Claims for Patent: 9,623,014

Summary for Patent: 9,623,014

Title:	β-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 Francois Durand-Reville, Satenig Guler
Assignee:	AstraZeneca UK Ltd, Entasis Therapeutics Ltd, AstraZeneca Pharmaceuticals LP
Application Number:	US15/056,090
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,623,014
Patent Claims:	1. A method for treating a bacterial infection in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of Formula (III): 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″; or a pharmaceutically acceptable salt thereof. 2. The method of claim 1, wherein, for the compound according to formula (III), or a pharmaceutically acceptable salt thereof, 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″. 3. The method of claim 1, wherein, for the compound according to formula (III), or a pharmaceutically acceptable salt thereof, 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; and R3 is hydrogen. 4. The method of claim 1, wherein, for the compound according to formula (III), or a pharmaceutically acceptable salt thereof, R2 is methyl and R3 is hydrogen. 5. The method of claim 1, wherein, for the compound according to formula (III), or a pharmaceutically acceptable salt thereof, R2 is hydrogen; 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. 6. The method of claim 5, wherein, for the compound according to formula (III), or a pharmaceutically acceptable salt thereof, 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. 7. The method of claim 5, wherein, for the compound according to formula (III), or a pharmaceutically acceptable salt thereof, R3 is methyl, —CH2OCH3, or —CONH2. 8. The method of claim 1, wherein, for the compound according to formula (III), or a pharmaceutically acceptable salt thereof, 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. 9. The method of claim 1, wherein, for the compound according to formula (III), or a pharmaceutically acceptable salt thereof, R1 is —CH2OCH3, —CONH(CH2)-siderophore, —CONH2, represents the point of attachment to the bridged bicyclic core. 10. The method of claim 1, wherein, for the compound according to formula (III), or a pharmaceutically acceptable salt thereof, R1 is —CH2OCH3 or —CONH2. 11. The method of claim 1, wherein, for the compound according to formula (III), or a pharmaceutically acceptable salt thereof: R1 is —CH2OCH3; —CONH2, R2 is —H or —CH3; and R3 is —H, —CH3, or —CONH2; provided that R and R3 are not both H; and when R is —CONH2, or then R3 is not —CONH2. 12. The method of claim 1, wherein, the compound according to formula (III) is: or a pharmaceutically acceptable salt thereof. 13. The method of claim 1, wherein, the compound according to formula (III) is: or a pharmaceutically acceptable salt thereof. 14. The method of claim 1, further comprising administering an effective amount of an additional antibiotic agent. 15. The method of claim 14, wherein the additional antibiotic compound is selected from the group consisting of penicillin, methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, temocillin, amoxicillin, ampicillin, co-amoxiclav, azlocillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, cephalexin, cephalothin, CXA-101, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceftriaxone, cefotaxime, cefpodoxime, cefixime, ceftazidime, ceftobiprole medocaril, cefepime, cefpirome, ceftaroline, imipenem, meropenem, ertapenem, faropenem, sulopenem, doripenem, PZ-601 (Protez Pharmaceuticals), ME1036 (Forest Labs), BAL30072, MC-1, tomopenem, tebipenemn, aztreonam, tigemonam, nocardicin A, or tabtoxinine-β-lactam. 16. The method of claim 15, wherein the second antibiotic agent is meropenem, aztreonam, or ceftazidime. 17. The method of claim 15, wherein the second antibiotic agent is imipenem. 18. The method of claim 14, wherein the bacterial infection is a Gram-negative bacterial infection. 19. The method of claim 18, wherein the Gram-negative bacterial infection is resistant to one or more antibiotics. 20. The method of claim 14, wherein the bacterial infection causes a disease selected from the group consisting of urinary tract infections, pneumonia, prostatitis, skin and soft tissue infections, sepsis, and intra-abdominal infections. 21. The method of claim 18, wherein the bacterial infection is caused by Acinetobacter spp. 22. The method of claim 18, wherein the bacterial infection is caused by Pseudomonas spp.