyclyl, wherein each alkyl and heterocyclyl of R′ and R″ is optionally and independently substituted with one or more —OH, C1-C3 alkyl, C1-C3 alkoxy, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, or a 5-7 membered heterocyclyl. 13. The compound of claim 2, or pharmaceutically acceptable salt thereof, wherein R1 is —CH2OCH3, —CONH(CH2)-siderophore, —CONH2, and represents the point of attachment to the bridged bicyclic core. 14. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 is —CH2OCH3 or —CONH2. 15. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: R1 is —CH2OCH3; —CONH2, or R2 is —H or —CH3; and R3 is —H, —CH3, or —CONH2; provided that R2 and R3 are not both H; and when R1 is —CONH2, or then R3 is not —CONH2. 16. The compound: or a pharmaceutically acceptable salt thereof. 17. The compound: or a pharmaceutically acceptable salt thereof. 18. A compound of claim 2, selected from the group consisting of: (2S,5R)-2-carbamoyl-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-2-cyano-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-4-methyl-7-oxo-2-(piperidinium-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sulfate; (2S,5R)-2-carbamoyl-4-isopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-2-cyano-4-isopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-2-(2-aminoethylcarbamoyl)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate; (2S,5R)-2-(methoxymethyl)-7-oxo-4-(prop-1-en-2-yl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-2-((5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methylcarbamoyl)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-2-carbamoyl-4-(methoxymethyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sodium sulfate; (2S,5R)-2-carbamoyl-3-isopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sodium sulfate; (2S,5R)-4-carbamoyl-2-(methoxymethyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate, monosodium salt; (2S,5R)-2,4-bis(methoxymethyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sulfate Sodium salt; (2S,5R)-2-(1-(tert-butoxycarbonyl)piperidin-4-ylcarbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sulfate sodium salt; (2S,5R)-4-(dimethylcarbamoyl)-2-(methoxymethyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sulfate sodium salt; (2S,5R)-2-(hydroxymethyl)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate Sodium Salt; (2S,5R)-3-methyl-7-oxo-2-(piperidin-1-ium-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sulfate; (2S,5R)-2-carbamoyl-3-(hydroxymethyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-4-(2-amino-2-oxoethyl)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-4-carbamoyl-2-(hydroxymethyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium Salt; (2S,5R)-2-carbamoyl-3,4-dimethyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-2-carbamoyl-3-ethyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-4-(2-aminoethyl)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate; (2S,5R)-2-carbamoyl-3-cyclopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-4-(2-acetamidoethyl)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sulfate sodium salt; (2S,5R)-2-(methoxymethyl)-4-(methylcarbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-2-carbamoyl-4-cyclopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; (2S,5R)-3-(2-methoxyethyl)-2-(methoxymethyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; and (2S,5R)-2-(((1,5-dihydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl)carbamoyl)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate sodium salt; or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt thereof, as claimed in claim 2, and at least one pharmaceutically acceptable carrier, diluent, or excipient. 20. The compound of claim 2, wherein R1 is —CONR′R″ or —CN.