Chroman amidine monobactam antibiotics

Abstract

To provide a monobactam compound suitable as an antibiotic for treatment of bacterial infection.SOLUTION: The present invention provides a compound represented by formula I, specifically, for example, compound 1. The inventive compound is used in a method for treating bacterial infection, either alone or in combination with a second beta-lactam antibiotic.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel monobactam compounds, processes for their preparation and their use as therapeutic agents. In particular, the present invention relates to monobactam compounds useful as antibiotics for the treatment of bacterial infections. [Background technology]

[0002] The introduction of antibiotics for the treatment of bacterial infections is one of the great medical achievements of the 20th century. However, over the past few decades, bacteria resistant to multiple antibiotics have begun to emerge worldwide, threatening the effectiveness of antibiotic therapy. In the United States alone, at least 23,000 people die each year as a direct result of infections caused by antibiotic-resistant bacteria, and many others die from the exacerbation of pre-existing conditions caused 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.

[0003] β-lactams are the most widely used antibiotics for treating serious bacterial infections. These include carbapenems, cephalosporins, penicillins, and monobactams. As has been observed with other antibiotic classes, resistance to β-lactams is emerging. In most Gram-negative bacteria, this resistance is primarily driven by the expression of β-lactamases, enzymes that hydrolyze β-lactam compounds. There are four distinct classes of β-lactamases (A, B, C, and D) that can hydrolyze overlapping but distinct subsets of β-lactams (Drawz and Bonomo, Clin. Micro. Rev., 2010, 23:160-201). Class B β-lactamases, also known as metallo-β-lactamases (MBLs), are not the most common β-lactamases seen in the clinic, but their frequency and distribution are increasing, representing a significant medical threat. This is because (i) MBL has the ability to hydrolyze all β-lactams except monobactams, and (ii) unlike class A and C β-lactamases, there are no available inhibitors for MBL.

[0004] The monobactam aztreonam was first approved in the United States in 1986 for the treatment of aerobic Gram-negative bacterial infections and remains the only monobactam used in the United States today. However, aztreonam has low activity against Pseudomonas and Acinetobacter strains. Because monobactams are inherently resistant to hydrolysis by MBL, several companies have begun developing novel monobactam compounds to treat infections caused by Gram-negative bacteria. Monobactam compounds containing a siderophore moiety have been disclosed in International Publication Nos. WO 2007 / 065288, WO 2012 / 073138, J. Medicinal Chemistry 56:5541-5552 (2013), and Bioorganic and Medicinal Chemistry Letters 22:5989 (2012).

[0005] International Publication No. WO 2019 / 070492 discloses chroman monobactam compounds for treating bacterial infections. International Publication No. WO 2017 / 106064 discloses biaryl monobactam compounds and their use for treating bacterial infections. International Publication No. WO 2013 / 110643 discloses novel amidine-substituted monobactam derivatives and their use as antibacterial agents. International Publication No. WO 2015 / 103583 discloses monobactam derivatives useful for treating infectious diseases, including bacterial infections. U.S. Patent Application Publication Nos. 2015 / 0045340 and 2014 / 0275007 disclose oxamazine monobactams and their use as antibacterial agents. U.S. Patent Application Publication No. 2015 / 0266867 discloses novel monobactam compounds for use as antibacterial agents.

[0006] There is a continuing need for new antibiotics to overcome multidrug resistance. The compounds disclosed in this invention are designed to meet this medical need by administration alone or in combination with an appropriate β-lactamase inhibitor. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2007 / 065288 [Patent Document 2] International Publication No. 2012 / 073138 [Patent Document 3] International Publication No. 2019 / 070492 [Patent Document 4] International Publication No. 2017 / 106064 [Patent Document 5] International Publication No. 2013 / 110643 [Patent Document 6] International Publication No. 2015 / 103583 [Patent Document 7] U.S. Patent Application Publication No. 2015 / 0045340 [Patent Document 8] U.S. Patent Application Publication No. 2014 / 0275007 [Patent Document 9] U.S. Patent Application Publication No. 2015 / 0266867 [Non-patent literature]

[0008] [Non-Patent Document 1] Antibiotic Resistance Threats in the United States, 2013, Centers for Disease Control, Atlanta, Georgia. [Non-patent document 2] Drawz and Bonomo, Clin.Micro.Rev.,2010, 23:160-201 [Non-patent document 3] J.Medicinal Chemistry 56:5541-5552(2013) [Non-patent document 4] Bioorganic and Medicinal Chemstry Letters 22:5989(2012) Summary of the Invention

[0009] The present invention relates to the design and synthesis of monobactam analogs, a novel class of highly potent antibiotics effective against a wide range of Gram-negative bacteria. These compounds and their pharmaceutically acceptable salts may be useful as therapeutic agents for the clinical treatment of various infections caused by Gram-negative bacteria, including strains that are multidrug-resistant. The compounds may be used alone or in combination with an appropriate β-lactamase inhibitor. The present invention relates to compounds of formula I: [ka]

[0010] and pharmaceutically acceptable salts thereof.

[0011] The present invention also relates to a pharmaceutical composition for treating a bacterial infection in a subject, including infections caused by multidrug-resistant Gram-negative bacterial strains, comprising a monobactam compound of structural formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0012] The compounds of formula (I) and pharmaceutically acceptable salts thereof, also referred to herein as "monobactam compounds," may be useful, for example, for inhibiting the growth of Gram-negative bacterial strains, including, but not limited to, Pseudomonas, Klebsiella, and Acinetobacter strains, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii, and / or for treating or preventing the clinical manifestations thereof in patients.

[0013] The present invention also relates to a method for treating a Gram-negative bacterial infection in a subject in need thereof, comprising administering to the subject an effective amount of a monobactam compound of the present invention. In certain embodiments of the present invention, the method comprises administering a beta-lactamase inhibitor compound. Embodiments, sub-embodiments and features of the present invention are further described in or will be apparent from the following description, examples and appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention provides novel compounds of structural formula I: [ka]

[0015] or a pharmaceutically acceptable salt thereof, wherein: when no more than two of T, U and V are N, T is CH or N; U is CH or N; V is CH or N; X is 1) O, and 2) selected from the group consisting of CH2; Y is O, NR 8 or S and X is not O, 1) O, 2)NR 8 , 3) S, and 4) CH2; Z is O, S or NH, and X is not O. 1) O, 2) S, 3) CH2, or 4 NH, W is 1) Bonding, and 2) O; Q is 1) N, and 2)CR 8 is selected from the group consisting of R 1 teeth, 1) -C3-12 cycloalkyl, 2) -C3-12 cycloalkenyl, 3) C2-11 cycloheteroalkyl, 4) C2-11 cycloheteroalkenyl, 5) aryl, and 6) heteroaryl; Alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, and heteroaryl are unsubstituted or R a is substituted with 1 to 5 substituents selected from R 2 teeth, 1) hydrogen, 2) C1-6 alkyl, 3) C1-6 alkyl-OR 4 , and 4) C1-6 alkyl-NHR 4 is selected from the group consisting of The alkyl is unsubstituted or substituted with 1 to 3 halogens; R 3 teeth, 1) hydrogen, and 2) OH; R 4 teeth, 1) hydrogen, 2) C1-3 alkyl, and 3) Ccycloalkyl; Alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 halogen or OC1-3 alkyl; R 5 teeth, 1)-CO2H, and 2) tetrazole; R 6 and R 7 teeth, 1) hydrogen, and 2) C1-6 alkyl; The alkyl is unsubstituted or substituted with 1 to 3 halogens, provided that R 6 and R 7 at least one of is hydrogen, R 8 teeth, 1) hydrogen, 2) C 1-4 Alkyl, 3) halogens, and 4) C 3-7 cycloalkyl; Alkyl and cycloalkyl are unsubstituted or substituted with -OH, halogen, NH2, and -OC. 1-3 substituted with 1 to 3 substituents selected from alkyl, R 9 and R 10 teeth, 1) hydrogen, and 2) C1-6 alkyl; The alkyl may be unsubstituted or may be substituted with halogen, OH, -OC 1-3 Alkyl, -NHC(O)C 1-3 Alkyl, -C(O)NHC 1-3 substituted with 1 to 3 substituents selected from alkyl, NHC1-3 alkyl, and SC1-3 alkyl, with the proviso that R9 and R 10 one or both of are C1-6 alkyl, Alternatively, R 9 and R 10 together with the carbons to which they are attached form a monocyclic C3-5 cycloalkyl or a monocyclic C2-5 cycloheteroalkyl, wherein the cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, -OH and -OC1-3 alkyl; Each R a teeth, 1) halogen, 2) -C1-6 alkyl, 3) -C0-6 alkyl-O-C1-6 alkyl, 4) -C0-6 alkyl-OH, 5)-C 0-6 Alkyl S(O) r R j , 6)-C 0-6 AlkylS(O) r NR k R l , 7)-C 0-6 Alkyl C(O)R i , 8)-C 0-6 Alkyl OC(O)R i , 9)-C 0-6 Alkyl C(O)OR i , 10)-C 0-6 Alkyl CN, 11)-C 0-6 Alkyl C(O)NR k R l , 12)-C 0-6 Alkyl C(NH)NR k R l , 13)-C0-6 alkyl NR k R l , 14)-C 0-6 Alkyl N(R k )(C(O)R i ), 15)-C 0-6 Alkyl N(R k )(C(O)OR h ), 16)-C 0-6 Alkyl N(R k )(C(O)NR f R g ), and 17)-C 0-6 Alkyl N(R k )(S(O) v R j ), independently selected from the group consisting of: The alkyl may be unsubstituted or may contain halogen, OH, -OC 1-3 Alkyl, -C 1-3 Alkyl, -CO2C 1-3 Alkyl, -C(O)NH2, -C 0-6 AlkylNH2 and -C 0-6 AlkylNH(C 1-3 alkyl), Each R b teeth, 1) hydrogen, 2) C 1-6 Alkyl, 3) C 0-6 Alkyl-OC 1-6 Alkyl, 4) C 0-6 alkyl-OH, 5) C 0-6 Alkyl-S(O) u R d 、 6) C 1-6 Alkyl-C(ON(R e )2, 7) C 1-6 AlkylN(R e )C(O)R e , 8) C 0-6 Alkyl-N(R e )2, and 9) halogen; The alkyl is unsubstituted or substituted with 1 to 3 halogens or two R bthe substituents, together with the atoms to which they are attached, can be cyclized to form a 3- to 6-membered ring; Each R c teeth, 1) hydrogen, 2) C 1-6 Alkyl, 3) C 0-6 Alkyl-OC 1-6 Alkyl, 4) C 0-6 alkyl-OH, 5) C 0-6 Alkyl-S(O) v R f 、 6) C 0-6 Alkyl-S(O) v N(R g ) 2、 7) C 1-6 Alkyl C(O)-N(R g )2, 8) C 1-6 AlkylN(R g )C(O)R g , 9) C 0-6 Alkyl-N(R g )2, and 10) halogen; The alkyl is unsubstituted or substituted with 1 to 3 halogens; Each R d teeth, 1) hydrogen, and 2)-C 1-6 alkyl; each alkyl is unsubstituted or substituted with 1 to 3 halogens; Each R e teeth, 1) hydrogen, and 2)-C 1-6 alkyl; each alkyl is unsubstituted or substituted with 1 to 3 halogens; Each R f teeth, 1) hydrogen, and 2)-C1-6 alkyl; each alkyl is unsubstituted or substituted with 1 to 3 halogens; Each R g teeth, 1) hydrogen, and 2)-C 1-6 alkyl; each alkyl is unsubstituted or substituted with 1 to 3 halogens; Each R h teeth, 1) hydrogen, and 2)-C 1-6 alkyl; each alkyl is unsubstituted or substituted with 1 to 3 halogens; Each R i -C 1-6 alkyl, each alkyl being unsubstituted or substituted with 1 to 3 halogens; Each R j teeth, 1) hydrogen, 2) OH, and 3)-C 1-6 alkyl; each alkyl is unsubstituted or substituted with 1 to 3 halogens; Each R k teeth, 1) hydrogen, 2) —C alkyl; each alkyl is unsubstituted or substituted with 1 to 3 halogens; Each R l teeth, 1) hydrogen, 2) —C alkyl, wherein each alkyl is unsubstituted or substituted with 1 to 3 halogens; 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; Each v is independently selected from 0, 1, or 2.

[0016] The present invention relates to novel monobactam analogs, a class of highly potent antibiotics effective against a broad range of Gram-negative bacteria. These compounds are useful as therapeutic agents for the clinical treatment of a variety of infections caused by Gram-negative bacteria, including strains that are multidrug-resistant, and for the treatment or prevention of associated clinical conditions.

[0017] In each of the various embodiments of the compounds of the invention described herein, each variable, including those of formula (I), and its various embodiments, is selected independently of the others, unless otherwise specified.

[0018] The present invention includes compounds of formula (I) and mixtures of their diastereoisomers and / or enantiomers, including individual diastereoisomers, enantiomers and epimers of compounds of formula (I), as well as racemic mixtures. The present invention also encompasses any solvates, hydrates, stereoisomers and tautomers of compounds of formula (I), and any pharmaceutically acceptable salts thereof.

[0019] In one embodiment of the present invention, when no more than two of T, U and V are N, T is CH or N. U is CH or N and V=CH or N.

[0020] In another embodiment of the present invention, when no more than two of T, U and V are N, then T is CH or N. In a class of this embodiment, T is CH or N. In another class of this embodiment, T is CH. In another class of this embodiment, T is N.

[0021] In another embodiment of the present invention, U is CH or N. In a class of this embodiment, U is CH. In another class of this embodiment, U is N.

[0022] In another embodiment of the present invention, V=CH or N. In a class of this embodiment, V is CH. In another class of this embodiment, V is N.

[0023] In another embodiment of the invention, T, U and V are CH.

[0024] In another embodiment of the present invention, W is a bond or O. In a class of this embodiment, W is a bond. In another class of this embodiment, W is O.

[0025] In another embodiment of the present invention, Q is N or CR 8 In a class of this embodiment, Q is N. In another class of this embodiment, Q is CR 8 is.

[0026] In another embodiment of the present invention, X is O or CH2. In a class of this embodiment, X is O. In another class of this embodiment, X is CH2.

[0027] In another embodiment, Y is O, NR 8 , S or CH2, provided that Y is O, NR 8 or S, then X is not O. In another embodiment, Y is O, NR 8 , S or CH2, provided that Y is O, NR 8 Or when S, X is CH2.

[0028] In another embodiment, Y is O, NR 8 , S, or CH2. In a class of this embodiment, Y is O or CH2. In another class of this embodiment, Y is NR 8 or S. In another class of this embodiment, Y is O. In another class of this embodiment, Y is NR 8 In another class of this embodiment, Y is S. In another class of this embodiment, Y is CH2.

[0029] In another embodiment, Z is O, S, CH2, or NH, provided that when Z is O, S, or NH, X is not O. 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.

[0030] In another embodiment of the present invention, R 1 is selected from the group consisting of -Ccycloalkyl, -Ccycloheteroalkyl, Ccycloheteroalkenyl, aryl, and heteroaryl, wherein cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, and heteroaryl are unsubstituted or a It is substituted with 1 to 5 substituents selected from:

[0031] In another embodiment of the present invention, R 1 is selected from the group consisting of -C3-9 cycloalkyl, -C2-7 cycloheteroalkyl, aryl, and heteroaryl; where cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl are unsubstituted or R a It is substituted with 1 to 5 substituents selected from:

[0032] In another embodiment of the present invention, R 1 is selected from the group consisting of -C3-9 cycloalkyl, -C2-8 cycloheteroalkyl, and aryl, wherein cycloalkyl, cycloheteroalkyl, and aryl are unsubstituted or a In a class of this embodiment, R 1are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.2]octane, spiro[3.3]heptane, spiro[3.5]nonane, spiro[2.3]hexane, azetidine, pyrrolidine, piperidine, azepane, 2-oxabicyclo[2.1.1]hexane, 3-azabicyclo[2.1.1]hexane, 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[2.2.2]octane, 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[2.2.2]octane, 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[2.2.2]octane, 2-azabicyclo[2.1.1]hexane, 3-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.2]hexane, 3 ... R is selected from the group consisting of cyclo[3.1.0]hexane, 3-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 3-azabicyclo[3.2.0]heptane, 1-azaspiro[3.3]heptane, 6-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 6-azaspiro[3.4]octane, and phenyl; 1 is unsubstituted or R a is substituted with 1 to 5 substituents selected from

[0033] In another embodiment of the present invention, R 1 is aryl, the aryl is unsubstituted, or R a In a class of this embodiment, R 1 is phenyl, wherein the phenyl is unsubstituted, or R a It is substituted with 1 to 5 substituents selected from:

[0034] In another embodiment of the present invention, R 1 is selected from the group consisting of -C3-9 cycloalkyl and C2-8 cycloheteroalkyl, where cycloalkyl and cycloheteroalkyl are unsubstituted or a In a class of this embodiment, R 1are cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.2]octane, spiro[3.3]heptane, spiro[3.5]nonane, spiro[2.3]hexane, azetidine, pyrrolidine, piperidine, azepane, 2-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[2.1.1]hexane, 4-oxabicyclo[2.1.2]hexane, 5-oxabicyclo[2.1.3]hexane, 6-oxabicyclo[2.1.4]hexane, 7-oxabicyclo[2.1.5]hexane, 8-oxabicyclo[2.1.6]hexane, 9-oxabicyclo[2.1.7]hexane, 10-oxabicyclo[2.1.8]hexane, 11-oxabicyclo[2.1.9]hexane, 12-oxabicyclo[2.1.1]hexane, 13-oxabicyclo[2.1.2]hexane, 14-oxabicyclo[2.1.3]hexane, 15-oxabicyclo[2.1.4]hexane, 16-oxabicyclo[2.1.5]hexane, 17-oxabicyclo[2.1.6]hexane, 18-oxabicyclo[2.1.7]hexane, 19-oxabicyclo[2.1.8]hexane, 20-oxabicyclo[2.1.9]hexane, 22-oxabicyclo[2.1.1]hexane, 23-oxabicyclo[2.1.1]hexane, 24-oxabicyclo[2.1.1]hexane, 25-oxabicyclo[2.1.2]hexane, 26-oxabicyclo[2.1.1]hexane, 27-oxabicyclo[2. is selected from the group consisting of azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 3-azabicyclo[3.2.0]heptane, 1-azaspiro[3.3]heptane, 6-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, and 6-azaspiro[3.4]octane; R 1 is unsubstituted or R a In another class of this embodiment, R 1 is selected from the group consisting of cyclobutane, cyclohexane, cycloheptane, bicyclo[4.1.0]heptane, piperidine, and azepane; R 1 is unsubstituted or R a It is substituted with 1 to 5 substituents selected from:

[0035] In another embodiment of the present invention, R 1 is selected from the group consisting of -Ccycloalkyl, wherein cycloalkyl is unsubstituted or R a In a class of this embodiment, R 1 is selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.2]octane, spiro[3.3]heptane, spiro[3.5]nonane, and spiro[2.3]hexane; R 1 is unsubstituted or R aIn another four classes of this embodiment, R 1 is selected from the group consisting of cyclobutane, cyclohexane, cycloheptane, and bicyclo[4.1.0]heptane; R 1 is unsubstituted or R a In another class of this embodiment, R 1 is cyclobutane and R 1 is unsubstituted or R a In another class of this embodiment, R 1 is cyclohexane and R 1 is unsubstituted or R a In another class of this embodiment, R 1 is bicyclo[4.1.0]heptane, and R 1 is unsubstituted or R a In another class of this embodiment, R 1 is cycloheptane and R 1 is unsubstituted or R a It is substituted with 1 to 5 substituents selected from:

[0036] In another embodiment of the present invention, R 1 is a C2-7 cycloheteroalkyl, wherein the cycloheteroalkyl is unsubstituted or R a In a class of this embodiment, R 1is selected from the group consisting of azetidine, pyrrolidine, piperidine, azepane, 2-oxabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 3-azabicyclo[3.2.0]heptane, 1-azaspiro[3.3]heptane, 6-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, and 6-azaspiro[3.4]octane; R 1 is unsubstituted or R a In another class of this embodiment, R 1 is selected from the group consisting of piperidine and azepane, R 1 is unsubstituted or R a In another class of this embodiment, R 1 is piperidine and R 1 is unsubstituted or R a In another class of this embodiment, R 1 is azepane, and R 1 is unsubstituted or R a It is substituted with 1 to 5 substituents selected from:

[0037] In another embodiment of the present invention, R 2 is hydrogen, -C1-6 alkyl, -C1-6 alkyl-OR 4 , and -C1-6 alkyl-NHR 4 wherein alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R 2 is selected from the group consisting of hydrogen and C alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, R 2 is C alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, R2 is C alkyl. In another class of this embodiment, R 2 is hydrogen.

[0038] In another embodiment of the present invention, R 3 is selected from the group consisting of hydrogen and OH. In a class of this embodiment, R 3 In another class of this embodiment, R is OH. 3 is hydrogen.

[0039] In another embodiment of the present invention, R 4 is selected from the group consisting of hydrogen, —C 1-3 alkyl, and C 3 cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 halogen or C 1-3 alkyl. In a class of this embodiment, R 4 is selected from the group consisting of hydrogen, CH3, and cyclopropane, wherein methyl and cyclopropane are unsubstituted or substituted with one to three halogens or O—C1-3 alkyl. In another class of this embodiment, R 4 is selected from the group consisting of hydrogen, CH3, and cyclopropane.

[0040] In another embodiment of the present invention, R 4 is selected from the group consisting of hydrogen and C alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens or C alkyl. In a class of this embodiment, R 4 is selected from the group consisting of: hydrogen, and C alkyl. In another class of this embodiment, R 4 is hydrogen. In another class of this embodiment, R 4 is C alkyl, wherein alkyl is unsubstituted or substituted with one to three halogen or O—C alkyl. In another class of this embodiment, R 4 is C1-3 alkyl. In a subclass of this class, R 4 is -CH3.

[0041] In another class of the invention, R 4 is selected from the group consisting of C alkyl, and C cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three halogens or C alkyl. In a class of this embodiment, R 4 is selected from the group consisting of C1-3 alkyl and C3 cycloalkyl.

[0042] In another class of the invention, R 4 is cyclopropyl, which is unsubstituted or substituted with 1 to 3 halogen or OC1-3 alkyl.

[0043] In another class of the invention, R 4 is C alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogen or C alkyl. In a class of this embodiment, R 4 is C1-3 alkyl.

[0044] In another embodiment of the present invention, R 5 is selected from the group consisting of: —COH and tetrazole. In a class of this embodiment, R 5 In another class of this embodiment, R is tetrazole. 5 is -CO2H.

[0045] In another embodiment of the present invention, R 6 and R 7 is selected from the group consisting of hydrogen and C alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens, with the proviso that R 6 and R 7 At least one of is hydrogen.

[0046] In another embodiment, R 6 are independently selected from the group consisting of hydrogen and C alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens, with the proviso that R 6 and R 7At least one of is hydrogen.

[0047] In another embodiment, R 6 is independently selected from the group consisting of hydrogen and C alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R 6 is C alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, R 6 is C alkyl. In another class of this embodiment, R 6 is hydrogen.

[0048] In another embodiment, R 7 are independently selected from the group consisting of hydrogen and C alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens, with the proviso that R 6 and R 7 At least one of is hydrogen.

[0049] In another embodiment, R 7 is independently selected from the group consisting of hydrogen and C alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R 7 is C alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens. In another class of this embodiment, R 7 is C alkyl. In another class of this embodiment, R 7 is hydrogen.

[0050] In another embodiment of the present invention, R 8 is hydrogen, C 1-4 independently selected from the group consisting of alkyl, halogen, and C3-C7 cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or selected from -OH, halogen, NH2, and -OC 1-3 In a class of this embodiment, R is substituted with 1 to 3 substituents selected from alkyl. 8 is hydrogen, C1-4 independently selected from the group consisting of alkyl and halogen, wherein C1-C4 alkyl is unsubstituted or selected from -OH, halogen, NH2, and -OC 1-3 In another class of this embodiment, R is substituted with 1 to 3 substituents selected from alkyl. 8 is hydrogen and C 1-4 alkyl, wherein C1-C4 alkyl is unsubstituted or is selected from the group consisting of -OH, halogen, NH2, and -OC 1-3 In another class of this embodiment, R is substituted with 1 to 3 substituents selected from alkyl. 8 is C 1-4 alkyl, wherein C1-C4 alkyl is unsubstituted or is selected from the group consisting of -OH, halogen, NH2, and -OC 1-3 In another class of this embodiment, R is substituted with 1 to 3 substituents selected from alkyl. 8 is hydrogen and C 1-4 In another class of this embodiment, R 8 is hydrogen.

[0051] In another embodiment of the present invention, R 9 and R 10 is selected from the group consisting of hydrogen and C1-6 alkyl, wherein alkyl is unsubstituted or selected from halogen, OH, -OC 1-3 Alkyl, -NHC(O)C 1-3 Alkyl, -C(O)NHC 1-3 substituted with 1 to 3 substituents selected from alkyl, NHC1-3 alkyl, and SC1-3 alkyl, with the proviso that R 9 and R 10 one or both of R 9 and R 10together with the carbons to which they are attached form a monocyclic C3-5 cycloalkyl or a monocyclic C2-5 cycloheteroalkyl, wherein the cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen, —OH, and —OC1-3 alkyl. In a class of this embodiment, R 9 and R 10 is selected from the group consisting of hydrogen and C1-6 alkyl, wherein alkyl is unsubstituted or selected from halogen, OH, -OC 1-3 Alkyl, -NHC(O)C 1-3 Alkyl, -C(O)NHC 1-3 substituted with 1 to 3 substituents selected from alkyl, NHC1-3alkyl, and SC1-3alkyl, with the proviso that R 9 and R 10 In another class of this embodiment, one or both of R 9 and R 10 is selected from the group consisting of: hydrogen, CH3, and -CH2CH3. In another class of this embodiment, R 9 and R 10 is selected from C alkyl, wherein alkyl is unsubstituted or selected from halogen, OH, -OC 1-3 Alkyl, -NHC(O)C 1-3 Alkyl, -C(O)NHC 1-3 substituted with 1 to 3 substituents selected from alkyl, NHC1-3 alkyl, or SC1-3 alkyl, with the proviso that R 9 and R 10 In another class of this embodiment, one or both of R 9 and R 10 is selected from C alkyl. In another class of this embodiment, R 9 and R 10 is selected from: -CH3, and -CH2CH3. In another class of this embodiment, R 9 and R 10 and R are each -CH2CH3. In another class of this embodiment, R 9 and R 10are -CH3, respectively.

[0052] In another embodiment of the present invention, R 9 are independently C1-6 alkyl, wherein alkyl is unsubstituted or selected from halogen, OH, -OC 1-3 Alkyl, -NHC(O)C 1-3 Alkyl, -C(O)NHC 1-3 substituted with 1 to 3 substituents selected from alkyl, NHC1-3 alkyl, and SC1-3 alkyl; or R 9 and R 10 together with the carbons to which they are attached form a monocyclic C3-5 cycloalkyl or a monocyclic C2-5 cycloheteroalkyl, wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, -OH, and -OC1-3 alkyl. In another class of this embodiment, R 9 is independently selected from the group consisting of C alkyl, wherein alkyl is unsubstituted or selected from halogen, OH, -OC 1-3 Alkyl, -NHC(O)C 1-3 Alkyl, -C(O)NHC 1-3 It is substituted with 1 to 3 substituents selected from alkyl, NHC1-3 alkyl, or SC1-3 alkyl.

[0053] In another class of this embodiment, R 9 is independently selected from the group consisting of: C alkyl. In another class of this embodiment, R 9 is independently selected from the group consisting of: -CH3, and -CH2CH3. In another class of this embodiment, R 9 In another class of this embodiment, R is -CH2CH3. 9 is -CH3.

[0054] In another embodiment of the present invention, R 10 are independently C1-6 alkyl, wherein alkyl is unsubstituted or selected from halogen, OH, -OC 1-3 Alkyl, -NHC(O)C 1-3Alkyl, -C(O)NHC 1-3 substituted with 1 to 3 substituents selected from alkyl, NHC1-3 alkyl, and SC1-3 alkyl; or R 9 and R 10 together with the carbons to which they are attached form a monocyclic C3-5 cycloalkyl or a monocyclic C2-5 cycloheteroalkyl, wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, -OH, and -OC1-3 alkyl. In another class of this embodiment, R 10 is independently selected from the group consisting of C alkyl, wherein alkyl is unsubstituted or selected from halogen, OH, -OC 1-3 Alkyl, -NHC(O)C 1-3 Alkyl, -C(O)NHC 1-3 It is substituted with 1 to 3 substituents selected from alkyl, NHC1-3 alkyl, or SC1-3 alkyl.

[0055] In another class of this embodiment, R 10 is independently selected from the group consisting of: C alkyl. In another class of this embodiment, R 10 is independently selected from the group consisting of: -CH3, and -CH2CH3. In another class of this embodiment, R 10 In another class of this embodiment, R is -CH2CH3. 10 is -CH3.

[0056] In another embodiment of the present invention, each R a is halogen, -C1-6 alkyl, -C0-6 alkyl-O-C1-6 alkyl, -C0-6 alkyl-OH, -C 0-6 Alkyl S(O) r R j , -C 0-6 Alkyl S(O) r NR k R l , -C 0-6 Alkyl C(O)R i , -C 0-6 Alkyl OC(O)R i, -C 0-6 Alkyl C(O)OR i , -C 0-6 Alkyl CN, -C 0-6 Alkyl C(O)NR k R l , -C 0-6 Alkyl C(NH)NR k R l , -C0-6 alkylNR k R l , -C 0-6 Alkyl N(R k )(C(O)R i ), -C 0-6 Alkyl N(R k )(C(O)OR h ), -C 0-6 Alkyl N(R k )(C(O)NR f R g ), and -C 0-6 Alkyl N(R k )(S(O) v R j ), wherein alkyl is unsubstituted or is selected from the group consisting of halogen, OH, -OC 1-3 Alkyl, -C 1-3 Alkyl, -CO2C 1-3 Alkyl, -C(O)NH2, -C 0-6 AlkylNH2 and -C 0-6 AlkylNH(C 1-3 alkyl).

[0057] In another embodiment of the present invention, each R a is halogen, -C1-6 alkyl, -C0-6 alkyl-O-C1-6 alkyl, -C0-6 alkyl-OH, and -C0-6 alkylNR k R l and wherein alkyl is unsubstituted or is selected from the group consisting of halogen, OH, -OC 1-3 Alkyl, -C 1-3 Alkyl, -CO2C 1-3 Alkyl, -C(O)NH2, -C 0-6 AlkylNH2, and -C 0-6 AlkylNH(C1-3 In a class of this embodiment, each R a is halogen, -C1-6 alkyl, -C0-6 alkyl-O-C1-6 alkyl, -C0-6 alkyl-OH, and -C0-6 alkylNR k R l and wherein alkyl is unsubstituted or is selected from the group consisting of halogen, OH, -OC 1-3 Alkyl, and -C 1-3 In another class of this embodiment, each R is substituted with 1 to 3 substituents selected from alkyl, a are independently selected from the group consisting of F, -CH3, -OCH3, -CH2OCH3, -(CH2)2OCH3, -OH, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH2OH, -CH2CH(OH)CH2OH, -NH2, -CH2NH2, -(CH2)2NH2, -C(CH3)2NH2, -(CH2)3NH2, -NH(CH3), -CH2NH(CH3) and -CH2CH(OH)CH2NH2.

[0058] In another embodiment of the present invention, each R a is halogen. In a class of this embodiment, each R a is F.

[0059] In another embodiment of the present invention, each R a is independently selected from the group consisting of -C0-6 alkyl-O-C1-6 alkyl, where alkyl is unsubstituted or is selected from the group consisting of halogen, OH, and -C 1-3 In a class of this embodiment, each R a are independently selected from the group consisting of -OCH3, -CH2OCH3, and -(CH2)2OCH3.

[0060] In another embodiment of the present invention, each R a is -C1-6 alkyl, -C0-6 alkyl-OH, and -C0-6 alkylNR k R land wherein alkyl is unsubstituted or is selected from the group consisting of halogen, OH, -OC 1-3 Alkyl, -C 1-3 Alkyl, -CO2C 1-3 Alkyl, -C(O)NH2, -C 0-6 AlkylNH2, and -C 0-6 AlkylNH(C 1-3 In a class of this embodiment, each R a is -C1-6 alkyl, -C0-6 alkyl-OH, and -C0-6 alkylNR k R l and wherein alkyl is unsubstituted or is selected from the group consisting of halogen, OH, and —C 1-3 In another class of this embodiment, each R is substituted with 1 to 3 substituents selected from alkyl, a is independently selected from the group consisting of: -CH3, -OH, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH2OH, -CH2CH(OH)CH2OH, -NH2, -CH2NH2, -(CH2)2NH2, -C(CH3)2NH2, -(CH2)3NH2, -NH(CH3), -CH2NH(CH3), and -CH2CH(OH)CH2NH2. In another class of this embodiment, each R a are independently selected from the group consisting of -CH3, -OH, -NH2, -CH2NH2, and -CH2CH(OH)CH2NH2.

[0061] In another embodiment of the present invention, each R a is independently selected from the group consisting of -Ci_6 alkyl, wherein alkyl is unsubstituted or selected from halogen, OH, -OC 1-3 Alkyl and -C 1-3 In a class of this embodiment, each R a is -CH3.

[0062] In another embodiment of the present invention, each R ais -C0-6 alkyl-OH, where alkyl is unsubstituted or is selected from halogen, OH, -OC 1-3 Alkyl, and -C 1-3 In a class of this embodiment, each R a are independently selected from the group consisting of -OH, -CHOH, -(CH)OH, -(CH)OH, -CH(OH)CHOH, and -CHCH(OH)CHOH.

[0063] In another embodiment of the present invention, each R a is -C0-6 alkylNR k R l and alkyl is unsubstituted or is selected from halogen, OH, -OC 1-3 Alkyl and -C 1-3 In a class of this embodiment, each R a are independently selected from the group consisting of -NH2, -CH2NH2, -(CH2)2NH2, -C(CH3)2NH2, -(CH2)3NH2, -NH(CH3), -CH2NH(CH3) and -CH2CH(OH)CH2NH2.

[0064] In another embodiment of the present invention, each R b is hydrogen, -C 1-6 Alkyl, -C 0-6 Alkyl-OC 1-6 Alkyl, -C 0-6 Alkyl-OH, -C 0-6 Alkyl-S(O) u R d 、 -C 1-6 Alkyl-C(ON(R e )2, -C 1-6 AlkylN(R e )C(O)R e , -C 0-6 Alkyl-N(R e ) 2, and halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens, and two R bSubstituents can be cyclized together with the atom to which they are attached to form a monocyclic C3_6 cycloalkyl or a monocyclic C2_6 cycloheteroalkyl ring.

[0065] In another embodiment of the present invention, each R b is hydrogen, -C 1-6 Alkyl, -C 0-6 Alkyl-OC 1-6 Alkyl, -C 0-6 and halogen, wherein the alkyl is unsubstituted or substituted with 1 to 3 halogens; and two R b Substituents can be cyclized together with the atom to which they are attached to form a monocyclic C3_6 cycloalkyl or a monocyclic C2_6 cycloheteroalkyl ring.

[0066] In another embodiment of the present invention, each R b is hydrogen, -C 1-6 Alkyl, -C 0-6 Alkyl-OC 1-6 Alkyl, -C 0-6 and halogen, wherein the alkyl is unsubstituted or substituted with 1 to 3 halogens; and two R b Substituents can be cyclized together with the atom to which they are attached to form a monocyclic C3_6 cycloalkyl or a monocyclic C2_6 cycloheteroalkyl ring.

[0067] In another embodiment of the present invention, each R b is hydrogen, -C 1-6 alkyl, and halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens; and two R b The substituents, together with the atom to which they are attached, can cyclize to form a 3- to 6-membered monocyclic ring. In this class of embodiments, each R b is hydrogen and -C 1-6 alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens; and two Rb The substituents, together with the atom to which they are attached, can be cyclized to form a 3- to 6-membered monocyclic ring. In another class of embodiments, each R b Ha-C 1-6 alkyl, wherein the alkyl is unsubstituted or substituted with 1 to 3 halogens, and two R b The substituents can be cyclized together with the atom to which they are attached to form a 3- to 6-membered monocyclic ring. In another class of this embodiment, each R b is C 1-6 and alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens. In another class of this embodiment, each R b is hydrogen.

[0068] In another embodiment of the present invention, each R c is hydrogen, -C 1-6 Alkyl, -C 0-6 Alkyl-OC 1-6 Alkyl, -C 0-6 Alkyl-OH, -C 0-6 Alkyl-S(O) v R f 、 -C 0-6 Alkyl-S(O) v N(R g ) 2、 -C 1-6 Alkyl C(O)-N(R g )2, -C 1-6 AlkylN(R g )C(O)R g , -C 0-6 Alkyl-N(R g ) 2, and halogen, wherein the alkyl is unsubstituted or substituted with 1 to 3 halogens.

[0069] In another embodiment of the present invention, each R c is hydrogen, -C 1-6 Alkyl, -C 0-6 Alkyl-OC 1-6 Alkyl, -C 0-6independently selected from the group consisting of alkyl-OH, and halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens.

[0070] In another embodiment of the present invention, each R c is hydrogen, -C 1-6 Alkyl, -C 0-6 Alkyl-OC 1-6 and halogen, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, each R c is hydrogen, -C 1-6 Alkyl, -OC 1-6 and halogen, wherein the alkyl is unsubstituted or substituted with 1 to 3 halogens.

[0071] In another embodiment of the present invention, each R c is hydrogen, -C 1-6 Alkyl and -C 0-6 Alkyl-OC 1-6 alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, each R c is hydrogen, -C 1-6 Alkyl, and -OC 1-6 In another class of this embodiment, each R is independently selected from the group consisting of: alkyl, unsubstituted or substituted with 1 to 3 halogens. c are independently selected from the group consisting of hydrogen, —CH3, and —OCH3.

[0072] In another embodiment of the present invention, each R c -C 1-6 Alkyl and -C 0-6 Alkyl-OC 1-6 alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, each R c -C 1-6 Alkyl, and -OC1-6 In another class of this embodiment, each R is independently selected from the group consisting of: alkyl, unsubstituted or substituted with 1 to 3 halogens. c is independently selected from the group consisting of -CH3 and -OCH3.

[0073] In another class of the invention, each R c is C 1-6 and alkyl, wherein alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, each R c is -CH3.

[0074] In another embodiment of the present invention, R d is hydrogen and C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R d Ha-C 1-6 and alkyl, each alkyl being unsubstituted or substituted with 1 to 3 halogens. In another class of this embodiment, R d is hydrogen.

[0075] In another embodiment of the present invention, R e is hydrogen and C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R e Ha-C 1-6 and alkyl, each alkyl being unsubstituted or substituted with 1 to 3 halogens. In another class of this embodiment, R e is hydrogen.

[0076] In another embodiment of the present invention, R f is hydrogen and C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R f Ha-C 1-6and alkyl, each alkyl being unsubstituted or substituted with 1 to 3 halogens. In another class of this embodiment, R f is hydrogen.

[0077] In another embodiment of the present invention, R g is hydrogen and C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R g Ha-C 1-6 and alkyl, each alkyl being unsubstituted or substituted with 1 to 3 halogens. In another class of this embodiment, R g is hydrogen.

[0078] In another embodiment of the present invention, R h is hydrogen and C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R h Ha-C 1-6 and alkyl, each alkyl being unsubstituted or substituted with 1 to 3 halogens. In another class of this embodiment, R h is hydrogen.

[0079] In another embodiment of the present invention, each R i is C 1-6 and alkyl, each alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, each R i Ha-C 1-6 In another class of this embodiment, each R i is -CH3.

[0080] In another embodiment of the present invention, R j are hydrogen, OH and C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R jis hydrogen and C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1 to 3 halogens. In another class of this embodiment, R j is hydrogen or OH. In another class of this embodiment, R j In another class of this embodiment, R is OH. j is hydrogen. In another class of this embodiment, R j Ha-C 1-6 alkyl, each alkyl being unsubstituted or substituted with 1 to 3 halogens.

[0081] In another embodiment of the present invention, R k is hydrogen and C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R k Ha-C 1-6 and alkyl, each alkyl being unsubstituted or substituted with 1 to 3 halogens. In another class of this embodiment, R k is hydrogen.

[0082] In another embodiment of the present invention, R l is hydrogen and C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1 to 3 halogens. In a class of this embodiment, R l Ha-C 1-6 and alkyl, each alkyl being unsubstituted or substituted with 1 to 3 halogens. In another class of this embodiment, R l is hydrogen.

[0083] In another embodiment of the present invention, 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.

[0084] In another embodiment of the present invention, 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.

[0085] In another embodiment of the present invention, 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.

[0086] In another embodiment of the present invention, 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.

[0087] In another embodiment of the present invention, 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.

[0088] In another embodiment of the present invention, the present invention provides a compound of structural formula Ia: [ka]

[0089] or a pharmaceutically acceptable salt thereof.

[0090] In another embodiment of the present invention, the present invention provides a compound of structural formula Ib: [ka]

[0091] or a pharmaceutically acceptable salt thereof.

[0092] In another embodiment of the present invention, the present invention provides a compound of structural formula Ic: [ka]

[0093] or a pharmaceutically acceptable salt thereof.

[0094] In another embodiment of the present invention, the present invention provides a compound of structural formula Id: [ka]

[0095] or a pharmaceutically acceptable salt thereof.

[0096] In another embodiment of the present invention, the present invention provides a compound of structural formula Ie: [ka]

[0097] or a pharmaceutically acceptable salt thereof.

[0098] In another embodiment of the present invention, the present invention provides a compound of structural formula If: [ka]

[0099] or a pharmaceutically acceptable salt thereof.

[0100] In another embodiment of the present invention, the present invention provides compounds of structural formula Ig: [ka]

[0101] or a pharmaceutically acceptable salt thereof.

[0102] In another embodiment of the present invention, the present invention provides compounds of structural formula Ih: [ka]

[0103] or a pharmaceutically acceptable salt thereof.

[0104] In another embodiment of the present invention, the present invention provides a compound of structural formula Ii: [ka]

[0105] or a pharmaceutically acceptable salt thereof.

[0106] In another embodiment of the present invention, the present invention provides a compound of structural formula Ij: [ka]

[0107] or a pharmaceutically acceptable salt thereof.

[0108] In another embodiment of the present invention, the present invention provides a compound of structural formula Ik: [ka]

[0109] or a pharmaceutically acceptable salt thereof.

[0110] In another embodiment of the present invention, the present invention provides a compound of structural formula II: [ka]

[0111] or a pharmaceutically acceptable salt thereof.

[0112] In another embodiment of the present invention, the present invention provides a compound of structural formula Im: [ka]

[0113] or a pharmaceutically acceptable salt thereof.

[0114] In another embodiment of the present invention, the present invention provides a compound of the structural formula In: [ka]

[0115] or a pharmaceutically acceptable salt thereof.

[0116] Compounds of structural formula I include compounds of structural formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, and In, and pharmaceutically acceptable salts, hydrates, and solvates thereof.

[0117] Another embodiment of the present invention is a compound of structural formula I, wherein: T is CH, U is CH, V is CH; X is CH2, Y is O or CH2; Z is O or CH2; W is a bond or O; Q is CR 8 and R 1 teeth, 1) -C3-9 cycloalkyl, 2) -C2-8 cycloheteroalkyl, 3) aryl, and 4) heteroaryl; The cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl are unsubstituted or R a is substituted with 1 to 5 substituents selected from R 2 is hydrogen, R 3 is hydrogen, R 4 teeth, 1) C1-3 alkyl, and 2) Ccycloalkyl; alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents selected from halogen and OC alkyl; R 5 is -CO2H or tetrazole, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is C1-6 alkyl, R 10 is C1-6 alkyl, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R l , r, s, t, u, and v are as defined above; or a pharmaceutically acceptable salt thereof.

[0118] Another embodiment of the present invention is a compound of structural formula I, wherein: T is CH, U is CH, V is CH; X is CH2, Y is CH2, Z is O, W is O, Q is CR 8 and R 1 teeth, 1) -C3-9 cycloalkyl, 2) -C2-8 cycloheteroalkyl, and 3) aryl; Cycloalkyl, cycloheteroalkyl and aryl are unsubstituted or R a is substituted with 1 to 5 substituents selected from R 2 is hydrogen, R 3is hydrogen, R 4 is C1-3 alkyl, R 5 is -CO2H, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is C1-6 alkyl, R 10 is C1-6 alkyl, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R l , r, s, t, u, and v are as defined above; or a pharmaceutically acceptable salt thereof.

[0119] Another embodiment of the present invention is a compound of structural formula I, wherein: T is CH, U is CH, V is CH; X is CH2, Y is CH2, Z is O, W is O, Q is CR 8 and R 1 teeth, 1) -C3-9 cycloalkyl, and 2) -C2-8 cycloheteroalkyl; Cycloalkyl and cycloheteroalkyl are unsubstituted or R a is substituted with 1 to 5 substituents selected from R 2 is hydrogen, R 3 is hydrogen, R 4 is C1-3 alkyl, R 5 is -CO2H, R 6 is hydrogen, R 7 is hydrogen, R 8 is hydrogen, R 9 is C1-6 alkyl, R 10 is C1-6 alkyl, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R l , r, s, t, u, and v are as defined above; or a pharmaceutically acceptable salt thereof.

[0120] Illustrative, but non-limiting examples of compounds of the present invention include the following compounds: 1) (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-(N-((S)-pyrrolidin-3-yl)carbamimidoyl)-chroman-2-yl)propanoic acid; 2) (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-(N-((R)-pyrrolidin-3-yl)-carbamimidoyl)-chroman-2-yl)propanoic acid; 3) (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-(N-((3S,5R)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamimidoyl)chroman-2-yl)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-(N-((3R,5R)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamimidoyl)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-(N-((S)-azepan-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 6) (S)-2-((R)-6-(N-((1s,4S)-4-aminocyclohexyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)-amino)-2-oxo-ethylidene)amino)oxy)propanoic acid; 7) (S)-2-((R)-6-(N-((1s,3S)-3-aminocyclobutyl)carbamimidoyl)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; 8) (S)-2-((R)-6-(N-((1r,3R)-3-aminocyclobutyl)carbamimidoyl)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-(N-(3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)carbamimidoyl)-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-((((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-(N-((R)-azepan-3-yl)carbamimidoyl)-chroman-2-yl)propanoic acid; 11) (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-(N-((S)-azepan-3-yl)carbamimidoyl)-chroman-2-yl)propanoic acid; 12) (S)-2-((R)-6-(N-(1-(aminomethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)carbamimidoyl)-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-(N-(2-azaspiro[3.5]nonan-7-yl)carbamimidoyl)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) (S)-2-((R)-6-(N-(2-azaspiro[3.3]heptan-6-yl)carbamimidoyl)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) (S)-2-((R)-6-(N-(5-aminobicyclo[3.1.1]heptan-1-yl)carbamimidoyl)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) (2S)-2-((2R)-6-(N-((1S,5R)-3-azabicyclo[3.2.0]heptan-6-yl)carbamimidoyl)-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-(N-((4R,6s)-1-azaspiro[3.3]heptan-6-yl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxo-ethylidene)amino)oxy)propanoic acid; 18) (S)-2-((R)-6-(N-((4S,6r)-1-azaspiro[3.3]heptan-6-yl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxo-ethylidene)amino)oxy)propanoic acid; 19) (S)-2-((R)-6-(N-((2s,4R)-6-azaspiro[3.5]nonan-2-yl)carbamimidoyl)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-(N-((2r,4S)-6-azaspiro[3.5]nonan-2-yl)carbamimidoyl)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-(N-(7-azaspiro[3.5]nonan-2-yl)carbamimidoyl)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-((R)-6-(N-((2r,4S)-6-azaspiro[3.4]octan-2-yl)carbamimidoyl)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; 23) (S)-2-((R)-6-(N-((2s,4R)-6-azaspiro[3.4]octan-2-yl)carbamimidoyl)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; 24) (S)-2-((R)-6-(N-((1S,2R,5R,6R)-5-aminobicyclo[4.1.0]heptan-2-yl)carbamimidoyl)-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; 25) (S)-2-((R)-6-(N-((1R,2R,5S,6S)-5-aminobicyclo[4.1.0]heptan-2-yl)carbamimidoyl)-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; 26) (S)-2-((R)-6-(N-((1S,2S,5R,6R)-5-aminobicyclo[4.1.0]heptan-2-yl)carbamimidoyl)-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-(N-((1R,2S,5S,6S)-5-aminobicyclo[4.1.0]heptan-2-yl)carbamimidoyl)-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-((((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-(N-(piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 29) (S)-2-((R)-6-(N-(1-((R)-3-amino-2-hydroxypropyl)piperidin-4-yl)carbamimidoyl)-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-(N-(1-((S)-3-amino-2-hydroxypropyl)piperidin-4-yl)carbamimidoyl)-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-((((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-(N-((R)-azepan-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 32) (S)-2-((R)-6-(N-((1r,4R)-4-aminocyclohexyl)carbamimidoyl)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-((((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-(N-((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 34) (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-(N-((1r,4R)-4-(methylamino)cyclohexyl)-carbamimidoyl)chroman-2-yl)propanoic acid; 35) (S)-2-((R)-6-(N-(4-aminobicyclo[2.2.2]octan-1-yl)carbamimidoyl)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-((((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-(N-(azetidin-3-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 37) (S)-2-((R)-6-(N-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamimidoyl)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-(N-(4-(aminomethyl)phenyl)carbamimidoyl)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-((((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-(N-((R)-piperidin-3-yl)carbamimidoyl)-chroman-2-yl)propanoic acid; 40) (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-(N-((S)-piperidin-3-yl)carbamimidoyl)-chroman-2-yl)propanoic acid; 41) (S)-2-((R)-6-(N-((1s,4S)-4-(aminomethyl)cyclohexyl)carbamimidoyl)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-(N-((1r,4R)-4-(aminomethyl)cyclohexyl)carbamimidoyl)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-(N-((2s,4R)-6-azaspiro[3.4]octan-2-yl)carbamimidoyl)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-(N-((2r,4S)-6-azaspiro[3.4]octan-2-yl)carbamimidoyl)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-(N-((1R,3S)-3-aminocyclopentyl)carbamimidoyl)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-(N-((1S,3R)-3-aminocyclopentyl)carbamimidoyl)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; 47) (S)-2-((R)-6-(N-((1S,3S)-3-aminocyclopentyl)carbamimidoyl)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; 48) (S)-2-((R)-6-(N-((1R,3R)-3-aminocyclopentyl)carbamimidoyl)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; 49) (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-(N-((S)-3,3-dimethylpiperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 50) (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-(N-((R)-3,3-dimethylpiperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 51) (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-(N-((3R,4S)-3-(hydroxymethyl)-piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 52) (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-(N-((3S,4R)-3-(hydroxymethyl)-piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 53) (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-(N-((2S,4S)-2-(hydroxymethyl)-piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 54) (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-(N-((2R,4R)-2-(hydroxymethyl)-piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 55) (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-(N-((2R,4R)-2-methylpiperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 56) (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-(N-((2S,4S)-2-methylpiperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 57) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-methylcyclohexyl)carbamimidoyl)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; 58) (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-methylcyclohexyl)carbamimidoyl)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; 59) (S)-2-((R)-6-(N-((1s,4S)-4-(aminomethyl)-4-hydroxycyclohexyl)carbamimidoyl)-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; 60) (S)-2-((R)-6-(N-((1r,4R)-4-(aminomethyl)-4-hydroxycyclohexyl)carbamimidoyl)-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; 61) (S)-2-((R)-6-(N-((2R,4r,6R)-6-aminospiro[3.3]2-yl)carbamimidoyl)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; 62) (S)-2-((R)-6-(N-((2S,4s,6S)-6-aminospiro[3.3]heptan-2-yl)carbamimidoyl)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; 63) (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(2-methoxyethyl)cyclohexyl)carbamimidoyl)-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; 64) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(2-methoxyethyl)cyclohexyl)carbamimidoyl)-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; 65) (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(2-hydroxyethyl)cyclohexyl)carbamimidoyl)-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; 66) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(2-hydroxyethyl)cyclohexyl)carbamimidoyl)-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; 67) (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-(N-(trans-3-(methylamino)cyclobutyl)carbamimidoyl)chroman-2-yl)propanoic acid; 68) (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-(N-(cis-3-(methylamino)cyclobutyl)carbamimidoyl)chroman-2-yl)propanoic acid; 69) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(hydroxymethyl)cyclohexyl)carbamimidoyl)-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; 70) (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(hydroxymethyl)cyclohexyl)carbamimidoyl)-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; 71) (S)-2-((R)-6-(N-((1r,4R)-4-amino-1-methylcyclohexyl)carbamimidoyl)-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; 72) (S)-2-((R)-6-(N-((1s,4S)-4-amino-1-methylcyclohexyl)carbamimidoyl)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; 73) (S)-2-((R)-6-(N-((1s,4S)-4-(aminomethyl)-4-methoxycyclohexyl)carbamimidoyl)-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; 74) (S)-2-((R)-6-(N-((1r,3R)-3-amino-3-methylcyclobutyl)carbamimidoyl)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; 75) (S)-2-((R)-6-(N-((1s,3S)-3-amino-3-methylcyclobutyl)carbamimidoyl)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; 76) (S)-2-((R)-6-(N-((1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-yl)carbamimidoyl)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; 77) (S)-2-((R)-6-(N-((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)carbamimidoyl)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; 78) (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-(hydroxymethyl)cyclobutyl)-carbamimidoyl)-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; 79) (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-(hydroxymethyl)cyclobutyl)-carbamimidoyl)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; 80) (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-hydroxycyclobutyl)carbamimidoyl)-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; 81) (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-hydroxycyclobutyl)carbamimidoyl)-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; 82) (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-methoxycyclobutyl)carbamimidoyl)-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; 83) (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-methoxycyclobutyl)carbamimidoyl)-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; 84) (S)-2-((R)-6-(N-((1r,3R)-3-amino-1-methylcyclobutyl)carbamimidoyl)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; 85) (S)-2-((R)-6-(N-((1s,3S)-3-amino-1-methylcyclobutyl)carbamimidoyl)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; 86) (S)-2-((R)-6-(N-((1s,3S)-3-amino-3-(2-hydroxyethyl)cyclobutyl)carbamimidoyl)-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; 87) (S)-2-((R)-6-(N-((1r,3R)-3-amino-3-(2-hydroxyethyl)cyclobutyl)carbamimidoyl)-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; 88) (S)-2-((R)-6-(N-((1r,3R)-3-amino-3-(hydroxymethyl)cyclobutyl)carbamimidoyl)-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; 89) (S)-2-((R)-6-(N-((1s,3S)-3-amino-3-(hydroxymethyl)cyclobutyl)carbamimidoyl)-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; 90) (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-(N-((1r,3R)-3-(hydroxymethyl)-3-(methylamino)cyclobutyl)carbamimidoyl)chroman-2-yl)propanoic acid; 91) (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-(N-((1s,3S)-3-(hydroxymethyl)-3-(methylamino)cyclobutyl)carbamimidoyl)chroman-2-yl)propanoic acid; 92) (S)-2-((R)-6-(N-((1r,3R)-3-amino-3-(2-methoxyethyl)cyclobutyl)carbamimidoyl)-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; 93) (S)-2-((R)-6-(N-((1s,3S)-3-amino-3-(2-methoxyethyl)cyclobutyl)carbamimidoyl)-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; 94) (S)-2-((R)-6-(N-((1S,3R)-3-amino-3-((S)-2,3-dihydroxypropyl)cyclobutyl)-carbamimidoyl)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; 95) (S)-2-((R)-6-(N-((1R,3R)-3-amino-3-((R)-2,3-dihydroxypropyl)cyclobutyl)-carbamimidoyl)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; 96) (S)-2-((R)-6-(N-((1R,3S)-3-amino-3-((S)-2,3-dihydroxypropyl)cyclobutyl)-carbamimidoyl)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; 97) (S)-2-((R)-6-(N-((1S,3S)-3-amino-3-((R)-2,3-dihydroxypropyl)cyclobutyl)-carbamimidoyl)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; 98) (S)-2-((R)-6-(N-((1S,3R)-3-amino-3-((S)-1,2-dihydroxyethyl)cyclobutyl)-carbamimidoyl)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; 99) (S)-2-((R)-6-(N-((1R,3R)-3-amino-3-((R)-1,2-dihydroxyethyl)cyclobutyl)-carbamimidoyl)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; 100) (S)-2-((R)-6-(N-((1S,3S)-3-amino-3-((R)-1,2-dihydroxyethyl)cyclobutyl)-carbamimidoyl)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; 101) (S)-2-((R)-6-(N-((1R,3S)-3-amino-3-((S)-1,2-dihydroxyethyl)cyclobutyl)-carbamimidoyl)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; 102) (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-(N-((1s,4S)-4-((methylamino)methyl)cyclohexyl)carbamimidoyl)chroman-2-yl)propanoic acid; 103) (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-(N-((1r,4R)-4-((methylamino)methyl)cyclohexyl)carbamimidoyl)chroman-2-yl)propanoic acid; 104) (S)-2-((R)-6-(N-((1R,4S)-4-aminocycloheptyl)carbamimidoyl)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; 105) (S)-2-((R)-6-(N-((1R,4R)-4-aminocycloheptyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxo-ethylidene)amino)oxy)propanoic acid; 106) (S)-2-((R)-6-(N-((1S,4S)-4-aminocycloheptyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxo-ethylidene)amino)oxy)propanoic acid; 107) (S)-2-((R)-6-(N-((1S,4R)-4-aminocycloheptyl)carbamimidoyl)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; 108) (S)-2-((R)-6-(N-((1R,3R)-3-aminocyclohexyl)carbamimidoyl)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; 109) (S)-2-((R)-6-(N-((1S,3S)-3-aminocyclohexyl)carbamimidoyl)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; 110) (S)-2-((R)-6-(N-((1R,3S)-3-aminocyclohexyl)carbamimidoyl)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; 111) (S)-2-((R)-6-(N-((1S,3R)-3-aminocyclohexyl)carbamimidoyl)-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; 112) (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)cyclobutyl)carbamimidoyl)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; 113) (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)cyclobutyl)carbamimidoyl)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; 114) (S)-2-((R)-6-(N-((1S,3S)-3-amino-2,2-dimethylcyclobutyl)carbamimidoyl)-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; 115) (S)-2-((R)-6-(N-((2S,4s,7S)-2-aminospiro[3.5]nonan-7-yl)carbamimidoyl)-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; 116) (S)-2-((R)-6-(N-((2R,4r,7R)-2-aminospiro[3.5]nonan-7-yl)carbamimidoyl)-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; 117) (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-methylcyclobutyl)carbamimidoyl)-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; 118) (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-methylcyclobutyl)carbamimidoyl)-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; 119) (S)-2-((R)-6-(N-(6-(aminomethyl)-6-fluorospiro[3.3]heptan-2-yl)carbamimidoyl)-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; 120) (S)-2-((R)-6-(N-((1R,3S)-3-(aminomethyl)-2,2-dimethylcyclobutyl)-carbamimidoyl)-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; 121) (2S)-2-((2R)-6-(N-(6-(aminomethyl)spiro[3.3]heptan-2-yl)carbamimidoyl)-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; 122) (2S)-2-((2R)-6-(N-((1S)-1-aminospiro[2.3]hexan-5-yl)carbamimidoyl)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; 123) (2S)-2-((2R)-6-(N-((1R)-1-aminospiro[2.3]hexan-5-yl)carbamimidoyl)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; 124) (S)-2-((R)-6-(N-((1s,3S)-3-aminocyclobutyl)carbamimidoyl)-5-(methoxymethyl)-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; 125) (S)-2-((R)-6-(N-((1s,3S)-3-aminocyclobutyl)carbamimidoyl)-7-(methoxymethyl)-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; 126) (S)-2-((R)-6-(N-((1s,4S)-4-amino-1-(methoxymethyl)cyclohexyl)-carbamimidoyl)-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; 127) (S)-2-((R)-6-(N-((1r,4R)-4-amino-1-(methoxymethyl)cyclohexyl)-carbamimidoyl)-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; 128) (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(methoxymethyl)cyclohexyl)-carbamimidoyl)-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; 129) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(methoxymethyl)cyclohexyl)-carbamimidoyl)-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; 130) (S)-2-((R)-6-(N-((1s,4S)-4-(aminomethyl)-1-methylcyclohexyl)carbamimidoyl)-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; 131) (S)-2-((R)-6-(N-((1r,4R)-4-(aminomethyl)-1-methylcyclohexyl)carbamimidoyl)-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; 132) (S)-2-((R)-6-(N-((1s,4S)-4-(2-aminopropan-2-yl)cyclohexyl)carbamimidoyl)-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; 133) (S)-2-((R)-6-(N-((1r,4R)-4-(2-aminopropan-2-yl)cyclohexyl)carbamimidoyl)-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; 134) (S)-2-((R)-6-(N-((1s,3S)-3-aminocyclobutyl)carbamimidoyl)-7-methylchroman-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; 135) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(hydroxymethyl)-1-methylcyclohexyl)-carbamimidoyl)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; 136) (S)-2-((R)-6-(N-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamimidoyl)-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; 137) (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-(N-((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 138) (S)-2-((R)-6-(N-(1-(2-aminoethyl)cyclopropyl)carbamimidoyl)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; 139) (S)-2-((R)-6-(N-(1-(3-aminopropyl)cyclopropyl)carbamimidoyl)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 140) (S)-2-((R)-6-(N-(1-(2-aminoethyl)cyclobutyl)carbamimidoyl)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 pharmaceutically acceptable salts thereof.

[0121] Illustrative, but non-limiting examples of compounds of the present invention include the following compounds: [ka] TIFF0007671398000018.tif185150

[0122] or a diastereomer thereof, and a pharmaceutically acceptable salt thereof.

[0123] Other embodiments of the present invention include the following.

[0124] (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.

[0125] (b) The pharmaceutical composition of (a), further comprising a second compound that is a beta-lactamase inhibitor.

[0126] (c) The pharmaceutical composition of (b), wherein the second compound is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacbactam, vaborbactam, didebactam, durobactam, enmetazobactam, and QPX7728 (xeruborbactam), or a pharmaceutically acceptable salt thereof.

[0127] (d) A pharmaceutical composition comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (ii) a second compound which is a beta-lactamase inhibitor compound, wherein the compound of formula (I) and the second compound are each used in amounts that provide a combined effect in the treatment or prevention of a bacterial infection.

[0128] (e) The combination of (d), wherein the second compound is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacbactam, vaborbactam, didebactam, durobactam, enmetazobactam, and QPX7728 (xeruborbactam), or a pharmaceutically acceptable salt thereof.

[0129] (f) A method of treating a bacterial infection in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0130] (g) A method for preventing and / or treating a bacterial infection, comprising 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.

[0131] (h) A method for treating a bacterial infection, comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition of (a), (b), (c), (d) or (e).

[0132] (i) A method for treating a bacterial infection according to (f), (g) or (h), wherein the bacterial infection is caused by a gram-negative bacterium.

[0133] (j) A method for treating a bacterial infection according to (f), (g), (h) or (i), wherein the bacterial infection is caused by Pseudomonas aeruginosa or Acinetobacter baumannii.

[0134] The present invention also includes a compound of formula (I) or a pharmaceutically acceptable salt thereof for (i) use in, (ii) use as, or (iii) use in the preparation (or manufacture) of a medicament for administering to or treating a bacterial infection, including infections caused by multidrug-resistant bacterial strains. In these uses, the compound of the invention can optionally be used in combination with one or more second therapeutic agents, including relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacbactam, vaborbactam, didebactam, durobactam, enmetazobactam, and QPX7728 (xeruborbactam), or pharmaceutically acceptable salts thereof.

[0135] Further embodiments of the present invention include the pharmaceutical compositions, combinations and methods described above in (a)-(j) and the uses described in the preceding paragraphs, where the compound of the invention as used herein is a compound of one of the above embodiments, subembodiments, classes or subclasses. The compound may be used in these embodiments, optionally in the form of a pharmaceutically acceptable salt.

[0136] In the compound and salt embodiments provided above, it is understood that each embodiment can be combined with one or more other embodiments, so long as such combinations provide stable compounds or salts and are consistent with the description of the embodiments. It should further be understood that the composition and method embodiments provided as (a) through (j) above are understood to include all embodiments of the compounds and / or salts, including those resulting from combinations of embodiments.

[0137] Further embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses described in the preceding paragraphs, wherein the compound of the present invention or its salt used 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, the term "substantially pure" is understood to refer to the purity of the compound of formula (I) or its salt itself, i.e., the active ingredient in the composition.

[0138] Definitions and Abbreviations Terms used herein have their usual meanings, and the meaning of such terms is independent at each occurrence. Nevertheless, unless otherwise specified, 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. When a compound is referred to using both a chemical structure and a chemical name, and there is ambiguity between the structure and the name, the structure prevails. These definitions apply regardless of whether the term is used alone or in combination with other terms, unless otherwise specified. Thus, the definition of "alkyl" applies not only to "alkyl" but also to the "alkyl" moieties of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc.

[0139] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0140] The term "β-lactamase inhibitor" refers to a compound capable of inhibiting enzymatic activity from β-lactamase. As used herein, inhibiting β-lactamase activity means inhibiting the activity of class A, C, and / or D β-lactamases. For antibacterial applications, inhibition at a 50% inhibitory concentration is preferably achieved at about 100 micrograms / mL or less, or about 50 micrograms / mL or less, or about 25 micrograms / mL or less. The terms "class A," "class B," "class C," and "class D" β-lactamase are understood by those skilled in the art and are described in S.G. Walley, β-lactamase: mechanisms of action, in The Chemistry of β-Lactams, M.I. Page, Ed.; Chapman and Hall, London, (1992) 198-228.

[0141] The term "metallo-β-lactamase" refers to a metalloprotein capable of inactivating β-lactam antibiotics. β-lactamases can be enzymes that catalyze the hydrolysis of the β-lactam ring of β-lactam antibiotics. Of particular interest herein are microbial metallo-β-lactamases. Metallo-β-lactamases can be, for example, zinc metallo-β-lactamases. β-lactamases of interest include, for example, those disclosed in S.G. Walley, β-lactamase: mechanisms of action, in The Chemistry of β-Lactams, M.I. Page, Ed.; Chapman and Hall, London, (1992) 198-228. Beta-lactamases of particular interest herein include Escherichia coli metallo-beta-lactamases (e.g., New Delhi metallo-beta-lactamase, NDM), Serratia marcescens metallo-beta-lactamases (e.g., IMP), and Klebsiella metallo-beta-lactamases (e.g., Verona integron-encoded metallo-beta-lactamase, VIM). Additional metallo-beta-lactamases of interest herein include SPM-, GIM-, SIM-, KHM-, AIM-, DIM-, SMB-, TMB-, and FIM-type enzymes.

[0142] The term "antibiotic" refers to a compound or composition that reduces the viability of or inhibits the growth or proliferation of microorganisms. The phrase "inhibiting growth or proliferation" means extending the generation time (i.e., the time required for bacterial cells to divide or for a population to double) by at least about two-fold. Preferred antibiotics are those that can extend the generation time by at least about 10-fold or more (e.g., at least about 100-fold, or even indefinitely, such as in the case of total cell death). As used in this disclosure, antibiotics are further intended to include antibacterial, bacteriostatic, or bactericidal agents. Examples of antibiotics include penicillin, cephalosporin, and carbapenem.

[0143] The term "β-lactam antibiotic" refers to a compound having antibiotic properties that includes a β-lactam function. Non-limiting examples of β-lactam antibiotics include penicillins, cephalosporins, penems, carbapenems, and monobactams.

[0144] The term "about," when modifying a quantity of a substance or composition (e.g., kg, L, or the like), 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 performed), etc., refers to variations in the numerical quantity that may occur, for example, due to typical measuring, handling, and sampling procedures involved in preparing, characterizing, and / or using the substance or composition, due to inadvertent errors in these procedures, due to differences in the manufacture, origin, or purity of ingredients used to make or use the composition or perform the procedure, etc. 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%.

[0145] Another embodiment of the present invention is a compound of Formula (I) or a pharmaceutically acceptable salt thereof as originally defined or as defined in any of the preceding embodiments, subembodiments, aspects, classes, or subclasses, wherein the compound or salt thereof is in substantially pure form. As used herein, "substantially pure" suitably means that a product containing a compound of Formula (I) or a salt thereof (e.g., a product isolated from a reaction mixture resulting in the compound or salt) is at least about 60% by weight, typically at least about 70% by weight, preferably at least about 80% by weight, more preferably at least about 90% by weight (e.g., about 90% to about 99% by weight), even more preferably at least about 95% by weight (e.g., about 95% to about 99% by weight, or about 98% to 100% by weight), and most preferably at least about 99% by weight (e.g., 100% by weight) of the compound or salt. Purity levels of compounds and salts can be determined using standard analytical methods, such as thin-layer chromatography, gel electrophoresis, high-performance liquid chromatography, and / or mass spectrometry. When two or more analytical methods are used and the methods result in an experimentally significant difference in the level of purity determined, the method yielding the higher purity takes precedence. A compound or salt that is 100% pure is one that is free of detectable impurities as determined by standard analytical methods.

[0146] With respect to the compounds of the present invention that have one or more asymmetric centers and may occur as a mixture of stereoisomers, a substantially pure compound can be either a substantially pure mixture of stereoisomers or a substantially pure individual diastereomer or enantiomer, unless otherwise specified. The present invention encompasses all stereoisomers of the compounds of formula (I). Unless a specific stereochemistry is indicated, the present invention is meant to encompass all such isomers of these compounds. All asymmetric centers present in the compounds of formula (I) can have, independently of one another, either the (R) or (S) configuration.

[0147] When a bond to a chiral carbon in a structural formula of the present invention is shown as a straight line, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof, are encompassed by the formula. Similarly, when a compound name is listed without a chiral designation for the chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore individual enantiomers and mixtures thereof, are encompassed by the name. The creation of specific stereoisomers or mixtures thereof may be specified in the examples in which 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 the present invention.

[0148] The present invention includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers in any ratio, for example, mixtures of enantiomers and / or diastereomers. Accordingly, enantiomers are subject of the present invention in their enantiomerically pure form, both as levorotatory and dextrorotatory antipodes, in the form of racemates, and in the form of mixtures of the two enantiomers in any ratio. In the case of cis / trans isomerism, the present invention includes both cis and trans forms, as well as mixtures of these forms in any ratio. Individual stereoisomers can be prepared, if desired, by conventional methods, for example, by separation of the mixture by chromatography or crystallization, by using stereochemically uniform starting materials for synthesis, or by stereoselective synthesis. Optionally, derivatization can be carried out before the separation of stereoisomers. Separation of the mixture of stereoisomers can be carried out at an intermediate stage during the synthesis of the compound of formula (I) or on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known configuration. Where the compounds of the present invention can tautomerize, all individual tautomers and mixtures thereof are included within the scope of the present invention. Unless a specific isomer, salt, solvate (including hydrate) or solvated salt of such a racemate, enantiomer, diastereomer or tautomer is indicated, the present invention includes all such isomers, as well as the salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0149] definition "Ac" is acetyl, CH3C(=O)-.

[0150] "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, may also 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.

[0151] "Aryl" refers to 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 the aryl group defined above fused to an aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, or heteroaryl ring. Examples of aryl include phenyl and naphthyl. In one embodiment of the present invention, the aryl is phenyl.

[0152] As used herein, "cycloalkyl" refers to a saturated monocyclic, bicyclic, tricyclic, fused, spirocyclic, or bridged ring system containing 3 to 14 carbon atoms. A cycloalkyl ring system can contain two or more rings, and the rings can be bonded through ring carbons. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, and the like. In one embodiment of the present invention, a cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, and cyclohexane. In another embodiment, a cycloalkyl is selected from cyclobutane and cyclohexane. In another embodiment, a cycloalkyl is cyclobutane. In another embodiment, a cycloalkyl is cyclohexane. In another embodiment, cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.2]octane, spiro[3.3]heptane, spiro[3.5]nonane, and spiro[2.3]hexane. In another embodiment of the present invention, —C cycloalkyl is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, bicyclo[1.1.1]pentane, bicyclo[3.1.1]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.2]octane, spiro[3.3]heptane, spiro[3.5]nonane, and spiro[2.3]hexane. In another embodiment of the present invention, -C3-9 cycloalkyl is selected from cyclobutane, cyclohexane, cycloheptane, and bicyclo[4.1.0]heptane. In another embodiment of the present invention, -C3-9 cycloalkyl is bicyclo[4.1.0]heptane. In another embodiment of the present invention, -C3-9 cycloalkyl is cycloheptane. In another embodiment of the present invention, -C3-9 cycloalkyl is cyclohexane. In another embodiment of the present invention, -C3-9 cycloalkyl is cyclobutane.

[0153] "Cycloalkenyl" means a monocyclic ring or a bicyclic, spirocyclic, fused or bridged carbocyclic ring system having the specified number of carbon atoms containing at least one double bond. Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cycloheptenyl, and the like.

[0154] As used herein, "cycloheteroalkyl" refers to a saturated monocyclic or bicyclic, tricyclic, spirocyclic, fused, or bridged ring system containing 3 to 14 ring atoms, where 1 to 4 ring atoms are independently N, NH, S (including SO and SO), and O, and the remaining ring atoms are carbon atoms. When a heterocycloalkyl contains more than one ring, the rings may be fused, bridged, or spirocyclic. A cycloheteroalkyl group can be attached through a ring carbon or ring nitrogen atom (if present). When a ring or ring system contains one or more N atoms, the N may be in the form of a quaternary amine. The nitrogen or sulfur atom (if present) of a heterocycloalkyl may be optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. A cycloheteroalkyl ring may be substituted on a ring carbon and / or a 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 of the invention, the cycloheteroalkyl is selected from azetidine, pyrrolidine, piperidine, azepane, 2-oxabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 3-azabicyclo[3.2.0]heptane, 1-azaspiro[3.3]heptane, 6-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, and 6-azaspiro[3.4]octane. In another embodiment, the cycloheteroalkyl is selected from piperidine and azepane.In another embodiment, the C2-8 cycloheteroalkyl is selected from the group consisting of azetidine, pyrrolidine, piperidine, azepane, 2-oxabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.1]octane, 8-azabicyclo[3.2.1]octane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.3]heptane, 3-azabicyclo[3.2.0]heptane, 1-azaspiro[3.3]heptane, 6-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, and 6-azaspiro[3.4]octane. In another embodiment, the C2-8 cycloheteroalkyl is piperidine. In another embodiment, the C2-8 cycloheteroalkyl is azepane.

[0155] "Cycloheteroalkenyl" means a monocyclic ring or a bicyclic, fused, spirocyclic, or bridged ring system containing 3 to 14 ring atoms and containing at least one double bond and at least one heteroatom. Examples of cycloheteroalkenyl include dihydropyran, dihydrofuran, and the like.

[0156] "Heteroaryl" means a monocyclic ring or a bicyclic or fused ring system containing 5 to 14 ring atoms containing at least one ring heteroatom selected from N, NH, S (including SO and SO), and O, wherein at least one of the heteroatom-containing rings is aromatic. The term heteroaryl encompasses heteroaryl groups as defined above fused to an aryl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, or heteroaryl ring. In the case of heteroaryl ring systems in which one or more of the rings are saturated or partially saturated and contain one or more N atoms, the N may be in the form of a quaternary amine. Any nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. A heteroaryl group may be optionally substituted with 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 the S-oxide and dioxide), benzotriazolyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, etc. In one embodiment of the present invention, heteroaryl is selected from pyridine.

[0157] "Halogen" includes fluorine, chlorine, bromine, and iodine. In one embodiment, the halogen is fluorine, chlorine, bromine, or iodine. In another embodiment, the halogen is fluorine or chlorine. In another embodiment, the halogen is chlorine, fluorine, or iodine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is chlorine. In another embodiment, the halogen is bromine. In another embodiment, the halogen is iodine.

[0158] "Me" stands for methyl.

[0159] "Oxo" means an oxygen atom that is double bonded to another atom, representing "=O".

[0160] "Quaternary salt" means a cation formed by four covalent bonds to a nitrogen.

[0161] When any variable (e.g., R, 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 wavy line across a bond of a substituent variable indicates the point of attachment.

[0162] "Saturated" means containing only single bonds.

[0163] "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.

[0164] When any variable (e.g., R, 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 wavy line across a bond of a substituent variable indicates the point of attachment.

[0165] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent corresponds to: [ka]

[0166] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, salts and / or dosage forms that are safe and suitable for administration to humans or animals using sound medical judgment and in accordance with all applicable government regulations.

[0167] The compounds of Formula I may contain one or more asymmetric centers and therefore may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to encompass all such isomeric forms of the compounds of Formula I.

[0168] 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, if necessary, by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized with an asymmetric center of known absolute configuration, or with a reagent containing an atom sufficiently heavy to make absolute assignment.

[0169] If desired, a racemic mixture of a compound can be separated so that individual enantiomers are isolated. Separation can be achieved by methods well known in the art, for example, by coupling a racemic mixture of a compound to an enantiomerically pure compound to form a diastereomeric mixture, and then separating the individual diastereoisomers by standard methods such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt with an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to a pure enantiomer by cleavage of the added chiral residue. A racemic mixture of a compound can also be directly separated by chromatography using a chiral stationary phase, methods of which are well known in the art.

[0170] 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.

[0171] Some of the compounds described herein contain olefinic double bonds, and unless otherwise specified, are meant to include both E and Z geometric isomers.

[0172] Tautomers are defined as compounds that undergo rapid proton shift from one atom of a compound to another atom of a compound.Some of the compounds described herein may exist as tautomers with different hydrogen attachment points.Such an example may be a ketone and its enol form, known as keto-enol tautomers.Individual tautomers and their mixtures are encompassed by the compounds of formula I.

[0173] In compounds of general formula I, atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The present invention is meant to include all suitable isotopic variations of compounds of structural formula I. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), Deuterium ( 2 H), and tritium ( 3H). Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium may provide certain therapeutic advantages, such as increased in vivo half-life or reduced dose requirements, or may provide compounds useful as standards for characterizing biological samples. Tritium is radioactive and may therefore provide radiolabeled compounds useful as tracers in metabolic or kinetic studies. Isotopically enriched compounds within structural formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by processes similar to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0174] Furthermore, some of the crystalline forms of the compounds of the present invention may exist as polymorphs, and as such are intended to be included in the present invention. Furthermore, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.

[0175] It is generally preferred to administer the compounds of the present invention as enantiomerically pure formulations. Racemic mixtures can be separated into individual enantiomers by any of several conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

[0176] A "stable" compound is one that can be prepared and isolated and whose structure and properties will persist or remain essentially unchanged for a period of time sufficient to permit use of the compound for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present invention are limited to stable compounds encompassed by Formula (I).

[0177] In selecting compounds of the present invention, one skilled in the art will recognize that the various substituents, ie, R1, R2, etc., should be selected according to well-known principles of connectivity and stability of chemical structures.

[0178] The term "substituted" shall be deemed to include multiple degrees of substitution by a specified substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound may be singly or multiply independently substituted with one or more of the disclosed or claimed substituent moieties. Independently substituted means that the (two or more) substituents may be the same or different. Where a group, e.g., C1-C8 alkyl, is indicated as substituted, such substitution may also occur when such group is part of a larger substituent, e.g., -C1-C6 alkyl-C3-C7 cycloalkyl and -C1-C8 alkyl-aryl.

[0179] Unless expressly stated otherwise in the specific context, any of the various cyclic rings and ring systems described herein may be attached to the remainder of the compound at any ring atom (i.e., any carbon atom or any heteroatom) which results in a stable compound.

[0180] Unless expressly stated otherwise, all ranges cited herein are inclusive. For example, a heteroaromatic ring described as containing "1 to 4 heteroatoms" means that the ring can contain 1, 2, 3, or 4 heteroatoms. Any range cited herein should also be understood to include within its scope all subranges within that range. Thus, for example, a heterocyclic ring described as containing "1 to 4 heteroatoms" is intended to include 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 in conjunction with a chain, e.g., 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, such as C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C3-C6, C4-C 6、Includes C5-C6 and all other possible combinations.

[0181] It should also be noted that in the text, schemes, examples, and tables herein, any carbon and heteroatom with unsatisfied valences is assumed to have the number of hydrogen atoms sufficient to satisfy the valences.

[0182] The compounds of the present invention have at least one asymmetric center and may have one or more additional centers as a result of the presence of certain substituents and / or substituent patterns.Therefore, the compounds of the present invention may exist as a mixture of stereoisomers or as individual diastereomers or enantiomers.All isomers of these compounds, whether alone or in mixture, are within the scope of the present invention.

[0183] The term "compound" refers to the free compound and any hydrates or solvates thereof, provided they are stable. A hydrate is a compound complexed with water, and a solvate is a compound complexed with an organic solvent.

[0184] As mentioned above, the compound of the present invention can be used in the form of pharmaceutically acceptable salts.As used herein, it is understood that the compound of the present invention can include pharmaceutically acceptable salts and non-pharmaceutically acceptable salts when they are used as a free compound or a precursor of its pharmaceutically acceptable salt, or in other synthetic operations.

[0185] The term "drug resistance," in relation to a Gram-negative bacterial strain, refers to a strain that is no longer susceptible to at least one previously effective drug and has developed the ability to withstand antibiotic challenge with at least one previously effective drug. "Multidrug resistance" refers to a strain that is no longer susceptible to two or more previously effective drugs and has developed the ability to withstand antibiotic challenge with two or more previously effective drugs. Drug-resistant strains can pass on their resistance to their progeny. This resistance can result from random genetic mutations in bacterial cells that alter susceptibility to a single drug or to various drugs.

[0186] The term "pharmaceutically acceptable salts" refers to salts that possess the effectiveness of the parent compound and that are not biologically or otherwise undesirable (e.g., not toxic or otherwise harmful to the recipient). The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.

[0187] Salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention, generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethyl acetate, digluconate, dihydrochloride, and dodecylsulfonate. , edetate, edisylate, estolate, esylate, ethanesulfonate, formate, formic acid, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic acid, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, paclitaxel These include hydroxybenzoates, palmitates, pantothenates, pectinates, persulfates, phosphates / diphosphates, pimelate, phenylpropionates, polygalacturonates, propionates, salicylates, stearate, sulfates, acetates, succinates, tannates, tartrates, teoclates, thiocyanates, tosylates, triethiodides, trifluoroacetates, undeconates, valerates, and the like.Furthermore, when a compound of the present invention possesses 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, manganese, mangamous, potassium, sodium, zinc, etc. Ammonium, calcium, magnesium, potassium, and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexylamine, 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. Additionally included are basic nitrogen-containing groups that can be quaternized with agents such as lower alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl; and diamyl sulfate, long chain halides, e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl bromide and phenethyl, etc.

[0188] These salts can be obtained by known methods, for example, by mixing the compound of the present invention with a solution containing the desired acid, base, etc. in equivalent amounts, and then recovering the desired salt by filtering the salt or evaporating the solvent. The compound of the present invention and its salts can form solvates with solvents such as water, ethanol, or glycerol. The compound of the present invention may simultaneously form acid addition salts and salts containing bases, depending on the type of substituents on the side chain.

[0189] As noted above, the present invention includes pharmaceutical compositions comprising a compound of Formula I of the present invention, optionally one other active ingredient (e.g., a β-lactamase inhibitor), and a pharmaceutically acceptable carrier. The characteristics of the carrier will depend on the route of administration. "Pharmaceutically acceptable" means that the components of the pharmaceutical composition must be compatible with each other, not interfere with the efficacy of the active ingredient(s), and not be deleterious (e.g., toxic) to the recipient thereof. Thus, in addition to the inhibitor, compositions according to the present invention may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.

[0190] Additionally, as noted above, the present invention includes a method for treating a bacterial infection, comprising 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. As used herein, the term "subject" (or "patient") refers to an animal, preferably a mammal, most preferably a human, who is the object of treatment, observation, or experiment. The term "administration" and variations thereof (e.g., "administering" a compound) with respect to a compound of Formula (I) means providing the compound or a pharmaceutically acceptable salt thereof to an individual in need of 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 variations thereof are understood to include providing the compound or a salt thereof and the other agent(s) at the same time or at different times, respectively. When agents of a combination are administered simultaneously, they can be administered together in a single composition, or they can be administered separately.

[0191] It is understood that a "combination" of active agents can be a single composition containing all active agents, or multiple compositions each containing one or more active agents. In the case of two active agents, the combination can be either a single composition containing both agents or two separate compositions each containing one of the agents. In the case of three active agents, the combination can be either a single composition containing all three agents, three separate compositions each containing one of the agents, or two compositions, one containing two of the agents and the other containing the third agent, etc.

[0192] The compositions and combinations of the present invention are suitably administered in an effective amount. As used herein, the term "effective amount" refers to an amount of active compound sufficient to inhibit bacterial growth and thereby induce the desired response in a cell, tissue, system, animal, or human (i.e., an "inhibitory effective amount"). In one embodiment, the effective amount is a "therapeutically effective amount" for alleviating the symptoms of the disease or condition being treated (e.g., curing a condition associated with bacterial infection and / or bacterial drug resistance). In another embodiment, the effective amount is a "prophylactically effective amount" for preventing the symptoms of the disease or condition being prevented. When the active compound (i.e., active ingredient) is administered as a salt, references to the amount of active ingredient are to the free acid or free base form of the compound.

[0193] The compositions of the present invention are suitably administered parenterally, orally, sublingually, transdermally, topically, intranasally, intratracheally, intraocularly, or rectally, and are 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 of Remington - The Science and Practice of Pharmacy, 21st Edition, 2006. In one embodiment, the compounds of the present invention are administered intravenously in a hospital setting. In another embodiment, administration is oral, such as in a tablet or capsule form. When administered systemically, therapeutic compositions are suitably administered at a dosage sufficient to achieve blood levels of the inhibitor of, for example, at least about 1 microgram / mL, and in further embodiments, at least about 10 micrograms / mL, and at least about 25 micrograms / mL. For local administration, much lower concentrations may be effective, and much higher concentrations may be tolerated.

[0194] Intravenous administration of the compounds of the present invention can be achieved by reconstituting the powder form of the compound with an acceptable solvent. Suitable solvents include, for example, saline (e.g., 0.9% sodium chloride injection) and sterile water (e.g., sterile water for injection, bacteriostatic water for injection containing methylparaben and propylparaben, or bacteriostatic water for injection containing 0.9% benzyl alcohol). Powder forms of the compounds can be obtained by gamma-irradiating the compound or lyophilizing a solution of the compound, after which the powder can be stored (e.g., in a sealed vial) at room temperature or below until reconstituted. The concentration of the compound in the reconstituted IV solution can range, for example, from about 0.1 mg / mL to about 20 mg / mL.

[0195] The present invention also includes a method for inhibiting bacterial growth, comprising administering an inhibitory-effective amount of a compound of Formula (I) to a bacterial cell culture or a bacterially-infected cell culture, tissue, or organism. Further embodiments of the present invention include the just-described bacterial growth inhibition methods, in which the compound of the present invention used therein is a compound of one of the above-described embodiments, subembodiments, or classes. The compound may, in these embodiments, optionally be used in the form of a pharmaceutically acceptable salt. The method may comprise administering a compound of Formula (I) to an experimental cell culture in vitro to prevent the growth of β-lactam-resistant bacteria. Alternatively, the method may comprise administering 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.

[0196] The methods of the presently disclosed subject matter are useful for treating these conditions in that they inhibit the onset, progression, or spread of a condition, cause regression of a condition, cure a condition, or improve the general well-being of a subject suffering from or at risk of suffering from a condition. Thus, according to 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, methods of treating an existing infection in a subject, and methods of preventing (i.e., preventing) an infection in a subject who has been exposed to, or is expected to be exposed to, a microorganism disclosed herein.

[0197] The compounds of the present invention can be used to treat, prevent, or inhibit bacterial growth or infection caused by bacteria resistant to β-lactam antibiotics. More specifically, the bacteria can be metallo-β-lactamase-positive strains highly resistant to β-lactam antibiotics. The terms "marginally resistant" and "highly resistant" are well understood by those skilled 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 purposes of the present invention, a bacterial strain highly resistant to imipenem is one with an imipenem MIC greater than 16 μg / mL, and a bacterial strain with marginal imipenem resistance is one with an imipenem MIC greater than 4 μg / mL.

[0198] R 4 is C1-3 alkyl such as CH3, or cyclopropyl, and R 5 Compounds where is CO2H or tetrazole are R 4 is hydrogen and R 5 has an unexpected advantage in stability compared to compounds where is COH or tetrazole.

[0199] The compounds of the present invention can be used in combination with β-lactamase inhibitors for the treatment of infections that are covered within the antibacterial spectrum of antibiotics, as well as infections caused by β-lactamase producing strains. 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, and Stenotrophomonas maltophilia. maltophilia, and Acinetobacter baumannii.

[0200] In general, it is advantageous to mix or combine the compounds of formula (I) with β-lactamase inhibitors or their prodrugs. Due to the class B β-lactamase resistance properties of the compounds, it is advantageous to use the compounds of formula I in combination with class A and C β-lactamase inhibitors. It is also advantageous to use the compounds of formula I in combination with one or more class A, C, or D β-lactamase inhibitors to further limit β-lactam susceptibility. As mentioned above, the compounds of formula I and the β-lactamase inhibitor can be administered separately (at the same time or at different times) or in the form of a single composition containing both active ingredients.

[0201] Relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacbactam, vaborbactam, didebactam, durobactam, enmetazobactam, QPX7728 (xeruborbactam), and other β-lactamase and metallo-β-lactamase inhibitors suitable for use in the present invention include those known to exhibit inhibitory activity against β-lactamases.

[0202] Abbreviation Ac is acetyl, ambient is room temperature, aq. is aqueous solution, ACN is acetonitrile, AcOH is acetic acid, Bn is benzyl, BOC (or Boc) is t-butyloxycarbonyl, BOCO is di-tert-butyl dicarbonate, BuBr is butyl bromide, CBZ (or Cbz) is carbobenzoxy (or benzyloxycarbonyl), CBZ-Cl is benzyloxycarbonyl chloride, CDCl is deuterated chloroform, CV or cv is column volume, DO is deuterium oxide, DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene, DCC is dicyclohexylcarbodiimide, DCE is dichloroethane, DCM is dichloromethane, DEAD is azo diethyl dicarboxylate, (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, 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, Et is ethyl, Et3N is triethylamine, Et2O is diethyl ether, EA or EtOAc is ethyl acetate, EtOH is ethanol, g is grams, FA is formic acid, h or hr or hrs is hours, HATU is 1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hex is hexane, HMDS is hexamethyldisilazide, HPLC is high performance liquid crystal display is chromatographic chromatography, Int is intermediate, IPA is isopropyl alcohol, L or l is liter, LAH is lithium aluminum hydride, LC / MS or LC-MS is liquid chromatography / mass spectrometry, LDA is lithium diisopropylamide, LiHMDS is lithium hexamethyldisilazide, M is mole, min is minute, mg is milligram, ml, mL or ML is milliliter, Me is methyl, MeCN is acetonitrile, MeO is methoxy, 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, NEt3 is triethylamine, NMR is nuclear magnetic resonance, MS is mass spectrometry, MW is molecular weight, Pd / C is palladium on carbon, PdCl 2(dppf)2 is [1,1'bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II), di-t-BuDPPF-PdCl2 is 1,1'-bis(di-tert-butylphosphino)-ferrocenepalladium dichloride, Pd(AcO)2 is palladium(II) acetate, PE is petroleum ether, PG is a protecting group, Ph is phenyl, Ph3P is triphenylphosphine, RP is reversed phase, RP-HPLC is reversed phase high performance liquid chromatography, rt, rt, RTor RT is room temperature, sat'd is saturated, SFC is supercritical fluid chromatography, tBu is tert-butyl, tBuOH is tert-butyl alcohol, TBAF is tetrabutylammonium fluoride, TB is tert-butyldimethylsilyl, TBS-Cl is tert-butyldimethylsilyl chloride, TBDPS-Cl is t-butyl(chloro)diphenylsilane, t-BuOH is tert-butyl alcohol, TEA is triethylamine, TFA is trifluoroacetic acid, THF is tetrahydrofuran, TLC is thin layer chromatography, TMS is trimethylsilyl, TMS-Cl is trimethylsilyl chloride, and wt% is weight percent.

[0203] Process for preparing compounds of formula (I): The compounds disclosed herein can be prepared and tested according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents, and conventional synthesis procedures. These reactions may utilize variations that are themselves known to those of ordinary skill in the art, but which are not mentioned in more detail herein. Additionally, other methods for preparing the compounds disclosed herein will be readily apparent to those of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise specified, all variables are as defined above. The following examples illustrate the invention and its practice. The examples should not be construed as limiting the scope or spirit of the invention. In these examples, all temperatures are degrees Celsius, and "room temperature" refers to a temperature in the range of about 20°C to about 25°C, unless otherwise specified. Moisture- or air-sensitive reactions were performed under nitrogen and using anhydrous solvents and reagents. The progress of the reaction can be determined either by analytical thin-layer chromatography (TLC) performed on precoated TLC plates from E. Merck or silica gel 60F-254 or GF254 from AnHui Liangchen Guiyuan Co., Ltd., layer thickness 0.25 mm, or by liquid chromatography-mass spectrometry (LC-MS). For HPLC / MS data of intermediates, unless otherwise specified, the two primary HPLC conditions were as follows: 1) LC1 (SHIMADZU C18 Xtimate 3um 2.1x30mm column, gradient 10:90 to 80:20 v / v CH3CN / H2O + 0.0375% TFA over 0.9 minutes, then hold at 80:20 v / v CH3CN / H2O + 0.0375% TFA for 0.6 minutes; flow rate 1.2mL / min, UV wavelengths 220 and 254nm); and 2) LC2 (Agilent C18 Xtimate 3um 2.1x30mm column, gradient 10:90 to 80:20 v / v CH3CN / H2O + 0.0375% TFA over 3 minutes, then hold at 80:20 v / v CH3CN / H2O + 0.0375% TFA for 0.6 minutes; flow rate 1.2mL / min, UV wavelengths 220 and 254nm). % TFA for 0.5 min; flow rate 0.8 mL / min, UV wavelengths 220 and 254 nm).For HPLC / MS data of the final product, the two main HPLC conditions used were: 1) LC1: Agilent Poroshell 120 EC-C18 1.9 μm 3.0 × 30 mm column, 5:95 to 80:20 v / v CH3CN (v 0.0375% TFA) / HO (v 0.0188% TFA) over 1.2 min, followed by a gradient of 80:20 to 95:5 v / v CH3CN (v 0.0375% TFA) / HO (v 0.0188% TFA) over 1.3 min, flow rate 1.5 mL / min, UV wavelengths 220 and 254 nm; and 2) LC2: Agilent Poroshell 120 EC-C18 1.9 μm 3.0 × 30 mm column, 0:100 to 30:70 v / v CH3CN (v 0.0375% TFA) / HO (v 0.0188% TFA) over 1.2 min. CHCN (v 0.0375% TFA) / HO (v 0.0188% TFA), followed by a gradient of 30:70 to 95:5 v / v CHCN (v 0.0375% TFA) / HO (v 0.0188% TFA) over 1.3 min; flow rate 1.5 mL / min, UV wavelengths 220 and 254 nm; mass spectrometry was performed using electrospray ionization in positive ion detection mode. 1 H NMR spectra were recorded on Varian or Bruker instruments at 400-500 MHz. Solutions were concentrated on a rotary evaporator under reduced pressure until volatiles were completely removed, or by bubbling a stream of nitrogen (connecting a pipette head to the end of a nitrogen tube inserted into the mixture), or by lyophilization. Silica gel chromatography was performed on pre-packed silica gel columns using a commercially available MPLC system. The names of the compounds in the examples were generated by Chemdraw™.

[0204] General Scheme [ka]

[0205] Chroman chloride A was converted to intermediate B by cyanation, which underwent functional group manipulation to give intermediate C. Amination of intermediate C gave intermediate D, which was then deprotected to give compound E. Alternatively, intermediate B was converted to intermediate F by functional group manipulation. Amination of intermediate F, followed by reduction of hydroxyamidine G and removal of the protecting group (PG) in intermediate H gave compound E. Condensation of compound E with intermediate I gave intermediate J, which was subsequently removed from the protecting group to give the final product. Alternatively, compound E was coupled with intermediate K to give the final product directly.

[0206] [Example] [Example 1] Preparation of intermediate 1c [ka]

[0207] Step A - Synthesis of Intermediate-1a: To a solution of tert-butyl 2-(diethoxyphosphoryl)-propanoate (2150.0 g, 8.06 mol, 0.95 eq) in THF (8400 mL) stirred at ambient temperature, NaH (339.3 g, 8.48 mol, 60% purity, 1.0 eq) was added portionwise. The mixture was stirred at 30-40 °C for 3 h. Then, a solution of 3-(2-bromo-5-chlorophenyl)propanal (2100.0 g, 8.48 mol, 1.0 eq) in THF (4200 mL) 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 concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (1:0 to 10:1) to give Intermediate 1a. 1H-NMR(400MHz, CDCl3):δ 7.47(d,J=8.5Hz,1H),7.22(d,J=2.6Hz,1H),7.07(dd,J=8.5,2.6Hz,1H),6.71(td,J=7. 5,1.5Hz,1H),2.93-2.71(m,2H),2.63-2.37(m,2H),1.78(d,J=1.3Hz,3H),1.52(s,9H). Step B—Synthesis of Intermediate 1b: To a 50 L four-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of 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 Intermediate 1a (1900 g, 5.28 mol) in tert-butanol / water (19 L / 19 L). The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was then extracted with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. The resulting solid was filtered off. The filtrate was concentrated under vacuum, and the resulting residue was purified on a silica gel column eluted with ethyl acetate / petroleum ether (1 / 100 to 1 / 10) to give Intermediate 1b. LC-MS: m / z 417.0 [M+Na] + . Step C—Synthesis of Intermediate 1c: A 20 L four-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with CsCO (2317.2 g, 7112.01 mmol) and Pd(AcO) (39.9 g, 177.80 mmol) in toluene (14 L). 2-(Di-tert-butylphosphino)biphenyl (106.1 g, 355.60 mmol) was then added slowly over 30 minutes. To this mixture was added Intermediate 1b (1400 g, 3556.01 mmol). The reaction mixture was stirred at 90° C. for 20 hours and then cooled to room temperature using a water / ice bath. The resulting solid was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified on a silica gel column eluted with ethyl acetate / petroleum ether (1 / 100 to 1 / 5) to give Intermediate 1c. 1H-NMR(400MHz, CDCl3):δ 7.07-7.00(m,2H),6.67(d,J=8.3Hz,1H),4.14(dd,J=11.0,2.4Hz,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 2b [ka]

[0208] Step A—Synthesis of Intermediate 2a A 2 L four-neck round-bottom flask was charged with a solution of Intermediate 1c (460 g, 1.47 mol) in toluene (4800 mL), followed by the addition of sodium hydride (60 wt %, 70.8 g, 1.77 mol) in several batches at 27° C. The mixture was stirred at 27° C. for 1 h. A solution of amino 2,4,6-trimethylbenzene-1-sulfonate (380.4 g, 1.77 mol) in DCM (1200 mL) was then added dropwise with stirring at 27° C. The reaction mixture was stirred at 27° C. for 2 h. The reaction was then quenched by adding water (2000 mL) and extracted with MTBE (2×2 L). The organic layers were combined, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under vacuum. The resulting residue was purified on a silica gel column eluted with EtOAc / PE (1:10) to give Intermediate 2a. 1 H-NMR(400MHz, CDCl3):δ 7.08-6.96(m,2H),6.96(overlap,1H),6.77(d,J=9.4Hz,1H),4.20(dd,J=11.4,1.9Hz,1H),2.99-2.62(m ,2H),2.06(ddt,J=13.6,5.9,2.1Hz,1H),1.87(dtd,J=13.6,12.0,5.8Hz,1H),1.54(s,9H),1.53(s,3H). Step B—Synthesis of Intermediate 2b A 5 L four-neck round-bottom flask was charged with Intermediate 2a (500 g, 1525.27 mmol) and di-tert-butyl dicarbonate (399.00 g, 1828.18 mmol) in ethyl alcohol (5 L). The reaction was stirred at 50° C. for 5 hours and then concentrated under vacuum. The resulting crude product was purified by slurrying with hexane. The solid was collected by filtration to provide Intermediate 2b. 1 H NMR (400MHz, 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). [Example 3] Preparation of intermediates 3a and 3c [ka]

[0209] 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) was added ACN (64 mL) and water (60 mL), both of which had been sparged with nitrogen for 1 hour. The reaction vessel was evacuated, filled with nitrogen, and then sealed. The reaction was then heated to 80° C. and stirred for 2 hours. 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 a Celite™ pad. The resulting filtrate was concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (ISCO 220 g; 0-70% EtOAc / hexanes) to give the desired compound. LC-MS: m / z 419.2 [M+H] + . Step B—Synthesis of Intermediate 3b. To a mixture of Intermediate 3a (4.81 g, 11.49 mmol), MgCl (1.641 g, 17.24 mmol), and NaSH (1.933 g, 34.5 mmol) was added nitrogen-sparged anhydrous DMF (20.5 mL) under a nitrogen atmosphere. The reaction mixture was evacuated, filled with nitrogen, capped, and stirred at ambient temperature for 21 h. The reaction was then cooled to 0 °C and quenched with saturated aqueous NH Cl and water. The resulting mixture was extracted with ethyl acetate. 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. The filtrate was concentrated in vacuo to give a crude residue, which was purified by silica gel chromatography (ISCO, 220 g; 0–100% EtOAc / hexanes) to give the desired compound. LC-MS: m / z 453.2 [M+H] + . 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. The ether supernatant was then decanted. The insoluble viscous oil was triturated with ether (15 mL). The resulting oil was 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 hexane / ether (30 mL), and the resulting solid material was collected by filtration, washed with 1:1 hexane / EtO (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 468.2 [M+H] + . [Example 4] Preparation of Intermediate 4 [ka]

[0210] Intermediate 4 was prepared using the methods described in WO 2017 / 106064.

[0211] [Example 5] Preparation of Intermediate 5 [ka]

[0212] A flask (250 mL) was charged with Intermediate 4 (10 g, 21.5 mmol) and CHCl (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 hours and then concentrated under vacuum without heating to give a residue (approximately 20 mL total volume). DCM (100 mL) was added to the residue, and the mixture was concentrated under vacuum without heating to a total volume of approximately 20 mL. This process was repeated four times to drive off most of the TFA. Finally, the solvent was completely removed under vacuum. Water (100 mL) was added to the resulting residue. After stirring for 30 minutes, the mixture was filtered, and the filter cake was rinsed with water (1 cake volume) and then collected. The filter cake was dissolved in 1:1 acetonitrile / water (50 mL), and the mixture was lyophilized overnight to give Intermediate 5. LC-MS: m / z 365.3 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ:9.67(d,J=7.7Hz,1H),7.88(s,1H),7.57(s,2H),4.59(d,J=7.9Hz,1H),1.44(s,3H),1.25(s,3H). [Example 6] Preparation of intermediate 6c [ka]

[0213] Step A—Synthesis of Intermediate 6a: To a solution of intermediate 3a (0.98 g, 2.342 mmol) in a premixed solution of AcOH (3 mL), pyridine (6 mL), and water (3 mL) was added sodium hypophosphite monohydrate (1.986 g, 18.73 mmol) and Raney nickel (1.45 g). The resulting mixture was stirred at 70° C. for 12 h. The mixture was then diluted with 100 mL of 50% EtOAc / hexane and filtered. The filtrate was washed with 100 mL of water (3×), then dried over anhydrous MgSO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (ISCO, 80 g column, gradient elution with 0–100% EtOAc / hexane) to give intermediate 6a. MS (ESI) m / z: 422.3 [M+H] + . Step B—Synthesis of Intermediate 6b To a mixture of intermediate 6a (300 mg, 0.712 mmol) in EtOH (3 mL) and water (3 mL), TEA (0.149 mL, 1.068 mmol) was added, followed by hydroxylamine hydrochloride (74.2 mg, 1.068 mmol). The reaction mixture was stirred at 25° C. for 3 hours, then diluted with water (40 mL) and extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by preparative TLC plate (SiO, 30% ethyl acetate in petroleum ether) to give intermediate 6b. MS (ESI) m / z: 459.0 [M+Na] + . Step C—Synthesis of Intermediate 6c: To a solution of intermediate 6b (500 mg, 1.145 mmol) in DMF (3.4 mL) was added 1-chloropyrrolidine-2,5-dione (199 mg, 1.489 mmol). The reaction was stirred at ambient temperature for 45 minutes. The reaction mixture was then diluted with 15 mL of EtO / hexane (2:1) and washed with 20 mL of water (twice). The organic layer was dried over anhydrous NaSO, then filtered, and the filtrate was concentrated in vacuo to give crude intermediate 6c, which was used in the subsequent reaction without further purification. MS (ESI) m / z: 471.3 [M+H] + . [Example 7] Preparation of Compound 1 (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-(N-((S)-pyrrolidin-3-yl)carbamimidoyl)chroman-2-yl)propanoic acid [ka]

[0214] Step A—Synthesis of Intermediate 7a. To a vial containing a mixture of Intermediate 3c (0.2470 g, 0.529 mmol) and (S)-(−)-1-Boc-3-aminopyrrolidine (0.184 mL, 1.059 mmol), a pre-made solution of potassium acetate (0.104 g, 1.059 mmol) and acetic acid (0.182 mL, 3.18 mmol) in anhydrous MeOH (5.3 mL) was added. The reaction was heated at 70° C. for 35 min. The reaction mixture was then directly purified by reverse-phase HPLC (ISCO C18Aq 50 g; 0–100% ACN + 0.05% TFA / water + 0.05% TFA). The desired fractions were collected and concentrated in vacuo. The resulting aqueous residue was lyophilized to afford the desired compound. LC-MS: m / z 605.5 [M+H] + . Step B - Synthesis of Intermediate 7b To a vial containing Intermediate 7a (0.2529 g, 0.418 mmol) was added a 2:1 mixture of trifluoroacetic acid / anhydrous dichloromethane (4.2 mL) at ambient temperature. The reaction mixture was stirred at room temperature for 16.5 hours. A 4:1 MeOH / toluene solution (10 mL) was then added to the reaction, and the solution was concentrated in vacuo. The resulting residue was azeotroped with 4:1 MeOH / toluene (10 mL), and the resulting residue was dried in vacuo to give the desired compound. LC-MS: m / z 349.2 [M+H] + . Step C - Synthesis of Intermediate 7c To a flask charged with Intermediate 7b (0.043 g, 0.123 mmol) and Intermediate 4 (0.057 g, 0.123 mmol) was added anhydrous methanol (1.2 mL) at ambient temperature. The mixture was stirred for 2 hours and then concentrated in vacuo. The crude residue was used in the next reaction without further purification. LC-MS: m / z 795.5 [M+H] + . Step D—Synthesis of Compound 1. A solution of intermediate 7c (0.123 mmol) in 2:1 anhydrous DCM / TFA (1.2 mL) was allowed to stand at ambient temperature for 1 hour. The reaction was then cooled to 0° C., and MTBE (3 mL) was added with stirring to precipitate a solid. The mixture was sonicated and then centrifuged (4000 rpm) to collect the insoluble solid. The supernatant was decanted. MTBE was then added again to the reaction with stirring to precipitate additional solid, which was isolated by centrifugation. The resulting solid was dried in vacuo and purified by RP HPLC (XSelect CSH Prep C18; 5 μM OBD; 30 × 150 mm; 0% to 20% (ACN + 0.1% FA) / (water + 0.1% FA) over 15 min). Product-containing fractions were collected and lyophilized to give the title compound as the formate salt. LC-MS: m / z 695.3 [M+H] + . 1 HNMR(500MHz,4:1 D2O / d-DMSO)δ:7.51(d,J=2.2Hz,1H),7.47(dd,J=8.6,2.4Hz,1H),6.98-6.88(m,2H), 4.69(s,1H),4.62-4.56(m,1H),4.45(dd,J=11.3,2.1Hz,1H),3.72(dd,J=13.0,6.8Hz, 1H),3.58-3.44(m,3H),2.95-2.78(m,2H),2.56-2.43(m,1H),2.35-2.22(m,1H),2.14( d,J=13.7Hz,1H),1.78(dd,J=13.5,6.0Hz,1H),1.58(s,3H),1.49(s,3H),1.30(s,3H). [Example 8] Preparation of compounds 2-6 Starting from the appropriate commercially available mono-Boc protected diamine or di-Boc protected triamine, the following compounds were prepared according to the procedure of Example 7. [Table 1] TIFF0007671398000029.tif200157

[0215] [Example 9] Preparation of Compound 7 (S)-2-((R)-6-(N-((1s,3S)-3-aminocyclobutyl)carbamimidoyl)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 [ka]

[0216] Step A—Synthesis of Intermediate 8a: To a vial containing a mixture of cis-tert-butyl N-(3-aminocyclobutyl)carbamate (0.065 mL, 0.385 mmol) in anhydrous acetonitrile (1 mL) was added a solution of Intermediate 3c (0.11 g, 0.238 mmol) and acetic acid (0.044 mL, 0.771 mmol) in anhydrous acetonitrile (1 mL). The reaction mixture was heated at 65°C for 2 h, then cooled to ambient temperature and purified by reverse-phase HPLC (ISCO C18Aq 50 g; product eluted with 65% ACN + 0.05% TFA / water + 0.05% TFA) using a gradient elution of 0 to 100% ACN + 0.05% TFA / water + 0.05% TFA. The desired fractions were collected and concentrated in vacuo. The resulting aqueous residue was partitioned between brine and ethyl acetate. The brine was back-extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give intermediate 8a. LC-MS: m / z 605.4 [M+H] + . Step B - Synthesis of Intermediate 8b To a vial containing Intermediate 8a (0.1108 g, 0.183 mmol) was added 2:1 trifluoroacetic acid / anhydrous dichloromethane (2 mL) at ambient temperature. The reaction mixture was stirred for 16.5 hours, then a solution of 4:1 MeOH / toluene (10 mL) was added to the reaction, and the mixture was concentrated in vacuo. The resulting residue was azeotroped with 4:1 MeOH / toluene (10 mL) and dried under high vacuum to give Intermediate 8b. LC-MS: m / z 349.16 [M+H] + . Step C—Synthesis of Compound 7 To a vial charged with Intermediate 8b (0.183 mmol), Intermediate 5 (79 wt%, 0.129 g, 0.199 mmol), and powdered molecular sieves 4 Å (325 mesh particles; 0.100 g, heat-dried under high vacuum) was added anhydrous dimethylacetamide (1.2 mL) at ambient temperature. The reaction mixture was stirred for 18 hours and then filtered through a Celite™ pad. The Celite™ pad was washed thoroughly with MeOH. The filtrate was concentrated in vacuo, and the remaining residue was cooled to 0° C., followed by the addition of DCM (6 mL) with stirring. The resulting precipitate was collected by centrifugation (4000 rpm). The supernatant was decanted, and the insoluble solid was triturated with DCM (3 mL). The centrifugation and supernatant transfer steps were repeated to give a crude solid, which was purified by RP HPLC (XSelect CSH Prep C18; 5 μM OBD; 50 × 250 mm; 0% to 13% ACN / (water + 0.16% TFA) over 11 min; isocratic at 13% ACN / (water + 0.16% TFA) for 14 min). Product fractions were collected and concentrated in vacuo to remove acetonitrile, and the aqueous layer was loaded directly onto an Amberchrom CG161M column (26 g), washed with 9 CV of (water + 0.1% FA), and eluted with 3 CV of 100% (ACN + 0.1% FA) followed by 3 CV of 50% (ACN + 0.1% FA) / (water + 0.1% FA). The desired fractions were collected and concentrated in vacuo, and the resulting aqueous residue was lyophilized to give the title compound as the formate salt. LC-MS: m / z 695.2 [M+H] + . 1HNMR(400MHz,4:1 D2O / d-DMSO)δ:7.36(s,1H),7.35-7.29(m,1H),6.82(d,J=8.6Hz,1H),6.81(s,1H),4.57(s,1H),4.32(d,J=11.6Hz,1H),3.96(t, J=8.0Hz,1H),3.62-3.51(m,1H),2.85(dt,J=7.5,2.6Hz,2H),2.72(m,2H),2.27(q,J=8.9Hz,2H),2.01(d,J=12.2Hz,1H),1.65(m 1H),1.45(s,3H),1.36(s,3H),1.18(s,3H). [Example 10] Preparation of compounds 8–20 Starting from the appropriate commercially available mono-Boc protected diamine, the following compounds were prepared according to the procedure of Example 9. [Table 2] TIFF0007671398000032.tif221154TIFF0007671398000033.tif232155TIFF0007671398 000034.tif220154TIFF0007671398000035.tif233155TIFF0007671398000036.tif48154

[0217] [Example 11] Preparation of Compound 21 (S)-2-((R)-6-(N-(7-azaspiro[3.5]nonan-2-yl)-carbamimidoyl)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 [ka]

[0218] Step A—Synthesis of Intermediate 9a. To a mixture of 2-amino-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (92.6 mg, 0.386 mmol) in anhydrous acetonitrile (1 mL) was added a solution of Intermediate 3c (0.11 g, 0.238 mmol) and acetic acid (0.044 mL, 0.771 mmol) in anhydrous acetonitrile (1 mL). The reaction mixture was heated at 65 °C for 2 h, then cooled to ambient temperature and purified by reverse-phase HPLC (ISCO C18Aq 50 g; product eluted with 65% ACN + 0.05% TFA / water + 0.05% TFA) using a gradient elution of 0–100% ACN + 0.05% TFA / water + 0.05% TFA. The desired fractions were collected and concentrated in vacuo. The resulting aqueous residue was partitioned between brine and ethyl acetate and further back-extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuo to give intermediate 9a. LC-MS: m / z 659.5 [M+H] + . Step B - Synthesis of Intermediate 9b To a vial containing Intermediate 9a (0.1145 g, 0.174 mmol) was added 2:1 trifluoroacetic acid / anhydrous dichloromethane (2 mL) at ambient temperature. The reaction was stirred for 16.5 hours, then a solution of 4:1 MeOH / toluene (10 mL) was added to the reaction, and the mixture was concentrated in vacuo. The resulting residue was azeotroped with 4:1 MeOH / toluene (10 mL), and the resulting residue was dried under high vacuum to provide Intermediate 9b. LC-MS: m / z 403.37 [M+H] + . Step C—Synthesis of Compound 21 To a vial charged with Intermediate 9b (0.174 mmol), Intermediate 5 (79 wt%, 0.12 g, 0.260 mmol), and powdered molecular sieves 4 Å (325 mesh particles; 0.100 g, heat-dried under high vacuum) was added anhydrous dimethylacetamide (1.2 mL) at ambient temperature. The reaction mixture was stirred for 19 hours and then filtered through a Celite™ pad. The Celite™ pad was washed with MeOH, and the filtrate was concentrated in vacuo. The remaining residue was cooled to 0° C., and then DCM (6 mL) was added and the mixture was stirred slowly. The resulting solid was collected by centrifugation (4000 rpm). The supernatant was decanted, and the insoluble solid was triturated with DCM (3 mL). Repeated centrifugation and transfer of the supernatant gave the crude product, which was purified by RP HPLC (XSelect CSH Prep C18; 5uM OBD; 50x250mm; 0% to 13% ACN / (water + 0.16% TFA) over 11 minutes; isocratic at 13% ACN / (water + 0.16% TFA) for 14 minutes. Product fractions were collected and concentrated in vacuo. The resulting aqueous layer was loaded directly onto an Amberchrom CG161M column (26g), washed with 9 CV of (water + 0.1% FA), and eluted with 3 CV of 100% (ACN + 0.1% FA) followed by 3 CV of 50% (ACN + 0.1% FA) / (water + 0.1% FA). Product fractions were collected and concentrated in vacuo, and the resulting aqueous residue was lyophilized to give compound 21 as the formate salt. LC-MS: m / z 749.6 [M+H] + . 1 HNMR(400MHz,4:1 D2O / CD3CN)δ:7.51-7.37(m,2H),7.01-6.86(m,2H),4.67(s,1H),4.48(d,J=10.5Hz,1H),4.23(t,J=7.8Hz,1H),3.13(dt,J=25.1,5 .6Hz,4H),2.85(m,2H),2.52(dd,J=11.8,9.5Hz,2H),2.19-2.01(m,3H),1.90-1.73(m,5H),1.58(s,3H),1.49(s,3H),1.30(s,3H). [Example 12] Preparation of compounds 22 and 23 (S)-2-((R)-6-(N-((2r,4S)-6-azaspiro[3.4]octan-2-yl)carbamimidoyl)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-(N-((2s,4R)-6-azaspiro[3.4]octan-2-yl)carbamimidoyl)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* [ka]

[0219] Step A—Synthesis of Intermediate 10a. To a vial containing a mixture of 2-amino-6-aza-spiro[3.4]octane-6-carboxylic acid tert-butyl ester (73.0 mg, 0.321 mmol) and Intermediate 3c (0.1496 g, 0.321 mmol), a pre-made solution of acetic acid (0.055 mL, 0.962 mmol) in anhydrous acetonitrile (2 mL) was added. The reaction mixture was heated at 70 °C for 2.5 h, then cooled to ambient temperature and purified by reverse-phase HPLC (ISCO C18Aq 50 g; product eluted with 65% ACN + 0.05% TFA / water + 0.05% TFA) using a gradient elution of 0–100% ACN + 0.05% TFA / water + 0.05% TFA. The desired fractions were collected and concentrated in vacuo. The resulting aqueous residue was partitioned between brine and ethyl acetate and back-extracted with more ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the desired compound. LC-MS: m / z 645.6 [M+H] + . Step B—Synthesis of Intermediate 10b: To a solution of intermediate 10a (0.1832 g, 0.284 mmol) in anhydrous DCM (1.5 mL) was added triethylamine (0.119 mL, 0.852 mmol), followed by a solution of (Boc)O (0.099 mL, 0.426 mmol) in DCM (1.5 mL). The reaction mixture was stirred at ambient room temperature for 6 hours. The reaction was then partitioned between EtOAc and saturated aqueous NH4Cl. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Isco 24 g column; 0–100% (3:1 EtOAc / EtOH) / hexanes) to afford the desired compounds as diastereomers. LC-MS: m / z 745.5 [M+H] + The diastereomers were separated by chiral chromatography (IA, 2 × 15 cm column; IPA + 0.25% IBA / CO2) to give two diastereomers: intermediate 10b-1 (peak 1); LC-MS: m / z 745.7 [M+H] + , and intermediate 10b-2 (peak 2); LC-MS: m / z 745.7 [M+H] + was obtained.

[0220] Step C—Synthesis of Intermediate 10c-2 To a vial containing intermediate 10b-2 (95 mg, 0.128 mmol) was added 2:1 trifluoroacetic acid / anhydrous dichloromethane (1.3 mL) at ambient temperature. The reaction was stirred for 16 hours. A 4:1 MeOH / toluene solution (5 mL) was then added and the mixture was concentrated in vacuo. The resulting residue was azeotroped with MeOH (5 mL) and then dried under high vacuum to give the desired compound. LC-MS: m / z 389.3 [M+H] + Intermediate 10c-1 was prepared according to step C using intermediate 10b-1 (37 mg, 0.050 mmol). LC-MS: m / z 389.3 [M+H] + . Step D—Synthesis of Compound 22 To a vial charged with intermediate 10c-2 (0.128 mmol), intermediate 5 (80 wt%, 0.0525 g, 0.115 mmol), and powdered molecular sieves 4 Å (325 mesh particles; 0.100 g, dried by heating under high vacuum), anhydrous dimethylacetamide (0.5 mL) was added at ambient temperature. The reaction mixture was stirred for 16.5 hours, then filtered to remove the molecular sieves, and the solid was washed with MeOH. The filtrate was concentrated in vacuo, and the resulting residue was cooled to 0° C., followed by the addition of DCM (5 mL) and gentle stirring. The resulting solid was collected by centrifugation (4000 rpm). The supernatant was decanted, and the insoluble solid was triturated with DCM (5 mL). Centrifugation and decantation were repeated to obtain a crude solid. The solid was purified by reverse-phase HPLC (XSelect CSH Prep C18; 5 μM OBD; 50 × 250 mm; 0%–30% ACN / (water + 0.16% TFA) over 12 min; isocratic at 17–18% ACN / (water + 0.16% TFA) for 5 min. Product fractions were collected and concentrated in vacuo, and the resulting aqueous layer was loaded directly onto an Amberchrom CG161M column (26 g), washed with 9 CV of (water + 0.1% FA), and eluted with 3 CV of 100% (ACN + 0.1% FA), followed by 3 CV of 50% (ACN + 0.1% FA) / (water + 0.1% FA). Product fractions were collected and concentrated in vacuo, and the resulting aqueous residue was lyophilized to give the title compound as the formate salt. 1 H NMR (500 MHz, 4:1 D2O / d-DMSO)δ:7.50-7.42(m,2H),6.99-6.91(m,2H),4.68(s,1H),4.48(d,J= 9.5Hz,1H),4.36(ddd,J=14.4,8.3,6.1Hz,1H),3.33(t,J=7.6Hz,2H),3.07-2 .99(m,2H),2.88(m,2H),2.63-2.55(m,2H),2.17(t,J=7.3Hz,3H),2.07-1.97 (m,2H),1.88-1.71(m,1H),1.59(s,3H),1.49(s,3H),1.30(s,3H).LC-MS:m / z 735.8 [M+H] +Compound 23 was prepared according to Step D of Example 12 using intermediate 10c-1 (0.050 mmol). 1 HNMR(500MHz,4:1 D2O / d-DMSO)δ:7.52-7.44(m,2H),6.98(d,J=8.6Hz,1H),6.92(s,1H),4.68 (s,1H),4.46(d,J=10.6Hz,1H),4.25-4.18(m,1H),3.29(t,J=7.3Hz,2H),2. 88-2.77(m,4H),2.74-2.67(m,2H),2.11-2.18(m,3H),2.05(p,J=8.2,7.6H z,2H),1.84-1.73(m,1H),1.58(s,3H),1.49(s,3H),1.31(s,3H).LC-MS:m / z 735.5 [M+H] + *Each compound is a single diastereomer and the stereochemistry at the carbon marked with an * is not assigned.

[0221] [Example 13] Preparation of intermediate 11f [ka]

[0222] Step A—Synthesis of Intermediate 11a: To a stirred solution of N-Boc-hydroxylamine (31.15 g, 0.233 mol) in dry methanol (1 L) cooled to 0° C., 1,3-cyclohexadiene (25 g, 0.311 mol) was added dropwise, followed by the dropwise addition of a solution of sodium metaperiodate (52.6 g, 0.246 mol) in water (750 mL) over 30 min. The reaction mixture was stirred at room temperature for 16 h and then filtered. The resulting solid was washed with EtOAc (2×200 mL), and the filtrate was concentrated under reduced pressure at 38° C. The resulting residue was dissolved in EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with a gradient of 3–10% EtOAc / DCM to give Intermediate 11a. 1H NMR (400MHz, CDCl3): δ 6.56-6.50(m,2H),4.75-4.70(m,2H),2.2-2.0(m,2H),1.46(s,9H),1.39-1.34(m,2H). Step B—Synthesis of Intermediate 11b To a stirred solution of Intermediate 11a (50 g, 0.2367 mol) in acetonitrile (2 L) / water (100 mL) heated to 55° C., molybdenum hexacarbonyl (31.27 g, 0.11848 mol) was added in one portion. The reaction mixture was refluxed at 100° C. for 3 hours, followed by stirring at room temperature for 16 hours. The reaction mixture was then filtered through Celite™, and the filtrate was concentrated under reduced pressure at 40° C. The resulting residue was purified by silica gel chromatography eluting with 40% EtOAc / petroleum ether to provide Intermediate 11b. 1 H NMR(300MHz,CDCl3)δ:5.86-5.80(m,1Η),5.78-5.75(m,1H),4.55(brs,1H),4.17-4.1(m,2H),1.9-1.75(m,2H),1.74-1.6(m,2H),1.46(s,9H). Step C—Synthesis of Intermediate 11c A stirred solution of intermediate 11b (30 g, 0.14 mol) in dry dichloromethane (600 mL) was purged with argon for 15 minutes, then cooled to 0° C., followed by the addition of Dess-Martin periodinane (89.5 g, 0.211 mol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with dichloromethane (500 mL), washed with 10% aqueous sodium thiosulfate solution (2×500 mL), 10% sodium bicarbonate (2×500 mL), water (500 mL), and brine (500 mL). The organic layer was separated, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to provide intermediate 11c, which was used in the next step without further purification. 1 H NMR(300MHz,CDCl3)δ:6.87-6.80(m,1H),6.1-5.9(m,1H),4.7(brs,1H),4.5( brs,1H),2.56-2.44(m,2H),2.4-2.3(m,1H),1.92-1.85(m,1H),1.47(s,9H). Step D—Synthesis of Intermediate 11d: To a suspension of NaH (7.4 g, 0.184 mol) in anhydrous DMSO (900 mL) was added trimethylsulfoxonium iodide (40.6 g, 0.184 mol). The mixture was cooled to 15° C., and then a solution of Intermediate 11c (30 g, 0.142 mol) in DMSO (300 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 5 hours, followed by the addition of ice. The mixture was extracted with 50% EtOAc in petroleum ether (3×500 mL). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (silica gel 60-120 mesh, 25% EtOAc in petroleum ether) to give Intermediate 11d. 1 H NMR (400MHz, CDCl3): δ 4.94(brs,1H),4.20(brs,1H),2.25-2.17(m,2H),1.8-1.7(m,4H),1.41(s,9H),1.9-1.65(m,2H). Step E—Synthesis of Intermediate 11e To a solution of intermediate 11d (0.3482 g, 1.546 mmol) in anhydrous CHCl (7 mL) was added benzylamine (219 μL, 2.009 mmol) at ambient temperature. The reaction was stirred for 10 min, then NaBH(OAc) (0.655 g, 3.09 mmol) and AcOH (1 μL, 0.017 mmol) were added. The reaction mixture was stirred for 2 h and then quenched at 0 °C by the slow addition of NaOH (1 N, 5 mL). The resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Isco Gold 12 g column; 0–100% EtOAc / hexanes) to give the desired compound. LC-MS: m / z 317.6 [M+H] + . Step F - Synthesis of Intermediate 11f A mixture of intermediate 11e (1.9206 g, 6.07 mmol) and Pd / C (10 wt%, 0.3942 g, 3.70 mmol) in absolute ethanol (20.23 mL) was hydrogenated under atmospheric H2 at ambient temperature for 48 hours. The reaction mixture was filtered through a Celite™ pad under a N2 atmosphere. The pad was washed with MeOH and the filtrate was concentrated in vacuo to give the desired compound. LC-MS: m / z 227.2 [M+H] + [Example 14] Preparation of compounds 24-27 The following compounds were prepared from intermediate 11f according to the procedures in Steps A-D of Example 12, where the diastereomers were separated in Step B by chiral chromatography (ChiralTek Enantiocel C9-5, 3 x 25 cm column; MeOH / CO2, followed by AD-H, 3 x 25 cm, iPrOH / CO2) to give the four individual diastereomers (absolute stereochemistry at the carbon centers marked * not assigned; depicted drawings represent relative stereochemistry). [Table 3] TIFF0007671398000041.tif115149

[0223] [Example 15] Preparation of Compound 28 (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-(N-(piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid [ka]

[0224] Step A—Synthesis of Intermediate 12a. To a vial containing a mixture of Intermediate 3c (1.264 g, 2.71 mmol) and 4-amino-1-Boc-piperidine (1.086 g, 5.42 mmol) was added a pre-made solution of potassium acetate (0.532 g, 5.42 mmol) and acetic acid (0.930 mL, 16.26 mmol) in anhydrous MeOH (27 mL). The reaction was heated at 70 °C for 30 min and then partitioned between EtOAc and cold saturated aqueous NaHCO3 / brine. The organic layer was separated, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give a foam. The foam was purified by reverse-phase chromatography (ISCO C18 130 g; 0–100% ACN + 0.05% TFA / water + 0.05% TFA). The product fractions were concentrated in vacuo, and the resulting aqueous residue was extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give the desired compound. LC-MS: m / z 619.6 [M+H] + . Step B - Synthesis of Intermediate 12b To a vial containing Intermediate 12a (0.9292 g, 1.502 mmol) was added 2:1 trifluoroacetic acid / anhydrous dichloromethane (15 mL) at ambient temperature. The reaction was stirred for 16.5 hours, then a solution of 4:1 MeOH / toluene (25 mL) was added to the reaction and the mixture was concentrated in vacuo. The resulting residue was azeotroped with 4:1 MeOH / toluene (25 mL) and dried in vacuo to give the desired compound. LC-MS: m / z 363.32 [M+H] + . Step C—Synthesis of Intermediate 12c: To a flask charged with Intermediate 12b (0.544 g, 1.502 mmol) and Intermediate 4 (0.6722 g, 1.447 mmol) at ambient temperature was added 30% toluene in anhydrous methanol (15 mL). The reaction was stirred for 3 hours and then concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (Isco C18Aq 415 g column; 0-40% ACN + 0.05% TFA / water + 0.05% TFA over 30 minutes), and the aqueous product fraction was concentrated in vacuo. The aqueous residue was then loaded onto an Amberchrom CG161M column (26 g), washed with 9 CV of (water + 0.05% TFA), and eluted with 3 CV of 100% (ACN + 0.05% TFA), followed by 3 CV of 50% (ACN + 0.05% TFA) / (water + 0.05% TFA). The product fractions were collected and concentrated in vacuo, and the resulting aqueous residue was lyophilized to give the desired compound. LC-MS: m / z 809.6 [M+H] + . Step D—Synthesis of Compound 28: To intermediate 12c (0.3580 g, 0.443 mmol) was added 2:1 anhydrous DCM / TFA (4.4 mL) at ambient temperature. The reaction mixture was stirred for 1 hour and then cooled to 0° C. MTBE (10 mL) was added to the reaction with stirring, causing the solid to precipitate. The reaction mixture was sonicated and then centrifuged (4000 rpm) to collect the insoluble solid. The supernatant was decanted, washed with MTBE (5 mL), and isolated by centrifugation twice. The resulting solid was dried in vacuo and then purified by reverse-phase HPLC (XSelect CSH Prep C18; 5 μM OBD; 30 × 150 mm; 0% to 15% (ACN + 0.1% FA) / (water + 0.1% FA) over 15 min). The product fractions were collected and lyophilized to give the title compound as the formate salt. LC-MS: m / z 709.6 [M+H] + . 1H NMR (400 MHz, 4:1 D2O / d-DMSO)δ:7.41-7.28(m,2H),6.85(d,J=8.7Hz,1H),6.80(s,1H),4.58(s, 1H),4.34(d,J=10.7Hz,1H),3.89-3.80(m,1H),3.41(d,J=13.4Hz,2H),3.01(t, J=11.9Hz,2H),2.82-2.68(m,2H),2.19(d,J=13.5Hz,2H),2.02(d,J=13.6Hz,1H ),1.87-1.72(m,2H),1.70-1.60(m,1H),1.45(s,3H),1.37(s,3H),1.19(s,3H). [Example 16] Preparation of compounds 29 and 30 (S)-2-((R)-6-(N-(1-((R)-3-amino-2-hydroxypropyl)piperidin-4-yl)carbamimidoyl)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 and (S)-2-((R)-6-(N-(1-((S)-3-amino-2-hydroxypropyl)piperidin-4-yl)carbamimidoyl)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 [ka]

[0225] Step A - Synthesis of Intermediate 13a. To a vial containing (S)-1-(tert-butoxycarbonyl)-2,3-oxiranylmethylamine (0.095 g, 0.546 mmol) and 4-CBZ-aminopiperidine (0.1066 g, 0.455 mmol) was added anhydrous methanol (4.6 mL) at ambient temperature. The reaction mixture was heated to 60 °C for 4 h and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Isco Gold 12 g column; 0-100% (3:1 EtOAc / EtOH) / hexanes) to give the desired compound. LC-MS: m / z 409.3 [M+H] + . Step B—Synthesis of Intermediate 13b. A vial containing intermediate 13a (0.185 g, 0.455 mmol) and Pd / C (10 wt%, 0.0527 g, 0.050 mmol) was evacuated and backfilled with N (3×). Anhydrous MeOH (4.6 mL) was then added under N, and the reaction vessel was evacuated and backfilled with N (3×) before being subjected to 1 atmosphere of H (balloon). The reaction mixture was stirred for 4 h and then filtered through a Celite™ pad. The Celite™ pad was washed with MeOH, and the resulting filtrate was concentrated in vacuo to give the desired compound. LC-MS: m / z 274.2 [M+H] + . Step C—Synthesis of Intermediate 13c: To a mixture of Intermediate 3c (95.9 mg, 0.161 mmol) and Intermediate 13b (81.4 mg, 0.298 mmol) was added a pre-made solution of potassium acetate (31.7 mg, 0.323 mmol) and acetic acid (0.055 mL, 0.968 mmol) in anhydrous MeOH (1.6 mL). The reaction mixture was stirred at room temperature for 1.5 h, then concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (ISCO C18 13g; 0–100% ACN + 0.05% TFA / water + 0.05% TFA). The product fractions were collected and lyophilized to give the desired compound. LC-MS: m / z 692.6 [M+H] + . Step D - Synthesis of Intermediate 13d To a vial containing Intermediate 13c (75.8 mg, 0.110 mmol) was added 2:1 trifluoroacetic acid / anhydrous dichloromethane (1.1 mL) at ambient temperature. The reaction mixture was stirred for 16.5 hours, then a solution of 4:1 MeOH / toluene (5 mL) was added to the reaction, and the resulting mixture was concentrated in vacuo. The resulting residue was azeotroped again with 4:1 MeOH / toluene (5 mL) and then dried in vacuo to give the desired compound. LC-MS: m / z 436.2 [M+H] + . Step E - Synthesis of Intermediate 13e To a flask charged with Intermediate 13d (0.048 g, 0.110 mmol) and Intermediate 4 (0.051 g, 0.110 mmol) at ambient temperature was added anhydrous methanol (1.1 mL). The reaction was stirred for 2 hours and then concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (Isco C18Aq 415 g column; 0-40% ACN + 0.05% TFA / water + 0.05% TFA over 30 minutes), and the aqueous product fraction was concentrated in vacuo. The resulting aqueous residue was loaded onto an Amberchrom CG161M column (26 g), washed with 9 CV of (water + 0.05% TFA), and eluted with 3 CV of 100% (ACN + 0.05% TFA), followed by 3 CV of 50% (ACN + 0.05% TFA) / (water + 0.05% TFA). The product fractions were collected and concentrated in vacuo, and the resulting aqueous residue was lyophilized to give the desired compound. LC-MS: m / z 882.7 [M+H] + . Step F—Synthesis of Compounds 29 and 30. To intermediate 13e (97 mg, 0.110 mmol) was added 2:1 anhydrous DCM / TFA (1.1 mL) at ambient temperature. The reaction mixture was stirred for 1 hour, then cooled to 0° C., followed by the addition of MTBE (3 mL) and stirring. The resulting mixture was sonicated and then centrifuged (4000 rpm) to collect the insoluble solid. The supernatant was decanted, and the MTBE washing and centrifugation isolation steps were repeated. The resulting solid was dried in vacuo and purified by RP HPLC (XSelect CSH Prep C18; 5 uM OBD; 30×150 mm; 0%-20% (ACN+0.1% FA) / (water+0.1% FA) over 15 min). The product fractions were collected and lyophilized to give the title compound as the formate salt. LC-MS: m / z 782.6 [M+H] + . 1 HNMR(500MHz,4:1 D2O / d-DMSO)δ:7.50-7.38(m,2H),6.96(d,J=8.6Hz,1H),6.90(s,1H),4.67(s,1H), 4.48(d,J=11.3Hz,1H),4.39-4.32(m,1H),4.02-3.93(m,1H),3.74-3.60(m,2H),3. 34-3.11(m,5H),2.97(dd,J=13.3,9.0Hz,1H),2.86(t,J=17.6Hz,2H),2.39-2.27(m ,2H),2.20-1.94(m,3H),1.84-1.72(m,1H),1.58(s,3H),1.48(s,3H),1.30(s,3H). Compound 30 was prepared starting from (R)-1-(tert-butoxycarbonyl)-2,3-oxiranyl-methylamine according to the procedure of Steps A to F of Example 16. Compound 30: LC-MS: m / z 782.3 [M+H] + . 1HNMR(500MHz,4:1 D2O / d-DMSO)δ:7.49-7.40(m,2H),6.96(d,J=8.6Hz,1H),6.90(s,1H),4.67(s,1H),4.46(d d,J=11.3,2.0Hz,1H),4.39-4.31(m,1H),4.02-3.93(m,1H),3.74-3.58(m,2H),3.32-3.20( m,3H),3.17(dd,J=13.3,3.2Hz,2H),2.97(dd,J=13.3,8.9Hz,1H),2.87(d,J=16.3Hz,2H), 2.33(bs,2H),2.20-1.96(m,3H),1.81-1.75(m,1H),1.57(s,3H),1.48(s,3H),1.30(s,3H). [Example 17] Preparation of Compound 31 (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-(N-((R)-azepan-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid [ka]

[0226] Step A—Synthesis of Intermediate 14a To a vial containing a mixture of 2-methyl-2-propanyl(4S)-4-amino-1-azepanecarboxylate (91.9 mg, 0.429 mmol) and Intermediate 3c (0.100 g, 0.214 mmol) was added a solution of potassium acetate (0.631 mg, 0.643 mmol) and acetic acid (0.07 mL, 1.286 mmol) in anhydrous MeOH (2 mL). The reaction was heated at 70° C. for 20 min, then cooled, diluted with EtOAc (2 mL), and washed with saturated aqueous NaHCO (1 mL). The organic layer was separated, dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give a residue that was purified by reverse-phase HPLC (XSelect CSH Prep C18; 5uM OBD; 30x150mm; 35% to 70% (ACN + 0.05% TFA) / (water + 0.05% TFA) over 8 minutes). The product fractions were collected and lyophilized to give the desired compound. LC-MS: m / z 633.5 [M+H] + . Step B - Synthesis of Intermediate 14b To a vial containing Intermediate 14a (0.0652 g, 0.166 mmol) was added 2:1 trifluoroacetic acid / anhydrous dichloromethane (1.4 mL) at ambient temperature. The reaction was stirred for 16.5 hours, then a solution of 4:1 MeOH / toluene (2 mL) was added to the reaction and the mixture was concentrated in vacuo. The resulting residue was azeotroped with 4:1 MeOH / toluene (2 mL) and dried in vacuo to give the desired compound. LC-MS: m / z 377.3 [M+H] + . Step C—Synthesis of Intermediate 14c: To a flask charged with Intermediate 14b (0.166 mmol) and Intermediate 4 (0.076 g, 0.164 mmol) at ambient temperature was added anhydrous methanol (1.7 mL). The reaction was stirred for 3 hours and then concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (XSelect CSH Prep C18; 5 uM OBD; 30×150 mm; 12% to 42% (ACN+0.05% TFA) / (water+0.05% TFA) over 15 minutes) to give the desired compound. LC-MS: m / z 823.9 [M+H] + . Step D—Synthesis of Compound 31 To intermediate 14c (47.1 mg, 0.057 mmol) was added 2:1 anhydrous DCM / TFA (572 μL) at ambient temperature. The reaction mixture was stirred for 1 hour and then cooled to 0° C., followed by the addition of MTBE (3 mL) with stirring to obtain a precipitate. The mixture was sonicated and then centrifuged (4000 rpm) to collect the insoluble solid. The supernatant was decanted, and the MTBE wash and centrifugation isolation steps were repeated. The resulting solid was dried in vacuo and purified by RP HPLC (XSelect CSH Prep C18; 5 uM OBD; 19 x 150 mm; 0% to 40% (ACN + 0.05% FA) / (water + 0.05% FA) over 24 min; flow rate = 17.0 mL / min; monitoring and collecting 254 nM and 215 nM; product eluted with 17% (ACN + 0.05% FA) / (water + 0.05% FA)). Product fractions were collected and lyophilized to give the title compound as the formate salt. LC-MS: m / z 723.4 [M+H] + . 1 HNMR(500MHz,4:1 D2O / d-DMSO)δ:7.47(s,1H),7.44(dd,J=8.6,2.3Hz,1H),6.97(d,J=8.6Hz,1H),6.91(s ,1H),4.69(s,1H),4.46(dd,J=11.1,2.0Hz,1H),3.95(dq,J=9.0,4.5Hz,1H),3.45(dd, J=13.5,6.5Hz,1H),3.40-3.30(m,1H),3.30-3.17(m,2H),2.92-2.82(m,2H),2.43-2.2 2(m,2H),2.20-1.99(m,3H),1.91-1.73(m,3H),1.57(s,3H),1.49(s,3H),1.31(s,3H). [Example 18] Preparation of Compound 32 (S)-2-((R)-6-(N-((1r,4R)-4-aminocyclohexyl)carbamimidoyl)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 [ka]

[0227] Step A—Synthesis of Intermediate 15a To a vial containing a mixture of trans-N-Boc-1,4-cyclohexanediamine (91.9 mg, 0.429 mmol) and Intermediate 3c (0.100 g, 0.214 mmol) was added a solution of potassium acetate (0.631 mg, 0.643 mmol) and acetic acid (0.07 mL, 1.286 mmol) in anhydrous MeOH (2 mL). The reaction was heated at 70° C. for 20 minutes, then cooled, diluted with EtOAc (2 mL), and washed with saturated NaHCO (1 mL). The organic layer was separated, dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give a foam. The foam was directly purified by reverse-phase HPLC (XSelect CSH Prep C18; 5uM OBD; 30x150 mm; 35% to 70% (ACN + 0.05% TFA) / (water + 0.05% TFA) over 8 min). The product fractions were collected and dried in a Genevac™ to give the desired compound. LC-MS: m / z 633.5 [M+H] + . Step B - Synthesis of Intermediate 15b To a vial containing Intermediate 15a (0.0567 g, 0.151 mmol) was added 2:1 trifluoroacetic acid / anhydrous dichloromethane (1.4 mL) at ambient temperature. The reaction was stirred for 16.5 hours, then a solution of 4:1 MeOH / toluene (2 mL) was added to the reaction and the mixture was concentrated in vacuo. The resulting residue was azeotroped with 4:1 MeOH / toluene (2 mL) and dried in vacuo to give the desired compound. LC-MS: m / z 377.3 [M+H] + . Step C—Synthesis of Intermediate 15c: To a flask charged with Intermediate 15b (0.151 mmol) and Intermediate 4 (0.067 g, 0.144 mmol) at ambient temperature was added anhydrous methanol (1.5 mL). The reaction was stirred for 3 hours and then concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (XSelect CSH Prep C18; 5 uM OBD; 30×150 mm; 12% to 42% (ACN+0.05% TFA) / (water+0.05% TFA) over 15 minutes) to give the desired compound. LC-MS: m / z 823.6 [M+H] + . Step D—Synthesis of Compound 32 To intermediate 15c (62.9 mg, 0.076 mmol) was added 2:1 anhydrous DCM / TFA (764 μL) at ambient temperature. The reaction mixture was stirred for 1 hour and then cooled to 0° C. MTBE (10 mL) was added to the reaction with stirring, causing the solid to precipitate. The mixture was sonicated and then centrifuged (4000 rpm) to collect the insoluble solid. The supernatant was decanted, washed with MTBE (5 mL), and isolated by centrifugation twice. The resulting solid was dried in vacuo and then purified by reverse-phase chromatography (Isco C18 Aq 30 g Gold column; 0% to 40% (ACN + 0.1% FA) / (water + 0.1% FA) over 12 min). The product fractions were collected and lyophilized to give the title compound as the formate salt. LC-MS: m / z 723.2 [M+H] + . 1 HNMR(400MHz,4:1 D2O / d-DMSO)δ:7.40-7.25(m,2H),6.84(d,J=8.6Hz,1H),6.80(s,1H),4.58(s,1H),4.34(d,J=10.7Hz,1H),3.56-3.42(m,1H),3.1 6-3.03(m,1H),2.80-2.68(m,2H),2.08-1.98(m,5H),1.73-1.59(m,1H),1.53-1.40(m,4H),1.45(s,3H),1.37(s,3H),1.19(s,3H). [Example 19] Preparation of Compound 33 (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-(N-((3R,5S)-5-(hydroxymethyl)-pyrrolidin-3-yl)carbamimidoyl)chroman-2-yl)propanoic acid [ka]

[0228] Step A—Synthesis of Intermediate 16a: To a vial containing a mixture of (2S,4R)-1-Boc-2-hydroxymethyl-4-aminopyrrolidine hydrochloride (108.3 mg, 0.429 mmol) and Intermediate 3c (0.100 g, 0.214 mmol) was added a solution of potassium acetate (0.631 mg, 0.643 mmol) and acetic acid (0.07 mL, 1.286 mmol) in anhydrous MeOH (2 mL). The reaction was heated at 70° C. for 20 minutes, then cooled, diluted with EtOAc (2 mL), and washed with saturated NaHCO (1 mL). The organic layer was separated, dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give a foam. The foam was purified by reverse phase HPLC (XSelect CSH Prep C18; 5uM OBD; 30x150 mm; 35% to 70% (ACN + 0.05% TFA) / (water + 0.05% TFA) over 8 min). The product fractions were collected and dried in a Genevac™ to give the desired compound. LC-MS: m / z 635.5 [M+H] + Step B - Synthesis of Intermediate 16b To a vial containing Intermediate 16a (0.0817 g, 0.19 mmol) was added 2:1 trifluoroacetic acid / anhydrous dichloromethane (1.4 mL) at ambient temperature. The reaction was stirred for 16.5 hours. A 4:1 MeOH / toluene solution (2 mL) was then added to the reaction, and the mixture was concentrated in vacuo. The resulting residue was azeotroped again with 4:1 MeOH / toluene (2 mL) and then dried in vacuo to give the desired compound. LC-MS: m / z 379.3 [M+H] + . Step C—Synthesis of Intermediate 16c: To a flask charged with Intermediate 16b (0.19 mmol) and Intermediate 4 (0.099 g, 0.213 mmol) at ambient temperature was added anhydrous methanol (1.5 mL). The reaction was stirred for 3 hours and then concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (XSelect CSH Prep C18; 5 μM OBD; 30 × 150 mm; 12% to 42% (ACN + 0.05% TFA) / (water + 0.05% TFA) over 15 minutes) to give the desired compound. LC-MS: m / z 826.0 [M+H] + . Step D—Synthesis of Compound 33: To intermediate 16c (87.7 mg, 0.106 mmol) was added 2:1 anhydrous DCM / TFA (1.1 mL) at ambient temperature. The resulting solution was stirred for 1 hour and then cooled to 0° C. MTBE (3 mL) was added to the reaction with stirring, causing the solid to precipitate. The mixture was sonicated and then centrifuged (4000 rpm) to collect the insoluble solid. The supernatant was decanted, washed with MTBE, and isolated by centrifugation twice. The resulting solid was dried in vacuo and then purified by reverse-phase HPLC (XSelect CSH Prep C18; 5 μM OBD; 19 × 150 mm; 0%–40% (ACN + 0.1% FA) / (water + 0.1% FA) over 24 min; flow rate = 17.0 mL / min; monitoring and collecting 254 nM and 215 nM). The product fractions were collected and lyophilized to give the title compound as the formate salt. LC-MS: m / z 725.5 [M+H] + . 1HNMR(500MHz,4:1 D2O / d-DMSO)δ:7.51(d,J=2.2Hz,1H),7.47(dd,J=8.6,2.4Hz,1H),6.96(d,J=8.6Hz,1H),6.91(s, 1H),4.69(s,1H),4.64(dt,J=6.5,3.3Hz,1H),4.44(dd,J=11.3,2.0Hz,1H),4.10-4.03(m,1H),3. 92(dd,J=12.5,3.7Hz,1H),3.83-3.71(m,2H),3.59(dd,J=13.0,3.4Hz,1H),2.94-2.79(m,2H),2. 43-2.27(m,2H),2.14(d,J=13.7Hz,1H),1.83-1.73(m,1H),1.57(s,3H),1.49(s,3H),1.31(s,3H). [Example 20] Preparation of Compound 34 (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-(N-((1r,4R)-4-(methylamino)cyclohexyl)carbamimidoyl)chroman-2-yl)propanoic acid [ka]

[0229] Step A - Synthesis of Intermediate 17a To a solution of trans-N-Boc-1,4-cyclohexane-diamine (0.1761 g, 0.822 mmol) in anhydrous MeOH (4.1 mL) was added methyl trifluoroacetate (0.085 mL, 0.838 mmol) at 0 °C. After the addition, the ice bath was removed and the reaction was stirred at ambient temperature for 3 h. Hunig's base (0.17 mL, 0.986 mmol) was then added and the reaction was stirred for an additional 16 h. The resulting mixture was cooled to 0 °C and the insoluble solid was collected by filtration, washed with cold ether (2 × 2 mL), and dried in vacuo to give the desired compound. LC-MS: m / z 333.1 [M+Na] + . Step B—Synthesis of Intermediate 17b: To a solution of intermediate 17a (0.0472 g, 0.152 mmol) in anhydrous DMF (1 mL) was added NaH (6.08 mg, 0.152 mmol) at ambient temperature. After 1 h, the reaction was cooled to 0° C. and MeI (8.56 μL, 0.137 mmol) was added dropwise. The reaction was then warmed to ambient temperature and stirred for 15 h, then cooled to 0° C. and quenched with water (5 mL). The resulting mixture was partitioned between EtOAc and brine. The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (Isco C18 26 g column; 0–100% ACN+0.05% TFA / water+0.05% TFA). The product fractions were collected and concentrated in vacuo, and the resulting aqueous residue was extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give the desired compound. LC-MS: m / z 347.2 [M+Na] + . Step C—Synthesis of Intermediate 17c To a solution of Intermediate 17b (60 mg, 0.185 mmol) in anhydrous DCM (1850 μL) was added TFA (356 μL, 4.62 mmol) at 0° C. After 1.5 h, the reaction was concentrated in vacuo and the resulting residue was azeotroped with MeOH (2×5 mL). The residue was then dried under high vacuum to give the desired compound. LC-MS: m / z 225.1 [M+H] + . Step D—Synthesis of Intermediate 17d. To a vial containing a mixture of Intermediate 3c (0.0944 g, 0.202 mmol) and Intermediate 17c (0.041 g, 0.185 mmol) in acetonitrile (1.3 mL) was added acetic acid (0.069 mL, 1.214 mmol), followed by Hunig's base (0.106 mL, 0.607 mmol). The reaction was heated to 70° C. for 1 h. The reaction mixture was then cooled to ambient temperature and purified by reverse-phase chromatography (Isco C18 Aq 50 g column; 0–100% ACN + 0.05% TFA / water + 0.05% TFA). The product fractions were collected and concentrated in vacuo, and the resulting aqueous residue was extracted with EtOAc (2×). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give the desired compound. LC-MS: m / z 643.5 [M+H] + . Step E—Synthesis of Intermediate 17e. To a solution of intermediate 17d (79.0 mg, 0.123 mmol) in THF (800 μL) / MeOH (400 μL) was added aqueous LiOH (3 M, 82 μL, 0.246 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 1.5 h and then at 3-4° C. for 16 h. The reaction mixture was then concentrated in vacuo, and the resulting residue was purified by reverse-phase chromatography (Isco C18 13 g column; 0-100% ACN+0.05% TFA / water+0.05% TFA) to afford the desired compound. LC-MS: m / z 547.5 [M+H] + . Step F - Synthesis of Intermediate 17f To a vial containing Intermediate 17e (0.046 g, 0.084 mmol) was added 2:1 TFA / DCM (0.841 mL) at ambient temperature. The reaction was stirred for 20.5 h, after which 30% toluene / MeOH (5 mL) was added and concentrated in vacuo. The resulting residue was further azeotroped with MeOH (2 x 5 mL) and dried under high vacuum to afford the desired compound. LC-MS: m / z 391.4 [M+H] + . Step G—Synthesis of Compound 34 To a vial charged with Intermediate 17f (32.8 mg, 0.084 mmol), Intermediate 5 (80 wt%, 34.4 mg, 0.076 mmol), and powdered molecular sieves 4 Å (325 mesh particles; 0.100 g, heat-dried under high vacuum) was added anhydrous dimethylacetamide (0.34 mL) at ambient temperature. The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was then filtered through a Celite™ pad to remove the molecular sieves, and the Celite™ pad was washed with MeOH. The filtrate was concentrated in vacuo. The resulting residue was cooled to 0° C., and DCM (5 mL) was added slowly with stirring to precipitate a solid. The solid was collected by centrifugation (4000 rpm). The supernatant was decanted, and the insoluble solid was triturated with DCM (3 mL). Repeated centrifugation and transfer of the supernatant gave the crude product as a solid, which was purified by reverse-phase HPLC (XSelect CSH Prep C18; 5uM OBD; 50x250mm; 0% to 17% ACN / (water + 0.16% TFA) over 11 minutes; isocratic at 17% ACN / (water + 0.16% TFA) for 14 minutes. Product fractions were collected and concentrated in vacuo, and the aqueous layer was loaded directly onto an Amberchrom CG161M column (26g), washed with 9 CV of (water + 0.1% FA), eluted with 3 CV of 100% (ACN + 0.1% FA), followed by 3 CV of 50% (ACN + 0.1% FA) / (water + 0.1% FA). Product fractions were collected and concentrated in vacuo, and the resulting aqueous residue was lyophilized to give compound 34 as the formate salt. LC-MS: m / z 737.7 [M+H] + . 1H NMR (500 MHz, 4:1 D2O / d-DMSO)δ:7.48-7.41(m,2H),6.99-6.90(m,2H),4.69(s,1H),4.49-4.43( m,1H),3.67-3.60(m,1H),3.11(t,J=11.3Hz,1H),2.91-2.80(m,2H),2.95-2.77 (m,2H),2.68(s,3H),2.24-2.18(m,4H),2.14(d,J=13.6Hz,1H),1.80(td,J=12 .9,12.2,5.7Hz,1H),1.58(s,3H),1.57-1.50(m,4H),1.49(s,3H),1.31(s,3H). [Example 21] Preparation of Compound 35 (S)-2-((R)-6-(N-(4-aminobicyclo[2.2.2]octan-1-yl)carbamimidoyl)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 [ka]

[0230] Step A—Synthesis of Intermediate 18a. To a solution of tert-butyl (4-aminobicyclo[2.2.2]octan-1-yl)carbamate (72.0 mg, 0.300 mmol) and Intermediate 6c (99 mg, 0.200 mmol) in anhydrous DMF (1.5 mL) was added NEt (0.056 mL, 0.399 mmol) at ambient temperature. The reaction was stirred for 30 min and then partitioned between EtOAc and saturated aqueous NH Cl / ice-cold HCl (1 N). The organic layer was separated, washed with brine, dried over Na SO , filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (Isco C18Aq 30 g column; 0–100% ACN + 0.05% TFA / water + 0.05% TFA). The product fractions were collected and concentrated in vacuo, and the resulting aqueous residue was extracted with EtOAc (2×). The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give the desired compound. LC-MS: m / z 675.4 [M+H] + . Step B—Synthesis of Intermediate 18b: To a mixture of KCO (121 mg, 0.875 mmol) in MeOH (1.5 mL) was added formic acid (0.067 mL, 1.750 mmol). After the mixture was stirred at ambient temperature for 10 minutes, it was added to a solution of Intermediate 18a (118.1 mg, 0.175 mmol) in AcOH (0.90 mL). Pd / C (10 wt%, 74.5 mg, 0.070 mmol) was then added, and the resulting mixture was stirred at ambient temperature for 21 hours. The reaction was then filtered through a Celite™ pad under a N atmosphere, and the Celite™ pad was washed with MeOH. The filtrate was then concentrated in vacuo, and the resulting residue was purified by reverse-phase chromatography (Isco C18Aq 30 g column; 0–100% ACN + 0.05% TFA / water + 0.05% TFA). The product fractions were collected and concentrated in vacuo. The resulting aqueous residue was diluted with brine and extracted with EtOAc (2x). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo to give the desired compound. LC-MS: m / z 659.5 [M+H] + . Step C - Synthesis of Intermediate 18c To a vial containing Intermediate 18b (0.1155 g, 0.175 mmol) was added 1:2 DCM / TFA (1.8 mL) at ambient temperature and the reaction was stirred for 23 hours. To the reaction was added 30% toluene / MeOH (5 mL) and the resulting mixture was concentrated in vacuo. The residue was azeotroped with MeOH (2 x 5 mL) and then dried under high vacuum to give the desired compound. LC-MS: m / z 403.3 [M+H] + . Step D—Synthesis of Compound 35 To a vial charged with Intermediate 18c (0.175 mmol), Intermediate 5 (0.159 mmol), and powdered molecular sieves 4 Å (325 mesh particles; 50 mg, heat-dried under high vacuum) was added anhydrous dimethylacetamide (0.6 mL) at ambient temperature. The reaction mixture was stirred for 19 hours and then filtered through a Celite™ pad to remove the molecular sieves, and the Celite™ pad was washed with MeOH. The filtrate was concentrated in vacuo, and the resulting residue was cooled to 0° C. DCM (10 mL) was then added slowly with stirring to precipitate the solid. The solid was collected by centrifugation (4000 rpm). The supernatant was decanted, and the insoluble solid was dried in vacuo. The dried solid was purified by reverse phase HPLC (XSelect CSH Prep C18; 5uM OBD; 50x250mm; 0% to 16% ACN / (water + 0.16% TFA) over 11 minutes; isocratic at 13% ACN / (water + 0.16% TFA) over 14 minutes. Product fractions were collected and concentrated in vacuo, and the aqueous layer was loaded directly onto an Amberchrom CG161M column (26g), washed with 10 CV of (water + 0.1% FA), and eluted with 3 CV of 100% (ACN + 0.1% FA), followed by 3 CV of 50% (ACN + 0.1% FA) / (water + 0.1% FA). Product fractions were collected and concentrated in vacuo, and the resulting aqueous residue was lyophilized to give the title compound as the formate salt. LC-MS: m / z 749.5 [M+H] + . 1H NMR(500MHz,4:1D2O / d-DMSO)δ:7.37(s,1H),7.36-7.29(m,1H),6.94-6.83(m,2H),4.66(s,1H),4.41(d,J=11.1Hz,1H ),2.88-2.75(s,2H),2.20-2.04(m,7H),1.96-1.88(m,6H),1.80-1.68(m,1H),1.53(s,3H),1.43(s,3H),1.25(s,3H). [Example 22] Preparation of Compound 36 (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-(N-(azetidin-3-yl)carbamimidoyl)chroman-2-yl)propanoic acid [ka]

[0231] Step A—Synthesis of Intermediate 19a To a solution of tert-butyl 3-aminoazetidine-1-carboxylate (90 mg, 0.523 mmol) and Intermediate 3c (300 mg, 0.505 mmol) in MeOH (5 mL) was added acetic acid (0.116 mL, 2.018 mmol) followed by potassium acetate (99 mg, 1.009 mmol) at 23° C. The reaction mixture was stirred at 83° C. for 20 minutes and then cooled to room temperature. The reaction mixture was directly purified by silica gel chromatography (Biotage; 12 g Agela silica flash column, eluent of 10% MeOH / DCM gradient at 40 mL / min) to give the crude product. The crude product was further purified by reverse phase HPLC (Boston Uni C18 40*150*5um. Conditions: water (0.1% TFA)-ACN; start B 30, end B 60; gradient time (min) 11; 100% B hold time (min) 2; flow rate (mL / min) 60; injection 1) to give intermediate 19a. LC-MS (ESI+): m / z 591.3 [M+H] + . Step B - Synthesis of Intermediate 19b A solution of intermediate 19a (204 mg, 0.345 mmol) in a 2:1 mixture of DCM:TFA (3 mL) was stirred at 25°C for 0.5 h. The reaction mixture was then dried under a stream of nitrogen gas to give intermediate 19b, which was used in the next reaction without further purification. LC-MS (ESI): m / z 391.3 [M+H] + . Step C - Synthesis of Intermediate 19c A solution of Intermediate 19b (135 mg, 0.346 mmol) and Intermediate 4 (161 mg, 0.346 mmol) in 3 mL of MeOH was stirred at 25 °C for 1.5 h. The reaction mixture was concentrated in vacuo to give Intermediate 19c, which was used in the next reaction without further purification. LC-MS (ESI): m / z 837.7 [M+H] + . Step D—Synthesis of Compound 36 A mixture of intermediate 19c (269 mg, 0.321 mmol) in a 3:1 mixture of TFA:DCM (3 mL) was stirred at 25° C. for 30 minutes. The reaction mixture was then dried under a stream of nitrogen gas, and the resulting residue was purified by preparative HPLC (column Boston Uni C18 40*150*5 μm. Conditions: water (0.1% TFA)-ACN; start B 1, end B 31; gradient time (min) 11; 100% B retention time (min) 2; flow rate (mL / min) 60; injection 1) to give the crude product. The crude product was further purified by preparative HPLC (column YMC-Actus Triart C18 150*30mm*5um. Conditions: water (0.225% FA)-ACN; start B 0, end B 20; gradient time (min) 19; 100% B retention time (min) 2; flow rate (mL / min) 25; injection 3) to give compound 36 as the formate salt form. LC-MS (ESI): m / z 681.2 [M+H] + . 1H NMR(400MHz,DMSO-d6):7.52(s,1H),7.38(br d,J=8.6Hz,1H),6.73(s,1H),6.70(br d,J=8.6Hz,1H),4.62-4.51(m,1H),4.44-4.26(m,5H),4.06-3.95(m,1H),2.86-2.61 (m,2H),2.06-1.93(m,1H),1.50(s,3H),1.43-1.38(m,1H),1.36(s,3H),1.21(s,3H). [Example 23] Preparation of compounds 37-44 Starting from intermediate 3c, compounds 37-44 were prepared using the procedure described in Steps A-D of Example 22, substituting the appropriate commercially available mono-Boc protected diamine for tert-butyl (1-(2-aminoethyl)piperidin-4-yl)carbamate in Step A. [Table 4] TIFF0007671398000051.tif198153TIFF0007671398000052.tif231153TIFF0007671398000053.tif22154

[0232] [Example 24] Preparation of compounds 45 and 46 (S)-2-((R)-6-(N-((1R,3S)-3-aminocyclopentyl)carbamimidoyl)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 and (S)-2-((R)-6-(N-((1S,3R)-3-aminocyclopentyl)carbamimidoyl)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* [ka]

[0233] Step A—Synthesis of Intermediate 20a Acetic acid (0.294 mL, 5.14 mmol) and potassium acetate (379 mg, 3.86 mmol) were added to a stirred mixture of racemic cis-3-((tert-butoxycarbonyl)-amino)cyclopentanaminium carboxyformate (448 mg, 1.543 mmol) and Intermediate 3c (600 mg, 1.286 mmol) in MeOH (6.0 mL). The reaction mixture was stirred at 80° C. for 10 minutes, then diluted with HO (50 mL), extracted with EtOAc (50 mL×3), washed with brine (150 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo and the resulting residue was purified by flash silica gel chromatography (Biotage; 4 g Agela silica flash column, elution with a 0-10% MeOH / DCM gradient at 35 mL / min) to afford intermediate 20a as a mixture of stereoisomers. LC-MS (ESI): m / z 619.4 [M+H] + . Step B—Synthesis of Intermediates 20b-1 and 20b-2. To a solution of intermediate 20a (460 mg, 0.743 mmol) in DCM (10 mL) stirred at 0 °C, EtN (0.518 mL, 3.72 mmol) and (Boc)O (0.345 mL, 1.487 mmol) were added. The reaction mixture was stirred at 26 °C for 2.5 h, then diluted with saturated aqueous NH4Cl (30 mL), and the mixture was extracted with DCM (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 4 g Agela silica flash column, eluting with a 0–60% petroleum ether / EtOAc gradient at 30 mL / min) to afford intermediate 20b as a mixture of stereoisomers. LC-MS (ESI): m / z 719.3 [M+H] +The mixture was further separated by SFC to give intermediate 20b-1 (first eluting isomer) and intermediate 20b-2 (second eluting isomer). LC-MS (ESI): m / z 719.4 [M+H] + . Step C—Synthesis of Intermediate 20c-1 Intermediate 20b-1 (140 mg, 0.195 mmol) was added to a stirred solution of 2:1 DCM / TFA (2.4 mL) at 0° C. The reaction mixture was stirred at 26° C. for 40 min, and then the solvent was removed under a stream of N gas to give intermediate 20c-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z 419.3 [M+H] + . Step D—Synthesis of Intermediate 20d-1 To a solution of intermediate 20c-1 (82 mg, 0.197 mmol) in MeOH (3.0 mL) was added intermediate 4 (91 mg, 0.197 mmol). The reaction mixture was stirred at 26° C. for 2.5 h. The reaction mixture was concentrated under a stream of N gas to give intermediate 20d-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z 865.2 [M+H] + . Step E - Synthesis of Compounds 45 and 46 A solution of intermediate 20d-1 (170 mg, 0.197 mmol) in 1:2 DCM:TFA (2.5 mL) was stirred at 26 °C for 55 minutes. The solvent was then removed under a stream of N2 gas, and the resulting residue was purified by reverse-phase HPLC (column: Boston Uni C18 250 * 50 * 5 μm; conditions: water (0.1% TFA)-ACN; start B 1, end B 31; gradient time (min) 11; 100% B retention time (min) 2; flow rate (mL / min) 60). The product fractions were combined and lyophilized to give compound 45 as its TFA salt. The TFA salt was converted to the formate salt by reverse-phase HPLC (column: Welch Xtimate C18 150*25mm*5um; conditions: water (0.225% FA)-ACN; start B 0, end B 18; gradient time (min) 15; 100% B retention time (min) 2; flow rate (mL / min) 25) to give compound 45 as the formate salt form. LC-MS (ESI): m / z 708.9 [M+H] + . 1H NMR(400MHz,CD3CN+D2O)δ:7.41-7.34(m,2H),6.86(d,J=8.6Hz,1H),6.79(s,1H),4.61(s,1H),4.34(br d,J=10.2Hz,1H),4.10-4.01(m,1H),3.67-3.57(m,1H),2.85-2.69(m,2H),2.67-2.57 (m,1H),2.15-1.99(m,3H),1.92-1.57(m,4H),1.48(s,3H),1.42(s,3H),1.24(s,3H). Starting from intermediate 20b-2, compound 46 was prepared using the procedures in steps C to E of Example 24. Compound 46: LC-MS (ESI): m / z 709.1 [M+H]+. 1 H NMR (400 MHz, CD3CN + DO) δ: 7.42-7.34 (m, 2H), 6.85 (d, J = 8.6 Hz, 1H), 6.79 (s, 1H), 4.61 (s, 1H), 4.34 (br d, J = 9.8 Hz, 1H), 4.10-4.01 (m, 1H), 3.63 (quin, J = 7.5 Hz, 1H), 2.84-2.68 (m, 2H), 2.68-2.58 (m, 1H), 2.14-2.00 (m, 3H), 1.90-1.63 (m, 4H), 1.49 (s, 3H), 1.42 (s, 3H), 1.24 (s, 3H). *Each compound is a single diastereomer, and the stereochemistry at the carbon center marked with an * is not assigned.

[0234] [Example 25] Preparation of compounds 47 and 48 (S)-2-((R)-6-(N-((1S,3S)-3-aminocyclopentyl)carbamimidoyl)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 and (S)-2-((R)-6-(N-((1R,3R)-3-aminocyclopentyl)carbamimidoyl)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* [ka]

[0235] Step A—Synthesis of Intermediates 21a-1 and 21a-2. To a solution of intermediate 3c (800 mg, 1.715 mmol) in MeOH (17 mL) was added trans-3-((tert-butoxycarbonyl)amino)cyclopentanaminium carboxyformate (572 mg, 1.972 mmol) and acetic acid (0.393 mL, 6.86 mmol) at 25 °C. Potassium acetate (505 mg, 5.14 mmol) was then added. The reaction mixture was stirred at 80 °C for 20 min (under N atmosphere). The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (ISCO; 12 g Agela silica flash column, elution with a 0–5% CHCl / MeOH gradient at 30 mL / min) to give intermediates 21a-1 and 21a-2. LC-MS(ESI):m / z 619.4 [M+H] +The intermediate mixture was further separated by SFC (DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); 0.1% NH₃·H₂O / EtOH; Start B: 30%; End B: 30%; Flow rate (mL / min): 60; Injection: 120) to give intermediate 21a-1 (first eluting compound) and intermediate 21a-2 (second eluting compound). LC-MS (ESI): m / z 619.3 [M+H] + . Step B—Synthesis of Intermediate 21b-1 A solution of intermediate 21a-1 (170 mg, 0.275 mmol) in DCM (0.9 mL) and TFA (1.8 mL) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated in vacuo to give intermediate 21b-1, which was used in the next step without further purification. LC-MS (ESI): m / z 418.9 [M+H] + . Step C—Synthesis of Intermediate 21c-1 A mixture of intermediate 21b-1 (115 mg, 0.275 mmol) and intermediate 4 (115 mg, 0.248 mmol) in MeOH (2.8 mL) was stirred at 25° C. for 3 hours. The reaction mixture was concentrated in vacuo to give intermediate 21c-1, which was used in the next step without further purification. LC-MS (ESI): m / z 865.7 [M+H] + . Step D—Synthesis of Compounds 47 and 48 To a solution of intermediate 21c-1 (238 mg, 0.275 mmol) in DCM (0.900 mL) was added TFA (1.8 mL). The reaction was stirred at 25° C. for 30 minutes, and then the solvent was removed with N to give the crude product, which was purified by reverse-phase HPLC (column: Boston Uni C18 40*150*5 μm; conditions: water (0.1% TFA)-ACN; start B 1, end B 31; gradient time (min) 10; 100% B retention time (min) 2; flow rate (mL / min) 60; injection 1) to give compound 47 as its TFA salt. The TFA salt was converted to the formate salt by passing it through reverse-phase HPLC (Column: Welch Xtimate C18 150*25mm*5um; Conditions: water (0.225% FA)-ACN; Start B 0, End B 19; Gradient time (min) 15; 100% B retention time (min) 2; Flow rate (mL / min) 25; Injection 2) to give compound 47 as the formate salt. MS(ESI) m / z: 709.4 [M+H] + . 1 H NMR(400MHz,D2O+CD3CN)δ:7.39-7.31(m,2H),6.87(br d,J=8.6Hz,1H),6.79(s,1H),4.61(s,1H),4.48-4.40(m,1H),4.25-4.14(m,1H),3.80-3.71(m,1H),2.84-2 .69(m,2H),2.31-2.17(m,3H),2.14-2.02(m,2H),1.83-1.61(m,3H),1.49(s,3H),1.42(s,3H),1.24(s,3H). Compound 48 was prepared from intermediate 21a-2 according to the procedures in Steps B to D of Example 25. LC-MS (ESI): m / z 709.3 [M+H] + . 1H NMR (400 MHz, DO + CDCN) δ: 7.39-7.29 (m, 2H), 6.90-6.77 (m, 2H), 4.61 (s, 1H), 4.38 (br d, J = 11.0 Hz, 1H), 4.23-4.13 (m, 1H), 3.83-3.72 (m, 1H), 2.83-2.69 (m, 2H), 2.31-2.17 (m, 3H), 2.16-2.00 (m, 2H), 1.83-1.63 (m, 3H), 1.49 (s, 3H), 1.41 (s, 3H), 1.23 (s, 3H). *Each compound is a single diastereomer, and the stereochemistry at the carbon center marked with an * is not assigned.

[0236] [Example 26] Preparation of compounds 49-50 Compounds 49-50 were prepared starting from intermediate 3c using the procedure described in Steps A-D of Example 25, substituting the appropriate racemic amine for trans-3-((tert-butoxycarbonyl)amino)cyclopentanaminium carboxyformate in Step A. [Table 5]

[0237] [Example 27] Preparation of Intermediates 22c-1 and 22c-2 [ka]

[0238] Step A—Synthesis of Intermediate 22a To a solution of racemic (3,4-cis)-1-tert-butyl 3-ethyl 4-(benzylamino)piperidine-1,3-dicarboxylate (2 g, 5.52 mmol) in THF (10 mL) stirred at 0° C., LAH (0.6 g, 15.81 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 0.5 h and then at 22° C. for 15 min. The reaction mixture was then quenched by the sequential addition of water (0.6 mL), 10% NaOH (1.2 mL), and water (1.8 mL). The resulting mixture was stirred at ambient temperature for 15 min and then filtered. The filtrate was concentrated under reduced pressure to provide Intermediate 22a, which was used in the next step without further purification. LC-MS (ESI): m / z 321.5 [M+H] + . Step B—Synthesis of Intermediate 22b. To a stirred solution of intermediate 22a (2 g, 6.24 mmol), imidazole (1.062 g, 15.60 mmol), and DMAP (0.153 g, 1.248 mmol) in DCM (50 mL) was added TBS-Cl (1.882 g, 12.48 mmol) in one portion. The reaction mixture was stirred at 25 °C for 12 h, then diluted with DCM (70 mL) and washed with saturated NH4Cl solution (100 mL) and brine (100 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 20 g Agela silica flash column, eluent: 0–28% EtOAc / petroleum ether gradient at 36 mL / min) to afford intermediate 22b as a racemic mixture. This mixture was further separated by SFC (Method: Column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm). Conditions: 0.1% NH₃·H₂O / EtOH; Start B 15%, End B 15%; Flow rate (mL / min) 180; Injection 150) to give Intermediate 22b-1 (first eluting compound) and Intermediate 22b-2 (second eluting compound). Intermediate 22b-1: LC-MS (ESI): m / z 436.1 [M+H] + .Intermediate 22b-2:LC-MS(ESI):m / z 435.6 [M+H] + . Step C—Synthesis of Intermediates 22c-1 and 22c-2 To a solution of intermediate 22b-1 (1 g, 2.301 mmol) in MeOH (30 mL) was added Pd / C (0.184 g, 0.345 mmol). The reaction mixture was stirred under an atmosphere of H (50 psi) at 25° C. for 20 hours. The mixture was then filtered through Celite™, and the filtrate was concentrated in vacuo to give intermediate 22c-1, which was used in the next reaction without further purification. 1 H NMR(400MHz,CDCl3)δ:3.67-3.58(m,2H),3.58-3.48(m,2H),3.41-3.23(m,2H),1.82(br s,1H),1.73-1.65(m,1H),1.61(br s,1H),1.58-1.51(m,1H),1.46(s,9H),0.90(s,9H),0.06(s,6H). Intermediate 22c-2 was prepared from intermediate 22b-2 using the procedure described in Example 27. 1 H NMR(400MHz,CDCl3-d)δ:3.66-3.52(m,4H),3.39-3.22(m,2H),1.82(br s,1H),1.73-1.61(m,2H),1.53(dt,J=4.7,9.2Hz,1H),1.46(s,9H),0.90(s,9H),0.06(s,6H). [Example 28] Preparation of compounds 51 and 52 (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-(N-((3R,4S)-3-(hydroxymethyl)piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid, and 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-(N-((3S,4R)-3-(hydroxymethyl)piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid* [ka]

[0239] Step A—Synthesis of Intermediate 23a. To a stirred mixture of intermediate 22c-1 (792 mg, 1.839 mmol), potassium acetate (246 mg, 2.508 mmol), and intermediate 3c (390 mg, 0.836 mmol) in MeOH (15 mL) was added acetic acid (0.191 mL, 3.34 mmol). The reaction was stirred at 80° C. for 20 minutes, and then the solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 20 g Agela silica flash column, eluent: 0–8% MeOH / CHCl gradient at 20 mL / min) to give intermediate 23a. LC-MS (ESI): m / z 763.5 [M+H] + . Step B - Synthesis of Intermediate 23b To a solution of intermediate 23a (500 mg, 0.655 mmol) in THF (2 mL) was added a solution of TBAF in THF (1 M, 0.917 mL, 0.917 mmol). The reaction mixture was stirred at 27 °C for 2 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to give intermediate 23b, which was used in the next reaction without further purification. LC-MS (ESI): m / z 649.4 [M+H] + . Step C - Synthesis of Intermediate 23c To a solution of intermediate 23b (500 mg, 0.771 mmol) in DCM (4 mL) was added TFA (2 mL, 26.0 mmol) dropwise at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The solvent was then removed under reduced pressure to give intermediate 23c, which was used in the next reaction without further purification. LC-MS (ESI): m / z 449.2 [M+H] + . Step D - Synthesis of Intermediate 23d To a solution of Intermediate 23c (400 mg, 0.892 mmol) in MeOH (8 mL) was added Intermediate 4 (331 mg, 0.713 mmol). The reaction was stirred at 25 °C for 2 h. The solvent was then removed under reduced pressure to give Intermediate 23d, which was used in the next reaction without further purification. LC-MS (ESI): m / z 448.0 [M / 2+H] + . Step E - Synthesis of Compound 51 To a solution of intermediate 23d (570 mg, 0.637 mmol) in DCM (2 mL) was added TFA (4 mL) dropwise at 0 ° C. The resulting solution was stirred at 25 ° C. for 60 minutes. The solvent was then removed under vacuum, and the resulting residue was purified by reverse-phase HPLC (column: Boston Uni C18 40 * 150 * 5 μm; conditions: water (0.1% TFA)-ACN; start B 1, end B 31; gradient time (min) 10; 100% B retention time (min) 2; flow rate (mL / min) 60). The product fractions were combined and lyophilized to give compound 51 as its TFA salt. The TFA salt was converted to the formate salt by reverse-phase HPLC (column: Welch Xtimate C18 150*25mm*5um; conditions: water (0.225% FA)-ACN; start B 0, end B 15; gradient time (min) 15; 100% B hold time (min) 2; flow rate (mL / min) 25). The resulting product was further purified by reverse-phase HPLC (column: Welch Xtimate C18 150*25mm*5um; conditions: water (10mM NH4HCO3)-ACN; start B 0, end B 28; gradient time (min) 15; 100% B hold time (min) 2; flow rate (mL / min) 25) to give compound 51 as the formate salt. LC-MS (ESI): m / z 739.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ:7.48-7.40(m,2H),6.96(d,J=8.6Hz,1H),6.76(s,1H),4.60(s,1H),4.42(br d,J=11.0Hz,1H),4.21-4.13(m,1H),3.54-3.42(m,2H),3.34-3.23(m,1H),3.23-3.03(m,3H),2.91-2.71(m,2H),2 .28-2.21(m,1H),2.08-1.97(m,2H),1.94-1.83(m,1H),1.65-1.52(m,1H),1.51(s,3H),1.40(s,3H),1.24(s,3H). Compound 52 was prepared starting from intermediate 22c-2 according to the procedure described in Steps A to E of Example 28. LC-MS (ESI): m / z 739.5 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:7.49-7.38(m,2H),6.97(d,J=8.6Hz,1H),6.75(s,1H),4.60(s,1H),4.43(br d, J = 12.1 Hz, 1H), 4.20-4.13 (m, 1H), 3.52-3.44 (m, 2H), 3.35-3.25 (m, 1H), 3.15-2.99 (m, 3H), 2.87-2.71 (m, 2H), 2.27-2.20 (m, 1H), 2.08-1.93 (m, 2H), 1.92-1.81 (m, 1H), 1.61-1.47 (m, 1H), 1.49 (s, 3H), 1.39 (s, 3H), 1.24 (s, 3H). *Each compound is a single diastereomer, and the stereochemistry at the carbon center marked with an * cannot be assigned.

[0240] [Example 29] Preparation of Intermediates 24e-1 and 24e-2 [ka]

[0241] Step A—Synthesis of Intermediate 24a To a solution of 1-tert-butyl 2-methyl 4-oxopiperidine-1,2-dicarboxylate (5 g, 19.43 mmol) in THF (10 mL) was added LiBH (1.693 g, 78 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 18 hours, then diluted with water (50 mL) and extracted with ethyl acetate (130 mL×3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give a cis / trans mixture of intermediate 24a, which was used in the next reaction without further purification.

[0242] Step B—Synthesis of Intermediates 24b-1 and 24b-2 To a solution of intermediate 24a (4 g, 10.38 mmol) in DMF (40 mL) was added TEA (2.169 mL, 15.56 mmol), imidazole (0.071 g, 1.038 mmol), and TBDPS-Cl (3.20 mL, 12.45 mmol) sequentially. The reaction was stirred at 20° C. for 16 hours. The resulting mixture was poured into 100 mL of water and then extracted with EtOAc (100 mL×3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent of 10% ethyl acetate / petroleum ether gradient at 45 mL / min) to give separated intermediates 24b-1 and 24b-2.

[0243] Intermediate 24b-1: 1 H NMR(400MHz,CDCl3)δ:7.69-7.61(m,4H),7.46-7.33(m,6H),4.24(br s,1H),4.08-4.03(m,1H),3.96(br d,J=12.2Hz,1H),3.90(dd,J=5.1,10.5Hz,1H),3.66(dd,J=4.3,10.4Hz,1H),3.46(br s,1H),3.35-3.25(m,1H),1.75-1.57(m,2H),1.44-1.35(m,11H),1.05(s,9H). Intermediate 24b-2:1 H NMR(400MHz,CDCl3)δ:7.68-7.62(m,4 H),7.47-7.37(m,6 H),4.47(br s,1 H),4.16-4.13(m,1 H),3.79(br s,1 H),3.64(br d,J=6.65Hz,2 H),2.75(br t,J=12.52Hz,1 H),2.24-2.11(m,1 H),1.91-1.78(m,1 H),1.47-1.64(m,2 H),1.43(s,9 H),1.06(s,9 H). Step C—Synthesis of Intermediate 24c To a solution of intermediate 24b-1 (3 g, 6.39 mmol) in DCM (10 mL) stirred at 0° C., TEA (3.56 mL, 25.5 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (2.237 mL, 28.7 mmol). The reaction mixture was stirred at 25° C. for 12 h, then poured into 50 mL of water and extracted with DCM (100 mL×3). The organic layers were combined, washed with brine (70 mL), dried over anhydrous NaSO, filtered, and concentrated to give intermediate 24c, which was used in the next reaction without further purification. LC-MS (ESI): m / z 548.1 [M+H] + . Step D - Synthesis of Intermediate 24d To a solution of intermediate 24c (3.5 g, 6.39 mmol) in DMF (30 mL) was added sodium azide (1.495 g, 23.00 mmol). The reaction mixture was stirred at 60 °C for 18 hours, then diluted with water (50 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give intermediate 24d, which was used in the next reaction without further purification. LC-MS (ESI): m / z 495.2 [M+H] + . Step E - Synthesis of Intermediate 24e-1 and Intermediate 24e-2 To a solution of intermediate 24d (3 g, 6.06 mmol) in MeOH (30 mL) was added 10% Pd / C (0.645 g, 0.606 mmol). The reaction mixture was stirred under 15 psi of H at 25 °C for 12 hours. The mixture was then filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column silica-CS (4 g) (SiO, 50% ethyl acetate in petroleum ether) to give a racemic mixture of enantiomers of intermediate 24e-1. LC-MS (ESI): m / z 369.2 [M+H-100] + The enantiomers of this racemic mixture were separated by SFC (Phenomenex-Cellulose-2 (250 mm x 50 mm, 10 μm) conditions: 0.1% NH₃·H₂O / MeOH; starting B 45%, ending B 45%; flow rate (mL / min) 200; injection 90) to give intermediate 24e-1 (first eluting component) and intermediate 24e-2 (second eluting component). Intermediate 24e-1: LC-MS (ESI): m / z 469.2 [M+H] + .Intermediate 24e-2:LC-MS(ESI):m / z469.2 [M+H] + . [Example 30] Preparation of compounds 53 and 54 (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-(N-((2S,4S)-2-(hydroxymethyl)piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid, and 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-(N-((2R,4R)-2-(hydroxymethyl)piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid* [ka]

[0244] Step A - Synthesis of Intermediate 25a To a stirred solution of intermediate 3c (500 mg, 1.072 mmol) and intermediate 24e-1 (552 mg, 1.179 mmol) in MeOH (10 mL) were added acetic acid (0.245 mL, 4.29 mmol) and potassium acetate (316 mg, 3.21 mmol) sequentially at 25 °C. The reaction mixture was stirred at 85 °C for 30 min and then concentrated under reduced pressure to provide intermediate 25a, which was used in the next step without further purification. LC-MS (ESI): m / z 887.5 [M+H] + . Step B—Synthesis of Intermediate 25b To a solution of intermediate 25a (900 mg, 1.014 mmol) in THF (8 mL) was added tetrabutylammonium fluoride (1.420 mL, 1.420 mmol) at 0° C. The reaction was stirred at 25° C. for 2 hours, then diluted with water (20 mL) and extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give intermediate 25b, which was used in the next step without further purification. LC-MS (ESI): m / z 649.4 [M+H] + . Step C—Synthesis of Intermediate 25c To a solution of intermediate 25b (600 mg, 0.925 mmol) in DCM (1 mL) was added TFA (2 mL) at 0° C. The reaction was stirred at 40° C. for 1 h and then concentrated in vacuo to give intermediate 25c, which was used in the next step without further purification. LC-MS (ESI): m / z 393.1 [M+H] + . Step D - Synthesis of Intermediate 25d To a solution of Intermediate 25c (350 mg, 0.892 mmol) in MeOH (4 mL) was added Intermediate 4 (373 mg, 0.803 mmol) at 25 °C. The reaction was stirred at 25 °C for 2 h. The reaction was concentrated under reduced pressure to provide Intermediate 25d, which was used in the next step without further purification. LC-MS (ESI): m / z 759.1 [M+H-SO] + . Step E—Synthesis of Compound 53 To a solution of intermediate 25d (700 mg, 0.834 mmol) in DCM (1 mL) was added TFA (2 mL) dropwise at 25° C. The reaction was stirred at 25° C. for 45 minutes. MTBE (1.5 mL) was then added dropwise at −10 to 0° C., and the resulting mixture was centrifuged. The collected solid was purified by reverse-phase HPLC (Column: Boston Uni C18 40*150*5 μm; Conditions: water (0.1% TFA)-ACN; Start B 1, End B 31; Gradient Time (min): 10; 100% B Retention Time (min): 2; Flow Rate: 60 mL / min). The product fractions were combined and lyophilized to give compound 53 as a TFA salt form. The TFA salt was converted to the formate salt by reverse-phase HPLC (column: Agela DuraShell C18 150*25mm*5um; mobile phase: water (0.225% FA)-acetonitrile; detection wavelength: 220nm), followed by lyophilization to give compound 53 as the formate salt. LC-MS (ESI): m / z 739.1 [M+H] + . 1 H NMR(400MHz,DMSO-D6)δ:7.53-7.41(m,2H),6.97(d,J=7.4Hz,1H),6.74(s,1H),4.62(s,1H),4.47(br d,J=11.7Hz,1H),4.07(br s,1H),3.50-3.45(m,1H),3.23-3.03(m,3H),2.98-2.65(m,3H),2.07-1.98(m,1H),1.9 2-1.84(m,3H),1.78-1.72(m,1H),1.62-1.52(m,1H),1.48(s,3H),1.39(s,3H),1.22(br s,3H). Compound 54 was prepared from intermediate 24e-2 according to the procedures in Steps A to E of Example 30. LC-MS (ESI): m / z 738.9 [M+H] + . 1H NMR (400 MHz, DMSO-D6) δ: 7.47 (br d, J = 16.8 Hz, 2H), 6.95 (br d, J = 8.2 Hz, 1H), 6.74 (br s, 1H), 4.59 (br s, 1H), 4.44 (br d, J = 10.6 Hz, 1H), 4.09 (br s, 1H), 3.69-3.64 (m, 1H), 3.30-3.04 (m, 3H), 2.98-2.65 (m, 3H), 2.11-1.74 (m, 5H), 1.64-1.52 (m, 1H), 1.49 (br s, 3H), 1.38 (br s, 3H), 1.23 (br s, 3H). *Each compound is a single diastereomer, and the stereochemistry at the carbon center marked with an * is not assigned.

[0245] [Example 31] Preparation of Compounds 55 and 56 (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-(N-((2R,4R)-2-methylpiperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid, and 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-(N-((2S,4S)-2-methylpiperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid* [ka]

[0246] Step A—Synthesis of Intermediates 26a-1 and 26a-2 To a solution of cis-tert-butyl 4-amino-2-methylpiperidine-1-carboxylate (755 mg, 3.52 mmol) in THF (18 mL) and water (9 mL) was added sodium carbonate (747 mg, 7.05 mmol) and benzyl chloroformate (0.480 mL, 3.52 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 16 h, then diluted with water (20 mL), extracted with EtOAc (10 mL×4), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by HPLC (Column: Boston Uni C18 40*150*5um; Conditions: Water (0.1% TFA)-ACN; Start B 45, End B 75; Gradient time (min) 10; 100% B Retention time (min) 2; Flow rate (mL / min) 60; Injection 3) to obtain the product as a racemic mixture (LC-MS(ESI): m / z 349.2 [M+H] + ), which was further purified by chiral SFC (Column: DAICEL CHIRALCEL OJ, 250 mm*30 mm, 10 μm. Conditions: 0.1% NH₃·H₂O / EtOH; Start B 10%, End B 10%; Flow rate (mL / min) 60; Injection 250) to give Intermediate 26a-1 (first eluting enantiomer) and Intermediate 26a-2 (second eluting enantiomer) separately.

[0247] Step B—Synthesis of Intermediates 26b-1 and 26b-2 A mixture of intermediate 26a-1 (166.8 mg, 0.479 mmol) and Pd / C (153 mg, 10 wt%) in MeOH (10 mL) was stirred under a hydrogen atmosphere (15 psi) at 20° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give intermediate 26b-1, which was used in the next reaction without further purification. 1 H NMR(400MHz,CD3OD)δ:3.97-3.87(m,1H),3.74-3.63(m,1H),3.35(s,2H),3.27-3.18(m, 1H),2.07-1.92(m,1H),1.89(s,1H),1.46(s,9H),1.44-1.37(m,1H),1.31-1.20(m,3H). Intermediate 26b-2 was prepared from intermediate 26a-2 following the procedure used to make 26b-1. 1 H NMR(400MHz,CD3OD)δ:3.98-3.86(m,1H),3.67(ddd,J=3.5,6.6,13.8Hz,1H),3.29-3.18(m,1H) ),3.17-3.04(m,1H),2.09-1.91(m,1H),1.89(s,1H),1.91-1.88(m,1H),1.46(s,9H),1.42(br d,J=3.5Hz,1H),1.33-1.21(m,3H). Step C—Synthesis of Intermediate 26c-1 To a solution of intermediate 3c (298 mg, 0.639 mmol) in MeCN (4 mL) was added potassium acetate (188 mg, 1.916 mmol), intermediate 26b-1 (137 mg, 0.639 mmol), and acetic acid (0.146 mL, 2.55 mmol). The reaction mixture was stirred at 80° C. under a N atmosphere for 10 minutes. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 5% CHCl / MeOH gradient at 30 mL / min) to give intermediate 26c-1. LC-MS (ESI): m / z 633.5 [M+H] + . Step D—Synthesis of Intermediate 26d-1 To a solution of intermediate 26c-1 (404 mg, 0.638 mmol) in DCM (2 mL) was added TFA (1 mL). The reaction was stirred at 28° C. for 40 min and then concentrated in vacuo (15° C.) to give intermediate 26d-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z: 433.3 [M+H] + . Step E - Synthesis of Intermediate 26e-1 To a solution of intermediate 26d-1 (276 mg, 0.638 mmol) in MeOH (4 mL) was added intermediate 4 (207 mg, 0.447 mmol) at 20 °C. The reaction was stirred at 28 °C for 2 h. The reaction mixture was then concentrated in vacuo to give intermediate 26e-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z 879.7 [M+H]+ . Step F—Synthesis of Compounds 55 and 56 To a solution of intermediate 26e-1 (561 mg, 0.638 mmol) in DCM (1 mL) was added TFA (2.000 mL) slowly at 20° C. The reaction mixture was stirred at 28° C. for 50 minutes and then concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (column: Boston Uni C18 40*150*5 μm; conditions: water (0.1% TFA)-ACN; start B 1, end B 31; gradient time (min) 10; 100% B retention time (min) 2; flow rate (mL / min) 60; injection 1) to give compound 55 as a TFA salt. The TFA salt was converted to the formate salt by reverse-phase HPLC (Column: Welch Xtimate C18 150*25mm*5um; Conditions: Water (0.225% FA)-ACN; Start B 0, End B 18; Gradient Time (min) 15; 100% Retention Time (min) 2; Flow Rate (mL / min) 25; Injection 1) to give Compound 55 as the formate salt. LC-MS (ESI): m / z 723.1 [M+H] + . 1 H NMR(400MHz,D2O+CD3CN)δ:7.36(s,1H),7.33(br d,J=9.4Hz,1H),6.91-6.78(m,2H),4.59(s,1H),4.40(br d,J=11.7Hz,1H),3.98-3.85(m,1H),3.49-3.40(m,1H),3.36-3.25(m,1H),3.08-2.99(m,1H),2.81-2.70(m,2H),2.33-2.22 (m,2H),2.07-1.98(m,1H),1.77-1.65(m,2H),1.62-1.55(m,1H),1.49(s,3H),1.38(s,3H),1.30-1.24(m,3H),1.17(s,3H). Compound 56 was prepared from intermediate 26b-2 according to the procedures in Steps C to E of Example 31. LC-MS (ESI): m / z 723.3 [M+H] + . 1H NMR(400MHz,D2O+CD3CN)δ:7.43-7.34(m,2H),6.87(d,J=8.6Hz,1H),6.84(s,1H),4.60(s,1H),4.40(br d,J=9.4Hz,1H), 3.98-3.86(m,1H), 3.53-3.44(m,1H), 3.37-3.24(m,1H), 3.10-3.01(m,1H), 2.86-2.71(m,2H), 2.35-2.21(m,2H), 2.13-2.02(m,1H), 1.85-1.65(m,2H), 1.65-1.52(m,1H), 1.50(s,3H), 1.41(s,3H), 1.29(d,J=6.7Hz,3H), 1.21(s,3H). *Each compound is a single diastereomer, and the stereochemistry at the carbon center marked with an * cannot be assigned.

[0248] [Example 32] Preparation of Compound 57 (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-methylcyclohexyl)carbamimidoyl)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 [ka]

[0249] Step A—Synthesis of Intermediate 27a To a solution of intermediate 3c (200 mg, 0.429 mmol) and tert-butyl ((trans)-4-amino-1-methylcyclohexyl)carbamate (117 mg, 0.514 mmol) in MeCN (2.5 mL) were added acetic acid (0.098 mL, 1.715 mmol) and potassium acetate (126 mg, 1.286 mmol) sequentially at 25° C. The reaction was stirred at 80° C. for 30 minutes, then diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with CHCl / MeOH (10:1) to afford intermediate 27a. LC-MS(ESI):m / z 647.5 [M+H] + . Step B—Synthesis of Intermediate 27b To a solution of intermediate 27a (300 mg, 0.464 mmol) in DCM (1.5 mL) was added aqueous HCl (12 N, 1.5 mL) at 0° C. The reaction was stirred at 25° C. for 30 minutes, and then the solvent was removed under a stream of N2 gas. The resulting residue was purified by reverse-phase HPLC (Boston Uni C18 40*150*5 μm; Conditions: water (0.1% TFA)-ACN; Start B 1, End B 31; Gradient Time (min) 11; 100% B Retention Time (min) 2; Flow Rate (mL / min) 60; Injection 2), followed by lyophilization, to give intermediate 27b. LC-MS (ESI): m / z 391.2 [M+H] + . Step C—Synthesis of Compound 57 A solution of intermediate 27b (60 mg, 0.154 mmol) and intermediate 5 (69.8 mg, 0.154 mmol) in DMA (0.6 mL) was stirred at 25° C. for 16 hours. The reaction mixture was then concentrated under a stream of N gas. The resulting residue was purified by preparative HPLC (Boston Uni C18 40*150*5 μm; Conditions: water (0.1% TFA)-ACN; Start B 1, End B 31; Gradient Time (min) 11; 100% B Retention Time (min) 2; Flow Rate (mL / min) 60; Injection 1), followed by lyophilization, to give compound 57 as the TFA salt. The TFA salt was dissolved in HO (2 mL) and a minimal amount of DMSO and purified by reverse-phase HPLC (Welch Xtimate C18 150*25 mm*5 um; Conditions: water (0.225% FA)-ACN; Start B 0, End B 1; 8 gradient time (min) 10; 100% B hold time (min) 2; Flow rate (mL / min) 25; Injection 2), followed by lyophilization, to give compound 57 as the formate salt. LC-MS (ESI): m / z 737.3 [M+H] + . 1 H NMR(400MHz,CD3CN)δ:7.44-7.34(m,2H),6.93-6.85(m,1H),6.79(s,1H),4.61(s,1H),4.35-4.43(m,1H),3.62-3.50(m,1H),2.90-2.72 (m,2H),2.13-2.04(m,1H),2.01-1.96(m,2H),1.90-1.80(m,2H),1.78-1.57(m,5H),1.51(s,3H),1.42(s,3H),1.34(s,3H),1.25(s,3H). [Example 33] Preparation of compound 58 (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-methylcyclohexyl)carbamimidoyl)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 [ka]

[0250] Compound 58 was prepared according to the procedures of Steps A-C of Example 32, by substituting tert-butyl((cis)-4-amino-1-methylcyclohexyl)carbamate for tert-butyl((trans)-4-amino-1-methylcyclohexyl)carbamate in Step A. LC-MS (ESI): m / z 759.4 [M+Na] + . 1 H NMR(400MHz,CD3CN)δ:7.44-7.35(m,2H),6.88(d,J=8.61Hz,1H),6.78(s,1H),4.62(s,1H),4.38(br d,J=9.78Hz,1H),3.69-3.55(m,1H),2.89-2.71(m,2H),2.13-2.03(m,1H),2.01-1.95(m,2H) ),1.91-1.81(m,2H),1.76-1.59(m,5H),1.50(s,3H),1.43(s,3H),1.30(s,3H),1.25(s,3H). [Example 34] Preparation of compound 59 (S)-2-((R)-6-(N-((1s,4S)-4-(aminomethyl)-4-hydroxycyclohexyl)carbamimidoyl)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 [ka]

[0251] Step A - Synthesis of Intermediate 28a MeSO in DMSO (30 mL) + I -A solution of 28a (6.41 g, 29.1 mmol) was treated with sodium hydride (60 wt% in oil) (1.067 g, 26.7 mmol). The mixture was stirred at 25 °C for 1 h, and then benzyl (4-oxocyclohexyl)carbamate (3.0 g, 12.13 mmol) was added. The resulting mixture was stirred at 25 °C for 16 h, then diluted with water (80 mL) and extracted with EtOAc (40 mL × 3). The organic layers were combined, washed with brine (60 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 12 g Agela silica flash column, eluent: 0–40% petroleum ether: EtOAc gradient at 30 mL / min) to give intermediate 28a. 1 H NMR(CDCl3,400MHz)δ:7.43-7.30(m,5H),5.11(s,2H),4.70(br s,1H),3.66(br d,J=8.3Hz,1H),2.67(s,2H),2.19-1.72(m,4H),1.67-1.28(m,4H). Step B—Synthesis of Intermediate 28b To a stirred solution of intermediate 28a (1.0 g, 3.83 mmol) in MeOH (60 mL) at 25° C. was added aqueous NH3·HO (20 mL, 3.83 mmol, 30 wt%). The reaction was stirred at 80° C. for 16 h and then concentrated under reduced pressure to provide intermediate 28b, which was used in the next step without further purification. 1 H NMR(CDCl3,400MHz)δ:7.42-7.29(m,5H),5.09(s,2H),4.77(br d,J=7.8Hz,1H),3.55-3.40(m,1H),2.64-2.55(m,2H),1.71-1.20(m,8H). Step C—Synthesis of Intermediates 28c-1 and 28c-2 To a stirred solution of intermediate 28b (1.05 g, 3.77 mmol) in EtOH (50 mL) was added di-tert-butyl dicarbonate (2.190 mL, 9.43 mmol) at 25° C. The reaction was stirred at 25° C. for 12 h. The solvent was then removed under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (ISCO; 12 g Agela silica flash column, eluent of 0–30% EtOAc / petroleum ether gradient at 30 mL / min) to afford a mixture of intermediates 28c-1 and 28c-2. The mixture was further purified by SFC (Column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um; Conditions: 0.1% NH₃·H₂O / EtOH; Start: B 20%, End: B 20%; Flow Rate (mL / min): 200; Injection: 80) to give intermediate 28c-1 (first eluting isomer; LC-MS (ESI): m / z 401.3 [M+Na] + ) and intermediate 28c-2 (second eluting isomer; LC-MS (ESI): m / z 379.3 [M+H] + ) was obtained.

[0252] Step D—Synthesis of Intermediate 28d-2 To a solution of intermediate 28c-2 (250 mg, 0.661 mmol) in MeOH (5 mL) was added Pd / C (70.3 mg, 0.066 mmol, 10 wt%). The reaction mixture was stirred under H atmosphere (15 psi) at 25° C. for 2 hours and then filtered through Celite™. The filtrate was concentrated under reduced pressure to give intermediate 28d-2, which was used in the next reaction without further purification. 1 H NMR(CDCl3,400MHz)δ:5.09(td,J=1.6,3.2Hz,2H),4.78(s,2H),4.43-4.22(m,1H),3.48-3.25(m,5H),3.22(s,9H),3.19-3.11(m,2H). Step E - Synthesis of Intermediate 28e-2 To a stirred mixture of intermediate 28d-2 (157 mg, 0.643 mmol) and intermediate 3c (300 mg, 0.643 mmol) in acetonitrile (6 mL), acetic acid (0.110 mL, 1.929 mmol) and potassium acetate (189 mg, 1.929 mmol) were added. The reaction mixture was stirred at 80 °C for 20 min. The solvent was then removed in vacuo, and the resulting residue was purified by preparative TLC (SiO, DCM:MeOH = 10:1) to give intermediate 28e-2. LC-MS (ESI): m / z 663.4 [M+H] + . Step F—Synthesis of Intermediate 28f-2 A mixture of intermediate 28e-2 (160 mg, 0.241 mmol) in aqueous HCl (12N, 0.4 mL) was stirred at 25° C. for 1 hour. The solvent was then removed with a stream of nitrogen gas, and the resulting residue was purified by reverse-phase HPLC (Column: Boston Uni C18 40*150*5 μm; Conditions: water (0.1% TFA)-ACN; Start B 1, End B 31; Gradient Time (min) 10; 100% B Retention Time (min) 2; Flow Rate (mL / min) 60; Injection 1) to give intermediate 28f-2. LC-MS (ESI): m / z 407.3 [M+H] + . Step G—Synthesis of Compound 59 To a mixture of intermediate 5 (53.6 mg, 0.148 mmol) and 4 Å molecular sieves (60 mg) in DMA (0.8 mL) was added intermediate 28f-2 (60 mg, 0.148 mmol) at 0° C. The reaction was stirred at 25° C. for 16 hours. The solvent was then removed with a stream of nitrogen gas, and the resulting residue was purified by reverse-phase HPLC (Column: Boston Uni C18 40*150*5 μm; Conditions: Start B 1, End B 31; Gradient Time (min) 11; 100% B Retention Time (min) 2; Flow Rate (mL / min) 60; Injection 1) to give compound 59 as a TFA salt. The TFA salt was converted to the formate salt by passing it through a second reverse-phase HPLC (Column: YMC-Actus Triart C18 150*30mm*5um; Conditions: Water (0.225% FA)-ACN; Start B 0, End B 18; Gradient Time (min) 11; 100% Retention Time (min) 2; Flow Rate (mL / min) 25; Injection 2) and lyophilizing the product fractions. LC-MS (ESI): m / z 753.2 [M+H] + . 1 H NMR(CD3CN+D2O,400MHz)δ:7.44-7.28(m,2H),6.94-6.80(m,2H),4.62(s,1H),4.39(br d,J=10.2Hz,1H),3.61-3.46(m,1H),2.89(s,2H),2.8-2.72(m,2H),2.12-1.99(m,1H) ),1.92-1.82(m,2H),1.80-1.62(m,5H),1.57-1.42(m,5H),1.41(s,3H),1.24(s,3H). [Example 35] Preparation of Compound 60 (S)-2-((R)-6-(N-((1r,4R)-4-(aminomethyl)-4-hydroxycyclohexyl)carbamimidoyl)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 [ka]

[0253] Compound 60 was prepared from intermediate 28c-1 according to the procedures in Steps D to G of Example 34. Compound 60: LC-MS (ESI): m / z 753.2 [M+H] + . 1 H NMR(CD3CN+D2O,400MHz)δ:7.41-7.30(m,2H),6.87(br d,J=9.0Hz,1H),6.81(s,1H),4.60(s,1H),4.38(br d,J=12.5Hz,1H),3.75-3.65(m,1H),3.03(s,2H),2.85-2.71(m,2H),2.1 2-1.95(m,2H),1.84-1.52(m,8H),1.49(s,3H),1.41(s,3H),1.22(s,3H). [Example 36] Preparation of Intermediates 29a-1 and 29a-2 [ka]

[0254] Step A—Synthesis of Intermediates 29a-1 and 29a-2. To a solution of tert-butyl (6-aminospiro-[3.3]heptan-2-yl)carbamate (1.055 g, 4.66 mmol) in THF (30 mL) and water (15 mL) stirred at 0° C. was added sodium carbonate (0.988 g, 9.32 mmol) and benzyl chloroformate (0.636 mL, 4.66 mmol). The reaction was stirred at 25° C. for 16 hours, then filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-15 petroleum ether / EtOAc gradient at 30 mL / min) to afford a racemic mixture of Intermediate 29a-1 and Intermediate 29a-2. The racemic mixture was separated by SFC (Column: DAICEL CHIRALCEL OJ 250 mm*30 mm, 10 μm; Conditions: 0.1% NH₃·H₂O / EtOH; Start: B 20%, End: B 20%; Flow Rate (mL / min): 70; Injection: 100) to give intermediate 29a-1 (first eluting isomer; LC-MS (ESI): m / z 383.2 [M+Na]). + ) and intermediate 29a-2 (second eluting isomer; LC-MS (ESI): m / z 383.2 [M+Na] + ) were obtained individually.

[0255] [Example 37] Preparation of compounds 61 and 62 (S)-2-((R)-6-(N-((2R,4r,6R)-6-aminospiro[3.3]heptan-2-yl)carbamimidoyl)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 and (S)-2-((R)-6-(N-((2S,4s,6S)-6-aminospiro[3.3]heptan-2-yl)carbamimidoyl)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 [ka]

[0256] Compounds 61 and 62 were prepared according to the procedures of Steps D to G of Example 34, by replacing intermediate 28c-2 in Step D with intermediate 29a-1 or intermediate 29a-2, respectively. Compound 61: LC-MS (ESI): m / z 735.5 [M+H] + . 1 H NMR(D2O+CD3CN,400MHz)δ:7.43-7.29(m,2H),6.92-6.79(m,2H),4.58(s,1H),4.39(br d,J=9.8Hz,1H),4.09-3.97(m,1H),3.72-3.61(m,1H),2.86-2.70(m,2H),2.62-2.55(m,1H),2.52-2.40(m,2H),2.38-2.28(m ,1H),2.23-2.10(m,4H),2.09-2.03(m,1H),1.79-1.64(m,1H),1.49(s,3H),1.41(s,3H),1.22(s,3H).Compound 62:LC-MS(ESI):m / z 735.3 [M+H] + . 1H NMR(D2O+CD3CN,400MHz)δ:7.39-7.31(m,2H),6.89-6.82(m,2H),4.59(s,1H),4.41(br d,J=9.0Hz,1H),4.08-4.01(m,1H),3.72-3.62(m,1H),2.86-2.68(m,2H),2.64-2.55(m,1H),2.50-2.38(m,2H),2 .37-2.26(m,1H),2.22-2.11(m,4H),2.08-2.02(m,1H),1.79-1.62(m,1H),1.50(s,3H),1.40(s,3H),1.21(s,3H). [Example 38] Preparation of Intermediates 30e-1 and 30e-2 [ka]

[0257] Step A - Synthesis of Intermediate 30a To a suspension of NaH (1.051 g, 26.3 mmol, 60% in oil) in THF (120 mL) was added methyl 2-(dimethoxyphosphoryl)acetate (4.42 g, 24.26 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min, and benzyl (4-oxocyclohexyl)carbamate (5 g, 20.22 mmol) was added. The reaction mixture was warmed to ambient temperature, stirred for 1 h, and then concentrated in vacuo. To the resulting residue was added saturated aqueous NH4Cl (80 mL), and the mixture was extracted with MTBE (150 mL). The combined organic layers were concentrated to provide Intermediate 30a, which was used in the next reaction without further purification. LC-MS (ESI): m / z 304.1 [M+H] + . Step B—Synthesis of Intermediate 30b. A solution of intermediate 30a (2 g, 6.59 mmol) in NH / MeOH (7 M, 47.1 mL, 330 mmol) was stirred in a sealed tube at 100° C. for 16 h. The solvent was then removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 12 g Agela silica flash column, eluent of 0-8% CHCl / MeOH (gradient) at 20 mL / min) to give intermediate 30b. LC-MS (ESI): m / z 321.2 [M+H] + . Step C—Synthesis of Intermediate 30c. To a mixture of intermediate 30b (4.9 g, 15.29 mmol) and (Boc)O (3.55 mL, 15.29 mmol) in THF (50 mL) and water (50.0 mL) was added DIEA (2.67 mL, 15.29 mmol). The reaction was heated at 85° C. for 4 hours, then cooled to ambient temperature and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 40 g Agela silica flash column, eluent of 25% petroleum ether / EtOAc gradient at 40 mL / min) to afford intermediate 30c. LC-MS (ESI): m / z 421.4 [M+H] + . Step D—Synthesis of Intermediate 30d. To a solution of intermediate 30c (2.6 g, 6.18 mmol) in THF (35 mL) at 0° C. was added LiBH (0.606 g, 27.8 mmol). The reaction mixture was stirred at 20° C. for 16 h, then quenched with saturated aqueous NH Cl (20 mL), extracted with EtOAc (50 mL), dried over anhydrous Na SO , and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 20 g Agela silica flash column, eluent 0–35% petroleum ether / EtOAc (gradient) at 30 mL / min) to afford intermediate 30d. LC-MS (ESI): m / z 293.2 [M-Boc+H] + . Step E—Synthesis of Intermediates 30e-1 and 30e-2. A mixture of intermediate 30d (1 g, 2.55 mmol), AgO (11.81 g, 51.0 mmol), and MeI (6.37 mL, 102 mmol) in MeCN (100 mL) was stirred under nitrogen at 25° C. in the dark for 36 hours. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO; 12 g Agela silica flash column, eluent: 0–30% EtOAc / petroleum ether gradient at 30 mL / min) to afford a mixture of intermediates 30e-1 and 30e-2. The intermediate mixture was further separated by reverse-phase HPLC (column: Phenomenex Synergi C18 150*30mm*4um; condition: water (0.1% TFA)-ACN; start B 51, end B 81; gradient time (min) 11; 100% B retention time (min) 2; flow rate (mL / min) 25; injection 9) to give intermediate 30e-1 and intermediate 30e-2, respectively.

[0258] Intermediate 30e-1: 1 H NMR(400MHz,CD3OD)δ:7.36-7.26(m,5H),5.05(s,2H),3.44(t,J=6.8Hz,2H),3.37(br t,J=11.5Hz,1H),3.29(s,3H),2.24(br d,J=12.5Hz,2H),1.89(br t,J=6.7Hz,2H),1.70(br d,J=10.0Hz,2H),1.43(s,10H),1.40-1.37(m,1H),1.33-1.25(m,2H). Intermediate 30e-2: 1 H NMR(400MHz,CD3OD)δ:7.37-7.26(m,5H),5.06(s,2H),3.54(br s,1H),3.44(t,J=6.7Hz,2H),3.30(s,3H),2.01(br t,J=6.7Hz,2H),1.81-1.71(m,5H),1.51-1.45(m,2H),1.42(s,10H). [Example 39] Preparation of compounds 63 and 64 (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(2-methoxyethyl)cyclohexyl)carbamimidoyl)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 and (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(2-methoxyethyl)cyclohexyl)carbamimidoyl)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 [ka]

[0259] Compounds 63 and 64 were prepared according to the procedures of Steps D to G of Example 34, starting from intermediates 30e-1 and 30e-2, respectively.

[0260] Compound 63:LC-MS(ESI):m / z 781.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:7.47-7.37(m,2H),6.88(d,J=8.2Hz,1H),6.75(s,1H),4.58(s,1H),4.34(br d,J=11.7Hz,1H),3.69-3.56(m,1H),3.50-3.41(m,2H),3.22(s,3H),2.84-2.68(m ,2H),2.03-1.74(m,8H),1.73-1.53(m,4H),1.44(s,3H),1.38(s,3H),1.22(s,3H). Compound 64:LC-MS(ESI):m / z 781.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ:7.48-7.35(m,2H),6.98(d,J=8.6Hz,1H),6.75(s,1H),4.59(s,1H),4.48(br d,J=12.1Hz,1H),3.54-3.40(m,3H),3.25(s,3H),2.90-2.68(m,2H),2.11-2.01(m ,1H),1.95-1.75(m,6H),1.71-1.50(m,5H),1.50(s,3H),1.39(s,3H),1.23(s,3H). [Example 40] Preparation of Intermediates 31-1 and 31-2 [ka]

[0261] The stereoisomers of intermediate 30d (0.9 g, 2.293 mmol) were separated by SFC (DAICEL CHIRALPAK AD (250 mm*50 mm, 10 μm); conditions: 0.1% NH₃·H₂O / IPA; start B 35, end B 35; flow rate (mL / min) 60; injection 80) to give intermediate 31-1 (LC-MS (ESI): m / z 415.4 [M+Na] + ) and intermediate 31-2 (LC-MS (ESI): m / z 415.4 [M + Na] + ) were obtained individually.

[0262] [Example 41] Preparation of compounds 65 and 66 (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(2-hydroxyethyl)cyclohexyl)carbamimidoyl)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 and (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(2-hydroxyethyl)cyclohexyl)carbamimidoyl)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 [ka]

[0263] Compounds 65 and 66 were prepared according to the procedures of Steps D to G of Example 34, starting from Intermediate 31-1 and Intermediate 31-2, respectively.

[0264] Compound 65:LC-MS(ESI):m / z 767.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:7.48-7.39(m,2H),6.88(br d,J=8.2Hz,1H),6.77(s,1H),4.62(s,1H),4.38(br d,J=10.6Hz,1H),3.68(br s,1H),3.51-3.49(m,2H),2.74-2.58(m,2H),2.22-2.04(m,1H),1.95-1.53(m,10H),1.39(s,3H),1.34(br s,3H),1.23(s,3H),1.07-0.83(m,1H). Compound 66:LC-MS(ESI):m / z 767.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ:7.49-7.36(m,2H),6.92(d,J=8.2Hz,1H),6.76(s,1H),4.57(s,1H),4.45-4.35(m,1H),3.80-3.75(m,1H),3.65- 3.53(m,2H),2.96-2.74(m,2H),2.09-2.01(m,1H),1.93-1.78(m,6H),1.68-1.46(m,7H),1.38(s,3H),1.22(s,3H),1.13(t,J=7.2Hz,1H). [Example 42] Preparation of Intermediates 32b-1 and 32b-2 [ka]

[0265] Step A—Synthesis of Intermediate 32a To a mixture of tert-butyl (3-oxocyclobutyl)carbamate (1.5 g, 8.10 mmol) and acetic acid (0.844 mL) in ethanol (9.71 mL) stirred at 0° C. was added methylamine (33% in ethanol) (9.71 mL, 81 mmol). The reaction was stirred at 0° C. for 1.5 hours, then warmed to 20° C. and stirred for an additional 2 hours. The mixture was cooled to −70° C., and LiBH (0.390 g, 17.90 mmol) was added in portions. The reaction was stirred at −70° C. for 1 hour, then warmed to 20° C. and stirred for 16 hours. The reaction mixture was then quenched with water (40 mL) and concentrated in vacuo. The resulting aqueous mixture was acidified to pH 2 with concentrated hydrochloric acid and washed with ethyl acetate (2×40 mL). The aqueous layer was then basified with 10% sodium hydroxide to pH 9-10 and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give intermediate 32a, which was used in the next reaction without further purification. 1H NMR(400MHz,CDCl3)δ:4.63(br s,1H),3.82(br d,J=7.3Hz,1H),2.96-2.80(m,1H),2.74-2.61(m,2H),2.33(s,3H),2.20-2.00(m,1H),1.50(br d,J=10.8Hz,2H),1.43(s,9H). Step B—Synthesis of Intermediates 32b-1 and 32b-2. To a solution of intermediate 32a (1.3 g, 6.49 mmol) in THF (40 mL) and water (20.00 mL) stirred at 0 °C, Na2CO3 (1.376 g, 12.98 mmol) and benzyl chloroformate (1.205 mL, 8.44 mmol) were added. The reaction was stirred at 20 °C for 16 h. The reaction was then diluted with water (50 mL), extracted with EtOAc (50 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO; 12 g Agela silica flash column, eluent: 0–30% EtOAc / petroleum ether (gradient) at 30 mL / min) to afford the desired product as a mixture of cis and trans stereoisomers. The mixture was separated by SFC (column: DAICEL CHIRALPAK AD-H 250mm*30mm, 5um; conditions: 0.1% NH3·H2O / EtOH; start: B 25, end: B 25; flow rate (mL / min): 60; injection: 180) to obtain intermediate 32b-1 (first eluting component, LC-MS (ESI): m / z 335.4 [M+H] + ) and intermediate 32b-2 (second eluting component, LC-MS (ESI): m / z 235.3 [M-Boc] + ) was obtained.

[0266] [Example 43] Preparation of intermediates 33c-1 and 33c-2 [ka]

[0267] Step A - Synthesis of Intermediate 33a-1 A solution of intermediate 32b-1 (400 mg, 1.196 mmol) in HCl / EtOAc (4 M, 8 mL) was stirred at 20 °C for 0.5 h. The reaction mixture was then concentrated under reduced pressure to give intermediate 33a-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z 235.1 [M+H] + . Step B—Synthesis of Intermediate 33b-1. To a solution of intermediate 33a-1 (261 mg, 1.114 mmol) in MeCN (8 mL) at 25 °C, intermediate 3c (400 mg, 0.857 mmol), acetic acid (0.196 mL, 3.43 mmol), and potassium acetate (252 mg, 2.57 mmol) were added sequentially. The reaction mixture was stirred at 80 °C under a N atmosphere for 30 min and then filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (Biotage; 20 g Agela C18 column, eluent: 0–40% MeCN / HO (0.5% TFA) gradient at 50 mL / min) to give intermediate 33b-1. LC-MS (ESI): m / z 653.7 [M+H] + . Step C—Synthesis of Intermediates 33c-1 and 33c-2. A mixture of intermediate 33b-1 (365 mg, 0.559 mmol) and Pd / C (179 mg, 0.168 mmol, 10 wt%) in EtOAc (8 mL) was stirred under H (15 psi) at 25° C. for 5 h. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo to give intermediate 33c-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z 519.5 [M+H] + . Intermediate 33c-2 was prepared from intermediate 32b-2 using the procedures in Steps A to C of Example 43. LC-MS (ESI): m / z 519.5 [M+H] + . [Example 44] Preparation of compounds 67 and 68 (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-(N-(trans-3-(methylamino)cyclobutyl)carbamimidoyl)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-(N-(cis-3-(methylamino)cyclobutyl)carbamimidoyl)chroman-2-yl)propanoic acid [ka]

[0268] Compounds 67 and 68 were prepared according to the procedures in Steps B to C of Example 32, starting from Intermediate 33c-1 and Intermediate 33c-2, respectively.

[0269] Compound 67:LC-MS(ESI):m / z 709.1 [M+H] + . 1 H NMR(400MHz,D2O+CD3CN)δ:7.45-7.31(m,2H),6.96-6.69(m,2H),4.60(s,1H),4.36(br d,J=11.3Hz,1H),4.07-3.88(m,1H),3.59-3.44(m,1H),2.98-2.67(m,4H),2.54(s,3H),2.3 7-2.23(m,2H),2.09-2.00(m,1H),1.74-1.59(m,1H),1.48(s,3H),1.41(s,3H),1.23(s,3H). Compound 68:LC-MS(ESI):m / z 709.1 [M+H] + . 1H NMR(400MHz,D2O+CD3CN)δ:7.45-7.29(m,2H),6.90-6.78(m,2H),4.60(s,1H),4.44-4.34(m,1H),4.30-4.16(m,1H) ,3.90-3.77(m,1H),2.90-2.48(m,9H),2.09-2.00(m,1H),1.77-1.60(m,1H),1.50(s,3H),1.41(s,3H),1.23(s,3H). [Example 45] Preparation of Intermediates 34g-1 and 34g-2 [ka]

[0270] Step A—Synthesis of Intermediate 34a To a stirred solution of 1-(((((9H-Fluoren-9-yl)methoxy)-carbonyl)amino)-4-oxocyclohexane-1-carboxylic acid (5 g, 13.18 mmol) in DCM (40 mL) and MeOH (10 mL) was added (trimethylsilyl)diazomethane (2 M in hexanes) (13.18 mL, 26.4 mmol) dropwise at 0° C. The reaction was stirred at 25° C. for 12 h, then cooled to 0° C. and AcOH (1 mL) was added dropwise. The reaction mixture was diluted with DCM (80 mL), washed sequentially with saturated aqueous NaHCO (50 mL) and brine (30 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to provide Intermediate 34a, which was used in the next reaction without further purification. LC-MS (ESI): m / z 394.1 [M+H] + . Step B—Synthesis of Intermediate 34b. To a stirred solution of intermediate 34a (3 g, 7.63 mmol) and ammonium acetate (5.88 g, 76 mmol) in MeOH (200 mL) was added sodium triacetoxyborohydride (8.08 g, 38.1 mmol) in one portion at 15° C. The reaction mixture was stirred at 25° C. for 12 h and then quenched by the addition of saturated aqueous NH4Cl (100 mL). The mixture was extracted with DCM (200 mL). The organic phase was separated, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 40 g Agela silica flash column, eluent: 0–10% MeOH / CHCl2 gradient at 30 mL / min) to give intermediate 34b. LC-MS (ESI): m / z 395.2 [M+H] + . Step C—Synthesis of Intermediate 34c A solution of intermediate 34b (1.7 g, 4.31 mmol) and (Boc)O (5.00 mL, 21.55 mmol) in CHCl (40 mL) was stirred at 80° C. for 16 hours. The reaction was cooled to room temperature and then purified by flash silica gel chromatography (ISCO; 20 g Agela silica flash column, eluent of 35% petroleum ether / EtOAc gradient at 30 mL / min) to give intermediate 34c. LC-MS (ESI): m / z 507.3 [M+Na] + . Step D—Synthesis of Intermediates 34d-1 and 34d-2. To a solution of intermediate 34c (1.3 g, 2.63 mmol) in THF (20 mL) stirred at 0° C. was added LiBH (0.258 g, 11.83 mmol). The reaction mixture was stirred at 20° C. for 16 h and then quenched with saturated aqueous NH4Cl (20 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic phase was separated, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 12 g Agela silica flash column, eluent: 0–35% petroleum ether / EtOAc gradient at 30 mL / min) to give intermediate 34d-1 (first eluting stereoisomer) and intermediate 34d-2 (second eluting stereoisomer). LC-MS(ESI):m / z 467.2 [M+H] + . Intermediate 34d-1: 1 H NMR(400MHz,CDCl3)δ:7.77(d,J=7.4Hz,2H),7.57(d,J=7.4Hz,2H),7.44-7.38(m,2H),7.35-7.30(m,2H),4.45(br s,3H),3.71(br s,2H),3.54(br s,1H),1.93(br s,2H),1.81(br s,1H),1.49(br s,1H),1.44(s,11H),1.37(br s,2H). Intermediate 34d-2: 1 H NMR(400MHz,CDCl3)δ:7.79(d,J=7.4Hz,2H),7.60(d,J=7.4Hz,2H),7.43(t,J=7.6Hz,2H),7.38-7.32(m,2H),4.52(br s,2H),4.39(br s,1H),3.58(br s,3H),2.02(br s,1H),1.86(br s,3H),1.47-1.45(m,11H),1.40-1.12(m,2H). Step E - Synthesis of Intermediate 34e-1 A solution of intermediate 34d-1 (200 mg, 0.429 mmol) in HCl / MeOH (4 M, 2 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was then concentrated in vacuo to give intermediate 34e-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z 367.1 [M+H] + . Step F—Synthesis of Intermediate 34f-1 Potassium acetate (88 mg, 0.900 mmol) was added to a stirred mixture of Intermediate 34e-1 (132 mg, 0.360 mmol), Intermediate 3c (140 mg, 0.300 mmol), and acetic acid (0.069 mL, 1.200 mmol) in MeCN (4 mL). The reaction was stirred at 80° C. for 30 minutes, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC plate (CHCl / MeOH=10:1) to give Intermediate 34f-1. LC-MS (ESI): m / z 785.8 [M+H] + . Step G—Synthesis of Intermediates 34g-1 and 34g-2 To a solution of intermediate 34f-1 (120 mg, 0.153 mmol) in DMF (2 mL) was added piperidine (15.62 mg, 0.183 mmol). The reaction was stirred at 25° C. for 0.5 h and then concentrated in vacuo to give intermediate 34g-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z 563.5 [M+H] + . Intermediate 34g-2 was prepared from intermediate 34d-2 according to the procedures in Steps E to G of Example 45s. LC-MS (ESI): m / z 563.3 [M+H] + . [Example 46] Preparation of compounds 69 and 70 (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(hydroxymethyl)cyclohexyl)carbamimidoyl)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 and (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(hydroxymethyl)cyclohexyl)carbamimidoyl)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 [ka]

[0271] Compounds 69 and 70 were prepared according to the procedures of Steps F to G of Example 34, starting from Intermediate 34g-1 and Intermediate 34g-2, respectively.

[0272] Compound 69:LC-MS(ESI):m / z 753.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:7.45-7.32(m,2H),6.91(d,J=8.6Hz,1H),6.74(s,1H),4.58(s,1H),4.39(br d,J=11.7Hz,1H),3.60-3.45(m,3H),2.85-2.66(m,2H),2.09-1.99(m,1H),1.92-1.71(m,4H),1.63-1.40(m,8H),1.38(s,3H),1.23(s,3H). Compound 70:LC-MS(ESI):m / z 753.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ:7.49-7.38(m,2H),6.91(br d,J=9.4Hz,1H),6.75(s,1H),4.61(s,1H),4.39(br d,J=11.7Hz,1H),3.48-3.34(m,3H),2.84-2.65(m,2H),2.05-1.44(m,10H),1.38(apparent s,6H),1.23(s,3H). [Example 47] Preparation of Intermediates 35b-1 and 35b-2 [ka]

[0273] Step A—Synthesis of Intermediate 35a-1 To a solution of tert-butyl ((1r,4r)-4-amino-1-methylcyclohexyl)carbamate (100 mg, 0.438 mmol) in THF (1.8 mL) and water (0.6 mL) was added sodium carbonate (139 mg, 1.314 mmol) and benzyl chloroformate (0.072 mL, 0.526 mmol) at 0° C. The reaction was stirred at 20° C. for 16 hours and then diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic fractions were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC plate (3:1 petroleum ether / EtOAc, eluted with SiO) to give Intermediate 35a-1. LC-MS(ESI):m / z 385.3 [M+Na] + . 1 H NMR(400MHz,CDCl3)δ:7.35-7.39(m,5H),5.07(s,2H),4.74(br s,1H),4.41(br s,1H),3.68-3.54(m,1H),1.93-1.77(m,2H),1.77-1.58(m,4H),1.43(s,9H),1.46-1.34(m,2H),1.32(s,3H). Step B—Synthesis of Intermediates 35b-1 and 35b-2 A solution of intermediate 35a-1 (500 mg, 1.379 mmol) in HCl / EtOAc (4 M, 10 mL) was stirred for 2 h at 20° C. The reaction mixture was concentrated in vacuo to give intermediate 35b-1, which was used in the next reaction without further purification. 1 H NMR(400MHz,CD3OD)δ:7.44-7.19(m,5H),5.07(s,2H),3.51-3.34(m,1H),1.94-1.80(m,4H),1.75-1.65(m,2H),1.56-1.44(m,2H),1.37(s,3H). Intermediate 35b-2 was prepared from tert-butyl ((1s,4s)-4-amino-1-methylcyclohexyl)-carbamate according to the procedures in Step A and Step B of Example 47. LC-MS (ESI): m / z 263.2 [M+H] + . [Example 48] Preparation of Compound 71 (S)-2-((R)-6-(N-((1r,4R)-4-amino-1-methylcyclohexyl)carbamimidoyl)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 [ka]

[0274] Step A - Synthesis of Intermediate 36a To a solution of intermediate 35b-1 (156 mg, 0.595 mmol) in DMF (6 mL) was added TEA (0.237 mL, 1.699 mmol) and intermediate 6c (400 mg, 0.849 mmol). The reaction was stirred at 25 °C for 2 hours. The reaction mixture was then diluted with ice water (20 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give intermediate 36a, which was used in the next reaction without further purification. LC-MS (ESI): m / z 697.2 [M+H] + . Step B—Synthesis of Intermediate 36b: To a solution of KCO (297 mg, 2.153 mmol) in MeOH (2.8 mL) at 20° C. under N was added formic acid (198 mg, 4.31 mmol). The reaction mixture was stirred at 20° C. for 10 minutes and then added to a solution of Intermediate 36a (300 mg, 0.431 mmol) in AcOH (1.8 mL) and acetic anhydride (48.3 mg, 0.474 mmol). Pd / C (183 mg, 0.172 mmol, 10 wt%) was then added and the reaction was stirred at 25° C. for 12 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to provide Intermediate 36b, which was used in the next reaction without further purification. LC-MS (ESI): m / z 681.6 [M+H] + . Step C—Synthesis of Intermediate 36c To a solution of intermediate 36b (400 mg, 0.588 mmol) in ethyl acetate (20 mL) was added Pd / C (31.3 mg, 0.294 mmol, 10 wt%) at 20° C. The reaction mixture was stirred under an H atmosphere at 25° C. for 1 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to give intermediate 36c, which was used in the next reaction without further purification. LC-MS (ESI): m / z 547.4 [M+H] + . Step D—Synthesis of Intermediate 36d To a solution of intermediate 36c (420 mg, 0.768 mmol) in DCM (1.5 mL) was added aqueous HCl (1.5 mL, 12N) at 0° C. The reaction mixture was stirred at 25° C. for 1.5 hours, and then the solvent was removed with a stream of nitrogen gas. The resulting residue was purified by reverse-phase HPLC (Boston Uni C18 40*150*5 μm; Conditions: water (0.1% TFA)-ACN; Start B 0, End B 30; Gradient Time (min) 10; 100% B Retention Time (min) 2; Flow Rate (mL / min) 60; Injection 1). The product fractions were combined and lyophilized to give intermediate 36d. LC-MS (ESI) m / z: 391.2 [M+H] + . Step E—Synthesis of Compound 71 To a solution of intermediate 36d (220 mg, 0.563 mmol) in DMA (4 mL) was added 4 Å molecular sieves (100 mg) and intermediate 5 (301 mg, 0.620 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 12 hours and then filtered. The filtrate was diluted with MeOH (1 mL) and purified by reverse-phase HPLC (Boston Uni C18 40*150*5 μm; conditions: water (0.1% TFA)-ACN; start B 0, end B 30; gradient time (min) 10; 100% B retention time (min) 2; flow rate (mL / min) 60; injection 1), followed by lyophilization, to give compound 71 as the TFA salt. The TFA salt was further purified by reverse-phase HPLC (Welch Xtimate C18 150*25mm*5um; Conditions: water (0.225% FA)-ACN; Start B 0, End B 20; Gradient time (min) 15; 100% B hold time (min) 2; Flow rate (mL / min) 25; Injection 2), followed by lyophilization, to give compound 71 as the formate salt. LC-MS (ESI): m / z 737.2 [M+H] + . 1H NMR(400MHz,D2O+CD3CN)δ:7.39-7.31(m,2H),6.88(d,J=8.6Hz,1H),6.79(s,1H),4.63(s,1H),4.38(br d,J=10.6Hz,1H),3.28-3.15(m,1H),2.92-2.70(m,2H),2.15-2.01(m,3H),2.01-1.92(m,2H ),1.94-1.66(m,3H),1.65-1.51(m,2H),1.50(s,3H),1.47(s,3H),1.43(s,3H),1.26(s,3H). [Example 49] Preparation of Compound 72 (S)-2-((R)-6-(N-((1s,4S)-4-amino-1-methylcyclohexyl)carbamimidoyl)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 [ka]

[0275] Compound 72 was prepared starting from intermediate 35b-2 and intermediate 6c according to the procedure of steps A to E of Example 48. Compound 72: LC-MS (ESI): m / z 737.3 [M+H] + . 1 H NMR(400MHz,D2O+CD3CN)δ:7.44-7.38(m,2H),6.89(d,J=8.2Hz,1H),6.79(s,1H),4.64(s,1H),4.37(br d,J=9.8Hz,1H),3.25-3.10(m,1H),2.90-2.70(m,2H),2.40-2.25(m,2H),2.17-2.02(m,1H),2.01-1. 88(m,2H),1.82-1.63(m,1H),1.64-1.47(m,4H),1.50(s,3H),1.43(s,3H),1.39(s,3H),1.26(s,3H). [Example 50] Preparation of intermediates 37d-1 and 37d-2 [ka]

[0276] Step A—Synthesis of Intermediate 37a. To a stirred solution of intermediate 28a (5.0 g, 22.00 mmol) in MeOH (100 mL) was added p-toluenesulfonic acid monohydrate (0.837 g, 4.40 mmol) at 0° C. The reaction was stirred at 25° C. for 2 h, then diluted with saturated aqueous NaHCO (60 mL) and extracted with EtOAc (40 mL×3). The organic layers were combined, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 40 g Agela silica flash column, eluent 0–50% EtOAc / petroleum ether gradient at 40 mL / min) to afford intermediate 37a. LC-MS (ESI): m / z 294.4 [M+H ] + . Step B—Synthesis of Intermediate 37b. To a solution of intermediate 37a (1.8 g, 6.94 mmol) in anhydrous THF (30 mL) was added Ph3P (2.185 g, 8.33 mmol) and phthalimide (1.328 g, 9.02 mmol) under nitrogen at 0° C. The reaction mixture was treated with DIAD (1.754 mL, 9.02 mmol) at 0° C. The reaction was warmed to 25° C., stirred at 25° C. for 16 h, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 20 g Agela silica flash column, eluent: 0–30% EtOAc / petroleum ether gradient at 30 mL / min) to afford intermediate 37b. LC-MS (ESI): m / z 777.4 [2M+H] + . Step C—Synthesis of Intermediate 37c A mixture of intermediate 37b (2.0 g, 5.15 mmol) and hydrazine hydrate (1.516 g, 25.7 mmol) in MeCN (20 mL) was stirred at 25° C. under a nitrogen atmosphere for 2 hours and then concentrated in vacuo. The resulting residue was diluted with water (25 mL) and extracted with a 10:1 DCM / MeOH mixture (20 mL×3). The combined organic layer was washed with brine (30 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated in vacuo to give intermediate 37c, which was used in the next reaction without further purification. LC-MS (ESI): m / z 259.3 [M+H] + . Step D—Synthesis of Intermediates 37d-1 and 37d-2 To a solution of intermediate 37c (1.3 g, 5.03 mmol) in THF (10 mL) and water (5 mL) was added benzyl chloroformate (1.288 g, 7.55 mmol) and sodium carbonate (1.067 g, 10.06 mmol) dropwise at 0° C. The reaction was stirred at 25° C. for 16 hours and then concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (Column: Boston Uni C18 40*150*5 μm; Conditions: water (0.1% TFA)-ACN; Start B 45, End B 75; Gradient Time (min) 10; 100% B Retention Time (min) 2; Flow Rate (mL / min) 60; Injection 2) to give the product as a mixture of stereoisomers. The mixture of stereoisomers (1.0 g, 2.55 mmol) was further separated by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm); conditions: 0.1% NH₃·H₂O-EtOH; starting B 25%; flow rate (mL / min) 60; injection 75) to give intermediate 37d-1 (first eluting stereoisomer) and intermediate 37d-2 (second eluting stereoisomer) separately.

[0277] Intermediate 37d-1: 1H NMR(CDCl3,400MHz)δ:7.42-7.29(m,5H),5.11(s,2H),4.99(br s,1H),4.50(br s,1H),3.58-3.45(m,1H),3.34(d,J=5.9Hz,2H),3.16(s,3H),1.95-1.75(m,2H),1.69-1.52(m,4H),1.49-1.33(m,2H),1.44(s,9H). Intermediate 37d-2: 1 H NMR(CDCl3,400MHz)δ:7.57-7.30(m,5H),5.07(s,2H),4.90(s,1H),4.48(s,1H),3.49-3.32( m,1H),3.20(d,J=5.2Hz,2H),3.14(s,3H),1.87-1.71(m,4H),1.44(s,9H),1.37-1.15(m,4H). [Example 51] Preparation of Compound 73 (S)-2-((R)-6-(N-((1s,4S)-4-(aminomethyl)-4-methoxycyclohexyl)carbamimidoyl)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 [ka]

[0278] Step A - Synthesis of Intermediate 38a A solution of intermediate 37d-2 (450 mg, 1.147 mmol) in HCl / EtOAc (4 M, 6 mL) was stirred at 25 °C for 0.5 h. The reaction mixture was then concentrated to give intermediate 38a, which was used in the next reaction without further purification. LC-MS (ESI): m / z 293.2 [M+H] + . Step B—Synthesis of Intermediate 38b. To a stirred solution of intermediate 3c (535 mg, 1.147 mmol) and intermediate 38a (335 mg, 1.147 mmol) in MeCN (10 mL) was added acetic acid (0.197 mL, 3.44 mmol) and potassium acetate (338 mg, 3.44 mmol) sequentially at 25° C. The reaction was stirred at 80° C. for 30 min, then diluted with water (30 mL) and extracted with EtOAc (50 mL×3). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 20 g Agela silica flash column, eluent: 0–5% DCM / MeOH gradient at 30 mL / min) to afford intermediate 38b. LC-MS (ESI): m / z 711.4 [M+H] + . Step C—Synthesis of Intermediate 38c A solution of intermediate 38b (400 mg, 0.563 mmol) in HBr / AcOH (8 mL, 40%) was stirred at 25° C. for 2 hours. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC (Column: Boston Uni C18 40*150*5 μm; Conditions: water (0.1% TFA)-ACN; Start B 0, End B 30; Gradient Time (min) 10; 100% B Retention Time (min) 2; Flow Rate (mL / min) 60; Injection 1) to give intermediate 38c. LC-MS (ESI): m / z 421.0 [M+H] + . Step D—Synthesis of Compound 73 To a solution of intermediate 38c (150 mg, 0.357 mmol) in DMA (5 mL) was added intermediate 5 (130 mg, 0.357 mmol) at 0° C. The reaction was stirred at 25° C. for 16 hours. The reaction solvent was then evaporated with a stream of nitrogen gas, and the resulting residue was purified by reverse-phase HPLC (Column: Boston Uni C18 40*150*5 μm; Conditions: water (0.1% TFA)-ACN; Start B 0, End B 30; Gradient Time (min) 10; 100% B Retention Time (min) 2; Flow Rate (mL / min) 60; Injection 2) to give the crude product. The crude product was purified by a second reverse-phase HPLC (column: Phenomenex Luna C18 75*30mm*3um; conditions: water (0.1% TFA)-ACN; start B 0, end B 30; gradient time (min) 11; 100% B hold time (min) 2; flow rate (mL / min) 30; injection 9) to give compound 73 as the TFA salt. The TFA salt was converted to the formate salt by reverse-phase HPLC (column: Welch Xtimate C18 150*25mm*5um; conditions: water (10mM NH4HCO3)-ACN; start B 0, end B 18; gradient time (min) 15; 100% B hold time (min) 2; flow rate (mL / min) 25; injection 2) to give compound 73 as the formate salt. LC-MS (ESI): m / z 767.4 [M+H ] + . 1 H NMR(CD3CN+D2O,400MHz)δ:7.42-7.33(m,2H),6.89(d,J=8.6Hz,1H),6.78(s,1H),4.61(s,1H),4.38(br d,J=10.2Hz,1H),3.62-3.46(m,1H),3.12(s,3H),2.96(s,2H),2.89-2.70(m,2H),2.15-2.00(m,1H),1.92-1 .78(m,4H),1.80-1.65(m,1H),1.60-1.47(m,2H),1.52(s,3H),1.43(s,3H),1.40-1.32(m,2H),1.26(s,3H). [Example 52] Preparation of intermediates 39d-1 and 39d-2 [ka]

[0279] Step A—Synthesis of Intermediate 39a To a solution of methyl 3-oxocyclobutane-1-carboxylate (13.48 g, 105 mmol) in THF (300 mL) and AcOH (6 mL, 105 mmol) was added dibenzylamine (20.76 g, 105 mmol). After stirring at room temperature (22° C.) for 10 minutes, sodium cyanoborohydride (19.83 g, 316 mmol) was added portionwise over 30 minutes. The reaction mixture was stirred at room temperature (22° C.) for 16 hours and then added to stirred saturated aqueous NaHCO (200 mL). After stirring at 22° C. for 10 minutes, the resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (150 mL×2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 80 g Agela silica flash column; eluent: 7.5-100% EtOAc / petroleum ether gradient at 45 mL / min) to give intermediate 39a. TLC: petroleum ether / EtOAc (20:1), R f =0.6 (ninhydrin staining) Step B—Synthesis of Intermediate 39b To a solution of diisopropylamine (9.58 mL, 67.9 mmol) in THF (50 mL) at −70° C. was added n-butyllithium (27.1 mL, 67.9 mmol, 2.5 M in hexanes). The reaction was stirred at −70° C. for 30 minutes. Then, a solution of Intermediate 39a (7.0 g, 22.62 mmol) in THF (25 mL) was added while maintaining the temperature at −70° C. The reaction mixture was stirred at −70° C. for 20 minutes, after which a solution of iodomethane (8.35 mL, 134 mmol) in THF (25 mL) was added. The reaction was stirred at −70° C. for 1 hour and then quenched with saturated aqueous NH4Cl (40 mL). The resulting mixture was stirred at 0° C. for 15 minutes and then extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 40 g Agela silica flash column; eluent: 0-9% EtOAc / petroleum ether gradient at 40 mL / min) to give intermediate 39b. LC-MS (ESI): m / z 324.6 [M+H] + . Step C—Synthesis of Intermediate 39c. To a solution of intermediate 39b (6.55 g, 20.25 mmol) in MeOH (150 mL) was added a solution of NaOH (2.430 g, 60.8 mmol) in HO (30 mL). The reaction was stirred at 70° C. for 1.5 h, and then the solvent was removed in vacuo. The resulting residue was diluted with HO (10 mL), and the pH was adjusted to pH 4-5 with aqueous HCl (2 M). The resulting mixture was filtered, and the filter cake was dried to afford intermediate 39c. Additional product was obtained by extracting the filtrate with EtOAc (40 mL×4) and concentrating the combined organic layers. LC-MS (ESI): m / z 310.2 [M+H] + . Step D—Synthesis of Intermediates 39d-1 and 39d-2 To a mixture of intermediate 39c (2000 mg, 4.85 mmol) in toluene (45 mL) was added 4 Å molecular sieves (50 mg) and triethylamine (2.70 mL, 19.39 mmol), followed by the slow addition of diphenylphosphinyl azide (1769 mg, 7.27 mmol) at 0° C. The reaction was warmed to 45° C. and stirred at 45° C. for 2 hours. The temperature was then increased to 85° C., and 2-(trimethylsilyl)ethanol (2293 mg, 19.39 mmol) was added. The reaction mixture was stirred at 85° C. for 16 hours. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 40 g Agela silica flash column, eluent: 0-8% EtOAc / petroleum ether gradient at 30 mL / min) to give the product as a mixture of stereoisomers. LC-MS (ESI): m / z 425.3 [M+H] + The mixture of stereoisomers was further purified by SFC (column: Daicel chiralpak IG (250 mm * 30 mm, 10 μm); conditions: 0.1% NH₃·H₂O-EtOH; starting B 30%; flow rate (mL / min) 200; injection 120) to give intermediate 39d-1 (first eluting stereoisomer) and intermediate 39d-2 (second eluting stereoisomer).

[0280] Intermediate 39d-1:LC-MS(ESI):m / z 425.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ:7.32-7.21(m,10H),4.66(br s,1H),4.13(br t,J=8.4Hz,2H),3.47(s,4H),3.32-3.18(m,1H),2.32-2.18(m,2H),1.97-1.81(m,2H),1.42(s,3H),0.97(t,J=8.4Hz,2H),0.04(s,9H). Intermediate 39d-2:LC-MS(ESI):m / z 425.3 [M+H] + . 1H NMR(400MHz,CDCl3)δ:7.34-7.16(m,10H),4.71(br s,1H),4.10(t,J=8.4Hz,2H),3.48(s,4H),3.06-2.93(m,1H),2.23-2.01(m,4H),1.37(s,3H),0.96(t,J=8.4Hz,2H),0.03(s,9H). [Example 53] Preparation of compound 74 (S)-2-((R)-6-(N-((1r,3R)-3-amino-3-methylcyclobutyl)carbamimidoyl)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 [ka]

[0281] Step A—Synthesis of Intermediate 40a To a solution of intermediate 39d-1 (700 mg, 1.648 mmol) in MeOH (20 mL) was added palladium hydroxide (579 mg, 0.824 mmol, 20 wt%). The mixture was stirred under an atmosphere of H (45 psi) at 20° C. for 20 h. The reaction mixture was then filtered, and the filtrate was concentrated in vacuo to afford intermediate 40a, which was used in the next reaction without further purification. 1 H NMR(400MHz,CDCl3)δ:4.69(br s,1H),4.12(t,J=8.0Hz,2H),3.62-3.48(m,1H),2.62-2.39(m,2H),1.75-1.61(m,2H),1.43(s,3H),0.97(t,J=8.0Hz,2H),0.04(s,9H). Step B—Synthesis of Intermediate 40b To a stirred mixture of Intermediate 40a (150 mg, 0.614 mmol) and Intermediate 3c (360 mg, 0.606 mmol) in MeCN (6 mL) was added acetic acid (0.141 mL, 2.455 mmol). The reaction was stirred at 80° C. for 20 minutes. The reaction mixture was then concentrated in vacuo to give crude Intermediate 40b, which was used in the next reaction without further purification. LC-MS (ESI): m / z 663.8 [M+H] + . Step C—Synthesis of Intermediate 40c A mixture of intermediate 40b (407 mg, 0.614 mmol) in DCM (2.5 mL) and aqueous HCl (2.5 mL, 12N) was stirred at 20° C. for 30 minutes. The reaction solvent was then removed in vacuo, and the resulting residue was purified by reverse-phase HPLC (Boston Uni C18 40*150*5 μm; conditions: water (0.1% TFA)-ACN; start B 0, end B 30; gradient time (min) 10; 100% B retention time (min) 2; flow rate (mL / min) 20; injection 1) to give intermediate 40c. LC-MS (ESI): m / z 363 [M+H] + . Step D—Synthesis of Compound 74 To a solution of intermediate 40c (200 mg, 0.386 mmol) in DMA (2.5 mL) was added intermediate 5 (194 mg, 0.425 mmol). The reaction mixture was stirred at 24° C. for 16 hours. The reaction mixture was diluted with MeOH (2.0 mL) and purified by reverse-phase HPLC (Boston Uni C18 40*150*5 μm; conditions: water (0.1% TFA)-ACN; start B 0, end B 30; gradient time (min) 10; 100% B retention time (min) 2; flow rate (mL / min) 60; injection 1) to give compound 74 as a TFA salt. The TFA salt was converted to the formate salt by reverse-phase HPLC (Welch Xtimate C18 150*25mm*5um; Conditions: water (0.225% FA)-ACN; Start B 0, End B 1; 8 gradient time (min) 15; 100% B hold time (min) 2; Flow rate (mL / min) 25; Injection 2) to give compound 74 as the formate salt. LC-MS (ESI): m / z 709.0 [M+H] + . 1H NMR(400MHz,D2O+CD3CN)δ:7.37-7.27(m,2H),6.86(d,J=8.6Hz,1H),6.79(s,1H),4.61(s,1H),4.39(br d,J=11.7Hz,1H),4.31-4.19(m,1H),2.94-2.71(m,4H),2.50-2.26(m,2H),2.20-2 .05(m,1H),1.82-1.65(m,1H),1.54(s,3H),1.48(s,3H),1.43(s,3H),1.26(s,3H). [Example 54] Preparation of Compound 75 (S)-2-((R)-6-(N-((1s,3S)-3-amino-3-methylcyclobutyl)carbamimidoyl)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 [ka]

[0282] Compound 75 was prepared from intermediate 39d-2 according to the procedures in Steps A to D of Example 53. Compound 75: LC-MS (ESI): m / z 709.3 [M+H] + . 1 H NMR(400MHz,D2O+CD3CN)δ:7.42-7.34(m,2H),6.86(d,J=8.6Hz,1H),6.78(s,1H),4.60(s,1H),4.35(br d,J=10.4Hz,1H),4.19-4.06(m,1H),2.86-2.68(m,2H),2.70-2.55(m,2H),2.54-2.44(m,2H) ),2.16-1.95(m,1H),1.76-1.58(m,1H),1.48(s,3H),1.45(s,3H),1.42(s,3H),1.24(s,3H). [Example 55] Preparation of Intermediates 41b-1 and 41b-2 [ka]

[0283] Step A—Synthesis of Intermediates 41a-1 and 41a-2. To a solution of tert-butyl (1R,5S)-8-amino-3-azabicyclo[3.2.1]octane-3-carboxylate (1.28 g, 5.66 mmol) in DCM (45 mL) was added TEA (1.971 mL, 14.14 mmol) and n-(benzyloxycarbonyloxy)succinimide (1.550 g, 6.22 mmol). The reaction was stirred at 25° C. for 16 hours, then diluted with water (50 mL) and extracted with DCM (50 mL×3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (ISCO; 12 g Agela silica flash column, elution with a 0-30% EtOAc / petroleum ether gradient at 30 mL / min) to give the product as a mixture of stereoisomers. LC-MS (ESI): m / z 383.3 [M+Na] + The mixture of stereoisomers was further purified by SFC (column: DAICEL CHIRALCEL OJ-H 250 mm*30 mm, 5 μm; conditions: 0.1% NH3HO / IPA; start B 15%, end B 15%; flow rate (mL / min) 60; injection 220) to give intermediate 41a-1 (first eluting stereoisomer; LC-MS (ESI): m / z 383.3 [M+Na]). + ) and intermediate 41a-2 (second eluting stereoisomer; LC-MS (ESI): m / z 383.3 [M+Na] + ) were obtained separately.

[0284] Step B—Synthesis of Intermediates 41b-1 and 41b-2 A mixture of intermediate 41a-1 (340 mg, 0.943 mmol) and Pd / C (10 wt%, 200 mg, 0.188 mmol) in MeOH (10 mL) was stirred under H (15 psi) at 25° C. for 2 h. The mixture was then filtered and the filtrate was concentrated in vacuo to give intermediate 41b-1, which was used in the next reaction without further purification. 1H NMR(400MHz,CD3OD)δ:3.89-3.75(m,2H),2.98-2.86(m,1H),2.94(s,1H),2.86-2.76(m,1H),2.01-1.89(m,2H),1.94-1.74(m,2H),1.47-1.43(br s,2H)1.47(s,9H). Intermediate 41b-2 was prepared from intermediate 41a-2 according to the procedure in Step B of Example 55.

[0285] [Example 56] Preparation of compounds 76 and 77 (S)-2-((R)-6-(N-((1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-yl)carbamimidoyl)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 and (S)-2-((R)-6-(N-((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)carbamimidoyl)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 [ka]

[0286] Compounds 76 and 77 were prepared according to the procedures of Steps E to G of Example 34, starting from Intermediate 41b-1 and Intermediate 41b-2, respectively.

[0287] Compound 76:LC-MS(ESI):m / z 735.3 [M+H] + . 1H NMR(400MHz,D2O+CD3CN)δ:7.39-7.27(m,2H),6.87(d,J=8.2Hz,1H),6.79(s,1H),4.62(s,1H),4.45-4.38(m,1H),3.89(s,1H), 3.24(s,4H),2.89-2.71(m,2H),2.71-2.56(m,2H),2.23-2.01(m,3H),1.84-1.61(m,3H),1.49(s,3H),1.42(s,3H),1.25(s,3H). Compound 77: LC-MS (ESI): m / z 735.6 [M+H] + . 1 H NMR(DMSO-d6+D2O,400MHz)δ:7.56-7.46(m,2H),6.93(d,J=8.6Hz,1H),6.75(s,1H),4.60(s,1H),4.38(br d,J=11.3Hz,1H),3.76 3.65(m,1H),3.55-3.41(m,1H),3.38-3.23(m,1H),3.01-2.89(m,2H),2.88-2.68(m,2H),2.56-2.48(m ,2H),2.01-1.85(m,3H),1.76-1.65(m,2H),1.45(s,3H),1.45-1.35(m,1H),1.39(s,3H),1.24(s,3H). [Example 57] Intermediate 42g-1および42g-2のmodulation

change

[0288] Step A - Synthesis of Intermediate 42a To a stirred solution of diisopropylamine (7.94 mL, 56.2 mmol) in THF (65 mL) at -70 °C was added n-butyllithium (24.05 mL, 60.1 mmol, 2.5 M in hexanes). The reaction was stirred at -70 °C for 30 minutes, and then a solution of methyl 3-(dibenzylamino)cyclobutane-1-carboxylate (6.0 g, 19.39 mmol) in THF (10 mL) was added. The reaction mixture was stirred at -70 °C for 30 minutes. (1H-Benzo[d][1,2,3]triazol-1-yl)methanol (8.26 g, 38.8 mmol) was then added in several portions, and the reaction was stirred at -70 °C for 1 hour. The reaction was then quenched with saturated aqueous NH4Cl (20 mL). The resulting mixture was stirred at 0° C. for 15 minutes and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash silica gel chromatography (Biotage; 80 g Agela silica flash column; eluent: petroleum ether / EtOAc = 23% gradient at 45 mL / min) to give intermediate 42a. LC-MS (ESI): m / z 340.5 [M+H] + . Step B—Synthesis of Intermediate 42b: To a stirred solution of intermediate 42a (5.0 g, 14.73 mmol) and TEA (4.11 mL, 29.5 mmol) in THF (130 mL) at 0° C. was added a solution of methanesulfonyl chloride (2.109 mL, 27.3 mmol) in THF (5 mL) dropwise. The reaction mixture was warmed to 25° C. and stirred at 25° C. for 1.5 h, then cooled to 0° C. and quenched by the dropwise addition of saturated aqueous NaHCO (60 mL). The resulting mixture was extracted with MTBE (60 mL×3). The organic layers were combined, dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure to provide intermediate 42b as a mixture of cis / trans stereoisomers, which was used in the next step without further purification. 1H NMR(400MHz,CDCl3)δ:=7.34-7.24(m,10H),4.42-4.37(two s,2H),3.76-3.72(two s,3H),3.57-3.45(two s,4H),3.44-3.20(m,1H),3.02-2.99(two s,3H),2.49-2.37(m,2H),2.15-1.94(m,2H). Step C—Synthesis of Intermediate 42c To a solution of intermediate 42b (6.0 g, 12.93 mmol) in DMF (60 mL) stirred at 20° C. was added sodium azide (1.360 g, 20.92 mmol) in one portion. The reaction mixture was warmed to 70° C. and stirred for 16 h. The reaction mixture was then diluted with water (400 mL) and extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give intermediate 42c, which was used in the next step without further purification. LC-MS (ESI): m / z 365.2 [M+H] + . Step D—Synthesis of Intermediate 42d To a stirred solution of intermediate 42c (4.7 g, 12.90 mmol) in water (18 mL) and THF (90 mL) was added Ph3P (5.75 g, 21.92 mmol). The reaction was stirred at 25° C. for 16 hours, and then most of the solvent was removed in vacuo. The resulting residue was dried by lyophilization to give intermediate 42d, which was used in the next step without further purification. LC-MS (ESI): m / z 339.1 [M+H] + . Step E—Synthesis of Intermediates 42e-1 and 42e-2. To a solution of intermediate 42d (4.36 g, 12.88 mmol) and TEA (2.155 mL, 15.46 mmol) in DCM (75 mL) was added di-tert-butyl dicarbonate (3.09 g, 14.17 mmol). The reaction was stirred at 25° C. for 16 h. The solvent was then removed from the filtrate under reduced pressure, and the resulting residue was purified by flash silica gel chromatography (Biotage; 80 g Agela silica flash column, eluent: 6% EtOAc / petroleum ether gradient at 60 mL / min) to afford the product as a mixture of stereoisomers. LC-MS (ESI): m / z 439.5 [M+H] + The mixture of diastereomers was further purified by SFC (Column: DAICEL CHIRALPAK AD 250mm*50mm, 10um; Conditions: 0.1% NH3HO EtOH; Start: 30% B, End: 30% B; Flow Rate (mL / min): 200; Injection: 120) to give intermediate 42e-1 (first eluting stereoisomer, LC-MS (ESI): m / z 439.3 [M+H]). + ) and intermediate 42e-2 (second eluting stereoisomer, LC-MS (ESI): m / z 439.6 [M+H] + ) was obtained.

[0289] Step F—Synthesis of Intermediate 42f-1 To a stirred solution of intermediate 42e-1 (650 mg, 1.482 mmol) in THF (14 mL) at 0° C. was slowly added lithium aluminum hydride (170 mg, 4.48 mmol). The reaction was stirred at 25° C. for 2.0 hours, then cooled to 0° C., followed by the slow, sequential addition of water (0.18 mL), 15% sodium hydroxide solution (0.36 mL), and water (0.540 mL). The resulting mixture was filtered through Celite™, and the filtrate was dried over anhydrous NaSO and concentrated in vacuo to provide intermediate 42f-1, which was used in the next step without further purification. 1H NMR(400MHz,CDCl3)δ:7.34-7.28(m,8H),7.28-7.21(m,2H),4.87(br s,1H),3.64-3.54(m,1H),3.47(s,4H),3.45(br s,2H),3.19(d,J=6.6Hz,2H),3.16-3.02(m,1H),1.99-1.90(m,2H),1.67-1.55(m,2H),1.45(s,9H). Step G—Synthesis of Intermediate 42g-1 To a solution of intermediate 42f-1 (600 mg, 1.461 mmol) and acetic acid (0.251 mL, 4.38 mmol) in MeOH (10 mL) was added Pd / C (10 wt%, 311 mg, 0.292 mmol). The reaction was stirred under an atmosphere of H (15 psi) at 25° C. for 16 hours and then filtered. The filtrate was concentrated in vacuo and lyophilized to provide intermediate 42g-1, which was used without further purification. 1 H NMR(400MHz,CD3OD)δ:3.76-3.61(m,1H),3.49(s,2H),3.13(s,2H),2.26-2.17(m,2H),1.96-1.86(m,2H),1.42(s,9H). Intermediate 42g-2 was prepared from intermediate 42e-2 according to the procedures described in Steps F and G of Example 57. 1 H NMR(400MHz,CD3OD)δ:3.78-3.61(m,1H),3.42(s,2H),3.18(s,2H),2.31-2.19(m,2H),2.03-1.84(m,2H),1.44(s,9H). [Example 58] Preparation of compound 78 (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-(hydroxymethyl)cyclobutyl)carbamimidoyl)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 [ka]

[0290] Step A—Synthesis of Intermediate 43a. To a mixture of intermediate 42g-1 (180 mg, 0.664 mmol) and intermediate 3c (355 mg, 0.598 mmol) in MeCN (8 mL) stirred at room temperature, acetic acid (0.152 mL, 2.66 mmol) was added. The reaction was stirred at 80° C. for 20 minutes and then concentrated in vacuo. The resulting residue was purified by reverse-phase HPLC (Biotage; 20 g Agela, C18, 20-35 μm, eluent of 50% MeCN / HO (0.5% TFA) gradient at 50 mL / min) to give intermediate 43a. LC-MS (ESI): m / z 649.4 [M+H] + . Step B - Synthesis of Intermediate 43b A solution of tert-butyl intermediate 43a (300 mg, 0.462 mmol) in TFA (7 mL) was stirred at 40° C. for 1.5 h. The reaction mixture was then concentrated in vacuo to give intermediate 43b, which was used in the next reaction without further purification. LC-MS (ESI): m / z 393.1 [M+H] + . Step C - Synthesis of Intermediate 43c A solution of intermediate 43b (180 mg, 0.459 mmol) and intermediate 4 (213 mg, 0.459 mmol) in MeOH (10 mL) was stirred at 25 °C for 16 h. The reaction mixture was then concentrated in vacuo to give intermediate 43c, which was used in the next reaction without further purification. LC-MS (ESI): m / z 839.4 [M+H] + . Step D—Synthesis of Compound 78 A solution of intermediate 43c (180 mg, 0.215 mmol) in 1:1 DCM / TFA (2 mL) was stirred for 50 minutes at 25° C. The reaction mixture was then concentrated in vacuo and the resulting residue was purified by preparative HPLC (Boston Uni C18, 40*150*5 μm; conditions: water (0.1% TFA)-ACN; start B 0, end B 30; gradient time (min) 10; 100% B retention time (min) 2; flow rate (mL / min) 60; injection 3) to give the product as a TFA salt. The TFA salt was further purified by preparative HPLC (Welch Xtimate C18 150*25mm*5um; Conditions: Water (0.225% FA)-ACN; Start B 0, End B 19; Gradient time (min) 15; 100% B Retention time (min) 2; Flow rate (mL / min) 25; Injection 2) to give compound 78 as the formate salt. LC-MS (ESI): m / z 739.2 [M+H] + . 1 H NMR(400MHz,D2O+CD3CN)δ:7.44-7.37(m,2H),6.90(d,J=8.6Hz,1H),6.78(s,1H),4.60(s,1H),4.38(br d,J=10.6Hz,1H),4.21-4.12(m,1H),3.67(s,2H),3.10(s,2H),2.89-2.68(m,2H),2.49-2 .39(m,2H),2.12-2.01(m,3H),1.85-1.62(m,1H),1.49(s,3H),1.43(s,3H),1.25(s,3H). [Example 59] Preparation of Compound 79 (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-(hydroxymethyl)cyclobutyl)carbamimidoyl)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 [ka]

[0291] Compound 79 was prepared starting from the corresponding intermediate 42g-2 according to the procedure shown in Steps A to C of Example 32. LC-MS (ESI): m / z 739.3 [M+H] + . 1 H NMR(400MHz,D2O+CD3CN)δ:7.46-7.32(m,2H),6.90(d,J=8.6Hz,1H),6.79(s,1H),4.60(s,1H),4.40(br d,J=10.6Hz,1H),4.35-4.22(m,1H),3.62(s,2H),3.18(s,2H),2.89-2.68(m,2H),2.47-2 .39(m,2H),2.12-2.01(m,3H),1.85-1.62(m,1H),1.51(s,3H),1.43(s,3H),1.25(s,3H). [Example 60] Preparation of Compounds 80 and 81 (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-hydroxycyclobutyl)carbamimidoyl)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 and (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-hydroxycyclobutyl)carbamimidoyl)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 [ka]

[0292] Step A—Synthesis of Intermediates 44a-1 and 44a-2 To a mixture of tert-butyl (3-(amino-methyl)-3-hydroxycyclobutyl)carbamate (3.36 g, 15.54 mmol) and sodium carbonate (4.12 g, 38.8 mmol) in THF (40 mL) and water (20 mL) stirred at 0° C. was added benzyl chloroformate (3.71 g, 21.75 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h, and then the solvent was removed under reduced pressure. The resulting residue was purified by flash silica gel chromatography (Biotage; 120 g Agela silica flash column, eluent of 8% EtOAc / petroleum ether gradient at 60 mL / min) to give the crude product as a cis / trans mixture. The cis / trans mixture was further purified by SFC (column: DAICEL CHIRALCEL OJ 250 mm*50 mm, 10 μm); conditions: 0.1% NH₃·H₂O / EtOH; start: B 25%, end: B 25%; flow rate (mL / min): 200; injection: 120) to give intermediate 44a-1 (the second eluted compound) and intermediate 44a-2 (the first eluted compound).

[0293] Intermediate 44a-1: 1 H NMR(CD3OD,400MHz)δ:7.48-7.27(m,5H),5.11(s,2H),3.70-3.52(m,1H),3.23(s,2H),2.61-2.40(m,2H),1.90-1.81(m,2H),1.43(s,9H). Intermediate 44a-2: 1 HNMR(CD3OD,400MHz)δ:7.56-7.27(m,5H),5.08(s,2H),4.28-4.06(m,1H)3.23(s,2H),2.48-2.26(m,2H),2.12-2.04(m,2H),1.40(s,9H). Step B—Synthesis of Intermediate 44b-1 A solution of intermediate 44a-1 (400 mg, 1.142 mmol) in HCl / EtOAc (8 mL, 4 M) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated in vacuo to give intermediate 44b-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z 251.1 [M+H] +. Step C—Synthesis of Intermediate 44c-1 To a stirred solution of intermediate 3c (380 mg, 0.814 mmol) and intermediate 44b-1 (285 mg, 0.814 mmol) in MeCN (8 mL) were added acetic acid (0.140 mL, 2.443 mmol) and potassium acetate (240 mg, 2.443 mmol) sequentially at 25° C. The reaction mixture was stirred at 80° C. for 30 minutes, then diluted with water (30 mL) and extracted with EtOAc (50 mL×3). The organic layers were combined, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO; 20 g Agela silica flash column, eluent of 5% DCM / MeOH gradient at 30 mL / min) to give intermediate 44c-1. LC-MS (ESI): m / z 669.3 [M+H] + . Step D—Synthesis of Intermediate 44d-1 A mixture of intermediate 44c-1 (366 mg, 0.547 mmol) and Pd / C (349 mg, 0.328 mmol, 10 wt%) in 8 mL of EtOAc was stirred under H (15 psi) at 25° C. for 3 h. The reaction mixture was then filtered, and the filtrate was concentrated to give intermediate 44d-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z 535.8 [M+H] + . Step E - Synthesis of Intermediate 44e-1 A solution of intermediate 44d-1 (250 mg, 0.468 mmol) in TFA (5 mL) was stirred at 40°C for 1 hour. The reaction mixture was filtered and concentrated to give intermediate 44e-1, which was used in the next reaction without further purification. LC-MS (ESI): m / z 379.1 [M+H] + . Step F—Synthesis of Compounds 80 and 81 To a stirred solution of intermediate 44e-1 (177 mg, 0.468 mmol) in MeOH (5 mL) was added intermediate 5 (189 mg, 0.468 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 12 hours. The solvent was then removed by purging with a stream of nitrogen gas, and the resulting residue was purified by preparative HPLC (Column: Boston Uni C18 40*150*5 um; Conditions: water (0.1% TFA)-ACN; Start B 0, End B 30; Gradient Time (min) 10; 100% B Retention Time (min) 2; Flow Rate (mL / min) 60; Inject 3) to give compound 80 as a TFA salt. The TFA salt was further purified by preparative HPLC (Column: Welch Xtimate C18 150*25mm*5um; Conditions: Water (0.225% FA)-ACN; Start B 0, End B 18; Gradient time (min) 15; 100% B Retention time (min) 2; Flow rate (mL / min) 25; Injection 3) to give compound 80 as the formate salt. LC-MS (ESI): m / z 725.3 [M+H] + . 1 H NMR(400MHz,D2O+CD3CN):δ:7.42-7.35(m,2H),6.88(d,J=8.6Hz,1H),6.79(s,1H),4.61(s,1H),4.38(br d,J=11.3Hz,1H),3.83-3.73(m,1H),3.07(s,2H),2.84-2.69(m,4H),2.35-2.24(m ,2H),2.09-2.01(m,1H),1.84-1.64(m,1H),1.49(s,3H),1.42(s,3H),1.25(s,3H). Compound 81 was prepared from intermediate 44a-2 according to the procedures in Steps B to F of Example 60. LC-MS (ESI): m / z 725.3 [M+H] + . 1H NMR(400MHz,D2O+CD3CN)δ:7.43-7.35(m,2H),6.88(d,J=8.6Hz,1H),6.80(s,1H),4.60 (s,1H),4.45-4.32(m,1H),4.32-4.26(m,1H),3.08(s,2H),2.92-2.76(m,2H),2.59(br dd,J=8.0,13.9Hz,2H),2.35(br dd,J=6.7,14.1Hz,2H),2.09-2.01(m,1H),1.75-1.64(m,1H),1.49(s,3H),1.42(s,3H),1.24(s,3H). [Example 61] Preparation of compounds 82 and 83 (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-methoxycyclobutyl)carbamimidoyl)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 and (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-methoxycyclobutyl)carbamimidoyl)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 [ka]

[0294] Compounds 82 and 83 were prepared according to the procedure of Steps A through F of Example 60, starting from commercially available tert-butyl (3-(amin...

Claims

1. A compound selected from the following: 1) (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-(N-((S)-pyrrolidin-3-yl)carbamimidoyl)-chroman-2-yl)propanoic acid; 2) (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-(N-((R)-pyrrolidin-3-yl)-carbamimidoyl)-chroman-2-yl)propanoic acid; 3) (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-(N-((3S,5R)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamimidoyl)chroman-2-yl)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-(N-((3R,5R)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamimidoyl)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-(N-((S)-azepan-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 6) (S)-2-((R)-6-(N-((1s,4S)-4-aminocyclohexyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)-amino)-2-oxo-ethylidene)amino)oxy)propanoic acid; 7) (S)-2-((R)-6-(N-((1s,3S)-3-aminocyclobutyl)carbamimidoyl)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; 8) (S)-2-((R)-6-(N-((1r,3R)-3-aminocyclobutyl)carbamimidoyl)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-(N-(3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)carbamimidoyl)-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-((((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-(N-((R)-azepan-3-yl)carbamimidoyl)-chroman-2-yl)propanoic acid; 11) (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-(N-((S)-azepan-3-yl)carbamimidoyl)-chroman-2-yl)propanoic acid; 12) (S)-2-((R)-6-(N-(1-(aminomethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)carbamimidoyl)-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-(N-(2-azaspiro[3.5]nonan-7-yl)carbamimidoyl)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) (S)-2-((R)-6-(N-(2-azaspiro[3.3]heptan-6-yl)carbamimidoyl)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) (S)-2-((R)-6-(N-(5-aminobicyclo[3.1.1]heptan-1-yl)carbamimidoyl)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) (2S)-2-((2R)-6-(N-((1S,5R)-3-azabicyclo[3.2.0]heptan-6-yl)carbamimidoyl)-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-(N-((4R,6s)-1-azaspiro[3.3]heptan-6-yl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxo-ethylidene)amino)oxy)propanoic acid; 18) (S)-2-((R)-6-(N-((4S,6r)-1-azaspiro[3.3]heptan-6-yl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxo-ethylidene)amino)oxy)propanoic acid; 19) (S)-2-((R)-6-(N-((2s,4R)-6-azaspiro[3.5]nonan-2-yl)carbamimidoyl)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-(N-((2r,4S)-6-azaspiro[3.5]nonan-2-yl)carbamimidoyl)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-(N-(7-azaspiro[3.5]nonan-2-yl)carbamimidoyl)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-((R)-6-(N-((2r,4S)-6-azaspiro[3.4]octan-2-yl)carbamimidoyl)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; 23) (S)-2-((R)-6-(N-((2s,4R)-6-azaspiro[3.4]octan-2-yl)carbamimidoyl)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; 24) (S)-2-((R)-6-(N-((1S,2R,5R,6R)-5-aminobicyclo[4.1.0]heptan-2-yl)carbamimidoyl)-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; 25) (S)-2-((R)-6-(N-((1R,2R,5S,6S)-5-aminobicyclo[4.1.0]heptan-2-yl)carbamimidoyl)-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; 26) (S)-2-((R)-6-(N-((1S,2S,5R,6R)-5-aminobicyclo[4.1.0]heptan-2-yl)carbamimidoyl)-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-(N-((1R,2S,5S,6S)-5-aminobicyclo[4.1.0]heptan-2-yl)carbamimidoyl)-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-((((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-(N-(piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 29) (S)-2-((R)-6-(N-(1-((R)-3-amino-2-hydroxypropyl)piperidin-4-yl)carbamimidoyl)-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-(N-(1-((S)-3-amino-2-hydroxypropyl)piperidin-4-yl)carbamimidoyl)-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-((((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-(N-((R)-azepan-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 32) (S)-2-((R)-6-(N-((1r,4R)-4-aminocyclohexyl)carbamimidoyl)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-((((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-(N-((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 34) (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-(N-((1r,4R)-4-(methylamino)cyclohexyl)-carbamimidoyl)chroman-2-yl)propanoic acid; 35) (S)-2-((R)-6-(N-(4-aminobicyclo[2.2.2]octan-1-yl)carbamimidoyl)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-((((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-(N-(azetidin-3-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 37) (S)-2-((R)-6-(N-((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamimidoyl)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-(N-(4-(aminomethyl)phenyl)carbamimidoyl)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-((((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-(N-((R)-piperidin-3-yl)carbamimidoyl)-chroman-2-yl)propanoic acid; 40) (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-(N-((S)-piperidin-3-yl)carbamimidoyl)-chroman-2-yl)propanoic acid; 41) (S)-2-((R)-6-(N-((1s,4S)-4-(aminomethyl)cyclohexyl)carbamimidoyl)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-(N-((1r,4R)-4-(aminomethyl)cyclohexyl)carbamimidoyl)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-(N-((1R,3S)-3-aminocyclopentyl)carbamimidoyl)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-(N-((1S,3R)-3-aminocyclopentyl)carbamimidoyl)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; 47) (S)-2-((R)-6-(N-((1S,3S)-3-aminocyclopentyl)carbamimidoyl)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; 48) (S)-2-((R)-6-(N-((1R,3R)-3-aminocyclopentyl)carbamimidoyl)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; 49) (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-(N-((S)-3,3-dimethylpiperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 50) (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-(N-((R)-3,3-dimethylpiperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 51) (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-(N-((3R,4S)-3-(hydroxymethyl)-piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 52) (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-(N-((3S,4R)-3-(hydroxymethyl)-piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 53) (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-(N-((2S,4S)-2-(hydroxymethyl)-piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 54) (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-(N-((2R,4R)-2-(hydroxymethyl)-piperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 55) (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-(N-((2R,4R)-2-methylpiperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 56) (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-(N-((2S,4S)-2-methylpiperidin-4-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 57) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-methylcyclohexyl)carbamimidoyl)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; 58) (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-methylcyclohexyl)carbamimidoyl)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; 59) (S)-2-((R)-6-(N-((1s,4S)-4-(aminomethyl)-4-hydroxycyclohexyl)carbamimidoyl)-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; 60) (S)-2-((R)-6-(N-((1r,4R)-4-(aminomethyl)-4-hydroxycyclohexyl)carbamimidoyl)-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; 61) (S)-2-((R)-6-(N-((2R,4r,6R)-6-aminospiro[3.3]heptan-2-yl)carbamimidoyl)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; 62) (S)-2-((R)-6-(N-((2S,4s,6S)-6-aminospiro[3.3]heptan-2-yl)carbamimidoyl)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; 63) (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(2-methoxyethyl)cyclohexyl)carbamimidoyl)-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; 64) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(2-methoxyethyl)cyclohexyl)carbamimidoyl)-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; 65) (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(2-hydroxyethyl)cyclohexyl)carbamimidoyl)-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; 66) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(2-hydroxyethyl)cyclohexyl)carbamimidoyl)-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; 67) (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-(N-(trans-3-(methylamino)cyclobutyl)-carbamimidoyl)chroman-2-yl)propanoic acid; 68) (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-(N-(cis-3-(methylamino)cyclobutyl)carbamimidoyl)chroman-2-yl)propanoic acid; 69) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(hydroxymethyl)cyclohexyl)carbamimidoyl)-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; 70) (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(hydroxymethyl)cyclohexyl)carbamimidoyl)-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; 71) (S)-2-((R)-6-(N-((1r,4R)-4-amino-1-methylcyclohexyl)carbamimidoyl)-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; 72) (S)-2-((R)-6-(N-((1s,4S)-4-amino-1-methylcyclohexyl)carbamimidoyl)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; 73) (S)-2-((R)-6-(N-((1s,4S)-4-(aminomethyl)-4-methoxycyclohexyl)carbamimidoyl)-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; 74) (S)-2-((R)-6-(N-((1r,3R)-3-amino-3-methylcyclobutyl)carbamimidoyl)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; 75) (S)-2-((R)-6-(N-((1s,3S)-3-amino-3-methylcyclobutyl)carbamimidoyl)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; 76) (S)-2-((R)-6-(N-((1R,5S,8s)-3-azabicyclo[3.2.1]octan-8-yl)carbamimidoyl)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; 77) (S)-2-((R)-6-(N-((1R,5S,8r)-3-azabicyclo[3.2.1]octan-8-yl)carbamimidoyl)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; 78) (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-(hydroxymethyl)cyclobutyl)-carbamimidoyl)-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; 79) (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-(hydroxymethyl)cyclobutyl)-carbamimidoyl)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; 80) (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-hydroxycyclobutyl)carbamimidoyl)-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; 81) (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-hydroxycyclobutyl)carbamimidoyl)-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; 82) (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-methoxycyclobutyl)carbamimidoyl)-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; 83) (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-methoxycyclobutyl)carbamimidoyl)-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; 84) (S)-2-((R)-6-(N-((1r,3R)-3-amino-1-methylcyclobutyl)carbamimidoyl)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; 85) (S)-2-((R)-6-(N-((1s,3S)-3-amino-1-methylcyclobutyl)carbamimidoyl)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; 86) (S)-2-((R)-6-(N-((1s,3S)-3-amino-3-(2-hydroxyethyl)cyclobutyl)carbamimidoyl)-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; 87) (S)-2-((R)-6-(N-((1r,3R)-3-amino-3-(2-hydroxyethyl)cyclobutyl)carbamimidoyl)-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; 88) (S)-2-((R)-6-(N-((1r,3R)-3-amino-3-(hydroxymethyl)cyclobutyl)carbamimidoyl)-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; 89) (S)-2-((R)-6-(N-((1s,3S)-3-amino-3-(hydroxymethyl)cyclobutyl)carbamimidoyl)-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; 90) (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-(N-((1r,3R)-3-(hydroxymethyl)-3-(methylamino)cyclobutyl)carbamimidoyl)chroman-2-yl)propanoic acid; 91) (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-(N-((1s,3S)-3-(hydroxymethyl)-3-(methylamino)cyclobutyl)carbamimidoyl)chroman-2-yl)propanoic acid; 92) (S)-2-((R)-6-(N-((1r,3R)-3-amino-3-(2-methoxyethyl)cyclobutyl)carbamimidoyl)-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; 93) (S)-2-((R)-6-(N-((1s,3S)-3-amino-3-(2-methoxyethyl)cyclobutyl)carbamimidoyl)-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; 94) (S)-2-((R)-6-(N-((1S,3R)-3-amino-3-((S)-2,3-dihydroxypropyl)cyclobutyl)-carbamimidoyl)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; 95) (S)-2-((R)-6-(N-((1R,3R)-3-amino-3-((R)-2,3-dihydroxypropyl)cyclobutyl)-carbamimidoyl)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; 96) (S)-2-((R)-6-(N-((1R,3S)-3-amino-3-((S)-2,3-dihydroxypropyl)cyclobutyl)-carbamimidoyl)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; 97) (S)-2-((R)-6-(N-((1S,3S)-3-amino-3-((R)-2,3-dihydroxypropyl)cyclobutyl)-carbamimidoyl)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; 98) (S)-2-((R)-6-(N-((1S,3R)-3-amino-3-((S)-1,2-dihydroxyethyl)cyclobutyl)-carbamimidoyl)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; 99) (S)-2-((R)-6-(N-((1R,3R)-3-amino-3-((R)-1,2-dihydroxyethyl)cyclobutyl)-carbamimidoyl)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; 100) (S)-2-((R)-6-(N-((1S,3S)-3-amino-3-((R)-1,2-dihydroxyethyl)cyclobutyl)-carbamimidoyl)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; 101) (S)-2-((R)-6-(N-((1R,3S)-3-amino-3-((S)-1,2-dihydroxyethyl)cyclobutyl)-carbamimidoyl)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; 102) (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-(N-((1s,4S)-4-((methylamino)methyl)cyclohexyl)carbamimidoyl)chroman-2-yl)propanoic acid; 103) (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-(N-((1r,4R)-4-((methylamino)methyl)cyclohexyl)carbamimidoyl)chroman-2-yl)propanoic acid; 104) (S)-2-((R)-6-(N-((1R,4S)-4-aminocycloheptyl)carbamimidoyl)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; 105) (S)-2-((R)-6-(N-((1R,4R)-4-aminocycloheptyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxo-ethylidene)amino)oxy)propanoic acid; 106) (S)-2-((R)-6-(N-((1S,4S)-4-aminocycloheptyl)carbamimidoyl)chroman-2-yl)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxo-ethylidene)amino)oxy)propanoic acid; 107) (S)-2-((R)-6-(N-((1S,4R)-4-aminocycloheptyl)carbamimidoyl)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; 108) (S)-2-((R)-6-(N-((1R,3R)-3-aminocyclohexyl)carbamimidoyl)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; 109) (S)-2-((R)-6-(N-((1S,3S)-3-aminocyclohexyl)carbamimidoyl)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; 110) (S)-2-((R)-6-(N-((1R,3S)-3-aminocyclohexyl)carbamimidoyl)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; 111) (S)-2-((R)-6-(N-((1S,3R)-3-aminocyclohexyl)carbamimidoyl)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; 112) (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)cyclobutyl)carbamimidoyl)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; 113) (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)cyclobutyl)carbamimidoyl)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; 114) (S)-2-((R)-6-(N-((1S,3S)-3-amino-2,2-dimethylcyclobutyl)carbamimidoyl)-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; 115) (S)-2-((R)-6-(N-((2S,4s,7S)-2-aminospiro[3.5]nonan-7-yl)carbamimidoyl)-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; 116) (S)-2-((R)-6-(N-((2R,4r,7R)-2-aminospiro[3.5]nonan-7-yl)carbamimidoyl)-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; 117) (S)-2-((R)-6-(N-((1s,3S)-3-(aminomethyl)-3-methylcyclobutyl)carbamimidoyl)-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; 118) (S)-2-((R)-6-(N-((1r,3R)-3-(aminomethyl)-3-methylcyclobutyl)carbamimidoyl)-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; 119) (S)-2-((R)-6-(N-(6-(aminomethyl)-6-fluorospiro[3.3]heptan-2-yl)carbamimidoyl)-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; 120) (S)-2-((R)-6-(N-((1R,3S)-3-(aminomethyl)-2,2-dimethylcyclobutyl)-carbamimidoyl)-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; 121) (2S)-2-((2R)-6-(N-(6-(aminomethyl)spiro[3.3]heptan-2-yl)carbamimidoyl)-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; 122) (2S)-2-((2R)-6-(N-((1S)-1-aminospiro[2.3]hexan-5-yl)carbamimidoyl)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; 123) (2S)-2-((2R)-6-(N-((1R)-1-aminospiro[2.3]hexan-5-yl)carbamimidoyl)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; 124) (S)-2-((R)-6-(N-((1s,3S)-3-aminocyclobutyl)carbamimidoyl)-5-(methoxymethyl)-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; 125) (S)-2-((R)-6-(N-((1s,3S)-3-aminocyclobutyl)carbamimidoyl)-7-(methoxymethyl)-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; 126) (S)-2-((R)-6-(N-((1s,4S)-4-amino-1-(methoxymethyl)cyclohexyl)-carbamimidoyl)-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; 127) (S)-2-((R)-6-(N-((1r,4R)-4-amino-1-(methoxymethyl)cyclohexyl)-carbamimidoyl)-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; 128) (S)-2-((R)-6-(N-((1s,4S)-4-amino-4-(methoxymethyl)cyclohexyl)-carbamimidoyl)-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; 129) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(methoxymethyl)cyclohexyl)-carbamimidoyl)-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; 130) (S)-2-((R)-6-(N-((1s,4S)-4-(aminomethyl)-1-methylcyclohexyl)carbamimidoyl)-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; 131) (S)-2-((R)-6-(N-((1r,4R)-4-(aminomethyl)-1-methylcyclohexyl)carbamimidoyl)-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; 132) (S)-2-((R)-6-(N-((1s,4S)-4-(2-aminopropan-2-yl)cyclohexyl)carbamimidoyl)-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; 133) (S)-2-((R)-6-(N-((1r,4R)-4-(2-aminopropan-2-yl)cyclohexyl)carbamimidoyl)-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; 134) (S)-2-((R)-6-(N-((1s,3S)-3-aminocyclobutyl)carbamimidoyl)-7-methylchroman-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; 135) (S)-2-((R)-6-(N-((1r,4R)-4-amino-4-(hydroxymethyl)-1-methylcyclohexyl)-carbamimidoyl)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; 136) (S)-2-((R)-6-(N-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)carbamimidoyl)-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; 137) (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-(N-((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamimidoyl)chroman-2-yl)propanoic acid; 138) (S)-2-((R)-6-(N-(1-(2-aminoethyl)cyclopropyl)carbamimidoyl)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; 139) (S)-2-((R)-6-(N-(1-(3-aminopropyl)cyclopropyl)carbamimidoyl)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 140) (S)-2-((R)-6-(N-(1-(2-aminoethyl)cyclobutyl)carbamimidoyl)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 pharma- ceutically acceptable salt or hydrate thereof.

2. The compound of claim 1 selected from the following: or a pharma- ceutically acceptable salt or hydrate thereof.

3. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 2, or a pharma- ceutically acceptable salt or hydrate thereof, and a pharma- ceutically acceptable carrier.

4. 4. The pharmaceutical composition of claim 3, further comprising a therapeutically effective amount of a beta-lactamase inhibitor compound.

5. 5. The pharmaceutical composition of claim 4, wherein the beta-lactamase inhibitor compound is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacubactam, vaborbactam, didebactam, enmethazobactam and durobactam.

6. 13. A pharmaceutical composition for a method of treating a bacterial infection comprising the compound of claim 1 or a pharma- ceutically acceptable salt thereof, said method comprising administering to a subject in need of such treatment a therapeutically effective amount of the compound of claim 1 or a pharma- ceutically acceptable salt thereof.

7. 7. The pharmaceutical composition of claim 6, wherein the method further comprises administering to a subject in need of such treatment a therapeutically effective amount of a beta-lactamase inhibitor compound.

8. 8. The pharmaceutical composition of claim 7, wherein the beta-lactamase inhibitor compound is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacubactam, vaborbactam, didebactam, enmethazobactam and durobactam.

9. 7. The pharmaceutical composition of claim 6, wherein the bacterial infection is caused by the genus Pseudomonas, Klebsiella, Enterobacter, Escherichia, Morganella, Citrobacter, Serratia or Acinetobacter.

10. 13. Use of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for a method of treating a bacterial infection.

11. 11. The use of claim 10, wherein the method further comprises administering a compound of claim 1 in combination with a beta-lactamase inhibitor compound for treating a bacterial infection, or wherein the use is in combination with a beta-lactamase inhibitor compound in the manufacture of a medicament for treating a bacterial infection.

12. The use according to claim 11, wherein the beta-lactamase inhibitor compound is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam, avibactam, taniborbactam, nacubactam, vaborbactam, didebactam, enmethazobactam and durobactam.

13. The use according to claim 11, wherein the bacterial infection is caused by the genus Pseudomonas, Klebsiella, Enterobacter, Escherichia, Morganella, Citrobacter, Serratia or Acinetobacter.

14. The following compounds Or a pharma- ceutically acceptable salt thereof.

15. The following compounds Or a pharma- ceutically acceptable salt thereof.

16. The following compounds Or a pharma- ceutically acceptable salt thereof.

17. The following compounds Or a pharma- ceutically acceptable salt thereof.

18. The following compounds Or a pharma- ceutically acceptable salt thereof.

19. The following compounds Or a pharma- ceutically acceptable salt thereof.

20. The following compounds Or a pharma- ceutically acceptable salt thereof.

21. The following compounds or a pharma- ceutically acceptable salt thereof.

22. The following compounds Or a pharma- ceutically acceptable salt thereof.

23. The following compounds Or a pharma- ceutically acceptable salt thereof.

24. The following compounds Or a pharma- ceutically acceptable salt thereof.

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