Chromane cyclic amidine monobactam compounds for the treatment of bacterial infections

Abstract

Provided are monobactam compounds of Formula (I), and pharmaceutically acceptable salts thereof. Also provided are compositions which comprise a monobactam compound of Formula (I) or a pharmaceutically acceptable salt therof, and a pharmaceutically acceptable carrier. Further provided are methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), either alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic.

Description

CHROMANE CYCLIC AMIDINE MONOBACTAM COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is an International Patent Application which claims priority from U.S. Provisional Application No.63 / 685527, filed August 21, 2025, each of which is incorporated by reference in its entirety herein. FIELD

[0002] This disclosure relates to novel monobactam compounds, processes for their preparation and their use as therapeutic agents. In particular disclosed are monobactam compounds useful as antibiotic agents for the treatment of bacterial infections. BACKGROUND

[0003] The introduction of antibiotics for treatment of bacterial infections is one of the great medical achievements of the 20thcentury. Over the past few decades, however, bacteria resistant to multiple antibiotics have begun to emerge throughout the world, threatening the effectiveness of antibiotic therapy. In the United States alone, at least 23,000 people each year die as a direct result of infections caused by antibiotic-resistant bacteria, and numerous others die from pre- existing conditions exacerbated by similar infections. Antibiotic Resistance Threats in the United States, 2013, Centers for Disease Control, Atlanta, Georgia. New antibiotics are needed to combat the current and future threat of multidrug resistant bacteria.

[0004] β-lactams are the most widely used antibiotics for treatment of serious bacterial infections. These include carbapenems, cephalosporins, penicillins, and monobactams. As has been observed for other antibiotic classes, resistance to β-lactams has emerged. For most Gram- negative bacteria, this resistance is primarily driven by the expression of β-lactamases, enzymes that hydrolyze β-lactam compounds. There are 4 different classes of β-lactamases (A, B, C, and D) capable of hydrolyzing overlapping but distinct subsets of β-lactams (Drawz and Bonomo, Clin. Micro. Rev., 2010, 23:160–201). While the class B β-lactamases, also known as metallo β- lactamases (MBLs), are not the most prevalent β-lactamases found in the clinic, the frequency and distribution of their expression is on the rise and represent a significant medical threat because (i) MBLs have the ability to hydrolze all β-lactams except monobactams, and (ii) unlike the class A and C β-lactamases, there are no inhibitors available for the MBLs.

[0005] Aztreonam, a monobactam, was first approved in the U.S in 1986 for the treatment of aerobic Gram-negative bacterial infections and remains the only monobactam in use in the U.S. today. However, aztreonam has poor activity against Pseudomonas and Acinetobacter strains. Because monobactams are inherently resistant to hydrolysis by MBLs, several companies have begun developing novel monobactam compounds for the treatment of infections caused by Gram-negative bacteria. Monobactam compounds comprising a siderophore moiety are disclosed in WO 2007 / 065288, WO2012 / 073138, J. Medicinal Chemistry 56: 5541-5552 (2013), and Bioorganic and Medicinal Chemstry Letters 22:5989 (2012).

[0006] WO 2019 / 070492 discloses chromane monobactam compounds for treating bacterial infections. WO2017 / 106064 discloses biaryl monobactam compounds and their use to treat bacterial infections. WO 2013 / 110643 discloses novel amidine substituted monobactam derivatives and their use as antimicrobial reagents. WO 2015 / 103583 discloses monobactam derivatives useful for treating infectious disease which is bacterial infection. U.S. Patent Application Publication No US 2015 / 0045340 and No. US 2014 / 0275007 disclose oxamazin monobactams and their use as antibacterial agents. U.S. Patent Application Publication No. US 2015 / 0266867 discloses novel monobactam compounds for the use as antibacterial agents. Additional monobactam compounds are disclosed in WO 2017 / 106064; WO 2017 / 155765; WO 2019 / 070492; WO 2023 / 091438; and WO 2024 / 019916.

[0007] The need for new antibiotics to overcome multidrug resistance continues. Compounds disclosed herein are designed to fill this medical need, through administration either on their own or in combination with a suitable β-lactamase inhibitor. SUMMARY

[0008] The present disclosure relates to the design and synthesis of monobactam analogs, a novel class of highly potent antibiotics effective against a broad range of Gram-negative bacteria. These compounds and their pharmaceutically acceptable salts may be useful as therapeutic agents for clinical treatment of various infections caused by Gram-negative bacteria, including strains that are multidrug resistant. The compounds can be used alone or in combination with a suitable β-lactamase inhibitor. The present disclosure includes the compounds of Formula (I):and pharmaceutically acceptable salts thereof.

[0009] Also disclosed are pharmaceutical compositions for treating a bacterial infection in a subject, including infection with multidrug resistant Gram-negative bacterial strains, comprising a monobactam compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0010] The compounds of Formula (I), also referred to herein as the “monobactam compounds”, and pharmaceutically acceptable salts thereof can be useful, for example, for inhibiting the growth of Gram-negative bacterial strains, including but not limited to, Pseudomonas, Klebsiella and Acinetobacter strains, including Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii, and / or for treating or preventing the clinical maifestations thereof in a patient.

[0011] Additionally, methods of treating Gram-negative bacterial infections in a subject in need of treatment thereof, comprising administering to the subject an effective amount of a monobactam compound of Formula (I) are disclosed. In specific embodiments, the method includes administration of a beta lactamase inhibitor compound. Embodiments, sub-embodiments and features of the present disclosure are either further described in or will be apparent from the ensuing description, examples and appended claims. DETAILED DESCRIPTION

[0012] Provided are novel compounds of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: A isT is CH, or N, provided that no more than two of T, U and V are N; U is CH, or N; V is CH or N; X is selected from: 1) O, and 2) CH2; Y is selected from: 1) O, 2) NR8, 3) S, and 4) CH2, provided that when Y is O, NR8or S then X is CH2; Z is 1) O, 2) S, 3) CH2, or 4) NH, provided that when Z is O, S or NH, then X is CH2;W is selected from: 1) bond, and 2) O; Q is selected from: 1) N, and 2) CR8; L is selected from: 1) -C1-6alkyl-, 2) -C1-6alkyl-O-C1-6alkyl-, 3) -C1-6alkyl-S-C1-6alkyl-, and 4) -C1-6alkyl-N(Rm)-C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, - C1-3alkyl, -C1-3alkyl-OH, OH, -C0-3alkyl-NH2, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1-3alkyl; R1is selected from: 1) -NH2, 2) -NH(-C1-6alkyl), 3) -N(C1-6alkyl)2, 4) -N+(C1-6alkyl)3, 5) -OH, 6) -OC1-6alkyl, 7) -SH, and 8) -SC1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra; R2is selected from: 1) hydrogen, 2) C1-6alkyl,3) C1-6alkyl-OR4, and4) C1-6alkyl-NHR4,wherein alkyl is unsubstituted or substituted with one to three halogens; R3is selected from: 1) -C1-6alkyl, 2) -C1-6alkyl-OH,3) -C1-6alkyl-O-C1-6alkyl, 4) -O-C1-6alkyl, 5) -C1-6alkyl-SH, 6) -S-C1-6alkyl, 7) -C1-6alkyl-S-C1-6alkyl, 8) -NH-C1-6alkyl, 9) -N(C1-6alkyl)2, 10) -C1-6alkyl-NH2, and 11) -C1-6alkyl-N(Rm)-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn; R4is selected from: 1) hydrogen, 2) C1-3alkyl, and3) cyclopropyl, wherein alkyl and cyclopropyl are unsubstituted or substituted with one to three halogens orOC1-3alkyl;R5is selected from: 1) -CO2H, and2) tetrazole; R6and R7are selected from: 1) hydrogen, and 2) C1-6alkyl,wherein alkyl is unsubstituted or substituted with one to three halogens, provided that at least one of R6and R7is hydrogen; R8is independently selected from: 1) hydrogen, 2) C1-4alkyl, 3) halogen, and 4) C3-7cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from: -OH, halogen, NH2, and -OC1-3alkyl; R9and R10are selected from: 1) hydrogen, and2) C1-6alkyl,wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, NHC1-3alkyl, and SC1-3alkyl,provided that one or both of R9 and R10 are C1-6alkyl,or alternatively R9and R10together with the carbon to which they are attached form amonocyclic C3-5cycloalkyl or a monocyclic C2-5cycloheteroalkyl, wherein cycloalkyl andcycloheteroalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, -OH and -OC1-3alkyl; each Rais independently selected from: 1) -CF3, 2) -CHF2, 3) -CH2F, 4) halogen, 5) -C1-6alkyl, 6) -C0-6alkyl-O-C1-6alkyl, 7) -C0-6alkyl-OH, 8) -C0-6alkyl S(O)rRj, 9) -C0-6alkyl S(O)rNRkRk, 10) -C0-6alkyl C(O)Ri,11) -C0-6alkyl OC(O)Ri,12) -C0-6alkyl C(O)ORi, 13) -C0-6alkyl CN, 14) -C0-6alkyl C(O)NRkRk, 15) -C0-6alkyl C(NH)NRkRk, 16) -C0-6alkylNRkRk, 17) -C0-6alkyl N(Rk)(C(O)Ri), 18) -C0-6alkyl N(Rk)(C(O)ORh), 19) -C0-6alkyl N(Rk)(C(O)NRfRg), and 20) -C0-6alkyl N(Rk)(S(O)vRj), wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl); each Rbis independently selected from:1) hydrogen, 2) C1-6alkyl, 3) C0-6alkyl-O-C1-6alkyl, 4) C0-6alkyl-OH, 5) C0-6alkyl-S(O)uRd, 6) C1-6alkyl-C(O-N(Re)2, 7) C1-6alkylN(Re)C(O)Re, 8) C0-6alkyl-N(Re)2, and 9) halogen, wherein alkyl is unsubstituted or substituted with one to three halogens, or wherein two Rbsubstituents together with the atoms they are attached to can cyclize to form a 3 to 6 membered ring; each Rcis independently selected from: 1) hydrogen, 2) C1-6alkyl, 3) C0-6alkyl-O-C1-6alkyl, 4) C0-6alkyl-OH, 5) C0-6alkyl-S(O)vRf,6) C0-6alkyl-S(O)vN(Rg)2, 7) C1-6alkyl C(O)-N(Rg)2, 8) C1-6alkylN(Rg)C(O)Rg, 9) C0-6alkyl-N(Rg) 2, and 10) halogen, wherein alkyl is unsubstituted or substituted with one to three halogens; each Rdis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Reis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rfis independently selected from: 1) hydrogen, and2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rgis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rhis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Riis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rjis independently selected from: 1) hydrogen, 2) OH, and 3) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rkis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rmis independently selected from: 1) hydrogen, and 2) -C1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rnis independently selected from: 1) -CF3, 2) -CHF2, 3) -CH2F, 4) halogen, 5) -C1-6alkyl, 6) -C0-6alkyl-O-C1-6alkyl, 7) -C0-6alkyl-OH, 8) -C0-6alkylS(O)rRj,9) -C0-6alkylS(O)rNRkRk, 10) -C0-6alkylC(O)Ri,11) -C0-6alkylOC(O)Ri,12) -C0-6alkylC(O)ORi, 13) -C0-6alkylCN, 14) -C0-6alkylC(O)NRkRk, 15) -C0-6alkylC(NH)NRkRk, 16) -C0-6alkylNRkRk, 17) -C0-6alkylN(Rk)(C(O)Ri), 18) -C0-6alkylN(Rk)(C(O)ORh), 19) -C0-6alkylN(Rk)(C(O)NRfRg), and 20) -C0-6alkylN(Rk)(S(O)vRj), wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl); q is 0, 1, 2 or 3; each r is independently 0, 1 or 2; each s is independently 0, 1, 2, 3, 4 or 5; each t is independently 0, 1, 2 or 3; each u is independently selected from 0, 1 or 2; and each v is independently selected from 0, 1 or 2.

[0013] The present disclosure relates to novel monobactam analogs, a class of highly potent antibiotics effective against a broad range of Gram-negative bacteria. These compounds have utility as therapeutic agents for clinical treatment of various infections caused by Gram-negative bacteria, including strains that are multidrug resistant, and for the treatment or prevention of the clinical pathologies associated therewith.

[0014] In each of the various embodiments of the compounds of Formula (I) described herein, each variable including those of Formula (I), and the various embodiments thereof, is selected independently of the others unless otherwise indicated.

[0015] The present disclosure includes the compounds of Formula (I), and the individual diastereoisomers, enantiomers, and epimers of the compounds of Formula (I), and mixtures of diastereoisomers and / or enantiomers thereof including racemic mixtures. Also included are anysolvates, hydrates, stereoisomers, and tautomers of the compounds of Formula (I), and of any pharmaceutically acceptable salts thereof.

[0016] In one embodiment,

[0017] In a class of this embodiment, A is

[0018] In another class of this embodiment,

[0019] In another embodiment, A is

[0020] In a class of this embodiment, A is

[0021] In another class of this embodiment, A is

[0022] In another class of this embodiment,

[0023] In another class of this embodiment, A is

[0024] In another class of this embodiment, A is

[0025] In another class of this embodiment,

[0026] In another class of this embodiment,

[0027] In another embodiment, A is

[0028] In another embodiment, A is

[0029] In a class of this embodiment, A is

[0030] In another class of this embodiment, A is

[0031] In another class of this embodiment, A is

[0032] In another class of this embodiment, A is

[0033] In another class of this embodiment, A is

[0034] In another class of this embodiment, A is R3 3.

[0035] In another class of this embodiment, A is

[0036] In another class of this embodiment, A is

[0037] In another class of this embodiment, A is .

[0038] In another class of this embodiment, A is

[0039] In another embodiment, T is CH or N, provided that no more than two of T, U and V are N; U is CH or N; and V is CH or N.

[0040] In another embodiment, T is CH or N, provided that no more than two of T, U and V are N. In a class of this embodiment, T is CH. In another class of this embodiment, T is N.

[0041] In another embodiment, U is CH or N. In a class of this embodiment, U is CH. In another class of this embodiment, U is N.

[0042] In another embodiment, V is CH or N. In a class of this embodiment, V is CH. In another class of this embodiment, V is N

[0043] In another embodiment, T, U and V are CH.

[0044] In another embodiment, W is a bond or O. In a class of this embodiment, W is a bond.

[0045] In another class of this embodiment, W is O.

[0046] In another embodiment, Q is N or CR8. In a class of this embodiment, Q is N. In another class of this embodiment, Q is CR8. In another class of this embodiment, Q is CH.

[0047] In another embodiment, X is O or CH2. In a class of this embodiment, X is O. In another class of this embodiment, X is CH2.

[0048] In another embodiment, Y is O, NR8, S or CH2, provided that when Y is O, NR8or S, then X is not O. In another embodiment, Y is O, NR8, S or CH2, provided that when Y is O, NR8or S, then X is CH2.

[0049] In another embodiment, Y is O, NR8, S or CH2. In a class of this embodiment, Y is O or CH2. In another class of this embodiment, Y is NR8or S. In another class of this embodiment, Y is O. In another class of this embodiment, Y is NR8. In another class of this embodiment, Y is S. In another class of this embodiment, Y is CH2.

[0050] In another embodiment, Z is O, S, CH2or NH, provided that when Z is O, S or NH, then X is not O. In another embodiment, Z is O, S, CH2or NH, provided that when Z is O, S or NH, then X is CH2. In a class of this embodiment, Z is O, S, CH2, or NH. In another class of this embodiment, Z is O or CH2. In another class of this embodiment, Z is S or NH. In another class of this embodiment, Z is S. In another class of this embodiment, Z is CH2. In another class of this embodiment, Z is NH. In another class of this embodiment, Z is O.

[0051] In another embodiment, L is selected from: -C1-6alkyl-, -C1-6alkyl-O-C1-6alkyl-, -C1-6alkyl-S-C1-6alkyl-, and -C1-6alkyl-N(Rm)-C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C1-3alkyl-OH, OH, -C0-3alkyl- NH2, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1- 3alkyl.

[0052] In another embodiment, L is selected from: -C1-6alkyl-, and -C1-6alkyl-O-C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, - C1-3alkyl, -C1-3alkyl-OH, OH, -C0-3alkyl-NH2, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1-3alkyl.

[0053] In another embodiment, L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C1-3alkyl-OH, OH, -C0-3alkyl- NH2, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1- 3alkyl.

[0054] In another embodiment, L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C1-3alkyl-OH, OH, -C0-3alkyl- NH2, -OC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1-3alkyl.

[0055] In another embodiment, L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, and -C1-3alkyl-OH, and OH.

[0056] In another embodiment, L is selected from: -CH2CH2-, -CH2CH2CH2-, -CH(OH)CH2-, - CH2CH(OH)CH2-, -CH2CH(CH3)-, -CH2CH2CH(CH3)-, -CH2CH2C(CH3)2-, and - CH2CH(CH2OH)-, wherein L is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C1-3alkyl-OH, and OH.

[0057] In another embodiment, L is selected from: -CH2CH2-, -CH2CH2CH2-, -CH(OH)CH2-, - CH2CH(OH)CH2-, -CH2CH(CH3)-, -CH2CH2CH(CH3)-, -CH2CH2C(CH3)2-, and - CH2CH(CH2OH)-.

[0058] In another embodiment, L is selected from: -CH2CH2-, -CH2CH2CH2-, -CH(OH)CH2-, - CH2CH(OH)CH2-, and -CH2CH(CH2OH)-, wherein L is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C1-3alkyl-OH, and OH.

[0059] In another embodiment, L is selected from: -CH2CH2-, -CH2CH2CH2-, -CH(OH)CH2-, - CH2CH(OH)CH2-, and -CH2CH(CH2OH)-.

[0060] In another embodiment, L is selected from: -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)-, - CH2CH2CH(CH3)-, -CH2CH2C(CH3)2- and -CH2CH(CH2OH)-, wherein L is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, and -C1-3alkyl-OH, and OH.

[0061] In another embodiment, L is selected from: -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)-, - CH2CH2CH(CH3)-, -CH2CH2C(CH3)2-, and -CH2CH(CH2OH)-.

[0062] In another embodiment, L is selected from: -CH2CH2- and -CH2CH2CH2-, wherein L is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, and - C1-3alkyl-OH, and OH. In another embodiment, L is selected from: -CH2CH2- and -CH2CH2CH2- . In another embodiment of the present invention, L is -CH2CH2. In another embodiment, L is - CH2CH2CH2-.

[0063] In another embodiment, R1is selected from: -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, - N+(C1-6alkyl)3, -OH, -OC1-6alkyl, -SH, and -SC1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra.

[0064] In another embodiment, R1is selected from: -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, - N+(C1-6alkyl)3, -OH, and -OC1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra.

[0065] In another embodiment, R1is selected from: -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, and - N+(C1-6alkyl)3, wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra.

[0066] In another embodiment, R1is selected from: -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, and - N+(C1-3alkyl)3, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from Ra.

[0067] In another embodiment, R1is selected from: -NH2, and -NH(C1-6alkyl), wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra. In another embodiment, R1is selected from: -NH2, and -NH(C1-3alkyl), wherein each alkyl is unsubstitutedor substituted with one to three substituents selected from Ra. In a class of this embodiment, R1is selected from: -NH2, and -NH(CH3).

[0068] In another embodiment, R1is -NH2.

[0069] In another embodiment, R1is -NH(C1-6alkyl), wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra. In a class of this embodiment, R1is - NH(C13alkyl), wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra. In another class of this embodiment, R1is -NH(CH3).

[0070] In another embodiment of the present invention, R2 is selected from: hydrogen, -C1-6alkyl, -C1-6alkyl-OR4, and -C1-6alkyl-NHR4, wherein alkyl is unsubstituted or substituted withone to three halogens. In a class of this embodiment, R2 is selected from: hydrogen and C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another classof this embodiment, R2 is C1-3alkyl, wherein alkyl is unsubstituted or substituted with one tothree halogens. In another class of this embodiment, R2 is C1-3alkyl. In another class of thisemobodiment, R2is hydrogen.

[0071] In another embodiment, R3is selected from: -C1-6alkyl, -C1-6alkyl-OH, -C1-6alkyl-O-C1-6alkyl, -O-C1-6alkyl, -C1-6alkyl-SH, -S-C1-6alkyl, -C1-6alkyl-S-C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)2, -C1-6alkyl-NH2, and -C1-6alkyl-N(Rm)-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In a class of this embodiment, R3is selected from: -C1-3alkyl, -C1-3alkyl-OH, -C1-3alkyl-O-C1-3alkyl, -O-C1-3alkyl, -C1-3alkyl-SH, -S- C1-3alkyl, -C1-3alkyl-S-C1-6alkyl, -NH-C1-3alkyl, -N(C1-3alkyl)2, -C1-3alkyl-NH2, and -C1-3alkyl- N(Rm)-C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn.

[0072] In another embodiment, R3is selected from: -C1-6alkyl, -C1-6alkyl-OH, -C1-6alkyl-O-C1-6alkyl, -O-C1-6alkyl, -NH-C1-6alkyl, -N(C1-6alkyl)2, -C1-6alkyl-NH2, and -C1-6alkyl-N(Rm)-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In a class of this embodiment, R3is selected from: -C1-3alkyl, -C136alkyl-OH, -C1-3alkyl-O-C1-6alkyl, -O-C1-3alkyl, -NH-C1-3alkyl, -N(C1-3alkyl)2, -C1-3alkyl-NH2, and -C1-3alkyl-N(Rm)-C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn.

[0073] In another embodiment, R3is selected from: -C1-6alkyl, -C1-6alkyl-OH, -C1-6alkyl-O-C1-6alkyl, -O-C1-6alkyl, -C1-6alkyl-SH, -C1-6alkyl-S-C1-6alkyl, -C1-6alkyl-NH2, and -C1-6alkyl-N(Rm)- C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In a class of this embodiment, R3is selected from: -C1-3alkyl, -C136alkyl-OH, -C1-3alkyl-O-C1-3alkyl, -O-C1-3alkyl, -C1-3alkyl-SH, -C1-3alkyl-S-C1-3alkyl, -C1-3alkyl-NH2, and -C1-3alkyl- N(Rm)C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn.

[0074] In another embodiment, R3is selected from: -C1-6alkyl, -C1-6alkyl-OH, -C1-6alkyl-O-C1- 6alkyl, -O-C1-6alkyl, -C1-6alkyl-NH2, and -C1-6alkyl-N(Rm)-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In a class of this embodiment, R3is selected from: -C1-3alkyl, -C1-3alkyl-OH, -C1-3alkyl-O-C1-3alkyl, -O-C1-3alkyl, -C1-3alkyl-NH2, and -C1-3alkyl-N(Rm)-C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn.

[0075] In another embodiment, R3is selected from: -C1-6alkyl, -C1-6alkyl-OH, -C1-6alkyl-O-C1-6alkyl, and -O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In a class of this embodiment, R3is selected from: -C1-3alkyl, -C1-3alkyl-OH, -C1-3alkyl-O-C1-6alkyl, and -O-C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn.

[0076] In another embodiment, R3is selected from: -C1-6alkyl, -C1-6alkyl-OH, and -C1-6alkyl-O- C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In a class of this embodiment, R3is selected from: -C1-3alkyl, -C1-3alkyl-OH, and -C1-3alkyl-O-C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In another class of this embodiment, R3is selected from: -CH3, -CH2OH, - CH2CH2OH, and -CH2OCH3.

[0077] In another embodiment, R3is -C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In a class of this embodiment, R3is -C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In another class of this embodiment, R3is -CH3.

[0078] In another embodiment, R3is -C1-6alkyl-OH, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In a class of this embodiment, R3is - C1-3alkyl-OH, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In another class of this embodiment, R3is -CH2OH or -CH2CH2OH.

[0079] In another embodiment, R3is -C1-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In a class of this embodiment, R3is - C1-3alkyl-O-C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn. In another class of this embodiment, R3is -CH2OCH3.

[0080] In another embodiment, R4 is selected from: hydrogen, -C1-3alkyl, and cyclopropyl,wherein alkyl and cyclopropyl are unsubstituted or substituted with one to three halogens orOC1-3alkyl.

[0081] In another embodiment, R4 is selected from: hydrogen, and C1-3alkyl, wherein alkyl isunsubstituted or substituted with one to three halogens or OC1-3alkyl. In a class of thisembodiment, R4 is selected from: hydrogen, and C1-3alkyl. In another class of this embodiment,R4is hydrogen.

[0082] In another class of this embodiment, R4 is C1-3alkyl, wherein alkyl is unsubstituted orsubstituted with one to three halogens or OC1-3alkyl. In another class of this embodiment, R4 isC1-3alkyl. In a subclass of this class, R4 is -CH3.

[0083] In another class, R4 is selected from: C1-3alkyl and cyclopropyl, wherein alkyl andcyclopropyl are unsubstituted or substituted with one to three halogens or OC1-3alkyl. In a classof this embodiment, R4 is selected from: C1-3alkyl, and cyclopropyl.

[0084] In another class, R4is cyclopropyl, wherein cyclopropyl is unsubstituted or substitutedwith one to three halogens or OC1-3alkyl.

[0085] In another embodiment, R5is selected from: -CO2H, and tetrazole. In a class of this embodiment, R5is tetrazole. In another class of this embodiment, R5is -CO2H.

[0086] In another embodiment, R6 and R7 are selected from: hydrogen, and C1-6alkyl, whereinalkyl is unsubstituted or substituted with one to three halogens, provided that at least one of R6and R7is hydrogen.

[0087] In another embodiment, R6 is selected from: hydrogen, and C1-6alkyl, wherein alkyl isunsubstituted or substituted with one to three halogens, provided that at least one of R6and R7is hydrogen.

[0088] In another embodiment, R6 is selected from: hydrogen, and C1-6alkyl, wherein alkyl isunsubstituted or substituted with one to three halogens. In a class of this embodiment, R6isselected from: hydrogen, and C1-3alkyl, wherein alkyl is unsubstituted or substituted with one tothree halogens. In another class of this embodiment, R6 is C1-6alkyl, wherein alkyl isunsubstituted or substituted with one to three halogens. In another class of this embodiment, R6isC1-6alkyl. In another class, R6 is C1-3alkyl. In another class, R6 is CH3. In another class of thisembodiment, R6is hydrogen.

[0089] In another embodiment, R7 is selected from: hydrogen, and C1-6alkyl, wherein alkyl isunsubstituted or substituted with one to three halogens, provided that at least one of R6and R7is hydrogen.

[0090] In another embodiment, R7 is selected from: hydrogen, and C1-6alkyl, wherein alkyl isunsubstituted or substituted with one to three halogens. In a class of this embodiment, R7isselected from: hydrogen, and C1-3alkyl, wherein alkyl is unsubstituted or substituted with one tothree halogens. In another class of this embodiment, R7 is C1-6alkyl, wherein alkyl isunsubstituted or substituted with one to three halogens. In another class of this embodiment, R7isC1-6alkyl. In another class, R7 is C1-3alkyl. In another class, R7 is CH3. In another class of thisembodiment, R7is hydrogen.

[0091] In another embodiment, R8is selected from: hydrogen, C1-4alkyl, halogen, and C3-C7cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from: -OH, halogen, NH2, and -OC1-3alkyl. In a class of this embodiment, R8is selected from: hydrogen, C1-4alkyl, and halogen, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: -OH, halogen, NH2, and -OC1-3alkyl. In another class of this embodiment, R8is selected from: hydrogen, and C1-4alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: -OH, halogen, NH2, and -OC1-3alkyl. In another class of this embodiment, R8is C1-4alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: -OH, halogen, NH2, and -OC1-3alkyl. In another class of this embodiment, R8is selected from: hydrogen, and C1-4alkyl. In another class of this embodiment, R8is hydrogen.

[0092] In another embodiment, R9 and R10 are selected from: hydrogen, and C1-6alkyl, whereinalkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, - OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, NHC1-3alkyl, and SC1-3alkyl, provided thatone or both of R9 and R10 are C1-6alkyl, or alternatively R9 and R10 together with the carbon towhich they are attached form a monocyclic C3-5cycloalkyl or a monocyclic C2-5cycloheteroalkyl, wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, -OH and -OC1-3alkyl. In a class ofthis embodiment, R9 and R10 are selected from: hydrogen, and C1-6alkyl, wherein alkyl isunsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, NHC1-3alkyl, and SC1-3alkyl, provided that one orboth of R9 and R10 are C1-6alkyl. In another class of this embodiment, R9 and R10 are selectedfrom: hydrogen, -CH3, and -CH2CH3. In another class of this embodiment, R9 and R10 areselected from C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to threesubstituents selected from: halogen, OH, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, NHC1-3alkyl, or SC1-3alkyl. In another class of this embodiment, R9and R10are selected fromC1-6alkyl. In another class of this embodiment, R9 and R10 are selected from: -CH3and -CH2CH3. In another class of this embodiment, R9 and R10 are each -CH2CH3. In another class ofthis embodiment, R9 and R10 are each -CH3.

[0093] In another embodiment, R9 is C1-6alkyl, wherein alkyl is unsubstituted or substitutedwith one to three substituents selected from: halogen, OH, -OC1-3alkyl, -NHC(O)C1-3alkyl, - C(O)NHC1-3alkyl, NHC1-3alkyl, and SC1-3alkyl, or alternatively R9and R10together with thecarbon to which they are attached form a monocyclic C3-5cycloalkyl or a monocyclic C2-5cycloheteroalkyl, wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, -OH and -OC1-3alkyl. In anotherclass of this embodiment, R9 is selected from: C1-6alkyl, wherein alkyl is unsubstituted orsubstituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, NHC1-3alkyl, and SC1-3alkyl.

[0094] In another class of this embodiment, R9 is selected from: C1-6alkyl. In another class ofthis embodiment, R9 is selected from: -CH3, and -CH2CH3. In another class of this embodiment,R9 is -CH2CH3. In another class of this embodiment, R9 is -CH3.

[0095] In another embodiment, R10 is C1-6alkyl, wherein alkyl is unsubstituted or substitutedwith one to three substituents selected from: halogen, OH, -OC1-3alkyl, -NHC(O)C1-3alkyl, - C(O)NHC1-3alkyl, NHC1-3alkyl, and SC1-3alkyl, or alternatively R9and R10together with thecarbon to which they are attached form a monocyclic C3-5cycloalkyl or a monocyclic C2-5cycloheteroalkyl, wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, -OH and -OC1-3alkyl. In anotherclass of this embodiment, R10 is independently selected from: C1-6alkyl, wherein alkyl isunsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, NHC1-3alkyl, and SC1-3alkyl. In another class ofthis embodiment, R10 is selected from: C1-6alkyl. In another class of this embodiment, R10 isselected from: -CH3, and -CH2CH3. In another class of this embodiment, R10 is -CH2CH3. Inanother class of this embodiment, R10 is -CH3.

[0096] In another embodiment, each Rais independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, -C0-6alkyl S(O)rRj, -C0-6alkylS(O)rNRkRk, -C0-6alkyl C(O)Ri,-C0-6alkyl OC(O)Ri,-C0-6alkyl C(O)ORi, -C0-6alkyl CN, -C0-6alkyl C(O)NRkRk, -C0-6alkyl C(NH)NRkRk, -C0-6alkylNRkRk, -C0-6alkyl N(Rk)(C(O)Ri), -C0-6alkyl N(Rk)(C(O)ORh), -C0-6alkyl N(Rk)(C(O)NRfRg), and -C0-6alkyl N(Rk)(S(O)vRj), wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, - OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl).

[0097] In another embodiment, each Rais independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, -C0-6alkyl CN, and -C0-6alkylNRkRk, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl).

[0098] In another embodiment, each Rais independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, -C0-6alkyl CN, and -C0-6alkylNRkRk, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, and -C1-3alkyl.

[0099] In another embodiment, each Rais independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, and -C0-6alkyl CN, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl).

[0100] In another embodiment, each Rais independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, and -C0-6alkyl CN, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, and -C1-3alkyl.

[0101] In another embodiment, each Rais independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, and -C0-6alkyl CN, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, and -C1-3alkyl.

[0102] In another embodiment, each Rais independently selected from: -CF3, -CHF2, -CH2F, halogen, and -C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl).

[0103] In another embodiment, each Rais independently selected from: -CF3, -CHF2, -CH2F, halogen, and -C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl.

[0104] In another embodiment, each Rais independently selected from: -CF3, -CHF2, -CH2F, halogen, and -C1-6alkyl.

[0105] In another embodiment, each Rais -C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, - CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl).

[0106] In another embodiment, each Rais independently selected from: -C1-6alkyl, and -C0- 6alkyl-OH, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, and -C1-3alkyl. In a class of this nother embodiment, each Rais independently selected from: -C1-6alkyl, and -C0-6alkyl-OH. In another class of this embodiment, each Rais independently selected from: -CH3, -CH2OH, and -OH.

[0107] In another embodiment, each Rbis independently selected from: hydrogen, -C1-6alkyl, - C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, -C0-6alkyl-S(O)uRd, -C1-6alkyl-C(O-N(Re)2, -C1-6alkylN(Re)C(O)Re, -C0-6alkyl-N(Re) 2, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens, and wherein two Rbsubstituents together with the atoms they areattached to can cyclize to form a monocyclic C3-6cycloalkyl or a monocyclic C2-6cycloheteroalkyl ring.

[0108] In another embodiment, each Rbis independently selected from: hydrogen, -C1-6alkyl, - C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens, and wherein two Rbsubstituents together with the atoms they areattached to can cyclize to form a monocyclic C3-6cycloalkyl or a monocyclic C2-6cycloheteroalkyl ring.

[0109] In another embodiment, each Rbis independently selected from: hydrogen, -C1-6alkyl, - C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens, and wherein two Rbsubstituents together with the atoms they areattached to can cyclize to form a monocyclic C3-6cycloalkyl or a monocyclic C2-6cycloheteroalkyl ring.

[0110] In another embodiment, each Rbis independently selected from: hydrogen, C1-6alkyl, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens, and wherein two Rbsubstituents together with the atoms they are attached to can cyclize to form a 3 to 6 membered ring. In a class of this embodiment, each Rbis independently selected from: hydrogen, and -C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens, and wherein two Rbsubstituents together with the atoms they are attached to can cyclize to form a 3 to 6 membered ring. In another class of embodiment, each Rbis C1-6alkyl, wherein alkyl isunsubstituted or substituted with one to three halogens, and wherein two Rbsubstituents together with the atoms they are attached to can cyclize to form a 3 to 6 membered ring. In another class of this embodiment, each Rbis C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In yet another class of this embodiment, each Rbis C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, each Rbis hydrogen.

[0111] In another embodiment, each Rcis independently selected from: hydrogen, -C1-6alkyl, - C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, -C0-6alkyl-S(O)vRf,-C0-6alkyl-S(O)vN(Rg)2,-C1-6alkyl C(O)- N(Rg)2, -C1-6alkylN(Rg)C(O)Rg, -C0-6alkyl-N(Rg) 2, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens.

[0112] In another embodiment, each Rcis independently selected from: hydrogen, -C1-6alkyl, - C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, each Rcis independently selected from: hydrogen, -C1-3alkyl, -C0-3alkyl-O-C1-3alkyl, -C0-3alkyl-OH, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens.

[0113] In another embodiment, each Rcis independently selected from: hydrogen, -C1-6alkyl, - C0-6alkyl-O-C1-6alkyl, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, each Rcis independently selected from: hydrogen, -C1-6alkyl, -O-C1-6alkyl, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, each Rcis independently selected from: hydrogen, -C1-3alkyl, -O-C1-3alkyl, and halogen, wherein alkyl is unsubstituted or substituted with one to three halogens.

[0114] In another embodiment, each Rcis independently selected from: hydrogen, -C1-6alkyl, and -C0-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, each Rcis independently selected from: hydrogen, -C1-3alkyl, and -C0-3alkyl-O-C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another embodiment, each Rcis independently selected from: hydrogen, -C1-6alkyl, and -C0-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, each Rcis independently selected from: hydrogen, -C1-6alkyl, and -O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, each Rcis independently selected from: hydrogen, -CH3, and -OCH3.

[0115] In another embodiment, each Rcis independently selected from: -C1-6alkyl, and -C0-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In aclass of this embodiment, each Rcis independently selected from: C1-6alkyl, and -O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, each Rcis independently selected from: -CH3, and -OCH3.

[0116] In another embodiment, each Rcis C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another embodiment, each Rcis C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, each Rcis -CH3.

[0117] In another embodiment, each Rcis hydrogen.

[0118] In another embodiment, Rdis independently selected from: hydrogen, and -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rdis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rdis -C1-3alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class, Rdis -CH3. In another class of this embodiment, Rdis hydrogen.

[0119] In another embodiment, Reis independently selected from: hydrogen, and -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Reis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Reis -C1-3alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class, Reis -CH3. In another class of this embodiment, Reis hydrogen.

[0120] In another embodiment, Rfis independently selected from: hydrogen, and -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rfis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rfis -C1-3alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class, Rfis -CH3. In another class of this embodiment, Rfis hydrogen.

[0121] In another embodiment, Rgis independently selected from: hydrogen, and -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rgis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rgis -C1-3alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class, Rgis -CH3. In another class of this embodiment, Rgis hydrogen.

[0122] In another embodiment, Rhis independently selected from: hydrogen, and -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of thisembodiment, Rhis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rhis -C1-3alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class, Rhis -CH3. In another class of this embodiment, Rhis hydrogen.

[0123] In another embodiment, each Riis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, each Riis -C1-6alkyl. In a class of this embodiment, Riis -C1-3alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class, Ri is -CH3. In another class of this embodiment, each Riis -CH3.

[0124] In another embodiment of the present invention, Rjis independently selected from: hydrogen, OH and -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rjis independently selected from: hydrogen, and -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, Rjis hydrogen or OH. In another class of this embodiment, Rjis OH. In another class of this embodiment, Rjis hydrogen. In another class of this embodiment, Rjis - C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, Rjis -C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, Rjis -C1-3alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens.

[0125] In another embodiment of the present invention, Rkis independently selected from: hydrogen, and -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rkis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rkis -C1-3alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class, Rkis -CH3. In another class of this embodiment, Rkis hydrogen.

[0126] In another embodiment, Rlis independently selected from: hydrogen, and -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rlis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rlis -C1-3alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class, Rlis -CH3. In another class of this embodiment, Rlis hydrogen.

[0127] In another embodiment, Rmis independently selected from: hydrogen, and -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In a class of this embodiment, Rmis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one tothree halogens. In a class of this embodiment, Rmis -C1-3alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens. In another class, Rmis -CH3. In another class of this embodiment, Rmis hydrogen.

[0128] In another embodiment, each Rnis independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, -C0-6alkylS(O)rRj, -C0-6alkylS(O)rNRkRk, -C0-6alkylC(O)Ri,-C0-6alkylOC(O)Ri,-C0-6alkylC(O)ORi, -C0-6alkylCN, -C0-6alkyl-C(O)NRkRk, -C0-6alkylC(NH)NRkRk, -C0-6alkylNRkRk, -C0-6alkylN(Rk)(C(O)Ri), -C0-6alkyl N(Rk)(C(O)ORh), -C0-6alkylN(Rk)(C(O)NRfRg), and -C0-6alkylN(Rk)(S(O)vRj), wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl).

[0129] In another embodiment, each Rnis independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, -C0-6alkyl CN, and -C0-6alkylNRkRk, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0- 6alkylNH(C1-3alkyl).

[0130] In another embodiment, each Rnis independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, -C0-6alkyl-OH, - C0-6alkyl CN, and -C0-6alkylNRkRk, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, and -C1-3alkyl.

[0131] In another embodiment, each Rnis independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, and -C0-6alkyl-OH, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, - CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl).

[0132] In another embodiment, each Rnis independently selected from: -CF3, -CHF2, -CH2F, halogen, -C1-6alkyl, -C0-6alkyl-O-C1-6alkyl, and -C0-6alkyl-OH, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, and -C1-3alkyl.

[0133] In another embodiment, each Rnis independently selected from: -C0-6alkyl-O-C1-6alkyl, and -C0-6alkyl-OH, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl).

[0134] In another embodiment, each Rnis independently selected from: -C0-6alkyl-O-C1-6alkyl, and -C0-6alkyl-OH, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, and -C1-3alkyl. In a class of this embodiment, each Rnisindependently selected from: -OCH3, and -OH, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, and -C1-3alkyl.

[0135] In another embodiment, Rnis -C0-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, and -C1-3alkyl. In a class of this embodiment, each Rnis -OCH3.

[0136] In another embodiment, Rnis -C0-6alkyl-OH, wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, and -C1-3alkyl. In a class of this embodiment, Rnis -OH.

[0137] In another embodiment, q is 0, 1, 2, or 3. In a class of this embodiment, q is 0, 1, or 2. In a class of this embodiment, q is 0 or 1. In another class of this embodiment, q is 1 or 2. In another class of this embodiment, q is 0 or 2. In another class of this embodiment, q is 0. In another class of this embodiment, q is 1. In another class of this embodiment, q is 2.

[0138] In another embodiment, each r is independently 0, 1, or 2. In a class of this embodiment, r is 0 or 1. In another class of this embodiment, r is 1 or 2. In another class of this embodiment, r is 0 or 2. In another class of this embodiment, r is 0. In another class of this embodiment, r is 1. In another class of this embodiment, r is 2.

[0139] In another embodiment, each s is independently 0, 1, 2, 3, 4 or 5. In a class of this embodiment, each s is independently 0, 1, 2, 3 or 4. In another class of this embodiment, each s is independently 0, 1, 2, or 3. In another class of this embodiment, each s is independently 1, 2, or 3. In another class of this embodiment, each s is independently 1 or 3. In another class of this embodiment, s is 0 or 1. In another class of this embodiment, s is 1 or 2. In another class of this embodiment, s is 0 or 2. In another class of this embodiment, s is 0. In another class of this embodiment, s is 1. In another class of this embodiment, s is 2. In another class of this embodiment, s is 3. In another class of this embodiment, s is 4. In another class of this embodiment, s is 5.

[0140] In another embodiment, each t is independently 0, 1, 2, or 3. In a class of this embodiment, t is 0, 1, or 2. In another class of this embodiment, t is 0 or 1. In another class of this embodiment, t is 1 or 2. In another class of this embodiment, t is 0 or 2. In another class of this embodiment, t is 0. In another class of this embodiment, t is 1. In another class of this embodiment, t is 2. In another class of this embodiment, t is 3.

[0141] In another embodiment, each u is independently 0, 1, or 2. In a class of this embodiment, u is 0 or 1. In another class of this embodiment, u is 1 or 2. In another class of this embodiment, u is 0 or 2. In another class of this embodiment, u is 0. In another class of this embodiment, u is 1. In another class of this embodiment, u is 2.

[0142] In another embodiment, each v is independently 0, 1, or 2. In a class of this embodiment, v is 0 or 1. In another class of this embodiment, v is 1 or 2. In another class of this embodiment, v is 0 or 2. In another class of this embodiment, v is 0. In another class of this embodiment, v is 1. In another class of this embodiment, v is 2.

[0143] In another embodiment, the invention relates to compounds of Formula Ia: ,wherein A isor a pharmaceutically acceptable salt thereof.

[0144] In another embodiment, are compounds of Formula Ib: ,whereinor a pharmaceutically acceptable salt thereof.

[0145] In another embodiment, are compounds of Formula Ic:,wherein A isor a pharmaceutically acceptable salt thereof.

[0146] In another embodiment, are compounds of Formula Id: ,whereinor a pharmaceutically acceptable salt thereof.

[0147] In another embodiment, are compounds of formula i.e.,,whereinor a pharmaceutically acceptable salt thereof.

[0148] In another embodiment, are compounds of Formula If:, If whereinor a pharmaceutically acceptable salt thereof.

[0149] In another embodiment, are compounds of Formula Ig:,wherein A isor a pharmaceutically acceptable salt thereof.

[0150] In another embodiment, are compounds of Formula Ih: ,or a pharmaceutically acceptable salt thereof.

[0151] In another embodiment, are compounds of Formula Ii:,whereinor a pharmaceutically acceptable salt thereof.

[0152] In another embodiment, are compounds of Formula Ij: ,wherein A isor a pharmaceutically acceptable salt thereof.

[0153] In another embodiment, are to compounds of Formula Ik:,whereinor a pharmaceutically acceptable salt thereof.

[0154] In another embodiment, are compounds of Formula Il: ,whereinor a pharmaceutically acceptable salt thereof.

[0155] In another embodiment, are compounds of Formula Im:,whereinor a pharmaceutically acceptable salt thereof.

[0156] In another embodiment, are compounds of Formula In: ,wherein A isor a pharmaceutically acceptable salt thereof.

[0157] The compound of Formula (I) includes the compounds of Formulas Ia, Ib, Ic, Id, i.e., If, Ig, Ih, Ii, Ij, Ik, Il, Im and In, and pharmaceutically acceptable salts, hydrates and solvates thereof.

[0158] Another embodiment relates to compounds of Formula (I) wherein:A isT is CH; U is CH; V is CH; X is CH2; Y is O or CH2; Z is O or CH2; W is bond or O; Q is CR8; L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C0-3alkyl-OH, -C0-3alkyl-NH2, -OC1-3alkyl, -NHC(O)C1-3alkyl, - C(O)NHC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1-3alkyl; R1is selected from: 1) -NH2, and 2) -NH(-C1-6alkyl), wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra; R2is hydrogen; R3is selected from: 1) -C1-6alkyl, 2) -C1-6alkyl-OH, and 3) -C1-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn; R4is selected from: 1) C1-3alkyl, and2) cyclopropyl, wherein alkyl and cyclopropyl are unsubstituted or substituted with one to three substituentsselected from: halogen and OC1-3alkyl;R5 is -CO2H or tetrazole;R6is hydrogen;R7is hydrogen; R8is hydrogen;R9 is C1-6alkyl,R10 is C1-6alkyl, andRa, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rm, Rn, q, r, s, t, u, and v are as defined above; or a pharmaceutically acceptable salt thereof.

[0159] Another embodiment relates to compounds of Formula (I) wherein: A isT is CH; U is CH; V is CH; X is CH2; Y is CH2; Z is O; W is O; Q is CR8; L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, and -C0-3alkyl-OH; R1is selected from: 1) -NH2, and 2) -NH(-C1-6alkyl), wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra; R2is hydrogen; R3is selected from: 1) -C1-6alkyl, 2) -C1-6alkyl-OH, and 3) -C1-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn;R4 is C1-3alkyl;R5 is -CO2H;R6is hydrogen; R7is hydrogen; R8is hydrogen;R9 is C1-6alkyl;R10 is C1-6alkyl; andRa, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rm, Rn, q, r, s, t, u, and v are as defined above; or a pharmaceutically acceptable salt thereof.

[0160] Another embodiment are compounds of Formula (I) wherein: A isT is CH; U is CH; V is CH; X is CH2; Y is O or CH2; Z is O or CH2; W is bond or O; Q is CR8; L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C0-3alkyl-OH, -C0-3alkyl-NH2, -OC1-3alkyl, -NHC(O)C1-3alkyl, - C(O)NHC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1-3alkyl; R1is selected from: 1) -NH2, and 2) -NH(-C1-6alkyl), wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra; R2is hydrogen; R3is selected from: 1) -C1-6alkyl, 2) -C1-6alkyl-OH, and 3) -C1-6alkyl-O-C1-6alkyl,wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn; R4is selected from: 1) C1-3alkyl, and2) cyclopropyl, wherein alkyl and cyclopropyl are unsubstituted or substituted with one to three substituentsselected from: halogen and OC1-3alkyl;R5 is -CO2H or tetrazole;R6is hydrogen; R7is hydrogen; R8is hydrogen;R9 is C1-6alkyl,R10 is C1-6alkyl, andRa, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rm, Rn, q, r, s, t, u, and v are as defined above; or a pharmaceutically acceptable salt thereof.

[0161] Another embodiment relates to compounds of Formula (I) wherein: A isT is CH; U is CH; V is CH; X is CH2; Y is CH2; Z is O; W is O; Q is CR8; L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, and -C0-3alkyl-OH; R1is -NH2; R2is hydrogen; R3is selected from: 1) -C1-6alkyl-OH, and2) -C1-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn;R4 is C1-3alkyl;R5 is -CO2H;R6is hydrogen; R7is hydrogen; R8is hydrogen;R9 is C1-6alkyl;R10 is C1-6alkyl; andRa, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rm, Rn, q, r, s, t, u, and v are as defined above; or a pharmaceutically acceptable salt thereof.

[0162] Another embodiment relates to compounds of Formula (I) wherein: A isT is CH; U is CH; V is CH; X is CH2; Y is O or CH2; Z is O or CH2; W is bond or O; Q is CR8; L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C0-3alkyl-OH, -C0-3alkyl-NH2, -OC1-3alkyl, -NHC(O)C1-3alkyl, - C(O)NHC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1-3alkyl; R1is selected from: 1) -NH2, and 2) -NH(-C1-6alkyl), wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra; R2is hydrogen;R3is selected from: 1) -C1-6alkyl, 2) -C1-6alkyl-OH, and 3) -C1-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn; R4is selected from: 1) C1-3alkyl, and2) cyclopropyl, wherein alkyl and cyclopropyl are unsubstituted or substituted with one to three substituentsselected from: halogen and OC1-3alkyl;R5 is -CO2H or tetrazole;R6is hydrogen; R7is hydrogen; R8is hydrogen;R9 is C1-6alkyl,R10 is C1-6alkyl, andRa, Rb, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk, Rm, Rn, q, r, s, t, u, and v are as defined above; or a pharmaceutically acceptable salt thereof.

[0163] Another embodiment relates to compounds of Formula (I) wherein: A isT is CH; U is CH; V is CH; X is CH2; Y is CH2; Z is O; W is O; Q is CR8;L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, and -C0-3alkyl-OH; R1is -NH2; R2is hydrogen;R4 is C1-3alkyl;R5 is -CO2H;R6is hydrogen; R7is hydrogen; R8is hydrogen;R9 is C1-6alkyl;R10 is C1-6alkyl; andare as defined above; or a pharmaceutically acceptable salt thereof.

[0164] Illustrative, but non-limiting, examples of compounds of Formula (I)are: 1) (S)-2-((R)-6-((S)-5-(2-aminoethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1- (2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 2) (S)-2-((R)-6-((R)-5-(3-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)- 1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 3) (S)-2-((R)-6-((S)-5-(3-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)- 1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 4) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-(2-(methylamino)ethyl)-4,5-dihydro-1H- imidazol-2-yl)chroman-2-yl)propanoic acid; 5) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((R)-5-(2-(methylamino)ethyl)-4,5-dihydro-1H- imidazol-2-yl)chroman-2-yl)propanoic acid; 6) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-(3-(methylamino)propyl)-4,5-dihydro- 1H-imidazol-2-yl)chroman-2-yl)propanoic acid;7) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((R)-5-(3-(methylamino)propyl)-4,5-dihydro- 1H-imidazol-2-yl)chroman-2-yl)propanoic acid; 8) (S)-2-((R)-6-((S)-5-(3-aminopropyl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)- 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 9) (S)-2-((R)-6-((R)-5-(3-aminopropyl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)- 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 10) (S)-2-((R)-6-((S)-5-((R)-2-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 11) (S)-2-((R)-6-((R)-5-((R)-2-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 12) (S)-2-((R)-6-((R)-5-((S)-2-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 13) (S)-2-((R)-6-((S)-5-((S)-2-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 14) (2S)-2-((2R)-6-(5-(3-aminopropyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 15) (2S)-2-((2R)-6-(5-(2-aminoethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2-((((Z)- 1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 16) (S)-2-((R)-6-((R)-5-(3-aminopropyl)-5-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 17) (S)-2-((R)-6-((S)-5-(3-aminopropyl)-5-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid;18) (S)-2-((R)-6-((R)-5-((S)-2-amino-1-hydroxyethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman- 2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 19) (S)-2-((R)-6-((R)-5-((R)-2-amino-1-hydroxyethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman- 2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 20) (S)-2-((R)-6-((S)-5-(3-amino-3-methylbutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)- 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 21) (S)-2-((R)-6-((R)-5-(3-amino-3-methylbutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)- 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 22) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-((R)-2-(methylamino)propyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid; 23) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((R)-5-((R)-2-(methylamino)propyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid; 24) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((R)-5-((S)-2-(methylamino)propyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid; 25) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-((S)-2-(methylamino)propyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid; 26) (S)-2-((R)-6-((S)-5-((S)-3-aminobutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 27) (S)-2-((R)-6-((R)-5-((S)-3-aminobutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 28) (S)-2-((R)-6-((R)-5-((R)-3-aminobutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid;29) (S)-2-((R)-6-((S)-5-((R)-3-aminobutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 30) (S)-2-((R)-6-((S)-5-((S)-3-amino-2-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 31) (S)-2-((R)-6-((R)-5-((S)-3-amino-2-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 32) (S)-2-((R)-6-((R)-5-((R)-3-amino-2-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 33) (S)-2-((R)-6-((S)-5-((R)-3-amino-2-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 34) (S)-2-((R)-6-((S)-5-((S)-2-amino-3-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 35) (S)-2-((R)-6-((R)-5-((S)-2-amino-3-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 36) (S)-2-((R)-6-((R)-5-((R)-2-amino-3-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 37) (S)-2-((R)-6-((S)-5-((R)-2-amino-3-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 38) (S)-2-((R)-6-((S)-4-(2-aminoethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 39) (S)-2-((R)-6-((R)-4-(2-aminoethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid;40) (S)-2-((R)-6-((4S,5S)-5-(2-aminoethyl)-4-(methoxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 41) (S)-2-((R)-6-((4R,5S)-5-(2-aminoethyl)-4-(methoxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 42) (S)-2-((R)-6-((4R,5R)-5-(2-aminoethyl)-4-(methoxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 43) (S)-2-((R)-6-((4S,5R)-5-(2-aminoethyl)-4-(methoxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 44) (S)-2-((R)-6-((4S,5S)-5-(2-aminoethyl)-4-(hydroxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 45) (S)-2-((R)-6-((4R,5S)-5-(2-aminoethyl)-4-(hydroxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 46) (S)-2-((R)-6-((4R,5R)-5-(2-aminoethyl)-4-(hydroxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; and 47) (S)-2-((R)-6-((4S,5R)-5-(2-aminoethyl)-4-(hydroxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; or a pharmaceutically acceptable salt thereof.

[0165] Other embodiments include the following: (a) A pharmaceutical composition comprising an effective amount of a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (b) The pharmaceutical composition of (a), further comprising a second compound, wherein the second compound is a beta-lactamase inhibitor. (c) The pharmaceutical composition of (b), wherein the second compound is selected from: relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacubactam,vaborbactam, zidebactam, durlobactam, enmetazobactam, and xeruborbactam, or a pharmaceutically acceptable salt thereof. (d) A pharmaceutical composition comprising (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (ii) a second compound, wherein the second compound is an beta-lactamase inhibitor compound, wherein the compound of Formula (I), and the second compound are each employed in an amount that renders the combination effective for treating or preventing bacterial infection. (e) The combination of (d), wherein the second compound is selected from: relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacubactam, vaborbactam, zidebactam, durlobactam, enmetazobactam, and xeruborbactam, or a pharmaceutically acceptable salt thereof. (f) A method for treating a bacterial infection in a subject which comprises administering to a subject in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. (g) A method for preventing and / or treating a bacterial infection which comprises administering to a subject in need of such treatment a pharmaceutical composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (h) A method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of the composition of (a), (b), (c), (d), or (e). (i) The method of treating a bacterial infection as set forth in (f), (g), or (h), wherein the bacterial infection is due to Gram negative bacteria. (j) The method of treating a bacterial infection as set forth in (f), (g), (h), or (i), wherein the bacterial infection is due to Pseudomonas aeruginosa or Acinetobacter baumannii.

[0166] Also included is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation (or manufacture) of a medicament for, medicine or treating bacterial infection, including infection with a multidrug resistant bacterial strain. In these uses, the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents including relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacubactam, vaborbactam, zidebactam, durlobactam, enmetazobactam, and xeruborbactam, or a pharmaceutically acceptable salt thereof.

[0167] Additional embodiments include the pharmaceutical compositions, combinations and methods set forth in (a)-(j) above and the uses set forth in the preceding paragraph, wherein the compound employed therein is a compound of one of the embodiments, sub-embodiments, classes or sub-classes described above. The compound may optionally be used in the form of a pharmaceutically acceptable salt in these embodiments.

[0168] In the embodiments of the compounds and salts provided above, it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and methods provided as (a) through (j) above are understood to include all embodiments of the compounds and / or salts, including such embodiments as result from combinations of embodiments.

[0169] Additional embodiments include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein or its salt employed therein is substantially pure. With respect to a pharmaceutical composition comprising a compound of Formula (I) or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term "substantially pure" is in reference to a compound of Formula (I) or its salt per se; i.e., the purity of this active ingredient in the composition. Definitions

[0170] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name and an ambiguity exists between the structure and the name, the structure predominates. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc.

[0171] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0172] The term “β-lactamase inhibitor" refers to a compound which is capable of inhibiting enzyme activity from β-lactamases. As used herein, inhibiting β-lactamase activity meansinhibiting the activity of a class A, C, and / or D β-lactamase. For antimicrobial applications inhibition at a 50% inhibitory concentration is preferably achieved at or below about 100 micrograms / mL, or at or below about 50 micrograms / mL, or at or below about 25 micrograms / mL. The terms "class A", "class B", "class C", and "class D" β-lactamases are understood by those skilled in the art and are described in S. G. Waley, β-lactamase: mechanisms of action, in The Chemistry of β-Lactams, M. I. Page, Ed.; Chapman and Hall, London, (1992) 198-228.

[0173] The term "metallo-β-lactamase" denotes a metalloprotein capable of inactivating a β-lactam antibiotic. The β-lactamase can be an enzyme which catalyzes the hydrolysis of the β-lactam ring of a β-lactam antibiotic. Of particular interest herein are microbial metallo- β-lactamases. The metallo-β-lactamase can be, for example, a zinc metallo-β-lactamase. β-Lactamases of interest include those disclosed in, e.g., S. G. Waley, β-lactamase: mechanisms of action, in The Chemistry of β-Lactams, M. I. Page, Ed.; Chapman and Hall, London, (1992) 198-228. β-Lactamases of particular interest herein include metallo-β-lactamases of Escherichia coli (such as New Delhi Metallo-β-lactamase, NDM), Serratia marcescens (such as IMP), and Klebsiella spp. (such as Verona integron-encoded metallo-β-lactamase, VIM).). Additional metallo-β-lactamases of interest herein include SPM-, GIM-, SIM-, KHM-, AIM-, DIM-, SMB-, TMB-, and FIM-type enzymes.

[0174] The term "antibiotic" refers to a compound or composition which decreases the viability of a microorganism, or which inhibits the growth or proliferation of a microorganism. The phrase "inhibits the growth or proliferation" means increasing the generation time (i.e., the time required for the bacterial cell to divide or for the population to double) by at least about 2-fold. Preferred antibiotics are those which can increase the generation time by at least about 10-fold or more (e.g., at least about 100-fold or even indefinitely, as in total cell death). As used in this disclosure, an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent. Examples of antibiotics include penicillins, cephalosporins and carbapenems.

[0175] The term "β-lactam antibiotic" refers to a compound with antibiotic properties that contains a β-lactam functionality. Non-limiting examples of β-lactam antibiotics include penicillins, cephalosporins, penems, carbapenems, and monobactams.

[0176] The term "about", when modifying the quantity (e.g., kg, L, or equivalents) of a substance or composition, or the value of a physical property, or the value of a parameter characterizing a process step (e.g., the temperature at which a process step is conducted), or the like refers to variation in the numerical quantity that can occur, for example, through typical measuring, handling and sampling procedures involved in the preparation, characterizationand / or use of the substance or composition; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make or use the compositions or carry out the procedures; and the like. In certain embodiments, “about” can mean a variation of ± 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 of the appropriate unit. In certain embodiments, “about” can mean a variation of ± 1%, 2%, 3%, 4%, 5%, 10%, or 20%.

[0177] Another embodiment is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as originally defined or as defined in any of the foregoing embodiments, sub- embodiments, aspects, classes or sub-classes, wherein the compound or its salt is in a substantially pure form. As used herein "substantially pure" means suitably at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt.% (e.g., from about 90 wt.% to about 99 wt.%), even more preferably at least about 95 wt.% (e.g., from about 95 wt.% to about 99 wt.%, or from about 98 wt.% to 100 wt.%), and most preferably at least about 99 wt.% (e.g., 100 wt.%) of a product containing a compound of Formula (I) or its salt (e.g., the product isolated from a reaction mixture affording the compound or salt) consists of the compound or salt. The level of purity of the compounds and salts can be determined using a standard method of analysis such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and / or mass spectrometry. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level of purity determined, then the method providing the highest level of purity governs. A compound or salt of 100% purity is one which is free of detectable impurities as determined by a standard method of analysis.

[0178] With respect to a compound which has one or more asymmetric centers and can occur as mixtures of stereoisomers, a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual diastereomer or enantiomer unless expressly depicted otherwise. The present disclosure encompasses all stereoisomeric forms of the compounds of Formula (I). Unless a specific stereochemistry is indicated, all such isomeric forms of these compounds are comprehended. Centers of asymmetry that are present in the compounds of Formula (I) can all independently of one another have (R) configuration or (S) configuration.

[0179] When bonds to the chiral carbon are depicted as straight lines in the structural Formulas of the disclosure, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individualenantiomers and mixtures thereof, are embraced by the name. The production of specific stereoisomers or mixtures thereof may be identified in the Examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of this disclosure.

[0180] This disclosure includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and / or diastereomers, in all ratios. Thus, enantiomers are a subject of the disclosure in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism both the cis form and the trans form as well as mixtures of these forms in all ratios are included. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula (I) or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Where compounds are capable of tautomerization, all individual tautomers as well as mixtures thereof are included. Unless a particular isomer, salt, solvate (including hydrates) or solvated salt of such racemate, enantiomer, diastereomer or tautomer is indicated, the present disclosure includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof. Definitions:

[0181] “Ac” is acetyl, which is CH3C(=O)-.

[0182] "Alkyl” means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Other groups having the prefix "alk", such as alkoxy and alkanoyl, also may be linear or branched, or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

[0183] "Aryl" means a monocyclic, bicyclic or fused carbocyclic aromatic ring or ring system containing carbon atoms, wherein at least one of the rings is aromatic. The term aryl also encompasses an aryl group, as defined above, which is fused to an aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl or heteroaryl ring. Examples of aryl include phenyl and naphthyl. In one embodiment, aryl is phenyl. In another embodiment, aryl is dihydroindene. In another embodiment, aryl is 2,3-dihydroindene.

[0184] "Cycloalkyl," as used herein, refers to a saturated monocyclic ring or bicyclic, tricyclic, fused, spirocyclic or bridged ring system comprising 3 to 14 carbon atoms. The cycloalkyl ring system contains more than one ring, the rings can be joined via a ring carbon. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, and the like. In one embodiment, cycloalkyl is selected from: cyclopropane, cyclobutane, cyclopentane, and cyclohexane. In another embodiment, cycloalkyl is cyclopropane. In another embodiment, cycloalkyl is cyclobutane. In another embodiment, cycloalkyl is cyclopentane. In another embodiment, cycloalkyl is cyclohexane. In another embodiment, cycloalkyl is selected from: cyclopropane, cyclobutane, cyclohexane, bicyclo[1.1.1]pentane, and spiro[3.3]heptane. In another embodiment, cycloalkyl is selected from: cyclopropane, cyclobutane, bicyclo[1.1.1]pentane, and spiro[3.3]heptane. In another embodiment, cycloalkyl is selected from: cyclopropane, cyclobutane, and cyclohexane. In another embodiment, cycloalkyl isselected from: cyclopropane and cyclobutane. In another embodiment, C3-12cycloalkyl isselected from: cyclopropane, cyclobutane, cyclohexane, bicyclo[1.1.1]pentane, andspiro[3.3]heptane. In another embodiment, C3-12cycloalkyl is selected from: cyclopropane,cyclobutane, bicyclo[1.1.1]pentane, and spiro[3.3]heptane. In another embodiment, C3-12cycloalkyl is selected from: cyclopropane, cyclobutane, and cyclohexane. In anotherembodiment, C3-12cycloalkyl is selected from: cyclopropane and cyclobutane.

[0185] "Cycloalkenyl" means a monocyclic ring or bicyclic, spirocyclic, fused or bridged carbocyclic ring system having a specified number of carbon atoms containing at least one double bond. Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cycloheptenyl, and the like.

[0186] "Cycloheteroalkyl," as used herein, refers to a saturated monocyclic ring or bicyclic, tricyclic, spirocyclic, fused or bridged ring system comprising 3 to 14 ring atoms, wherein from 1 to 4 of the ring atoms are independently N, NH, S (including SO and SO2) and O, and the remainder of the ring atoms are carbon atoms. When a heterocycloalkyl contains two or more rings, the rings may be fused, bridged or spirocyclic. The cycloheteroalkyl group can be joinedvia a ring carbon or ring nitrogen atom (if present). Where the ring or ring system contains one or more N atoms, the N can be in the form of quaternary amine. The nitrogen or sulfur atom of the heterocycloalkyl (if present) can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. The cycloheteroalkyl ring may be substituted on the ring carbons and / or the ring nitrogen or sulfur. Examples of cycloheteroalkyl include, oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, delta- lactam, delta-lactone, silacyclopentane, silapyrrolidine, pyrrolidinyl, azetidinyl, piperidine, piperazine, azepane, azocane, morpholine, thiomorpholine, and the like. In one embodiment, cycloheteroalkyl is selected from azetidine, pyrrolidine, piperidine, morpholine, and diazabicyclo[2.2.1]heptane. In another embodiment, cycloheteroalkyl is selected from azetidine, pyrrolidine, piperidine, and morpholine. In another embodiment, cycloheteroalkyl is selectedfrom azetidine, and pyrrolidine. In another embodiment, C2-11cycloheteroalkyl is selected from:azetidine, pyrrolidine, piperidine, morpholine, and diazabicyclo[2.2.1]heptane. In anotherembodiment, C2-11cycloheteroalkyl is selected from azetidine, pyrrolidine, piperidine, andmorpholine. In another embodiment, C2-11cycloheteroalkyl is selected from azetidine, andpyrrolidine.

[0187] "Cycloheteroalkenyl" means a monocyclic ring or bicyclic, fused, spirocyclic or bridged ring system comprising 3 to 14 ring atoms and containing at least one double bond and at least one heteroatom. Examples of cycloheteroalkenyl include dihydropyran and dihydrofuran, and the like.

[0188] "Heteroaryl" means a monocyclic ring or bicyclic or fused ring system containing 5-14 ring atoms containing at least one ring heteroatom selected from N, NH, S (including SO and SO2) and O, wherein at least one of the heteroatom containing rings is aromatic. The term heteroaryl encompasses a heteroaryl group, as defined above, which is fused to an aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl or heteroaryl ring. In the case of a heteroaryl ring system where one or more of the rings are saturated or partially saturated and contain one or more N atoms, the N can be in the form of quaternary amine. Any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The heteroaryl group can be optionally substituted by one or more ring system substituents which may be the same or different. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide),benzotriazolyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like. In one embodiment, heteroaryl is selected from: pyridine.

[0189] "Halogen" includes fluorine, chlorine, bromine and iodine. In one embodiment, halogen is fluorine, chorine, bromine or iodine. In another embodiment, halogen is fluorine or chlorine. In another embodiment, halogen is chlorine, fluorine or iodine. In another embodiment, halogen is fluorine. In another embodiment, halogen is chlorine. In another embodiment, halogen is bromine. In another embodiment, halogen is iodine.

[0190] “Me” represents methyl.

[0191] “Oxo” means an oxygen atom connected to another atom by a double bond and represents“=O”.

[0192] “Quaternary salt” means a cation formed by four covalent bonds to nitrogen. Whenany variable (e.g., R1, Ra, etc.) occurs more than one time in any constituent or in Formula (I),its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A squiggly line across a bond in a substituent variable represents the point of attachment.

[0193] “Saturated”means containing only single bonds.

[0194] “Unsaturated” means containing at least one double or triple bond. In one embodiment, unsaturated means containing at least one double bond. In another embodiment, unsaturated means containing at least one triple bond.

[0195] When any variable (e.g., R1, Ra, etc.) occurs more than one time in any constituent or inFormula (I), its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A squiggly line across a bond in a substituent variable represents the point of attachment.

[0196] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward thepoint of attachment. For example, a C1-5alkylcarbonylamino C1-6alkyl substituent isequivalent to:

[0197] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, salts and / or dosage forms which are, using sound medicaljudgment, and following all applicable government regulations, safe and suitable for administration to a human being or an animal.

[0198] Compounds of Formula (I) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present disclosure is meant to encompass all such isomeric forms of the compounds of Formula (I).

[0199] The independent syntheses of optical isomers and diastereoisomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the X- ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration or sufficient heavy atoms to make an absolute assignment.

[0200] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereoisomeric mixture, followed by separation of the individual diastereoisomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0201] Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0202] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

[0203] Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.

[0204] In the compounds of general Formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotopehaving the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. Included are all suitable isotopic variations of the compounds of Formula (I). For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Tritium is radioactive and may therefore provide for a radiolabeled compound, useful as a tracer in metabolic or kinetic studies. Isotopically-enriched compounds within Formula (I), can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0205] Furthermore, some of the crystalline forms for compounds of Formula (I) may exist as polymorphs and as such are intended to be included in the present disclosure. In addition, some of the compounds of Formula (I) may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this disclosure.

[0206] It is generally preferable to administer compounds of Formula (I) as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

[0207] A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present disclosure are limited to stable compounds embraced by Formula (I).

[0208] In choosing compounds of Formula (I), one of ordinary skill in the art will recognizethat the various substituents, i.e., i.e., R1, R2, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.

[0209] The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. When a group, e.g., C1-C8 alkyl, is indicated asbeing substituted, such substitutions can also occur where such group is part of a larger substituent, e.g., –C1-C6alkyl-C3-C7cycloalkyl and –C1-C8alkyl-aryl.

[0210] Unless expressly stated to the contrary in a particular context, any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.

[0211] Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaromatic ring described as containing from "1 to 4 heteroatoms" means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from "1 to 4 heteroatoms" is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms. Similarly, C1-C6 when used with a chain, for example an alkyl chain, means that the chain can contain 1, 2, 3, 4, 5 or 6 carbon atoms. It also includes all ranges contained therein including C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C3-C6, C4-C6, C5-C6, and all other possible combinations.

[0212] It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0213] The compounds of Formula (I) have at least one asymmetric center and can have one or more additional centers as a result of the presence of certain substituents and / or substituent patterns. Accordingly, compounds of Formula (I) can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether individually or in mixtures, are within the scope of the present disclosure.

[0214] The term "compound" refers to the free compound and, to the extent they are stable, any hydrate or solvate thereof. A hydrate is the compound complexed with water, and a solvate is the compound complexed with an organic solvent.

[0215] As indicated above, the compounds of Formula (I) can be employed in the form of pharmaceutically acceptable salts. It will be understood that, as used herein, the compounds of the instant disclosure can also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.

[0216] The term “Drug resistant” means, in connection with a Gram-negative bacterial strain, a strain which is no longer susceptible to at least one previously effective drug; which hasdeveloped the ability to withstand antibiotic attack by at least one previously effective drug. “Multi-drug resistant” means a strain that is no longer susceptible to two or more previously effective drugs; which has developed the ability to withstand antibiotic attack by two or more previously effective drugs. A drug resistant strain may relay that ability to withstand to its progeny. This resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs.

[0217] The term "pharmaceutically acceptable salt" refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non- toxic bases or acids including inorganic or organic bases and inorganic or organic acids.

[0218] Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this disclosure which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of Formula (I) include, but are not limited to, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethylacetic, digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, formic, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2- hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate / diphosphate, pimelic, phenylpropionic, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate and the like. Furthermore, where the compounds of Formula (I) carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, andtertiary amines, cyclic amines, dicyclohexyl amines and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Also, included are the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

[0219] These salts can be obtained by known methods, for example, by mixing a compound of Formula (I) with an equivalent amount and a solution containing a desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent. The compounds of Formula (I) and salts thereof may form solvates with a solvent such as water, ethanol, or glycerol. The compounds of Formula (I) may form an acid addition salt and a salt with a base at the same time according to the type of substituent of the side chain.

[0220] As set forth above, the present disclosure includes pharmaceutical compositions comprising a compound of Formula (I), optionally one other active components (e.g., a β- lactamase inhibitor), and a pharmaceutically acceptable carrier. The characteristics of the carrier will depend on the route of administration. By “pharmaceutically acceptable” is meant that the ingredients of the pharmaceutical composition must be compatible with each other, do not interfere with the effectiveness of the active ingredient(s), and are not deleterious (e.g., toxic) to the recipient thereof. Thus, compositions according to the present disclosure may, in addition to the inhibitor, contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.

[0221] Also as set forth above, also disclosed is 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 of Formula (I), or a pharmaceutically acceptable salt thereof, optionally in combination with a β-lactamase inhibitor. The term "subject" (or, alternatively, "patient") as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of Formula (I) mean providing the compound, or a pharmaceutically acceptable salt thereof, to the individual in needof treatment. When a compound or a salt thereof is provided in combination with one or more other active agents (e.g., a β-lactamase inhibitor), "administration" and its variants are each understood to include provision of the compound or its salt and the other agents at the same time or at different times. When the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately.

[0222] It is understood that a "combination" of active agents can be a single composition containing all of the active agents or multiple compositions each containing one or more of the active agents. In the case of two active agents a combination can be either a single composition comprising both agents or two separate compositions each comprising one of the agents; in the case of three active agents a combination can be either a single composition comprising all three agents, three separate compositions each comprising one of the agents, or two compositions one of which comprises two of the agents and the other comprises the third agent; and so forth.

[0223] The compositions and combinations of the present disclosure are suitably administered in effective amounts. The term “effective amount” as used herein means the amount of active compound sufficient to inhibit bacterial growth and thereby elicit the response being sought (i.e., an "inhibition effective amount") in a cell, tissue, system, animal or human. In one embodiment, the effective amount is a "therapeutically effective amount" for the alleviation of the symptoms of the disease or condition being treated (e.g., the healing of conditions associated with bacterial infection, and / or bacterial drug resistance). In another embodiment, the effective amount is a "prophylactically effective amount" for prophylaxis of the symptoms of the disease or condition being prevented. When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound.

[0224] The administration of a composition of Formula (I) is suitably parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intraocular, or intrarectal, wherein the composition is suitably formulated for administration by the selected route using formulation methods well known in the art, including, for example, the methods for preparing and administering formulations described in chapters 39, 41, 42, 44 and 45 in Remington – The Science and Practice of Pharmacy, 21stedition, 2006. In one embodiment, compounds of Formula (I) are administered intravenously in a hospital setting. In another embodiment, administration is oral in the form of a tablet or capsule or the like. When administered systemically, a therapeutic composition is for example, suitably administered at a sufficient dosage to attain a blood level of inhibitor of at least about 1 microgram / mL, and in additional embodiment at least about 10 micrograms / mL, and at least about 25 micrograms / mL. Forlocalized administration, much lower concentrations than this may be effective, and much higher concentrations may be tolerated.

[0225] Intravenous administration of a compound of Formula (I) can be conducted by reconstituting a powdered form of the compound with an acceptable solvent. Suitable solvents include, for example, saline solutions (e.g., 0.9% Sodium Chloride Injection) and sterile water (e.g., Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol). The powdered form of the compound can be obtained by gamma-irradiation of the compound or by lyophilization of a solution of the compound, after which the powder can be stored (e.g., in a sealed vial) at or below room temperature until it is reconstituted. The concentration of the compound in the reconstituted IV solution can be, for example, in a range of from about 0.1 mg / mL to about 20 mg / mL.

[0226] Also disclosed is a method for inhibiting bacterial growth which comprises administering to a bacterial cell culture, or to a bacterially infected cell culture, tissue, or organism, an inhibition effective amount of a compound of Formula (I). Additional embodiments include the bacterial growth inhibiting method just described, wherein the compound Formula (I) employed therein is a compound of one of the embodiments, sub-embodiments or classes described above. The compound may optionally be used in the form of a pharmaceutically acceptable salt in these embodiments. The method can involve administration of a compound of Formula (I) to an experimental cell culture in vitro to prevent the growth of β-lactam resistant bacteria. The method can alternatively involve administration of a compound of Formula (I) to an animal, including a human, to prevent the growth of β-lactam resistant bacteria in vivo. In these cases the compound of Formula (I) is typically co-administered with a β-lactamase inhibitor.

[0227] The methods of the presently disclosed subject matter are useful for treating these conditions in that they inhibit the onset, growth, or spread of the condition, cause regression of the condition, cure the condition, or otherwise improve the general well-being of a subject afflicted with, or at risk of, contracting the condition. Thus, in accordance with the presently disclosed subject matter, the terms “treat”, “treating”, and grammatical variations thereof, as well as the phrase “method of treating”, are meant to encompass any desired therapeutic intervention, including but not limited to a method for treating an existing infection in a subject, and a method for the prophylaxis (i.e., preventing) of infection, such as in a subject that has been exposed to a microbe as disclosed herein or that has an expectation of being exposed to a microbe as disclosed herein.

[0228] Compounds of Formula (I) can be employed for the treatment, prophylaxis or inhibition of bacterial growth or infections due to bacteria that are resistant to β-lactam antibiotics. More particularly, the bacteria can be metallo-β-lactamase positive strains that are highly resistant to β-lactam antibiotics. The terms "slightly resistant" and "highly resistant" are well-understood by those of ordinary skill in the art (see, e.g., Payne et al., Antimicrobial Agents and Chemotherapy 38:767-772 (1994); Hanaki et al., Antimicrobial Agents and Chemotherapy 30:11.20-11.26 (1995)). For the purposes of this disclosure, bacterial strains which are highly resistant to imipenem are those against which the MIC of imipenem is >16 µg / mL, and bacterial strains which are slightly resistant to imipenem are those against which the MIC of imipenem is >4 µg / mL.

[0229] The compounds wherein R4 is C1-3alkyl, such as CH3, or cyclopropyl and R5 is CO2Hor tetrazole have the unexpected benefit of stability compared to compounds wherein R4ishydrogen and R5 is CO2H or tetrazole.

[0230] Compounds of Formula (I) can be used in combination with a β-lactamase inhibitor for the treatment of infections caused by β-lactamase producing strains, in addition to those infections which are subsumed within the antibacterial spectrum of the antibiotic agent. Examples of β-lactamase producing bacteria are Pseudomonas aeruginosa, Pseudomonas putida, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Serratia marcescens, Enterobacter aerogenes, Enterobacter asburiae, Citrobacter freundii, Proteus mirabilis, Morganella morganii, Providencia rettgeri, Stenotrophomonas maltophilia and Acinetobacter baumannii.

[0231] It is generally advantageous to use a compound of Formula (I) in admixture or conjunction with a β-lactamase inhibitor, or a prodrug thereof. It is advantageous to use a compound of Formula I in combination with a class A and C β-lactamase inhibitor because of the class B β-lactamase resistant properties of the compounds. It is also advantageous to use a compound of Formula I in combination with one or more Class A, C, or D β-lactamase inhibitors to further limit β-lactam susceptability. As already noted, the compound of Formula I and the β- lactamase inhibitor can be administered separately (at the same time or as different times) or in the form of a single composition containing both active ingredients.

[0232] Relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacubactam, vaborbactam, zidebactam, durlobactam, enmetazobactam, xeruborbactam, and other β-lactamase and metallo-β-lactamase inhibitors suitable for use in the present methods and compositions include those known to show inhibitory activity to β-lactamases.Abbreviations

[0233] Ambient is room temperature; aq. is aqueous; ACN is acetonitrile; AcOH is acetic acid; Bn is benzyl; 9-BBN is 9-Borabicyclo[3.3.1]nonane; BOC (or Boc) is t-butyloxycarbonyl; BOC2O is di-tert-butyl dicarbonate; BuBr is butyl bromide; CBZ (or Cbz) is carbobenzoxy (alternatively, benzyloxycarbonyl); CBZ-Cl is benzyloxycarbonyl chloride; CDCl3is deuterated chloroform; CV or cv is column volume(s); D2O is deuterium oxide; DBU is 1,8- diazabicyclo[5.4.0]undec-7-ene; DCC is dicyclohexyl carbodiimide; DCE is dichloroethane; DCM is dichloromethane; DEAD is diethyl azodicarboxylate; (DHQD)2AQN is 1,4-bis[(5-ethyl- 1-azabicyclo[2.2.2]octan-2-yl)-(6-methoxyquinolin-4-yl)methoxy]anthracene-9,10-dione; DIAD is diisopropyl azodicarboxylate; DIBAL-H is diisobutyl aluminum hydride; DIEA or DIPEA is diisopropylethylamine; DMA is dimethylacetamide; DMAP is 4-dimethylaminopyridine or N,N- dimethylamino-pyridine; DME is dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; DPPA is diphenylphosphoryl azide; EDC is 1-ethyl-3-(3- dimethylaminopropyl) carbodiimide; eq. or equiv. is equivalent(s); Et is ethyl; Et3N is triethyl amine; Et2O is diethyl ether; EA or EtOAc is ethyl acetate; EtOH is ethanol; g is gram(s); FA is formic acid; h or hr or hrs is hour(s); HATU is 1-[Bis(dimethyl-amino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluoro-phosphate; hex is hexane; HMDS is hexamethyl- disilazide; HPLC is high-performance liquid chromatography; Int is intermediate; IPA is isopropyl alcohol; L or l is liter(s); LC / MS or LC-MS is liquid chromatography / mass spectrometry; LDA is lithium diisopropylamide; LiHMDS is lithium hexamethyl-disilazide M is molar; min is minute(s); mg is milligram(s); ml, mL or ML is milliliter(s); Me is methyl; MeCN is acetonitrile; MeOH is methanol; MeI is methyl iodide; MPLC is medium pressure liquid chromatography; MTBE is methyl tert-butyl ether; N is normal; NaBH(OAc)3 is sodium triacetoxyborohydride; NBS is N-bromo-succinimide; NCS is N-chlorosuccinimide; NEt3is trietheyl amine; NMR is nuclear magnetic resonance; MS is mass spectrometry; MW is molecular weight; Pd / C is palladium on carbon; PdCl2(dppf)2is [1,1’ bis(diphenyl-phosphino)- ferrocene] dichloropalladium(II); di-t-BuDPPF-PdCl2 is 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride; Pd(AcO)2is palladium (II) acetate; pet. ether or PE is petroleum ether; PG is protective group; Ph is phenyl; Ph3P is triphenyl phosphine; RP is reverse phase; RP-HPLCis reverse-phase high-performance liquid chromatography; rt, r.t., R.T. or RT is room temperature; sat’d is saturated; SFC is super critical fluid chromatography; tBu is tert-butyl; tBuOH is tert- butyl alcohol; TBAF is tetrabutylammonium fluoride; TB is tert-butyl-dimethylsilyl; TBS-Cl is tert-butyldimethylsilyl chloride; t-BuOH is tert-butyl alcohol; TEA is triethylamine; Teoc is 2-(trimethylsilyl)ethoxycarbonyl; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TLC is thin layer chromatography; TMS is trimethylsilyl; TMS-Cl is trimethyl-silyl chloride; W is watts; and wt. % is weight percentage. GENERAL SCHEME

[0234] The chroman chloride A was converted via cyanation to intermediate B, which underwent functional group manipulations to provide intermediate C. Amination of the diamineintermediate C afforded intermediate D, which was then deprotected to give compound E. Alternatively, a Suzuki coupling reaction between intermediate F and a substituted 2 chloro- pyrimidine afforded intermediate G. Reduction of the pyrimidine provided cyclic amidine intermediate H, which was then deprotected to give compound I. The condensation reaction of compound E or compound I with intermediate J afforded intermediate K, whose protecting group was removed to give the final product. Alternatively, compound E or I was coupled with intermediate L to afford the final product directly. EXAMPLE 1: Preparation of Intermediate 1c

[0235] Step A: Synthesis of Intermediate 1a: To a stirred solution of tert-butyl 2- (diethoxyphosphoryl)-propanoate (2150 g, 8.06 mol) in THF (8.4 L) at ambient temperature, was added NaH (339.3 g, 8.48 mol, 60% purity) in several portions. The mixture was stirred at 30- 40°C for 3 h. Then a solution of 3-(2-bromo-5-chlorophenyl)propanal (2100 g, 8.48 mol) in THF (4.2 L) was added dropwise to the above mixture at 30-50°C. After the addition, the mixture was stirred at 20-40°C for 1 h, then poured into ice water (10 L), and diluted with EtOAc (10 L). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 L). The combined organic layers were washed with brine (10 L), and then concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with petroleum ether:ethyl acetate (1: 0~10: 1) to give intermediate 1a.1H-NMR (400 MHz, CDCl3): δ 7.47 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 7.07 (dd, J = 8.5, 2.6 Hz, 1H), 6.71 (td, J = 7.5, 1.5 Hz, 1H), 2.93 – 2.71 (m, 2H), 2.63 – 2.37 (m, 2H), 1.78 (d, J = 1.3 Hz, 3H), 1.52 (s, 9H).

[0236] Step B: Synthesis of Intermediate 1b: To a 50 L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, were added K2CO3 (2188 g, 15.84 mol), potassium ferricyanide (5218 g, 15.84 mol), tetraoxodipotassium osmium (38.1 g, 0.105 mol), (DHQD)2AQN (90.1 g, 0.105 mol) and a solution of intermediate 1a (1900 g, 5.28 mol) in tert- butanol / water (19 L / 19 L). The resulting reaction mixture was stirred at room temperature for 2 days. Then the reaction mixture was extracted with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. The resulting solids were filtered out, andthe filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column eluting with ethyl acetate / petroleum ether (1 / 100-1 / 10) to give intermediate 1b. LC-MS: m / z 417.0 [M+Na]+.

[0237] Step C: Synthesis of Intermediate 1c: A 20-L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with Cs2CO3 (2317.2 g, 7112.01 mmol) and Pd(OAc)2(39.9 g, 177.80 mmol) in toluene (14 L). Then 2-(di-tert-butylphosphino)- biphenyl (106.1 g, 355.60 mmol) was slowly added over 30 min. To this mixture was added intermediate 1b (1400 g, 3556.01 mmol). The reaction mixture was stirred for 20 h at 90oC, then cooled to room temperature with a water / ice bath. The resulting solids were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified on a silica gel column eluting with ethyl acetate / petroleum ether (1 / 100-1 / 5) to give intermediate 1c.1H- NMR (400 MHz, CDCl3): δ 7.07-7.00 (m, 2H), 6.67 (d, J = 8.3 Hz, 1H), 4.14 (dd, J = 11.0, 2.4 Hz, 1H), 3.03 – 2.60 (m, 2H), 2.23 – 1.86 (m, 2H), 1.53 (s, 9H), 1.41 (s, 3H). EXAMPLE 2: Preparation of Intermediate 2c

[0238] Step A: Synthesis of Intermediate 2a: Into a 2-L 4-necked round-bottom flask was placed a solution of intermediate 1c (460 g, 1.47 mol) in toluene (4.8 L), followed by the addition of sodium hydride (60wt.%, 70.8 g, 1.77 mol) in several batches at 27oC. The mixture was stirred at 27oC for 1 h. Then a solution of amino 2,4,6-trimethylbenzene-1-sulfonate (380.4 g, 1.77 mol) in DCM (1.2 L) was added dropwise with stirring at 27oC. The reaction mixture was stirred at 27oC for 2 h. Then the reaction was quenched by the addition of water (2 L) and extracted with MTBE (2 x 2 L). The organic layers were combined, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified on a silica gel column eluting with EtOAc / PE (1:10) to give intermediate 2a.1H-NMR (400 MHz, CDCl3): δ 7.08-6.96 (m, 2H), 6.96 (overlap, 1H), 6.77 (d, J = 9.4 Hz, 1H), 4.20 (dd, J = 11.4, 1.9 Hz, 1H), 2.99 – 2.62 (m, 2H), 2.06 (ddt, J = 13.6, 5.9, 2.1 Hz, 1H), 1.87 (dtd, J = 13.6, 12.0, 5.8 Hz, 1H), 1.54 (s, 9H), 1.53 (s, 3H).

[0239] Step B: Synthesis of Intermediate 2b: Into a 5-L 4-necked round-bottom flask were placed intermediate 2a (500 g, 1525.27 mmol) and di-tert-butyl dicarbonate (399.00 g, 1828.18mmol) in ethyl alcohol (5 L). The reaction was stirred for 5 h at 50oC, then concentrated under vacuum. The resulting crude product was purified by slurrying with hexanes. The resulting solids were collected by filtration to afford intermediate 2b.CDCl3): δ 7.53 (s, 1H), 6.99 (t, 2H), 6.68 (t, 1H), 4.21 (q, 1H), 2.82 (t, 2H), 2.17-2.12 (m, 2H), 1.55-1.45 (m, 21H).

[0240] Step C: Synthesis of Intermediate 2c: To a flask charged with intermediate 2b (2 g, 4.67 mmol), bis(pinacolato)diboron (1.4 g, 5.51 mmol), potassium acetate (1.4 g, 14.27 mmol), 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.192 g, 0.467 mmol) and palladium acetate (52 mg, 0.234 mmol), was added THF (25 mL). The reaction was stirred at ambient temperature under N2 for 1 minute, and then heated to 68 °C. After 16 h, the reaction was cooled to ambient temperature. The reaction was partitioned between EtOAc (150 mL), hexanes (50 mL), and water (150 mL). The organic layer was collected, filtered through CeliteTM, and the filtrate was concentrated under vacuum. To the resulting residue was added 4 mL of EtOAc, followed by 40 mL of hexanes. The resulting mixture was stirred at ambient temperature for 4 h to provide a solid, which was collected by filtration to give crude intermediate 2c, which was used in the next reaction without further purification. LC-MS: m / z 520.5 [M+H]+. EXAMPLE 3: Preparation of Intermediates 3a and 3c

[0241] Step A: Synthesis of Intermediate 3a: To a mixture of intermediate 2b (8.0 g, 18.69 mmol), potassium hexacyanoferrate(II) trihydrate (3.95 g, 9.35 mmol), sodium carbonate (0.248 g, 2.337 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'- amino-1,1'-biphenyl-2-yl) palladium(II) (1.471 g, 1.869 mmol) were added ACN (64 mL) and water (60 mL), both of which had been sparged with nitrogen for 1 h. The reaction vessel was evacuated and filled with nitrogen before sealing. Then the reaction was sealed, and the reaction was heated at 80 °C and stirred for 2 h. The reaction was then partitioned between ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered through aCeliteTMpad. The resulting filtrate was concentrated in vacuo to give a crude residue, which was purified via silica gel chromatography (ISCO 220 g; 0-70% EtOAc / hexanes to give the title compound. LC-MS: m / z 419.2 [M+H]+.

[0242] Step B: Synthesis of Intermediate 3b: To a mixture of intermediate 3a (4.81 g, 11.49 mmol), MgCl2 (1.641 g, 17.24 mmol), and NaSH (1.933 g, 34.5 mmol) was added nitrogen- sparged anhydrous DMF (20.5 mL) under an atmosphere of nitrogen. The reaction mixture was evacuated and filled with nitrogen, then capped and stirred at ambient temperature for 21 h. Then the reaction was cooled to 0°C, and quenched with saturated aqueous NH4Cl and water. The resulting mixture was extracted with ethyl acetate, and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give a crude residue, which was purified via silica gel chromatography (ISCO, 220 g; 0-100% EtOAc / hexanes) to give the title compound. LC-MS: m / z 453.2 [M+H]+.

[0243] Step C: Synthesis of Intermediate 3c: To a solution of intermediate 3b (4.85 g, 10.72 mmol) in anhydrous ether (35 mL) was added iodomethane (0.804 mL, 12.86 mmol) at ambient temperature. The reaction was sealed and stirred for 24 h. Then the ether supernatant was decanted off. The resulting insoluble sticky oil was triturated with ether (15 mL), then dried under high vacuum to give intermediate 3c. The decanted ether layers were also combined and concentrated in vacuo. To the resulting residue was added 1:1 hexanes / ether (30 mL), and the resulting solid material was collected by filtration, washed with 1:1 hexanes / Et2O (20 mL) and dried under vacuum to give an additional amount of intermediate 3c. The combined crude product was used in subsequent reactions without further purification. LC-MS: m / z 467.3 [M+H]+. EXAMPLE 4: Preparation of Intermediate 4

[0244] Intermediate 4 was prepared using the method described in Patent Publication No. WO 2017 / 106064. EXAMPLE 5: Preparation of Intermediate 5

[0245] A flask (250 mL) was charged with Intermediate 4 (10 g, 21.5 mmol) and CH2Cl2 (43 mL), and the solution was cooled to 0 °C. Then TFA (86 mL, 1116 mmol) was added via syringe. The reaction mixture was stirred at 0 °C for 5 h, then concentrated under vacuum without heating to give a residue (~20 mL of total volume). DCM (100 mL) was added to the residue, and the mixture was concentrated under vacuum without heating to ~20 mL total volume. This process was repeated four times to drive out most of the TFA. Finally, the solvent was removed completely under vacuum. To the resulting residue was added water (100 mL). The mixture was stirred for 30 min, then filtered. The filter cake was rinsed with water (1 volume of cake) and then collected and dissolved in 1:1 acetonitrile / water (50 mL). The resulting mixture was lyophilized overnight to provide intermediate 5. LC-MS: m / z 365.3 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ: 9.67 (d, J = 7.7 Hz, 1H), 7.88 (s, 1H), 7.57 (s, 2H), 4.59 (d, J = 7.9 Hz, 1H), 1.44 (s, 3H), 1.25 (s, 3H). EXAMPLE 6: Preparation of Compound 1 (S)-2-((R)-6-((S)-5-(2-aminoethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2- aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid

[0246] Step A: Synthesis of Intermediate 6a: To a solution of (S)-4-amino-2-((tert- butoxycarbonyl)-amino)butanoic acid (10 g, 45.8 mmol) in dioxane (300 mL) stirred at 25 °C was added sodium hydroxide (1 M, 133 mL, 133 mmol). The mixture was cooled to 0 °C, then benzyl-chloroformate (8.38 mL, 59.6 mmol) was added. The reaction was stirred at 25 °C for 12 h, then washed with EtOAc (100 mL × 3). The aqueous phase was collected and acidified to pH = 4-5 with 1 M HCl, and then extracted with EtOAc (100 mL × 3). The organic layer was concentrated in vacuo to provide intermediate 6a, which was used in the next step without further purification.1H NMR (400 MHz, CD3OD) δ: 7.47 - 7.23 (m, 5H), 5.07 (s, 2H), 4.17 - 4.06 (m, 1H), 3.28 - 3.10 (m, 2H), 2.10 - 2.02 (m, 1H), 1.85 - 1.73 (m, 1H), 1.44 (s, 9H).

[0247] Step B: Synthesis of Intermediate 6b: To a stirred solution of intermediate 6a (10 g, 28.4 mmol) in acetone (150 mL), was added K2CO3 (11.77 g, 85 mmol), followed by dimethyl sulfate (5.34 g, 42.3 mmol). The reaction mixture was heated to 55 °C for 4 h. Then the solvent was removed under vacuum. To the resulting residue was added water (100 mL), and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give crude intermediate 6b, which was used in the next step without further purification.1H NMR (500 MHz, CD3OD) δ: 7.43 - 7.27 (m, 5H), 5.09 (s, 2H), 4.19 (br dd, J = 4.7, 9.1 Hz, 1H), 3.75 - 3.64 (m, 3H), 3.30 - 3.12 (m, 2H), 2.02 - 1.97 (m, 1H), 1.87 - 1.76 (m, 1H), 1.46 (s, 9H).

[0248] Step C: Synthesis of Intermediate 6c: To a stirred solution of intermediate 6b (10 g, 27.3 mmol) in EtOH (150 mL) was added sodium borohydride (3.10 g, 82 mmol). The reaction mixture was stirred at 25 °C for 12 h, then diluted with water (100 mL) and extracted with ethyl acetate (80 mL X 3). The combined organic layers were washed with brine (90 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography MPLC (ISCO®; 80 g SepaFlash® Silica Flash Column, eluting with 0-40% ethyl acetate / petroleum ether gradient; flow rate = 45 mL / min) to give intermediate 6c.1H NMR (400 MHz, CDCl3) δ: 7.40 - 7.27 (m, 5H), 5.70 - 5.50 (m, 1H), 5.16 - 5.02 (m, 2H), 4.87 (br s, 1H), 3.88 - 3.64 (m, 3H), 3.46 (br s, 1H), 3.01 (br s, 1H), 1.70 (br s, 1H), 1.58 (br s, 1H), 1.43 (s, 9H).

[0249] Step D: Synthesis of Intermediate 6d: To a solution of intermediate 6c (5 g, 14.78 mmol) in DCM (35 mL) was added TEA (6.18 mL, 44.3 mmol) at 25 °C. The reaction was cooled to 0 °C, then methanesulfonyl chloride (2.8 g, 24.44 mmol) was added dropwise. The reaction mixture was stirred at 25 °C for 12 h. Then additional TEA (6.18 mL, 44.3 mmol) was added to the reaction mixture at 25 °C, followed by the addition of additional methanesulfonyl chloride (3.7 g, 32.3 mmol) at 0oC. After stirring for 1 h at 0oC, the reaction mixture was dilutedwith ice water (20 mL) and extracted with MTBE (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography MPLC (ISCO®; 40 g SepaFlash® Silica Flash Column; eluting with 0~3% ethyl acetate / petroleum ether gradient; flow rate = 30 mL / min) to give intermediate 6d. LC-MS: m / z 416.7 [M+H]+.

[0250] Step E: Synthesis of Intermediate 6e: To a solution of intermediate 6d (2.7 g, 6.48 mmol) in DMF (25 mL) were added ammonium chloride (3.47 g, 64.8 mmol) and sodium azide (1.700 g, 26.1 mmol) at 25 °C. The reaction mixture was stirred at 70 °C for 12 h, then diluted with water (40 mL) and extracted with ethyl acetate (20 mL× 3). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give crude intermediate 6e, which was used in the next step without further purification. LC-MS: m / z 363.8 [M+H]+.

[0251] Step F: Synthesis of Intermediate 6f: To a solution of intermediate 6e (2.356 g, 6.48 mmol) in THF (35 mL) and water (3.5 mL) was added triphenylphosphine (3.40 g, 12.97 mmol) at 25 °C. The reaction was stirred at 25 °C for 12 h, then diluted with acetonitrile (20 mL × 3). The mixture was concentrated in vacuo to give crude intermediate 6f, which was used in the next step without further purification. LC-MS: m / z 337.9 [M+H]+.

[0252] Step G: Synthesis of Intermediate 6g: To a solution of intermediate 6f (2.187 g, 6.48 mmol) in DCM (35 mL) was added TFA (11 mL). The reaction was stirred at 25 °C for 3 h, and then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, eluting with 50-100% EtOAc / Petroleum ether gradient) to give intermediate 6g. LC-MS: m / z 238.2 [M+H]+.

[0253] Step H: Synthesis of Intermediate 6h To a solution of intermediate 3c (500 mg, 1.072 mmol) in CH3OH (5 mL) were added intermediate 6g (458 mg, 1.929 mmol), potassium acetate (316 mg, 3.21 mmol) and acetic acid (0.245 mL, 4.29 mmol). The reaction was sealed under a N2 atmosphere, then stirred at 85 °C for 16 h. The reaction solvent was removed in vacuo. The resulting residue was purified by MPLC (Biotage; 20 g Agela, C18, 20~35 μm; eluting with 0- 45% MeCN / H2O (0.5% TFA) gradient; flow rate = 50 mL / min) to give intermediate 6h. LC-MS: m / z 639.5 [M+H]+.

[0254] Step I: Synthesis of Intermediate 6i: To a solution of intermediate 6h (300 mg, 0.470 mmol) in DCM (5 mL) was added 48% HBr / acetic acid (132 mg, 0.939 mmol). The reaction was stirred at 20 °C for 1 h, then concentrated in vacuo. The resulting residue was purified by prep- HPLC (Boston Uni C1840 × 150 × 5 μm; Condition: water (0.1% TFA)-ACN; Begin B 0, End B25; Gradient Time (min) 11; 100% B Hold Time (min) 2; FlowRate (mL / min) 25; Injections 2) to give intermediate 6i. LC-MS: m / z 349.0 [M+H]+.

[0255] Step J: Synthesis of Compound 1: To a solution of intermediate 6i (130 mg, 0.373 mmol) in DMA (3 mL) was added intermediate 5 (136 mg, 0.373 mmol). The reaction was stirred at 25 °C for 8 h, then diluted with H2O (1 mL). The resulting mixture was purified by reverse-phase HPLC (Boston Uni C18, 40 × 150 × 5 μm; Condition: water (0.1% TFA)-ACN; Begin B 0, End B 30; Gradient Time (min) 10; 100% B Hold Time (min) 2; FlowRate (mL / min) 60; Injections 2), followed by lyophilization to give compound 1 as the TFA salt. This TFA salt was further purified by reverse-phase HPLC (Waters Xselect C18, 150 × 19 mm × 5 μm; Condition water (0.225% FA)-ACN; Begin B 0, End B 13; Gradient Time (min) 23; 100% B Hold Time (min) 2; FlowRate (mL / min) 20; Injections 2), followed by lyophilization to give compound 1 as the formic acid salt. LC-MS: m / z 695.4 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.49 - 7.41 (m, 2H), 6.88 (d, J = 9.0 Hz, 1H), 6.77 (s, 1H), 4.50 (s, 1H), 4.42 - 4.35 (m, 2H), 4.06 (t, J = 11.5 Hz, 1H), 3.63 (dd, J = 7.2, 11.5 Hz, 1H), 3.09 - 2.96 (m, 2H), 2.80 - 2.65 (m, 2H), 2.11 - 2.00 (m, 3H), 1.75 - 1.60 (m, 1H), 1.49 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H). EXAMPLE 7: Preparation of Compounds 2 and 3 (S)-2-((R)-6-((R)-5-(3-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2- aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid and (S)-2-((R)-6-((S)-5-(3-aminopropyl)-4,5-dihydro- 1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[0256] Step A: Synthesis of Intermediate 7a: To a solution of (R)-2-amino-5-((tert- butoxycarbonyl)-amino)pentanoic acid (1 g, 4.31 mmol) in water (20 mL) stirred at 20 °C was added benzyl chloroformate (0.922 ml, 6.46 mmol). The resulting mixture was stirred for 18 h, then the excess benzyl chloroformate was removed by extracting the reaction mixture with diethyl ether (20 mL). The resulting aqueous layer was acidified with 3 N aqueous hydrochloric acid to pH 3 and extracted with DCM (50 mL×3). The combined organic layers were dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (ISCO, 12g gold), eluting with 0-60% EtOAc / Pet. ether gradient) to give intermediate 7a. Rf: 0.59 (Pet. ether / EtOAc = 2:1).

[0257] Step B: Synthesis of Intermediate 7b: To a solution of intermediate 7a (1.53 g, 4.18 mmol) in dimethoxyethane (10 mL) stirred at -15 °C were added 4-methylmorpholine (0.473 g, 4.68 mmol) and isobutyl chloroformate (0.570 g, 4.18 mmol). The reaction was stirred at -15 °C for 15 minutes, then filtered. The filtrate was concentrated under vacuum to give crude intermediate 7b, which was used in the next step without further purification. LC-MS: m / z 489.2[M+Na]+.

[0258] Step C: Synthesis of Intermediate 7c To a solution of intermediate 7b (2 g, 4.29 mmol) in dimethoxyethane (5 mL) stirred at -15 °C were added NaBH4 (0.48 g, 12.69 mmol) and water(3 mL). The reaction was stirred at -15 °C for 10 min, then quenched by adding saturated aqueous NH4Cl (50 mL). The resulting mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with brine (3 X 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified on a silica column eluting with 0-70% ethyl acetate / Pet. ether gradient to give intermediate 7c.1H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 9 H) 1.54 - 1.62 (m, 4 H) 3.14 (br s, 2 H) 3.57 - 3.64 (m, 1 H) 3.70 (br d, J = 9.78 Hz, 2 H) 5.11 (s, 2 H) 7.31 - 7.40 (m, 5 H).

[0259] Step D: Synthesis of Intermediate 7d: To a solution of intermediate 7c (1.87 g, 5.31 mmol) in DCM (20 mL) stirred at 0°C, were added triethylamine (2.219 mL, 15.92 mmol) and methane-sulfonyl chloride (0.729 g, 6.37 mmol). The reaction mixture was stirred at 20 °C for 2 h, then diluted with DCM (100 mL) and washed with 5% aqueous NaHCO3 (60 mL X 3). The organic layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give crude intermediate 7d, which was used in the next step without further purification. LC-MS: m / z 331.1[M+1-Boc]+.

[0260] Step E: Synthesis of Intermediate 7e: To a solution of intermediate 7d in DMF (20 mL) stirred at 0°C was added sodium azide (0.544 g, 8.36 mmol). The reaction mixture was stirred at 60 °C for 18 h, then diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (50 mL). The organic layer was separated, washed with brine (120 mL X 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (ISCO; 20 g Agela Silica Flash Column, eluting with 0 ~55 % EtOAc / Petroleum ether gradient; flow rate = 30 mL / min) to give intermediate 7e. LC-MS: m / z 399.7[M+Na]+.

[0261] Step F: Synthesis of Intermediate 7f: To a solution of intermediate 7e (1.1 g, 2.91 mmol) in EtOH (100 mL) stirred at 0°C, was added 10% Pd-C (0.310 g, 0.291 mmol). The resulting mixture was stirred under H2(45 psi) at 25 °C for 18 h. Then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude intermediate 7f, which was used in the next step without further purification. LC-MS: m / z 218.0 [M+H]+.

[0262] Step G: Synthesis of Intermediate 7g: Acetic acid (0.196 ml, 3.43 mmol) was added to a stirred mixture of intermediate 3c (400 mg, 0.857 mmol), potassium acetate (252 mg, 2.57 mmol) and intermediate 7f (683 mg, 1.886 mmol) in MeOH (15 mL). The resulting mixture was stirred at 90 °C for 16 h, then cooled to ambient temperature. The solvent was removed under reduced pressure to give a residue, which was purified by silica gel chromatography (ISCO, 40 g gold), eluting with 0-12% MeOH / CH2Cl2gradient to give intermediate 7g. LC-MS: m / z 619.1 [M+H]+.

[0263] Step H: Synthesis of Intermediate 7h: To a solution of intermediate 7g (380 mg, 0.614 mmol) in DCM (4 mL) stirred at 0 °C was added TFA (2 mL) dropwise. The reaction was stirred at 25 °C for 1 h. Then the reaction mixture was concentrated under reduced pressure to give crude intermediate 7h, which was used in the next step without further purification. LC-MS: m / z 418.7 [M+H]+.

[0264] Step I: Synthesis of Intermediate 7i: To a solution of intermediate 7h (380 mg, 0.572 mmol) in MeOH (6 mL) was added intermediate 4 (213 mg, 0.458 mmol). The reaction was stirred at 25 °C for 5 h. Then the reaction mixture was concentrated under vacuum to give crude intermediate 7i, which was used in the next step without further purification. LC-MS: m / z 864.8 [M+H]+.

[0265] Step J: Synthesis of Compounds 2 and 3: To a solution of intermediate 7i (600 mg, 0.545 mmol) in DCM (2 mL) stirred at 0 °C, was added TFA (4 mL) dropwise. The resulting solution was stirred at 25 °C for 60 minutes. Then the reaction was cooled to 0 °C and ice-cold MTBE (5 mL) was added with stirring to give a solid. The solid was collected by centrifugation, and the supernatant was decanted. The resulting solid pellet was stirred with an additional 5 mL of ice-cold MTBE, and collected again by centrifugation. After decanting the supernatant, the solid pellet was dried in vacuo and purified by reverse-phase HPLC (Column: Welch Xtimate C18, 150*30mm*5μm; Condition: water (0.225% FA)-ACN; Begin B 0, End B 25; Gradient Time(min) 10; 100% B Hold Time(min) 2; FlowRate (ml / min) 25; Injections 9 ) to give compound 2 as its formic acid salt form. LC-MS: m / z 708.9 [M+H]+.1H NMR (400 MHz, D2O) δ: 7.71 - 7.65 (m, 2H), 7.09 (d, J = 9.4 Hz, 1H), 7.03 (s, 1H), 4.70 (s, 1H), 4.65 (d, J = 9.8 Hz, 1H), 4.60 - 4.45 (m, 1H), 4.25 (t, J = 11.2 Hz, 1H), 3.87 - 3.70 (m, 1H), 3.19 - 3.12 (m, 2H), 3.02 - 2.90 (m, 2H), 2.28 (d, J = 12.5 Hz, 1H), 1.99 - 1.82 (m, 5H), 1.70 (s, 3H), 1.62 (s, 3H), 1.44 (s, 3H).

[0266] Compound 3 was prepared from (S)-2-amino-5-((tert-butoxycarbonyl)amino)pentanoic acid using the method described in Steps A to J of Example 7. LC-MS: m / z 709.4 [M+H]+.1H NMR (400 MHz, D2O) δ: 7.62 - 7.56 (m, 2H), 6.99 (d, J = 9.0 Hz, 1H), 6.95 (s, 1H), 4.84 (s, 1H), 4.60 - 4.50 (m, 1H), 4.50 - 4.40 (m, 1H), 4.15 (t, J = 11.3 Hz, 1H), 3.78 - 3.65 (m, 1H), 3.11 - 3.03 (m, 2H), 2.92 - 2.75 (m, 2H), 2.21 - 2.10 (m, 1H), 1.95 - 1.75 (m, 5H), 1.61 (s, 3H), 1.53 (s, 3H), 1.34 (s, 3H). EXAMPLE 8: Preparation of Compounds 4 and 5 (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-(2-(methylamino)ethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid and (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2- dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((R)-5- (2-(methylamino)ethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid

[0267] Step A: Synthesis of Intermediate 8a: To a solution of benzyl (3- hydroxypropyl)(methyl)-carbamate (10 g, 44.8 mmol) in DCM (220 mL) stirred at 15 °C was added pyridinium chlorochromate (14.48 g, 67.2 mmol) in one portion. The reaction mixture was stirred at 15 °C for 16 h and then diluted with diisopropyl ether (200 mL) and filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column, gradient elution with 0-45% EtOAc / Pet. ether; flow rate = 40 mL / min) to give intermediate 8a.1H NMR (400 MHz, CDCl3) δ: 9.87 - 9.66 (m, 1H), 7.42 - 7.26 (m, 5H), 5.11 (s, 2H), 3.70 - 3.52 (m, 2H), 2.95 (s, 3H), 2.79 - 2.60 (m, 2H).

[0268] Step B: Synthesis of Intermediate 8b: To a suspension of potassium cyanide (1.9 g, 29.2 mmol) in water (41 mL) was added ammonium chloride (1.65 g, 30.8 mmol) and ammonium hydroxide (7 N, mediate 8a (6.77 g, 30.6 mmol) in dioxane (110 mL) dropwise over 20 min. Thereaction mixture was allowed to warm to 30 °C and stirred for 72 h. Then the reaction was quenched by addition of water (150 mL), basified to pH = 12 with 1 N NaOH and extracted with MBTE (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage; 80 g Agela Silica Flash Column, gradient elution with 0-48% EtOAc / Pet.ether, flow rate = 50 mL / min) to give intermediate 8b. LC-MS: m / z 248.2 [M+H]+.

[0269] Step C: Synthesis of Intermediate 8c: To a stirred solution of intermediate 8b (3g, 12.13 mmol) in THF (81 mL) at 15 °C were added di-tert-butyl dicarbonate (4.22 mL, 18.20 mmol) and NaHCO3(2.038 g, 24.26 mmol). The resulting mixture was stirred at 15 °C for 40 h, then quenched with water (100 mL) and extracted with EtOAc (80 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage; 40 g Agela Silica Flash Column, gradient elution with 0-45% EtOAc / Pet. ether, flow rate = 40 mL / min) to give intermediate 8c. LC-MS: m / z 348.2 [M+H]+.

[0270] Step D: Synthesis of Intermediate 8d: To a stirred solution of intermediate 8c (4 g, 11.51 mmol) in MeOH (88 mL) at 0 °C were added di-tert-butyl dicarbonate (5.03 g, 23.03 mmol) and nickel (II) chloride hexahydrate (0.274 g, 1.151 mmol). Then sodium borohydride (3.05 g, 81 mmol) was added portion wise over a period of 1 h. The resulting mixture was stirred at 15 °C for 16 h, then quenched by the slow addition of isopropanol (25 mL) and water (120 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 20 minutes, then filtered through a pad of CeliteTMand washed with DCM (100 mL × 3) and water (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage; 40 g Agela Silica Flash Column, gradient elution with 0-50% EtOAc / Pet. ether flow rate = 40 mL / min) to give intermediate 8d. LC-MS: m / z 452.2 [M+H]+.

[0271] Step E: Synthesis of Intermediates 8e-1 and 8e-2: The enantiomers of intermediate 8d (4.08 g, 9.04 mmol) were separated by SFC (DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm); Condition: 0.1% NH3·H2O / EtOH; Begin B 35%, End B 35%; Flow Rate (mL / min) 200; Injections 200) to give intermediate 8e-1 (the first eluting isomer, LC-MS m / z: 452.2 [M+H]+) and intermediate 8e-2 (the second eluting isomer, LC-MS: m / z 452.2 [M+H]+).

[0272] Step F: Synthesis of Intermediate 8f-1: A solution of intermediate 8e-1 (0.9 g, 1.993 mmol) in a solution of 4 N HCl in 1,4-dioxane (14 mL) was stirred at 25 °C for 1 h. Then thereaction mixture was concentrated under reduced pressure to give crude intermediate 8f-1, which was used in the next step without further purification. LC-MS: m / z 252.2 [M+H]+.

[0273] Step G: Synthesis of Intermediate 8g-1: To a solution of intermediate 3c (371 mg, 0.796 mmol) and intermediate 8f-1 (200 mg, 0.796 mmol) in EtOH (16 mL) stirred at 15 °C were added acetic acid (0.182 mL, 3.18 mmol) and potassium acetate (234 mg, 2.387 mmol) sequentially. The reaction mixture was stirred at 85 °C for 2 h. After cooling to ambient temperature, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by reverse-phase MPLC (Biotage; 20 g Agela C18, 20~35 μm, gradient elution with 0 - 47% MeCN / H2O (with 0.5% TFA) flow rate = 50 mL / min) to give intermediate 8g-1. LC-MS: m / z 653.3 [M+H]+.

[0274] Step H: Synthesis of Intermediate 8h-1: To a solution of intermediate 8g-1 (250 mg, 0.383 mmol) in DCM (3.8 mL) stirred at 0 °C was added 33% HBr in acetic acid (491 mg, 1.149 mmol). The reaction was stirred at 15 °C for 1 h. Then the reaction mixture was concentrated under vacuum. The resulting residue was triturated with cold MTBE (5 mL). The resulting solid was collected by filtration to give intermediate 8h-1, which was used in the next step without further purification. LC-MS: m / z 363.2 [M+H]+.

[0275] Step I: Synthesis of Compound 4: To a solution of intermediate 8h-1 (139 mg, 0.384 mmol) in DMA (3.8 mL) were added 4Å molecular sieves (60 mg) and intermediate 5 (140 mg, 0.384 mmol). The reaction was stirred at 28 °C for 16 h, then filtered and the filtrate was diluted with DMA (3 mL). The resulting solution was purified by reverse-phase HPLC (Boston Uni C18 40 × 150 × 5μm; Condition: water (0.1% TFA)-ACN; Begin B 0, End B 30; Gradient Time (min) 10; 100% B Hold Time (min) 2; Flow Rate (mL / min) 60; Injections 1) to give compound 4 as the TFA salt. The TFA salt was then dissolved in water (5 mL), and purified by reverse-phase HPLC (Welch Xtimate C18150 × 25mm × 5μm; Condition: water (0.225% FA)-ACN; Begin B 0, End B 18; Gradient Time(min) 15; 100%B Hold Time(min) 2; Flow Rate (mL / min) 25; Injections 2) and lyophilized to give compound 4 as the formic acid salt. LC-MS: m / z 709.3 [M+H]+.1H NMR (400 MHz, D2O + MeCN) δ: 7.49 - 7.38 (m, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.80 (br s, 1H), 4.60 - 4.31 (m, 3H), 4.07 (t, J = 11.5 Hz, 1H), 3.72 - 3.57 (m, 1H), 3.18 - 2.97 (m, 2H), 2.70 - 2.85 (m, 2H), 2.65 (s, 3H), 1.97 - 2.15 (m, 3H), 1.59 - 1.79 (m, 1H), 1.49 (s, 3H), 1.39 (s, 3H), 1.19 (s, 3H).

[0276] Compound 5 was prepared from intermediate 8e-2 using the method described in Steps F to I of Example 8. LC-MS: m / z 709.2 [M+H]+.1H NMR (500 MHz, D2O + MeCN) δ: 7.52 - 7.43 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.79 (s, 1H), 4.46 - 4.35 (m, 3H), 4.08 (t, J = 11.4 Hz,1H), 3.64 (dd, J = 7.4, 11.5 Hz, 1H), 3.15 - 2.96 (m, 2H), 2.85 - 2.73 (m, 2H), 2.63 (s, 3H), 2.10 - 1.99 (m, 3H), 1.78 - 1.67 (m, 1H), 1.48 (s, 3H), 1.40 (s, 2H), 1.22 (s, 3H). EXAMPLE 9: Preparation of Compounds 6 and 7 (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-(3-(methylamino)propyl)-4,5-dihydro- 1H-imidazol-2-yl)chroman-2-yl)propanoic acid and (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)- 2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6- ((R)-5-(3-(methylamino)propyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid

[0277] Compounds 6 and 7 were prepared from benzyl methyl(4-oxobutyl)carbamate using the method described in Steps B to I of Example 8.

[0278] Compound 6: LC-MS: m / z 723.2 [M+H]+.1H NMR (400 MHz, D2O + MeCN) δ: 7.50 - 7.45 (m, 2H), 6.90 (d, J = 8.9 Hz, 1H), 6.80 (s, 1H), 4.53 (s, 1H), 4.38 - 4.27 (m, 2H), 4.03 (t, J = 11.3 Hz, 1H), 3.62 - 3.55 (m, 1H), 3.01 - 2.90 (m, 2H), 2.85 - 2.70 (m, 2H), 2.59 (s, 3H), 2.10 - 2.01 (m, 1H), 1.77 - 1.59 (m, 5H), 1.48 (s, 3H), 1.40 (s, 3H), 1.22 (s, 3H).

[0279] Compound 7: LC-MS: m / z 723.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.53 - 7.45 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H), 4.51 (s, 1H), 4.44 - 4.40 (m, 1H), 4.32 - 4.29 (m, 1H), 4.02 (t, J = 11.4 Hz, 1H), 3.63 - 3.55 (m, 1H), 2.99 - 2.92 (m, 2H), 2.81 - 2.74 (m, 2H), 2.59 (s, 3H), 2.13 - 2.03 (m, 1H), 1.75 - 1.65 (m, 5H), 1.48 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H). EXAMPLE 10: Preparation of Compounds 8 and 9 (S)-2-((R)-6-((S)-5-(3-aminopropyl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid and (S)-2-((R)-6-((R)-5-(3-aminopropyl)-5-methyl-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl- 4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[0280] Compounds 8 and 9 were prepared from benzyl (4-oxopentyl)carbamate using the method described in Steps B to I of Example 8.

[0281] Compound 8: LC-MS: m / z 723.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.50 - 7.43 (m, 2H), 6.90 (d, J = 8.6 Hz, 1H), 6.78 (s, 1H), 4.55 (s, 1H), 4.42 (d, J = 11.0 Hz, 1H), 3.75 (d, J = 11.6 Hz, 1H), 3.64 (d, J = 12 Hz, 1H), 2.90 (t, J = 7.0 Hz, 2H), 2.81 - 2.70 (m, 2H), 2.12 - 2.05 (m, 1H), 1.75 - 1.53 (m, 5H), 1.48 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H), 1.23 (s, 3H).

[0282] Compound 9: LC-MS: m / z 723.2 [M+H]+.1H NMR 505266-0170-001 (400 MHz, D2O + CD3CN) δ: 7.50 - 7.43 (m, 2H), 6.90 (d, J = 8.6 Hz, 1H), 6.78 (s, 1H), 4.55 (s, 1H), 4.41 (d, J = 9.6 Hz, 1H), 3.75 (d, J = 11.6 Hz, 1H), 3.64 (d, J = 12 Hz, 1H), 2.97 - 2.85 (m, 2H), 2.85 - 2.67 (m, 2H), 2.14 - 2.05 (m, 1H), 1.77 - 1.52 (m, 5H), 1.48 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H),1.23 (s, 3H). EXAMPLE 11: Preparation of Compounds 10 to 13 (S)-2-((R)-6-((S)-5-((R)-2-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)- 1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6-((R)-5-((R)-2-aminopropyl)-4,5-dihydro- 1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6-((R)-5- ((S)-2-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4- yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid, and (S)-2-((R)-6-((S)-5-((S)-2-aminopropyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl- 4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[0283] Step A: Synthesis of Intermediate 9a: To a solution of tert-butyl (4-oxobutan-2- yl)carbamate (2.7 g, 14.42 mmol) in DCM (145 mL) were added phenylmethanamine (1.733 mL, 15.86 mmol) and MgSO4(17.36 g, 144 mmol). The resulting mixture was stirred at 20 °C for 2 h. Then the resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in DCM (145 mL), followed by the addition of trimethylsilane-carbonitrile (3.85 mL, 28.8 mmol). The reaction was stirred at 25 °C for 1.5 h, then added to saturated aqueous NaHCO3(300 mL), and extracted with DCM (50 mL × 2). The organic layers were combined, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column, gradient elution with 0 - 18% EtOAc / Pet. ether, flow rate = 35 mL / min) to give intermediate 9a.1H NMR (400 MHz, CD3OD) δ: 7.49 - 7.18 (m, 5H), 4.05 - 3.95 (m, 1H), 3.92 - 3.73 (m, 2H), 3.65 - 3.55 (m, 1H), 1.91 - 1.83 (m, 2H), 1.42-1.40 (m, 9H), 1.12 (br d, J = 6.8 Hz, 3H).

[0284] Step B: Synthesis of Intermediate 9b: To a suspension of LiAlH4 (0.610 g, 16.07 mmol) in ethyl ether (40 mL) stirred at -10 °C under argon, was added dropwise a solution of intermediate 9a (2.43 g, 8.01 mmol) in ethyl ether (12 mL). The resulting mixture was stirred at - 10 °C for 1 h, then quenched by adding water (0.61 mL), 15% NaOH (0.61 mL) and water (1.22 mL) sequentially. The resulting mixture was stirred for 10 minutes and then filtered. The filter cake was rinsed with MeOH, and the filtrate was concentrated under reduced pressure to give crude intermediate 9b, which was used in the next step without further purification. LC-MS: m / z 308.2 [M+H]+.

[0285] Step C: Synthesis of Intermediate 9c: To a solution of intermediate 9b (2.46 g, 8 mmol) in MeOH (60 mL) was added acetic acid (2.403 g, 40.0 mmol), followed by 10 weight % palladium on carbon (0.850 g, 0.799 mmol). The mixture was stirred at 25 °C under H2(15 psi) for 16 h, then filtered. The filtrate was concentrated in vacuo to give intermediate 9c, which was used in the next step without further purification.NMR (400 MHz, CD3OD) δ: 3.81 - 3.61 (m, 1H), 3.28 - 3.19 (m, 1H), 3.18 - 3.03 (m, 1H), 3.01 - 2.90 (m, 1H), 1.74 - 1.58 (m, 2H), 1.45 (s, 9H), 1.22 - 1.13 (m, 3H)

[0286] Step D: Synthesis of Intermediate 9d: To a solution of intermediate 3c (2.0 g, 4.29 mmol) and intermediate 9c (2.6 g, 4.43 mmol) in EtOH (56 mL) stirred at 20 °C were added AcOH (1.014 mL, 17.71 mmol) and potassium acetate (1.303 g, 13.28 mmol) sequentially. The reaction was stirred at 85 °C for 2 h, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by reverse-phase MPLC (Biotage; 20 g Agela, C18, 20~35 μm, gradient elution with 0 - 52% MeCN / H2O (0.5% TFA), flow rate = 50 mL / min) to give intermediate 9d. LC-MS: m / z 619.4 [M+H]+.

[0287] Step E: Synthesis of Intermediates 9e-1, 9e-2, 9e-3, and 9e-4: The four diastereomers of intermediate 9d (1.7 g, 2.75 mmol) were separated by running the fractions through two SFCs as provided below. The first SFC (DAICEL CHIRALPAK IC 250 mm × 30 mm,10 μm; Condition: 0.1% NH3·H2O / MeOH; Begin B 30, End B 30; FlowRate (mL / min) 80; Injections 370) afforded two fractions, each containing a mixture of two diastereomers:

[0288] Fraction 1 (first eluting peak; 500 mg, 0.808 mmol) was further separated using SFC (DAICEL CHIRALCEL OD-H 250 mm × 30 mm, 5 μm; Condition: 0.1% NH3·H2O / EtOH; Begin B 15%, End B 15%; FlowRate (mL / min) 60; Injections 750) to give intermediate 9e-1 (the first eluting stereoisomer, LC-MS: m / z 619.5 [M+H]+) and intermediate 9e-2 (the second eluting stereoisomer, LC-MS: m / z 619.3 [M+H]+).

[0289] Fraction 2 (second eluting peak; 700 mg, 1.131 mmol) was further separated using SFC (DAICEL CHIRALPAK IC 250 mm × 30 mm,10 μm; Condition: 0.1% NH3·H2O / MeOH; Begin B 30, End B 30; FlowRate (mL / min) 80; Injections 180) to give intermediate 9e-3 (the first eluting stereoisomer, LC-MS: m / z 619.8 [M+H]+) and intermediate 9e-4 (the second eluting stereoisomer, LC-MS: m / z 619.6 [M+H]+).

[0290] Step F: Synthesis of Intermediate 9f-1: A solution of intermediate 9e-1 (165 mg, 0.267 mmol) in TFA (2.0 mL, 26.9 mmol) was stirred at 40 °C for 1.5 h. Then the reaction mixture was concentrated in vacuo to give crude intermediate 9f-1, which was used in the next step without further purification. LC-MS: m / z 363.2 [M+H]+.

[0291] Step G: Synthesis of Compound 10: To a solution of intermediate 9f-1 (97 mg, 0.268 mmol) in DMA (2.0 mL) were added 4Å molecular sieves (10 mg) and intermediate 5 (96 mg, 0.262 mmol). The reaction was stirred at 28 °C for 16 h, then filtered. The filtrate was diluted with MeOH (1.5 mL) and purified by reverse-phase HPLC (Boston Uni C1840 × 150 *5 μm; Condition: water (0.1% TFA)-ACN; Begin B 0, End B 30; Gradient Time (min) 10; 100% B Hold Time (min) 2; FlowRate (mL / min) 60; Injections 1) to give compound 10 as the TFA salt. This material was further purified by reverse-phase HPLC (Welch Xtimate C18150 × 25 mm × 5 μm; Condition: water (0.225% FA)-ACN; Begin B 0, End B 18; Gradient Time (min) 15; 100% B Hold Time (min) 2; FlowRate (mL / min) 25; Injections 2) to give compound 10 as the formic acid salt. LC-MS: m / z 709.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.53 - 7.43 (m, 2H), 6.88 (d, J = 8.6 Hz, 1H), 6.78 (s, 1H), 4.54 (s, 1H), 4.45 - 4.41 (m, 2H), 4.15 - 4.02 (m, 1H), 3.66 - 3.57 (m, 1H), 3.53 - 3.38 (m, 1H), 2.81 - 2.68 (m, 2H), 2.14 - 2.05 (m, 1H), 1.98 - 1.95 (m, 1H), 1.88 - 1.80 (m, 1H), 1.80 - 1.61 (m, 1H), 1.49 (s, 3H), 1.41 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H), 1.23 (s, 3H).

[0292] Compounds 11 to 13 were prepared from the corresponding intermediates 9e-2, 9e-3, and 9e-4 using the procedure described in Steps F to G of Example 11.

[0293] Compound 11 (from intermediate 9e-2): LC-MS: m / z 709.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.52 - 7.45 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H), 4.50 (s, 1H), 4.43 - 4.35 (m, 2H), 4.09 (t, J = 11.2 Hz, 1H), 3.67 - 3.58 (m, 1H), 3.50-3.40 (m, 1H), 2.85 - 2.70 (m, 2H), 2.13 - 2.02 (m, 2H), 1.88 - 1.77 (m, 1H), 1.74 - 1.60 (m, 1H), 1.47 (s, 3H), 1.41 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H), 1.23 (s, 3H).

[0294] Compound 12 (from intermediate 9e-3): LC-MS: m / z 709.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.53 - 7.45 (m, 2H), 6.91 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H), 4.54 (s, 1H), 4.44 - 4.42 (m, 1H), 4.39 - 4.37 (m, 1H), 4.07 (t, J = 11.3 Hz, 1H), 3.69 - 3.54 (m, 1H), 3.47 - 3.33 (m, 1H), 2.86 - 2.72 (m, 2H), 2.11 - 2.05 (m, 1H), 2.01 - 1.97 (m, 2H), 1.79 - 1.62 (m, 1H), 1.49 (s, 3H), 1.41 (s, 3H), 1.27 (d, J = 6.7 Hz, 3H), 1.23 (s, 3H).

[0295] Compound 13 (from intermediate 9e-4): LC-MS: m / z 709.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.43 - 7.36 (m, 2H), 6.83 (d, J = 8.3 Hz, 1H), 6.78 (s, 1H), 4.46 (s, 1H), 4.45 - 4.36 (m, 2H), 4.07 (t, J = 11.3 Hz, 1H), 3.66 - 361 (m, 1H), 3.49 - 3.40 (m, 1H), 2.75 - 2.72 (m, 2H), 2.10 - 2.00 (m, 1H), 2.00 - 1.96 (m, 2H), 1.73 - 1.62 (m, 1H), 1.50 (s, 3H), 1.39 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H), 1.21 (s, 3H). EXAMPLE 12: Preparation of Compound 14(2S)-2-((2R)-6-(5-(3-aminopropyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2-((((Z)-1- (2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid

[0296] Step A: Synthesis of Intermediate 10a: To a solution of tert-butyl allylcarbamate (1626 mg, 10.34 mmol) in THF (40 mL) was added 9-BBN (0.5 M in THF) (26.9 mL, 13.44 mmol) under N2. The reaction was stirred at 25 °C for 3 hours. Then a solution of 5-bromo-2- chloropyrimidine (2000 mg, 10.34 mmol) in THF (26 mL) was added to the reaction, followed by Pd(Ph3P)4 (597 mg, 0.517 mmol), and then a solution of NaOH (1241 mg, 31.0 mmol) in water (13 mL). The reaction mixture was stirred at 50 °C for 12 h, then cooled to ambient temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (50 mL × 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column, gradient elution with 0-23% EtOAc / Pet. ether, flow rate = 40 mL / min) to give intermediate 10a. LC-MS: m / z 272.0 [M+H]+.

[0297] Step B: Synthesis of Intermediate 10b: To a stirred suspension of intermediate 2c (1500 mg, 2.89 mmol), intermediate 10a (863 mg, 3.18 mmol), a solution of K3PO4 (1839 mg, 8.66 mmol) in dioxane (22.4 mL), and H2O (5.6 mL) was added Pd(dppf)Cl2·DCM (354 mg, 0.433 mmol) at 25 °C under N2. The reaction was stirred at 100 °C for 12 h, then cooled to ambient temperature. Then water (50 mL) was added, and the resulting mixture was extracted with EtOAc (30 mL × 3). The organic layers were combined, washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (ISCO; 20 g Agela Silica Flash Column, gradientelution with 0 - 22% EtOAc / Pet. ether, flow rate = 35 mL / min) to give intermediate 10b. LC- MS: m / z 629.3 [M+H]+.

[0298] Step C: Synthesis of Intermediate 10c: To a stirred solution of intermediate 10b (1.14 g, 1.813 mmol) in 5% formic acid in MeOH (v / v) (40 mL) was added 10% wt. Pd-C (1.1 g, 1.034 mmol). The reaction mixture was stirred at 25 °C for 12 h, then filtered. The filtrate was concentrated under vacuum to give crude intermediate 10c, which was used in the next step without further purification. LC-MS: m / z 633.7 [M+H]+.

[0299] Step D: Synthesis of Intermediate 10d: A solution of intermediate 10c (1.1 g, 1.738 mmol) in TFA (11 mL, 143 mmol) was stirred at 40 °C for 70 min. Then the reaction mixture was concentrated under reduced pressure to give crude intermediate 10d, which was used in the next step without further purification. LC-MS: m / z 377.2 [M+H]+.

[0300] Step E: Synthesis of Compound 14: To a solution of intermediate 10d (645 mg, 1.713 mmol) in MeOH (18 mL) was added intermediate 5 (593 mg, 1.628 mmol). The reaction was stirred at 25 ºC for 12 h, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 8 mL MeOH and purified by reverse-phase HPLC (Boston Uni C1840 × 150 × 5 μm; Condition: water (with 0.1%TFA)-ACN; Begin B 0, End B 30; Gradient Time (min) 10; 100% B Hold Time (min) 2; Flow Rate (mL / min) 60; Injections 3) and lyophilized to give compound 14 as the TFA salt. This material was dissolved in water (4 mL), and purified by reverse-phase HPLC (Welch Xtimate C18150 × 25 mm × 5 μm; Condition water (0.0225% FA)-ACN; Begin B 0, End B 19; Gradient Time (min) 15; 100% B Hold Time (min) 2; Flow Rate (mL / min) 25; Injections 7) and lyophilized to give compound 14 as the formic acid salt. LC-MS: m / z 723.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.40 - 7.26 (m, 2H), 6.88 (d, J = 8.30 Hz, 1H), 6.80 (s, 1H), 4.56 (s, 1H), 4.38-4.34 (m, 1H), 3.53 (dd, J = 4.1, 13.2 Hz, 2H), 3.16 - 3.04 (m, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.82 - 2.68 (m, 2H), 2.12-1.95 (m, 2H), 1.78 - 1.57 (m, 3H), 1.48 (s, 3H), 1.41 (s, 3H), 1.41 - 1.30 (m, 2H), 1.23 (s, 3H). EXAMPLE 13: Preparation of Compound 15 (2S)-2-((2R)-6-(5-(2-aminoethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2-((((Z)-1-(2- aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid

[0301] Compound 15 was prepared from tert-butyl (2-(2-chloropyrimidin-5-yl)ethyl)carbamate using the method described in Steps B to E of Example 12. LC-MS: m / z 709.3 [M+H]+.1H NMR (400 MHz, D2O + MeCN) δ: 7.37 - 7.30 (m, 2H), 6.88 (d, J = 8.5 Hz, 1H), 6.81 (s, 1H), 4.56 (s, 1H), 4.39 (d, J = 8.9 Hz, 1H), 3.57 (dd, J = 4.6, 13.1 Hz, 2H), 3.22 - 3.12 (m, 2H), 3.06 - 2.98 (m, 2H), 2.86 - 2.72 (m, 2H), 2.18 - 2.11 (m, 1H), 2.10 - 2.14 (m, 1H), 1.75 - 1.64 (m, 3H), 1.49 (s, 3H), 1.40 (s, 3H), 1.21 (s, 3H). EXAMPLE 14: Preparation of Compounds 16 and 17 (S)-2-((R)-6-((R)-5-(3-aminopropyl)-5-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid and (S)-2-((R)-6- ((S)-5-(3-aminopropyl)-5-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid

[0302] Step A: Synthesis of Intermediate 11a: To a solution of 4- (((benzyloxy)carbonyl)amino)butanoic acid (10 g, 42.1 mmol) in THF (120 mL) stirred at 28 °C was added N,N′-carbonyldiimidazole (8.20 g, 50.6 mmol) in one portion. The resulting mixture was stirred for 3 h, then magnesium chloride (4.01 g, 42.1 mmol) and potassium 3-methoxy-3- oxopropanoate (13.17 g, 84 mmol) were added sequentially. The reaction was stirred at 28 °C for 16 h, then partitioned between MTBE (200 mL) and aqueous 1 M HCl (150 mL). The layers were separated, and the aqueous phase was extracted with MTBE (50 mL × 2). The combined organic layer was washed with saturated aqueous NaHCO3solution (80 mL), brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum to give crude intermediate 11a, which was used in the next step without further purification.1H NMR (400 MHz, CD3OD) δ: 7.39 - 7.25 (m, 5H), 5.06 (s, 2H), 3.70 - 3.68 (m, 3H), 3.51 (s, 2H), 3.18 - 3.07 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H), 1.78 - 1.70 (m, 2H).

[0303] Step B: Synthesis of Intermediate 11b: To a solution of LiBH4 (3.47 g, 159 mmol) in THF (160 mL) stirred at 0 °C, was added dropwise a solution of intermediate 11a (12.5 g, 48.2 mmol) in THF (80 mL). Then the cooling bath was removed and the reaction was stirred at 20 °C for 12 h. The reaction was then cooled in an ice bath, and 1 M aqueous hydrochloric acid (80 mL) was added dropwise. Then the reaction mixture was extracted with EtOAc (30 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (ISCO; 80 g Agela Silica Flash Column, gradient elution with 80 - 100% EtOAc / Pet. ether, flow rate = 60 mL / min) to give intermediate 11b.1H NMR (400 MHz, CD3OD) δ: 7.39 - 7.25 (m, 5H), 5.06 (s, 2H), 3.74 - 3.64 (m, 3H), 3.13 (br t, J = 6.7 Hz, 2H), 1.73 - 1.59 (m, 3H), 1.57 - 1.38 (m, 3H).

[0304] Step C: Synthesis of Intermediate 11c: To a solution of intermediate 11b (7.36 g, 27.5 mmol), 4-dimethylaminopyridine (0.505 g, 4.13 mmol), 1H-imidazole (3.75 g, 55.1 mmol) and tetra-n-butylammonium iodide (1.525 g, 4.13 mmol) in DMF (400 mL) stirred at 25 °C under N2, was added tert-butylchlorodiphenylsilane (7.88 mL, 30.3 mmol). The reaction was stirred at 25 °C for 16 h, then diluted with water (750 mL) and extracted with EtOAc (80 mL × 3). The organic layers were combined, washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (ISCO; 80 g Agela Silica Flash Column, gradient elution with 0 - 35% EtOAc / Pet. ether, flow rate = 60 mL / min) to give intermediate 11c.1H NMR (400 MHz, CD3OD) δ: 7.70 - 7.64 (m, 4H), 7.48 - 7.22 (m, 11H), 5.06 (s, 2H), 3.87 - 3.72 (m, 3H), 3.11 (t, J = 6.8 Hz, 2H), 1.77 - 1.58 (m, 3H), 1.56 - 1.35 (m, 3H), 1.03 (s, 9H).

[0305] Step D: Synthesis of Intermediate 11d: To a solution of intermediate 11c (7.35 g, 14.53 mmol) in DCM (140 mL) stirred at 28 °C was added pyridinium chlorochromate (4.70 g, 21.80 mmol) in one portion. The reaction was stirred at 28 °C for 3 h, then diluted with diisopropyl ether (30 mL), stirred for 10 minutes, and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column, gradient elution with 0 - 27% EtOAc / Pet. ether, flow rate = 35 mL / min) to give intermediate 11d.1H NMR (400 MHz, CD3OD) δ: 7.68 - 7.62 (m, 4H), 7.48 - 7.22 (m, 11H), 5.05 (s, 2H), 3.92 (t, J = 6.0 Hz, 2H), 3.14 - 3.08 (m, 2H), 2.63 (br t, J = 6.0 Hz, 2H), 2.58 - 2.47 (m, 2H), 1.77- 1.68 (m, 2H), 1.00 (s, 9H).

[0306] Step E: Synthesis of Intermediate 11e: To a solution of intermediate 11d (5.73 g, 11.38 mmol) and (S)-2-methylpropane-2-sulfinamide (2.482 g, 20.48 mmol) in THF (55 mL) was added titanium (IV) ethoxide (5.05 mL, 23.89 mmol) at 20 °C. The reaction was then stirred at 70 °C for 16 h, cooled down to ambient temperature and quenched with brine (40 mL). The mixture was stirred for 20 min, then filtered through a pad of CeliteTM. The filtrate was diluted with EtOAc (50 mL) and washed with brine (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column, gradient elution with 0 - 22% EtOAc / Pet. ether, flow rate = 30 mL / min) to give intermediate 11e. LC-MS: m / z 607.4 [M+H]+.

[0307] Step F: Synthesis of Intermediate 11f: To a solution of intermediate 11e (3.55 g, 5.85 mmol) in DCM (55 mL) stirred at 0 °C, was added trimethylsilanecarbonitrile (1.464 mL, 11.70 mmol), followed by the dropwise addition of titanium(IV) ethoxide (1.235 mL, 5.85 mmol). The reaction mixture was stirred at 25 °C for 16 h, then filtered and the filtrate was concentrated invacuo. The resulting crude product was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column, gradient elution with 27 - 33% EtOAc / Pet. ether, flow rate = 35 mL / min) to give intermediate 11f. LC-MS: m / z 634.3 [M+H]+.

[0308] Step G: Synthesis of Intermediate 11g: To a solution of intermediate 11f (1.53 g, 2.414 mmol) in MeOH (20 mL) cooled to 0 °C were added di-tert-butyl dicarbonate (1.109 mL, 4.83 mmol) and nickel (II) chloride hexahydrate (0.172 g, 0.724 mmol). Sodium borohydride (0.913 g, 24.14 mmol) was then added in several portions over a period of 1 h. The resulting mixture was stirred at 20 °C for 16 h, then cooled to 0 °C, and quenched by addition of 2-propanol (30 mL) and water (30 mL). The resulting mixture was stirred at ambient temperature for 20 minutes, then filtered through a pad of CeliteTMand washed with DCM (50 mL × 3) and water (30 mL). The organic phase of the filtrate was separated and dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 20 g Agela Silica Flash Column, gradient elution with 0 ~ 30 % EtOAc / Pet.ether, flow rate = 30 mL / min) to give intermediate 11g. LC-MS: m / z 738.4 [M+H]+.

[0309] Step H: Synthesis of Intermediate 11h-1 and 11h-2: The two diastereomers of intermediate 11g (0.75 g, 1.016 mmol) was further separated by SFC (DAICEL CHIRALPAK IC 250 mm × 30 mm, 10 μm; Condition :0.1% NH3·H2O / EtOH; Begin B 35, End B 35; FlowRate (mL / min) 50; Injections 120) to give intermediate 11h-1 (the first eluting isomer, LC-MS: m / z 738.5 [M+H]+) and intermediate 11h-2 (the second eluting isomer, LC-MS: m / z 738.5 [M+H]+).

[0310] Step I: Synthesis of Intermediate 11i-1; To a solution of intermediate 11h-1 (185 mg, 0.251 mmol) in DCM (3.0 mL) stirred at 25 °C was added dropwise HCl in dioxane (4 M, 2.0 mL). The reaction was stirred at 25 °C for 1 h, then concentrated in vacuo to give the intermediate 11i-1, which was used in the next step without further purification. LC-MS: m / z 534.3 [M+H]+.

[0311] Step J: Synthesis of Intermediate 11j-1: To a solution of intermediate 3c (111 mg, 0.238 mmol) and intermediate 11i-1 (134 mg, 0.251 mmol) in EtOH (5.3 mL) stirred at 20 °C, were added sequentially AcOH (0.057 mL, 1.004 mmol) and potassium acetate (73.9 mg, 0.753 mmol). The reaction mixture was stirred at 85 °C for 2 h, then filtered and the filtrate was concentrated in vacuo. The resulting residue was diluted with MeCN / H2O (3 mL, 1:1) and purified by reverse-phase MPLC (Biotage; 20 g Agela C18; gradient elution with 0 - 53% MeCN / H2O (with 0.05% TFA); flow rate = 50 mL / min) to give intermediate 11j-1. LC-MS: m / z 935.5 [M+H]+.

[0312] Step K: Synthesis of Intermediate 11k-1: To a solution of intermediate 11j-1 (195 mg, 0.209 mmol) in DCM (2 mL) was added 33% HBr in acetic acid (312 mg, 0.730 mmol). Thereaction was stirred at 25 °C for 1 h, then concentrated in vacuo. The resulting residue was triturated with MTBE (6 mL × 2) to give crude intermediate 11k-1, which was used in the next step without further purification. LC-MS: m / z 407.2 [M+H]+.

[0313] Step L: Synthesis of Compounds 16 and 17: To a mixture of intermediate 11k-1 (85 mg, 0.209 mmol) and 4Å molecular sieves (15 mg) in DMA (1.5 mL) was added intermediate 5 (76 mg, 0.209 mmol). The reaction was stirred at 25 °C for 16 h, then filtered. The filtrate was diluted with MeOH (1.5 mL) and purified by reverse-phase HPLC (Waters Xbridge BEH C18 100 × 25 mm × 5 μm; Condition: water (0.1% TFA)-ACN; Begin B 0, End B 20; Gradient Time (min) 14; 100% B Hold Time (min) 2; FlowRate (mL / min) 25; Injections 2) to give the title compound as the TFA salt. The TFA salt was purified by reverse-phase HPLC (Welch Xtimate C18150 × 25 mm × 5 μm; Condition: water (0.225% FA)-ACN; Begin B 0, End B 20; Gradient Time (min) 15; 100%B Hold Time (min) 2; FlowRate (mL / min) 25; Injections 1) to give the title compound as the formic acid salt. LC-MS: m / z 753.4 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.51 - 7.47 (m, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.77 (s, 1H), 4.55 (s, 1H), 4.46 - 4.39 (m, 1H), 3.85 (d, J = 12.0 Hz, 1H), 3.73 (d, J = 12.0 Hz, 1H), 3.70 - 3.56 (m, 2H), 2.93 - 2.87 (m, 2H), 2.85 - 2.73 (m, 2H), 2.13 - 2.03 (m, 1H), 1.97 - 1.95 (m, 2H), 1.77 - 1.64 (m, 4H), 1.62 - 1.52 (m, 1H), 1.48 (s, 3H), 1.41 (s, 3H), 1.24 (s, 3H).

[0314] Compound 17 was prepared from intermediate 11h-2 using the method described in Steps I to L of Example 14. LC-MS: m / z 753.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.54 - 7.45 (m, 2H), 6.91 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H), 4.56 (s, 1H), 4.42 (d, J = 9.7 Hz, 1H), 3.84 (d, J = 12.0 Hz, 1H), 3.73 (d, J = 12.0 Hz, 1H), 3.68 - 3.55 (m, 2H), 2.94 - 2.87 (m, 2H), 2.87 - 2.70 (m, 2H), 2.11 - 2.02 (m, 1H), 2.00 - 1.95 (m, 2H), 1.77 - 1.65 (m, 4H), 1.62 - 1.54 (m, 1H), 1.48 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H). EXAMPLE 15: Preparation of Compounds 18 and 19 (S)-2-((R)-6-((R)-5-((S)-2-amino-1-hydroxyethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)- 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid and (S)-2-((R)-6-((R)-5-((R)-2-amino-1-hydroxyethyl)- 4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2- dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[0315] Step A: Synthesis of Intermediate 12a: To a solution of tert-butyl (S)-2,2-dimethyl-4- vinyloxazolidine-3-carboxylate (7.0 g, 30.8 mmol) in CHCl3(140 mL) was added 3- chloroperoxybenzoic acid (18 g, 89 mmol) under N2. The reaction was stirred at 20 °C for 18 h, then diluted with 10% aqueous sodium thiosulfate solution (350 mL) and stirred vigorously for 5 minutes. The mixture was extracted with DCM (2 × 70 mL). The organic layers were combined. washed with saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL, then dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, gradient elution with 0-8% ethyl acetate / petroleum ether, flow rate = 50 mL / min) to give intermediate 12a.1H NMR (400 MHz, CDCl3) δ: 4.12 - 3.95 (m, 2H), 3.63 - 3.37 (m, 1H), 3.02 (br s, 1H), 2.91 (br s, 1H), 2.75 (br d, J = 3.7 Hz, 1H), 1.63 (br d, J = 19.3 Hz, 3H), 1.52 - 1.46 (m, 12H).

[0316] Step B: Synthesis of Intermediate 12b; To a solution of intermediate 12a (5 g, 20.55 mmol) in MeOH (100 mL) stirred at 25 °C, was added 27% aqueous ammonium hydroxide solution (30 mL, 198 mmol). The reaction was stirred for 16 h at 85 °C, then concentrated invacuo to give intermediate 12b, which was used in the next step without further purification.1H NMR (400 MHz, CD3OD) δ: 4.06 (br d, J = 8.6 Hz, 1H), 4.01 - 3.82 (m, 2H), 3.81 - 3.55 (m, 1H), 2.81 - 2.57 (m, 2H), 1.54 (br s, 3H), 1.52 - 1.48 (m, 12H)

[0317] Step C: Synthesis of Intermediate 12c: To a solution of intermediate 12b (5.35 g, 20.55 mmol) in DCM (140 mL) was added triethylamine (14 mL, 100 mmol). The mixture was stirred at 0 °C for 5 minutes, then benzylchloroformate (5.8 mL, 40.6 mmol) was added at 0 °C. The reaction was stirred at 25 °C for 3 h, then diluted with H2O (200 mL), and extracted with DCM (50 mL × 3). The organic layers were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column, gradient elution with 0-35% EtOAc / Pet. ether, flow rate = 40 mL / min) to give intermediate 12c.1H NMR (400 MHz, CD3OD) δ: 7.41 - 7.23 (m, 5H), 5.16 - 5.01 (m, 2H), 4.05 (br d, J = 8.6 Hz, 1H), 3.95 - 3.66 (m, 2H), 3.40 (br d, J = 11.7 Hz, 1H), 3.24 (br s, 1H), 3.01 (br s, 1H), 1.61 - 1.52 (m, 3H), 1.49 (br s, 12H).

[0318] Step D: Synthesis of Intermediates 12d-1 and 12d-2: The two diastereomers of intermediate 12c (5.5 g, 13.94 mmol) were separated by SFC (DAICEL CHIRALPAK AD, 250 mm × 50 mm, 10 μm; Condition: 0.1% NH3·H2O / IPA; Begin B 20%, End B 20%; FlowRate (mL / min) 200; Injections 210) to give intermediate 12d-1 (the first eluting stereoisomer, LC-MS: m / z 417.1 [M+23]+) and intermediate 12d-2 (the second eluting stereoisomer, LC-MS: m / z 417.1 [M+23]+).

[0319] Step E: Synthesis of Intermediate 12e-1: To a solution of intermediate 12d-1 (2.1 g, 5.32 mmol) in DCM (45 mL) stirred at -65oC, was added triethylamine (2.97 mL, 21.29 mmol), followed by tert-butyldimethylsilyl trifluoromethanesulfonate (2.447 mL, 10.65 mmol). The reaction was stirred at -65 °C for 2.5 h, then warmed to ambient temperature, quenched with H2O (100 mL) and extracted with DCM (25 mL x 2). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column; gradient elution with 0-12% Pet.ether / EtOAc; flow rate = 30 mL / min) to afford intermediate 12e-1. LC- MS: m / z 509.2 [M+H]+.

[0320] Step F: Synthesis of Intermediate 12f-1: A mixture of intermediate 12e-1 (1.90 g, 3.73 mmol), cerium (III) chloride (3.15 g, 12.78 mmol) and oxalic acid (0.034 g, 0.373 mmol) in acetonitrile (29 mL) was stirred at 20 °C for 4 h. Then the reaction was filtered, and the filtrate was cooled at 0 °C, and quenched by the addition of saturated aqueous NaHCO3solution (100 mL). The resulting mixture was stirred at 0 °C for 10 minutes, then extracted with EtOAc (40 mL× 3). The organic layers were combined and washed with brine (150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO; 20 g Agela Silica Flash Column, gradient elution with 0- 20% EtOAc / Pet. ether, flow rate = 30 mL / min) to give intermediate 12f-1. LC-MS: m / z 469.2 [M+H]+.

[0321] Step G: Synthesis of Intermediate 12g-1: To a solution of intermediate 12f-1 (1.24 g, 2.65 mmol) and triethylamine (1.291 mL, 9.26 mmol) in THF (18 mL) stirred at 0 °C, was added dropwise methanesulfonyl chloride (0.628 mL, 8.12 mmol). The mixture was stirred at 20 °C for 1.5 h, then diluted with ice cold water (50 mL) and extracted with EtOAc (15 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give crude intermediate 12g-1, which was used in the next step without further purification. LC-MS: m / z 547.2 [M+H]+.

[0322] Step H: Synthesis of Intermediate 12h-1: To a stirred solution of intermediate 12g-1 (1.44 g, 2.63 mmol) in DMF (17 mL) was added sodium azide (0.470 g, 7.23 mmol) at 20 °C. The reaction mixture was warmed to 75 °C, stirred for 16 h, then cooled to 20 °C and quenched with H2O (80 mL). The mixture was basified to pH>9 with saturated aqueous NaHCO3, then stirred at ambient temperature for 10 minutes and extracted with EtOAc (15 mL × 3). The organic layers were combined, washed with brine (40 mL × 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum at 25 °C to give intermediate 12h-1, which was used in the next step without further purification. LC-MS: m / z 494.2 [M+H]+.

[0323] Step I: Synthesis of Intermediate 12i-1: To a stirred solution of intermediate 12h-1 (1.3 g, 2.63 mmol) in H2O (1.5 mL) and THF (15 mL) was added triphenylphosphine (1.243 g, 4.74 mmol) portionwise at 25 °C. The reaction was stirred at for 2.5 h, then concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (YMC-Actus Triart C18150 × 30 mm × 5 μm; Condition: water (TFA) –ACN; Begin B 57, End B 87; Gradient Time (min) 10.5; 100% B Hold Time (min) 1.5; FlowRate (mL / min) 40; Injections 15) to give intermediate 12i-1. LC- MS: m / z 468.5 [M+H]+.

[0324] Step J: Synthesis of Intermediate 12j-1: A solution of intermediate 12i-1 (130 mg, 0.278 mmol) in 5:1 DCM / TFA (4 mL) was stirred at 20 °C for 1.5 h. Then the reaction mixture was concentrated in vacuo to give intermediate 12j-1, which was used in the next step without further purification. LC-MS: m / z 368.2 [M+H]+.

[0325] Step K: Synthesis of Intermediate 12k-1: To a stirred solution of intermediate 3c (129 mg, 0.278 mmol) and intermediate 12j-1 (102 mg, 0.278 mmol) in EtOH (5.5 mL) were added AcOH (0.064 mL, 1.110 mmol) and potassium acetate (82 mg, 0.833 mmol) sequentially at 20°C. The reaction mixture was stirred at 85 °C for 1.5 h, then cooled to ambient temperature, and filtered. The filtrate was concentrated in vacuo. The resulting residue was diluted with 1:1 MeCN / H2O (4 mL) and purified by reverse-phase MPLC (Biotage; 20 g Agela, C18, 20~35 μm, gradient elution with 0-70% MeCN / H2O (with 0.5% TFA) flow rate = 50 mL / min) to give intermediate 12k-1. LC-MS: m / z 769.4 [M+H]+.

[0326] Step L: Synthesis of Intermediate 12l-1; To a solution of intermediate 12k-1 (190 mg, 0.247 mmol) in DCM (2.5 mL) was added 33% HBr in acetic acid (370 mg, 0.866 mmol). The reaction was stirred at 20 °C for 1 h, then concentrated in vacuo. The resulting residue was triturated with ice-cold MTBE (8 mL × 2) to give crude intermediate 12l-1, which was used in the next step without further purification. LC-MS: m / z 365.2 [M+H]+.

[0327] Step M: Synthesis of Compounds 18 and 19: To a solution of intermediate 12l-1 (90 mg, 0.247 mmol) in DMA (1.5 mL) was added intermediate 5 (85 mg, 0.235 mmol). The reaction was stirred at 25 °C for 16 h, then diluted with MeOH (1.5 mL). The resulting mixture was purified by reverse-phase HPLC (Boston Uni C1840 × 150 × 5 μm; Condition: water (TFA)- ACN; Begin B 0, End B 30; Gradient Time (min) 10; 100% B Hold Time (min) 2; FlowRate (mL / min) 60; Injections: 1) to give compound 18 as the TFA salt. The TFA salt was dissolved in H2O (2 mL) and purified by reverse-phase HPLC (Welch Xtimate C18150 × 25 mm × 5 μm; Condition: water (0.225% FA)-ACN; Begin B 0, End B 18; Gradient Time (min) 15; 100% B Hold Time (min) 2; FlowRate (mL / min) 25; Injections 2) to give compound 18 as the formic acidsalt. LC-MS: m / z 711.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.52 - 7.47 (m, 2H),6.91 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H), 4.52 (s, 1H), 4.44 - 4.39 (m, 1H), 4.32 - 4.20 (m, 1H), 4.05 (t, J = 11.7 Hz, 1H), 3.92 - 3.86 (m, 1H), 3.83 - 3.75 (m, 1H), 3.13 - 3.07 (m, 1H), 3.05 - 2.92 (m, 1H), 2.83 - 2.72 (m, 2H), 2.10 - 2.06 (m, 1H), 1.76 - 1.62 (m, 1H), 1.48 (s, 3H), 1.41 (s, 3H), 1.24 (s, 3H).

[0328] Compound 19 was prepared from intermediate 12d-2 using the method described in Steps E to M of Example 15. LC-MS: m / z 711.2 [M+H]+.1H NMR (400 MHz,D2O + CD3CN) δ: 7.53 - 7.44 (m, 2H), 6.87 (d, J = 8.6 Hz, 1H), 6.77 (s, 1H), 4.53 (s, 1H), 4.45 - 4.29 (m, 2H), 4.07 - 3.93 (m, 2H), 3.91 - 3.83 (m, 1H), 3.17 - 3.10 (m, 1H), 2.90 - 2.78 (m, 1H), 2.78 - 2.65 (m, 2H), 2.10 - 2.02 (m, 1H), 1.75 - 1.56 (m, 1H), 1.48 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H). EXAMPLE 16: Preparation of Intermediates 13d-1 and 13d-2

[0329] Step A: Synthesis of Intermediate 13a: To a mixture of benzyl (2-methylhex-5-en-2- yl)carbamate (5 g, 20.22 mmol) and 0.02 M iron (II) trifluoromethanesulfonate in MeOH (50.5 mL, 1.011 mmol) stirred at 20 °C, were added sodium azide (1.446 g, 22.24 mmol) and O- pivaloylhydroxylammonium trifluoromethanesulfonate (13.50 g, 50.5 mmol). The reaction was stirred at 20 °C for 16 h, then quenched with water (60 mL), and the pH was adjusted with saturated aqueous Na2CO3solution (100 mL) to pH > 9. The mixture was stirred for 15 minutes, then extracted with EtOAc (50 mL × 3). The organic layers were combined, washed with brine (50 mL × 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column, 0-100% EtOAc / Pet. ether elution gradient; flow rate = 30 mL / min) to give intermediate 13a. LC-MS: m / z 306.4 [M+H]+.

[0330] Step B: Synthesis of Intermediate 13b: To a stirred solution of intermediate 13a (1.9 g, 6.22 mmol) in H2O (2 mL) and THF (20 mL) stirred at 25 °C was added triphenylphosphine (3.26 g, 12.44 mmol) portionwise. The reaction was stirred at same temperature for 2.5 h, then concentrated in vacuo. The resulting residue was dissolved in MeOH (30 mL), then stirred at 0 °C, followed by the addition of triethylamine (2.168 mL, 15.55 mmol) and di-tert-butyl dicarbonate (3.61 mL, 15.55 mmol). The reaction was warmed to 20 °C and stirred for 16 h, then concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO; 20 g Agela Silica Flash Column, 0-20% EtOAc / Pet. ether elution gradient; flow rate = 30 mL / min) to give intermediate 13b. LC-MS: m / z 502.2 [M+Na]+.1H NMR (400 MHz, CDCl3) δ: 7.44 - 7.28 (m, 5H), 5.10 - 5.00 (m, 2H), 4.92 (br s, 1H), 4.75 (br s, 1H), 3.64 - 3.46 (m, 1H), 3.18 - 3.02 (m, 2H), 1.73 (t, J = 8.2 Hz, 2H), 1.50 - 1.41 (m, 2H), 1.44 (s, 9H), 1.42 (s, 9H), 1.28 (s, 3H), 1.27 (s, 3H).

[0331] Step C: Synthesis of Intermediate 13c-1 and 13c-2: The enantiomers of intermediate 13b (2.4 g, 5.00 mmol) were separated by SFC (DAICEL CHIRALPAK IG 250 mm × 50 mm, 10 μm; Condition: 0.1% NH3·H2O / IPA; Begin B 30%, End B 30%; FlowRate (mL / min) 200; Injections: 180) to give intermediate 13c-1 (the first eluting isomer, LC-MS: m / z 480.3 [M+H]+) and intermediate 13c-2 (the second eluting isomer, LC-MS: m / z 480.3 [M+H]+).EXAMPLE 17: Preparation of Compounds 20 and 21 (S)-2-((R)-6-((S)-5-(3-amino-3-methylbutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid and (S)-2-((R)-6-((R)-5-(3-amino-3-methylbutyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl- 4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[0332] Compounds 20 and 21 were prepared from the corresponding intermediates 13c-1 and 13c-2 using the method described in Steps F to I of Example 8.

[0333] Compound 20 (from intermediate 13c-1): LC-MS: m / z 737.3 [M+H]+.1H NMR (400 MHz, D2O+CD3CN) δ 7.54 - 7.46 (m, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.78 (s, 1H), 4.55 (s, 1H), 4.45 - 4.35 (m, 1H), 4.30 - 4.25 (m, 1H), 4.03 (t, J = 11.3 Hz, 1H), 3.65 - 3.55 (m, 1H), 2.80 - 2.72 (m, 2H), 2.10 - 2.05 (m, 1H), 1.79 - 1.63 (m, 4H), 1.61 - 1.52 (m, 1H), 1.50 (s, 3H), 1.42 (s, 3H), 1.25 (s, 6H), 1.24 (s, 3H).

[0334] Compound 21 (from intermediate 13c-2): LC-MS: m / z 737.2 [M+H]+.1H NMR (400 MHz, D2O+CD3CN) δ 7.53 - 7.44 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 4.51 (s, 1H), 4.43 - 4.27 (m, 1H), 4.35 - 4.26 (m, 1H), 4.20 - 3.99 (m, 1H), 3.75 - 3.55 (m, 1H), 2.83 - 2.74 (m, 2H), 2.10 - 2.01 (m, 1H), 1.78 - 1.64 (m, 4H), 1.64 - 1.50 (m, 1H), 1.49 (s, 3H), 1.41 (s, 3H), 1.25 (s, 6H), 1.23 (s, 3H). EXAMPLE 18: Preparation of Intermediates 14d-1 to 14d-4

[0335] Step A: Synthesis of Intermediate 14a: To a solution of oxalyl chloride (6.05 mL, 77 mmol) in DCM (10 mL) stirred at -65 °C was added DMSO (11.05 mL, 156 mmol). After stirring at -65oC for 15 minutes, a solution of benzyl(4-hydroxybutan-2-yl)(methyl)carbamate (5.85 g, 24.65 mmol) in DCM (140 mL) was added. The reaction was stirred at -65oC for 1 h, and triethylamine (22.62 mL, 163 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h, then quenched with saturated aqueous NH4Cl solution (100 mL) and extracted with DCM (150 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO; 20 g Agela Silica Flash Column, 0-32% EtOAc / Pet. ether elution gradient; flow rate = 35 mL / min) to afford intermediate 14a. LC-MS: m / z 236.2 [M + H]+.

[0336] Step B: Synthesis of Intermediate 14b: To a suspension of potassium cyanide (1.19 g, 18.27 mmol) in H2O (24 mL) were added ammonium chloride (0.955 g, 17.85 mmol) and ammonium hydroxide (13.49 mL, 95 mmol). The reaction mixture was stirred at 0 °C for 15 minutes, then a solution of the intermediate 14a (4.2 g, 17.85 mmol) in dioxane (65 mL) was added dropwise over 20 min. The reaction mixture was allowed to warm to 30 °C and stirred for 16 h. Then the reaction was quenched with water (100 mL), basified with 1 M NaOH to pH = 12, and extracted with MBTE (3 × 80 mL). The combined organic layer was dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain intermediate 14b, which was used in the next step without further purification. LC-MS: m / z 262.2 [M+H]+.

[0337] Step C: Synthesis of Intermediate 14c: To a solution of intermediate 14b (3.6 g, 13.78 mmol) in THF (92 mL) stirred at 20 °C were added di-tert-butyl dicarbonate (4.80 mL, 20.66 mmol) and sodium bicarbonate (2.315 g, 27.6 mmol). The resulting mixture was stirred at 20 °C for 20 h, then quenched with water (100 mL), and extracted with EtOAc (50 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, that was purified by flash silica gel chromatography (Biotage; 20 g Agela Silica Flash Column, 0-100% EtOAc / Pet.ether elution gradient; flow rate = 35 mL / min) to give intermediate 14c. LC-MS: m / z 362.1 [M+H]+.

[0338] Step D: Synthesis of Intermediates 14d-1 to 14d-4: To a solution of intermediate 14c (3.2 g, 8.85 mmol) in MeOH (70 mL) stirred at 0 °C were added di-tert-butyl dicarbonate (4.07 ml, 17.71 mmol) and nickel (II) chloride hexahydrate (0.210 g, 0.885 mmol). Then sodium borohydride (2.345 g, 62.0 mmol) was added in several portions over 1 h. The reaction was stirred at 15 °C for 1 h, then quenched by the slow addition of IPA (100 mL), followed by water (50 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 20 minutes, then filtered through a CeliteTMpad. The CeliteTMpad was rinsed with DCM (150 mL × 3) and water(10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give a residue, that was purified by flash silica gel chromatography (Biotage; 20 g Agela Silica Flash Column, gradient elution with 0-100% EtOAc / Pet.ether; flow rate = 35 mL / min) to give two fractions, each containing a mixture of 2 isomers.

[0339] Fraction 1 (the first eluting fraction) was further separated by chiral SFC (DAICEL CHIRALCEL OD (250 mm × 50 mm, 10 μm); Condition: 0.1% NH3·H2O / IPA; Begin B 15%, End B 15%; Flow Rate (mL / min) 200; Injections 120) to give intermediate 14d-1 (the first eluting stereoisomer, LC-MS: m / z 466.2 [M+H]+) and intermediate 14d-2 (the second eluting stereoisomer, LC-MS: m / z 466.3 [M+H]+).

[0340] Fraction 2 (the second eluting fraction) was further separated by chiral SFC (DAICEL CHIRALCELOD (250 mm × 50 mm, 10 μm); Condition: 0.1% NH3·H2O / IPA; Begin B 15%, End B 15%; FlowRate (mL / min) 200; Injections 120) to give intermediate 14d-3 (the first eluting stereoisomer, LC-MS: m / z 466.3 [M+H]+) and intermediate 14d-4 (the second eluting stereoisomer, LC-MS: m / z 466.3 [M+H]+). EXAMPLE 19: Preparation of Compounds 22 to 25 (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-((R)-2-(methylamino)propyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid, (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2- (((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)- 6-((R)-5-((R)-2-(methylamino)propyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid, (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((R)-5-((S)-2-(methylamino)propyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid, and (S)-2-((((Z)-1-(2-aminothiazol-4- yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2- ((R)-6-((S)-5-((S)-2-(methylamino)propyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2- yl)propanoic acid

[0341] Compounds 22 to 25 were prepared from the corresponding intermediates 14d-1 to 14d- 4 using the method described in Steps F to I of Example 8.

[0342] Compound 22 (from intermediate 14d-1): LC-MS: m / z 723.2 [M+H]+.1H NMR (400 MHz, DMSO_d6 + D2O) δ: 7.59 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 4.55 (s, 1H), 4.46 - 4.31 (m, 2H), 4.10 (t, J = 11.3 Hz, 1H), 3.63 - 3.51 (m, 1H), 3.40 - 3.30 (m, 1H), 2.80 - 2.65 (m, 2H), 2.50 (s, 3H), 2.36 - 1.99 (m, 2H), 1.80 - 1.66 (m, 1H), 1.57 - 1.44 (m, 1H), 1.46 (s, 3H), 1.38 (s, 3H), 1.29 - 1.17 (m, 6H).

[0343] Compound 23 (from intermediate 14d-2): LC-MS: m / z 723.2 [M+H]+.1H NMR (500 MHz, DMSO_d6 + D2O) δ: 7.60 - 7.51 (m, 2H), 6.94 (d, J = 8.7 Hz, 1H), 6.74 (s, 1H), 4.55 (s, 1H), 4.39 (d, J = 12.4 Hz, 2H), 4.09 (t, J = 11.1 Hz, 1H), 3.63 - 3.57 (m, 1H), 3.40 - 3.32 (m, 1H), 2.82 - 2.64 (m, 2H), 2.52 (s, 3H), 2.16 - 1.99 (m, 2H), 1.80 - 1.70 (m, 1H), 1.60 - 1.50 (m, 1H), 1.47 (s, 3H), 1.37 (s, 3H), 1.26 - 1.19 (m, 6H).

[0344] Compound 24 (from intermediate 14d-3 LC-MS: m / z 723.2 [M+H]+.1H NMR (400 MHz, D2O and CD3CN) δ: 7.45 - 7.37 (m, 2H), 6.84 (d, J = 8.6 Hz, 1H), 6.77 (s, 1H), 4.43 (s, 1H), 4.42 - 4.26 (m, 2H), 4.05 (t, J = 11.2 Hz, 1H), 3.72 - 3.58 (m, 1H), 3.34 - 3.21 (m, 1H), 2.83 - 2.66 (m, 2H), 2.60 (s, 3H), 2.14 - 2.03 (m, 2H), 2.01 - 1.96 (m, 1H), 1.77 - 1.60 (m, 1H), 1.50 (s, 3H), 1.39 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H), 1.20 (s, 3H).

[0345] Compound 25 (from intermediate 14d-4): LC-MS: m / z 723.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.50 - 7.43 (m, 2H), 6.90 (d, J = 8.9 Hz, 1H), 6.78 (s, 1H), 4.53 (s, 1H), 4.53 - 4.47 (m, 2H), 4.06 (t, J = 11.6 Hz, 1H), 3.17 - 3.09 (m, 1H), 3.32 - 3.20 (m, 1H), 2.84 - 2.69 (m, 2H), 2.59 (s, 3H), 2.13 - 2.03 (m, 2H), 2.01 - 1.96 (m, 1H), 1.78 - 1.60 (m, 1H), 1.47 (s, 3H), 1.41 (s, 3H), 1.28 (d, J = 6.7 Hz, 3H), 1.22 (s, 3H). EXAMPLE 20: Preparation of Intermediates 15d-1 to 15d-4

[0346] Step A: Synthesis of Intermediate 15a: A solution of 2-methylhex-5-enoic acid (10.75 g, 84 mmol) in toluene (60 mL) was treated with TEA (14.03 mL, 101 mmol) and DPPA (19.88 mL, 92 mmol). The reaction was heated at 110°C for 1 h, then cooled to 85 °C, and treated with phenylmethanol (9.59 mL, 92 mmol) and TEA (14.03 mL, 101 mmol). The reaction mixture was heated at 85 °C for 16 h, then diluted with H2O (150 mL) and extracted with EtOAc (100 × 3 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO; 120 g Agela Silica Flash Column; 0-10% EtOAc / Pet. ether elution gradient; flow rate = 70 mL / min) to give intermediate 15a.1H NMR (400 MHz, CDCl3) δ: 7.38 - 7.28 (m, 5H), 5.89 - 5.71 (m, 1H), 5.09 (s, 2H), 5.05 - 4.94 (m, 2H), 4.55 (br s, 1H), 3.75 (td, J = 6.8, 13.8 Hz, 1H), 2.16 - 2.06 (m, 2H), 1.57 - 1.46 (m, 2H), 1.15 (d, J = 6.6 Hz, 3H).

[0347] Step B: Synthesis of Intermediate 15b: To a mixture of intermediate 15a (10.7 g, 45.9 mmol) and 0.02 M solution of iron(II) trifluoromethanesulfonate in MeOH (115 mL, 2.293 mmol) stirred at 25 °C, was added sodium azide (3.30 g, 50.8 mmol) and O-pivaloylhydroxyl- ammonium trifluoromethanesulfonate (30.6 g, 115 mmol). The reaction was stirred at 25 °C for 16 h, then diluted with EtOAc (100 mL), and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient elution with Pet. ether: EtOAc = 5: 1 to 100% EtOAc) to give intermediate 15b. LC-MS: m / z 292.1 [M+H]+.

[0348] Step C: Synthesis of Intermediate 15c To a solution of intermediate 15b (13.36 g, 45.9 mmol) in MeOH (250 mL) stirred at 0 °C was added Boc2O (63.2 mL, 275 mmol) and nickel (II) chloride hexahydrate (1.090 g, 4.59 mmol). Then sodium borohydride (12.14 g, 321 mmol) was added in several portions over 1 h. The resulting mixture was stirred at 25 °C for 16 h, then quenched at 0 °C by the slow addition of water (200 mL). The resulting mixture was stirred at ambient temperature for 20 minutes, then filtered through a CeliteTMpad. The pad was further washed with EtOAc (150 mL × 3) and water (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 120 g Agela Silica Flash Column, 0-50% EtOAc / Pet.ether elution gradient; flow rate = 50 mL / min) to give intermediate 15c. LC-MS: m / z 466.2 [M+H]+.

[0349] Step D: Synthesis of Intermediates 15d-1 to 15d-4: Intermediate 15c (10.7 g, 22.98 mmol) was further separated by chiral SFC (DAICEL CHIRALPAK AD 250 mm × 50 mm, 10 μm; Condition: 0.1% NH3·H2O / EtOH; Begin B 35%, End B 35%; Flow Rate (mL / min) 200; Injections 200) to give intermediate 15d-1 (the first eluting isomer; LC-MS: m / z 466.2 [M+H]+),intermediate 15d-2 (the second eluting isomer; LC-MS: m / z 466.2 [M+H]+), and a third fraction containing a mixture of two additional stereoisomers, which were further separated by SFC (DAICEL CHIRALPAK IG 250 mm × 50 mm, 10 μm; Condition: 0.1% NH3H2O / EtOH; Begin B 35, End B 35; FlowRate (mL / min) 200; Injections 120) to give intermediate 15d-3 (the first eluting isomer; LC-MS: m / z 466.2 [M+H]+), and intermediate 15d-4 (the second eluting isomer; LC-MS: m / z 466.2 [M+H]+). EXAMPLE 21: Preparation of Compounds 26 to 29 (S)-2-((R)-6-((S)-5-((S)-3-aminobutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1- (2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6-((R)-5-((S)-3-aminobutyl)-4,5-dihydro- 1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6-((R)-5- ((R)-3-aminobutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4- yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid, and (S)-2-((R)-6-((S)-5-((R)-3-aminobutyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl- 4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[0350] Compounds 26 to 29 were prepared from the corresponding intermediate 15d-1 to 15d-4 using the method described in Steps F to I of Example 8.

[0351] Compound 26 (from intermediate 15d-1): LC-MS: m / z 723.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.52 - 7.44 (m, 2H), 6.91 (d, J = 8.5 Hz, 1H), 6.79 (s, 1H), 4.51 (s, 1H), 4.45 - 4.41 (m, 1H), 4.37 - 4.27 (m, 1H), 4.03 (t, J = 11.5 Hz, 1H), 3.66 - 3.56 (m, 1H), 3.35 - 3.22 (m, 1H), 2.85 - 2.71 (m, 2H), 2.10 - 2.01 (m, 1H), 1.78 - 1.66 (m, 3H), 1.65 - 1.57 (m, 2H), 1.48 (s, 3H), 1.40 (s, 3H), 1.24 - 1.18 (m, 6H).

[0352] Compound 27 (from intermediate 15d-2): LC-MS: m / z 723.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.54 - 7.44 (m, 2H), 6.91 (d, J = 9.2 Hz, 1H), 6.78 (s, 1H), 4.54 (s, 1H), 4.46 - 4.40 (m, 1H), 4.35 - 4.20 (m, 1H), 4.02 (t, J = 11.2 Hz, 1H), 3.65 - 3.52 (m, 1H), 3.31 - 3.22 (m, 1H), 2.82 - 2.73 (m, 2H), 2.13 - 2.04 (m, 1H), 1.76 - 1.65 (m, 4H), 1.55 - 1.51 (m, 1H), 1.49 (s, 3H), 1.41 (s, 3H), 1.24 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H).

[0353] Compound 28 (from intermediate 15d-3): LC-MS: m / z 723.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.52 - 7.44 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 4.55 (s, 1H), 4.51 - 4.41 (m, 1H), 4.35 - 4.27 (m, 1H), 4.03 (t, J = 11.1 Hz, 1H), 3.65 - 3.54 (m, 1H), 3.34 - 3.21 (m, 1H), 2.78 - 2.62 (m, 2H), 2.10 - 2.01 (m, 1H), 1.77 - 1.56 (m, 5H), 1.48 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H), 1.20 (d, J = 6.4 Hz, 3H).

[0354] Compound 29 (from intermediate 15d-4): LC-MS: m / z 723.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.51 - 7.45 (m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 6.80 (s, 1H), 4.58 (s, 1H), 4.45 - 4.40 (m, 1H), 4.37 - 4.26 (m, 1H), 4.03 (t, J = 11.4 Hz, 1H), 3.65 - 3.52 (m, 1H), 3.33 - 3.24 (m, 1H), 2.80 - 2.70 (m, 2H), 2.10 - 2.01 (m, 1H), 1.80 - 1.65 (m, 4H), 1.55 - 1.42 (m, 1H), 1.48 (s, 3H), 1.40 (s, 3H), 1.24 - 1.17 (m, 6H). EXAMPLE 22: Preparation of Intermediates 16d-1 to 16d-4

[0355] Step A: Synthesis of Intermediate 16a: To a solution of benzyl (2-hydroxypent-4-en-1- yl)carbamate (5.3 g, 22.53 mmol) in DCM (3 mL) stirred at - 65 °C, was added TEA (9.42 mL, 67.6 mmol), followed by the dropwise addition of tert-butyldimethylsilyl trifluoromethane- sulfonate (11.39 ml, 49.6 mmol). The reaction was stirred at - 65 °C for 0.5 h, then diluted with water (80 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography MPLC (ISCO®;80 g SepaFlash® Silica Flash Column, 0 ~ 5% ethyl acetate / petroleum ether elution gradient; flow rate = 56 mL / min) to give intermediate 16a. LC-MS: m / z 350.3 [M+H]+.

[0356] Step B: Synthesis of Intermediate 16b: To a mixture of intermediate 16a (4 g, 11.44 mmol) and 0.02 M iron (II) trifluoromethanesulfonate in MeOH (28.6 mL, 0.572 mmol) stirred at 25 °C, were added sodium azide (0.85 g, 13.07 mmol) and O-pivaloylhydroxylammonium trifluoromethanesulfonate (8.56 g, 32.0 mmol). The reaction mixture was stirred for 12 h at 25 °C. Then the solvent was removed under vacuum, and the resulting residue was purified by silica gel column chromatography (SiO2, petroleum ether / EtOAc = 10: 1 to 5: 1 (gradient), then DCM: MeOH = 10: 1) to give intermediate 16b. LC-MS: m / z 294.1 [M+H]+.

[0357] Step C: Synthesis of Intermediate 16c: To a solution of intermediate 16b (3 g, 10.23 mmol) in MeOH (30 mL) stirred at 0 °C, were added sequentially nickel (II) chloride hexahydrate (0.243 g, 1.023 mmol), di-tert-butyl dicarbonate (13.39 g, 61.4 mmol), and NaBH4(2.71 g, 71.6 mmol). The reaction was stirred at 25 °C for 12 h, then diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (SiO2, petroleum ether / EtOAc = 10: 1 to 5: 1 (gradient), then 100% EtOAc) to give intermediate 16c. LC-MS: m / z 490.2 [M + Na]+.1H NMR (400 MHz, CD3OD) δ: 7.42 - 7.24 (m, 5H), 5.07 (s, 2H), 3.87 - 3.61 (m, 2H), 3.24 - 2.98 (m, 4H), 1.66 - 1.56 (m, 1H), 1.55-1.35 (m, 19H).

[0358] Step D: Synthesis of Intermediates 16d-1 to 16d-4: The four stereoisomers of intermediate 16c (5 g, 10.69 mmol) were separated using 3 chiral columns sequentially: 1) SFC (DAICEL CHIRALPAK AD 250 mm × 50 mm, 10 μm; Condition: 0.1% NH3·H2O / EtOH; Begin B 50, End B 50; FlowRate (mL / min) 200; Injections 120) to give a mixed fraction containing three stereoisomers (earlier eluting fraction), and intermediate 16d-1 (the last eluting stereoisomer), LC-MS: m / z 490.2 [M + Na]+); 2) The mixed fraction (2.8 g, 5.99 mmol) was further separated by SFC (DAICEL CHIRALPAK AD 250 mm × 30 mm, 10 μm; Condition: 0.1% NH3·H2O / EtOH; Begin B 25, End B 25; FlowRate (mL / min) 70; Injections 245) to give a mixed fraction containing two stereoisomers (earlier eluting fraction), and intermediate 16d-2 (the last eluting stereoisomer, LC-MS: m / z 490.2 [M + Na]+); and 3) the mixed fraction (1.9 g, 4.06 mmol) was further separated by SFC (Phenomenex-Cellulose-2250mm × 50 mm, 10 μm; Condition: 0.1% NH3·H2O / MeOH; Begin B 30, End B 30; FlowRate (mL / min) 200; Injections 150) to give intermediate 16d-3 (the first eluting stereoisomer, LC-MS: m / z 490.2 [M + Na]+) and intermediate 16d-4 (the second eluting stereoisomer, LC-MS: m / z 490.2 [M + Na]+).EXAMPLE 23: Preparation of Compounds 30 to 33 (S)-2-((R)-6-((S)-5-((S)-3-amino-2-hydroxypropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2- yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6-((R)-5-((S)-3-amino-2- hydroxypropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)- 2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6-((R)-5-((R)-3-amino-2-hydroxypropyl)- 4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2- dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, and (S)-2-((R)-6-((S)-5-((R)-3-amino-2-hydroxypropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman- 2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[0359] Compounds 30 to 33 were prepared from the corresponding intermediates 16d-1 to 16d- 4 using the method described in Steps F to I of Example 8.

[0360] Compound 30 (from intermediate 16d-1): LC-MS: m / z 725.2 [M+H]+.1HNMR (400 MHz, D2O + CD3CN) δ: 7.52 - 7.45 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H), 4.53 (s, 1H), 4.49 - 4.46 (m, 2H), 4.05 - 4.10 (m, 1H), 3.92 - 4.01 (m, 1H), 3.68 - 3.60 (m, 1H), 2.99 - 3.07 (m, 1H), 2.87 - 2.72 (m, 3H), 2.03 - 2.13 (m, 1H), 1.92 - 1.86 (m, 1H), 1.65 - 1.78 (m, 2H), 1.48 (s, 3H), 1.41 (s, 3H), 1.24 (s, 3H).

[0361] Compound 31 (from intermediate 16d-2): LC-MS: m / z 725.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.48 - 7.42 (m, 2H), 6.88 (d, J = 9.2 Hz, 1H), 6.77 (s, 1H), 4.56 (s, 1H), 4.47 - 4.41 (m, 2H), 4.05 (t, J = 11.2 Hz, 1H), 3.94 - 3.85 (m, 1H), 3.70 - 3.62 (m, 1H), 3.07 - 3.01 (m, 1H), 2.89-2.80 (m, 1H), 2.79 - 2.69 (m, 2H), 2.12 - 2.03 (m, 1H), 1.92 - 1.75 (m, 2H), 1.73 - 1.61 (m, 1H), 1.47 (s, 3H), 1.41 (s, 3H), 1.24 (s, 3H).

[0362] Compound 32 (from intermediate 16d-3): LC-MS: m / z 725.1 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.47 - 7.40 (m, 2H), 6.83 (d, J = 8.3 Hz, 1H), 6.76 (s, 1H), 4.53 (s, 1H), 4.48 - 4.36 (m, 2H), 4.12 - 3.99 (m, 2H), 3.67 - 3.56 (m, 1H), 3.07 - 2.99 (m, 1H), 2.87 - 2.78 (m, 1H), 2.77 - 2.68 (m, 2H), 2.12 - 2.02 (m, 1H), 1.91 - 1.84 (m, 1H), 1.77 - 1.60 (m, 2H), 1.48 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H).

[0363] Compound 33 (from intermediate 16d-4): LC-MS: m / z 725.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.50 - 7.42 (m, 2H), 6.89 (d, J = 8.3 Hz, 1H), 6.78 (s, 1H), 4.52 (s, 1H), 4.49 - 4.44 (m, 2H), 4.05 (t, J = 11.3 Hz, 1H), 3.94 - 3.85 (m, 1H), 3.72 - 3.63 (m, 1H), 3.08 - 3.00 (m, 1H), 2.89 - 2.80 (m, 1H), 2.79 - 2.70 (m, 2H), 2.12 - 2.02 (m, 1H), 1.91 - 1.76 (m, 2H), 1.74 - 1.62 (m, 1H), 1.47 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H). EXAMPLE 24: Preparation of Intermediates 17e-1 to 17e-4

[0364] Step A: Synthesis of Intermediate 17a: A solution of 2-(benzyloxy)acetaldehyde (10 g, 66.6 mmol) in DCM (200 mL) was treated with (S)-2-methylpropane-2-sulfinamide (8.88 g, 73.2 mmol), followed by copper (II) sulfate (26.6 g, 166 mmol) at 25 °C. The reaction was stirred at 25oC for 12 h, then filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography MPLC (ISCO®; 80 g SepaFlash® Silica Flash Column, 0-5% ethyl acetate / petroleum ether elution gradient; flow rate = 35 mL / min) to give intermediate 17a.1H NMR (400 MHz, CDCl3) δ: 8.16 - 8.00 (m, 1H), 7.39 - 7.28 (m, 5H), 4.63 (s, 2H), 4.43 - 4.36 (m, 2H), 1.21 (s, 9H).

[0365] Step B: Synthesis of Intermediate 17b To a solution of intermediate 17a (7.7 g, 30.4 mmol) in DCM (100 mL) stirred at -65 °C was added allylmagnesium bromide in diethyl ether (1 M, 63.8 mL, 63.8 mmol). The reaction was stirred at -65oC for 2 h, then diluted with water (80mL) and extracted with DCM (30 mL × 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography MPLC (ISCO®; 80 g SepaFlash® Silica Flash Column, 0-5% ethyl acetate / petroleum ether elution gradient; flow rate = 35 mL / min) to give intermediate 17b.1H NMR (400 MHz, CDCl3) δ: 7.39 - 7.27 (m, 5H), 5.83 - 5.68 (m, 1H), 5.19 - 5.01 (m, 2H), 4.63 - 4.44 (m, 2H), 3.72 - 3.42 (m, 3H), 2.56 - 2.28 (m, 2H), 1.205 and 1.185 (s s, 9H).

[0366] Step C: Synthesis of Intermediate 17c: To a mixture of intermediate 17b (5.5 g, 18.62 mmol) and 0.02 M iron (II) trifluoromethanesulfonate in MeOH (46.5 mL, 0.931 mmol) stirred at 25 °C, were added sodium azide (1.3 g, 20.00 mmol) and O-pivaloylhydroxylammonium trifluoro-methanesulfonate (12.44 g, 46.5 mmol). The reaction was stirred at 25 °C for 12 h. Then the solvent was removed under vacuum, and the resulting residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 10: 1 to 5: 1 (gradient), then DCM: MeOH = 10: 1) to give intermediate 17c. LC-MS: m / z 354.3 [M+H]+.

[0367] Step D: Synthesis of Intermediate 17d: To a solution of intermediate 17c (2.5 g, 7.07 mmol) in MeOH (80 mL) cooled at 0 °C, were added di-tert-butyl dicarbonate (9.26 g, 42.4 mmol) and nickel(II) chloride hexahydrate (0.168 g, 0.707 mmol). Then sodium borohydride (1.873 g, 49.5 mmol) was added in several portions over 1 h. The resulting mixture was stirred at 45 °C for 12 h, then diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc = 10: 1 to 5: 1 (gradient), then 100% EtOAc) to give intermediate 17d. LC-MS: m / z 528.3 [M+H]+.

[0368] Step E: Synthesis of Intermediates 17e-1 to 17e-4: Four diasteromers of intermediate 17d (5 g, 9.47 mmol) were separated by SFC (DAICEL CHIRALPAK AD 250 mm × 50 mm, 10 μm; Condition: 0.1% NH3·H2O / IPA; Begin B 20, End B 20; FlowRate (mL / min) 200; Injections 550) to give intermediate 17e-1 (the first eluting stereoisomer, LC-MS: m / z 550.5 [M+Na]+), impure intermediate 17e-2 (the second eluting stereoisomer, LC-MS: m / z 550.5 [M+Na]+) which was contaminated by 11% intermediate 17e-1, intermediate 17e-3 (the third eluting stereoisomer, LC-MS: m / z 528.3 [M+H]+), and intermediate 17e-4 (the last eluting stereoisomer, LC-MS: m / z 528.3 [M+H]+). The impure intermediate 17e-2 was further separated by SFC (DAICEL CHIRALPAK AD 250 mm × 50 mm, 10 μm; Condition 0.1% NH3·H2O / IPA; Begin B 15, End B 15; FlowRate (mL / min) 60; Injections 250) to give diastereomerically pure intermediate 17e-2 (LC-MS: m / z 528.3 [M+H]+).EXAMPLE 25: Preparation of Compounds 34 to 37 (S)-2-((R)-6-((S)-5-((S)-2-amino-3-hydroxypropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2- yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6-((R)-5-((S)-2-amino-3- hydroxypropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)- 2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6-((R)-5-((R)-2-amino-3-hydroxypropyl)- 4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2- dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, and (S)-2-((R)-6-((S)-5-((R)-2-amino-3-hydroxypropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman- 2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[0369] Step A: Synthesis of Intermediate 18a: To a solution of intermediate 17e-2 (450 mg, 0.853 mmol) in THF (8 mL) and water (2 mL) stirred at 20 °C, was added iodine (43.3 mg, 0.171 mmol). The reaction mixture was stirred at 55 °C for 2 h, then diluted with saturated aqueous Na2SO3 (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give crude intermediate 18a, which was used in the next step without further purification. LC-MS: m / z 424.4 [M+H]+.

[0370] Step B: Synthesis of Intermediate 18b: To a solution of intermediate 18a (361 mg, 0.852 mmol) in THF (8 mL) and water (2 mL) stirred at 0 °C, were added Na2CO3 (271 mg, 2.56 mmol) and benzyl carbonochloridate (189 mg, 1.108 mmol). The reaction was stirred at 25 °C for 12 h, then diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography (SiO2, petroleum ether / EtOAc = 5: 1 to 1: 1 (gradient), then 100% EtOAc) to give intermediate 18b. LC-MS: m / z 580.5 [M+Na]+.

[0371] Step C: Synthesis of Intermediate 18c: To a stirred solution of intermediate 18b (400 mg, 0.717 mmol) in DCM (6 mL) was added TFA (3 mL). The reaction mixture was stirred at 25 °C for 3 h. Then the solvent was removed under reduced pressure to give crude intermediate 18c, which was used in the next step without further purification. LC-MS: m / z 358.3 [M+H]+.

[0372] Step D: Synthesis of Intermediate 18d: To a solution of intermediate 18c (240 mg, 0.671 mmol) in EtOH (8 mL) stirred at 25 °C, were added sequentially intermediate 3c (300 mg, 0.643 mmol), acetic acid (116 mg, 1.929 mmol), and potassium acetate (379 mg, 3.86 mmol). The reaction was heated to 85 °C and stirred for 2 h. Then the mixture was cooled to ambient temperature, and filtered. The filtrate was concentrated in vacuo to give a residue that was purified by reverse-phase MPLC (Biotage; 20 g Agela, C18, 20~35 μm, 0-47% MeCN / H2O with 0.5% TFA elution gradient; flow rate = 50 mL / min) to give intermediate 18d. LC-MS: m / z 759.6 [M+H]+.

[0373] Step E: Synthesis of Intermediate 18e To a solution of intermediate 18d (300 mg, 0.395 mmol) in DCM (4 mL) was added boron trichloride in DCM (1 M, 1.186 mL, 1.186 mmol). The reaction was stirred at 25 °C for 12 h. Then the solvent was removed under vacuum to give crude intermediate 18e, which was used in the next step without further purification. LC-MS: m / z 379.2 [M+H]+.

[0374] Step F: Synthesis of Compounds 34 to 37: To a solution of intermediate 18e (100 mg, 0.264 mmol) in DMA (2 mL) was added intermediate 5 (96 mg, 0.264 mmol). The reaction wasstirred at 25 °C for 12 h, and then filtered. The filtrate was purified by reverse-phase HPLC (Boston Uni C1840 × 150 × 5 μm; Condition: water (0.01% TFA)-ACN; Begin B 0, End B 30; Gradient Time (min) 10; 100% B Hold Time (min) 2; FlowRate (mL / min) 60; Injections 1), followed by lyophilization to give compound 34 as the TFA salt. The TFA salt was purified by reverse-phase HPLC (Welch Xtimate C18150 × 25 mm × 5 μm; Condition: water (0.225% FA)- ACN; Begin B 0 - End B 18; Gradient Time (min) 17; 100% B Hold Time (min) 2; FlowRate (mL / min) 25; Injections 2) followed by lyophilization to give compound 34 as the formic acid salt. LC-MS: m / z 725.1 [M+H]+.1H NMR (500 MHz, D2O + CD3CN) δ: 7.52 - 7.47 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.79 (s, 1H), 4.56 (s, 1H), 4.46 - 4.41 (m, 2H), 4.12 - 4.06 (m, 1H), 3.77 - 3.71 (m, 1H), 3.66 - 3.61 (m, 1H), 3.59 - 3.54 (m, 1H), 3.43 - 3.37 (m, 1H), 2.82 - 2.7 (m, 2H), 2.12 - 2.01 (m, 2H), 1.92 - 1.89 (m 1H), 1.77 - 1.67(m, 1H), 1.49 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H).

[0375] Compounds 35 to 37 were prepared from the corresponding intermediates 18d-1, 18d-3, and 18d-4 using the method described in Steps A to F of Example 25.

[0376] Compound 35 (from intermediate 18d-1): LC-MS: m / z 725.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.50 - 7.44 (m, 2H), 6.88 (d, J = 8.5 Hz, 1H), 6.80 (s, 1H), 4.45 - 4.36 (m, 3H), 4.09 ( t, J = 11.3 Hz, 1H), 3.80 - 3.76 (m 1H), 3.67 - 3.56 (m, 2H), 3.50 - 3.40 (m, 1H), 2.80 - 2.72 (m, 2H), 2.10 - 1.97 (m, 3H), 1.76 - 1.61 (m, 1H), 1.47 (s, 3H), 1.40 (s, 3H), 1.21 (s, 3H).

[0377] Compound 36 (from intermediate 18d-3): LC-MS: m / z 725.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.51 - 7.45 (m, 2H), 6.90 (d, J = 8.5 Hz, 1H), 6.78 (s, 1H), 4.55 (s, 1H), 4.44 - 4.40 (m, 1H), 4.22 - 4.19 (m, 1H), 4.09 ( t, J = 11.7 Hz, 1H), 3.80 - 3.74 (m, 1H), 3.66 - 3.56 (m, 2H), 3.45 - 3.35 (m, 1H), 2.85 - 2.69 (m, 2H), 2.1 - 2.04 (m, 1H), 2.04 - 1.97 (m, 2H), 1.70 - 1.50 (m, 1H), 1.48 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H).

[0378] Compound 37 (from intermediate 18d-4): LC-MS: m / z 725.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.39 - 7.33 (m, 2H), 6.85 - 6.70 m, 2H), 4.47 (s, 1H), 4.45 - 4.39 (m, 2H), 4.10 ( t, J = 11.3 Hz, 1H), 3.79 - 2.72 (m, 1H), 3.69 - 2.62 (m, 1H), 3.61 - 3.54 (m, 1H), 3.51 - 3.44 (m, 1H), 2.75 - 2.68 (m, 2H), 2.13 - 2.03 (m, 2H), 2.01 - 1.96 (m, 1H), 1.71 - 1.60 (m, 1H), 1.51 (s, 3H), 1.39 (s, 3H), 1.20 (s, 3H). EXAMPLE 26: Preparation of Compounds 38 and 39 (S)-2-((R)-6-((S)-4-(2-aminoethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2-((((Z)-1- (2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid and (S)-2-((R)-6-((R)-4-(2-aminoethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4- oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[0379] Step A: Synthesis of Intermediate 19a: To a solution of (S)-2,4- bis(((benzyloxy)carbonyl)amino)-butanoic acid (10 g, 25.9 mmol) in DMF (520 mL) stirred at 25 °C under N2, were added benzyl acrylate (4.20 g, 25.9 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'- bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (0.581 g, 0.518 mmol), and potassium carbonate (4.29 g, 31.1 mmol). The reaction mixture was degassed by bubbling N2stream for 15 min, then stirred under irradiation with a 50 W blue LED for 3 h. The reaction was quenched with saturated aqueous NaHCO3 solution (200 mL) and extracted with MBTE (3 × 100 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 20 g Agela Silica Flash Column; 0~30% EtOAc / Pet.ether elution gradient, flow rate = 35 mL / min) to give intermediate 19a. LC-MS: m / z 505.2 [M+H]+.

[0380] Step B: Synthesis of Intermediate 19b-1 and 19b-2: The enantiomers of intermediate 19a (12 g, 23.78 mmol) were separated by SFC (DAICEL CHIRALCEL OD 250 mm × 50 mm, 10 μm; Condition: 0.1% NH3H2O / EtOH; Begin B 45%, End B 45%; Flow Rate (mL / min) 200; Injections 1200) to give intermediate 19b-1 (the first eluting enantiomer; LC-MS: m / z 505.2 [M+H]+) and intermediate 19b-2 (the second eluting enantiomer; LC-MS: m / z 505.2 [M+H]+).

[0381] Step C: Synthesis of Intermediate 19c-1: To a solution of intermediate 19b-1 (4.5 g, 8.92 mmol) in MeOH (28 mL) and THF (28 mL) stirred at 0 °C, was added sodium hydroxide (26.8 mL, 53.5 mmol). The reaction was stirred at 25 °C for 5 h, then the pH was adjusted to 7 with 2 N aqueous HCl. The reaction mixture was concentrated in vacuo. The resulting residue was diluted with brine (20 mL), and the pH was adjusted to 2 with 2 N aqueous HCl. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined ethyl acetate layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column, 0-50 % EtOAc / Pet. ether elution gradient, flow rate = 40 mL / min) to give intermediate 19c-1. LC-MS: m / z 415.1 [M+H]+.

[0382] Step D: Synthesis of Intermediate 19d-1: To a solution of intermediate 19c-1 (950 mg, 2.292 mmol) in toluene (14.5 mL) stirred at 28 °C, was added DPPA (946 mg, 3.44 mmol). The reaction stirred at 28 °C for 30 min before adding 2-(trimethylsilyl)ethan-1-ol (1084 mg, 9.17 mmol). Then the reaction was stirred at 100 °C for 12 h, diluted with water (50 mL), and extracted with EtOAc (20 mL×4). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO; 12 g Agela Silica Flash Column, 0-27% EtOAc / Pet. ether elution gradient, flow rate = 30 mL / min) to give intermediate 19d-1. LC-MS: m / z 552.2 [M+Na]+.

[0383] Step E: Synthesis of Intermediate 19e-1: To a solution of intermediate 19d-1 (500 mg, 0.944 mmol) and AcOH (0.216 mL, 3.78 mmol) in MeOH (25 mL) was added 10% wt. Pd / C (200 mg, 0.188 mmol). The reaction was stirred at 28 °C under hydrogen atmosphere (15 psi) for 12 h, and then filtered. The filtrate was concentrated in vacuo to give crude intermediate 19e-1, which was used in the next step without further purification.

[0384] Step F: Synthesis of Intermediate 19f-1: To a solution of intermediate 3c (441 mg, 0.945 mmol) and intermediate 19e-1 (247 mg, 0.945 mmol) in EtOH (18 mL) stirred at 28 °C, were added acetic acid (0.216 mL, 3.78 mmol) and potassium acetate (278 mg, 2.83 mmol) sequentially. The reaction was stirred at 85 °C for 2 h, then concentrated under vacuum. The resulting residue was diluted with saturated aqueous NaHCO3 (30 mL), and extracted withEtOAc (20 mL×3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by reverse-phase MPLC (Biotage; 20 g Agela, C18, 20~35 μm, 0-46% MeCN / H2O (with 0.5% TFA) elution gradient; flow rate = 50 mL / min) to give intermediate 19f-1. LC-MS: m / z 663.3 [M+H]+.

[0385] Step G: Synthesis of Intermediate 19g-1: A solution of intermediate 19f-1 (330 mg, 0.498 mmol) in TFA (3.3 mL, 42.8 mmol) was stirred at 40 °C for 70 min. Then the reaction mixture was concentrated in vacuo to give crude intermediate 19g-1, which was used in the next step without further purification. LC-MS: m / z 363.2 [M+H]+.

[0386] Step H: Synthesis of Compounds 38 and 39: To a solution of intermediate 19g-1 (180 mg, 0.497 mmol) in MeOH (5 mL) was added intermediate 5 (181 mg, 0.497 mmol). The reaction was stirred at ambient temperature for 12 h, then filtered. The filtrate was concentrated under vacuum to give a residue, which was diluted with MeOH (5 mL) and purified by reverse- phase HPLC (Column: Boston Uni C1840×150×5 μm; Condition: water (with 0.5% TFA)-ACN; Begin B 0, End B 30; Gradient Time (min) 10; 100% B Hold Time (min) 2; Flow Rate (mL / min) 60; Injections 2) and lyophilized to give compound 38 as the TFA salt. The TFA salt was dissolved with water (4 mL), and purified by reverse-phase HPLC (Column: Boston Green ODS 150 × 30 mm × 5 μm; Condition: water (0.225% FA)-ACN; Begin B 0, End B 19; Gradient Time (min) 17; 100% B Hold Time (min) 2; Flow Rate (mL / min) 25; Injections 2) and lyophilized to give compound 38 as the formic salt. LC-MS: m / z 709.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.39 - 7.28 (m, 2H), 6.86 (d, J = 8.5 Hz, 1H), 6.80 (s, 1H), 4.57 (s, 1H), 4.35 (d, J = 11.9 Hz, 1H), 3.78 - 3.62 (m, 1H), 3.46 (t, J = 5.8 Hz, 2H), 3.06 (t, J = 8.1 Hz, 2H), 2.86 - 2.69 (m, 2H), 2.10 - 1.97 (m, 3H), 1.92 - 1.86 (m, 1H), 1.85 - 1.75 (m, 1H), 1.75 - 1.60 (m, 1H), 1.47 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H).

[0387] Compound 39 was prepared from intermediate 19b-2 using the method described in Steps C to H of Example 26. LC-MS: m / z 709.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.36 - 7.29 (m, 2H), 6.87 (d, J = 8.5 Hz, 1H), 6.81 (s, 1H), 4.58 (s, 1H), 4.40 - 4.34 (m, 1H), 3.77 - 3.68 (m, 1H), 3.47 (t, J = 5.9 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.88 - 2.67 (m, 2H), 2.11 - 1.97 (m, 3H), 1.93 - 1.87 (m, 1H), 1.86 - 1.76 (m, 1H), 1.76 - 1.62 (m, 1H), 1.48 (s, 3H), 1.41 (s, 3H), 1.22 (s, 3H). EXAMPLE 27: Preparation of Intermediates 20j-1 to 20j-4

[0388] Step A: Synthesis of Intermediate 20a: To a suspension of sodium hydride (60% wt. in mineral oil, 2.64 g, 66.0 mmol) in THF (438 mL) was added triethyl phosphonoacetate (14.19 mL, 71.5 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and then cooled to - 65 °C, followed by the addition of a solution of benzyl (3-oxopropyl)carbamate (11.4 g, 55.0 mmol) in THF (20 mL). The reaction was warmed to 25 °C and stirred for 1 h, then quenched with saturated NH4Cl solution (300 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO; 80 g Agela Silica Flash Column; 0-20% EtOAc / Pet. Ether, elution gradient; flow rate = 60 mL / min) to give intermediate 20a. LC-MS: m / z 278.1[M+H]+.

[0389] Step B: Synthesis of Intermediate 20b: To a solution of intermediate 20a (11.40 g, 41.1 mmol) in DCM (411 mL) stirred at -65 °C, was added DIBAL-H in toluene (1 M, 90 mL, 90 mmol). The reaction mixture was stirred at -65 °C for 1.5 h, then quenched with MeOH (400 mL) and diluted with saturated aqueous potassium sodium tartrate solution (300 mL) and EtOAc (400 mL). The mixture was stirred at 25 °C for 20 h. Then organic layer was separated, washed withbrine (500 mL × 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO; 80 g Agela Silica Flash Column; 0-30% EtOAc / Pet. ether elution gradient; flow rate = 60 mL / min) to give intermediate 20b. LC-MS: m / z 258.1 [M+Na]+.

[0390] Step C: Synthesis of Intermediate 20c: To a solution of intermediate 20b (6.82 g, 29.0 mmol) in MeCN (211 mL) was added silver(I) oxide (20.15 g, 87 mmol), followed by methyl iodide (9.02 mL, 145 mmol) at 25 °C. The reaction mixture was protected from light and stirred for 48 h at 35 °C, then filtered through a CeliteTMpad. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column; 0-20% EtOAc / Pet. ether elution gradient; flow rate = 40 mL / min) to give intermediate 20c. LC-MS: m / z 272.1[M+Na]+.

[0391] Step D: Synthesis of Intermediate 20d: A solution of intermediate 20c (5 g, 20.06 mmol) in DMF (105 mL) was cooled to 0 °C and sodium hydride (60% wt. in mineral oil, 3.21 g, 80 mmol) was added. Then 1-(chloromethyl)-4-methoxybenzene (9.42 g, 60.2 mmol) was added dropwise, followed by TBAI (0.741 g, 2.006 mmol). The reaction mixture was stirred at 25 °C for 12 h, then quenched by adding H2O (150 mL). The resulting mixture was extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL × 2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column; 0~20% EtOAc / Pet. Ether elution gradient; flow rate = 40 mL / min) to give intermediate 20d. LC- MS: m / z 392.1 [M+Na]+.

[0392] Step E: Synthesis of Intermediate 20e: To a mixture of intermediate 20d (5.35 g, 14.48 mmol) and 0.02 M iron(II) trifluoromethanesulfonate in MeOH (36.2 mL, 0.724 mmol) stirred at 25 °C, was added sodium azide (1.90 g, 29.2 mmol), followed by the addition of O- pivaloylhydroxyl-ammonium trifluoromethanesulfonate (19.35 g, 72.4 mmol). The reaction was stirred at 25 °C for 20 h, then basified with saturated aqueous Na2CO3 to pH > 10, and extracted with EtOAc (50 mL × 3). The combined extract was dried over anhydrous Na2SO4and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with petroleum ether / EtOAc = 5:1 to 2:1 (gradient) and then 100% EtOAc to give intermediate 20e. LC-MS: m / z 428.2 [M+H]+.

[0393] Step F: Synthesis of Intermediate 20f To a solution of intermediate 20e (5.57 g, 13.03 mmol) in MeOH (82 mL) stirred at 25 °C were added nickel(II) chloride hexahydrate (0.310 g, 1.303 mmol) and di-tert-butyl dicarbonate (17.96 mL, 78 mmol). The reaction was cooled to 0 °C, then sodium borohydride (3.47 g, 92 mmol) was added in several portions over 20 min. Thereaction mixture was stirred at 25 °C for 24 h, then quenched with H2O (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (ISCO; 40 g Agela Silica Flash Column; 0-20% EtOAc / Pet. ether elution gradient; flow rate = 40 mL / min) to give intermediate 20f. LC-MS: m / z 624.3[M + Na]+.

[0394] Step G: Synthesis of Intermediates 20g-1 to 20g-4: The four diastereomers of intermediate 20f (5.4 g, 8.97 mmol) were separated by SFC (Column: DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm); Condition: 0.1% NH3H2O / IPA; Begin B 30%, End B 30%; FlowRate (mL / min) 200; Injections 250) to give intermediate 20g-1 (the first eluting diastereomer, LC-MS: m / z 624.3[M + Na]+); intermediate 20g-2 (the second eluting diastereomer, LC-MS: m / z 624.3[M + Na]+); and a fraction containing a mixture of other two diasteromers. The mixed fraction was separated by a second SFC (Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); Condition 0.1% NH3H2O / MeOH; Begin B 45%, End B 45%; FlowRate (mL / min) 80; Injections 180) to give intermediate 20g-3 (the first eluting diastereomer, LC-MS: m / z 624.3[M + Na]+); and intermediate 20g-4 (the second eluting diastereomer, LC-MS: m / z 624.3[M + Na]+).

[0395] Step H: Synthesis of Intermediate 20h-1: To a solution of intermediate 20g-1 (650 mg, 0.724 mmol) in acetonitrile (36 mL) and water (9.00 mL) was added ammonium cerium(IV) nitrate (1587 mg, 2.89 mmol). The reaction was stirred at 25 °C for 1 h, then diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (Biotage; 12 g Agela Silica Flash Column; 0-33% EtOAc / Pet.ether elution gradient; flow rate = 30 mL / min) to give intermediate 20h-1. LC-MS: m / z 504.2 [M+Na]+.

[0396] Step I: Synthesis of Intermediate 20i-1: To a stirred solution of intermediate 20h-1 (268 mg, 0.556 mmol) in DCM (5 mL) was added TFA (1.667 mL) in one portion at 25 °C. The reaction was stirred for 1.5 h, and then concentrated in vacuo to give intermediate 20i-1, which was used in the next step without further purification. LC-MS: m / z 282.2 [M+H]+.

[0397] Step J: Synthesis of Intermediates 20j-1 to 20j-4: To a solution of intermediate 20i-1 (157 mg, 0.558 mmol) in EtOH (9 mL) stirred at 25 °C, were added sequentially intermediate 3c (325 mg, 0.558 mmol), acetic acid (0.128 mL, 2.232 mmol), and potassium acetate (164 mg, 1.674 mmol). The reaction was stirred at 85 °C for 2.0 h, and then filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by reverse-phase MPLC (Biotage; 20g Agela, C18, 20~35 μm, 0-60% MeCN / H2O (with 0.5% TFA) elution gradient; flow rate = 50 mL / min) to give intermediate 20j-1. LC-MS: m / z 683.3[M+H]+.

[0398] Intermediates 20j-2 to 20j-4 were prepared from the corresponding intermediates 20g-2 to 20g-4 using the method described in Steps H to J of Example 27. Intermediate 20j-2: LC-MS: m / z 683.4[M+H]+. Intermediate 20j-3: LC-MS: m / z 683.4[M+H]+. Intermediate 20j-4: LC-MS: m / z 683.4[M+H]+. EXAMPLE 28: Preparation of Compounds 40 to 43 (S)-2-((R)-6-((4S,5S)-5-(2-aminoethyl)-4-(methoxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6- ((4R,5S)-5-(2-aminoethyl)-4-(methoxymethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6-((4R,5R)-5-(2-aminoethyl)-4- (methoxymethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)- 2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid, and (S)-2-((R)-6-((4S,5R)-5-(2-aminoethyl)-4- (methoxymethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)- 2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid

[0399] Step A: Synthesis of Intermediate 21a: A solution of intermediate 20j-3 (519 mg, 0.646 mmol) in TFA (9.6 mL) was stirred at 45 °C for 6 h. Then the reaction mixture was concentrated in vacuo to give crude intermediate 21a, which was used without further purification. LC-MS: m / z 393.2 [M+H]+.

[0400] Step B: Synthesis of Compounds 40 to 43: To a solution of intermediate 21a (150 mg, 0.382 mmol) in DMA (2 mL) were added 4Å molecular sieves (20 mg), followed by the addition of intermediate 5 (139 mg, 0.382 mmol). The reaction was stirred at 25 °C for 16 h, then filtered. The filtrate was diluted with DMA (3 mL) and directly purified by reverse-phase HPLC (Boston Uni C1840 × 150 × 5 μm; Condition: water (0.1% TFA)-ACN; Begin B: 0, End B: 30; Gradient Time (min): 10; 100% B Hold Time (min): 2; FlowRate(mL / min): 60; Injections: 1) and lyophilized to give compound 40 as the TFA salt. The TFA salt was dissolved in water (3 mL) and purified by reverse-phase HPLC (Welch Xtimate C18150 × 25 mm × 5 μm; Condition: water (0.225% FA)-ACN; Begin B: 0, End B: 18; Gradient Time (min): 17; 100% B Hold Time (min): 2; FlowRate (mL / min): 25; Injections: 2) and lyophilized to give compound 40 as the formic acid salt. LC-MS: m / z 739.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.53 - 7.46 (m, 2H), 6.90 (d, J = 8.2 Hz, 1H), 6.80 (s, 1H), 4.55 (s, 1H), 4.47 - 4.40 (m, 1H), 4.18 - 4.10 (m, 2H), 3.49 - 3.60 (m, 2H), 3.32 (s, 3H), 3.15 - 2.94 (m, 2H), 2.85 - 2.70 (m, 2H), 2.13 - 1.97 (m, 3H), 1.81 - 1.63 (m, 1H), 1.48 (s, 3H), 1.40 (s, 3H), 1.22 (s, 3H).

[0401] Compounds 41, 42 and 43 were prepared from the corresponding intermediates 20j-1, 20j-2 and 20j-4 using the method described in Example 28.

[0402] Compound 41: LC-MS: m / z 739.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.55 - 7.43 (m, 2H), 6.92 - 6.86 (m, 1H), 6.80 (s, 1H), 4.48 (s, 1H), 4.46 - 4.40 (m, 1H), 4.19 - 4.06 (m, 2H), 3.60 - 3.50 (m, 2H), 3.32 (s, 3H), 3.14 - 2.95 (m, 2H), 2.85 - 2.70 (m, 2H), 2.12 - 1.98 (m, 3H), 1.80 - 1.62 (m, 1H), 1.48 (s, 3H), 1.39 (s, 3H), 1.20 (s, 3H).

[0403] Compound 42: LC-MS: m / z 739.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.52 - 7.44 (m, 2H), 6.86 (d, J = 8.5 Hz, 1H), 6.81 (s, 1H), 4.53 (s, 1H), 4.49 - 4.44 (m, 1H), 4.43- 4.36 (m, 2H), 3.69 - 3.55 (m, 2H), 3.30 (s, 3H), 3.21 - 2.99 (m, 2H), 2.82 - 2.66 (m, 2H), 2.13 - 2.00 (m, 3H), 1.76 - 1.61 (m, 1H), 1.48 (s, 3H), 1.39 (s, 3H), 1.20 (s, 3H).

[0404] Compound 43: LC-MS: m / z 739.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.54 - 7.45 (m, 2H), 6.88 (d, J = 8.3 Hz, 1H), 6.81 (s, 1H), 4.52 (s, 1H), 4.50 - 4.46 (m, 1H), 4.45 - 4.36 (m, 2H), 3.68 - 3.56 (m, 2H), 3.30 (s, 3H), 3.22 - 2.98 (m, 2H), 2.82- 2.70 (m, 2H), 2.14 - 2.00 (m, 3H), 1.78 - 1.63 (m, 1H), 1.48 (s, 3H), 1.40 (s, 3H), 1.21 (s, 3H). EXAMPLE 29: Preparation of Compounds 44 and 45 (S)-2-((R)-6-((4S,5S)-5-(2-aminoethyl)-4-(hydroxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6- ((4R,5S)-5-(2-aminoethyl)-4-(hydroxymethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid, (S)-2-((R)-6-((4R,5R)-5-(2-aminoethyl)-4- (hydroxymethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)- 2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid, and (S)-2-((R)-6-((4S,5R)-5-(2-aminoethyl)-4- (hydroxymethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)- 2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid (Any two of the fous stereoisomers. The stereochemistry was undetermined.)

[0405] Step A: Synthesis of Intermediate 22a: To a stirred solution of intermediate 21a (140 mg, 0.357 mmol) in DCM (2 mL) at 0 °C was added 33% HBr in acetic acid (0.409 mL, 1.427 mmol). The reaction was stirred at 25 °C for 24 h, then concentrated in vacuo to give intermediate 22a, which was used in the next step without further purification. LC-MS: m / z 379.2 [M+H]+.

[0406] Step B: Synthesis of Compounds 44 and 45; To a solution of intermediate 22a (100 mg, 0.264 mmol) in DMA (1 mL) were added 4Å molecular sieves (20 mg), followed by the addition of intermediate 5 (96 mg, 0.264 mmol). The reaction was stirred at 25 °C for 16 h, then filtered. The filtrate was diluted with DMA (1 mL) and purified by reverse-phase HPLC (Boston Uni C1840 × 150 × 5 μm; Condition: water (with 0.1% TFA)-ACN; Begin B: 0, End B: 28; Gradient Time (min): 10; 100% B Hold Time (min): 2; FlowRate (mL / min): 60; Injections 2) and lyophilization to give compound 44 as the TFA salt. The TFA salt was dissolved in water (1 mL) and purified by a second reverse-phase HPLC (Welch Xtimate C18150 × 25 mm × 5 μm; Condition: water (with 0.225% FA)-ACN; Begin B: 0, End B: 18; Gradient Time (min): 17; 100% B Hold Time (min): 2; FlowRate (mL / min): 25; Injections: 1) and lyophilized to give compound 44 as the formic acid salt. LC-MS: m / z 725.2 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.55 - 7.46 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.81 (s, 1H), 4.56 (s, 1H), 4.56 - 4.50(m, 1H), 4.20 - 4.00 (m, 2H), 3.72 - 3.58 (m, 2H), 3.15 - 2.95 (m, 2H), 3.87 - 2.69 (m, 2H), 2.14 - 1.97 (m, 3H), 1.82 - 1.63(m, 1H), 1.49 (s, 3H), 1.41 (s, 3H), 1.22 (s, 3H).

[0407] Compound 45 was prepared from intermediate 20j-1 using the method described in Step A of Example 28 and Steps A to B of Example 29. LC-MS: m / z 725.3 [M+H]+.1H NMR (400 MHz, D2O + CD3CN) δ: 7.60 - 7.45 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 4.50 (s, 1H), 4.50 - 4.40 (m, 1H), 4.40 - 4.20 (m, 1H), 4.19 - 3.99 (m, 1H), 3.72 - 3.58 (m, 2H), 3.13 - 2.95 (m, 2H), 2.85 - 2.71 (m, 2H), 2.11 - 1.99 (m, 3H), 1.72 - 1.65 (m, 1H), 1.48 (s, 3H), 1.40 (s, 3H), 1.22 (s, 3H). BIOLOGICAL ASSAYS Antibiotic Activity: Determination of Growth Inhibitory Concentration

[0408] The concentrations of compounds required to inhibit the growth of various strains of bacteria were determined in an assay that assessed bacterial growth by measuring optical density at 600 nm (OD600). The bacterial strains tested included the clinical strains Escherichia coli expressing NDM-1 (CLB30016), Klebsiella pneumoniae expressing KPC-1 (CL6569), Acinetobacter baumannii expressing TEM-1, AmpC, and Oxa-24 / 40 (CL6188) and Pseudomonas aeruginosa expressing AmpC (CL5701). All compounds were tested in the presence of a β lactamase inhibitor (BLi, Relebactam) in 384-well microplates.

[0409] The clinical strains were stored as frozen single use stocks, thawed and diluted into 1.1X cation-adjusted Mueller-Hinton II broth to achieve approximately 2 x 105CFU / mL. Test compounds were dissolved in DMSO and diluted 1:50 in the assay, resulting in a final concentration range of 100 μM to 0.098 μM. On the day of the assay, 1 μL of test compound was added to the plate followed by 4 μL of 50 μg / mL BLi in MOPS buffer and 45 μL of diluted bacteria. Plates were centrifuged at 1000 rpm for 30 seconds, shaken at approximately 800 rpm for 1 minute, and incubated at 35 ± 2°C for 22 hours. The concentration of BLi used in the assay was 4μg / mL. At the end of the incubation, absorbance at 600 nm was determined using a spectrophotometer. Inhibition was quantitated by identifying the lowest concentration of test compound that was required to inhibit 95% of the growth of the bacteria. The results for Examples 1-39 are reported in Table I, expressed as the concentration of compound that inhibited 95% of bacterial growth (Minimum Inhibitory Threshold Concentration; MITC95).

[0410] Representative compounds of Formula (I) display a growth inhibitory effect. For example, representative Compounds 1-45 were determined to inhibit growth at concentrations of 100 μM or less.Table I. Antibacterial activity of Compounds 1-45

Claims

1. WHAT IS CLAIMED IS:

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: A is T is CH, or N, provided that no more than two of T, U and V are N; U is CH, or N; V is CH or N; X is selected from: 1) O, and 2) CH2; Y is selected from: 1) O, 2) NR8, 3) S, and 4) CH2, provided that when Y is O, NR8or S, then X is CH2; Z is 1 2) S, 3) CH2, or 4) NH, provided that when Z is O, S or NH, then X is CH2; W is selected from: 1) bond, and 2) O; Q is selected from: 1) N, and 2) CR8; L is selected from: 1) -C1-6alkyl-, 2) -C1-6alkyl-O-C1-6alkyl-, 3) -C1-6alkyl-S-C1-6alkyl-, and 4) -C1-6alkyl-N(Rm)-C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, - C1-3alkyl, -C1-3alkyl-OH, OH, -C0-3alkyl-NH2, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1-3alkyl; R1is selected from: 1) -NH2, 2 -NH(-C1-6alkyl), 3) -N(C1-6alkyl)2, 4) -N+(C1-6alkyl)3, 5) -OH, 6) -OC1-6alkyl, 7) -SH, and 8) -SC1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra; R2is selected from: 1) hydrogen, 2) C1-6alkyl,3) C1-6alkyl-OR4, and4) C1-6alkyl-NHR4, wherein alkyl is unsubstituted or substituted with one to three halogens; R3is selected from: 1) -C1-6alkyl, 2) -C1-6alkyl-OH, 3) -C1-6alkyl-O-C1-6alkyl, 4) -O-C1-6alkyl, 5) -C1-6alkyl-SH, 6) -S-C1-6alkyl, 7) -C1-6alkyl-S-C1-6alkyl, 8) -NH-C1-6alkyl, 9) -N(C1-6alkyl)2, 10) -C1-6alkyl-NH2, and 11) -C1-6alkyl-N(Rm)-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn; R4is selected from: 1) hydrogen, 2) C1-3alkyl, and3) cyclopropyl, wherein alkyl and cyclopropyl are unsubstituted or substituted with one to three halogens orOC1-3alkyl;R5is selected from: 1) -CO2H, and2) tetrazole; R6and R7are selected from: 1) hydrogen, and 2) C1-6alkyl,wherein alkyl is unsubstituted or substituted with one to three halogens, provided that at least one of R6and R7is hydrogen; R8is selected from: 1) hydrogen, 2) C1-4alkyl, 3) halogen, and 4) C3-7cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three substituents selected from: -OH, halogen, NH2, and -OC1-3alkyl; R9and R10are selected from: 1) hydrogen, and 2) C1-6alkyl,wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, NHC1-3alkyl, and SC1-3alkyl,provided that one or both of R9 and R10 are C1-6alkyl,or alternatively R9and R10together with the carbon to which they are attached form amonocyclic C3-5cycloalkyl or a monocyclic C2-5cycloheteroalkyl, wherein cycloalkyl andcycloheteroalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, -OH and -OC1-3alkyl; each Rais independently selected from: 1) -CF3, 2) -CHF2, 3) -CH2F, 4) halogen, 5) -C1-6alkyl, 6) -C0-6alkyl-O-C1-6alkyl, 7) -C0-6alkyl-OH, 8) -C0-6alkyl S(O)rRj, 9) -C0-6alkyl S(O)rNRkRk, 10) -C0-6alkyl C(O)Ri,11) -C0-6alkyl OC(O)Ri,12) -C0-6alkyl C(O)ORi, 13) -C0-6alkyl CN, 14) -C0-6alkyl C(O)NRkRk, 15) -C0-6alkyl C(NH)NRkRk, 16) -C0-6alkylNRkRk, 17) -C0-6alkyl N(Rk)(C(O)Ri), 18) -C0-6alkyl N(Rk)(C(O)ORh), 19) -C0-6alkyl N(Rk)(C(O)NRfRg), and 20) -C0-6alkyl N(Rk)(S(O)vRj), wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl); each Rbis independently selected from: 1) hydrogen, 2) C1-6alkyl, 3) C0-6alkyl-O-C1-6alkyl, 4) C0-6alkyl-OH, 5) C0-6alkyl-S(O)uRd, 6) C1-6alkyl-C(O-N(Re)2, 7) C1-6alkylN(Re)C(O)Re, 8) C0-6alkyl-N(Re)2, and 9) halogen, wherein alkyl is unsubstituted or substituted with one to three halogens, or wherein two Rbsubstituents together with the atoms they are attached to can cyclize to form a 3 to 6 membered ring; each Rcis independently selected from: 1) hydrogen, 2) C1-6alkyl, 3) C0-6alkyl-O-C1-6alkyl, 4) C0-6alkyl-OH, 5) C0-6alkyl-S(O)vRf, 6) C0-6alkyl-S(O)vN(Rg)2, 7) C1-6alkyl C(O)-N(Rg)2, 8) C1-6alkylN(Rg)C(O)Rg, 9) C0-6alkyl-N(Rg) 2, and 10) halogen, wherein alkyl is unsubstituted or substituted with one to three halogens; each Rdis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Reis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rfis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rgis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rhis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Riis -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rjis independently selected from: 1) hydrogen, 2) OH, and 3) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rkis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rmis independently selected from: 1) hydrogen, and 2) -C1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to three halogens; each Rnis independently selected from: 1) -CF3, 2) -CHF2, 3) -CH2F, 4) halogen, 5) -C1-6alkyl, 6) -C0-6alkyl-O-C1-6alkyl, 7) -C0-6alkyl-OH, 8) -C0-6alkyl S(O)rRj, 9) -C0-6alkyl S(O)rNRkRk, 10) -C0-6alkyl C(O)Ri,11) -C0-6alkyl OC(O)Ri,12) -C0-6alkyl C(O)ORi, 13) -C0-6alkyl CN, 14) -C0-6alkyl C(O)NRkRk, 15) -C0-6alkyl C(NH)NRkRk, 16) -C0-6alkylNRkRk, 17) -C0-6alkyl N(Rk)(C(O)Ri), 18) -C0-6alkyl N(Rk)(C(O)ORh), 19) -C0-6alkyl N(Rk)(C(O)NRfRg), and 20) -C0-6alkyl N(Rk)(S(O)vRj), wherein alkyl is unsubstituted or substituted with one to three substituents selected from: halogen, OH, -OC1-3alkyl, -C1-3alkyl, -CO2C1-3alkyl, -C(O)NH2, -C0-6alkylNH2, and -C0-6alkylNH(C1-3alkyl); q is 0, 1, 2 or 3; each r is independently 0, 1 or 2; each s is independently 0, 1, 2, 3, 4 or 5; each t is independently 0, 1, 2 or 3; each u is independently selected from 0, 1 or 2; and each v is independently selected from 0, 1 or 2.

2. The compound of Claim 1 wherein T is CH; U is CH; and V is CH; or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 wherein X is CH2; or a pharmaceutically acceptable salt thereof.

4. The compound of Claim 1 wherein Y is O or CH2; and Z is O or CH2; or a pharmaceutically acceptable salt thereof.

5. The compound of Claim 4 wherein Y is CH2; and Z is O; or a pharmaceutically acceptable salt thereof.

6. A compound of Claim 1 wherein W is O; or a pharmaceutically acceptable salt thereof.

7. The compound of Claim 1 wherein Q is CR8; and R8is hydrogen; or a pharmaceutically acceptable salt thereof.

8. The compound of Claim 1 wherein R2is hydrogen; or a pharmaceutically acceptable salt thereof.

9. The compound of Claim 5 wherein R5is -CO2H; or a pharmaceutically acceptable salt thereof.

10. The compound of Claim 1 wherein R4is selected from: 1) C1-3alkyl, and2) cyclopropyl, wherein alkyl and cyclopropyl are unsubstituted or substituted with one to three substituentsselected from: halogen and OC1-3alkyl; or a pharmaceutically acceptable salt thereof.

11. The compound of Claim 1 wherein R4 is C1-3alkyl, wherein alkyl is unsubstitutedor substituted with one to three substituents selected from: halogen or OC1-3alkyl; or apharmaceutically acceptable salt thereof.

12. The compound of Claim 1 wherein R6is hydrogen; and R7is hydrogen; or a pharmaceutically acceptable salt thereof.

13. The compound of Claim 1 whereinR9 is C1-6alkyl, andR10 is C1-6alkyl;or a pharmaceutically acceptable salt thereof.

14. The compound of Claim 1 wherein A is or a pharmaceutically acceptable salt thereof.

15. The compound of Claim 1 wherein A is or a pharmaceutically acceptable salt thereof.

16. The compound of Claim 1 wherein A is or a pharmaceutically acceptable salt thereof.

17. The compound of Claim 1 wherein L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C1-3alkyl-OH, OH, -C0-3alkyl-NH2, -OC1-3alkyl, -NHC(O)C1-3alkyl, -C(O)NHC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1-3alkyl; or a pharmaceutically acceptable salt thereof.

18. The compound of Claim 1 wherein L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C1-3alkyl-OH, and OH; or a pharmaceutically acceptable salt thereof.

19. The compound of Claim 1 wherein R1is selected from: 1) -NH2, 2) -NH(C1-6alkyl), 3) -N(C1-6alkyl)2, 4) -N+(C1-6alkyl)3, 5) -OH, and 6) -OC1-6alkyl, wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra; or a pharmaceutically acceptable salt thereof.

20. The compound of Claim 1 wherein R1is selected from: 1) -NH2, and 2) -NH(C1-6alkyl), wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra; or a pharmaceutically acceptable salt thereof.

21. The compound of Claim 1 wherein R1is -NH2; or a pharmaceutically acceptable salt thereof.

22. The compound of Claim 1 wherein R3is selected from: 1) -C1-6alkyl, 2) -C1-6alkyl-OH, and 3) -C1-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn; and q is 0 or 1; or a pharmaceutically acceptable salt thereof.

23. The compound of Claim 1 wherein R3is selected from: 1) -C1-6alkyl-OH, and 2) -C1-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn; and q is 0 or 1; or a pharmaceutically acceptable salt thereof.

24. The compound of Claim 1 wherein A isT is CH; U is CH; V is CH; X is CH2; Y is O or CH2; Z is O or CH2; W is bond or O; Q is CR8;L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C1-3alkyl-OH, OH, -C0-3alkyl-NH2, -OC1-3alkyl, -NHC(O)C1-3alkyl, - C(O)NHC1-3alkyl, -C0-3alkyl-NHC1-3alkyl, and SC1-3alkyl; R1is selected from: 1) -NH2, and 2) -NH(-C1-6alkyl), wherein each alkyl is unsubstituted or substituted with one to five substituents selected from Ra; R2is hydrogen; R3is selected from: 1) -C1-6alkyl, 2) -C1-6alkyl-OH, and 3) -C1-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn; R4is selected from: 1) C1-3alkyl, and2) cyclopropyl, wherein alkyl and cyclopropyl are unsubstituted or substituted with one to three substituentsselected from: halogen and OC1-3alkyl;R5 is -CO2H or tetrazole;R6is hydrogen; R7is hydrogen; R8is hydrogen;R9 is C1-6alkyl,R10 is C1-6alkyl; andq is 0 or 1; or a pharmaceutically acceptable salt thereof.

25. The compound of Claim 1 wherein A isT is CH; U is CH; V is CH; X is CH2; Y is CH2; Z is O; W is O; Q is CR8; L is -C1-6alkyl-, wherein alkyl is unsubstituted or substituted with one to six substituents selected from: halogen, -C1-3alkyl, -C1-3alkyl-OH, and OH; R1is -NH2; R2is hydrogen; R3is selected from: 1) -C1-6alkyl-OH, and 2) -C1-6alkyl-O-C1-6alkyl, wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rn;R4 is C1-3alkyl;R5 is -CO2H;R6is hydrogen; R7is hydrogen; R8is hydrogen;R9 is C1-6alkyl, andR10 is C1-6alkyl; andq is 0 or 1; or a pharmaceutically acceptable salt thereof.

26. The compound of Claim 1 which is selected from: 1) (S)-2-((R)-6-((S)-5-(2-aminoethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)-1- (2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid;2) (S)-2-((R)-6-((R)-5-(3-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)- 1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 3) (S)-2-((R)-6-((S)-5-(3-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2-((((Z)- 1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 4) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-(2-(methylamino)ethyl)-4,5-dihydro-1H- imidazol-2-yl)chroman-2-yl)propanoic acid; 5) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((R)-5-(2-(methylamino)ethyl)-4,5-dihydro-1H- imidazol-2-yl)chroman-2-yl)propanoic acid; 6) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-(3-(methylamino)propyl)-4,5-dihydro- 1H-imidazol-2-yl)chroman-2-yl)propanoic acid; 7) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((R)-5-(3-(methylamino)propyl)-4,5-dihydro- 1H-imidazol-2-yl)chroman-2-yl)propanoic acid; 8) (S)-2-((R)-6-((S)-5-(3-aminopropyl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)- 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 9) (S)-2-((R)-6-((R)-5-(3-aminopropyl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)- 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 10) (S)-2-((R)-6-((S)-5-((R)-2-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 11) (S)-2-((R)-6-((R)-5-((R)-2-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 12) (S)-2-((R)-6-((R)-5-((S)-2-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid;13) (S)-2-((R)-6-((S)-5-((S)-2-aminopropyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 14) (2S)-2-((2R)-6-(5-(3-aminopropyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 15) (2S)-2-((2R)-6-(5-(2-aminoethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2-((((Z)- 1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 16) (S)-2-((R)-6-((R)-5-(3-aminopropyl)-5-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 17) (S)-2-((R)-6-((S)-5-(3-aminopropyl)-5-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 18) (S)-2-((R)-6-((R)-5-((S)-2-amino-1-hydroxyethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman- 2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 19) (S)-2-((R)-6-((R)-5-((R)-2-amino-1-hydroxyethyl)-4,5-dihydro-1H-imidazol-2-yl)chroman- 2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 20) (S)-2-((R)-6-((S)-5-(3-amino-3-methylbutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)- 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 21) (S)-2-((R)-6-((R)-5-(3-amino-3-methylbutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)- 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 22) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-((R)-2-(methylamino)propyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid; 23) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((R)-5-((R)-2-(methylamino)propyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid;24) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((R)-5-((S)-2-(methylamino)propyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid; 25) (S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-((R)-6-((S)-5-((S)-2-(methylamino)propyl)-4,5- dihydro-1H-imidazol-2-yl)chroman-2-yl)propanoic acid; 26) (S)-2-((R)-6-((S)-5-((S)-3-aminobutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 27) (S)-2-((R)-6-((R)-5-((S)-3-aminobutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 28) (S)-2-((R)-6-((R)-5-((R)-3-aminobutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 29) (S)-2-((R)-6-((S)-5-((R)-3-aminobutyl)-4,5-dihydro-1H-imidazol-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 30) (S)-2-((R)-6-((S)-5-((S)-3-amino-2-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 31) (S)-2-((R)-6-((R)-5-((S)-3-amino-2-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 32) (S)-2-((R)-6-((R)-5-((R)-3-amino-2-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 33) (S)-2-((R)-6-((S)-5-((R)-3-amino-2-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid;34) (S)-2-((R)-6-((S)-5-((S)-2-amino-3-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 35) (S)-2-((R)-6-((R)-5-((S)-2-amino-3-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 36) (S)-2-((R)-6-((R)-5-((R)-2-amino-3-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 37) (S)-2-((R)-6-((S)-5-((R)-2-amino-3-hydroxypropyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 38) (S)-2-((R)-6-((S)-4-(2-aminoethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 39) (S)-2-((R)-6-((R)-4-(2-aminoethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)chroman-2-yl)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)propanoic acid; 40) (S)-2-((R)-6-((4S,5S)-5-(2-aminoethyl)-4-(methoxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 41) (S)-2-((R)-6-((4R,5S)-5-(2-aminoethyl)-4-(methoxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 42) (S)-2-((R)-6-((4R,5R)-5-(2-aminoethyl)-4-(methoxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 43) (S)-2-((R)-6-((4S,5R)-5-(2-aminoethyl)-4-(methoxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid;44) (S)-2-((R)-6-((4S,5S)-5-(2-aminoethyl)-4-(hydroxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 45) (S)-2-((R)-6-((4R,5S)-5-(2-aminoethyl)-4-(hydroxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; 46) (S)-2-((R)-6-((4R,5R)-5-(2-aminoethyl)-4-(hydroxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; and 47) (S)-2-((R)-6-((4S,5R)-5-(2-aminoethyl)-4-(hydroxymethyl)-4,5-dihydro-1H-imidazol-2- yl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid; or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition according to Claim 27, which further comprises a therapeutically effective amount of a beta-lactamase inhibitor compound.

29. The pharmaceutical composition according to Claim 28 wherein the beta- lactamase inhibitor compound is selected from: relebactam, tazobactam, clavulanic acid, sulbactam, and avibactam.

30. 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 of Claim 1, or a pharmaceutically acceptable salt thereof.

31. The method of Claim 30 further comprising administering to a subject in need of such treatment a therapeutically effective amount of a beta-lactamase inhibitor compound.

32. The method of Claim 31 wherein the beta-lactamase inhibitor compound is selected from: relebactam, tazobactam, clavulanic acid, sulbactam, and avibactam.

33. The method of Claim 30 wherein the bacterial infection is due to Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichia spp., Morganella spp., Citrobacter spp., Serratia spp. or Acintetobacter spp.

34. Use of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, for treating a bacterial infection, or in the manufacture of a medicament for treating a bacterial infection.

35. The use of Claim 34 further comprising administering the compound of Claim 1 in combination with a beta-lactamase inhibitor compound for treating a bacterial infection, or in combination with a beta-lactamase inhibitor compound in the manufacture of a medicament for treating a bacterial infection.

36. The use of Claim 35 wherein the beta-lactamase inhibitor compound is selected from: relebactam, tazobactam, clavulanic acid, sulbactam, and avibactam.

37. The use of Claim 34, wherein the bacterial infection is due to Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichia spp., Morganella spp., Citrobacter spp., Serratia spp. or Acintetobacter spp.

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