BR112018010962B1 - COMPOUND, TRIFLUOROACETIC ACID SALT, PHARMACEUTICAL COMPOSITION, AND, USE OF A COMPOUND - Google Patents

Abstract

COMPOUND, TRIFLUOROACETIC ACID SALT, PHARMACEUTICAL COMPOSITION, AND USE OF A COMPOUND. The present invention relates to biaryl monobactam compounds of Formula I and pharmaceutically acceptable salts thereof, wherein X, Y, Z, Al, Q, A2, M, W, Rx and Rz are as defined herein. The present invention also relates to compositions comprising a biaryl monobactam compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates to methods of treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic.

Description

FIELD OF INVENTION

[001] This invention relates to novel biaryl monobactam compounds, processes for their preparation and their use as therapeutic agents. More particularly, the invention relates to biaryl monobactam compounds and their use as antibiotic agents for the treatment of bacterial infections.

FUNDAMENTALS OF THE INVENTION

[002] The introduction of antibiotics to treat bacterial infections is one of the great medical achievements of the 20th century. In recent decades, however, 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 more die from preexisting conditions exacerbated by similar infections. Antibiotic Resistance Threats in the United States, 2013, Centers for Disease Control, Atlanta, Georgia. New antibiotics are needed to combat the current and future threat of multidrug-resistant bacteria.

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

[004] Aztreonam, a monobactam, was initially approved in the US in 1986 for the treatment of aerobic Gram-negative bacterial infections and remains the only monobactam used in the US today. However, aztreonam has weak activity against Pseudomonas and Acinetobacter strains. Because monobactams are inherently resistant to hydrolysis by MBLs, several companies have begun developing novel monobactam compounds for the treatment of infections caused by Gram-negative bacteria. Monobactam compounds comprising a siderophore moiety are described in WO 2007/065288, WO2012/073138, J. Medicinal Chemistry 56:55415552 (2013), and Bioorganic and Medicinal Chemistry Letters 22:5989 (2012).

[005] U.S. Patent Application Publication No. US 2014/0275007 describes oxoborazine monobactams and their use as antibacterial agents, and U.S. Patent Application Publication No. US 2015/0266867 also describes novel monobactam compounds for use as antibacterial agents. International Patent Application Publication No. WO 2013/110643 describes novel amidine-substituted monobactam derivatives and their use as antimicrobial reagents.

[006] The need for new antibiotics to overcome multidrug resistance continues. The compounds described in this invention are intended to fill this medical need, through administration, either by themselves or in combination with a suitable β-lactamase inhibitor.

SUMMARY OF THE INVENTION

[007] The invention relates to the design and synthesis of a series of analogues of biaryl monobactam, a novel class of highly potent antibiotics effective against a broad range of Gram-negative bacteria. These compounds and pharmaceutically acceptable salts thereof 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 a suitable β-lactamase inhibitor. More particularly, the present invention includes compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein: W is a bond or O; Rx and Rz are independently hydrogen, -SC1-C3 alkyl, C1-C3 alkyl, -(C1-C3 alkylene)nOC1-C3 alkyl, or -(C1-C3 alkylene)nNC1-C3 alkyl, wherein the -SC1-C3 alkyl, C1-C3 alkyl, -(C1-C3 alkylene)nOC1-C3 alkyl and -(C1-C3 alkylene)nNC1-C3 alkyl are optionally substituted with one to seven fluorines; or, alternatively, Rx and Rz, together with the carbon to which they are attached, form a monocyclic C4-C7 cycloalkyl or a monocyclic C4-C7 heterocycloalkyl having 1, 2, or 3 heteroatom ring atom(s) independently selected from N, O, and S, wherein said C4-C7 cycloalkyl and said C4-C7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from -F, -OH, and -OC1-C3 alkyl; X is N or CR1; R1 is hydrogen, C1-C3 alkyl, or halogen; wherein said C1-C3 alkyl is optionally substituted with one to three Ra; each occurrence of Ra is independently hydrogen, halogen, C1-C3 alkyl, -NRcRd, or -ORe; Z is C1-C3 alkylene optionally substituted with one to three Rb; each occurrence of Rb is independently -C1-C8 alkyl, -C3-C7 cycloalkyl, -C(O)ORe, -C(O)NRcRd, tetrazolyl, oxadiazolonyl, HetA, AriA, -S(O)mRe, -S(O)mNRcRd, or -P(O)(Re)p wherein said -C1-C8 alkyl and said -C3-C7 cycloalkyl are optionally substituted with one to three Ra; HetA is a 4- to 6-membered saturated or monounsaturated monocyclic ring having 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; AriA is a 5- to 6-membered monocyclic aromatic ring having 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; Y is a bond, O, NR2, S, or CH2; R2 is hydrogen, - and cd and cd C1-C3 alkyl, -C(O)R , -C(O)NR R , -S(O)mR , or -S(O)mNR R , wherein said -C1-C3 alkyl is optionally substituted with one to three Ra; A1 is AriA; A2 is -(CH2)nN(R3)2-, C3-C7 cycloalkyl, AriC, or HetC, wherein said C3-C7 cycloalkyl is optionally substituted with one to four R4; AriC is a 5- to 6-membered monocyclic aromatic ring having 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; HetC is a 4- to 7-membered saturated or monounsaturated monocyclic ring having 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; each occurrence of R4 is independently: -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, halogen, -ORe, -S(O)mRe, -S(O)mNRcRd, eee cd cd -C(O)R , -OC(O)R , —C(O)OR , -CN, —C(O)NR R , —NR R , - cd cecec cd (^^^T-2)nl N^v ; NR \^(^v)^x , NR V^(^^)^^X , NR C(O)NR , NRcS(O)mRe, =NH, -CF3, -OCF3, -OCHF2, -C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, -C1-C10 alkylene-C3-C6 cycloalkyl, -O-C1-C10 alkylene-C3-C6 cycloalkyl, HetB, -O-HetB, -C1-C10 alkylene-HetB, -O-C1-C10 alkylene-HetB, AriA, -O-AriA, -C1-C10 alkylene-AriA or -O-C1-C10 alkylene-AriA, wherein each R4 is unsubstituted or substituted with one to four substituents selected from halogen, -C1-C6 alkyl and -(CH2)nNRcRd, or wherein R4 and M, together with the atoms to which they are attached, form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S, and -NRg; HetB is a 3- to 6-membered saturated or monounsaturated monocyclic ring having 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to three Ra; Q is a bond, CH2, O, S, -(CH2)nNR3-, or -NR3(CH2)n-, wherein each CH2 is unsubstituted or substituted with one to two substituents selected from halogen, -C1-C6 alkyl, ORe, and -(CH2)nNRcRd; R3 is hydrogen or -C1-C3 alkyl, wherein said -C1-C3 alkyl is optionally substituted with one to three Ra; M is R5, -NHR5, -N(R5)2, -OR5, -(CH2)nR5, -C(O)R5, -C(NH)R5 or -S(O)mR5; R5 is H, C2-C10 alkyl, C3-C7 cycloalkyl, C1-C6 alkyl-C3-C7 cycloalkyl, HetB, AriB or -NH(C1-C6 alkyl), wherein said C1-C6 alkyl, said C2-C10 alkyl and said C3-C7 cycloalkyl are optionally substituted with one to four R6; AriB is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, O, and S, optionally substituted with one to four R4; each occurrence of R6 is independently selected from the group consisting of: halogen, -ORe, -S(O)mRe, -S(O)mNRcRd, - eee cd cd C(O)R , -OC(O)R , -C(O)OR , -CN, -C(O)NR R , -C(NH)NR R , - cd cd cece NR R , -(CH2)nNR R , -N(R )(C(O)R ), -N(R )(C(O)OR ), - N(Rc)(C(O)NRcRd), -N(Rc)(S(O)mRe) and HetB; each occurrence of Rc and Rd is independently: hydrogen, -C1-C10 alkyl, -C2-C10 alkenyl, -C3-C6 cycloalkyl, -C1-C10 alkylene-C3-C6 cycloalkyl, HetA, -C1-C10 alkylene-HetB, AriB, -C1-C10 alkylene-AriB, and -C1-C10 alkylene-HetB or, alternatively, Rc and Rd together with the nitrogen atom to which they are attached form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S, and -NRg, and wherein each Rc and Rd is optionally substituted with one to three Rf; each occurrence of Re is independently: hydrogen, -C1-C10 alkyl, -C2-C10 alkenyl, -OH, -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C10 alkylenylene-C3-C6 cycloalkyl, HetB, -C1-C10 alkylene-HetB, AriB, -C1-C10 alkylene-AriB, or -C1-C10 alkylene-HetB; wherein each Re is optionally substituted with one to three Rh; each occurrence of Rf is independently: halogen, -C1-C10 alkyl, -OH, -OC1-C4 alkyl, -S(O)C1-C4 alkyl, -CN, -CF3, -OCHF2, -OCF3 or NH2, wherein said -C1-C10 alkyl is optionally substituted with one to three substituents independently selected from: -OH, halogen, cyano, and -S(O)2CH3; each occurrence of Rg is independently: hydrogen, -C(O)Re, and -C1-C10 alkyl, wherein said -C1-C10 alkyl is optionally substituted with one to five fluorine atoms; each occurrence of Rh is independently: halogen, -C1-C10alkyl, -OH, -OC1-C4 alkyl, -S(O)mC1-C4 alkyl, -CN, -CF3, -OCHF2 or -OCF3; wherein said -C1-C10 alkyl is optionally substituted with one to three substituents independently selected from: -OH, halogen, cyano, or -S(O)2CH3; each n is independently 0, 1, 2, 3, or 4; each m is independently 0, 1, or 2, and each p is independently 1 or 2.

[008] The present invention also includes compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein: W is a bond or O; Rx and Rz are independently hydrogen, -SC1-C3 alkyl, C1-C3 alkyl, -(C1-C3 alkylene)nOC1-C3 alkyl, or -(C1-C3 alkylene)nNC1-C3 alkyl, wherein the -SC1-C3 alkyl, C1-C3 alkyl, -(C1-C3 alkylene)nOC1-C3 alkyl and -(C1-C3 alkylene)nNC1-C3 alkyl are optionally substituted with one to seven fluorines; or, alternatively, Rx and Rz, together with the carbon to which they are attached, form a monocyclic C4-C7 cycloalkyl or a monocyclic C4-C7 heterocycloalkyl having 1, 2, or 3 heteroatom ring atom(s) independently selected from N, O, and S, wherein said C4-C7 cycloalkyl and said C4-C7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from -F, -OH, and -OC1-C3 alkyl; X is N or CR1; R1 is hydrogen, C1-C3 alkyl, or halogen; wherein said C1-C3 alkyl is optionally substituted with one to three Ra; each occurrence of Ra is independently hydrogen, halogen, C1-C3 alkyl, -NRcRd, or -ORe; Z is C1-C3 alkylene, optionally substituted with one to three Rb; each occurrence of Rb is independently -C1-C8 alkyl, -C3-C7 cycloalkyl, -C(O)ORe, -C(O)NRcRd, tetrazolyl, oxadiazolonyl, HetA, AriA, -S(O)mRe, -S(O)mNRcRd, or -P(O)(Re)p, wherein said -C1-C8 alkyl and said C3-C7 cycloalkyl are optionally substituted with one to three Ra; HetA is a 4- to 6-membered saturated or monounsaturated monocyclic ring having 1, 2, or 3 heteroatom ring atom(s) independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; AriA is a 5- to 6-membered monocyclic aromatic ring having 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; Y is a bond, O, NR2, S, or CH2; R2 is hydrogen, -C1-C3 alkyl, -C(O)Re, -C(O)NRcRd, -S(O)mRe, or -S(O)mNRcRd, wherein said -C1-C3 alkyl is optionally substituted with one to three Ra; A1 is AriA; A2 is C3-C7 cycloalkyl, AriC, or HetC, wherein said C3-C7 cycloalkyl is optionally substituted with one to four R4; AriC is a 5- to 6-membered monocyclic aromatic ring having 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; HetC is a 4- to 7-membered saturated or monounsaturated monocyclic ring having 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; each occurrence of R4 is independently: -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, halogen, -ORe, -S(O)mRe, -S(O)mNRcRd, eee cd cd -C(O)R , —OC(O)R , —C(O)OR , -CN, -C(O)NR R , —NR R , — cecec cd ce NR C(O)R , -NR C(O)OR , -NR C(O)NR R , -NR S(O)mR , =NH, —CF3, -OCF3, -OCHF2, -C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, -C1-alkylene- C10-C3-C6 cycloalkyl, -O-C1-C10-cycloalkylC3-C6, HetB, -O- HetB, -C1-C10 alkylene-HetB, -O-C1-C10 alkylene-HetB, AriA, -O-AriA, -C1-C10 alkylene-AriA, or -O-C1-C10 alkylene-AriA; HetB is a 3- to 6-membered saturated or monounsaturated monocyclic ring having 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to three Ra; Q is a bond, CH2, O, S, -(CH2)nNR3-, or -NR3(CH2)n-; R3 is hydrogen or -C1-C3 alkyl, wherein said -C1-C3 alkyl is optionally substituted with one to three Ra; M is R5, -NR5, -OR5, -(CH2)nR5, -C(O)R5, -CH(NH)R5 or -S(O)mR5; R5 is C2-C10 alkyl, C3-C7 cycloalkyl, HetB or AriB, wherein said C2-C10 alkyl and said C3-C7 cycloalkyl are optionally substituted with one to four R6; AriB is a 5- to 6-membered monocyclic aromatic ring having 0, 1, 2 or 3 ring atoms independently selected from N, O and S, optionally substituted with one to four R4; each occurrence of R6 is independently selected from the group consisting of: halogen, -ORe, -S(O)mRe, -S(O)mNRcRd, - eee cd cd C(O)R , -OC(O)R , -C(O)OR , -CN, -C(O)NR R , -C(NH)NR R , - cd cecec cd NR R , -N(R )(C(O)R ), -N(R )(C(O)OR ), - N(R )(C(O)NR R ) and - N(Rc)(S(O)mRe); each occurrence of Rc and Rd is independently: hydrogen, -C1-C10 alkyl, -C2-C10 alkenyl, -C3-C6 cycloalkyl, -C1-C10 alkylene-C3-C6 cycloalkyl, HetA, -C1-C10 alkylene-HetB, AriB, -C1-C10 alkylene-AriB, and -C1-C10 alkylene-HetB or, alternatively, Rc and Rd together with the nitrogen atom to which they are attached form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S, and -NRg, and wherein each Rc and Rd is optionally substituted with one to three Rf; each occurrence of Re is independently: hydrogen, -C1-C10 alkyl, -C2-C10 alkenyl, -OH, -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C1 alkylenylene-C3-C6 cycloalkyl, HetB, -C1-C10 alkylene-HetB, AriB, -C1-C10 alkylene-AriB or -C1-C10 alkylene-HetB; wherein each Re is optionally substituted with one to three Rh; each occurrence of Rf is independently: halogen, -C1-C10 alkyl, -OH, -OC1-C4 alkyl, -S(O)mI-C1-C4 alkyl, -CN, -CF3, —OCHF2 or -OCF3; wherein said -C1-C10 alkyl is optionally substituted with one to three substituents independently selected from: -OH, halogen, cyano, and -S(O)2CH3; each occurrence of Rg is independently: hydrogen, -C(O)Re, and -C1-C10 alkyl, wherein said -C1-C10 alkyl is optionally substituted with one to five fluorine atoms; each occurrence of Rh is independently: halogen, -C1-C10 alkyl, -OH, -OC1-C4 alkyl, -S(O)mI-C1-C4 alkyl, -CN, -CF3, -OCHF2, or -OCF3; wherein said -C1-C10 alkyl is optionally substituted with one to three substituents independently selected from: -OH, halogen, cyano, or -S(O)2CH3; each n is independently o, i, 2, 3, or 4; each m is independently o, i, or 2, and each p is independently i or 2.

[009] The present invention also relates to a pharmaceutical composition for treating a bacterial infection in a subject, including infection with multidrug-resistant Gram-negative bacterial strains, comprising a biaryl monobactam compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.

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

[0011] The present invention is also directed to methods of treating Gram-negative bacterial infections in a subject in need thereof, comprising administering to the subject an effective amount of a biaryl monobactam compound of the invention. In specific embodiments of the invention, the method includes administering a beta-lactamase inhibitor compound.

[0012] Embodiments, sub-embodiments and features of the present invention are further described or will be apparent from the following description, examples and appended claims. DETAILED DESCRIPTION OF THE INVENTION

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

[0014] In each of the various embodiments of the compounds of the invention described herein, each variable including those of Formulas I, II-1, II-2, II-3, III-1, III-2 and III-3, and the various embodiments thereof, each variable is selected independently of the others, unless otherwise indicated.

[0015] The present invention encompasses all compounds of Formulas I, II-1, II-2, II-3, III-1, III-2 and III-3, and the various embodiments thereof, for example, any solvates, hydrates, stereoisomers and tautomers of said compounds and any pharmaceutically acceptable salts thereof.

Compounds of formula (I)

[0016] In one aspect, the present invention includes compounds of Formula I: or pharmaceutically acceptable salt thereof, wherein X, Y, Z, A1, Q, A2, M, W, Rx and Rz are as defined herein for the Compounds of Formula (I); wherein the compounds may be suitable for use in the treatment of bacterial infections.

[0017] A first embodiment of the invention (Embodiment E1) is a compound of Formula I, or pharmaceutically acceptable salt thereof, wherein X, Y, Z, A1, Q, A2, M, W, Rx and Rz are as defined in Formula I in the Summary of the Invention.

[0018] A second embodiment (Embodiment E2) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is a bond, and all other variables are as defined in Embodiment E1.

[0019] A third embodiment (Embodiment E3) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is O, and all other variables are as defined in Embodiment E1.

[0020] A fourth embodiment (Embodiment E4) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is N, and all other variables are as defined in Embodiment E1.

[0021] A fifth embodiment (Embodiment E5) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is CR1, and R1 is hydrogen, halogen, or C1-C3 alkyl optionally substituted with one to three Ra, and all other variables are as defined in Embodiment E1.

[0022] In a sub-embodiment of Embodiment E5 (Embodiment E5-A), R1 is hydrogen.

[0023] In another sub-embodiment of Embodiment E5 (Embodiment E5-B), R1 is halogen.

[0024] In a further embodiment of Embodiment E5 (Embodiment E5-C), R1 is chlorine.

[0025] In yet another sub-embodiment of Embodiment E5 (Embodiment E5-D), R1 is fluorine.

[0026] In a further embodiment of Embodiment E5 (Embodiment E5-E), R1 is C1-C3 alkyl optionally substituted with one to three Ra, wherein each occurrence of Ra is independently hydrogen, halogen, C1-C3 alkyl, -NRcRd, or -ORe.

[0027] A sixth Embodiment (Embodiment E6) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C1-C3 alkylene optionally substituted with one to three Rb, wherein each occurrence of Rb is independently hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, -C(O)ORe, -C(O)NRcRd, tetrazolyl, oxadiazolonyl, HetA, AriA, -S(O)mRe, -S(O)mNRcRd, or -P(O)(Re)p, wherein said C1-C8 alkyl and said C3-C7 cycloalkyl are optionally substituted with one to three Ra and all other variables are as defined in Embodiment E1.

[0028] In a sub-embodiment of Embodiment E6, Z is C1-C3 alkylene substituted with one occurrence of Rb. In a further sub-embodiment of Embodiment E6, Z is C1-C3 alkylene substituted with two occurrences of Rb. In a further further embodiment of Embodiment E6, Z is C1-C3 alkylene substituted with three occurrences of Rb.

[0029] A seventh Embodiment (Embodiment E7) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C1-C3 alkylene substituted with -C(O)ORe; and all other variables are as defined in Embodiment E1.

[0030] An eighth Embodiment (Embodiment E8) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C1-C3 alkylene substituted with -C(O)OH; and all other variables are as defined in Embodiment E1.

[0031] A ninth embodiment (Embodiment E9) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is tetrazolyl-substituted C1-C3 alkylene; and all other variables are as defined in Embodiment E1.

[0032] A tenth Embodiment (Embodiment E10) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C1-C3 alkylene substituted with C1-C8 alkyl, optionally substituted with one to three Ra, and all other variables are as defined in Embodiment E1.

[0033] An eleventh embodiment (Embodiment E11) is a compound of Formula I, or pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is methyl-substituted C1-C3 alkylene; and all other variables are as defined in Embodiment E1.

[0034] A twelfth Embodiment (Embodiment E12) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is C1-C3 alkylene substituted with methyl and -C(O)OH; and all other variables are as defined in Embodiment E1.

[0035] A thirteenth embodiment (Embodiment E13) is a compound of Formula I, or pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is -CH(C(O)OH)CH2-, and all other variables are as defined in Embodiment E1.

[0036] A fourteenth embodiment (Embodiment E14) is a compound of Formula I, or pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is oxadiazolonyl-substituted C1-C3 alkylene, and all other variables are as defined in Embodiment E1.

[0037] A fifteenth embodiment (Embodiment E15) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is a bond, and all other variables are as defined in Embodiment E1.

[0038] A sixteenth embodiment (Embodiment E16) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B E5-C, E5D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is O, and all other variables are as defined in Embodiment E1.

[0039] A seventeenth Embodiment (Embodiment E17) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is NR2, and all other variables are as defined in Embodiment E1.

[0040] In one sub-embodiment of Embodiment E17, R2 is hydrogen. In another sub-embodiment of Embodiment E17, R2 is C1-C3 alkyl optionally substituted with one to three Ra. In a further further embodiment of Embodiment E17, R2 is C(O)Re. In yet another sub-embodiment of Embodiment E17, R2 is -C(O)NRcRd. In yet another sub-embodiment of Embodiment E17, R2 is -S(O)mRe. In a further further embodiment of Embodiment E17, R2 is -S(O)mNRcRd.

[0041] An eighteenth embodiment (Embodiment E18) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is S, and all other variables are as defined in Embodiment E1.

[0042] A nineteenth Embodiment form (Embodiment E19) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is CH2, and all other variables are as defined in Embodiment E1.

[0043] A twentieth embodiment (Embodiment E20) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is a 5- to 6-membered monocyclic aromatic ring having 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4, and all other variables are as defined in Embodiment E1.

[0044] A twenty-first Embodiment (Embodiment E21) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is a 5-membered monocyclic aromatic ring having 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4, and all other variables are as defined in Embodiment E1.

[0045] A twenty-second Embodiment (Embodiment E22) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is a 6-membered monocyclic aromatic ring having 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4, and all other variables are as defined in Embodiment E1.

[0046] In a sub-embodiment of Embodiment E21 or E22, A1 has 1 ring atom independently selected from N, N as a quaternary salt, O, and S. In a further embodiment of Embodiment E21 or E22, A1 has 2 ring atoms independently selected from N, N as a quaternary salt, O, and S. In a further sub-embodiment of Embodiment E21 or E22, A1 has 2 ring atoms independently selected from N, N as a quaternary salt, O, and S. In yet a further sub-embodiment of Embodiment E21 or E22, A1 has 3 ring atoms independently selected from N, N as a quaternary salt, O, and S.

[0047] A twenty-third Embodiment (Embodiment E23) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is a 6-membered monocyclic aromatic ring optionally substituted with one to four R4, and all other variables are as defined in Embodiment E1.

[0048] A twenty-fourth Embodiment (Embodiment E24) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is an unsubstituted 6-membered monocyclic aromatic ring, and all other variables are as defined in Embodiment E1.

[0049] A twenty-fifth Embodiment (Embodiment E25) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is: and all other variables are as defined in Embodiment E1.

[0050] A twenty-sixth embodiment (Embodiment E26) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is a bond, and all other variables are as defined in Embodiment E1.

[0051] A twenty-seventh embodiment (Embodiment E27) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is CH2, and all other variables are as defined in Embodiment E1.

[0052] A twenty-eighth embodiment (Embodiment E28) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is O, and all other variables are as defined in Embodiment E1.

[0053] A twenty-ninth embodiment (Embodiment E29) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is S, and all other variables are as defined in Embodiment E1.

[0054] A thirtieth Embodiment (Embodiment E30) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is -(CH2)nNR3-, and all other variables are as defined in Embodiment E1.

[0055] A thirty-first embodiment (Embodiment E31) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is -NR3(CH2)n-, and all other variables are as defined in Embodiment E1.

[0056] A thirty-second Embodiment (Embodiment E32) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is NH, and all other variables are as defined in Embodiment E1.

[0057] A thirty-third Embodiment (Embodiment E33) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is N(C1-C3 alkyl) optionally substituted with one to three Ra, and all other variables are as defined in Embodiment E1.

[0058] A thirty-fourth Embodiment (Embodiment E34) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is C3-C7 cycloalkyl optionally substituted with one to four R4; and all other variables are as defined in Embodiment E1.

[0059] A thirty-fifth Embodiment (Embodiment E35) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is AriC; and all other variables are as defined in Embodiment E1.

[0060] A thirty-sixth embodiment (Embodiment E36) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is a 5-membered monocyclic aromatic ring having 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; and all other variables are as defined in Embodiment E1.

[0061] A thirty-seventh embodiment (Embodiment E37) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is a 6-membered monocyclic aromatic ring having 0, 1, 2 or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R4 and all other variables are as defined in Embodiment Form E1.

[0062] A thirty-eighth Embodiment (Embodiment E38) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is HetC; and all other variables are as defined in Embodiment E1.

[0063] A thirty-ninth Embodiment (Embodiment E39) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is a 4- to 7-membered saturated or mono-saturated monocyclic ring having 1 heteroatom ring atom selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R4; and all other variables are as defined in Embodiment E1.

[0064] A fortieth Embodiment (Embodiment E40) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is a 4- to 7-membered saturated or mono-saturated monocyclic ring having 2 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R4; and all other variables are as defined in Embodiment E1.

[0065] A forty-first Embodiment (Embodiment E41) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is a 4- to 7-membered saturated or mono-saturated monocyclic ring having 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R4; and all other variables are as defined in Embodiment E1.

[0066] In sub-embodiments of Embodiments E34-E41, A2 is unsubstituted. In other sub-embodiments, A2 is replaced with one R4. In other sub-embodiments, A2 is replaced with two R4. In additional sub-embodiments, A2 is replaced with three R4. In still other sub-embodiments, A2 is replaced with four R4.

[0067] In sub-embodiments of Embodiments E34-E41, A2 is substituted with methyl. In additional sub-embodiments, A2 is substituted with -NH2. In other sub-embodiments, A2 is substituted with =NH. In other sub-embodiments, A2 is substituted with one to four substituents selected from: =NH, -NH2, and -CH3.

[0068] A forty-second Embodiment (Embodiment E42) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: where * indicates binding to Q and ** indicates binding to M, and all other variables are as defined in Embodiment E1.

[0069] A forty-third Embodiment (Embodiment E43) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0070] A forty-fourth Embodiment (Embodiment E44) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0071] A forty-fifth Embodiment (Embodiment E45) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0072] A forty-sixth embodiment (Embodiment E46) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0073] A forty-sixth Embodiment (Embodiment E47) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0074] A forty-eighth embodiment (Embodiment E48) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0075] A forty-ninth Embodiment (Embodiment E49) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0076] A fiftieth Embodiment (Embodiment E50) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0077] A fifty-first Embodiment (Embodiment E51) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0078] A fifty-second Embodiment (Embodiment E52) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0079] A fifty-third Embodiment (Embodiment E53) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0080] A fifty-fourth Embodiment (Embodiment E54) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0081] A fifty-fifth Embodiment (Embodiment E55) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0082] A fifty-sixth Embodiment (Embodiment E56) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0083] A fifty-seventh Embodiment (Embodiment E57) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0084] A fifty-eighth Embodiment (Embodiment E58) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is: and all other variables are as defined in Embodiment E1.

[0085] A fifty-ninth Embodiment (Embodiment E59) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiments E34-E58, M is R5, and all other variables are as defined in Embodiment E1.

[0086] A sixtieth embodiment (Embodiment E60) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is C2-C10 alkyl optionally substituted with one to four R6, and all other variables are as defined in Embodiment E1.

[0087] A sixty-first embodiment (Embodiment E61) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiments E34-E58, M is C3-C7 cycloalkyl optionally substituted with one to four R6, and all other variables are as defined in Embodiment E1.

[0088] A sixty-second embodiment (Embodiment E62) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiments E34-E58, M is HetB, and all other variables are as defined in Embodiment E1.

[0089] A sixty-third Embodiment (Embodiment E63) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiments E34-E58, M is AriB, and all other variables are as defined in Embodiment E1.

[0090] A sixty-fourth Embodiment (Embodiment E64) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiments E34-E58, M is -NR5, and all other variables are as defined in Embodiment E1.

[0091] A sixty-fifth embodiment (Embodiment E65) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is -OR5, and all other variables are as defined in Embodiment E1.

[0092] A sixty-sixth embodiment (Embodiment E66) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is -(CH2)nR5, and all other variables are as defined in Embodiment E1.

[0093] A sixty-sixth Embodiment (Embodiment E67) is a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiments E34-E58, M is -C(O)R5, and all other variables are as defined in Embodiment E1.

[0094] A sixty-eighth embodiment (Embodiment E68) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiments E34-E58, M is -CH(NH)R5, and all other variables are as defined in Embodiment E1.

[0095] A sixty-ninth embodiment (Embodiment E69) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiments E34-E58, M is -S(O)mR5, and all other variables are as defined in Embodiment E1.

[0096] A seventieth embodiment (Embodiment E70) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is -(CH2)3NH2, and all other variables are as defined in Embodiment E1.

[0097] A seventy-first embodiment (Embodiment E71) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiments E34-E58, M is -(CH2)1-2HetB, and all other variables are as defined in Embodiment E1.

[0098] A seventy-second embodiment (Embodiment E72) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is -CH2AriB, and all other variables are as defined in Embodiment E1.

[0099] A seventy-third embodiment (Embodiment E73) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is defined in any of Embodiment E59-E72, Rx and Rz are methyl, and all other variables are as defined in Embodiment E1.

[00100] A seventy-fourth Embodiment (Embodiment E74) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is defined in any of Embodiment E59-E72, Rx is hydrogen and Rz is methyl, and all other variables are as defined in Embodiment Achievement E1.

[00101] A seventy-fifth embodiment (Embodiment E75) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiment E34-E58, M is defined in any of Embodiment E59-E72, one of Rx and Rz is SCH3, and all other variables are as defined in Embodiment E1.

[00102] A seventy-sixth embodiment (Embodiment E76) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is defined in any of Embodiment E59-E72, one of Rx and Rz is SC1-C3 alkyl, optionally substituted with one to seven fluorines, and all other variables are as defined in Embodiment E1.

[00103] A seventy-seventh Embodiment (Embodiment E77) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiments E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiments E6-E13, Y is defined in any of Embodiments E15-E19, A1 is defined in any of Embodiments E20-E25, Q is defined in any of Embodiments E26-E33, A2 is defined in any of Embodiments E34-E58, M is defined in any of Embodiments E59-E72, one of Rx and Rz is SCH3, optionally substituted with one to three fluorines and all other variables are as defined in Embodiment E1.

[00104] A seventy-eighth embodiment (Embodiment E78) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is defined in any of Embodiment E59-E72, one of Rx and Rz is C1-C3 alkyl, optionally substituted with one to seven fluorines, and all other variables are as defined in Embodiment E1.

[00105] A seventy-ninth embodiment (Embodiment E79) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is defined in any of Embodiment E59-E72, one of Rx and Rz is - (C1-C3 alkylene)nOC1-C3 alkyl, optionally substituted with one to seven fluorines, and all other variables are as defined in Embodiment E1.

[00106] An eightieth embodiment (Embodiment E80) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is defined in any of Embodiment E59-E72, one of Rx and Rz is -(C1-C3 alkylene)nNC1-C3 alkyl, optionally substituted with one to seven fluorines, and all other variables are as defined in Embodiment E1.

[00107] An eighty-first embodiment (Embodiment E81) is a compound of Formula I, or pharmaceutically acceptable salt thereof, wherein W is defined in Embodiment E2 or E3, X is defined in any of Embodiment E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E, Z is defined in any of Embodiment E6-E13, Y is defined in any of Embodiment E15-E19, A1 is defined in any of Embodiment E20-E25, Q is defined in any of Embodiment E26-E33, A2 is defined in any of Embodiment E34-E58, M is defined in any of Embodiment E59-E72, Rx and Rz, together with the carbon to which they are attached, join to form a monocyclic C4-C7 cycloalkyl or a monocyclic C4-C7 heterocycloalkyl having 1, 2 or 3 heteroatom ring atom(s) independently selected from N, O and S, wherein said C4-C7 cycloalkyl and said C4-C7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from -F, -OH and -OC1-C3 alkyl; and all other variables are as defined in Embodiment E1.

[00108] An eighty-second embodiment (Embodiment E82) is a compound of Formula II-1, II-2, II-3, III-1, III-2, or III-3, or pharmaceutically acceptable salt thereof, wherein X is defined in any of Embodiments E1, E4, E5, E5-A, E5-B, E5-C, E5-D, or E5-E; A1 is defined in any of Embodiments E1, E20-E25; A2 is defined in any of Embodiments E1, E34-E58; M is defined in any of Embodiments E1, E59-E72; Rx and Rz are defined in any of Embodiments E1, E73-E81; Rb1, Rb2, and Rb3 are independently hydrogen, C1-Cs alkyl, C3-C7 cycloalkyl, -C(O)ORe, -C(O)NRcRd, tetrazolyl, oxadiazolonyl, HetA, AriA, -S(O)mRe, -S(O)mNRcRd, or -P(O)(Re)p, wherein said C1-C8 alkyl and said C3-C7 cycloalkyl are optionally substituted with one to three Ra; and all other variables are as defined in Embodiment E1.

[00109] An eighty-third Embodiment (Embodiment E83) is a compound of Formula II-1, II-2, II-3, III-1, III-2, or III-3, or a pharmaceutically acceptable salt thereof, wherein Rb1 and Rb2 are independently hydrogen, C1-C3 alkyl, tetrazolyl, oxadiazolonyl, or -C(O)ORe; and Rb3 is hydrogen, and all other variables are as defined in Embodiment E82.

[00110] An eighty-fourth embodiment (Embodiment E84) a compound having the structure: or a pharmaceutically acceptable salt thereof.

[00111] In an eighty-fifth embodiment, each occurrence of R4 is independently: -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, halogen, -ORe, -S(O)mRe, -S(O)mNRcRd, -C(O)Re, - c e c e c cd c e NR C(O)R , -NR C(U)UR , -NR C(U)NR R , -NR S(O)mR , =NH, —CF3, -OCF3, —OCHF2, -C3-C6 cycloalkyl, —O-C3-C6 cycloalkyl, -C1-C10 alkylene-C3-C6 cycloalkyl, -O-C1-C10 alkylene-C3-C6 cycloalkyl, HetB, -O- HetB, -C1-C10 alkylene-HetB, -O-C1-C10 alkylene-HetB, AriA, -O-AriA, -C1-C10 alkylene-AriA or -O-C1-C10 alkylene-AriA, wherein each R4 is unsubstituted or substituted with one to four substituents selected from halogen, -C1-C6 alkyl and -(CH2)nNRcRd .

[00112] In an eighty-sixth embodiment, R5 is C2-C10 alkyl, C3-C7 cycloalkyl, C1-C6 alkyl-C3-C7 cycloalkyl, HetB, AriB, or -NH(C1-C6 alkyl), wherein said C1-C6 alkyl, C2-C10 alkyl, and said C3-C7 cycloalkyl are optionally substituted with one to four R6.

[00113] Reference to different embodiments with respect to compounds of Formula I specifically includes different embodiments of Formula II and Formula III such as Formula II-1, II-2, II-3, III-1, III-2 and III-3, sub-embodiments of Formula I, II-1, II-2, II-3, III-1, III-2 and III-3, other embodiments provided herein, and individual compounds described herein.

[00114] Other embodiments of the present invention include the following: (a) A pharmaceutical composition comprising an effective amount of a compound of Formula I, II-1, II-2, II-3, III-1, III-2 or III-3, as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[00115] (b) The pharmaceutical composition of (a), further comprising a second compound, wherein the second compound is a beta-lactamase inhibitor.

[00116] (c) The pharmaceutical composition of (b), wherein the second compound is selected from the group consisting of: relebactam, tazobactam, clavulanic acid, sulbactam and avibactam.

[00117] (d) A pharmaceutical composition comprising (i) a compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3, or pharmaceutically acceptable salt thereof, and (ii) a second compound, wherein the second compound is a beta-lactamase inhibiting compound, wherein the compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3, and the second compound are each used in an amount that makes the combination effective to treat or prevent bacterial infection.

[00118] (e) The combination of (d), wherein the second compound is selected from the group consisting of: relebactam, tazobactam, clavulanic acid, sulbactam and avibactam.

[00119] (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, II-1, II-2, II-3, III-1, III-2, or III-3, or a pharmaceutically acceptable salt thereof.

[00120] (g) A method of 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, II-1, II-2, II-3, III-1, III2, and III-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[00121] (h) A method of treating a bacterial infection comprising administering to a subject in need of such treatment a therapeutically effective amount of the composition of (a), (b), (c), (d) or (e).

[00122] (i) The method of treating a bacterial infection as set forth in (f), (g), or (h), wherein the bacterial infection is due to Gram-negative bacteria.

[00123] (j) The method of treating a bacterial infection as set forth in (f), (g), (h), or (i), wherein the bacterial infection is due to Pseudomonas aeruginosa or Acinetobacter baumannii.

[00124] The present invention also includes a compound of Formula I, II-1, II-2, II-3, III-1, III-2 or III-3, or a pharmaceutically acceptable salt thereof, (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation (or manufacture) of a medicament for, medicine or treatment of bacterial infection, including infection with a multidrug resistant bacterial strain. In these uses, the compounds of the present invention may optionally be employed in combination with one or more second therapeutic agents including relebactam, tazobactam, clavulanic acid, sulbactam and avibactam.

[00125] Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(j) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the following embodiments, sub-embodiments, classes or subclasses described above. The compound may optionally be used in the form of a pharmaceutically acceptable salt in these embodiments.

[00126] In the embodiments of the compounds and salts provided above, it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such combination provides a stable compound or salt consistent with the description of the embodiment. It is further to be understood that the embodiments of the compositions and methods provided as (a) through (j) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as a result of combinations of embodiments.

[00127] Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein the compound of the present invention or the salt thereof employed therein is substantially pure. With respect to a pharmaceutical composition comprising a compound of Formula I, II-1, II-2, II-3, III-1, III-2 or III-3 or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term “substantially pure” refers to a compound of Formula I, II-1, II-2, II-3, III-1, III-2 or III-3 or its salt per se; that is, the purity of this active ingredient in the composition. Definitions and Abbreviations

[00128] The terms used herein have their ordinary meaning and the meaning of such terms is independent in each occurrence thereof. Notwithstanding this and unless otherwise indicated, the following definitions apply throughout the specification and claims. Chemical names, common names and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using a chemical structure and a chemical name and there is an ambiguity between the structure and the name, the structure predominates. These definitions apply regardless of whether a term is used alone or in combination with other terms, unless otherwise indicated. Thus, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “hydroxyalkyl”, “haloalkyl”, “-O-alkyl”, etc.

[00129] As used herein and throughout this description, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[00130] The term “β-lactamase inhibitor” refers to a compound that is capable of inhibiting the enzymatic activity of β-lactamases. As used herein, inhibiting β-lactamase activity means inhibiting the activity of a class A, C, and/or D β-lactamase. For antimicrobial applications inhibition at a 50% inhibitory concentration is preferably achieved at or below about 100 micrograms/mL, or below about 50 micrograms/mL, or below about 25 micrograms/mL. The terms “class A”, “class B”, “class C” and “class D” β-lactamases are understood by those skilled in the art and are described in S. G. Waley, β-lactamase: mechanisms of action, in The Chemistry of β-Lactams, M. I. Page, Ed.; Chapman and Hall, London, (1992) 198-228.

[00131] The term “metallo-β-lactamase” denotes a metalloprotein capable of inactivating an β-lactam antibiotic. The β-lactamase may be an enzyme that catalyzes the hydrolysis of the β-lactam ring of a β-lactam antibiotic. Of particular interest here are microbial metallo-β-lactamases. The metallo-β-lactamase may be, for example, a zinc metallo-β-lactamase. Lactamases of interest include those described in, for example, S. G. Waley, β-lactamase: mechanisms of action, in The Chemistry of β-Lactams, M. I. Page, Ed.; Chapman and Hall, London, (1992) 198-228. β-Lactamases of particular interest include the metallo-β-lactamases from Escherichia coli (such as New Delhi Metallo-β-lactamase, NDM), Serratia marcescens (such as IMP), and Klebsiella spp. (such as Verona integron-encoded metallo-β-lactamase, VIM). Additional metallo-β-lactamases of interest include the SPM, GIM, SIM, KHM, AIM, DIM, SMB, TMB, and FIM-type enzymes.

[00132] The term “antibiotic” refers to a compound or composition that decreases the viability of a microorganism, or that inhibits the growth or proliferation of a microorganism. The phrase “inhibits growth or proliferation” means increasing the generation time (i.e., the time required for the bacterial cell to divide or for the population to double) by at least about 2-fold. Preferred antibiotics are those that can increase the generation time by at least about 10-fold or more (e.g., at least about 100-fold or even indefinitely, as in total cell death). As used in this description, an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent. Examples of antibiotics include penicillins, cephalosporins, and carbapenems.

[00133] The term “β-Lactam antibiotic” refers to a compound with antibiotic properties that contains a β-Lactam functionality. Non-limiting examples of β-lactam antibiotics include penicillins, cephalosporins, penems, carbapenems, and monobactams.

[00134] The term “about,” when modifying the amount (e.g., kg, L, or equivalents) of a substance or composition, or the value of a physical property, or the value of a parameter characterizing a process step (e.g., the temperature at which a process step is conducted), or the like, refers to the variation in numerical quantity that may occur, for example, through typical measuring, handling, and sampling procedures involved in the preparation, characterization, and/or use of the substance or composition; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make or use the compositions or perform the procedures; and the like. In certain embodiments, “about” may 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 from the appropriate unit. In certain embodiments, “about” may mean a range of ±1%, 2%, 3%, 4%, 5%, 10%, or 20%.

[00135] Another embodiment of the present invention is a compound of Formula I, II-1, II-2, II-3, III-1, III-2 or III-3, or a pharmaceutically acceptable salt thereof, as originally defined or as defined in any of the preceding embodiments, sub-embodiments, aspects, classes or subclasses, wherein the compound or its salt is in a substantially pure form. As used herein “substantially pure” suitably means at least about 60 wt %, typically at least about 70 wt %, preferably at least about 80 wt %, more preferably at least about 90 wt % (e.g., 90 wt % to about 99 wt %), still more preferably at least about 95 wt % (e.g., from about 95 wt % to about 99 wt %, or from about 98 wt % to 100 wt %), and most preferably at least about 99 wt % (e.g., 100 wt %) of a product containing a compound of Formula I, II-1, II-2, II-3, III-1, III-2, or III-3 or its salt (e.g., the product isolated from a reaction mixture providing the compound or salt) consists of the compound or salt. The purity level of compounds and salts can be determined using a standard method of analysis such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and/or mass spectrometry. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level of purity determined, then the method that provides the highest level of purity governs. A compound or salt of 100% purity is one that is free of detectable impurities, as determined by a standard method of analysis.

[00136] With respect to a compound of the invention that has one or more asymmetric centers and can occur as mixtures of stereoisomers, a substantially pure compound can be a substantially pure mixture of the stereoisomers or a substantially pure individual diastereoisomer or enantiomer, unless expressly described otherwise. The present invention encompasses all stereoisomeric forms of the compounds of Formulas I, II-1, II-2, II-3, III-1, III-2, and III-3. Unless a specific stereochemistry is indicated, the present invention is intended to encompass all such isomeric forms of these compounds. Centers of asymmetry that are present in the compounds of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3 may, independently of one another, have either the (R) or (S) configuration. When bonds to the chiral carbon are represented as straight lines in the structural formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof, are encompassed within the formula. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore individual enantiomers and mixtures thereof, are encompassed by the name. The production of specific stereoisomers or mixtures thereof can be identified 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 this invention.

[00137] The invention includes all possible enantiomers and diastereoisomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereoisomers, in all ratios. Thus, the enantiomers are a subject of the invention in enantiomerically pure form, as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis/trans isomerism, the invention includes the cis form and the trans form as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally, a derivatization may be performed prior to a separation of stereoisomers. The separation of a mixture of stereoisomers may be performed at an intermediate step during the synthesis of a compound of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3 or this may be done on a final racemic product. The absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. When the compounds of this invention are capable of tautomerization, all individual tautomers, as well as mixtures thereof, are included within the scope of this invention. Unless a particular isomer, salt, solvate (including hydrates) or solvated salt of such a racemate, enantiomer, diastereoisomer or tautomer is indicated, the present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereoisomers and tautomers and mixtures thereof.

[00138] “Ac” is acetyl, which is CH3C(=O)-.

[00139] “Alkyl” means saturated carbon chains which may be straight or branched, or combinations thereof, unless the carbon chain is otherwise defined. Other groups having the prefix “alk”, such as alkoxy and alkanoyl, may also be straight or branched, or combinations thereof, unless the carbon chain is otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

[00140] “Alkylene,” as used herein, refers to an alkyl group, as defined above, in which one of the hydrogen atoms of the alkyl group has been replaced with a bond. Non-limiting examples of alkylene groups include -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH(CH3)-, and - CH2CH(CH3)CH2-. In one embodiment, an alkylene group has from 1 to about 6 carbon atoms. In one embodiment, an alkylene group has from 1 to about 3 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is -CH2-. The term "C1-C6 alkylene" refers to an alkylene group having 1 to 6 carbon atoms.

[00141] “Alkenyl” means carbon chains that contain at least one carbon-carbon double bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

[00142] “Alkynyl” means carbon chains that contain at least one carbon-carbon triple bond, and which may be straight or branched, or combinations thereof, unless otherwise defined. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like.

[00143] “Aromatic ring system” or “aromatic” in reference to a ring means a monocyclic, bicyclic or tricyclic aromatic ring or ring system containing 5-14 ring atoms, in which at least one of the rings is aromatic. The term may be used to describe a saturated or monounsaturated carbocyclic ring fused to an aryl group. For example, a 5-7 membered cycloalkyl may be fused through two adjacent ring atoms to a 5-6 membered heteroaryl containing 1, 2 or 3 ring heteroatoms selected from N, O and S. In another example, a heteromonocyclic ring is fused through two ring atoms to a 5-6 membered phenyl or heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S. In the case of a heteromonocyclic ring containing one or more N atoms, the N may be in the form of a quaternary amine. In certain embodiments, a ring N atom may be in the form of an N-oxide.

[00144] “Aryl” means a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring containing 6-14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl and naphthyl. In one embodiment of the present invention, aryl is phenyl.

[00145] “Cycloalkyl” means a saturated monocyclic, bicyclic or bridged carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl and the like. In one embodiment of the present invention, the cycloalkyl is selected from: cyclopropane, cyclobutane, cyclopentane and cyclohexane.

[00146] “Cycloalkenyl” means a non-aromatic monocyclic or bicyclic carbocyclic ring containing at least one double bond. Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooxtenyl, and the like.

[00147] The term "heterocycloalkyl", as used herein, refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 11 ring atoms, wherein from 1 to 4 of the ring atoms are independently N, NH, S (including SO and SO2), and O, and the remaining ring atoms are carbon atoms. A heterocycloalkyl group may be attached through a ring carbon atom or ring nitrogen (if present). Where the ring or ring system contains one or more N atoms, the N may be in the quaternary amine form. In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic of from about 4 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 7 to about 11 ring atoms. When a heterocycloalkyl contains two rings, the rings may be fused or spirocyclic. In a further embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any -NH group in a heterocycloalkyl ring may exist protected, such as, for example, as a -N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention. A heterocycloalkyl group may be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein below. The nitrogen or sulfur atom of the heterocycloalkyl (if present) may be optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-oxide. Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, delta-lactam, delta-lactone, silacyclopentane, silapyrrolidine, and the like, and all isomers thereof.

[00148] “Drug-resistant” means, in connection with a Gram-negative bacterial strain, a strain that is no longer susceptible to at least one previously effective drug; that has developed the ability to resist antibiotic attack by at least one previously effective drug. “Multi-drug-resistant” means a strain that is no longer susceptible to two or more previously effective drugs; that has developed the ability to resist antibiotic attack by two or more previously effective drugs. A drug-resistant strain may pass on this ability to support its progeny. Such resistance may be due to random genetic mutations in the bacterial cell that alter its sensitivity to a single drug or to different drugs.

[00149] “Heterocycloalkenyl” means a non-aromatic monocyclic, bicyclic or bridged carbocyclic ring or ring system containing at least one double bond and containing at least one heteroatom selected from N, NH, S and O.

[00150] “Heteroaryl” means a monocyclic, bicyclic or tricyclic ring or ring containing 5-14 carbon atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO2) and O, wherein at least one of the ring heteroatoms is aromatic. In the case of a heteroaryl ring system wherein one or more of the rings are saturated and contain one or more N atoms, the N may be in the quaternary amine form. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is bicyclic. A heteroaryl group may be optionally substituted with one or more ring system substituents which may be the same or different. Any nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. The term "heteroaryl" also encompasses a heteroaryl group, as defined above, that is fused to a benzene ring. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzothiophenyl (including S-oxide and di-oxide), benzotriazolyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like. In one embodiment of the present invention, heteroaryl is selected from: pyridine, pyrimidine, thiazole, benzimidazole, benzothiazole, benzoxazole, and benzisoxazole. In another embodiment of the present invention, heteroaryl is pyridine. Examples of bicyclic rings include:

[00151] “Heterocycle” means a saturated, partially unsaturated or unsaturated monocyclic or bicyclic ring system containing 510 atoms and containing at least one ring heteroatom selected from N, S and O. In selected embodiments, the ring system contains 1-4 heteroatoms selected from N, S and O. When a heterocycle contains two rings, the rings may be fused, bridged or spirocyclic. Examples of monocyclic heterocyclic rings include piperazine, piperidine and morpholine. Examples of bicyclic heterocyclic rings include 1,4-diazabicyclo[2,2,2]octane and 2,6-diazaspiroheptane.

[00152] “Halogen” includes fluorine, chlorine, bromine and iodine.

[00153] “Oxo means an oxygen atom connected to another atom by a double bond and can be represented “=O”.

[00154] When any variable (e.g., R1, ra, etc.) occurs more than once in any constituent or in Formula I, II-1, II-2, II-3, III-1, III-2, or III-3, its definition in each occurrence is independent of its definition in all other occurrences. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A wavy line through a bond in a substituent variable represents the point of bonding.

[00155] A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be left 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, II-1, II-2, II-3, III-1, III-2, and III-3.

[00156] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described last, preceded by the adjacent functionality toward the point of attachment.

[00157] In choosing the compounds of the present invention, one skilled in the art will recognize that the various substituents, i.e., R1, R2, etc., should be chosen in accordance with well-known principles of connectivity and stability of the chemical structure.

[00158] The term “substituted” should be taken to include varying degrees of substitution by a named substituent. Where multiple substituent groups are described or claimed, the substituted compound may be independently substituted with one or more of the described or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents may be the same or different. Where a group, e.g., C1-C8 alkyl, is indicated as being substituted, such substitutions may also occur where such group is part of a larger substituent, e.g., -C1-C6 alkyl-C3-C7 cycloalkyl and -C1-C8 alkyl-aryl.

[00159] In the compounds of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3, the atoms may exhibit their natural isotopic abundances, 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 the atomic mass or mass number predominantly found in nature. It is intended that the present invention include all suitable isopic variations of the compounds of Formula I, II-1, II-2, II-3, III-1, III-2, and III-3. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H or D). Protium is the predominant isotope of hydrogen found in nature. Enrichment for deuterium may provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. The isotopically enriched compounds of Formulas I, II-1, II-2, II-3, III-1, III-2, and III-3 may be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically enriched reagents and/or intermediates.

[00160] Unless expressly stated otherwise in a particular context, any of the various rings and cyclic 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) so long as a stable compound results.

[00161] Unless expressly stated otherwise, all ranges recited herein are inclusive. For example, a heteroaromatic ring described as containing from “1 to 4 heteroatoms” means that the ring may contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range recited herein includes within its scope all subranges within that range. Thus, for example, a heterocyclic ring described as containing from “1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatom(s), 1 heteroatom, 2 heteroatoms, 3 heteroatoms and 4 heteroatoms. Similarly, C1-C6 when used with a chain, for example an alkyl chain, means that the chain can contain 1, 2, 3, 4, 5 or 6 carbon atoms. It also includes all ranges contained within, including C1-C5, C1-C4, C1-C3, C1-C5, C2-C6, C3-C6, C4-C6, C5-C6 and all other possible combinations.

[00162] It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, diagrams, examples and tables herein are assumed to have sufficient number of hydrogen atom(s) to satisfy the valences.

[00163] 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. Accordingly, the compounds of the invention may occur as mixtures of stereoisomers, or as individual diastereoisomers, or enantiomers. All isomeric forms of these compounds, individually or in mixtures, are within the scope of the present invention.

[00164] The term “compound” refers to the free compound and, to the extent that they are stable, any hydrate or solvate thereof. A hydrate is the compound complexed with water, and a solvate is the complex complexed with an organic solvent.

[00165] As indicated above, the compounds of the present invention may be employed in the form of pharmaceutically acceptable salts. It will be understood that, as used herein, the compounds of the present invention may also include pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or pharmaceutically acceptable salts thereof or in other synthetic manipulations.

[00166] The term “pharmaceutically acceptable salt” refers to a salt that possesses the efficacy of the parent compound and that is not biologically or otherwise undesirable (e.g., is not toxic or harmful to the recipient thereof). The term “pharmaceutically acceptable salt” refers to salts prepared from non-toxic pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed by the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of this invention that are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of base compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethylacetic, digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formic, fumarate, gluceptate, glycoheptanoate, gluconate, glutamate, glycerophosphate, glycolylearsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate/diphosphate, pimelic, phenylpropionic, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate and the like. Furthermore, when the compounds of the invention contain an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, cyclic amines, dicyclohexyl amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Also included are nitrogen-containing basic groups that can be quaternized with agents such as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; and diamyl sulfates, long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides such as benzyl and phenethyl bromides, and others.

[00167] These salts can be obtained by known methods, for example, by mixing a compound of the present invention with an equivalent amount and a solution containing a desired acid, base or the like, and then collecting the desired salt by filtration of the salt or distillation of the solvent. The compounds of the present invention and salts thereof can form solvates with a solvent such as water, ethanol or glycerol. The compounds of the present invention can form an acid addition salt and a salt with a base at the same time, according to the type of side chain substituent.

[00168] The compound of the invention may also be employed in the form of a prodrug. Any prodrug precursor known in the art may be used to form a prodrug of the invention. In certain aspects of this embodiment, the hydrogen at -COOH in formula I may be substituted with any of the following groups: C1-6 alkyl, C3-6 cycloalkyl, -C1-6 alkyl-C3-6 cycloalkyl, C3-7 cycloalkyl, -C1-6 alkylene-C3-7 cycloalcycloalkyl, aryl, -C1-10 alkylene-aryl, heteroaryl, and -C1-10 alkylene-heteroaryl. In certain aspects of this embodiment, the C1-6 cycloalkyl, C3-6 cycloalkyl, or C3-7 cycloalkyl may be substituted. In other aspects of this embodiment, each aryl and heteroaryl may be substituted.

[00169] As set forth above, the present invention includes pharmaceutical compositions comprising a compound of Formula I of the present invention, optionally another active component (e.g., a β-lactamase inhibitor), and a pharmaceutically acceptable carrier. The characteristics of the carrier will depend on the route of administration. By “pharmaceutically acceptable” it is meant that the ingredients of the pharmaceutical composition must be compatible with each other, do not interfere with the efficacy of the active ingredient(s), and are not harmful (e.g., toxic) to the recipient thereof. Thus, the compositions according to the invention may, in addition to the inhibitor, contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.

[00170] Also as set forth 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, II-1, II-2, II-3, III-1, III-2 and III-3, or a pharmaceutically acceptable salt thereof, optionally in combination with a β-Lactamase inhibitor. The term “subject” (or alternatively “patient”) as used herein refers to an animal, preferably a mammal, more preferably a human, who has been the subject of treatment, observation or experiment. The term “administration” and variants thereof (e.g., “administering” a compound) in reference to a compound of Formula I, II-1, II-2, II-3, III-1, III-2 and III-3 means providing the compound, or a pharmaceutically acceptable salt thereof, to the subject 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 its variants are understood to include the provision of the compound or its salt and the other agents at the same time or at different times. When the agents of a combination are administered at the same time, they may be administered together in a single composition or they may be administered separately. It is understood that a “combination” of active agents may be a single composition containing all of the active agents or multiple compositions containing each one or more of the active agents. In the case of two active agents, a combination may be a composition comprising one of the agents or two separate compositions each comprising one of the agents; in the case of three active agents, a combination may be a single composition comprising all three agents, three separate compositions each comprising one of the agents, or two compositions, one of which comprises two of the agents and the other comprising the third agent; and so on.

[00171] The compositions and combinations of the present invention are suitably administered in effective amounts. The term “effective amount,” as used herein, means the amount of active compound sufficient to inhibit bacterial growth and thereby induce the response to be sought (i.e., an “effective inhibiting amount”) in a cell, tissue, system, animal or human. In one embodiment, the effective amount is a “therapeutically effective amount” for the alleviation of the symptoms of the disease or condition to be treated (e.g., the cure of conditions associated with bacterial infection and/or bacterial drug resistance). In another embodiment, the effective amount is a “prophylactically effective amount” for the prophylaxis of the symptoms of the disease or condition to be prevented. When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound.

[00172] Administration of a composition of the present invention is suitably parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intraocular, or intrarectal, wherein the composition is suitably formulated for administration by the selected route using formulation methods well known in the art, including, for example, the methods for preparing and administering formulations described in Chapters 39, 41, 42, 44, and 45 in Remington - The Science and Practice of Pharmacy, 21st edition, 2006. In one embodiment, the compounds of the invention are administered intravenously in a hospital setting. In another embodiment, administration is oral in the form of a tablet or capsule or the like. When administered systemically, a therapeutic composition is, for example, suitably administered in a dosage sufficient to achieve a blood level of inhibitor of at least about 1 microgram/mL, and in a further embodiment at least about 10 micrograms/mL, and at least about 25 micrograms/mL. For localized administration, much lower concentrations than these may be effective, and much higher concentrations may be tolerated.

[00173] Intravenous administration of a compound of the invention may be accomplished by reconstituting a powder form of the compound with an acceptable solvent. Suitable solvents include, for example, saline solutions (e.g., 0.9% Sodium Chloride Injection) and sterile water (e.g., Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol). The powder form of the compound may be obtained by gamma irradiation of the compound or by lyophilization of a solution of the compound, after which the powder may be stored (e.g., in a sealed vial) at or below room temperature until reconstituted. The concentration of the compound in the reconstituted IV solution may be, for example, in a range of about 0.1 mg/mL to about 20 mg/mL.

[00174] The present invention also includes a method of inhibiting bacterial growth comprising administering to a bacterial cell culture, or to a bacterially infected cell culture, tissue or organism, an effective inhibiting amount of a compound of Formula I, II-1, II-2, II-3, III-1, III-2 and III-3. Additional embodiments of the invention include the method of inhibiting bacterial growth just described, wherein the compound of the present invention employed therein is a compound of one of the embodiments, sub-embodiments or classes described above. The compound may optionally be used in the form of a pharmaceutically acceptable salt in these embodiments. The method may involve administering a compound of Formula I, II-1, II-2, II-3, III-1, III-2 and III-3 to an in vitro experimental cell culture to prevent the growth of β-Lactam resistant bacteria. The method may alternatively involve administering a compound of Formula I to an animal, including a human, to prevent the growth of β-Lactam resistant bacteria in vivo. In such cases, the compound of Formula I, II1, II-2, II-3, III-1, III-2 and III-3 is typically co-administered with a β-lactamase inhibitor.

[00175] The methods of the subject matter herein described are useful for treating these conditions in that they inhibit the onset, growth or spread of the condition, cause regression of the condition, cure the condition or otherwise improve the general well-being of an individual afflicted with, or at risk of contracting, the condition. Thus, in accordance with the subject matter herein described, the terms “treat”, “treating”, and grammatical variations thereof, as well as the phrase “method of treatment”, are intended to encompass any desired therapeutic intervention, including but not limited to, a method for treating an existing infection in an individual, and a method for the prophylaxis (i.e., prevention) of infection, such as in an individual who has been exposed to a microbe as described herein or who has a microbe as described herein.

[00176] The compounds of the invention can be used for the treatment, prophylaxis or inhibition of bacterial growth or infections due to bacteria that are resistant to β-lactam antibiotics. More particularly, the bacteria can be metallo-β-lactamase positive strains that are highly resistant to β-lactam antibiotics. The terms “mildly resistant” and “highly resistant” are well understood by those skilled in the art (see, for example, Payne et al., Antimicrobial Agents and Chemotherapy 38:767-772 (1994); Hanaki et al., Antimicrobial Agents and Chemotherapy 30:11.20-11.26 (1995)). For the purposes of this invention, bacterial strains that are highly resistant to imipenem are those against which the MIC of imipenem is >16 μg/mL, and bacterial strains that are slightly resistant to imipenem are those against which the MIC of imipenem is >4 μg/mL.

[00177] The compounds of the invention may be used in combination with a β-lactamase inhibitor for the treatment of infections caused by β-lactamase producing strains, in addition to those infections that are subsumed within the antibacterial spectrum of the antibiotic agent. Examples of β-lactamase producing bacteria are Pseudomonas aeruginosa, Pseudomonas putida, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Serratia marcescens, Enterobacter aerogenes, Enterobacter asburiae, Citrobacter freundii, Proteus mirabilis, Morganella morganii, Providencia rettgeri, Stenotrophomonas maltophilia and Acinetobacter baumannii.

[00178] It is generally advantageous to use a compound of Formula I, II1, II-2, II-3, III-1, III-2, and III-3 in admixture or conjunction with a β-lactamase inhibitor, or a prodrug thereof. It is advantageous to use a compound of Formula I in combination with a Class A and C β-lactamase inhibitor because of the β-lactamase resistant properties of the compounds. It is also advantageous to use a compound of Formula I in combination with one or more Class A, C, or D β-lactamase inhibitors to further limit susceptibility to β-lactams. As already noted, the compound of Formula I and the β-lactamase inhibitor may be administered separately (at the same time or at different times) or in the form of a single composition containing both active ingredients.

[00179] Relebactam, tazobactam, clavulonic acid, sulbactam, avibactam and other β-lactamase and metallo β-lactamase inhibitors suitable for use in the present invention include those known to exhibit inhibitory activity for β-lactamases.

[00180] Abbreviations used herein include the following: aq. = aqueous; ACN = acetonitrile; BLI = β-lactamase inhibitor; Bn = benzyl; BOC (or Boc) = t-butyloxycarbonyl; BOC2O = di-tert-butyl dicarbonate; CAN = ceric ammonium nitrate; CBZ (or Cbz) = carbobenzoxy (alternatively, benzyloxycarbonyl); CDCl3 = deuterated chloroform; CH3CN = acetonitrile; Co-Catalyst = (R,R’)-N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanedialminocobalt(III) 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-olate; cv = column volume; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC = dicyclohexylcarbodiimide; DCE = dichloroethane; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIAD = diisopropyl azodicarboxylate; DIPEA = diisopropylethylamine; DMA = dimethylacetamide; DMAP = 4-dimethylaminopyridine or N,N-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; eq. or equiv. = equivalent(s); Et = ethyl; Et3N = triethyl amine; Et2O = ethylene oxide; EA or EtOAc = ethyl acetate; EtOH = ethanol; g = gram(s); h or hr = hour; hex = hexane; HiVac = high vacuum; HMDS = hexamethyldisilazide; HOBT = 1-hydroxy benzotriazole; HPLC = high-performance liquid chromatography; IPA = isopropyl alcohol; iPrMgCl = isopropyl magnesium chloride; IPAc = isopropyl acetate; L or l = liter(s); LC/MS or LC-MS = liquid chromatography/mass spectrometry; LDA = lithium diisopropylamide; min = minute(s); mg = milligram(s); ml or ML = milliliter(s); m-CPBA = m-chloroperoxybenzoic acid; MBL = metallo-β-lactamase; Me = methyl; MeCN = acetonitrile; MeOH = methanol; MeI = methyl iodide; MITC = minimum inhibitory threshold concentration; MOPS = 3-(N-morpholino)propanesulfonic acid; MPLC = medium pressure liquid chromatography; MTBE = methyl-tert-butyl ether; NBS = N-bromosuccinimide; NCS = N-chlorosuccinimide; NMR = nuclear magnetic resonance; MS = mass spectrometry; MW = molecular weight; Pd/c = palladium on carbon; PdCl2 (dppf) = [1,2´-bis(diphenylphosphino)ferrocene]dichloropalladium(II); di-t-BuDPPF-PdCl2 = 1,1´-bis(di-tert-butylphosphino)ferrocenepalladium dichloride; PE = petroleum ether; PG = protecting group; Ph = phenyl; PPTS = pyridinium p-toluenesulfonate; RP-HPLC = reversed-phase high-performance liquid chromatography; ta or TA = room temperature; satd = saturated; tBu = tert-butyl; TBAI = tetrabutylammonium iodide; TBAF = tetrabutylammonium fluoride; TBS = tert-butyldimethylsilyl; TBS-Cl = tert-butyldimethylsilyl chloride; TBDMS-Cl = tert-butyldimethylsilyl chloride; t-BuOH = tert-butanol; TBSO = tert-butyldimethylsilyl; TEA = triethylamine; TEMPO is (2,2,6,6-tetramethylpiperidin-1-yl)oyl; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TMS = trimethylsilyl; TMS-Cl = trimethylsilyl chloride; TMS-I = trimethylsilyl iodide; and TMS-N3 = trimethylsilyl azide. Methods for preparing compounds of formula (I):

[00181] The compounds described 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 synthetic procedures. In these reactions, use can also be made of variations that are themselves known to those skilled in the art but are not discussed in greater detail herein. In addition, other methods for preparing the compounds described herein will be readily apparent to one skilled in the art in light of the following reaction scheme and Examples. Unless otherwise indicated, all variables are as defined above. Scheme 1

[00182] The β-lactam intermediate can be purchased from commercial sources or synthesized following the scheme below, which shows the synthesis of β-lactam analogues in which Rx and Rz join to form a 4-membered spirocyclic ring. The synthetic scheme has been discussed in detail in the literature. (See EP 0229012). This amine can be converted to the final monobactam compounds with a similar procedure demonstrated in the following Examples. INTERMEDIATE 1 tert-Butyl oxirane-2-carboxylate

[00183] To a 1 L 2-necked round bottom flask equipped with a condenser, a solution of tert-butyl acrylate (20 g, 156 mmol) in DCM (200 mL) was added portionwise to m-CPBA (48.5 g, 281 mmol). The resulting solution was heated to 58-60 °C with an oil bath and refluxed for 2 and a half days. The mixture was then cooled to room temperature, to which saturated sodium thiosulfate solution (approximately 40 mL, exothermic, added in small portions until no more heat was generated) was added. After stirring for approximately 1 hour, a large amount of precipitate occurred. Approximately 60-100 mL of water and 100-200 mL of DCM were added to dissipate the emulsion and generate a two-phase system. The aqueous phase was separated, and the organic phase was washed with saturated NaHCO3 (2x200 mL) and brine (100 mL), dried over MgSO4, and concentrated to dryness (35 °C water bath temperature). The solid was suspended in 150 mL of hexane and allowed to stand at room temperature for 1 h. The mixture was then filtered, and the filtrate was concentrated to remove the hexane on a rotavapor (<35 °C) to give the title compound. 1H NMR (500 MHz, CDCl3) δ 3.35 (m, 1H), 2.86 (m, 2H), 1.52 (s, 9H). INTERMEDIATE 2 (R,R)-Co Catalyst

[00184] Reference: J. Am. Chem. Soc. 1999, 121, 6086-6087. To a solution of perfluoro-tert-butanol (1.96 g, 8.28 mmol) in DCM (97 mL) was added (R,R)-(-)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) (5 g, 8.28 mmol). The solution was then stirred at 30 °C for 45 min open to air. The reaction was then concentrated, HiVac dried to afford the title compound. INTERMEDIATE 3 (R)-3-(4-bromophenoxy)-2-hydroxypropanoate tert-Butyl

[00185] To the mixture of 4-bromophenol (2 g, 11.56 mmol), molecular sieves 4Â (4 g), and tert-butyl oxirane-2-carboxylate (3.67 g, 25.4 mmol) was added tert-butyl methyl ether (50 mL) and (R,R)-Co catalyst (0.97 g, 1.15 mmol) under N2. The resulting suspension was stirred at room temperature under N2 over the weekend. LC-MS indicated about 60% conversion. Additional epoxide intermediate 1 (0.5 g) and Co catalyst (100 mg) were added and stirred overnight. LC-MS indicated about 80% conversion. Additional epoxide (0.5 g) and catalyst (100 mg) were added and stirred overnight. The mixture was worked up by filtration, and the residue was washed with EtOAc. The filtrate was concentrated, and the residue was purified on a silica gel column (240 g) using 0100% EtOAc/Hex to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J=7.2 Hz, 2H), 6.83 (d, J=7.2 Hz, 2H). 4.45 (m, 1H), 4.28 (m, 2H), 1.52 (s, 9H). INTERMEDIATE 4 tert-Butyl (R)-2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate

[00186] To a solution of (R)-tert-butyl 3-(4-bromophenoxy)-2-hydroxypropanoate (1.95 g, 6.15 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.342 g, 9.22 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (0.309 g, 0.378 mmol) in 1,4-dioxane (22 mL) was added potassium acetate (1.81 g, 18.4 mmol). The mixture was degassed and recharged with nitrogen and heated at 85 °C overnight. The mixture was filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography over silica gel (120 g) and eluted with hexane/EtOAc (0-50%) to obtain the title compound. LC-MS [M + H + Na]: m/z 387.00. 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J=7.2 Hz, 2H), 6.82 (d, J=7.2 Hz, 2H). 4.33 (m, 1H), 4.16 (m, 2H), 1.41 (s, 9H), 1.29 (s, 12H). INTERMEDIATE 5 2-(2-((tert-Butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid

[00187] Step A: Ethyl 2-(2-((tert-Butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetate: To a solution of ethyl 2-(2-aminothiazol-4-yl)-2-oxoacetate (10 g, 49.9 mmol) in acetonitrile (250 mL) was added BOC-anhydride (23.2 mL, 100 mmol) followed by N,N,N',N'-tetramethyl-ethylenediamine (9.80 mL, 64.9 mmol). The mixture was stirred at room temperature for 3 h. The solvent was removed, and the residue was partitioned between EtOAc and 1N HCl. The organic layer was washed with NaHCO3 (saturated aqueous solution), brine, dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (flash 220 g), eluted with EtOAc/hexane (0-30%, 5 hp; 30%, 10 hp) to afford the title compound. Step B: 2-(2-((tert-Butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid

[00188] Ethyl 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetate (10.2 g, 34.1 mmol) was dissolved in THF (140 mL)/MeOH (50 mL) and sodium hydroxide (68.3 mL, 68.3 mmol, 1M) was added. The solution was stirred at room temperature for 4 h. The reaction mixture was poured into water (1 L) and extracted with EtOAc (3 × 200 mL). The aqueous layer was acidified with HCl solution (1 N) and re-extracted with EtOAc (3 × 200 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford the title compound. LC-MS [M + H] +: m/z 273. 1H NMR (500 MHz, CDCl3) δ 8.35 (s,1H), 1.55 (s, 9H). INTERMEDIATE 6 2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoacetic acid

[00189] To a suspension of 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (intermediate 5) (1 g, 3.67 mmol) in DMF (10.0 mL) was added NCS (0.589 g, 4.41 mmol). The mixture was heated at 50 °C overnight. It was then diluted with EtOAc (100 mL), washed with water (3 x 30 mL) and brine. The organic layer was dried over Na2SO4. The solvent was removed in vacuo to afford the title compound. LC-MS [M + H]+: m/z 307. INTERMEDIATE 7 2-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid

[00190] Step A: tert-Butyl (3-methyl-1,2,4-thiadiazol-5-yl)carbamate To a 5-L 4-neck round bottom flask loop purged and maintained with an inert nitrogen atmosphere were placed 3-methyl-1,2,4-thiadiazol-5-amine (167 g, 1.45 mol, 1.00 equiv), 4-dimethylaminopyridine (17.7 g, 144.88 mmol, 0.10 equiv), di- tert-butyl dicarbonate (348 g, 1.59 mol, 1.10 equiv), and butan-1-ol (1670 mL). The resulting solution was stirred for 1 h at 40 °C. The resulting mixture was concentrated in vacuo. The residue was washed with hexane. This afforded the title compound. Step B: 2-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)acetic acid

[00191] In a 5000 mL 4-necked round bottom flask, purged and maintained with an inert nitrogen atmosphere, was placed a solution of N-(3-methyl-1,2,4-thiadiazol-5-yl) tert-butyl carbamate (128 g, 595 mmol, 1.00 equiv) in tetrahydrofuran (640 mL). The resulting solution was stirred at -78°C, LDA (1190.69 mL, 4.00 equiv) was added. 30 min later, CO2 (g) was introduced over 30 min at -30°C. The reaction was then quenched by the addition of 1280 mL of water. The resulting solution was extracted with 640 mL of ethyl acetate, and the aqueous layers were combined. The pH of the solution was adjusted to 2 with HCl (2M mol/L). The resulting solution was extracted with 2.5 L of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 2000 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo, which afforded the title compound. Step C: 2-(5-((tert-Butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid

[00192] In a 2000 mL 4-neck round bottom flask purged and maintained with an inert nitrogen atmosphere, was placed a solution of 2-(5-[[(tert-butoxycarbonyl]amino]-1,2,4-thiadiazol-3-yl)acetic acid (76 g, 293.12 mmol, 1.00 equiv) in dioxane (1520 mL), SeO2 (65.14 g, 587 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 80°C in an oil bath and then concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H2O (0.5% HCl) = 10/90-30/70 increasing to ACN/H2O (0.5% HCl) = 90/10 to 70/30 in 20 min; Detector, UV 254 nm. This gave the title compound. LC-M: (ES, m/z): [M+H] += 274. H-NMR (300MHz, DMSO, ppm): δ 1.523–1.502 (s, 9H), 12.806 (s, 1H). INTERMEDIATE 8 tert-Butyl 2-((tert-butyldimethylsilyl)oxy)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate

[00193] To a solution of tert-butyl 2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate (0.5 g, 1.37 mmol) (Intermediate 4), imidazole (0.467 g, 6.86 mmol) and TBS-Cl in DCM (3.43 mL, 3.43 mmol) in acetonitrile (5 mL) was added DMAP (0.017 g, 0.137 mmol). A solution was made at room temperature for 3 h. After concentration, the residue was purified on a gel column (40 g) using 0-10% EtOAc/hexane as a gradient to the title compound. INTERMEDIATE 9

[00194] Step A: tert-Butyl 3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoate Potassium carbonate (7.94 g, 57.5 mmol) was added to a stirred mixture of 6-bromopyridin-3-ol (5 g, 28.7 mmol) and tert-butyl oxirane-2-carboxylate (20.7 g, 144 mmol) in CH3CN (60 mL) and the mixture was stirred at 90 °C for 3 h. The mixture was cooled and filtered through a short Celite pad and washed with EtOAc. The solvent was removed under pressure and it was purified with ISCO column (gold, 120 g) with 0-60% EtOAc/hexane gradient to afford the title compound. LC-MS [M + H] + : m/z 318.2.

[00195] Step B: tert-Butyl 3-((6-bromopyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate To a solution of tert-butyl 3-((6-bromopyridin-3)oxy)-2-((tert-butyldimethylsilyl)oxy)proponoate (6700 mg, 21.1 mmol), imidazole (3440 mg, 50.5 mmol), and TBDMS-Cl (3800 mg, 25.3 mmol) in acetonitrile (100 mL) was added DMAP (257 mg, 2.11 mmol). The resulting solution was stirred at room temperature overnight. The reaction was concentrated and the residue was purified by ISCO column (gold, 120g), eluting with 0-25% EtOAc/hexane gradient to afford the title compound. LC-MS [M + H] + : m/z 432.4. INTERMEDIATE 10 2-(Difluoromethyl)-6-(1-(trifluoromethyl)cyclopropyl)benzoic acid

[00196] Step A: tert-Butyl 2-methylaxirane-2-carboxylate To a 2000 mL 3-necked round bottom flask equipped with a condenser was added a solution of tert-butyl methacrylate (44 g, 309 mmol) in CH2Cl2 (1000 mL) in m-CPBA (120 g, 557 mmol) portionwise. The resulting solution was stirred at 30°C for 20 h, resulting in a large amount of precipitate. The slurry was filtered, and to the filtrate was added small portions of saturated sodium thiosulfate solution (approximately 100 mL, added in small portions until no more heat was generated). The aqueous phase was separated and the organic phase was washed with saturated NaHCO3 (2 x 400 mL) and brine (400 mL), dried over Na2SO4, filtered, and concentrated to give the title compound. 1H NMR (400 MHz, Chloroform-d) δ 3.02 (d, J= 5.95 Hz, 1 H), 2.68 (d, J= 6.17 Hz, 1 H), 1.51 (s, 3 H), 1.46 (s, 9 H).

[00197] Step B: tert-Butyl 3-(4-bromophenoxy)-2-hydroxy-2-methylpropanoate A mixture of 4-bromophenol (15 g, 87 mmol), K2CO3 (17.97 g, 130 mmol), and tert-butyl 2-methylaxirane-2-carboxylate (20.6 g, 130 mmol) in DMF (200 mL) was heated and stirred at 80 °C for 16 h. TLC indicated complete conversion. The mixture was diluted with water (100 mL) and extracted with CH2Cl2 (3 x 100 mL), washed with brine (2 x 40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE:EtOAc = 1:0 - 9:1) to provide the title compound. 1H NMR (400 MHz, Chloroform-d) δ 7.37 (d, J= 8.61 Hz, 2 H), 6.77 (d, J= 9.00 Hz, 2 H), 4.09 (d, J= 9.00 Hz, 1 H), 3.95 (d, J= 9.00 Hz, 1 H), 3.60 (s, 1 H), 1,441.47 (m, 12 H).

[00198] Step C: O-(mesitylsulfonyl)hydroxylamine A solution of (E)-ethyl-N-(mesitylsulfonyl)oxy-acetimidate (20 g, 70.1 mmol) in 1,4-dioxane (20 mL) was cooled to 0 °C. Perchloric acid (8.45 g, 84 mmol) was added dropwise (slowly). After stirring for 15 min, the mixture solidified. The reaction contents were transferred to 200 mL of ice-cold water and the flask washed with water (100 mL) and tert-butyl methyl ether (100 mL).

[00199] The contents were transferred to a separatory funnel and extracted with tert-butyl methyl ether (2 × 100 mL). The organic layer was neutralized and partially dried over anhydrous potassium carbonate and then filtered. The filtrate was concentrated to a total volume of less than 80 mL and then poured into 400 mL of ice-cold hexane and allowed to crystallize for 30 min. White crystals were isolated by filtration to afford the title compound, which was transferred to a plastic Falcon tube and stored at -20 °C. 1H NMR (400 MHz, chloroform-d) δ 7.01 (s, 2 H), 2.65 (s, 6 H), 2.33 (s, 3 H).

[00200] Step D: tert-Butyl 2-(aminooxy)-3-(4-bromophenoxy)-2-methylpropanoate_Tert-Butyl 3-(4-bromophenoxy)-2-hydroxy-2-methylpropanoate (9 g, 27.2 mmol) was dissolved in anhydrous THF (120 mL) under N2, cooled to 0°C. NaH (1.96 g, 48.9 mmol, (60% in paraffin)) was added in 3 portions. The mixture was stirred at 0 °C for 30 min. Then O-(mesitylsulfonyl)hydroxylamine (6.43 g, 29.9 mmol) was added to this mixture. The mixture was stirred at 0 °C for 2 h, LCMS showed that the starting material was consumed, the desired compound was formed, the mixture was quenched with saturated NH 4 Cl (20 mL), extracted with EtOAc (3x 45 mL). The combined organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , PE:EtOAc = 1:0-10:1) to afford the title compound. 1 H NMR (400 MHz, chloroform-d) δ 7.38 (d, J= 8.61 Hz, 2 H), 6.84 (d, J= 8.61 Hz, 2 H), 4.34 (d, J= 9.78 Hz, 1 H), 4.07 (d, J= 9.78 Hz, 1 H), 1.47 - 1.52 (m, 12 H). INTERMEDIATE 11 (R )-3-(4-bromophenoxy)-2-hydroxypropanoate ethyl

[00201] The title compound was prepared following similar procedures to Intermediate 3, replacing ethyl oxirane-2-carboxylate with tert-butyl oxirane-2-carboxylate. LC-MS [M+H]: m/z 289.1. INTERMEDIATE 12 tert-butyl (R)-3-((6-bromopyridazin-3-yl)oxy)-2-hydroxypropanoate

[00202] The title compound was prepared following similar procedures to Intermediate 3, substituting 3-bromo-6-hydroxypyridazine for 4-bromophenol. LC-MS [M + Na]: m/z 341.0. INTERMEDIATE 13 Ethyl (R)-2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate

[00203] The title compound was prepared following procedures similar to those for Intermediate 8, substituting tert-butyl oxirane-2-carboxylate for ethyl oxirane-2-carboxylate. LC-MS [M+H]: m/z 337.3. INTERMEDIATE 14 tert-butyl (S)-2-(aminooxy)-3-(4-bromo-3-fluorophenoxy)-2-methylpropanoate

[00204] Step A: 1-Bromo-2-fluoro-4-((2-methylallyl)oxy)benzene 3-Bromo-2-methylprop-1-ene (5.3 mL, 52 mmol) was added to a stirred suspension of 4-bromo-3-fluorophenol (10 g, 52 mmol) and K2CO3 (8.7 g, 63 mmol) in DMF (105 mL). The reaction mixture was stirred at rt for 1.5 h, then partitioned between ether and water. The layers were separated and the organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound, which was used without further purification.

[00205] Step B: (R)-3-(4-bromo-3-fluorophenoxy)-2-methylpropane-1,2-diol. AD-mix α (12 g, 0.035 mmol osmium) was added to a suspension of 1-bromo-2-fluoro-4-((2-methyl-allyl)oxy)benzene (2.1 g, 8.5 mmol) in tert-butanol (41 mL) and water (41 mL). The reaction was stirred at rt for 4 h, then partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (0-100% EtOAc in hexanes as eluent) to afford the title compound. LC-MS [M + H]: m/z 279.0.

[00206] Step C: (S)-3-(4-Bromo-3-fluorophenoxy)-2-hydroxy-2-methylpropanoic acid A mixture of NaH2PO4 (2.43 g, 20.2 mmol) in water (41 mL) was added to a stirred solution of (R)-3-(4-bromo-3-fluorophenoxy)-2-methylpropane-1,2-diol (2.26 g, 8.10 mmol) in THF (41 mL). Then, TEMPO (0.127 g, 0.81 mmol) was added, followed by solutions of sodium chlorite (1.83 g, 16.2 mmol) and sodium hypochlorite (0.83 mL, 0.81 mmol) in water (1.5 mL each). The reaction mixture was stirred at rt overnight. for 24 h, then additional portions of TEMPO (0.127 g, 0.81 mmol) and sodium hypochlorite (0.83 mL, 0.81 mmol) were added. After 2 h, the reaction was partitioned between EtOAc and saturated aqueous sodium thiosulfate. The layers were separated, and the organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound. LC-MS [M + 2Na]: m/z 336.9.

[00207] Step D: tert-Butyl (S)-3-(4-bromo-3-fluorophenoxy)-2-hydroxy-2-methylpropanoate. tert-Butyl N,N'-diisopropylcarbamimidate (1.87 mL, 8.0 mmol) was added to a stirred solution of (S)-3-(4-bromo-3-fluorophenoxy)-2-hydroxy-2-methylpropanoic acid (1.17 g, 4.0 mmol) in THF (20 mL). The resulting mixture was heated to 60 °C. After 3 h, the reaction was cooled to rt, filtered through a Celite™ pad, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (080% EtOAc in hexanes as eluent) to afford the title compound. LC-MS [M + (Na - tBu)]: m/z 314.6.

[00208] Step E: (S)-2-(aminooxy)-3-(4-bromo-3-fluorophenoxy)-2- tert-butyl methylpropanoate_The title compound was prepared following a similar procedure to the procedure for Intermediate 10, Step D. LC-MS [M+H]: m/z 364.2. INTERMEDIATE 15 Methyl (R)-3-(4-bromophenoxy)-2-hydroxypropanoate

[00209] Step A: (R)-3-(4-Bromophenoxy)-2-hydroxypropanoic acid TFA (850 μL, 11.0 mmol) was added to a stirred solution of intermediate 3 (350 mg, 1.10 mmol) in DCM (5.5 mL). The reaction mixture was stirred at rt. After 1.5 h, the reaction was concentrated in vacuo and the resulting solid was continued without further purification. LC-MS [M + Na]: m/z 283.2.

[00210] Step B: Methyl (R)-3-(4-bromophenoxy)-2-hydroxypropanoate Trimethylsilyldiazomethane (2.2 mL of a 2.0 M solution in hexanes, 4.41 mmol) was added to a (1:1) mixture of DCM:CH3OH (2 mL). The resulting mixture was added to a stirred solution of (R)-3-(4-bromophenoxy)-2-hydroxypropanoic acid (288 mg, 1.10 mmol) in (1:1) DCM:CH3OH (10 mL). The reaction mixture was stirred at rt for 30 min. Then, the reaction was concentrated in vacuo to afford the title compound, which was used without further purification. LC-MS [M + H]: m/z 275.2. INTERMEDIATE 16 tert-butyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)-3-fluoroazetidin-1-carboxylate

[00211] Step A: tert-Butyl 3-fluoro-3-((tosyloxy)methyl)azetidin-1-carboxylate p-Toluenesulfonyl chloride (1.02 g, 5.32 mmol) was added to a stirred solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidin-1-carboxylate (993 mg, 4.84 mmol) and triethylamine (742 μL, 5.32 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was allowed to warm to rt, then additional triethylamine (337 μL, 2.66 mmol) was added. After stirring overnight, the reaction mixture was concentrated in vacuo, and the resulting residue was purified by column chromatography on silica gel (0-60% EtOAc in hexanes as eluent) to afford the title compound. LC-MS [M - (tBu + H)]: m/z 304.2.

[00212] Step B: tert-Butyl 3-((4-bromo-1H-pyrazol-1-yl)methyl)-3-fluoroazetidin-1-carboxylate Sodium hydride (116 mg of a 60% dispersion in mineral oil, 2.89 mmol) was added in several portions to a stirred solution of tert-butyl 3-fluoro-3-((tosyloxy)methyl)azetidin-1-carboxylate (1.04 g, 2.89 mmol) and 4-bromo-1H-pyrazole (425 mg, 2.89 mmol) in DMF (13 mL) at 0 °C. The reaction mixture was allowed to warm to rt and stirred overnight. Then, the reaction mixture was diluted with EtOAc and poured over ice. The layers were separated, and the organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (0-100% EtOAc in hexanes as eluent) to afford the title compound. LC-MS [M+H]: m/z 334.0. INTERMEDIATE 17 3-Azidopropyl trifluoromethanesulfonate

[00213] The title compound was prepared using a procedure similar to the procedure for intermediate 16, Step A, substituting 3-azidopropane-1-ol for 3-fluoro-3-(hydroxymethyl)-azetidin-1- tert-butyl carboxylate, and triflic anhydride for p-tosyl chloride. INTERMEDIATE 18 tert-butyl (2-((5-bromopyridin-2-yl)amino)ethyl)carbamate

[00214] Step A: N1-(5-Bromopyridin-2-yl)ethane-1,2-diamine Ethylenediamine (25.4 mL, 380 mmol) was added to a stirred solution of 2,5-dibromopyridine (5.00 g, 21.1 mmol). The reaction was heated at 100 °C for 16 h, then cooled to rt and concentrated in vacuo. The resulting residue was diluted in DCM. The organic layers were washed with water, dried (MgSO4), filtered, and concentrated in vacuo to afford the title compound, which was used in the next step without purification. LC-MS [M + H]: m/z 215.8.

[00215] Step B: tert-Butyl (2-((5-bromopyridin-2-yl)amino)ethyl)carbamate Di-tert-Butyl dicarbonate (5.53 g, 25.3 mmol) was added to a stirred suspension of N1-(5-bromopyridin-2-yl)ethane-1,2-diamine (4.56 g, 21.1 mmol) and sodium carbonate (2.35 g, 22.2 mmol) in a (1:1) dioxane:water solution (64 mL total volume). The reaction mixture was stirred at rt overnight, then the reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (0-30% EtOAc in hexanes as eluent) to afford the title compound. LC-MS [M + H]: m/z 316.3. INTERMEDIATE 19 tert-butyl (3-((6-chloropyridazin-3-yl)amino)propyl)carbamate

[00216] Step A: tert-Butyl (3-((6-chloropyridazin-3-yl)amino)propyl)carbamate To a stirred solution of 3,6-dichloropyridazine (1.00 g, 6.71 mmol) in DMSO (10.0 mL) in a microwave vial was added tert-butyl (3-aminopropyl)carbamate (1.23 g, 7.05 mmol), followed by triethylamine (1.50 mL, 10.8 mmol). The microwave vial was sealed and the reaction mixture was heated in a microwave reactor at 130 °C for 15 min. After cooling to rt, the reaction mixture was partitioned between EtOAc and saturated aqueous NH4Cl. The layers were separated and the organic layer was washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel (0-50% (3:1 EtOAc:EtOH) in hexanes as eluent) to afford the title compound. LC-MS [M+H]: m/z 287.2. INTERMEDIATE 20 tert-butyl (3-(4-bromo-1H-pyrazol-1-yl)-2-fluoropropyl)carbamate

[00217] Step A: 3-((tert-Butoxycarbonyl)amino)-2-fluoropropyl 4-methyl benzenesulfonate The title compound was prepared using a procedure similar to the procedure for Intermediate 16, Step A substituting tert-butyl (2-fluoro-3-hydroxypropyl)carbamate for tert-butyl 3-fluoro-3-(hydroxymethyl)azetidin-1-carboxylate. LC-MS [M + Na]: m/z 370.2.

[00218] Step B: (3-(4-bromo-1H-pyrazol-1-yl)-2-fluoropropyl) tert-butyl carbamate The title compound was prepared according to the procedure for intermediate 16 Step B. LC-MS [M+H]: m/z 322.2. INTERMEDIATE 21 (3-(1H-imidazol-4-yl)propyl) tert-butyl carbamate

[00219] Step A: 3-(1-trityl-1H-imidazol-4-yl)propan-1-ol Lithium aluminum hydride (2.5 mL of a 1 M THF solution, 2.5 mmol) was added to a stirred solution of methyl 3-(1-trityl-1H-imidazol-4-yl)propanoate (500 mg, 1.26 mmol) in THF (4.0 mL) at 0 °C. The resulting mixture was heated to 70 °C and allowed to stir at 70 °C for 2 h. Then, the reaction was cooled to rt and quenched by the addition of water, followed by 2 N NaOH. The resulting slurry was filtered through a Celite™ column, which was washed with EtOAc. The filtrate was concentrated in vacuo to afford the title compound, which was used without further purification. LC-MS [M + H]: m/z 369.4.

[00220] Step B: 2-(3-(1-Trityl-1H-imidazol-4-yl)propyl)isoindoline-1,3-dione Phthalimide (278 mg, 1.89 mmol) was added to a stirred solution of 3-(1-trityl-1H-imidazol-4-yl)propan-1-ol (465 mg, 1.26 mmol) and triphenylphosphine (496 mg, 1.89 mmol) in THF (12 mL). The reaction was cooled to 0 °C, then DIAD (0.37 mL, 1.89 mmol) was added slowly dropwise, and the resulting mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was filtered, and the solids were washed with THF to afford the title compound. LC-MS [M + H]: m/z 498.5.

[00221] Step C: 3-(1-Trityl-1H-imidazol-4-yl)propan-1-amine methylamine (11 mL of a 33% w/v EtOH solution, 88 mmol) was added to a stirred solution of 2-(3-(1-trityl-1H-imidazol-4-yl)propyl)isoindoline-1,3-dione (1.92 g, 3.86 mmol) in EtOH (40 mL) and water (3.5 mL). The resulting mixture was stirred at room temperature overnight, then the reaction mixture was concentrated in vacuo and azeotroped several times with toluene to afford the title compound, which was used without further workup or purification. LC-MS [M + H]: m/z 368.4.

[00222] Step D: tert-Butyl (3-(1-trityl-1H-imidazol-4-yl)propyl)carbamate Di-tert-butyl dicarbonate (1.69 g, 7.72 mmol) was added to a stirred solution of 3-(1-trityl-1H-imidazol-4-yl)propan-1-amine (1.42 g, 3.86 mmol) and triethylamine (1.08 mL, 7.72 mmol) in DCM (30 mL). The reaction mixture was stirred at rt. When complete, the reaction was concentrated in vacuo on a Celite™ pad and the resulting suspension was purified by column chromatography on silica gel (0-100% EtOAc in hexanes as eluent) to afford the title compound. LC-MS [M + H]: m/z 468.4.

[00223] Step E: tert-Butyl (3-(1H-imidazol-4-yl)propyl)carbamate Anisole (377 mg, 3.49 mmol) was added to a stirred solution of tert-butyl (3-(1-trityl-1H-imidazol)4-yl)propyl)carbamate (1.63 g, 3.49 mmol) in acetic acid (5.0 mL), and the reaction mixture was heated to 60 °C. After 24 h, the reaction mixture was concentrated in vacuo and azeotroped successively with toluene and acetonitrile. The resulting residue was suspended in EtOAc and DCM, and the mixture was adsorbed onto Celite™. The resulting suspension was purified by column chromatography on silica gel (0-100% (3:1 EtOAc:EtOH) in hexanes as eluent) to afford the title compound. LC-MS [M+H]: m/z 226.2. INTERMEDIATE 22 (S)-3-(2-(2-((tert-Butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetamido)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate

[00224] To a solution of 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (Intermediate 5, 2 g, 7.4 mmol), (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (3.1 g, 14.7 mmol, from commercial sources CAS: 102507-49-3), and pyridine (1.8 mL, 22 mmol) in MeCN (37 mL) was added EDC (3.5 g, 18 mmol) at 0 °C. The reaction was allowed to warm to room temperature overnight. After 16 h, the reaction was poured into brine (100 mL) and extracted with MeCN (50 mL). The organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on SiO2 and eluted with 0.100% hexanes/(EtOAc/EtOH 3:1) to afford the title compound. LC-MS [M + H]: m/z 465.2 INTERMEDIATE 23 (S)-(3-(4-Bromo-1H-pyrazol-1-yl)-2-((tert-butyldimethylsilyl)oxy)propyl)carbamate tert-butyl OTBS

[00225] Step A: tert-Butyl N-[(2S)-2,3-dihydroxypropyl]carbamate In a 500 mL 4-necked round bottom flask was placed a solution of (2S)-3-aminopropane-1,2-diol (20 g, 220 mmol, 1 eq) in methanol (200 mL) and di-tert-butyl dicarbonate (57 g, 261 mmol, 1.2 eq). The reaction was stirred overnight at room temperature and then concentrated in vacuo. The resulting residue was purified on a silica gel column with dichloromethane/methanol (10:1) to afford the title compound.

[00226] Step B: tert-Butyl (S)-(2,3-bis(tert-butyldimethylsilyl)oxy)propyl)carbamate In a 500 mL 3-neck round bottom flask was placed a solution of tert-butyl N-[(2S)-2,3-dihydroxypropyl]carbamate (20 g, 105 mmol, 1 eq) in N,N-dimethylformamide (200 mL) and imidazole (32 g, 470 mmol, 4.50 equiv). Then, tert-butyl (chloro)dimethylsilane (40.8 g, 271 mmol, 2.6 eq) was added in several batches at 0 °C. The reaction was stirred overnight at room temperature and then diluted with ethyl acetate (500 mL). The resulting mixture was washed with water (2x400 mL) and brine (400 mL) and then concentrated under vacuum. The resulting residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:20) to afford the title compound.

[00227] Step C: (S)-(2-(( tert-butyldimethylsilyl)oxy)-3-hydroxypropyl) tert-butyl carbamate In a 5 L 4-neck round bottom flask was placed a solution of N-[(2S)-2,3-bis[( tert-butyldimethylsilyl)oxy]propyl] tert-butyl carbamate (200 g, 476 mmol, 1 eq) in ethanol (2 L), and PPTS (110 g, 1 eq). The reaction was stirred overnight at room temperature and then quenched by the addition of TEA (100 mL). The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 2 L of ethyl acetate, then washed with H2O (2 L). The mixture was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:3) to afford the title compound.

[00228] Step D: (S)-3-(( tert-butoxycarbonyl)amino)-2-(( tert-butyldimethylsilyl)oxy)propyl methanesulfonate A solution of tert-butyl N-[(2S)-2-[( tert-butyldimethylsilyl)oxy]-3-hydroxypropyl]carbamate (40 g, 131 mmol, 1 equiv) in dichloromethane (400 mL), TEA (36.5 mL, 2 eq), and methanesulfonyl chloride (14.5 mL, 1.5 eq) was stirred for 2 h at room temperature. The reaction was then quenched by the addition of sodium bicarbonate (aqueous, 200 mL). The resulting solution was extracted with ethyl acetate (300 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford the title compound.

[00229] Step E: tert-Butyl (S)-(3-bromo-2-((tert-butyldimethylsilyl)oxy)propyl)carbamate A solution of N-[(2S)-2-[(tert-butyldimethylsilyl)oxy]]-3-(methanesulfonylaxy)propyl]-carbamate (47 g, 123 mmol, 1 eq) in tetrahydrofuran (1600 mL) and bromolithium (53 g, 610 mmol, 5 eq) was stirred for 2 days at 70 °C. Then, the reaction mixture was diluted with H2O (500 mL), and the resulting solution was extracted with 500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:30) to afford the title compound.

[00230] Step F: tert-butyl (S)-(3-(4-Bromo-1H-pyrazol-1-yl)-2-((tert-butyldimethylsilyl)oxy)-propyl)carbamate A solution of tert-butyl N-[(2S)-3-bromo-2-[(tert-butyldimethylsilyl)oxy]propyl]carbamate (210 g, 570 mmol, 1.20 equiv), N,N-dimethylformamide (2 L), 4-bromo-1H-pyrazole (70 g, 476 mmol, 1 eq), and Cs2CO3 (313 g, 957 mmol, 2 eq) was stirred overnight at 70 °C. Then, the reaction mixture was diluted with 2 L of EA. The resulting mixture was washed with H2O (2x4 L). The mixture was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:10) to afford the title compound. LC-MS: (ES, m/z): 434 [MH]- 1H-NMR: (400MHz, d-DMSO, ppm): δ -0.32(3H, s), 0.05(3H, s), 0.76(9H, s), 1.38(9H, s), 2.93-3.00(2H, m), m), 4.10-4.15(2H, m), 6.93-6.96(1H, t), 7.54(1H, s), 7.87(1H, s) EXAMPLE 1 (S )-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((S)-2-(4-(1-(3-ammonopropyl)-2- methyl-1H-pyrazol-2-yl-4-yl)phenoxy)-1-carboxyethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate 2,2,2-trifluoroacetate (C1)

[00231 ] Step A: tert-Butyl (3-(4-bromo-1H-pyrazol-1-yl)propyl)carbamate A solution of 4-bromo-1H-pyrazole (3 g, 20.4 mmol), tert-butyl (3-bromopropyl)carbamate (4.86 g, 20.4 mmol), and calcium carbonate (9.98 g, 30.6 mmol) in DMF (20 mL) was stirred at room temperature overnight. The mixture was diluted with water (30 mL) and extracted with EtOAc (3x10 mL). The extracts were combined, dried over MgSO4, and concentrated to dryness. The residue was purified by flash column chromatography (Biotage 80 g gold silica column), eluted with a DCM/MeOH gradient (0-10%) to obtain the title compound. LC-MS [M + H]+: m/z 304.19. 1H NMR (500 MHz, CDCl3) δ 7.45 (s, 2H), .4.15 (m, 2H), 3.10 (m, 2H), 1.99 (m, 2H), 1.27 (s, 9H)

[00232] Step B: (R )-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-hydroxypropanoate of tert-butyl

[00233] To a solution of (S)-tert-butyl 2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate (5 g, 13.7 mmol), tert-butyl (3-(4-bromo-1H-pyrazol-1-yl)propyl)carbamate (4.18 g, 13.7 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.895 g, 1.37 mmol) in THF (150 mL) was added 1 M aqueous potassium phosphate tribasic solution (41.2 mL, 41.2 mmol) in a 25 mL flask. The vial was sealed, degassed (3x) and replenished with N2 and stirred at 60°C overnight. LC-MS indicated complete conversion. The reaction mixture was diluted with saturated NH4Cl solution (100 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (2x60 mL). The organic extracts were combined, dried over MgSO4 and concentrated to dryness. The residue was purified on a Flash SiO2 column (120 g gold) with Hexane/EtOAc (0-100%) to obtain the title compound. LC-MS [M + H]+: m/z 462.56. 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.61 (s, 1H), 7.40 (d, J=7.5 Hz, 2H), 6.96 (d, J=7.5 Hz, 2H).4.92 (s, 1H), 4.40 (m, 2H), 4.23 (m, 2H), (m, 2H), 2.01 (m, 2H), 1.48 (s, 9H).

[00234] Step C: (S )-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)- 1H-pyrazol-4-yl)phenoxy)-2-((1,3 tert-butyl)-dioxoisoindolin-2-yl)oxy)propanoate to a solution of 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazole-4 (S)-tert-butyl-yl)phenoxy)-2-hydroxypropanoate (2.2 g, 4.77 mmol), 2-hydroxyisoindoline-1,3-dione (0.933 g, 5.72 mmol), and triphenylphosphine (1.50 g, 5.72 mmol) in DCM (100 ml), DIAD (1.11 ml, 5.72 mmol). The mixture was stirred at room temperature for 2 h. LC-MS indicated complete conversion. The mixture was concentrated to dryness and purified by SiO2 flash chromatography (120 g gold), eluting with hexane/EtOAc at 0-100% to obtain the title compound. LC-MS [M + H]+: m/z 607.59. 1H NMR (500 MHz, CDCl3) δ 7.82-7.92 (m, 4H), 7.78 (s, 1H), 7.61 (s, 1H), 7.41 (d, J=7.5 Hz, 2H), 6.92 (d, J= 7.5 Hz, 2H).5.12 (s, 1H), 4.54 (m, 2H), 4.25 (s, 2H), 3.18 (m, 2H), 2.12 (m, 2H), 1.48 (s, 9H).

[00235] Step D: (5)-4-(4-(3-(tert-Butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1- (3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io A solution of 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl) (5)-tert-butyl-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (1.8 g, 2.97 mmol) in acetonitrile (100 ml) was added iodomethane (4.21 g, 29.7 mmol). The mixture was sealed in a 250 ml pressure flask and stirred at 70°C for 16 h. LC-MS indicated completion of the conversion. The mixture was then cooled to room temperature and concentrated under vacuum to dryness to provide the title compound, which was used directly in the next step without further purification. LC-MS [M]+: m/z 621.61

[00236] Step E: (5)-4-(4-(2-(Amino-oxy)-3-( tert-butoxy)-3-oxopropoxy)phenyl)-1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazole-2-ium To a solution of (5)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazole-2-ium iodide (2 g, 2.67 mmol) in acetonitrile (20 mL) was added hydrazine (0.092 mL, 2.94 mmol). The mixture was stirred at room temperature for 2 h. LC-MS indicated completion of the conversion. The mixture was then concentrated under vacuum to dryness to afford the title compound, which was used directly in the next step without further purification. LC-MS [M]+: m/z 491.35

[00237] Step F: (S,Z)-4-(4-(3-( tert -butoxy)-2-((((2-(( tert -butoxycarbonyl)amino)-thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazole-2-ium iodide. To a solution of (S)-4-(4-(2-(amino-oxy)-3-(tert -butoxy)-3-oxopropoxy)phenyl)-1-(3-((tert -butoxycarbonyl)amino)-propyl)-2-methyl-1H-pyrazole-2-ium iodide (1.6 g, 2.59 mmol) in ethanol (100 mL) and ClCH2CH2Cl (20 mL) was added ether 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (0.775 g, 2.85 mmol, intermediate 5). The mixture was stirred at room temperature for 4 h. LC-MS indicated complete conversion. The mixture was concentrated to afford the title compound, which was used directly in the next step without further purification. LC-MS [M]+: m/z 745.43

[00238] Step G: Sulfate of (S )-3-((Z)-2-(((( S )-1-( tert-butoxy)-3-(4- (1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-yl-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-(( tert-butoxycarbonyl )amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl To a solution of

[00239] (S,Z)-4-(4-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene) amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-2-methyl-1H-pyrazol-2-io (1.9 g, 2.17 mmol ) in DMF (20 ml) DCC (0.898 g, 4.35 mmol) and HOBt (0.667 g, 4.35 mmol) were added. The mixture was then stirred at room temperature for 30 min, followed by the addition of (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (0.915 g, 4.35 mmol, from sources commercial CAS:102507-49-3) and sodium bicarbonate (1.10 g, 13.1 mmol). The final mixture was stirred at room temperature overnight (16 h). LC-MS indicated complete conversion. The solution of DMF was dried under a stream of N2 overnight. The residue was redissolved in MeCN/water (2:1, 2.5 mL) and purified by reversed-phase ISCO column (130 g), eluted with MeCN/H2O/ 0.05% TFA (0-100%). Fractions were collected and lyophilized to obtain the title compound. 1H NMR (500 MHz, CDCl3) δ 9.53 (s, 1H), 8.94 (m, 2H), 7.68 (m, 2H), 7.14 (m, 2H), 4.95 (s, 1H), 4.60 (m, 2H) , 4.42 (s, 2H), 3.08 (m, 2H), 2.14 (m, 2H), 1.47 (s, 9H), 1.40 (s, 9H), 1.37 (s, 9H).

[00240] Step H: Mono(2,2,2-trifluoroacetate) mono(4-(4-(( S )-2- ((((Z)-1-(2-aminothiazol-4-yl)- 2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phenyl)- 1-(3-aminopropyl)-2-methyl-1H-pyrazol- 2-io) To a solution of 4-(4-((S)-3-(tert-butoxy)-2-(((E)- (1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2- dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxo-propoxy)phenyl)-1-(3-((tert-butoxycarbonyl )amino)propyl)-2-methyl-1H-pyrazol-2-ium (40 mg, 0.043 mmol) in DCM (1 mL) was added with 1 mL of TFA. The mixture was stirred at room temperature for 30 min. LC- MS indicated complete conversion. The mixture was concentrated to dryness under vacuum (no heat), DCM (10 mL) was added and concentrated three times to remove TFA. The residue was washed with dry MeCN (2x2 mL) to remove impurities. The residue was dissolved in H2O and purified on prep HPLC. with a MeCN/H2O (0.05% TFA in both) gradient 0-40% in 10 min. Product fractions were collected and lyophilized to obtain the title compound. LC-MS [M]+: m/z 681.48 . 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 8.68 (s, 1H), 7.78 (d, J=6.8 Hz, 2H), 7.16 (d, J=6.8, 2H), 7.08 (s , 1H), 5.18 (s, 1H), 4.63 (m, 2H), 4.58 (m, 2H), 4.19 (s, 3H), 3.16 (m, 2H), 2.39 (m, 2H). EXAMPLE 2 (S )-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((S)-2-(4-(1-(3-ammonopropyl)-3 sulfate -methyl-1H-imidazol-3-yl-4-yl)phenoxy)-1-carboxyethoxy)-imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl (C2)

[00241 ] Step A: tert-Butyl (3-(4-bromo-1H-imidazol-1-yl)propyl)carbamate To a solution of 4-bromo-1H-imidazole (1 g, 6.80 mmol) in DMF (20 mL) was added NaH (0.272 g, 6.80 mmol) at 0 °C. The mixture was stirred for 10 min. tert-Butyl (3-bromopropyl)carbamate (1.62 g, 6.80 mmol) was added. The solution was stirred at room temperature for 2 h and then heated to 50 °C for 1 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (3x20 mL). The organic layer was washed with water (30 mL), brine (30 mL), and dried over Na2SO4. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (Redi 40g gold column) and eluted with EtOAc/Hexane (0-100%, 6hp; 100%, 10hp) to afford the title compound. LC-MS [M + H]+: m/z 304.19. 1H NMR (500 MHz, CDCl3) d 7.40 (s, 1 H); 6.94 (s, 1 H); 4.67 (s, 1 H); 3.98 (t, J = 7.0 Hz, 2 H); 3.17 (d, J = 7.5 Hz, 2 H); 1.98 (p, J = 6.8 Hz, 2 H); 1.47 (s, 9 H).

[00242] Step B: (R)-3-(4-(1-(3-(( tert-butoxycarbonyl)amino) propyl)-1 H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate of tert- butyl. The procedure was the same as in step B of example 1 with the reagent tert-butyl (3-(4-bromo-1H-imidazol-1-yl)propyl)carbamate, 2-hydroxy-3-(4-( (R)-tert-Butyl 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate (300 mg, 0.824 mmol), (3-(4-bromo-1H -imidazol-1-yl)propyl)carbamate (276 mg, 0.906 mmol)(intermediate 4), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (53.7 mg, 0.082 mmol), THF (4 mL) and potassium phosphate (2.471 mL, 2.471 mmol, 1M aq.).LC-MS [M + H]+: m/z 462.

[00243] Step C: (S)-3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate tert-butyl The procedure was the same as Step C in Example 1 with the reagent (R)-3-(4-(1-(3-(( tert-butoxycarbonyl)-amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate (0.25 g, 0.542 mmol), 2-hydroxyisoindoline-1,3-dione (0.097 g, 0.596 mmol), triphenylphosphine (0.170 g, 0.650 mmol), DIAD (0.126 mL, 0.650 mmol) and THF (2 ml). LC-MS [M + H]: m/z 607.

[00244] Step D: (S)-4-(4-(3-( tert-Butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-3-methyl-1H-imidazol-3-ium iodide The procedure was the same as Step D of Example 1 with reactants (S)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)tert-butyl propanoate (0.17 g, 0.280 mmol) MeI (0.105 mL, 1.681 mmol) in MeCN (2 mL). LC-MS [M]+: m/z 621.

[00245] Step E: (S)-4-(4-(2-(Amino-oxy)-3-( tert -butoxy)-3-oxopropoxy)phenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-3-methyl-1H-imidazole-3-ium iodide The procedure was the same as step E in Example 1 with the reactants (S)-4-(4-(3-(tert -butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-3-methyl-1H-imidazole-3-ium iodide (0.210 g, 0.28 mmol), hydrazine (8.79 g, 0.280 mmol) in EtOH (4 mL). LC-MS [M]+: m/z 491.

[00246] Step F: (S,Z)-4-(4-(3-( tert -butoxy)-2-((((2-(( tert -butoxycarbonyl)amino)-thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-3-methyl-1H-imidazole-3-ium iodide The procedure was identical to Step Fin Example 1 with reagents (S)-4-(4-(2-(amino-oxy)-3-(tert -butoxy)-3-oxopropoxy)phenyl)-1-(3-((tert -butoxycarbonyl)amino)propyl)-3-methyl-1H-imidazole-3-ium (0.173 g, 0.28 mmol), 2-(2-((tert-butoxycarbonyl)-amino)thiazol-4-yl)-2-oxoacetic acid (0.080 g, 0.294 mmol) (intermediate 5) in EtOH (4 mL) and ClCH2CH2Cl (2 mL). LC-MS [M]+: m/z 745.

[00247] Step G: Sulfate of (S )-3-((Z)-2-(((( S )-1-( tert-Butoxy)-3-(4- (1-(3-(( tert -butoxycarbonyl)amino)propyl)-3-methyl-1H-imidazol-3-yl-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-(( tert -butoxycarbonyl )amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl The procedure was the same as step G in Example 1 with the reagent (S,Z)-4-(4 -(3-(tert-butoxy)-2-(((((2-((tert-butoxycarbonyl)amino) thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-3-methyl-1H-imidazole-3-ium , I- (0.244 g, 0.280 mmol) in DMF (4 ml), DCC (0.144 g, 0.699 mmol), HOBT (0.107 g, 0.699 mmol, (S)-3-amino-2,2-dimethyl- 4-oxoazetidin-1-yl (0.118 g, 0.559 mmol) and sodium bicarbonate (0.117 g, 1.398 mmol) After completion of the reaction, the crude mixture was filtered and purified directly by RP-HPLC (Gilson) (column C -18), eluting with ACN/H2O/TFA at 0.05% (20-100%, 10 min) The product fraction was lyophilized to afford the title compound LC-MS: [M]+ m/z 937.85.

[00248] Step H: Mono(2,2,2-trifluoroacetate) of mono(4-(4-(( S )-2- ((((Z)-1-(2-aminothiazol-4-yl)- 2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phenyl)- 1-(3-aminopropyl)-3-methyl-1H-imidazole 3-io) To a solution of 4-(4-((S)-3- (tert-butoxy)-2-(((Z)- (1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)- 2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl )amino)propyl)-3-methyl-1H-imidazole-3-ium (0.17 g, 0.162 mmol) in CH2Cl2 (0.5 ml) was added TFA (0.5 ml). The solution was stirred at room temperature room temperature for one hour. The solvent was removed under vacuum. The residue was washed with Et2O twice and dried under vacuum to afford the crude solid. The crude product was dissolved in water (2 mL) and DMSO (0.5 mL) and then purified on RP-HPLC (Gilson) (C-18 column), eluted with MeCN/water (0.05% formic acid in both), 0-60% gradient in 15 minutes. Product fractions were collected and lyophilized to obtain the title compound. LC-MS [M]+: m/z 681.38. 1H NMR (500 MHz, MeOD): δH 8.97 (d, J = 1.8 Hz, 1 H) ; 7.73 (s, 1 H); 7.49 (d, J = 8.4 Hz, 2 H); 7.15-7.17 (m, 2 H); 6.93 (s, 1 H); 5.15-5.16 (m, 1 H); 4.64-4.67 (m, 1 H); 4.53-4.57 (m, 2 H); 4.38 (t, J = 7.0 Hz, 2 H); 3.86 (s, 3 H); 3.07-3.10 (m, 2 H) ; 2.30-2.33 (m, 2 H); 1.53 (s, 3 H); 1.18 (s, 3 H). Table 1. Using generally the same procedures as in Example 2, substituting the appropriate reagents, Example 3 was synthesized and characterized by LC/MS. EXAMPLE 4 (S,Z)-3-(2-((2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenoxy) sulfate ethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl (C4).

[00249] Step A: tert-Butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 10.3 mmol), tert-butyl (3-bromopropyl)carbamate (2.45 g, 10.3 mmol), and cesium carbonate (3.36 g, 10.3 mmol) in DMF (20 mL) was stirred at 60 °C overnight. The mixture was partitioned between EtOAc and water. The layers were separated, and the organic layer was washed with water. The organics were washed with brine, dried (Na2SO4), and concentrated to dryness. The resulting title compound was carried forward to the next step without purification. LC-MS [M + H]+: m/z 352.6.

[00250] Step B: 1-Bromo-4-(2-bromoethoxy)benzene-1,2-dibromoethane (4.26 mL, 49.4 mmol) and cesium carbonate (6.83 g, 49.4 mmol) were added to a stirred solution of 4-bromophenol (1.40 g, 8.09 mmol) in acetone (10 mL). The reaction mixture was heated at 80 °C for 8 h, at which time, the reaction was cooled to room temperature and filtered. The organic filtrate was concentrated, and the resulting crude residue was purified by column chromatography on silica gel (10-100% EtOAc:hexane gradient as eluent) to afford the title compound. 1H NMR (500 MHz, CDCl3) d 7.42 (br, 2H), 6.90 (br, 2H), 4.31 (m, 2H), 3.71 (m, 2H).

[00251 ] Step C: tert-Butyl (3-(4-(4-(2-bromoethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate 2.0 M aqueous sodium carbonate (1.60 mL, 3.20 mmol) was added to a microwave vial containing a stirred solution of 1-bromo-4-(2-bromoethoxy)benzene (300 mg, 1.07 mmol), tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)-carbamate (565 mg, 1.61 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (78 mg, 0.11 mmol) in 1,4-dioxane (4.3 mL). The mixture was degassed via a stream of nitrogen gas for approximately 5 min, at which point the vial was sealed and heated in a microwave reactor at 120 °C for 20 min. After cooling to room temperature, the mixture was filtered through a Celite™ (diatomaceous earth) pad, and the solid layer was rinsed with EtOAc. The combined organics were concentrated, and the resulting crude residue was purified by silica gel column chromatography (0-60% EtOAc:hexanes as eluent) to afford the title compound. LC-MS [M + Na]+: m/z 446.3.

[00252] Step D: (3-(4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)-phenyl)-1 H-pyrazol-1-yl)propyl)carbamate tert-butyl

[00253] Hydroxyphthalimide (185 mg, 1.13 mmol) was added to a stirred solution of tert-butyl (3-(4-(4-(2-bromoethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate (320 mg, 0.754 mmol) and DBU (138 mg, 0.905 mmol) in DMF (3.8 mL), and the resulting mixture was heated to 50 °C. After 16 h, the reaction mixture was cooled to room temperature and EDC (117 mg, 0.754 mmol) was added. After stirring at room temperature for 30 min, the reaction mixture was partitioned between EtOAc and water. The layers were separated, and the organic layer was washed with water, followed by brine. The organics were dried (Na2SO4), filtered, and concentrated to afford a crude residue that was purified by column chromatography on silica gel (0-50% EtOAc:hexanes gradient as eluent) to afford the title compound. LC-MS [M + H]+: m/z 507.3.

[00254] The above intermediate (the product of Step D) was converted to (S,Z)-3-(2-((2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenoxy)ethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate following procedures similar to those described in Steps DH for Example 1. LC-MS [M + H]+: m/z 637.2. EXAMPLE 5 (S,Z)-3-(2-((2-(4-(1-(3-aminopropyl)-1H-pyrazol-4-yl)phenoxy)ethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl (C5).

[00255] Compound 5 was prepared from tert-butyl (3-(4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate following procedures similar to those described in steps EH for Example 1. LC-MS [M + H] + : m/z 623.3. EXAMPLE 6 (S )-3-(4-(1-(3-aminopropyl)-1H-pyrazol-4-yl)phenoxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((2 S ,3 S )-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (C6).

[00256] Compound 6 was prepared following similar procedures to those described above for Example 1, omitting step D and substituting (2S,3S)-3-amino-2-methyl-4-oxoazetidin-1-sulfonic acid (from commercial sources CAS: 80080-65-1) for (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate where appropriate. LC-MS [M + H]+: m/z 637.4. (C7)

[00257] Compound 7 was prepared following similar procedures to those described above for Example 1, substituting (2S,3S)-3-amino-2-methyl-4-oxoazetidin-1-sulfonic acid (CAS: 80582-09-8) for (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate. LC-MS [M + H] + : m/z 651.4. EXAMPLE 8 (S )-3-(4-(1-(3-aminopropyl)-1H-pyrazol-4-yl)phenoxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (C8).

[00258] Compound 8 was prepared following procedures similar to those described above for Example 1, omitting step D and substituting (2R,3S)-3-amino-2-methyl-4-oxoazetidin-1-sulfonic acid with (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate where appropriate. LC-MS [M + H]+: m/z 637.4. (C9)

[00259] Compound 9 was prepared following procedures similar to those described above for Example 1, substituting (2R,3S)-3-amino-2-methyl-4-oxoazetidin-1-sulfonic acid for (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate. LC-MS [M + H] + : m/z 651.3. example anoic (C10).

[00260] Step A: (S)-2-(aminooxy)-3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)propanoate The procedure was the same as in step E in Example 1 with reagents (S)-tert-butyl 3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (80 mg, 0.109 mmol) (from step C of Example 2), hydrazine (3.42, 0.109 mmol) in EtOH (4 mL). LC-MS [M+H]+: m/z 477.26.

[00261] Step B: (S,Z)-2-(((1-( tert -butoxy)-3-(4-(1-(3-(( tert -butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-(( tert -butoxycarbonyl)-amino)thiazol-4-yl)acetic acid The procedure was the same as in step Fin in Example 1 with the reagents 2-(2-((tert -butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (42.0 mg, 0.154 mmol) (intermediate 6) and 2-(aminooxy)-3-(4-(1-(3-((tert - (S)-tert-butyl butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)propanoate (70 mg, 0.147 mmol) in EtOH (4 mL) and ClCH2CH2Cl (2 mL). LC-MS [M+H]+: m/z 731.34.

[00262] Step C: (S)-3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-(( ((Z)-1-(2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate tert-butyl The procedure was the same as step G in Example 1 with the (S,Z)-2-(((1-(tert-butoxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H- acid reagents (S)-3-amino-2,2-dimethyl hydrogensulfate (S)-3-amino-2,2-dimethyl -4-oxoazetidin-1-yl (61.6 mg, 0.293 mmol) and sodium bicarbonate (61.5 mg, 0.732 mmol) in DMF (4 mL). The purification method was the same as in step G in Example 2. LC-MS [M+HM+H]+: m/z 923.48.

[00263] Step D: (S)-3-(4-(1-(3-aminopropyl)-1H-imidazol-4-yl)phenoxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid The procedure was the same as in step H in Example 2 with reactants 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4- (S)-tert-butyl oxo-1-(sulfo-oxyl)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate (36 mg, 0.035 mmol) in CH2Cl2 (0.5 mL) and TFA (0.5 mL, 6.49 mmol). LC-MS [M]+: m/z 667.24. 1H NMR (500 MHz, DMSO): δH 9.42 (d, J = 8.0 Hz, 1 H); 7.76 (s, 1H); 7.27 (s, 2 H); 7.00 (d, J = 8.4 Hz, 2 H); 6.79 (s, 1 H); 4.93 (s, 1 H); 4.61 (d, J = 7.9 Hz, 1 H); 4.34 (d, J = 32.5 Hz, 2 H); 4.14 (s, 2 H); 2.78 (s, 2H); 2.06 (br s, 2 H); 1.36 (s, 3H); 1.12 (s, 3 H). example (C11).

[00264] Step A: (S,Z)-4-(4-(3-(tert-Butoxy)-2-((((2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide The procedure was the same as Step F in Example 1 with the reagents 2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoacetic iodide (0.052 g, 0.170 mmol, Intermediate 6) and (S)- 4-(4-(2-(amino-oxy)-3-(tert-butoxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium, (0.1 g, 0.162 mmol) (from step E in Example 1), EtOH (4 mL) and ClCH2CH2Cl (2 mL). LC-MS [M]+: m/z 779.30.

[00265] Step B: Sulfate of (5 )-3-((Z)-2-(((( 5 )-1-( tert -butoxy)-3-(4- (1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-yl-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-(( tert-butoxycarbonyl )amino)-5-chlorothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl The procedure was the same as step G in Example 2 with the reagents (S,Z) iodide -4-(4-3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)-5- chlorothiazol-4-yl)(carboxy)-methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3- ((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2- io (0.14 g, 0.154 mmol), DCC (0.080 g, 0.386 mmol), HOBT (0.059 g, 0.386 mmol, (5)-3-amino-2,2-dimethyl-4-oxoazetidin-1- hydrogensulfate ila (0.065 g, 0.309 mmol), sodium bicarbonate (0.065 g, 0.772 mmol) in DMF (4 ml) [M]+: m/z 971.43.

[00266] Step C: (5 )-3-((Z)-2-(2-Amino-5-chlorothiazol-4-yl)-2-((((5)-2-(4-(1) sulfate -(3-aminopropyl)-2-methyl-1H-pyrazol-2-yl-4-yl)phenoxy)-1-carboxyethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl procedure was the same as in Step H in Example 2 with the reagents 4-(4-((5)-3-(tert-butoxy)-2-(((Z)-(1-(2-((tert- butoxycarbonyl)amino)-5-chloro-thiazol-4-yl)-2-(((5)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3- yl)amino)-2-oxo-ethylidene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io (36 mg, 0.033 mmol), CH2Cl2 (0.5 mL) and TFA (1 mL, 6.49 mmol). LC-MS [M]+: m/z 715.22. 1H NMR (500 MHz, DMSO): δH 8.77 (br s, 1 H); 8.65 (br s, 1 H); 7.34 (br s, 4 H); 6.97 (s, 2H); 4.82 (s, 1H); 4.72 (br s, 1 H); 4.57 (br s, 2 H); 4.50 (br s, 2 H); 4.27 (br s, 1 H); 4.19 (s, 3H); 3.01 (br s, 2 H); 2.21 (br s, 1 H); 2.11 (br s, 1 H); 1.42 (s, 3H); 1.30 (br s, 3 H). EXAMPLE 12 (5)-3-((Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(((5)-2-(4-(1) sulfate -(3-(aminopropyl)-2-methyl-1H-pyrazol-2-yl-4-yl)phenoxy)-1-carboxyethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl ( C12)

[00267] Step A: (S,Z)-4-(4-(3-(tert-Butoxy)-2-((((5-((tert-butoxycarbonyl)amino)-1,2,4 -thiadiazol-3-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-(( tert-butoxycarbonyl)-amino)propyl)- 2-methyl-1H-pyrazole-2 -io

[00268] The procedure was the same as in step Fin Example 1 with reagents 2-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (0.046 g, 0.170 mmol) (Intermediate 7) and (S)-4-(4-(2-(amino-oxy)-3-(tert-butoxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide (0.1 g, 0.162 mmol) in EtOH (4 mL) and ClCH2CH2Cl (2 mL). LC-MS [M]+: m/z 746.31.

[00269] Step B: (5 )-3-((Z)-2-(((( 5 )-1-( tert-Butoxy)-3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-yl-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(5-(( tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate The procedure was the same as in step G in Example 2 with the reactants (S,Z)-4-(4-(3-(tert-butoxy)-2-(((5-((tert- butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)(carboxy)-methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (0.14 g, 0.160 mmol), DCC (0.083 g, 0.401 mmol), HOBT (0.0 61 g, 0.401 mmol), (5)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogensulfate (0.067 g, 0.320 mmol) and sodium bicarbonate (0.067 g, 0.801 mmol) in DMF (4 ml). LC-MS [M]+: m/z 938.61.

[00270] Step C: (5 )-3-((Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(((S)-2-( 4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenoxy)-1-carboxyethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin- 1 -yl The procedure was the same as step H in Example 2 with the reagents 4-(4-((S)-3-(tert-butoxy)-2-(((Z)-(1-(5 -((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin- 3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io (0.14 g, 0.133 mmol) in CH2Cl2 (0.5 mL) and TFA (0.5 mL, 6.49 mmol). LC-MS [M]+: m/z 682.27. 1H NMR (500 MHz, DMSO): δH 8.72 (s, 1 H); 8.61 (s, 1 H); 8.11 (s, 2 H); 7.29 (s, 2 H); 6.93 (d, J = 8.2 Hz, 2 H); 4.83 (s, 1 H); 4.73 (d, J = 7.6 Hz, 1 H); 4.60 (br s, 1 H); 4.51 (s, 2 H); 4.24 (d, J = 10.3 Hz, 1 H); 4.20 (s, 3H); 3.02 (d, J = 23.8 Hz, 2 H); 2.21 (br s, 1 H); 2.09 (br s, 1 H); 1.44 (s, 3 H); 1.30 (s, 3 H). Table 2. Using generally the same procedure as in Example 12, without step D, Example 13 was synthesized and characterized by LC/MS. EXAMPLE 14 4-(2-(4-(4-((S)-2-((((Z)-1-(2-aminothiazol-4-yl)-2- () ((S )-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phenyl)-1H-pyrazole -1-yl)ethyl)-4-methylmorpholin-4-io (C14).

[00271] Step A: (R)-2-hydroxy-3-('4-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)phenoxy)propanoate tert-Butyl To a solution of intermediate (R)-tert-Butyl 3,3-(4-bromophenoxy)-2-hydroxypropanoate (500 mg, 1.58 mmol), 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (726 mg, 2.36 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (103 mg, 0.158 mmol) in THF (10 mL) was added 1 M aqueous phosphate solution potassium tribasic (4.73 mL, 4.73 mmol). The 20 mL microwave vial was sealed, degassed (3x) and replenished with N2, and stirred at 60 °C overnight. LC-MS indicated complete conversion. The reaction mixture was diluted with saturated NH4Cl solution and extracted with EtOAc (2 × 50 mL). The organic extract was combined, dried over MgSO4, and concentrated to dryness. The residue was purified on a Flash SiO2 column (40 g gold) with MeOH in DCM (0-15%) to afford the title compound. LC-MS [M+H]+: m/z 418.42.

[00272] Step B: (S)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-(4-(1-(2-morpholinoethyl)-1 H-pyrazol-4-yl) tert-butyl phenoxy)propanoate The procedure was the same as in step C of Example 1 with the reagent: (R)- 2-hydroxy-3-(4-(1-(2-morpholinoethyl)-1H-pyrazol-4 tert-butyl-yl)phenoxy)propanoate (0.480 g, 1.15 mmol), 2-hydroxyisoindoline-1,3-dione (0.225 g, 1.38 mmol), triphenylphosphine (0.362 g, 1.38 mmol), DIAD (0.272 mL, 1.380 mmol) and THF (4 mL)). LC-MS [M + H]+: m/z 563.47.

[00273] Step C: (S)-4-(2-(4-(4-(3-(tert-Butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)-phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-ium iodide To a solution of (S)-tert-butyl 2-((1,3-dioxoisoindolin-2-yl)oxy)-3-(4-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-phenoxy)propanoate (250 mg, 0.444 mmol) in acetonitrile (4 mL) was added iodomethane (0.167 mL, 2.67 mmol), the reaction mixture was stirred at room temperature overnight and concentrated under high vacuum to afford the title compound. LC-MS [M]+: m/z 577.56.

[00274] Step D: (5)-4-(2-(4-(4-(2-(amino-oxy)-3-(tert-butoxy)-3-oxopropoxy)phenyl)-1 H- pyrazol-1-yl)ethyl)-4-methylmorpholine-4-io The procedure is the same as in step E of Example 1 with the reagent (5)-4-(2-(4-(4-() iodide 3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-io (310 mg, 0.440 mmol), hydrazine (14.0 μl, 0.440 mmol) in EtOH (4 ml). LC-MS [M]+: m/z 447.50.

[00275] Step E: (S,Z)-4-(2-(4-(4-(3-( tert -butoxy)-2-((((2-((tert -butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-ium iodide The procedure was the same as in Step F of Example 1 with the reagents 2-(5-((tert -butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (0.118 g, 0.435 mmol) (Intermediate 7) and (5)-4-(2-(4-(4-(2- (amino-oxy)-3-(tert-butoxy)-3-oxopropoxy)phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-ium (0.250 g, 0.435 mmol) in EtOH (6 ml) and ClCH2CH2Cl (2 ml). LC-MS [M]+: m/z 701.00.

[00276] Step F: 4-(2-(4-(4-(( 5 )-3-( tert-butoxy)-2-((((Z)- 1-(2-(( tert- butoxycarbonyl)amino)thiazol-4-yl)-2-(((5)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino )oxy)-3-oxopropoxy) phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-ium The procedure was the same as in step Fin Example 2 with the reagents (S,Z) iodide -4-(2- (4-(4-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl) (carboxy)methylene)amino)oxy)-3-oxopropoxy )phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-io (0.250 g, 0.302 mmol), DCC (0.124 g, 0.603 mmol), HOBT (0.092 g, 0.603 mmol, hydrogen sulfate ( S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl (0.127 g, 0.603 mmol), sodium bicarbonate (0.101 g, 1.207 mmol) in DMF (4 mL). ]+: m/z 894.00.

[00277] Step G: (5)-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((S)-1-carboxy-2-(4-(1) sulfate -(2-4-methyl-morpholino-4-io)ethyl)-1H-pyrazol-4-yl)phenoxy)ethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl The procedure was the same as step H in Example 2 with the 4-(2-(4-(4-((S)-3-(tert-butoxy)-2-((((Z)-1 -(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo- oxy)azetidin-3-yl)amino)-2-oxoethylidene)-amino)-i)-3-oxopropoxy)phenyl)-1H-pyrazol-1-yl)ethyl)-4-methylmorpholin-4-ium (0.070 g , 0.069 mmol) in CH2Cl2 (0.5 mL) and TFA (0.5 mL, 6.49 mmol). LC-MS [M+H]+: m/z 737.43. Table 3. Using the same procedures as in Example 1, Examples 15-22 were synthesized and characterized by LC/MS EXAMPLES 23A and 23B 23A: 1-(3-aminopropyl)-4-(4-(2-((((Z)-1-(2-aminothiazol-4-yl)-2 2,2,2-trifluoroacetate -(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxypropoxy)phenyl)-2 -methyl-1Hpyrazol-2-ium 23B: 1-(3-aminopropyl)-4-(4-(2-((((Z)-1-(2-aminothiazol-4-) il)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3- yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxypropoxy)phenyl)-2-methyl-1Hpyrazol-2-io

[00278] Step A: (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate tert-Butyl Cesium carbonate (12.2 g, 37.5 mmol) was added to a room temperature mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.85 g, 25.00 mmol), (3-bromopropyl)tert-butylcarbamate (5.95 g, 25.0 mmol) in 40 mL of DMF and the mixture was stirred at room temperature overnight. LC-MS showed the reaction to be complete. The mixture was diluted with EtOAc and water. Extracted with EtOAc. The combined organic layer was washed with brine and dried over MgSO4. Filtered and concentrated down. The residue was purified by column chromatography on silica gel, eluted with EtOAc/isohexane (10-80% gradient) to obtain the title compound. LC-MS [M + H]+: m/z 352.33.

[00279] Step B: 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin- tert-butyl 2-yl)oxy)-2-methylpropanoate To a solution of tert-butyl 2-(aminooxy)-3-(4-bromophenoxy)-2-methylpropanoate (100 mg, 0.289 mmol), tert -butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl) carbamate (101 mg, 0.289 mmol) and 1,1'-bis(di-tert-butylphosphine)ferrocenepalladium dichloride (18.82 mg, 0.029 mmol) in dioxane (1 mL) were added to 1 M aqueous potassium phosphate solution (0.871 mL, 0.867 mmol). The flask was sealed, degassed and replenished with N2, and stirred at 70 °C for 1 hour. LC-MS indicated complete conversion. Dilute with water. Extract with EtOAc x 2. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel column, eluting with CH2Cl2/MeOH (100~90%) to provide the title compound. LC- MS [M + H]+: m/z 491.43.

[00280] Step C: 3-(4-(1-(3-(( tert -butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin- tert -butyl 2-yl)oxy)-2-methylpropanoate

[00281] 4-Methylbenzenesulfonic acid (12% in acetic acid) (63.2 mg, 0.044 mmol) was added to a room temperature mixture of tert-butyl 2-(aminooxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-methylpropanoate (540 mg, 1.10 mmol), molecular sieves (200 mg) in toluene, and the mixture was stirred at 100 °C for 4 h. LC-MS showed the reaction nearly complete. Filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with CH 2 Cl 2 /MeOH (100~90%) to obtain the title compound. LC-MS [M + H]+: m/z 622.56.

[00282] Step D: 4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methyl-3-oxopropoxy)-phenyl) -1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io The procedure was the same as step D in Example 1 with the reagent 3-(4-( tert-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate butyl (0.495 g, 0.797 mmol), MeI (0.399 ml, 6.38 mmol) in MeCN (3 ml). LC-MS [M]+: m/z 635.58

[00283] Step E: (Z)-4-(4-(3-( tert-Butoxy)-2-((((2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide Hydrazine (0.024 mL, 0.763 mmol) in 0.3 mL DCM was added to a stirred mixture at room temperature of 4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methyl-3-oxopropoxy)phenyl)- 1-(3-((tert-Butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (485 mg, 0.763 mmol) in EtOH/DCM, and the mixture was stirred at room temperature for 4 h. LC-MS showed that the intermediate was generated. Then 2-(2-((tert-Butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (228 mg, 0.839 mmol) was added and stirred at room temperature overnight. LC-MS showed the reaction complete. The solution was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC, eluting with acetonitrile/water + 0.05% TFA (0~100%) to give the title compound. LC-MS [M + H]+: m/z 759.58.

[00284] Step F: 4-(4-(3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2 -((((2R,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methyl-3-oxopropoxy) phenyl) -1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io To a solution of (Z)-4-(4-(3-(tert-) iodide butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-2-methyl-3- (oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (80 mg, 0.105 mmol) in DMF (1 mL) were added DCC ( 87 mg, 0.421 mmol) and HOBT (60.5 mg, 0.316 mmol). The mixture was then stirred at room temperature for 30 min, followed by the addition of (S)-3-amino-2,2-dimethyl- 4-oxoazetidin-1-yl (76 mg, 0.421 mmol) and sodium bicarbonate (35.4 mg, 0.421 mmol). The final mixture was stirred at room temperature overnight (16 hours). LC-MS indicated complete conversion . The reaction mixture was filtered and the filtrate was purified by reverse-phase ISCO (130 g, 0-100%, H2O/MeCN/0.05% TFA), fractions were collected and lyophilized to obtain the title compound. LC-MS [M + H]+: m/z 921.76.

[00285] Step G: (5 )-3-((Z)-2-((((5)-1-(4-(1- (3-aminopropyl)-2-methyl-1 H) sulfate compound -pyrazol-2-io-4-yl)phenoxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin - 1-yl with 2 2,2-trifluoroacetic acid (1:1) To a solution of 4-(4-(3-(tert-butoxy)-2-((((Z)-1-(2-( (tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((5)-2,2- dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert (-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (110 mg, 0.116 mmol) in DCM was added, 2 mL of TFA. The mixture was stirred at room temperature for 90 min. LC- MS indicated complete conversion. The mixture was concentrated to dryness under vacuum (no heat). DCM (10 mL) was added and concentrated three times to remove TFA. The residue was washed with dry MeCN (2x2 mL) to remove impurities. The residue was dissolved in DMSO and purified on preparative HPLC with a gradient of MeCN/H2O (0.05% TFA in both) from 2-25% in 10 minutes. The fastest eluting isomer was Compound 23A and the slowest was Compound 23B. Product fractions were collected and lyophilized to obtain the title compounds. Compound 23A: LC-MS [M + H]: m/z 695.33. Compound 23B: LC-MS [M + H]: m /z 695.16. EXAMPLE 24 (S )-3-((Z)-2-(((S )-2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-sulfate 4-yl)-3-fluorophenoxy)-1-carboxyethoxy)imino)-2-(2-ammothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl (C24).

[00286] Step A: (R )-tert-butyl 3-(4-bromo-3-fluorophenoxy)-2-hydroxypropanoate The procedure was the same as Intermediate 3 with tert-butyl oxirane-2-carboxylate reagent (4.19 g, 29.1 mmol), (R,R)-Co catalyst (0.595 g, 0.709 mmol), 4-bromo-3-fluorophenol (2.71 g, 14.19 mmol). LC-MS [M + Na]+: m/z 358.92.

[00287] Step B: (R )-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-hydroxypropanoate tert-butyl The procedure was the same as in Step B in Example 1 with the reagent tert-butyl (R)-3-(4-bromo-3-fluorophenoxy)-2-hydroxypropanoate (470 mg, 1.40 mmol), tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate (512 mg, 1.458 mmol), 1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride (91 mg, 0.140 mmol), 1,4-dioxane (4 ml) and potassium phosphate (4.21 ml, 4.21 mmol, 1M aq.). LC-MS [M + H]+: m/z 480.84.

[00288] Step C: (S )-3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)- 1H-pyrazol-4-yl)-3-fluorophenoxy)-2-(( tert-butyl 1,3-dioxoisoindolin-2-yl)oxy)propanoate The procedure was the same as Step C in Example 1 with the reagent of (R)-3-(4-(1-(3-( tert-butyl (tert-butoxycarbonyl))-amino)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-hydroxypropanoate (0.451 g, 0.94 mmol), 2-hydroxyisoindoline-1 ,3-dione (0.153 g, 0.94 mmol), triphenylphosphine (0.271 g, 1.04 mmol), DEAD (0.164 ml, 1.04 mmol) and THF (4 ml). LC-MS [M + H]+: m/z 625.51.

[00289] Step D: (S )-4-(4-(3-( tert -butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)-2- iodide fluorophenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io The procedure was the same as step D in Example 1 with the reagent (S)- 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-((1,3-dioxoisoindolin-2-yl) tert-butyl oxy)propanoate (0.576 g, 0.922 mmol), MeI (0.461 mL, 7.38 mmol) in MeCN (3 mL). LC-MS [M]+: m/z 639.55

[00290] Step E: (S,Z)-4-(4-(3-( tert-Butoxy)-2-((((2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)-(carboxy)methylene)amino)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide The procedure was the same as in step E of Example 1 with the reagents hydrazine (0.028 mL, 0.89 mmol), (S)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)- 2-fluorophenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io (712 mg, 0.89 mmol), 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (267 mg, 0.979 mmol). LC-MS [M + H]+: m/z 763.53.

[00291] Step F: 4-(4-(( S )-3-( tert-butoxy)-2-((((Z)-1-(2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((( S )-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium The procedure was the same as that in Step F in Example 1 with the reagents (S,Z)-4-(4-(3-(tert-butoxy)-2-((((2-((tert- butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)-amino)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (0.679 g, 0.889 mmol), DCC (0.550 g, 2.67 mmol), HOBT (0.510 g, 2.67 mmol), (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogensulfate (0.280 g, 1.33 mmol) and sodium bicarbonate (0.299 g, 3.56 mmol) in DMF (3 ml). LC-MS [M]+: m/z 955.69.

[00292] Step G: (5)-3-((Z)-2-((( 5)-2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)-3-fluorophenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate compound with formic acid (1:1) The procedure was the same as that in step G in Example 1 with the reactants 4-(4-((5)-3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((5)-2,2- dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (0.13 g, 0.136 mmol), TFA (2 ml, 26 mmol). LC-MS [M]+: m/z 699.69 EXAMPLE 25 1-(3-Aminopropyl)-4-(4-((S)-2-(((Z)-1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-o xoethylidene)amino)oxy)-2-carboxypropoxy)phenyl)-2-methyl-1H-pyrazol-2-io (C25)

[00293] Step A: 4-(4-(3-( tert -butoxy)-2-((((Z)-1-(2-(( tert -butoxycarbonyl)-amino)thiazol-4-yl)-2-(((2R,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium The procedure was the same as that in Step F in Example 1 with the (Z)-4-(4-(3-(tert)-butoxy)-2-((((2-((tert -butoxycarbonyl) amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io (0.080 g, 0.105 mmol), DCC (0.087 g, 0.421 mmol), HOBT (0.0605 g, mmol), (2R,3S)-3-amino-2-methyl-4-oxoazetidin-1-sulfonic acid (0.076 g, 1.05 mmol) and sodium bicarbonate (0.0354 g, 0.421 mmol). LC-MS [M]+: m/z 921.76.

[00294] Step B: (2 R ,3 S )-3-((Z)-2-(((( S )-1-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenoxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2-methyl-4-oxoazetidin-1-sulfonate with 2,2,2-trifluoroacetic acid (1:1) The procedure was the same as that in step G in Example 1 with the reactants 4-(4-(3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-methyl-4-oxo-1- sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (0.086 g, 0.093 mmol), TFA (2.5 mL, 32.4 mmol). TFA (2.5 ml, 32.4 mmol). LC-MS [M]: m/z 665.20 EXAMPLE 26 2-(1-(3-aminopropyl)-1H-pyrazol-4-yl)-5-((S)-2-(((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy) zetidin-3-yl)amino)-2-oxo-ethylidene)amino)oxy)-2-carboxyethoxy)-1-methylpyridin-1-ium (C26)

[00295] Step A: tert-Butyl 3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoate K2CO3 (6.35 g, 46.0 mmol) was added to a stirred mixture at room temperature of tert-butyl oxirane-2-carboxylate (6.63 g, 46.0 mmol), 6-bromopyridin-3-ol (4 g, 22.99 mmol) in acetonitrile, and the mixture was stirred at 90 °C for 3 h, cooled to room temperature, and filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/isohexane (0% to 50%) to give the title compound.

[00296] Example 26 (S)-3-((Z)-2-(((S)-2-((6-(1-(3-aminopropyl)-1H-pyrazol-4-yl sulfate compound )-1-methylpyridin-1-io-3-yl)oxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1- yl with 2,2,2-trifluoroacetic acid (1:1) was prepared from tert-butyl 3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoate in 6 steps. The procedures of the six steps were the same as in step B, C, D, E, F, G of Example 2. LC-MS [M]+: m/z 682.20 EXAMPLE 27 (S )-3-(4- (3-amino-1-(3-aminopropyl)-1H-pyrazol-4-yl)phenoxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(( ( S )-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (C27)

[00297] Step A: tert-butyl (3-(3-amino-4-bromo-1H-pyrazol-1-yl)propyl)carbamate The procedure was the same as in Step A of Example 1 with the reactants 4-bromo-1H-pyrazol-3-amine and tert-butyl (3-bromopropyl)carbamate.

[00298] Step B: (S )-3-(4-(3-amino-1-(3-((tert-butoxycarbonyl)amino)-propyl)-1 H-pyrazol-4-yl)phenoxy)-2 -((tert-butyldimethylsilyl)oxy) tert-butyl propanoate The procedure was the same as step B in Example 1 with the reagents 2-((tert-butyldimethylsilyl)oxy)-3-(4- (4, tert-butyl 4,5,5)-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-propanoate (0.21 g, 0.439 mmol) (Intermediate 8), (3-(3-amino tert-butyl-4-bromo-1H-pyrazol-1-yl)propyl)carbamate (0.17 g, 0.533 mmol) and 1,1'-bis(di-tert-butylphosphine)-ferrocene-palladium dichloride (0.029 g, 0.044 mmol) in THF (3 mL). LC-MS [M+H]+: m/z 592.00

[00299] Step C: 3-(4-(3-(((allyloxy)carbonyl)amino)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-1 H-pyrazol-4-yl)phenoxy tert-butyl )-2-((tert-butyldimethylsilyl)oxy)propanoate A solution of 3-(4-(3-amino-1-(3-((tert-butyl)-butoxycarbonyl)amino)propyl)- tert-Butyl 1H-pyrazol-4-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (0.54 g, 0.914 mmol) in CH2Cl2 (10 mL), DIPEA (0.319 mL, 1.83 mmol) followed by allyl carbonate (0.194 ml, 1.828 mmol) at room temperature. The mixture was stirred for 4 hours, then the solvent was removed. The residue was purified by column chromatography on silica gel (40g Redi gold column), eluted with EtOAc/hexane (0-50%, 6hp; 50%, 10hp) to afford the title compound. LC-MS [M+H]+: m/z 676.71.

[00300] Step D: tert-Butyl 3-(4-(3-(((allyloxy)carbonyl)amino)-1-(3-(( tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-hydroxypropanoate To a solution of tert-butyl 3-(4-(3-(((allyloxy)carbonyl)amino)-1-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-(( tert-butyldimethylsilyl)oxy)propanoate (0.54 g, 0.80 mmol), was added TBAF in THF (0.80 mL, 0.80 mmol, 1M) at room temperature. The mixture was stirred for 1 h, the solvent was removed. The residue was purified by column chromatography on silica gel (24g Redi gold column), eluted with EtOAc/Hexane (0-80%, 6hp; 80%, 10hp) to afford the title compound. LC-MS [M+H]+: m/z 561.11

[00301] Step E: 3-(4-(3-(((allyloxycarbonyl)amino)-1-(3-(( tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate tert-butyl The procedure was the same as step C of Example 1 with the reactants 3-(4-(3-(((allyloxycarbonyl))amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-hydroxypropanoate (0.3 g, 0.535 mmol), 2-hydroxyisoindoline-1,3-dione (0.096 g, 0.589 mmol), triphenylphosphine (0.168 g, 0.642 mmol), DIAD (0.125 mL, 0.642 mmol) in THF (1 mL). LC-MS [M+H]+: m/z 706.

[00302] Step F: tert-butyl 3-(4-(3-(((allyloxycarbonyl)amino)-1-(3-(( tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-(aminooxy)propanoate The procedure was the same as that in step E in Example 1 with the reagents 3-(4-(3-(((allyloxy)carbonyl)-amino)-1-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (35 mg, 0.050 mmol) and hydrazine (3.11 μg, 0.099 mmol) in THF (2 mL). LC-MS [M+H]+: m/z 576.47

[00303] Step G: (Z)-2-(((3-(4-(3-(((Allyloxy)carbonyl)amino)-1-(3-(( tert-butoxycarbonyl)amino)-propyl)-1H-pyrazol-4-yl)phenoxy)-1-( tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid The procedure was the same as step Fin of Example 1 with the reagents 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (0.028 g, 0.101 mmol) and 3-(4-(3- Tert-butyl (((allyloxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-(aminooxy)propanoate (0.053 g, 0.092 mmol) in EtOH (2 ml). LC-MS [M+H]+: m/z 830.64

[00304] Step H: 3-(4-(3-(((allyloxycarbonyl)amino)-1-(3-(( tert-butoxycarbonyl)amino)-propyl)-1H-pyrazol-4-yl)phenoxy)-2-((((Z)-1-(2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-propanoate tert-butyl The procedure was the same as that in step G in Example 1 with the (Z)-2-(((3-(4-(3-(((allyloxycarbonyl)amino)-1-(3-((tert- (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (77 mg, 0.366 mmol), and sodium bicarbonate (77 mg, 0.916 mmol) in DMF (4 mL). The reaction mixture was filtered and transferred to the next step without purification. LC-MS [M+H]+: m/z 1023.31

[00305] Step I: 3-(4-(3-amino-1-(3-((tert-butoxycarbonyl)-amino) propyl)-1 H-pyrazol-4-yl)phenoxy)-2-((( (Z)-1-(2-(( tert-butoxycarbonyl)amino) thiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin tert-butyl -3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate To the crude reaction mixture of 3-(4-(3-(((allyloxycarbonyl)amino)-1-(3-((tert -butoxy)-carbonyl)amino) propyl)-1H-pyrazol-4-yl)phenoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)- amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy ) tert-butyl propanoate (70 mg, 0.068 mmol) in DMF (2 mL) were added Tetracis (23.7 mg, 0.021 mmol) and phenylsilane (74.1 mg, 0.685 mmol). The mixture was stirred at room temperature for 10 minutes. The mixture was filtered and purified on RP-HPLC (Gilson) (C-18 column), eluted with ACN/water with 0.05% TFA (20-100%, 8 min; 100% 10 min). The product fraction was freeze-dried to provide the title compound. LC-MS [M+H]+: m/z 938.88

[00306] Step J: (S)-3-(4-(3-Amino-1-(3-aminopropyl)-1H-pyrazol-4-yl)phenoxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid The procedure was the same as in Step H in Example 2 with the 3-(4-(3-amino-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino) reagents tert-butyl thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate, TFA (40 mg, 0.038 mmol), TFA (0.5 ml, 6.49 mmol) in DCM (0.5 ml). LC-MS [M+H]+: m/z 682.45. 1H NMR (500 MHz, D2O) d 7.62 (s, 1 H); 7.30 (d, J = 8.4 Hz, 2 H); 6.96 (t, J = 4.4 Hz, 3 H); 4.94-4.96 (m, 1H); 4.40-4.43 (m, 2H); 4.04-4.07 (m, 2H); 2.87-2.90 (m, 2H); 2.07-2.10 (m, 2H); 1.33 (s, 3H); 1.07 (s, 3 H). example -ila (C28)

[00307] Step A: (S )-3-(((Allyloxycarbonyl)amino)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl) lodide oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io The procedure was the same as in step D of Example 1 with the reagents 3-(4-(3-(((allyloxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-( (S)-tert-butyl(1,3-dioxoisoindolin-2-yl)oxy)propanoate (110 mg, 0.156 mmol), MeI (0.078 mL, 1.247 mmol) in CAN (1.5 mL). LC-MS [M]+: m/z 720.09.

[00308] The procedures in Step BF were the same as in Step FJ in Example 28 to afford the title compound. LC-MS [M+H]+: m/z 696.41. 1H NMR (500 MHz, D2O) δ 7.97 (1H, s), 7.38 (2H, d, J = 8.3 Hz), 7.01-7.08 (3H, m), 4.99 (1H, d, J = 5.8 Hz), 4.43-4.51 (2H, m), 4.33 (2H, t, J = 7.2 Hz), 3.77 (3H, s), 3.06 (2H, t, J = 7.9 Hz), 2.14-2.20 (2H, m), 1.44 (3H, s), 1.10 (3H, s). EXAMPLE 29 1-(3-Aminopropyl)-4-(4-(( R )-2-((((Z)-1-(2-aminothiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1 -(sulfo-oxy)azetidin-3 -yl)amino)-2-oxoethylidene)amino)oxy)-2-(2H -tetrazol-5-yl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium (C29)

[00309] Step A: (R)-Ethyl 3-(4-bromophenoxy)-2-hydroxypropanoate To a mixture of 4-bromophenol (2 g, 11.6 mmol), R,R-Co(III) catalyst (0.485 g, 0.578 mmol) (J. Am. Chem. Soc., 1999, 121, 6086-6087), 4Â molecular sieves (4 g), ethyl oxirane-2-carboxylate (2.95 g, 25.4 mmol), tert-butyl methyl ether (6 mL) was added under N2, the resulting suspension was stirred at room temperature under N2 over the weekend. The filtrate was concentrated after filtration, and the residue was purified on silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 288.9, 290.9.

[00310] Step B: (R)-3-(4-Bromophenoxy)-2-hydroxypropanoic acid To a solution of (R)-ethyl 3-(4-bromophenoxy)-2-hydroxypropanoate (3.13 g, 10.8 mmol) in THF (60 mL) and MeOH (20 mL) at 0 °C was added NaOH (21.6 mL, 21.6 mmol) and the resulting solution was stirred at 0 °C for 4 h. The solution was then acidified with 4N HCl/dioxane (5.5 mL) and the resulting solution was concentrated and the residue was partitioned between EtOAc and water, the aqueous phase was extracted with EtOAc, the combined organic phase was dried over Na2SO4, and concentrated to afford the title compound. 1H NMR (CDCl3, 500 MHz): δ 7.42-7.40(d, J = 9.0Hz, 2H), 6.84-6.82(d, J = 9.0Hz, 2H), 4.63-4.62(t, J = 3.5Hz, 1H), 4.32-4.31(d, J = 3.5Hz, 2H).

[00311 ] Step C: (R)-3-(4-bromophenoxy)-2-hydroxypropanamide To a suspension of (R)-3-(4-bromophenoxy)-2-hydroxypropanoic acid (2.81 g, 10.8 mmol) in DCM (80 mL) was added 1-hydroxy-2,5-pyrrolidinedione monohydrate (1.50 g, 11.3 mmol) and EDC (3.10 g, 16.1 mmol). The resulting mixture was stirred at room temperature for 2 h. The mixture was partitioned between water and DCM, the organic phase was washed with water, brine, dried over Na2SO4, concentrated, and the residue was dissolved in dioxane (80 mL) and cooled to 0 °C. To the above solution was added ammonium hydroxide (15.0 mL, 108 mmol), the resulting solution was stirred at 0 °C for 30 min, then concentrated and the residue was treated with DCM, the solid was collected by filtration. The filtrate was concentrated and the residue was purified on a silica gel column using EtOAc/hexane as eluting solvents, combined with the solid obtained above, to afford the title compound. LC/MS: [M+H]+: 260.0; 262.0.

[00312] Step D: (R)-3-(4-bromophenoxy)-2-((tert-butyldimethylsilyl)oxy)-propanamide

[00313] To a solution of (R)-3-(4-bromophenoxy)-2-hydroxypropanamide (1.8 g, 6.92 mmol) in acetonitrile (20 mL) were added imidazole (2.36 g, 34.6 mmol), TBS-Cl (2.61 g, 17.3 mmol), and DMAP (0.085 g, 0.692 mmol). The resulting solution was stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc and sat. NaHCO3, the aqueous phase was extracted with EtOAc three times, the combined organic phase was dried over Na2SO4, concentrated, and the residue was purified on silica gel column using EtOAc/hexane as eluting solvents to afford the title compound. LC/MS: [M+H]+: 374.1; 376.1.

[00314] Step E: (S)-3-(4-bromophenoxy)-2-((tert-butyldimethylsilyl)oxy)-propanenitrile

[00315] To a solution of (R)-3-(4-bromophenoxy)-2-((tert-butyldimethyl)silyl)oxy)propanamide (2.51 g, 6.71 mmol) in DMF (8 mL) at 0°C was added cyanuric chloride (0.663 g, 3.60 mmol), and the resulting solution was stirred at 0°C for 1 h. The mixture was quenched by the addition of saturated NaHCO3, the mixture was diluted in EtOAc and washed with saturated NaHCO3. NaHCO3 was evaporated three times, dried over Na2SO4, concentrated, and the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. 1H NMR (CDCl3, 500 MHz): δ 7.43-7.42(d, J=8.9Hz, 2H), 6.83-6.81(d, J=8.9Hz, 2H), 4.82-4.79(dd, J=5.6Hz, 1H), 4.18-4.15(dd, J=5.6Hz, 2H), 0.95(s), , 9H), 0.25(s, 3H), 0.20(s, 3H).

[00316] Step F: (S )-5-(2-(4-bromophenoxy)-1 -((tert - butyldimethylsilyl)oxy)ethyl)-2H-tetrazol

[00317] To a solution of (S)-3-(4-bromophenoxy)-2-((tert-butyldimethylsilyl)oxy)propanenitrile (1.82 g, 5.11 mmol) in toluene (30 mL) was added dibutyltin oxide (0.381 g, 1.53 mmol) and TMS-N3 (2.03 mL, 15.3 mmol). The resulting mixture was heated at 110 °C overnight. After concentration, the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 399.1; 401.1.

[00318] Step G: (S)-5-(2-(4-bromophenoxy)-1-((tert-butyldimethylsilyl)oxy)ethyl)-2-(4-methoxybenzyl)-2H-tetrazole A mixture of K2CO3 (1.13 g, 8.19 mmol), tetrabutylammonium chloride hydrate (0.162 g, 0.546 mmol), 4-methoxybenzyl chloride (0.407 mL, 3.00 mmol), and (S)-5-(2-(4-bromophenoxy)-1-((tert-butyldimethylsilyl))oxy)-ethyl)-2H-tetrazole (1.09 g, 2.73 mmol) in water (4 mL) and ClCH2CH2Cl (16 mL) was heated at 40 °C overnight. The mixture was partitioned between EtOAc/water, the mixture was extracted with DCM three times, the combined organic phase was dried over Na2SO4, concentrated and the residue was purified on silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 519.2; 521.2.

[00319] Step H: (3-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl) -1H-pyrazol-1-yl)propyl) (S)-tert-butyl carbamate To (S)-5-(2-(4-bromophenoxy)-1- ((tert-butyldimethylsilyl)oxy)ethyl) solution -2-(4-methoxybenzyl)-2H-tetrazol (0.57 g, 1.10 mmol) and (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 tert-butyl-yl)-1H-pyrazol-1-yl)propyl)carbamate (0.424 g, 1.21 mmol) in dioxane (20 mL) was added Na2CO3 (1.646 mL, 3.29 mmol), the resulting solution was bubbled with N2 for 1 h before addition of PdCl2(dppf)-CH2Cl2 adduct (0.090 g, 0.110 mmol) . The resulting mixture was continued to be bubbled with N2 for 20 minutes, then heated at 100°C overnight. After filtration through Celite®, the filtrate was concentrated and the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to provide the title compound. LC/MS: [M+H]+: 664.6.

[00320] Step I: (S)-tert-Butyl (3-(4-(4-(2-hydroxy-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate To a solution of (3-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate (0.25 g, 0.377 mmol) in THF (15 mL) at 0 °C, TBAF (1 M in THF) (0.377 mL, 0.377 mmol) was added dropwise, the resulting solution was stirred at room temperature for 0.5 h, the solution was concentrated and the residue was purified on silica gel column using EtOAc/hexane as elution solvents to obtain the title compound. LC/MS: [M+H]+: 550.5.

[00321] Step J: (3-(4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)ethoxy)feml)-1H-pyrazol-1-yl)propyl) (R)-tert-butyl carbamate To solution of (3-(4-(4-(2-hydroxy-2-(2-(4 - methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl) (S)-tert-butyl carbamate (0.19 g, 0.346 mmol) in THF (10 mL ), 2-hydroxyisoindoline-1,3-dione (0.068 g, 0.415 mmol), triphenylphosphine was added (0.136 g, 0.519 mmol) and DEAD (0.082 mL, 0.519 mmol), the resulting solution was stirred at room temperature for 2 h. The solution was then concentrated and the residue was purified on a silica gel column using EtOAc/hexane to provide the title compound. LC/MS: [M+H]+: 695.5.

[00322] Step K: (R)-1-(3-((tert-butoxycarbonyl)amino) propyl)-4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy) lodeide) -2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-io Mixture of (3-(4-(4-( 2- ((1,3-dioxoisoindolin-2-yl)oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl )(R)-tert-butyl carbamate (240 mg, 0.345 mmol) in acetonitrile (3 mL), MeI (0.108 mL, 1.73 mmol). The resulting mixture was heated at 60°C overnight. Additional Mel (0.108 mL, 1.727 mmol) was added and the resulting solution was heated at 60°C for 24 h. The solution was concentrated to provide the title compound. LC/MS: [M]+: 709.6.

[00323] Step L: (R )-4-(4-(2-(amino-oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-1- (3-((tert-butoxycarbonyl)amino)propyl)-2-methyl- 1H-pyrazol-2-io (R)-1-(3-((tert-butoxycarbonyl)amino)propyl)- 4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-2-methyl -1H-pyrazol-2-io (301 mg, 0.360 mmol) in ethanol (4 mL) and CH2Cl2 (4 mL) at 0°C was added hydrazine (0.011 mL, 0.360 mmol), the resulting solution was stirred at 0°C for 30 min, the solution was then concentrated to afford the title compound. LC/MS: [M]+: 579.5.

[00324] Step M: (R,Z)-1-(3-(( tert -butoxycarbonyl)ammo)propyl)-4- (4-(2-((((2-(( tert-butoxycarbonyl)amino) thiazol-4-yl)(carboxy)methylene)amino)oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2 -io

[00325] To a suspension of (R)-4-(4-(2-(amino-oxy)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-1-(3-(tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (209 mg, 0.361 mmol) in ethanol (6 mL) and CH2Cl2 (6 mL) was added 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (196 mg, 0.721 mmol). The resulting solution was stirred at room temperature for 1 h, after concentration the residue was purified on reversed-phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as mobile phase to afford the title compound. LC/MS: [M]+: 833.6.

[00326] Step N: (R,Z)-4-(4-(2-((((2-aminothiazol-4-yl)(carboxy) methylene)-amino)oxy)-2-(2H-tetrazol- 5-yl)ethoxy)phenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io A a flask containing (R,Z)-1-(3 -((tert-butoxycarbonyl)-amino)propyl)-4-(4-(2-((((2- ((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)-methylene)amino)oxy )-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-io (230 mg, 0.276 mmol), TFA (4 mL, 51.9 mmol) was added), the resulting solution was stirred at room temperature for 30 min, the solution was concentrated, and the residue was dissolved in TFA (4 mL), the resulting solution was heated to 70° C for 45 min. The solution was concentrated and the residue was dissolved in DMF (16 mL), to the resulting solution at 0 °C were added TEA (0.231 mL, 1.655 mmol) and BOC2O (0.077 mL, 0.331 mmol). The resulting solution was stirred at 0°C for 1 hour, then purified on reversed-phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as the mobile phase to afford the title compound. LC/MS : [M]+: 613.5.

[00327] Step O: (5)-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((R)-2-(4-(1-(3-) sulfate ((tert-butoxycarbonyl)-amino)propyl)-2-methyl-1H-pyrazol-2-yl-4-yl)phenoxy)-1-(2H-tetrazol-5-yl)ethoxy)-imino)acetamido) -2,2-dimethyl-4- oxoazetidin-1-yl To solution of (R,Z)-4-(4-(2-((((2-aminothiazol-4- yl)(carboxy)methylene)amino) oxy)-2-(2H-tetrazol-5-yl)ethoxy)phenyl)-1-(3-((tert- To (47 mg, 0.077 mmol) in DMF (4 mL) was added (butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (47 mg, 0.077 mmol), DCC (79 mg, 0.383 mmol), and HOBT (58.6 mg , 0.383 mmol). The resulting solution was stirred at room temperature for 30 min, then (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (64.4 mg, 0.306 mmol) and sodium bicarbonate (77 mg, 0.919 mmol) was added. The resulting mixture was stirred at room temperature overnight. Additional DCC (79 mg, 0.383 mmol) and (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (64.4 mg, 0.306 mmol) were added and the resulting solution was stirred at room temperature for 1 hour. After filtration of the reaction mixture, the filtrate was purified by reverse-phase HPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as the mobile phase to afford the title compound. LC/MS: [M]+: 805.4.

[00328] Step P: 1-(3-aminopropyl)-4-(4-((R)-2-((((Z)-1-(2-aminothiazol-4-) yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-(2H -tetrazol-5-yl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-io To (S)-3-((Z)- 2-(2-aminothiazol-4-yl) Sulfate solution -2-(((R)-2-(4-(1-(3-((tert-butoxycarbonyl)amino) (propyl)-2-methyl-1H-pyrazol-2-yl-4-yl)phenoxy)-1-(2H-tetrazol-5-yl)ethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin- 1-yl (30 mg, 0.037 mmol) in CH2Cl2 (2 mL), TFA (2 mL, 26.0 mmol) was added. The resulting solution was stirred at room temperature for 30 min. After concentration, the residue was purified by Reversed-phase HPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as mobile phase to afford the title compound. LC/MS: [M]+: 705.4. 1H NMR (DMSO-d6, 500 MHz): δ 9.48-9.46(d, J=7.7Hz, 1H), 8.98(s, 1H), 8.94(s, 1H), 7.77(s, 1H), 7.66-7.63 (d, J = 8.5Hz, 2H), 7.31(s, 1H), 7.11-7.09(d, J = 8.6Hz, 2H), 5.92(s, 1H), 4.59-4.52(m, 6H), 4.12( s,3H), 2.94-2.90(m, 2H), 2.20-2.17(m, 2H), 1.38(s, 3H),1.15(s, 3H). EXAMPLE 30 1-(3-Aminopropyl)-4-(4-((R )-2-((((Z)-1-(2-aminothiazol-4-yl)-2 2,2,2-trifluoroacetate -(((2S,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-(2H-tetrazol-5-yl) ethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium (C30)

[00329] Step A: 4-(4-((R )-2-(((Z)-(1-(2-aminothiazol-4-yl)-2- (((2 S , 3 S )-2 -methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-(2H-tetrazol-5-yl)ethoxy)phenyl)-1-(3-(( tert-butoxycarbonyl)amino) propyl)-2-methyl-1 H-pyrazol-2-io To solution of (R,Z)-4-(4-(2-((((2-aminothiazol-4-yl) (carboxy)methylene)amino)oxy)-2-(2H-tetrazol-5-yl)ethoxy) phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (18.8 mg, 0.031 mmol) in DMF (2 mL) were added DCC ( 63.2 mg, 0.306 mmol) and HOBT (23.46 mg, 0.153 mmol). The resulting solution was stirred at room temperature for 30 min, then (2S,3S)-3-amino-2-methyl-4-amino acid -oxoazetidin-1-sulfonic acid (22.1 mg, 0.123 mmol) and sodium bicarbonate (30.9 mg, 0.368 mmol) were added. The resulting mixture was stirred at room temperature for 1 h. After filtration of the reaction mixture, the filtrate was purified by reverse-phase HPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as the mobile phase to afford the title compound. LC/MS: [M] +: 775.6.

[00330] Step B: 1-(3-aminopropyl)-4-(4-((R)-2-((((Z)-1-(2-aminothiazol-4-) yl)-2-(((2S,3S))-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-(2H-tetrazol -5- yl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-io To the solution of 4-(4-((R)-2-((((Z)-(1- (2-aminothiazole -4-yl)-2-(((2S,3S)-2-methyl-4-oxo-1-sulfoazetidin-3-yl)amino)- 2-(2-oxoethylidene)amino)oxy)-2-(2H-tetrazol-5-yl)ethoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazole-2 -io (11 mg, 0.014 mmol) in CH2Cl2 (2 mL), TFA (2 mL, 26.0 mmol) was added. The resulting solution was stirred at room temperature for 30 min, the volatile was evaporated, and the residue was purified by reversed-phase HPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as mobile phase to afford the title compound. LC/MS: [M+H]+: 675.4. 1H NMR (DMSO -d6, 500 MHz): δ 9.29-9.27(d,J=6.7Hz, 1H), 8.98(s,1H), 8.95(s, 1H), 7.78(m, 3H), 7.66-7.63(d, J = 10.2Hz, 2H), 7.31(s, 2H), 7.15-7.13(d, J = 9.6Hz, 2H), 6.82(s, 1H), 5.91(t, J = 7.3Hz, 1H), 4.62-4.59(m, 2H), 4.55- 4.53(t, J = 7.0Hz, 2H), 4.43- 4.41(d, J = 9.7Hz, 1H), 4.12(s, 3H), 3.72- 3.71(m, 1H), 2.94-2.90(m, 2H), 2.21-2.17(t, J = 7.8Hz, 2H), 1.30-1.28(d, J = 6.1Hz, 3H). EXAMPLE 31 3-(2-Amino-4-(4-((S))-2-((((Z)-1-(2-aminothiazol-4-yl)-2- 2,2,2-trifluoroacetate (((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phenyl)-1H- imidazol-1 -yl)propane-1 - ammonium (C31)

[00331 ] Step A: tert-Butyl (3-(2-nitro-1H-imidazol-1-yl)propyl)carbamate Calcium carbonate (2240 mg, 6.88 mmol) was added to a stirred mixture of 3-(boc-amino)propyl bromide (901 mg, 3.78 mmol) and 2-nitro-1H-imidazole (389 mg, 3.44 mmol) in DMF (20 mL), and the mixture was stirred at 60 °C overnight. The mixture was diluted with ethyl acetate, washed with water three times and brine, dried over NaSO4, filtered, and the solvent was evaporated under reduced pressure to afford crude product. The crude product was purified on silica gel column using EtOAc/hexane as elution solvent to afford the title compound. LC/MS: [M+H]+: 271.1.

[00332] Step B: tert-butyl (3-(4-bromo-2-nitro-1H-imidazol-1-yl)propyl)carbamate To a solution of (3-(2-nitro-1H-imidazol-1-yl)propyl)tert-butyl carbamate (1.17 g, 4.33 mmol) in DMF (8 mL), NBS (0.847 g, 4.76 mmol) was added. The resulting solution was stirred at 60 °C for 3 h. The solution was partitioned between EtOAc and sat. NaHCO3, the organic phase was washed with saturated NaHCO3 three times, dried over Na2SO4, concentrated, and the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 349.1, 351.1.

[00333] Step C: (R)-tert-Butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-nitro-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate To a solution of tert-butyl (3-(4-bromo-2-nitro-1H-imidazol-1-yl)propyl)carbamate (0.82 g, 2.348 mmol) in dioxane (20 mL) was added (R)-tert-butyl 2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate (1.112 g, 3.05 mmol) and Na2CO3 (3.52 mL, 7.05 mmol). The resulting mixture was bubbled with N2 for 20 min before addition of the PdCl2 (dppf)-CH2Cl2 adduct (0.192 g, 0.235 mmol). The mixture was further bubbled with N2 for 15 min, then heated at 100 °C overnight. After filtration through Celite®, the filtrate was concentrated and the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 507.4.

[00334] Step D: (R)-tert-Butyl 3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-nitro-1H-imidazol-4-yl)phenoxy)-2-(( tert-butyldimethylsilyl)oxy)propanoate To a solution of (R)-tert-butyl 3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-nitro-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate (2460 mg, 4.86 mmol) in DMF (20 mL), imidazole (1653 mg, 24.28 mmol), TBS-Cl (1464 mg, 9.71 mmol), and DMAP (59.3 mg, 0.486 mmol) were added. The resulting solution was stirred at room temperature for 1 h, then partitioned between EtOAc and saturated NaHCO3. The organic phase was washed with saturated NaHCO3 three times, dried over Na2SO4, concentrated, and the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 621.5.

[00335] Step E: 3-(4-(2-amino-1-(3-((tert-butoxycarbonyl)-amino) propyl)-1 H-imidazol-4-yl)phenoxy)-2-((tert (R)-tert-butyl-butyldimethylsilyl)oxy)propanoate To 3-(4-(1-(3-((tert-butoxycarbonyl)amino) propyl)-2-nitro-1H-imidazol-4-yl solution )phenoxy)-2-((tert-butyldimethylsilyl)oxy) (R)-tert-butyl propanoate (2.4 g, 3.87 mmol) in MeOH (50 mL), 10% Pd/C was added (0.411 g, 0.387 mmol). The resulting mixture was hydrogenated at 42 psi (289.58 KPa) overnight. After filtration through Celite® the filtrate was concentrated to afford the title compound. LC/MS: [M+H]+: 591.5.

[00336] Step F: (R)-tert-Butyl 3-(4-(2-(bis( tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate To a solution of (R)-tert-butyl 3-(4-(2-amino-1)-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (2.53 g, 4.28 mmol) in CH2Cl2 (40 mL) were added BOC2O (2.98 mL, 12.85 mmol), TEA (1.194 mL, 8.56 mmol) and DMAP (0.052 g, 0.428 mmol). The resulting solution was stirred at room temperature for 30 min. After concentration, the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 791.6.

[00337] Step G: (R)-tert-Butyl (3-(4-(2-(bis-tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate To a solution of (R)-tert-butyl 3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (1.80 g, 2.28 mmol) in THF (20 mL) at 0 °C was added TBAF (1 M in THF) (2.275 mL, 2.275 mmol). The resulting solution was stirred at 0°C for 30 min. After concentrating the solution, the residue was purified on a silica gel column using EtOAc/hexane as eluting solvents to afford the title compound. LC/MS: [M+H]+: 677.5.

[00338] Step H: (S)-tert-Butyl 3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)-oxy)propanoate To a solution of (R)-tert-butyl 3-(4-(2-(bis-tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate (1.39 g, 2.05 mmol) in THF (20 mL), were added 2-hydroxyisoindoline-1,3-dione (0.402 g, 2.46 mmol), triphenylphosphine (0.808 g, 3.08 mmol) and DEAD (0.488 ml, 3.08 mmol). The resulting solution was stirred at room temperature for 1.5 h. After concentration of the reaction solution, the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 822.5.

[00339] Step I: 2-(amino-oxy)-3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1 H -imidazol-4-yl)phenoxy) (S)-tert-butyl propanoate

[00340] To a solution of (S)-tert-butyl 3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (0.58 g, 0.706 mmol) in EtOH (8 mL) and CH2Cl2 (8.00 mL) was added hydrazine (0.022 mL, 0.706 mmol) at 0°C. The resulting solution was stirred at 0°C for 0.5 h. After concentration, the residue was dissolved in DCM (10 mL) and stirred at room temperature for 5 min and then filtered. The filtrate was concentrated to afford the title compound. LC/MS: [M+H]+: 692.5.

[00341 ] Step J: (S,Z)-2-(((3-(4-(2-(bis-tert-butoxycarbonyl) amino acid)-1-(3-((tert-butoxycarbonyl)-amino) propyl)-1H-imidazol-4-yl)phenoxy)-1 -(tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol- 4-yl)acetic To the solution of 2-(amino-oxy)-3-(4- (2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)-propyl (S)-tert-Butyl )-1H-imidazol-4-yl)phenoxy)propanoate (0.61 g, 0.882 mmol) in ethanol (8 mL) and DCM (8 mL), 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (0.240 g, 0.882 mmol) was added. The resulting solution was stirred at room temperature for overnight. The solution was then concentrated to afford the title compound. LC/MS: [M+H]+: 946.6.

[00342] Step K: 3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-4-yl)phenoxy) -2-(( (Z)-( 1 - (2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1- (sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)(S )-tert-butylpropanoate To the acid solution (S,Z)-2-(((3-(4 -(2-(bis)(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H- (imidazol-4-yl)phenoxy)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)-amino)thiazol-4-yl) acetic acid (0.42 g, 0.444 mmol) in DMF (4 mL), DCC (0.275 g, 1.33 mmol) and HOBT (0.204 g, 1.332 mmol) were added. The resulting mixture was stirred at room temperature for 30 minutes before the addition of (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (0.187 g, 0.888 mmol) and sodium bicarbonate (0.298 g, 3.55 mmol). The mixture resulting mixture was stirred at room temperature for 5 hours. After filtration of the mixture, the filtrate was purified on reversed-phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as mobile phase to afford the title compound. LC/MS: [M+H ]+: 1139.5.

[00343] Step L: 3-(2-amino-4-(4-((S)-2- ((((Z)-1-(2-aminothiazol-4-yl) 2,2,2-trifluoroacetate )-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phenyl )- 1H-imidazol-1-yl)propan-1-aminium To the solution of 3-(4-(2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl )-1H- imidazol-4-yl)phenoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4- (S)-(2-yl)-2-((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate tert-butyl (184 mg, 0.162 mmol) in CH2Cl2 (2 mL), TFA (4 mL, 51.9 mmol) was added. The resulting solution was stirred at room temperature for 1 hour. After concentrating the solution on the rotary evaporator to At room temperature, the residue was treated with Et2O and concentrated again. The solid residue was dissolved in DMSO and purified by reversed-phase HPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as the mobile phase to afford the title compound. LC/MS: [M+H] +: 682.3. 1H NMR (D2O, 500 MHz): δ 7.29-7.27(d, J = 10.8Hz, 2H), 6.99(s, 1H), 6.89(s, 1H), 6.89- 6.87(d, J = 10.2Hz, 2H ), 5.04-5.02(m, 1H), 4.54(s, 1H), 4.43-4.41(m, 2H), 3.83-3.81(d, J = 9.0Hz), 3.00-2.98(m, 2H), 2.08- 2.04(m, 2H), 1.33(s, 3H), 1.02(s, 3H). EXAMPLE 32 3-(4-(4-(( S )-2-((((Z)-1-(2-aminothiazol-4-yl)-2- (((S) 2,2,2-trifluoroacetate )-2,2-dimethyl-4-oxo-1-(sulfo-oxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phenyl)-2-imino-3 -methyl-2,3-dihydro-1H-imidazol-1-yl)propan-1-amino (C32)

[00344] Step A: 3-(4-(1-(3-((tert-butoxycarbonyl)-amino)propyl)-2-((tert-butoxycarbonyl)immo)-3-methyl-2,3-di- mdro-1 H-imidazol-4-yl)phenoxy)-2-(( 1,3-dioxoisoindolin-2-yl)oxy)propanoate (S,E)-tert-butyl To the solution of 3-(4-( 2-(bis(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindoline- (S)-tert-butyl 2)-yl)oxy)propanoate (157 mg, 0.191 mmol) in acetonitrile (2 mL), MeI (0.036 mL, 0.573 mmol) was added. The resulting solution was heated at 60°C overnight. The solution was concentrated to afford the title compound. LC/MS: [M+H]+: 736.5 .

[00345] Step B: 2-(amino-oxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl (S,E)-tert-butyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)propanoate To the solution of 3-(4-(1- (3-((tert-butyl )butoxycarbonyl)amino)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-((1,3- (S,E)-tert-butyl dioxo-isoindoline-2-yl)oxy)propanoate (0.18 g, 0.245 mmol) in EtOH (4.00 mL) and CH2Cl2 (4 mL) at 0°C, hydrazine (0.015 mL, 0.489 mmol) was added. The resulting solution was stirred at 0°C for 2 h and then concentrated to afford the title compound . LC/MS: [M + H] +: 606.5.

[00346] Step C: (Z)-2-((((S)-1-(tert-butoxy)-3-(4-((E)-1-(3-((tert-butoxycarbonyl)amino acid )propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-1-oxo-propan-2-yl)oxy )imino)-2-(2- ((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic To the solution of 2-(amino-oxy)- 3-(4-(1-(3-(((tert -butoxycarbonyl)amino)propyl)-2-((tert-butoxycarbonyl) (S,E)-tert-butyl (imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)propanoate (126 mg, 0.208 mmol) in ethanol (8 mL) and DCM (8 mL), 2-(2-((tert-butoxycarbonyl)-amino)thiazol-4-yl)-2-oxoacetic acid (142 mg, 0.520 mmol) was added. The resulting solution was stirred at room temperature for 3 hours. The solution was then concentrated and the residue was purified on reversed-phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as the mobile phase to afford the title compound. LC/MS: [M+H]+: 860.4.

[00347] Step D: 3-(4-((E)-1-(3-(( tert-butoxycarbonyl)-amino) propyl)-2-(( tert-butoxycarbonyl)imino)-3-methyl-2, 3-dihydro-1H-imidazol-4-yl)phenoxy)-2-(((Z)-(1-(2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)-2-( ((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)(S)-tert-butylpropanoate In solution of acid (Z)-2-((((S)-1-(tert- butoxy)-3-(4-((E)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-di- hydro-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (152 mg, 0.177 mmol) in DMF (5 mL), DCC (292 mg, 1.41 mmol) and HOBT (122 mg, 0.795 mmol) were added. The resulting solution was stirred at room temperature for 30 min before the addition of (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (130 mg, 0.619 mmol) and sodium bicarbonate ( 297 mg 3.53 mmol). The resulting mixture was stirred at room temperature for 28 h, then filtered and the filtrate was purified on reversed-phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA ) as mobile phase to provide the title compound. LC/MS: [M+H]+: 1052.6.

[00348] Step E: 3-(4-(4-((5))-2-((((Z)-1-(2-aminothiazol-4-yl)-2- ((( S )-2,2-dimethyl-4-oxo-1 -(sulfo-oxy)azetidin-3 -yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)phenyl)-2- imino-3-methyl- 2,3-dihydro-1 H-imidazol-1 -yl)propan-1 -aminium To the solution of 3-(4-((E)-1- (3-((tert- butoxycarbonyl))amino)propyl)-2-((tert-butoxycarbonyl)imino)-3- methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-(((Z)-(1-2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2 -(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate (S)-tert-butyl (140 mg, 0.133 mmol) in CH2Cl2 (2 mL), TFA (4 mL, 51.9 mmol) was added. The resulting solution was stirred at room temperature for 40 min, then concentrated, and the residue was treated with Et2O and concentrated again. The dried solid residue was purified by reversed-phase HPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as the mobile phase to afford the title compound. LC/MS: [M+H]+: 696.3. 1H NMR (D2O, 500 MHz): δ 7.29-7.27 (d, J = 10.3Hz, 2H), 7.04(s, 1H), 6.99-6.97(d, J = 10.3Hz, 2H), 6.80(s, 1H ), 5.08(s, 1H), 4.66(m, 1H), 4.63(s, 1H), 4.48-4.43(m, 2H), 3.91-3.89(t, J = 7.1Hz, 2H), 3.29( s, 3H), 3.0-2.96(m, 2H), 2.09-2.05(m, 2H), 1.35(s, 3H), 0.97(s, 3H). EXAMPLE 33 1-(3-Aminopropyl)-4-((5-(( S )-2-((((Z)-1-(2-aminothiazol-4-yl)- 2-((( S )-2,2-dimethyl-4-oxo-1 -(sulfo-oxy)azetidin-3 -yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)pyridin-2 -yl)amino) pyridin-1-amino (C33)

[00349] Step A: tert-Butyl 2-(( tert-Bromdimethylsilyl)oxy)-3-((6-(pyridin-4-ylamino)pyridin-3-yl)oxy)propanoate The mixture of precatalyst G3 J00 (Aldrich #88755, 250 mg, 0.27 mmol), Cs2CO3 (2.64 g, 8.12 mmol), tert-butyl 3-((6-bromopyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (1170 mg), 2.71 mmol), and pyridin-4-amine (306 mg, 3.25 mmol) in a sealed tube was degassed by vacuum/N2 refill three times prior to the addition of dioxane (12 mL). The resulting mixture was further degassed by vacuum/N2, replenished three times, then heated at 100°C for 16 h. The mixture was filtered through Celite®, the filtrate was concentrated, and the residue was purified on a silica gel column using MeOH/DCM as elution solvents to afford the title compound. LC/MS: [M+H]+: 446.36.

[00350] Step B: tert-Butyl 3-((6-(( tert-butoxycarbonyl)(pyridin-4-yl)amino)pyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate To a solution of tert-butyl 2-((tert-butyldimethylsilyl)oxy)-3-((6-(pyridin-4-ylamino)pyridin-3-yl)oxy)propanoate (0.61 g, 1.37 mmol) in CH2Cl2 (25 mL) was added TEA (0.382 mL, 2.74 mmol), BOC2O (0.381 mL, 1.64 mmol), and DMAP (0.167 g, 1.37 mmol). The resulting solution was stirred at room temperature overnight. After concentration, the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 546.47.

[00351 ] Step C: tert-Butyl 3-((6-(( tert-butoxycarbonyl)(pyridin-4-yl)amino)pyridin-3-yl)oxy)-2-hydroxypropanoate To a solution of tert-butyl 3-((6-(( tert-butoxycarbonyl)(pyridin-4-yl)amino)pyridin-3-yl)oxy)-2-(( tert-butyldimethylsilyl)oxy)propanoate (0.28 g, 0.513 mmol) in THF (10 mL) was added TBAF (0.513 mL, 0.513 mmol) at 0 °C. The resulting solution was stirred at 0 °C for 0.5 h. After concentration, the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 432.32.

[00352] Step D: 3-((6-((tert-butoxycarbonyl)(pyridin-4-yl)amino) pyridin-3-yl)oxy)-2-((1,3-dioxoisoindolin-2-yl) tert-butyl oxy)propanoate To the solution of tert-butyl 3-((6-((tert-butoxycarbonyl)(pyridin-4-yl)amino)pyridin-3-yl)oxy)-2-hydroxypropanoate (0, 23 g, 0.533 mmol) in THF (6 ml), added 2-hydroxyisoindoline-1,3-dione (0.104 g, 0.640 mmol), triphenylphosphine (0.210 g, 0.80 mmol) and DEAD (0.127 ml, 0.800 mmol). The resulting solution was stirred at room temperature for 3 h. After concentration of the solution, the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H ]+: 577.41.

[00353] Step E: 4-((5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolino-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)( tert -butoxycarbonyl)amino)-1-(3-(( tert - butoxycarbonyl)amino)propyl)pyridin-1 -ium To the solution of 3-((6-(( tert - butoxycarbonyl)(pyridin-4-yl)amino) tert-butyl pyridin-3-yl)oxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (0.25 g, 0.434 mmol) in acetonitrile (4 ml), tert- butyl (3-iodopropyl)carbamate (0.148 g, 0.520 mmol). The resulting solution was heated at 60°C for three days. Sodium bicarbonate (0.146 g, 1.73 mmol) and an additional 0.296 g of tert-butyl (3-iodopropyl)carbamate were added, and the resulting solution was heated still at 60°C overnight. The solution was filtered, the filtrate was concentrated and the residue was purified on reversed phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as mobile phase for provide the title compound. LC/MS: [M]+: 734.41.

[00354] Step F:4-((5-(2-(amino-oxy)-3-( tert-butoxy)-3-oxopropoxy)pyridin-2-yl)( tert-butoxycarbonyl)amino)-1-( 3-(( tert - butoxycarbonyl)amino)propyl)pyridin-1 -io In solution of 4-((5-(3-( tert - butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy )-3-oxopropoxy)pyridin-2-yl)(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)pyridin-1-ium (110 mg, 0.150 mmol) in CH2Cl2 ( 4 ml) and Ethanol (4.00 ml) hydrazine (5.64 μl, 0.180 mmol) was added at 0°C. The resulting solution was stirred at 0°C for 1 h, then concentrated. The residue was treated with CH2Cl2 (4 mL), filtered, and the filtrate was concentrated to afford the title compound. LC/MS: [ M]+: 604.54.

[00355] Step G: (Z)-4-((5-(3-( tert-butoxy)-2-((((2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)-(carboxy)methylene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)( tert-butoxycarbonyl)amino)-1-(3-(( tert-butoxycarbonyl)amino)propyl)pyridin-1-ium To a solution of 4-((5-(2-(amino-oxy)-3-(tert-butoxy)-3-oxopropoxy)pyridin-2-yl)(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)pyridin-1-ium (100 mg, 0.165 mmol) in ethanol (4 mL) and CH2Cl2 (4 mL), was added 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (58.5 mg, 0.215 mmol). The resulting solution was stirred at room temperature for 1 h. The solution was concentrated and the residue was purified on reversed-phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as the mobile phase to afford the title compound. LC/MS: [M]+: 858.52.

[00356] Step H: 4-((5-(3-( tert -butoxy)-2-(((Z)-(1-(2-(( tert -butoxycarbonyl)-amino)thiazol-4-yl) -2-(((S)-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)pyridin- 2-yl)(tert-butoxycarbonyl)amino)-1-(3-(( tert-butoxycarbonyl)amino)- propyl)pyridin-1 -io To the solution of (Z)-4-((5-(3-( tert-butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy-methylene)amino)oxy)-3- (oxopropoxy)pyridin-2-yl)(tert-butoxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)pyridin-1-ium (16 mg, 0.019 mmol) in DMF (1 mL) was DCC (30.7 mg, 0.149 mmol) and HOBT (11.41 mg, 0.075 mmol) were added. The resulting solution was stirred at room temperature for 30 min before the addition of (S)-3-amino-2-hydrogen sulfate, 2-dimethyl-4-oxoazetidin-1-yl (19.58 mg, 0.093 mmol) and sodium bicarbonate (31.3 mg, 0.373 mmol). The resulting solution was stirred at room temperature overnight. After filtration of the reaction mixture , the residue was purified by reverse-phase HPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) to afford the title compound. LC/MS: [M]+: 1050.41.

[00357] Step K: 1-(3-aminopropyl)-4-((5-((S)-2-((((Z)-1-(2-aminothiazol-4) 2,2,2-trifluoroacetate -yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy )- pyridin-2-yl)amino)pyridin-1 -io To the solution of 4-((5-(3-(tert-butoxy)-2-(((Z)- (1-(2-((tert -butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)(tert-butoxycarbonyl)amino)-1-(3-((tert- (butoxycarbonyl)amino)propyl)pyridin-1-ium (22 mg, 0.021 mmol) in CH2Cl2 (1 mL) was added TFA (2.5 mL, 32.4 mmol). The resulting solution was stirred at room temperature for 1. 5 hours. The reaction solution was concentrated on a rotary evaporator at room temperature and the residue was further dried under high vacuum. The solid was purified by reverse-phase HPLC using acetonitrile (0.05% TFA)/water (0.05% TFA ) to afford the title compound (the more polar diastereoisomer). LC/MS: [M+H]+: 694.17. 1H NMR (D2O, 500 MHz): δ 8.13-8.11 (d, J = 8.8 Hz, 2H0, 8.01-8.00 (d, J = 1.6 Hz, 1H), 7.50-7.42 (m, 3H), 7.08-7.07 ( d, J = 8.8 Hz, 1H), 7.02 (s, 1H), 5.05 (s, 1H), 4.66 (s, 1H), 4.48 (s, 2H), 4.27-4.24(t, J = 7.1 Hz, 2H ), 2.992.96 (t, J = 7.4 Hz, 2H), 2.21-2.18 (t, J = 7.4 Hz, 2H), 1.35 (s, 3H), 1.05 (s, 3H). EXAMPLE 34 1-(3-Aminopropyl)-4-((5-(( S )-2-((((Z)-1-(2-aminothiazol-4-yl)- 2-((( S )-2,2-dimethyl-4-oxo-1 -(sulfo-oxy)azetidin-3 - yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)pyridin-2 - yl)oxy)pyridin-1-io (C34)

[00358] Step A: tert-Butyl 2-(( tert-Butyldimethylsilyl)oxy)-3-((6-(pyridin-4-yloxy)pyridin-3-yl)oxy)propanoate A mixture of the precursor G3 J009 (7Aldrich #88755, 2.7 mg, 0.079 mmol), Cs2CO3 (1025 mg, 3.15 mmol), tert-butyl 3-((6-bromopyridin-3-yl)oxy)-2-(( tert-butyldimethylsilyl)oxy)propanoate (680 mg, 1.57 mmol), and pyridin-4-ol (179 mg, 1.887 mmol) in a sealed tube was degassed by vacuum/N2 refill three times prior to the addition of dioxane (12 mL). The resulting mixture was further degassed by vacuum/N2, replenished three times, then heated at 90°C for 16 h. The mixture was filtered through Celite®, the filtrate was concentrated, and the residue was purified on a silica gel column using EtOAc/hexane to afford the title compound (the less polar regioisomer). LC/MS: [M+H]+: 447.71.

[00359] Step B: tert-Butyl 2-hydroxy-3-((6-(pyridin-4-yloxy)pyridin-3-yl)oxy)propanoate To a solution of tert-butyl 2-((tert-butyldimethylsilyl)oxy)-3-((6-(pyridin-4-yloxy)pyridin-3-yl)oxy)propanoate (220 mg, 0.493 mmol) in THF (6 mL) at 0 °C was added TBAF (0.493 mL, 0.493 mmol). The resulting solution was stirred at 0 °C for 30 min. After concentrating the solution, the residue was purified on a silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+H]+: 333.21.

[00360] Step C: tert-Butyl 2-((1,3-dioxoisoindolin-2-yl)oxy)-3-((6-(pyridin-4-yloxy)pyridin-3-yl)oxy)propanoate To a solution of tert-butyl 2-hydroxy-3-((6-(pyridin-4-yloxy)pyridin-3-yl)oxy)propanoate (331 mg, 0.996 mmol) in THF (6 mL) was added 2-hydroxyisoindoline-1,3-dione (195 mg, 1.20 mmol), triphenylphosphine (392 mg, 1.49 mmol), and DEAD (0.237 mL, 1.494 mmol). The resulting solution was stirred at room temperature for 2 hours, then concentrated on rotary evaporator, the residue was purified on silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LCMS [M+H]+: 478.26.

[00361] Step D: 4-((5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)oxy)-1-(3-(( tert -butoxycarbonyl)amino)propyl)pyridin-1 -ium To a solution of 2-((1,3-dioxoisoindolin-2-yl)oxy)-3-((6-(pyridin)-4-yloxy)pyridin-3-yl)oxy) tert-butyl (3-iodopropyl)carbamate (1.451 g, 5.09 mmol) in acetonitrile (10 mL) was added, the resulting solution was heated at 60 °C overnight. After concentrating the reaction solution, the residue was purified on reversed phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as mobile phase to afford the title compound. [M]+: 635.50.

[00362] Step E: (Z)-4-((5-(3-( tert-butoxy)-2-((((2-(( tert -butoxycarbonyl)amino)thiazol-4-yl)-(carboxy )methylene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)oxy)-1-(3-(( tert-butoxycarbonyl)amino)propyl) pyridin-1-io To the solution of 4-((5- (3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)oxy)-1-(3-((tert-butoxycarbonyl) -amino)propyl)pyridin-1-io (100 mg, 0.157 mmol) in CH2Cl2 (4 mL) and ethanol (4.00 mL) at 0°C, hydrazine (8.89, 0.283 mmol) was added. The resulting solution was stirred at 0°C for 1 h, then 2-(2-((tert-butoxycarbonyl)amino)thiazole-4-acid was added. -yl)-2-oxoacetic acid (86 mg, 0.315 mmol) was added to the above solution. The resulting solution was stirred at room temperature for 1 h, then the mixture was concentrated and the residue was purified on reversed-phase MPLC using acetonitrile (0 ,05% TFA)/water (0.05% TFA) as mobile phase to afford the title compound. LC/MS: [M]+: 759.49.

[00363] Step F: 4-((5-(3-( tert -butoxy)-2-(((Z)-(1-(2-(( tert -butoxycarbonyl)-amino)thiazol-4-yl) -2-(((S)-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)pyridin- 2-yl)oxy)-1-(3-((tert-butoxycarbonyl)amino)propyl)pyridin-1-io To the solution of (Z)-4-((5-(3-(tert-butoxy)-2 -(((2-((tert-butoxycarbonyl)amino)thiazol-4- yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)oxy)-1-(3-((tert-butoxy-carbonyl)amino)propyl)pyridin-1-ium (28 mg , 0.037 mmol) in DMF (20 mL) were added DCC (60.8 mg, 0.295 mmol) and HOBT (22.57 mg, 0.147 mmol). The resulting solution was stirred at room temperature for 30 min before the addition of hydrogen sulfate of (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl (38.7 mg, 0.184 mmol) and sodium bicarbonate (61.9 mg, 0.737 mmol), the resulting solution was stirred at room temperature overnight. After filtration of the reaction mixture, the residue was purified by Gilson reverse-phase HPLC using 20-100% acetonitrile (0.05% TFA) to afford the title compound. LC/MS: [M]+: 951.51.

[00364] Step G: 1-(3-aminopropyl)-4-((5-((S)-2-((((Z)-1-(2-aminothiazol-4) 2,2,2-trifluoroacetate -yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy )- pyridin-2-yl)oxy)pyridin-1 -io To the solution of 4-((5-(3-(tert-butoxy)-2-(((Z)-(1- (2-((tert -butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)oxy)-1-(3-((tert-butoxycarbonyl)amino)propyl )pyridin-1-iodine (28 mg, 0.029 mmol) in CH2Cl2 (1 mL), TFA (2 mL 26.0 mmol) was added. The resulting solution was stirred at room temperature for 75 min. The solution was concentrated and the The residue was treated with Et2O (10 mL). The Et2O was removed and the solid residue was dried under high vacuum. The dried residue was dissolved in DMSO (2 mL) and purified by reversed-phase HPLC using acetonitrile (0.05% TFA )/water (0.05% TFA) as the mobile phase to afford the title compound (the more polar diastereoisomer). LC/MS: [M+H]+: 695.19. 1H NMR (D2O, 500 MHz): δ 8.648.62 (d, J = 7.1 Hz, 2H), 7.98-7.97 (d, J = 2.4 Hz, 1H), 7.61-7.58 (m, 1H), 7.46-7.45 (d, J = 7.4 Hz, 2H), 7.21-7.20 (d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 5.03 (s, 1H), 4.75 (s, 1H), 4.52-4.46 ( m, 4H), 3.03-3.00 (t, J = 7.9 Hz, 2H), 2.30-2.26 (t, J = 7.9 Hz, 2H), 1.43 (s, 3H), 1.12 (s, 3H). EXAMPLE 35 (S,Z)-3-(2-((2-((6-(3-(3-aminopropyl)-1H-imidazol-3-io-1-yl)pyridin-3-yl)oxy )ethoxy)(imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate 2,2,2-trifluoroacetate (C35). Step A: 2-((6-bromopyridin-3-yl)oxy)ethan-1-ol

[00365] 6-Bromopyridin-3-ol (700 mg, 4.02 mmol), 2-chloroethanol (972 mg, 12.1 mmol), and K2CO3 (1.39 g, 10.1 mmol) were combined and suspended in acetonitrile (18 mL). A stream of N2 gas was bubbled through a septum into the solution for 10 min, and the resulting solution was heated at 80 °C for 18 h. After standing at room temperature for two days, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (24 g column) using a 0-100% EtOAc/Hexanes gradient as eluent to afford the title compound. LC-MS [M + H]+: m/z 218.03. 1H NMR (CHCl3-d, 500 MHz): δ 8.11 (1H, d, J = 3.2 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.16 (1H, dd, J = 8.7, 3.2 Hz), 4.14 (2H, t, J = 4.5 Hz), 4.03-4.00 (2H, m ), 2.07-2.03 (1H, m).

[00366] Step B: 2-Bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridine To a solution of 2-((6-bromopyridin-3-yl)oxy)ethan-1-ol (315 mg, 1.445 mmol), and imidazole (492 mg, 7.22 mmol) in acetonitrile (9 mL), was added 1M tert-butyldimethylchlorosilane in CH2Cl2 (3.2 mL, 3.2 mmol) followed by DMAP (17.65 mg, 0.144 mmol). After stirring for 3 h at room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with saturated NaHCO3(aq) solution (2X), brine (1X). The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (24 g column) using a 0-40% EtOAc/Hexanes gradient as eluent to afford the title compound. LC-MS [M + H]+: m/z 332.10. 1H NMR (CHCl3-d, 500 MHz): δ 8.09 (1H, d, J = 3.1 Hz), 7.38 (1H, d, J = 8.7 Hz), 7.15 (1H, dd, J = 8.7, 3.2 Hz), 4.09 (2H, t, J = 4.9 Hz), 3.99 (2H, t, J = 4 .9 Hz), 0.93 (9H, d, J = 8.8 Hz), 0.12 (6H, d, J = 5.7 Hz).

[00367] Step C: 5-(2-(( tert-Butyldimethylsilyl)oxy)ethoxy)-2-(1H-imidazol-1-yl)pyridine 2-Bromo-5-(2-(( tert-butyldimethylsilyl)oxy)ethoxy)pyridine (480 mg, 1.44 mmol), imidazole (148 mg, 2.17 mmol), L-proline (27 mg, 0.231 mmol), K2CO3 (399 mg, 2.89 mmol), and CuI (13.8 mg, 0.072 mmol) were combined and suspended in DMSO (3 mL). A stream of N2 gas was bubbled through a septum into the solution for 10 min, and the resulting solution was heated at 90 °C overnight. The mixture was cooled, diluted with EtOAc, and washed with H2O (1X) and brine (1X). The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (12 g column) using a 0-100% (3:1 EtOAc/MeOH)/Hexanes gradient as eluent to afford the title compound. LC-MS [M + H]+: m/z 320.33. 1H NMR (CHCl3-d, 500 MHz): δ 8.24 (1H, s), 8.19 (1H, d, J = 2.9 Hz), 7.58 (1H, s), 7.40 (1H, dd, J = 8.8, 3.0 Hz), 7.31-7.28 (1H, m)7.21 (1H, s), 5 (2H, t, J = 4.9 Hz), 4.02 (2H, t, J = 4.9 Hz), 0.93 (9H, s), 0.13 (6H, s).

[00368] Step D: 2-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)ethan-1-ol To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-(1H-imidazol-1-yl)pyridine (140 mg, 0.438 mmol) in THF (5 mL) was added a 1 M solution of TBAF in CH2Cl2 (0.438 mL, 0.438 mmol). After stirring at room temperature for 45 min, the mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel (4 g column) using a 0-100% gradient (3:1 EtOAc/MeOH)/Hexanes as eluent to afford the title compound. LC-MS [M + H]+: m/z 205.90.

[00369] Step E: 2-(2-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)ethoxy)isoindoline-1,3-dione To a solution of 2-((6-(1H)-imidazol-1-yl)pyridin-3-yl)oxy)ethan-1-ol (80 mg, 0.390 mmol) in THF (4 mL) were added N-hydroxyphthalimide (76 mg, 0.468 mmol) and triphenylphosphine (123 mg, 0.468 mmol). DIAD (0.091 mL, 0.468 mmol) was added dropwise, and the resulting solution was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (12 g column) using a 0-100% (3:1 EtOAc/MeOH)/Hexanes gradient as eluent to afford the title compound. LC-MS [M + H]+: m/z 350.98. 1H NMR (CHCl3-d, 500 MHz): δ 8.24 (1H, s), 8.14 (1H, d, J = 2.9 Hz), 7.89-7.86 (2H, m), 7.82-7.79 (2H, m), 7.58 (1H, s), 7.40 (1H, dd, J = 8.8, 3.0 Hz ), 7.33-7.30 (1H, m) 7.21 (1H, s), 4.65-4.63 (2H, m), 4.48-4.46 (2H, m).

[00370] Step F: 3-(3-((tert-butoxycarbonyl)amino)propyl)-1-(5-(2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)pyridin-2-yl)-1H-imidazol-3-ium To a solution of 2-(2-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)ethoxy)isoindoline-1,3-dione (131 mg, 0.374 mmol) in dioxane (3 mL) were added 3-(boc-amino)propyl bromide (214 mg, 0.89 mmol) and DMAP (5 mg, 0.041 mmol) and the mixture was stirred at 60 °C overnight. Additional DMAP (5 mg, 0.041 mmol) and a catalytic amount of sodium iodide were added, heating at 60 °C continued for 4 h, after which the mixture was concentrated in vacuo. The residue was triturated with EtOAc to remove starting materials and impurities, affording the title compound. LC-MS [M]+: m/z 508.29.

[00371] Step G: 1-(5-(2-(aminooxy)ethoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazole-3-ium 3-(3-((tert-butoxycarbonyl)amino)propyl)-1-(5-(2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)pyridin-2-yl)-1H-imidazole-3-ium (0.19 g, 0.374 mmol) was suspended in MeOH (3 mL), and a 1 M solution of hydrazine in MeOH (0.41 mL, 0.41 mmol) was added. After stirring at room temperature for 2 h the mixture was concentrated in vacuo, removing excess hydrazine by azeotroping with MeOH followed by CH2Cl2. The residue was taken to the next step without further purification. LC-MS [M]+: m/z 378.25.

[00372] Step H: (Z)-3-(3-(( tert-butoxycarbonyl)amino)propyl)-1-(5- (2-((((2-(( tert-butoxycarbonyl)amino)thiazol- 4-yl(carboxy)methylene)amino)oxy)ethoxy)pyridin-2-yl)-1 H-imidazol-3-io

[00373] To a solution of 1-(5-(2-(amino-oxy)ethoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazole-3-ium (0.141 g, 0.373 mmol) in EtOH (2 mL) and ClCH2CH2Cl (4 mL) was added Intermediate 6 (0.107 g, 0.392 mmol). After stirring at room temperature overnight, the solvents were removed in vacuo and the residue taken to the next step without further purification. LC-MS [M]+: m/z 632.35.

[00374] Step I: (S,Z)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1- (5-(2-(((1-(2-((tert-butoxycarbonyl) amino)thiazol-4-yl)-2-((2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)ethoxy) pyridin -2-yl)-1H-imidazol-3-ium A mixture of (Z)-3-(3-(( tert -butoxycarbonyl)amino)propyl)-1-(5-(2-(((2- ((tertbutoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)ethoxy)pyridin-2-yl)-1H-imidazol-3-ium (237 mg, 0.374 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (176 mg, 0.636 mmol), (S)-3-amino hydrogen sulfate was added -2,2-dimethyl-4-oxoazetidin-1-yl (102 mg, 0.486 mmol) as a solution in DMF (4 mL). After stirring at room temperature overnight, an additional amount of (S)- 3-amino-2,2-dimethyl-4-oxoazetidin-1-yl (102 mg, 0.486 mmol) was added and 4-(4,6-dimethoxy)-1,3,5-triazin-2- yl)-4-methyl-morpholinium (176 mg, 0.636 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O and purified by reverse-phase chromatography (Gilson SunFire C-18 30X150 mm column) using a 10-90% CH3CN/H2O gradient (with 0.5% of TFA) as eluent. Lyophilization afforded the title compound. LC-MS [M + H]+: m/z 824.78.

[00375] Step J: (S,Z)-3-(2-((2-((6-(3-(3-aminopropyl)-1 H-imidazol-3-yl-1-yl)pyridin-3 -yl)oxy)ethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate 2,2,2-trifluoroacetate To a solution of ( S,Z)-3-(3-((tert-butoxycarbonyl)amino)-propyl)-1-(5-(2-(((1-(2-((tert-butoxycarbonyl)-amino)thiazol-4 -yl)-2-((2,2-dimethyl-4-oxo-1-(sulfo- )oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)ethoxy)pyridin-2-yl)-1H-imidazole-3-ium (56 mg, 0.068 mmol) in CH2Cl2 (1 mL, was added TFA (1 mL, 12.98 mmol). After stirring at room temperature for 30 min the mixture was concentrated in vacuo and excess TFA was removed by azeotropic distillation from CH2Cl2. After trituration with Et2O the residue was purified by reversed phase chromatography (Gilson SunFire C-18 column 30X150 mm) using a gradient of 5-40% CH3CN/H2O (with 0.5% TFA) as eluent and the lyophilized product to afford the title compound. LC- MS [M + H]+: m/z 624.36. EXAMPLE 36 (S)-3-((Z)-2-(((S)-2-((6-(3-(3-aminopropyl)-1 H-imidazol-3-yl-1 sulfate compound -yl)pyridin-3-yl)oxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl with acid 2, 2,2- trifluoroacetic acid (1:1)(C36)

[00376] Step A: (R)-Ethyl 3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoate Ethyl oxirane-2-carboxylate was suspended (1.47 g, 12.6 mmol) in MTBE (25 mL) and 6-bromopyridin-3-ol (1.0 g, 5.75 mmol) and 4 Å molecular sieves (2 g) were added. Intermediate 2 (0.482 g, 0.575 mmol) was added and the resulting mixture was stirred at room temperature for 3 days. The solids were removed by filtration, the filtrate was concentrated in vacuo , and the residue was purified by column chromatography on silica gel (40 g column) using a 0-60% EtOAc/Hexanes gradient as eluent to afford the title compound. LC-MS [M + H]+: m/z 290.10. 1H NMR (CHCl3-d, 500 MHz): δ 8.10 (1H, d, J = 3.1 Hz), 7.40 (1H, d, J = 8.7 Hz), 7.16 (1H, dd, J = 8.7, 3.2 Hz), 4.53 (1H, t, J = 3.2 Hz), 4.35-4.31 (4H, m ), 3.24 (1H, br s),1.32 (3H, t, J = 7.1 Hz).

[00377] Step B: (R)-3-((6-Bromopyridin-3-yl)oxy)-2-hydroxypropanoic acid To a solution of (R)-3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoate (513 mg, 1.77 mmol) in THF (14 mL) at 0 °C was added 1 M NaOH (3.54 mL, 3.54 mmol). After stirring for 3 h at 0 °C, the pH was adjusted to 3 with 1 N HCl and the mixture was partitioned between EtOAc and water. The layers were separated and the organic phase was washed with brine (3X), dried over MgSO 4 , filtered, and concentrated in vacuo to afford the title compound, which was used in the next step without further purification. LC-MS [M + H]+: m/z 261.76.

[00378] Step C: (R)-3-((6-bromopyridin-3-yl)oxy)-2-tert-Butyl hydroxypropanoate To a solution of (R)-3-((6-bromopyridin-3-yl)oxy)-2-hydroxypropanoic acid (464 mg, 1.77 mmol) in THF (6 mL) was added 2-tert-butyl-1,3-diisopropylisourea (886 mg, 4.43 mmol) and the resulting mixture was heated at 60 °C for 2 h 45 min. The solids were removed by filtration, the filtrate was concentrated in vacuo , and the residue was purified by column chromatography on silica gel (12 g column) using a gradient of 0-60% EtOAc/Hexanes as eluent to afford the title compound. LC-MS [M + H]+: m/z 318.17. 1H NMR (CHCl3-d, 500 MHz): δ 8.09 (1H, d, J = 3.1 Hz), 7.40 (1H, d, J = 8.7 Hz), 7.16 (1H, dd, J = 8.7, 3.1 Hz), 4.41 (1H, s), 4.324.26 (2H, m), 3.26 (1H , br s), 1.51 (9H, s).

[00379] Step D: tert-Butyl (R)-3-((6-Bromopyridin-3-yl)oxy)-2-(( tert-butyldimethylsilyl)oxy)-propanoate To a solution of tert-butyl (R)-3-((6-bromopyridin-3-yl)oxy)-2-hydroxy-propanoate (265 mg, 0.833 mmol) in CH2Cl2 (6 mL) at 0°C was added triethylamine (0.348 mL, 2.50 mmol). tert-Butyldimethylsilyl trifluoromethanesulfonate (0.287 mL, 1.25 mmol) was added dropwise and after stirring at 0°C for 30 min. The mixture was partitioned between CH2Cl2 and H2O. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (12 g column) using a gradient of 0-30% EtOAc/hexanes as eluent to afford the title compound. LC-MS [M + H]+: m/z 432.07. 1H NMR (CHCl3-d, 500 MHz): δ 8.09 (1H, d, J = 3.1 Hz), 7.39 (1H, d, J = 8.7 Hz), 7.15 (1H, dd, J = 8.7, 3.1 Hz), 4.47 (1H, dd, J = 6.8, 3.4 Hz), 4.27 (1H, dd, J = 9.7, 3.4 Hz), 4.16 (1H, dd, J = 9.7, 6.8 Hz), 1.50 (9H, s), 0.93 (9H, s), 0.16 (3H, s), 0.10 (3H, s).

[00380] Step E: tert-Butyl (R)-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate The procedure was the same as described for Step C, Example 35, using reagents (R)-3-((6-bromopyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (318 mg, 0.735 mmol), imidazole (90 mg, 1.32 mmol), L-proline (51 mg, 0.44 mmol), K2CO3 (102 mg, 0.735 mmol), and CuI (42 mg, 0.22 mmol) in DMSO (3 mL). LC-MS [M + H]: m/z 420.45.

[00381] Step F: (R )-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-tert-butyl hydroxypropanoate The procedure is the same as described for Step D of Example 35 using reagents (R)-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (80 mg, 0.191 mmol) in THF (4 mL) and 1 M TBAF in THF (0.191 mL, 0.191 mmol). LC-MS [M + H]+: m/z 306.27.

[00382] Step G: (S)-tert-butyl 3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate The procedure was the same as described for Step E in Example 35 using reagents (R)-tert-butyl 3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-hydroxypropanoate (76 mg, 0.249 mmol), N-hydroxyphthalimide (48.7 mg, 0.299 mmol), triphenylphosphine (78 mg, 0.299 mmol), and DIAD (0.058 mL, 0.299 mmol) in THF (3 mL). LC-MS [M + H]+: m/z 451.33.

[00383] Step H: (S)-3-(3-aminopropyl)-1-(5-(3-( tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)-1H-imidazol-3-ium To a solution of tert-butyl (S)-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (85 mg, 0.189 mmol) in dioxane (2 mL) was added 3-(boc-amino)propyl bromide (67.4 mg, 0.283 mmol) and the mixture was stirred at 60 °C overnight. Sodium iodide (10 mg, 0.067 mmol) was added and heating at 60 °C was continued for 6 h, then additional amounts of 3-(boc-amino)propyl bromide (67.4 mg, 0.283 mmol) and sodium iodide (34 mg, 0.22 mmol) were added. Acetone (0.2 mL) was added, and the mixture was heated at 60 °C overnight. The mixture was concentrated in vacuo and triturated with EtOAc to afford the title compound as a residue which was taken to the next step without further purification. LC-MS [M]+: m/z 508.39.

[00384] Step I: (S)-1-(5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolino-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl )-3-(3-(( tert-butoxycarbonyl)amino) propyl)-1H-imidazol-3-ium A solution of (S)-3-(3-aminopropyl)-1-(5-(3- ( tert-butoxy))-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)- 1H-imidazol-3-ium (46 mg, 0.090 mmol) in CH2Cl2 (3 mL), BOC-anhydride (29.6 mg, 0.136 mmol) and N,N,N',N'- tetramethylethylenediamine (15 μL, 0.099 mmol), and the resulting mixture was stirred at room temperature for 3 days. After concentration in vacuo and trituration with Et2O, the residue was lyophilized from CH3CN/H2O. LC-MS [M + H] +: m/z 608.10.

[00385] Step J: (S)-1-(5-(2-(amino-oxy)-3-( tert-butoxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-imidazole-3-ium The procedure was the same as described for Step F of Example 35 using reagents (S)-1-(5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-imidazole-3-ium (26 mg, 0.043 mmol) of 1 M hydrazine in MeOH (47 µL, 0.047 mmol) in MeOH (1 mL). LC-MS [M]+: m/z 478.40.

[00386] Step K: (S,Z)-1-(5-(3-( tert -butoxy)-2-((((2-(( tert -butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-(( tert -butoxycarbonyl)amino)propyl)-1H-imidazole-3-ium The procedure was the same as described for step H of Example 35 using reagents (S)-1-(5-(2-(amino-oxy)-3-(tert -butoxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-((tert -butoxycarbonyl)amino)propyl)-1H-imidazole-3-ium (21 mg, 0.044 mmol) and Intermediate 6 (12.6 mg, 0.046 mmol). mmol) in Ethanol (0.5 mL) and ClCH2CH2Cl (1 mL). LC-MS [M]+: m/z 732.51.

[00387] Step L: 1-(5-((S)-3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazole-3-ium The procedure was the same as described for Step I of Example 35 using reagents (S,Z)-1-(5-(3-(tert-butoxy)-2-(((2-((tert-butoxycarbonyl)amino) thiazol-4-yl(carboxy)methylene)-amino)oxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-3-io (32 mg, 0.044 mmol), (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogensulfate (11.93 mg, 0.057 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholino chloride (20.54 mg, 0.074 mmol) in DMF (1 mL). LC-MS [M + H]+: m/z 924.83.

[00388] Step M: (5 )-3-((Z)-2-(((5)-2-((6(3-( 3-aminopropyl)-1H-imidazol-3-io) sulfate compound -1 -yl)pyridine-3 -yl)oxy)-1 - carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl with 2 ,2,2-trifluoroacetic acid (1:1) The procedure was identical to that described for Step J of Example 35 using the reagents 1-(5-((5)-3-(tert-butoxy)-2-((( (Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol- 4-yl)-2-(((5)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3- oxopropoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-3-io (7 mg, 7.57 μmol) and TFA (0.6 ml, 7.79 mmol) in CH2Cl2 (0.6 ml). LC-MS [M + H]+: m/z 668.37. EXAMPLE 37A AND 37B 3-(2-((5-((5)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-( ((5 )-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)pyridin-2-yl) amino)-1H-imidazol-1-yl)propan-1 - amino (C37A) and 2,2,2-trifluoroacetate of 3-(2-((5-((R)-2-((((Z) -1-(2-aminothiazol-4-yl)-2-(((5)-2,2-dimethyl-4-oxo-1 -(sulfo-oxy)azetidin-3 - yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)pyridin-2-yl)amino)- 1H-imidazol-1-yl)propan-1-aminium (C37B)

[00389] Step A: tert-Butyl (3-(2-nitro-1H-imidazol-1-yl)propyl)carbamate Cesium carbonate (576 mg, 1.77 mmol) was added to a stirred mixture of 3-(Boc-amino)propyl bromide (232 mg, 0.973 mmol) and 2-nitro-1H-imidazole (100 mg, 0.884 mmol) in DMF (2 mL) and the mixture was stirred at room temperature for 1 h before being stirred overnight at 60 °C. The mixture was diluted with ethyl acetate, washed with water (3x) and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford the crude product which was purified by ISCO column (gold, 40 g) eluting with EtOAc/hexane gradient 0-100% to afford the title compound. LC-MS [M + H]+: m/z 271.3.

[00390] Step B: tert-Butyl (3-(2-amino-1H-imidazol-1-yl)propyl)carbamate A mixture of tert-butyl (3-(2-nitro-1H-imidazol-1-yl)propyl)carbamate (500 mg, 1.85 mmol) and 3% Pt/0.6% V/C (100 mg, 0.015 mmol) in methanol (10 mL) was evaporated under vacuum, backfilled with H2 (3x) and stirred at room temperature for 2.5 h. The reaction mixture was diluted with EtOAc, and filtered through Celite®. The filtrate was concentrated under reduced pressure to afford the title compound, which was used as is for the next step. LC-MS [M + H]+: m/z 241.6.

[00391] Step C: 3-((6-((1-(3-((tert-butoxycarbonyl)amino)propyl)- 1H-imidazol-2-yl)amino)pyridin-3-yl)oxy)-2 tert-butyl -((tert-butyldimethylsilyl)oxy)propanoate A mixture of tert-butyl 3-((6-bromopyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (178 mg , 0.412 mmol), tert-butyl (3-(2-amino-1H-imidazol-1-yl)propyl)carbamate (90 mg, 0.375 mmol), palladium precatalyst G3 J009 and cesium carbonate (366 mg , 1.12 mmol) in dioxane (3.5 mL) was exchanged 3 times in vacuum/N2 before the mixture was heated at 100°C overnight. The mixture was diluted with EtOAc and filtered through a short pad of celite and washed with EtOAc. The solvent was removed under pressure reduced to provide the title compound, which was used directly in the next step. LC-MS [M + H]+: m/z 592.7.

[00392] Step D: 3-((6-((1-(3-(bis(tert-butoxycarbonyl)amino) propyl)-1 H-imidazol-2-yl)(tert-butoxycarbonyl)amino)pyridin-3 tert-butyl-yl)oxy)-2- ((tert-butyldimethylsilyl)oxy)propanoate A mixture of 3-((6- ((1-(3-((tert-butoxycarbonyl)amino)propyl)-1H- tert-butyl imidazol-2-yl)amino)pyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (120 mg, 0.203 mmol) in Boc2O (0.5 ml) was stirred at 120°C for 2.5 hours. The reaction mixture was quenched directly with an ISCO column (gold, 40 g) eluting with 0-100% EtOAc/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 792.9.

[00393] Step E: 3-((6-((1-(3-(bis( tert-butoxycarbonyl)amino) propyl)-1 H-imidazol-2-yl)( tert-butoxycarbonyl)ammo)pyridm-3 -tert-butyl-yl)oxy)-2-hydroxypropanoate TBAF (1.0 M in THF, 0.606 mL, 0.606 mmol) was added to a stirred mixture of 3-((6-((1-(3 -(bis(tert-butoxycarbonyl)amino)propyl)-1H-imidazol-2-yl)(tert-butoxycarbonyl)amino)-pyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate tert-butyl (320 mg, 0.404 mmol) in THF (3 ml) and the mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified with an ISCO silica gel column (gold, 40 g) eluting with a 0-100% EtOAc/hexane gradient to afford the compound title. LC-MS [M + H]+: m/z 678.8.

[00394] The product of step E (tert-butyl 3-((6-((1-(3-(bis(tert-butoxycarbonyl)amino)propyl)-1H-imidazol-2-yl)(tert-butoxycarbonyl)amino)pyridin-3-yl)oxy)-2-hydroxypropanoate) was converted to C37A and C37B as TFA salts following a similar procedure to step C, step E and step H in Example 1.

[00395] Compound 37A: 3-(2-((5-((S)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2 -(((S)-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)pyridin- 2- yl)amino)-1H-imidazol-1-yl)propan-1-ammonium. LC-MS [M + H]+: m/z 683.6. 1H NMR (500 MHz, Deuterium Oxide) δ 7.88 (d, J = 2.9 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.04 - 6.96 (m, 2H), 6.93 (s, 2H) , 4.99 (s, 1H), 4.62 (br s, 1H), 4.47 - 4.34 (m, 2H), 4.04 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 8.0 Hz, 2H), 2.08 (m, 2H), 1.31 (s, 3H), 1.00 (s, 3H).

[00396] Compound 37B: 2,2,2-trifluoroacetate of 3-(2-((5-((R)-2- ((((Z)-1-(2-aminothiazol-4-yl)-2 -(((S)-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-carboxyethoxy)pyridin- 2- yl)amino)-1H-imidazol-1-yl)propan-1-amino. LC-MS [M + H]+: m/z 683.6. 1H NMR (500 MHz, Deuterium oxide) δ 7.89 - 7.85 (s, 1H), 7.39 - 7.32 (d, 1H), 7.03 - 6.95 (m, 2H), 6.93 (s, 2H), 4.95 (s, 1H ), 4.62 (br s, 1H), 4.45 - 4.35 (m, 2H), 4.04 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 8.0 Hz, 2H), 2.08 (m, 2H), 1.31 (s, 3H), 1.02 (s, 3H). EXAMPLE 38 (S )-3-((Z)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-sulfate 4-yl)-3-chlorophenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00397] Step A: (R )-tert-Butyl 3-(4-bromo-3-chlorophenoxy)-2-hydroxypropanoate (R,R)-Catalyst Co (0.24 g, 0.29 mmol) was added to a stirred mixture at room temperature of tert-butyl oxirane-2-carboxylate (1.7 g, 12 mmol) and 4-bromo-3-chlorophenol (1.2 g, 5.8 mmol) in t-butylmethyl ether. Then, molecular sieves (2.3 g) were added, and the mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated, and the resulting residue was purified on a silica gel column (80 g), eluting with EtOAc/Hexane (5~40%) to afford the title compound.

[00398] Step B: (R)-3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-chlorophenoxy)-2-hydroxypropanoate tert-butyl To a solution of (R)-tert-butyl 3-(4-bromo-3-chlorophenoxy)-2-hydroxypropanoate (0.42 g, 1.2 mmol)), (R)-3-(4-bromo-3-chlorophenoxy)-2-hydroxypropanoate tert-butyl (0.42 g, 1.2 mmol)), and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.078 g, 0.12 mmol)) in dioxane (1 mL) was added to 1 M aqueous potassium phosphate solution. (3.6 mL, 3.6 mmol)). The reaction flask was sealed, degassed, and replenished with N2. The reaction was stirred at 72 °C for 1 h, then diluted with water and extracted with EtOAc twice. The combined organic layers were dried over MgSO4, filtered, and concentrated. The resulting residue was purified on a silica gel column (25 g), eluting with CH2Cl2/MeOH (100~90%) to afford the title compound. LC-MS [M + H]+: m/z 496.34.

[00399] Step C: (5 )-3-(4-(1-(3-(( tert -butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl)-3-chlorophenoxy)-2-( (R)-tert-butyl diazene-1,2-dicarboxylate (0.20 ml, 1.3 mmol) was added to a mixture at 0°C of 3-(4-(1- (3-((tert-Butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-chlorophenoxy)-2-hydroxypropanoate of (E)- diethyl (580 mg, 1.2 mmol), 2-hydroxyisoindoline-1,3-dione (190 mg, 1.2 mmol), triphenylphosphine (340 mg, 1.3 mmol) in THF. The reaction mixture was stirred at RT for 4 h and then concentrated. The resulting residue was purified by column chromatography on a silica gel column (25 g), eluting with EtOAc /5~50% isohexane to afford the title compound. LC-MS [M + H]+: m/z 641.44.

[00400] Step D: (5 )-4-(4-(3-( tert -butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)-2- iodide chlorophenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-yl Mel (610, 9.8 mmol) was added to a mixture of 3-(4 -(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-chlorophenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (5)-tert-butyl (625 mg, 0.98 mmol) in CH3CN. The reaction mixture was stirred at 74 °C overnight and then cooled to rt. The reaction mixture was concentrated to afford the title compound. LC-MS [M]+: m/z 655.40.

[00401] Step E: (S,Z)-4-(4-(3-( tert-butoxy)-2-((((2-(( tert -butoxycarbonyl)amino)thiazol-4-yl) iodide -(carboxy)methylene)amino)oxy)-3-oxopropoxy)-2-chlorophenyl)-1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io Hydrazine ( 28 mg, 0.86 mmol) was added to a mixture of (5)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy) iodide) -3-oxopropoxy)-2-chlorophenyl)-1-(3-((tert-butoxycarbonyl)amino) 2-(propyl)-2-methyl-1H-pyrazol-2-ium (610 mg, 0.78 mmol) in CHCl3/ethanol. The reaction was stirred at room temperature for 1 h, then 2-(2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (230 mg, 0.86 mmol). The reaction was stirred at RT for 3 h, then concentrated to afford the title compound. LC-MS [M ]+: m/z 779.33.

[00402] Step F: 4-(4-(( 5 )-3-( tert -butoxy)-2-((((Z)-1-(2-(( tert -butoxycarbonyl)amino)thiazol-4- il)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy) -2- chlorophenyl)-1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-methyl-1 H-pyrazol-2- io To the solution of (S,Z)-4-(4-(3 -(tert-butoxy))-2-(((((2-((tert-butoxycarbonyl)- amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)-2-chlorophenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H- pyrazol-2-ium (810 mg, 1.0 mmol) in DMF (1 mL) was added N,N'-methanediylidenedicyclohexanamine (DCC) (540 mg, 2.6 mmol) and 1H-benzo[ d][1,2,3]triazol-1-ol (HOBt) (500 mg, 2.6 mmol). The reaction mixture was stirred at rt. for 20 min, then (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (330 mg, 1.6 mmol) and sodium hydrogen carbonate (520 mg, 6.2 mmol ) were added. The reaction mixture was stirred at RT for 2 h and then filtered. The filtrate was purified on a 150g C-18 reverse phase column using 0~75~100% acetonitrile (with 0.05% TFA) over 25 min to afford the title compound. LC-MS [M + H]+: m/z 971.27.

[00403] Step G: (S )-3-((Z)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-methyl-1 H-pyrazol-sulfate 2-io-4-yl)-3-chlorophenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl TFA ( 2 mL, 26 mmol) was added to a stirred mixture, at room temperature, of 4-(4-((S)-3-(tert-butoxy)-2-(((Z)-(1-(2- ((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo- oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)-2-chlorophenyl)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-2-methyl -1H-pyrazol-2-ium (175 mg, 0.18 mmol) in DCM. The reaction mixture was stirred at room temperature for 1 h 20 min and then concentrated. The resulting crude product was dissolved in water and purified via SFC with water/acetonitrile (0.1% HCOOH) to afford the title compound. LC-MS [M]+: m/z 715.68. EXAMPLE 39 (S)-3-((Z)-2-((((S)-1-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-ium sulfate -4-yl)phenoxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00404] Step A: (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate tert-butyl Cesium carbonate (12 g, 38 mmol) was added to a room temperature mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.8 g, 25 mmol), (3-bromopropyl)tert-butylcarbamate (6.0 g, 25 mmol) in DMF (40 mL). The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc and water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (10~80%) to afford the title compound. LC-MS [M + H]+: m/z 352.33.

[00405] Step B: 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-phenoxy)-2-((1,3-dioxoisoindolin tert-butyl -2-yl)oxy)-2-methylpropanoate To a solution of tert-butyl 2-(aminooxy)-3-(4-bromophenoxy)-2-methylpropanoate (100 mg, 0.29 mmol )), tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate (100 mg, 0.29 mmol)) and 1,1-bis(di-tert-butylphosphine)ferrocenepalladium dichloride (19 mg, 0.029 mmol)) in dioxane (1 mL) was added to 1 M aqueous potassium phosphate solution (0.87 mL, 0.87 mmol). The flask was sealed, degassed, backfilled with N2, and stirred at 70°C for 1 h. Then the reaction was diluted with water, extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with CH2Cl2/ MeOH (100~90%) to afford the title compound. LC-MS [M + H]+: m/z 491.43.

[00406] Step C: tert-Butyl 3-(4-(1-(3-(( tert-Butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-(( 1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate 4-Methylbenzenesulfonic acid (12% in acetic acid, 63 mg, 0.044 mmol) was added to a room temperature mixture of tert-butyl 2-(aminooxy)-3-(4-(1-(3-(( tert-Butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-methylpropanoate (540 mg, 1.1 mmol) and molecular sieves (200 mg) in toluene. The reaction mixture was stirred at 100 °C for 4 h, then filtered and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with CH2Cl2/MeOH (100~90%) to afford the title compound. LC-MS [M + H]+: m/z 622.56.

[00407] Step D: 4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methyl-3-oxopropoxy)phenyl)- iodide 1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io The title compound was prepared according to the procedure of Example 1, Step D, using 3-(4 -(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate tert-butyl (0.50 g, 0.80 mmol) and MeI (0.40 ml, 6.4 mmol) in MeCN (3 ml). LC-MS [M]+: m/z 635.58

[00408] Step E: (Z)-4-(4-(3-( tert -butoxy)-2-((((2-(( tert -butoxycarbonyl)amino)thiazol-4-yl)(carboxy) )methylene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io Hydrazine (0.024 mL, 0.76 mmol) in 0.3 mL of DCM was added to a mixture of 4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy) -2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)-amino) 2-( ... (tert-butoxycarbonyl)-amino)thiazol-4-yl)-2-oxoacetic acid (230 mg, 0.84 mmol). The reaction was stirred at room temperature overnight and then filtered. The filtrate was concentrated and the resulting residue was purified by preparative HPLC, eluting with acetonitrile/water + 0.05% TFA (0~100%) to afford the title compound. LC-MS [M + H]+: m/z 759.58.

[00409] Step F: 4-(4-(3-(tert-butoxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)-amino)thiazol-4-yl)- 2-(((S)-2,2-dimethyl-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1 -(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io A a solution of (Z)-4-(4-(3-(tert-butoxy) iodide) -2-(((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-2-methyl-3- (oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (80 mg, 0.105 mmol) in DMF (1 ml) was added DCC (87 mg, 0.42 mmol) and HOBT (60 mg, 0.32 mmol). The reaction mixture was stirred at rt for 30 min, followed by the addition of (S)-3-amino-2,2-dimethyl- 4-oxoazetidin-1-yl (76 mg, 0.42 mmol) and sodium bicarbonate (35 mg, 0.42 mmol). The reaction was then stirred at rt for 16 h and then filtered. The filtrate was purified by reversed-phase ISCO (130 g, 0-100%, H2O/MeCN/0.05% TFA) to afford the title compound. LC-MS [M + H]+: m/z 921.76

[00410] Step G: (5 )-3-((Z)-2-((((5 )-1-(4-(1-(3-aminopropyl)-2-methyl-1 H-pyrazole sulfate -2-io-4-yl)phenoxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin- 1 -yl To a solution of 4-(4-(3-( tert -butoxy)-2-((((Z)-1-(2-(( tert -butoxycarbonyl)amino)thiazol-4-yl)-2 -((S)-2,2-dimethyl-4-oxo-1-(sulfooxy) azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methyl-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H -pyrazol-2-ium (110 mg, 0.12 mmol) in DCM, 2 mL of TFA was added. The reaction mixture was stirred at RT for 90 min, then concentrated in vacuo without heat. DCM (10 mL ) and the mixture was concentrated three times to remove TFA. The resulting residue was washed with dry MeCN (2x2 mL). Then the residue was dissolved in DMSO and purified on prep HPLC with a gradient of 2-25% MeCN/ H2O (0.05% TFA in both) in 10 min to afford the title compound. LC-MS [M + H]+: m/z 695.14. EXAMPLE 40 (3S)-3-((Z)-2-((2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl) sulfate phenoxy)-1-phosphonoethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00411] Step A: 1-Bromo-4-(2,2-diethoxyethoxy)benzene Potassium carbonate (11 g, 78 mmol) was added to a stirred, room temperature, mixture of 4-bromophenol (5.4 g, 31 mmol) and 2-bromo-1,1-diethoxyethane (1.8 mL, 12 mmol) in DMF. The reaction mixture was stirred at 80 °C overnight, then cooled to room temperature and diluted with EtOAc. The mixture was washed with water and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (0~40%) to afford the title compound.

[00412] Step B: 2-(4-Bromophenoxy)acetaldehyde HCl (3.7 mL, 22 mmol) was added to a stirred room temperature mixture of 1-bromo-4-(2,2-diethoxyethoxy)benzene (2.6 g, 9.0 mmol) in THF. The reaction mixture was stirred at room temperature overnight, then the mixture was extracted with ether. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered, and concentrated to afford the title compound.

[00413] Step C: Dimethyl (2-(4-bromophenoxy)-1-hydroxyethyl)phosphonate Dimethyl dimethylphosphonate (1.20 mL, 13 mmol) was added dropwise to a stirred mixture of 0 °C, (2-bromophenoxy)-acetaldehyde (1.2 g, 5.3 mmol), and triethylamine (1.8 mL, 13 mmol) in THF. The reaction mixture was stirred at 0 °C for 1 h and then at RT for 1 h. Then the reaction mixture was concentrated. The resulting residue was purified by column chromatography on a 40 g silica gel column, eluting with CH 2 Cl 2 /MeOH (100~90%) to afford the title compound. LC-MS [M+H]+: m/z 325.00.

[00414] Step D: tert-Butyl (3-(4-(4-(2-(dimethoxyphosphoryl)-2-hydroxyethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate The title compound was prepared according to the procedure of Example 38, Step B. LC-MS [M+H]+ : m/z 470.29

[00415] Step E: tert-butyl (3-(4-(4-(2-(dimethoxyphosphoryl)-2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate The title compound was prepared according to the procedure for Example 38, Step C. LC-MS [M+H]+ : m/z 615.29

[00416] Step F: 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-(dimethoxyphosphoryl)-2-((1,3-dioxoisoindolin-2-yl) trifluoromethanesulfonate oxy)ethoxy)phenyl)-2-Methyl-1H-pyrazol-2-io Methyl trifluoromethanesulfonate (0.069 mL, 0.63 mmol) was added to a stirred mixture cooled to 0°C of (3-(4-( tert-butyl 4-2-(dimethoxyphosphoryl)-2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate (370 mg, 0. 60 mmol) in CH3CN. The mixture was stirred at 0°C for 10 min, at room temperature overnight, and then concentrated. The resulting residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (100~80%) to afford the title compound. LC-MS [M]+: m/z 629.33

[00417] Step G: 1-(3-Aminopropyl)-4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-phosphonoethoxy)-phenyl)-2-methyl-1H-pyrazol-2-ium trifluoromethanesulfonate Bromotrimethylsilane (0.77 mL, 5.9 mmol) was added to a stirred room temperature mixture of 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-(dimethoxyphosphoryl))-2-((1,3-dioxoisoindolin-2-yl)oxy)-ethoxy)phenyl)-2-methyl-1H-pyrazol-2-ium trifluoromethanesulfonate (570 mg, 0.59 mmol) in DCM. The reaction mixture was stirred at room temperature overnight and then concentrated to afford the title compound. LC-MS [M]+: m/z 501.26

[00418] Step H: 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-phosphonoethoxy)phenyl )-2-methyl-1H-pyrazol-2-io Triethylamine (0.31 mL, 2.2 mmol) was added to a stirred and cooled room temperature mixture of 1-(3-aminopropyl)-4-(trifluoromethanesulfonate 4-(2-((1,3)dioxoisoindolin-2-yl)oxy-2-phosphonoethoxy)phenyl)-2-methyl-1H-pyrazol-2-io (0.28 g, 0.56 mmol) and dicarbonate of di-tert-butyl (0.24 g, 1.12 mmol)) in DMF. The reaction mixture was stirred at room temperature overnight. The mixture was purified by preparative reversed-phase (C-18) HPLC, eluting with 0.05% TFA in CH3CN/water (2~100%) to afford compound of the title. LC-MS [M]+: m/z 601.32

[00419] Step I: 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-((((Z)-1-(2-((tert-butoxycarbonyl)-amino )thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxo-ethylidene)amino) oxy)-2-phosphonoethoxy)phenyl)-2-methyl-1H-pyrazol-2-io Hydrazine (10, 0.33 mmol) was added to a stirred mixture, at room temperature, of 1-(3-((tert - butoxycarbonyl)amino)propyl)-4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2- (S)-3-(2 ... (2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoaetamido)-2,2-dimethyl-4-oxoazetidin-1-yl and the reaction was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was collected. The resulting residue was dissolved in DMF and purified by preparative reversed-phase HPLC (C-18), eluting with acetonitrile/water + 0.1% TFA (2~100%), to proportion the compound of the title. LC-MS [M+H]+: m/z 917.24

[00420] Step J: (3S)-3-((Z)-2-((2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4 sulfate -yl)phenoxy) 1-phosphonoethoxy)imino)-2-(2-aminothiazol-4-yl)aethamido)-2,2-dimethyl-4-oxoazetidin-1-yl The title compound was prepared in accordance with the procedure of Example 2, Step G, using 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-((((Z)-1-(2- ((tert-butoxycarbonyl) amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo- oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-phosphonoethoxy)phenyl)-2-methyl-1H-pyrazol-2-io (0.13 g, 0.14 mmol) and TFA (1.5 ml, 19 mmol). LC-MS [M+H]+: m/z 717.36 EXAMPLE 41 (3S)-3-((Z)-2-(((1R)-2-(4-(1-(3-aminopropyl)) compound -2-methyl-1H- pyrazol-2-io-4-yl)phenoxy)-1 - (hydroxy(methoxy)phosphoryl)ethoxy)imino)-2- (2-aminothiazol-4-yl)acetamido)-2 ,2-dimethyl-4-oxoazetidin-1-yl sulfate with 2,2,2-trifluoroacetic acid (1:1)

[00421] Step A: 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-2-( hydroxy(methoxy)phosphoryl)ethoxy)feml)-2-methyl-1H-pyrazol-2-ioMeI (0.145 mL, 2.327 mmol) was added to a stirred mixture at room temperature of (3-(4-(4-( tert-Butyl 2-(dimethoxyphosphoryl)-2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)phenyl)-1H-pyrazol-1-yl)propyl)carbamate (from Example 40, Step E, 143 mg, 0.23 mmol) in CH3CN. The reaction mixture was stirred at 72°C overnight, then concentrated to afford the title compound. LC-MS [M]+: m/z 615.36

[00422] Step B: 1-(3-(( tert -butoxycarbonyl)ammo)propyl)-4-(4-((2R)-2-((((Z)-(2-(( tert -butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-2-(hydroxyl-(methoxy)phosphoryl)ethoxy)phenyl)-2-methyl-1H-pyrazole-2-ium The title compound was prepared according to the procedure of Example 38, Step E. LC-MS [M]+: m/z 739.46.

[00423] Step C: 1-(3-((tert-butoxycarbonyl)amino)propyl)-4-(4-(2- ((((Z)-1-(2-((tert-butoxycarbonyl)amino) thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)- 2-(hydroxy(methoxy)phosphoryl)ethoxy)phenyl)-2-methyl-1H-pyrazol-2-io The title compound was prepared according to the procedure of Example 38, Step F. LC-MS [M]+ : m/z 931.38.

[00424] Step D: (3S)-3-((Z)-2-(((1R)-2-(4-(1-( 3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenoxy)-1-(hydroxy(methoxy)phosphoryl)ethoxy)imino)-2-(2-ammothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate compound with 2,2,2-trifluoroacetic acid (1:1) The title compound was prepared according to the procedure in Example 38 Step G. LC-MS [M + H]+: m/z 731.68. EXAMPLE 42 (3S)-3-((Z)-2-(((1S)-2-(4-(1-(3-amino-2-hydroxypropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1 sulfate -ila

[00425] Step A: tert-Butyl 2,2-dimethyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)oxazolidine-3-carboxylate Cesium carbonate (3.3 g, 10.2 mmol) was added to a room temperature mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3 g, 6.8 mmol)) and tert-butyl 5-(bromomethyl)-2,2-dimethylaxazolidine-3-carboxylate (2 g, 6.8 mmol)) in DMF (10 mL). The reaction mixture was stirred at 60 °C for 5 h, then cooled to rt. and filtered. The filtrate was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (10% to 80%) to afford the title compound. LC-MS [M + H]+: m/z 408.33.

[00426] Step B: 5-((4-(4-(( S )-3-( tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1H-pyrazol-1-yl)methyl)-2,2- tert-butyl dimethylaxazolidine-3-carboxylate The title compound was prepared according to the procedure of Example 38, Steps A-C. LC-MS [M + H]+: m/z 663.45.

[00427] Step C: 4-(4-((S)-3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-((3-(tert-butoxycarbonyl)-2,2-dimethylaxazolidin-5-yl)methyl)-2-methyl-1H-pyrazole-2-ium trifluoromethanesulfonate The title compound was prepared according to the procedure for Example 40, Step D. LC-MS [M]+ : m/z 677.47

[00428] Step D: 1-(3-Amino-2-hydroxypropyl)-4-(4-((S)-3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-2-methyl-1H-pyrazol-2-ium trifluoromethanesulfonate DL-10-camphorsulfonic acid (0.028 g, 0.122 mmol) was added to a stirred mixture at room temperature of 4-(4-((S)-3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)-phenyl)-1-((3-(tert- (2,2-dimethyl)-( ...

[00429] Step E: 4-(4-((S)-3-(tert-butoxy)-2-((1,3-dioxoisoindolino-2-yl)oxy)-3-oxopropoxy)phenyl)- trifluoroacetate 1-(3-2,2,2-(( tert -butoxycarbonyl)amino)-2-hydroxypropyl)-2-methyl-1H-pyrazol-2-io Et3N (170, 1.2 mmol) was added to a mixture stirred, at room temperature, of 1-(3-Amino-2-hydroxypropyl)-4-(4-((S)-3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2) trifluoromethanesulfonate -yl)oxy)-3-oxopropoxyl)phenyl)-2-methyl-1H-pyrazol-2-io (830 mg, 1.2 mmol) and BOC-Anhydride (225, 0.97 mmol) in CHCl3. The reaction mixture was stirred at room temperature overnight, then concentrated. The resulting residue was purified by column chromatography over a 40 g silica gel column, eluting with CH2Cl2/MeOH (100~90%) to give a mixture. The mixture was dissolved in CH3CN/water and purified again by reverse phase preparative HPLC (C-18), eluting with acetonitrile/water + 0.1% TFA (5~80~100%), to afford the title compound. LC-MS [M]+: m/z 637.33

[00430] Step E: (3S)-3-((Z)-2-(((1S)-2-(4-(1-(3-amino-2-hydroxypropyl)-2-methyl-1H-pyrazol-2-(io-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate The title compound was prepared according to the procedure of Example 38. Steps EG. LC-MS [M + H] + : m/z 697.24 EXAMPLE 43 Compound (S )-3-((Z)-2-((( S )-2-(4-(1-(( S )-3-amino-2- hydroxypropyl)-2-methyl-1H-pyrazol-2-io-4-yl)-3-fluorophenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl with formic acid (1:1)

[00431] Step A: (R)-Benzhydryl 3-(4-Bromo-3-fluorophenoxy)-2-hydroxypropanoate To a solution of (R)-3-(4-bromo-3-fluorophenoxy)-2-hydroxypropanoic acid (6 g, 22 mmol) and Et3N (4.5 mL, 32 mmol) in acetonitrile (40 mL) at rt was added dropwise (bromomethylene)dibenzene (6.9 g, 28 mmol) in acetonitrile (20 mL) over 5 min. The reaction mixture was heated at 80 °C for 4 h, then concentrated. The resulting residue was partitioned between H2O/DCM (75 mL/75 mL), and the aqueous layer was extracted with DCM (2 x 75 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated. The resulting residue was purified by ISCO (80 g, 0-30% EtOAc/hexanes) to afford the title compound. LC-MS [M + H]+: m/z 468.91

[00432] Step B: (R)-benzhydryl 3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-hydroxypropanoate Potassium acetate (3.0 g, 31 mmol) was added to a stirred mixture at room temperature of (R)-benzhydryl 3-(4-bromo-3-fluorophenoxy)-2-hydroxypropanoate (4.6 g, 9.4 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolan) (3.2 g, 12 mmol), and di-t-BuDPPF-PdCl2 (0.34 g, 0.52 mmol) in dioxane. The reaction mixture was degassed with N2 twice and stirred at 70 °C for 4 h. Then, the reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography on a 40 g silica gel column, eluting with EtOAc/isohexane (10~50%) to afford the title compound. LC-MS [M + H]+: m/z 493.35

[00433] Step C: (2R)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-hydroxypropanoate Aqueous potassium phosphate (2.6 mL, 2.6 mmol) was added to a room temperature mixture of (R)-benzhydryl 3-(3-fluoro-4-(4,4,5,5)-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-hydroxypropanoate (480 mg, 0.97 mmol), (3-(4-bromo-1H-pyrazol-1-yl)-2-((tert-butyldimethylsilyl)oxy)propyl)carbamate (S)-tert-butyl (380 mg, 0.88 mmol) and Di-t-BuDPPF-PdCl2 (34 mg, 0.053 mmol) in dioxane. The reaction mixture was degassed with N2 and stirred at 65 °C for 1.5 h. Then, the reaction mixture was cooled to rt and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (5~80%) to afford the title compound. LC-MS [M + H]+: m/z 720.50

[00434] Step D: (Z)-2-((((2S)-1-(benzhydryloxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-( (tert-butyldimethylsilyl)oxy)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid DEAD (0.12 mL, 0.78 mmol) was added to a stirred and cooled to 0 °C mixture of (2R)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propyl)-1H- English: benzhydryl pyrazol-4-yl)-3-fluorophenoxy)-2-hydroxypropanoate (0.51 g, 0.71 mmol), 2-hydroxyisoindoline-1,3-dione (116 mg, 0.71 mmol), and triphenylphosphine (200 mg, 0.78 mmol) in THF. The reaction mixture was stirred at RT for 1 h and then concentrated. The resulting residue was purified by column chromatography on silica gel [40 g column], eluting with hexane/EtOAc (100~60% to afford the title compound. LC-MS [M + H]+ : m/z 865.56

[00435] Step E: (Z)-2-((((S)-1-(benzhydryloxy)-3-(4-(1-((S)-3-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propyl)-2-methyl- 1H-2,4-pyrazol-4-yl)-3-fluorophenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid, trifluoromethanesulfonate salt The title compound was prepared according to the procedure for Example 40, Step D. LC-MS [M]+: m/z 1003.60.

[00436] Step F: 4-(4-(( S )-3-(benzhydryloxy)-2-((((Z)-(2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-(( tert-butoxycarbonyl)amino)-2-hydroxypropyl)-2-methyl-1H-pyrazol-2-ium TBAF (0.28 g, 1.06 mmol) was added to a stirred and cooled to 0 °C mixture of (Z)-2-((((S)-1-(benzhydryloxy)-3-(4-(1-((S)-3-(tert-butoxycarbonyl)amino)-2-((tert- English:(1H-2-butyldimethylsilyl)oxy)propyl)-2-methyl-1H-2-14-pyrazol-4-yl)-3-fluorophenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid trifluoromethanesulfonate salt (0.80 g, 0.53 mmol) in THF. The reaction mixture was stirred at room temperature for 2 h, then diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by preparative reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA to afford the title compound. LC-MS [M]+: m/z 889.45

[00437] Step G: 4-(4-(( S )-3-(benzhydryloxy)-2-((((Z)-1-(2-(( tert -butoxycarbonyl)amino)thiazol-4-yl) -2-(((S)-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)-amino)oxy)-3-oxopropoxy)- 2-fluorophenyl)-1-(( S )-3-(( tert-butoxycarbonyl)amino)-2-hydroxypropyl)-2-methyl- 1H-pyrazol-2-ium A 4-(4-(( S)-3-(benzhydryloxy))-2- ((((Z)-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-( (tert-butoxycarbonyl)amino)-2-hydroxypropyl)-2-methyl-1H-pyrazol-2-io (220 mg, 0.24 mmol) and (S)-3-amino-2,2-dimethyl-4- oxoazetidin-1-yl (102 mg, 0.48 mmol)) in acetonitrile (12 mL) at -10°C, pyridine (0.059 mL, 0.73 mmol) was added under N2. Then, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (102 mg, 0.53 mmol) was added. The reaction was stirred at -10~0°C for 1 h, then concentrated. The resulting residue was purified by preparative reverse phase (C-18), eluting with acetonitrile/water + 0.1% TFA to afford the title compound.

[00438] Step H: ((3S)-3-((Z)-2-(((1S)-2-(4-(1-( 3-amino-2-hydroxypropyl)-2-methyl-1H-pyrazol-2-io-4-yl)-3-fluorophenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate compound with formic acid (1:1). TFA (2 ml) was added to a stirred mixture at room temperature of 4-(4-((S)-3-(benzhydryloxy)-2-((((Z)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2- (((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-((S)-3-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)-2-methyl-1H-pyrazol-2-ium (240 mg, 0.22 mmol) in DCM. The reaction mixture was stirred at room temperature for 45 min, then concentrated and treated with ether twice. The resulting residue was dissolved in DMSO (3 mL) and ether (2 mL) and concentrated in vacuo for 5 min. The resulting solution was diluted with DMSO (4 mL) and subjected to reverse-phase purification to afford the title compound as a single isomer. LC-MS [M + H]+: m/z 715.30. EXAMPLE 44 (3S)-3-((Z)-2-(((1S)-2-(4-(1-(3-amino-2-hydroxypropyl)-2-methyl-1H-pyrazol-2-io-4-yl)-3-fluorophenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoa sulfate compound zetidin-1-yl with formic acid (1:1)

[00439] The title compound was prepared according to the procedure for Example 43 starting from the appropriate starting materials. LC-MS [M + H] + : m/z 715.28. EXAMPLE 45 and EXAMPLE 46 (S )-3-((Z)-2-(2-Aminothiazol-4-yl)-2-((( S )-1-carboxy-2-(4-(1-(( R )-2,3-diaminopropyl)-2-methyl-1H-pyrazol-2-yl-4-yl)-3-fluorophenoxy)ethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate (Diastereomeric at the amine)

[00440] Step A: (2-((tert-butyldimethylsilyl)oxy)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole tert-butyl -1-yl)propyl)carbamate Potassium acetate (3.48 g, 36 mmol) was added to a stirred mixture at room temperature of 4,4,4',4',5,5,5' ,5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.6 g, 14 mmol), (3-(4-bromo-1H-pyrazol-1-yl)-2- tert-butyl ((tert-butyldimethylsilyl)oxy)propyl)carbamate (5.1 g, 12 mmol) and di-t-BuDPPF PdCl2 (0.38 g, 0.591 mmol) in dioxane. The reaction mixture was degassed with N2 twice and stirred at 70 °C for 4 h. Then, the reaction mixture was filtered and the filtrate was concentrated. The resulting residue was purified by column chromatography on a 120 g silica gel column, eluting with EtOAc/isohexane (0~50%) to afford the title compound. LC-MS [M + H]+: m/z 482.49

[00441] Step B: (2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl )tert-butylcarbamate TBAF (0.61 g, 2.3 mmol) was added to a stirred 0°C mixture of (2-((tert-butyldimethylsilyl)oxy)-3-(4-(4 tert-Butyl ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate (0.93 g, 1.9 mmol) in THF . The reaction mixture was stirred at room temperature for 2 h, then concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane (5~80%) to afford the title compound. LC-MS [M + H]+: m/z 368.27

[00442] Step C: 1-((tert-Butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-yl methanesulfonate MsCl (0.104 mL, 1.33 mmol) was added in one portion to a stirred solution of tert-butyl (2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate (480 mg, 1.30 mmol) and Et3N (0.24 mL, 1.7 mmol) in dichloromethane (5 mL) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 1 h, then concentrated in vacuo and partitioned between water (50 mL) and ethyl acetate (40 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with brine (40 mL), dried (magnesium sulfate), and concentrated in vacuo to afford the title compound.

[00443] Step D: (2-azido-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl ) tert-butyl carbamate

[00444] Sodium azide (173 mg, 2.7 mmol) was added in one portion to a stirred solution of 1-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-yl methanesulfonate (590 mg, 1.33 mmol)) in dimethylformamide (5 mL). The reaction mixture was heated to 80 °C and stirred for 18 h, and cooled to room temperature. Then, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried (magnesium sulfate), and concentrated in vacuo to afford the title compound. LC-MS [M + H]+: 393.38.

[00445] Step E: tert-Butyl (2-amino-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate Pd-C (280 mg, 0.27 mmol) was added to a room temperature mixture of tert-butyl (2-azido-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate (525 mg, 1.34 mmol) in MeOH. The reaction mixture was stirred at room temperature under H2 overnight. Then the mixture was filtered and the filtrate was concentrated to dryness to afford the title compound. LC-MS [M + H]+: 367.24.

[00446] Step F: Di-tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propane-1,2-diyl)dicarbamate BOC- Anhydride (0.34 mL, 1.5 mmol) was added to a stirred mixture at room temperature of (2-amino-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)tert-butyl carbamate (570 mg, 1.3 mmol) in THF. The mixture was stirred at room temperature for 1 h and then concentrated to afford the title compound. LC-MS [M + H]+: 467.36.

[00447] Step G: Benzhydryl (2R)-3-(4-(1-(2,3-bis(( tert -butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-hydroxypropanoate Aqueous potassium phosphate (4.0 mL, 4.0 mmol) was added to a room temperature mixture of (R)-benzhydryl 3-(4-bromo-3-fluorophenoxy)-2-hydroxypropanoate (590 mg, 1.3 mmol), di-tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propane-1,2-diyl)dicarbamate (630 mg, 1.3 mmol), and di-t-BuDPPF PdCl 2 (52 mg, 1.3 mmol). 0.079 mmol) in dioxane. The reaction mixture was degassed with N2 and stirred at 65 °C for 1.5 h, then cooled to rt and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by column chromatography, eluting with CH2Cl2/MeOH (100-90%) to afford the title compound as a diastereomeric mixture. LC-MS [M + H]+: 705.45. The diastereomers were separated using an OJ-H column under SFC conditions to afford the title compounds. Example 45 was prepared from the faster eluting isomer according to the procedure in Example 1, Steps BH. LC-MS [M + H]+: m/z 714.20. Example 46 was prepared from the slower eluting isomer according to the procedure of Example 1, Steps B- H. LC-MS [M + H] + : m/z 714.36. EXAMPLE 47 (S)-3-((Z)-2-((( S )-2-(4-(3-Amino-1-(3-aminopropyl)-2-methyl-1 H-pyrazol-2-io-4-yl)-3-fluorophenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00448] Step A: (R )-3-(4-(3-amino-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1 H-pyrazol-4-yl)-3-fluorophenoxy tert -butyl )-2-((tert-butyldimethylsilyl)oxy)propanoate A solution of 2-((tert-butyldimethylsilyl)oxy)-3-(3-fluoro-4-(4,4,5,5) (R)-tert-butyl-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate (2.6 g, 5.24 mmol), (3-(3-amino-4-bromo- tert-butyl 1H-pyrazol-1-yl)propyl)carbamate (2.0 g, 6.3 mmol) and tert-butyl dichloride 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium (0.34 g, 0.52 mmol) in THF (15 mL) in a microwave vial was added to 1 M aqueous solution of potassium phosphate potassium (7.8 mL, 7.8 mmol). The microwave vial was sealed, degassed, and recharged with N2 (3x). The reaction was stirred at 70°C for 2 h, then diluted with NH4Cl solution ( saturated) and extracted with EtOAc. The organic layer was combined, dried over MgSO4 and concentrated. The resulting residue was purified by flash column chromatography on SiO2 (80 g gold, eluting with EtOAc/Hexane (0.100% 3hp, 100% 6hp) to afford the title compound. LC-MS [M+1]: m /z 609.00

[00449] Step B: (R)-3-(4-(3-(((allyloxycarbonyl)amino)-1-(3-(tert-butyl)butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate To a solution of (R)-tert-butyl 3-(4-(3-amino-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (2.3 g, 3.8 mmol) in CH2Cl2 (100 mL), was added DIPEA (1.3 mL, 7.6 mmol) followed by addition of allyl carbonate (0.80 mL, 7.6 mmol). The mixture was stirred at room temperature for 4 h, then the solvent was removed. The resulting residue was purified by column chromatography on silica gel (80 g of gold), eluting with EtOAc/hexane (0-50%, 6 hp; 50%, 10 hp) to afford the title compound. LC-MS [M+1]: m/z 693.48.

[00450] Step C: (R)-3-(4-(3-(((allyloxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-tert-butylhydroxypropanoate To a solution of (R)-tert-butyl 3-(4-(3-(((allyloxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)-propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (2.6 g, 3.8 mmol) in THF (30 mL) was added a solution of TBAF in THF (3.75 mL, 3.75 mmol, 1 M). The reaction was stirred for 1 h at room temperature ambient temperature, then the solvent was removed. The resulting residue was purified by column chromatography on silica gel (40 g gold), eluting with EtOAc/Hexane (0-80%, 6 hp; 80%, 10 hp) to afford the title compound. LC-MS [M+1]: m/z 580.30

[00451] Step D: (S)-3-(4-(3-(((allyloxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl tert-butyl )-3-fluorophenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-propanoate A a solution of 3-(4- (3-(((allyloxy)carbonyl)amino) (R)-tert-butyl-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-3-fluorophenoxy)-2-hydroxypropanoate (1.13 g, 2, 0 mmol) in THF (5 ml), 2-hydroxyisoindoline-1,3-dione (0.38 g, 2.3 mmol) and triphenylphosphine were added (0.62 g, 2.3 mmol), followed by the addition of DIAD (0.46 ml, 2.3 mmol) at room temperature. The mixture was stirred at room temperature for 3 h, then the solvent was removed . The resulting residue was purified by column chromatography on Redi 40 g gold silica gel, eluting with EtOAc/hexane (0-70%, 6hp; 70%, 10hp) to afford the title compound. LC-MS [M +1]: m/z 725.25.

[00452] Step E: (S )-3-(((Allyloxycarbonyl)amino)-4-(4-(2-(amino-oxy)-3-(tert-butoxy)-3-oxopropoxy)-2 triphthlate -fluorophenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io A a solution of 3- (4-(3-(((allyloxycarbonyl)amino) -1-(3-((tert-butoxycarbonyl)amino)propyl)LH-pyrazol-4-yl)-3-fluorophenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy) propanoate (S )-tert-butyl (0.7 g, 0.97 mmol) in acetonitrile (12 ml) at 0°C, trifluoromethanesulfonate was added. methyl (0.11 mL, 0.97 mmol). The reaction was stirred at room temperature for 1 h, then a solution of ammonia in MeOH (1.4 mL, 9.7 mmol, 7 M) was added. The mixture The reaction mixture was stirred at room temperature overnight, then the solvent was removed in vacuo to afford the title compound. LC-MS [M+1]: m/z 608.44

[00453] Step F: (S,Z)-3-(((Allyloxycarbonyl)amino)-4-(4- (3-( tert-butoxy)-2-(((((2-(( tert-) butoxy-carbonyl))amino)thiazol-4-yl) (carboxy)methylene)amino)oxy)-3-oxopropoxy)-2-fluoro-phenyl)-1-(3-(( tert - butoxycarbonyl)amino)propyl) -2-methyl -1H-pyrazol-2-io A solution of 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (0.16 g, 0.60 mmol) and (S)-3-(((allyloxycarbonyl)amino)-4-(4-(2-(amino-) triphthlate oxy)-3-(tert-butoxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium (0 ,38 g, 0.50 mmol) in EtOH (1 mL) and CH2ClCH2Cl (0.5 mL) was stirred at room temperature overnight. Then, the reaction mixture was concentrated to afford the title compound. LC-MS [M+1]: m/z 862.39.

[00454] Step G: (S )-3-((Z)-2-(((( S )-3-(4-(3- (((Allyloxycarbonyl)amino)-1-(3-() Sulfate (tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-yl-4-yl)-3-fluorophenoxy)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy) imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl To (S,Z)-3 triphthlate solution - (((allyloxycarbonyl)amino)-4-(4-(3-(tert-butoxy)-2-((((2-((tert- (carboxy)-methylene)amino)oxy)-3-oxopropoxy)-2-fluorophenyl)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-2 - methyl-1H-pyrazol-2-ium (0.49 g, 0.50 mmol) in DMF (5 mL), DCC (0.31 g, 1.50 mmol) and HOBt (0.23 g, 1.50 mmol). The resulting solution was stirred at room temperature for 30 min, then (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (0.26 g, 1 ,25 mmol) and sodium bicarbonate (0.25 g, 3.0 mmol) were added. The reaction mixture was stirred at room temperature overnight. The resulting solid was filtered. The filtrate was purified by RP C-18 silica gel column, eluting with ACN/water with 0.05% TFA, (20-100% 8 hp, 100% 6 hp) to afford the title compound. LC- MS [M+1]: m/z 1054.77

[00455] Step H: (S )-3-((Z)-2-((((S)-3-(4-(3-Amino-1-(3-((tert-butoxycarbonyl)amino) sulfate )propyl)-2-methyl-1H-pyrazol-2-yl-4-yl)-3-fluorophenoxy)-1-( tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-( 2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl, trifluoroacetate A (S)-3-((Z) sulfate solution -2-((((S)-3-(4-(3- (((allyloxycarbonyl)amino)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-yl-4-yl)-3-fluorophenoxy)-1-(tert -butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1 -yl TFA (0.5 g, 0.43 mmol) in DMF (4 mL), Tetracycline Palladium (0.049 g, 0.043 mmol) and phenylsilane (0.53 mL, 4.3 mmol) were added at 0 °C. The reaction mixture was stirred for 10 min and then filtered. The filtrate was purified on a RPHPLC (Gilson) (column C-18) eluting with ACN/water containing 0.05% TFA (20-100%, 8 min; 100% 10 min) to afford the title compound. LC-MS [M+1]: m/z 970.48

[00456] Step I: (S)-3-((Z)-2-(((S)-2-(4-(3-Amino-1-(3-aminopropyl)-2-methyl-1 sulfate H-pyrazol-2-io-4-yl)-3-fluorophenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1 -yl To a solution of (S)-3-((Z)-2-((((S)-3-(4-(3-amino-1-(3-((tert-butoxycarbonyl)amino) sulfate )propyl)-2-methyl-1H-pyrazol-2-yl-4-yl)-3-fluorophenoxy)- 1-(tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4 -oxoazetidin-1-ylTFA (170 mg, 0.16 mmol) in CH2Cl2 (1 mL), TFA (2 mL, 26 mmol) was added. The solution was stirred at room temperature for 40 min, then the solvent was removed . The resulting residue was washed with Et2O (3x) and dried under vacuum. The resulting solid was dissolved in DMSO and purified on RPHPLC (Gilson) (C-18 column), eluting with ACN/water containing 0.05% TFA ( 0-40%, 12 min) to afford the title compound as the TFA salt. LC-MS [M+1]: m/z 712.30. 1H NMR (500 MHz, D2O) δH 7.96 (1H, s), 7.31 (1H, t, J = 8.6 Hz), 7.09 (1H, s), 6.85 (2H, d, J = 10.8 Hz), 5.14 (1H , s), 4.51 (2H, t, J = 14.7 Hz), 4.32 (2H, t, J = 7.2 Hz), 3.74 (3H, s), 3.02 (2H, t, J = 7.7 Hz), 2.66 (1H , s), 2.15 (2H, t, J = 8.0 Hz), 1.42 (3H, s), 1.08 (3H, s). EXAMPLE 48 (S )-3-((Z)-2-(((S)-2-(4-(3-Amino-1-(3-aminopropyl)-2-methyl-1H-pyrazol-sulfate 2-io-4-yl)-3-fluorophenoxy)-1-carboxyethoxy)imino)-2-(2-ammo-5-chlorothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1 -ila

[00457] The title compound was prepared using the procedure of Example 47 using 2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoacetic acid in Step F. LC-MS [M+1]: m/z 746.26. 1H NMR (D2O, 500 MHz) ), 3.75 (3H, s), 3.02 (2H, t, J = 7.8 Hz), 2.15 (2H, t, J = 7.9 Hz), 1.42 (3H, s), 1.07 (3H, s). example zetidin-1-yl

[00458] The title compound was prepared using the procedure of Example 47. LC-MS [M+1]: m/z 728.36. 1H NMR (D2O, 500 MHz): δH 7.93 (1H, s), 7.34 (2H, d, J = 8.2 Hz), 7.02 (2H, d, J = 8.2 Hz), 5.15 (1H, s), 4.29 ( 2H, t, J = 7.2 Hz), 3.73 (3H, s), 3.02 (2H, t, J = 7.7 Hz), 2.14 (2H, t, J = 8.0 Hz), 1.40 (3H, s), 1.04 ( 3H, s). EXAMPLE 50 (S )-3-((Z)-2-(((S)-2-(4-(5-Amino-1-(3-aminopropyl)-2-methyl-1H-pyrazol-sulfate 2-io-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00459] The title compound was prepared using the procedure of Example 47. LC-MS [M+1]: m/z 696.21. 1H NMR (D2O, 500 MHz) Hz), 3.81-3.83 (4H, m), 3.08 (2H, t, J = 7.9 Hz), 2.67 (1H, s), 2.15 (2H, t, J = 8.1 Hz), 1.42 (3H, s), 1.09 (3H, s). EXAMPLE 51A and 51B (S )-3-((Z)-2-(2-Amino-5-chlorothiazol-4-yl)-2-((((R )-1-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-yl-4-yl)phenoxy)-2-carboxypropan-2- sulfate dimethyl-4-oxoazetidin-1-yl (51A) Sulfate (S )-3-((Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(((( R )-1-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-yl-4-yl)phenoxy)-2-carboxypropan-2- yl)oxy)imino)acetamido)- 2,2-dimethyl-4-oxoazetidin-1-yl (51B)

[00460] The title compounds were prepared using the procedure of Examples 23A and 23B. Example 51A: LC-MS [M+1]: m/z 727.36. 1H NMR (500 MHz, D2O) δH 8.49 (1H, s), 8.43 (1H, s), 7.49 (2H, d), 7.02 (2H, s), 4.57-4.53 (3H, m), 4.48 (1H, d), 4.40 (1H, d), 4.11 (3H, s), 3.12(2H, t), 2.32 (2H, m), 1.60 (3H, s), 1.38 (3H, s), 1.17 (3H, s ). Example 51B: LC-MS [M+1]: m/z 727.36. 1H NMR (500 MHz, D2O) δH 8.50 (1H, s), 8.44 (1H, s), 7.50 (2H, d), 7.04 (2H, s), 4.59-4.53 (4H, m), 4.37 (1H, d), 4.11 (3H, s), 3.12(2H, t), 2.32 (2H, m), 1.61 (3H, s), 1.39 (3H, s), 1.13 (3H, s). EXAMPLE 52 (S )-3-((Z)-2-((( S )-2-(4-(1-(( S )-3-Amino-2-hydroxypropyl)-2-(azetidin-) sulfate 3-ylmethyl)-1H-pyrazol-2-yl-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4- oxoazetidin-1 -yl

[00461] Step A: (R )-3-(4-(1-(( S )-3-(( tert-butoxycarbonyl)amino)-2- ((tert-butyldimethylsilyl)oxy)propyl)- 1H-pyrazole tert-butyl-4-yl)phenoxy)-2-((tert-butyldimethylsilyl)-oxy)propanoate The mixture of (3-(4-bromo-1H-pyrazol-1-yl)-2-(tert-butyldimethylsilyl tert-butyl)oxy)propyl)carbamate (0.53 g, 1.22 mmol), 2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- tert-butyl 2-yl)phenoxy)propanoate (1 g, 2.8 mmol), tert-butyl dichloride 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium (0.18 g, 0.28 mmol) and potassium phosphate (4.12 ml, 8.24 mmol, 2 M aq) in THF (15 ml) was degassed and backfilled with N2 three times. The reaction mixture was heated at 60 °C for 2 h, then diluted with NH4Cl solution (saturated) and extracted with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. The resulting residue was purified by chromatography on an 80 g gold Redi silica gel column, eluting with EtOAc/hexane (0-35%, 6 hp; 35%, 10 hp) to afford the title compound. LC-MS [ M+1]: m/z 592.34.

[00462] Step B: (S)-3-(4-(1-((S)-3-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propyl)- 1H-pyrazole tert-butyl -4-yl)phenoxy)-2-((1,3- dioxoisoindolin-2-yl)oxy)propanoate To a solution of (2R)- 3-(4-(1-(3-(tert tert-butyl-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)-propyl)-1H-pyrazol-4-yl)phenoxy)-2-hydroxypropanoate (1.12 g, 1.9 mmol) in THF (10 mL), 2-hydroxyisoindoline-1,3-dione (0.37 g, 2.3 mmol) were added, triphenylphosphine (0.60 g, 2.3 mmol), followed by the addition of DIAD (0.44 mL, 2.3 mmol) at room temperature. The reaction was stirred overnight, then the solvent was removed. The resulting residue was purified by chromatography on an 80 g gold Redi silica gel column, eluting with EtOAc/hexane (0-50%, 5 hp, 50% 10 hp) to afford the title compound. LC-MS [M+1] : m/z 737.41.

[00463] Step C: 4-(4-((S)-3-(tert-Butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-((S)-3-(( tert -butoxycarbonyl)amino)-2-((tert -butyldimethylsilyl)oxy)propyl)-2-((1-( tert -butoxycarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-2-ium trifluoromethanesulfonate A solution of tert-butyl 3-(hydroxymethyl)azetidin-1-carboxylate (510 mg, 2.7 mmol) in CH2Cl2 (5 mL) was cooled to -78 °C and trifluoromethanesulfonic anhydride (0.56 mL, 3.4 mmol) and Hunig's base (0.95 mL, 5.4 mmol) were added. The reaction was stirred at -78 °C for 20 min, then quenched with water. The reaction mixture was warmed to room temperature and partitioned between EtOAc and water. The organic layer was separated, washed with saturated NaHCO 3 and brine, dried over Na 2 SO 4 , and concentrated in vacuo to afford an intermediate. To a flask containing the intermediate was added a solution of tert-butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (500 mg, 0.68 mmol) and sodium bicarbonate (570 mg, 6.8 mmol) in anhydrous CH 3 CN (10 mL). The reaction was heated at 60 °C for 1 h, then the solvent was removed. The resulting residue was triturated with Et2O (2 × 15 mL) and then purified by column chromatography on a 24 g gold Redi silica gel, eluting with MeOH/DCM (0-15%, 8 hp; 15%, 8 hp) to afford the title compound. LC-MS [M+1]: m/z 906.9.

[00464] Step D: 4-(4-(( S )-2-(Amino-oxy)-3-( tert-butoxy)-3-oxopropoxy)phenyl)-1-(( S )-3- trifluoromethanesulfonate ((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propyl)-2-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-2-ium

[00465] To 4-(4-((S)-3-(tert-Butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-((S)-3-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propyl)-2-((1-(tert-butoxycarbonyl)-azetidin-3-yl)methyl)-1H-pyrazol-2-ium trifluoromethanesulfonate (0.16 g, 0.18 mmol) in MeOH (1 mL), a solution of ammonia in MeOH (0.50 mL, 3.5 mmol, 7 M) was added. The reaction was stirred at room temperature for 5 h, then the solvent was removed to afford the title compound. LC-MS [M+1]: m/z 776.98.

[00466] Step E: 4-(4-((S)-3-(tert-Butoxy)-2-((((Z)-(2-((tert-butoxycarbonyl)amino)thiazol-4-trifluoromethanesulfonate yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-((S)-3-((tert-butoxy-carbonyl)-amino)-2-((tert-butyldimethylsilyl)oxy) propyl)-2-((1-( tert-butoxycarbonyl) azetidin-3 -yl)methyl)-1H-pyrazol-2-io A a solution of 4-(4-((S)-2-(Amino) trifluoromethanesulfonate -oxy)-3-(tert-butoxy)-3- oxopropoxy)phenyl)-1-((S)-3-((tert-butoxycarbonyl)amino)-2-((1-(tert-butyldimethylsilyl)oxy)propyl)-2-((1-(tert-butoxycarbonyl) azetidin-3-yl)methyl)-1H-pyrazol-2-ium (500 mg, 0.64 mmol) in EtOH (4 mL) and ClCH2CH2Cl (2 mL) was added 2-(2-((tert- (175 mg, 0.64 mmol) at room temperature. The reaction was stirred overnight, then the solvent was removed to afford the title compound. LC- MS [M+1]: m/z 1030.51.

[00467] Step F: 4-(4-(( 5 )-3-( tert-Butoxy)-2-((((Z)-(2-(( tert -butoxycarbonyl)amino)thiazol-4-yl) (carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-((5)-3-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)- 2-((1-(tert-butoxycarbonyl) )azetidin-3-yl)methyl)-1 H-pyrazol-2-io A a solution of 4-(4-((5)-3-(tert-butoxy)-2-((((Z) trifluoromethanesulfonate - (2-(((tert-butoxycarbonyl)amino)-thiazol-4-yl)(carboxy)methylene)amino)oxy)- 3-((5)-3-((tert-butoxycarbonyl)amino)-2-((1-(tert-butyldimethylsilyl)oxy)propyl)-2-((1-(tert- To (1H-pyrazol-2-yl)-(1-butoxycarbonyl)-azetidin-3-yl)methyl)-1H-pyrazol-2-ium (0.66 g, 0.64 mmol) in THF (2 ml) was added TBAF in THF (1.9 ml, 1. 9 mmol, 1M). The reaction was stirred at room temperature overnight. Then the solvent was removed to afford the title compound. LC-MS [M+1]: m/z 917.10.

[00468] Step G: Sulfate of (5 )-3-((Z)-2-(((( 5 )-1-( tert-Butoxy)-3-(4- (1-(( 5 )-3 -((tert-butoxycarbonyl)amino)-2-hydroxypropyl)-2-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-2-yl-4-yl)phenoxy)- 1 - oxopropane-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00469] To a solution of 4-(4-((5)-3-(tert-butoxy)-2-((((Z)-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)-oxy)-3-oxopropoxy)phenyl)-1-((5)-3-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)-2-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-2-ium trifluoromethanesulfonate (290 mg, 0.32 mmol) in DMF (6 mL) were added DCC (198 mg, 0.96 mmol) and HOBt (147 mg, 0.96 mmol). The reaction was stirred at room temperature for 30 min before addition of (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (168 mg, 0.80 mmol) and sodium bicarbonate (134 mg, 1.6 mmol). The reaction mixture was stirred at room temperature overnight, then filtered. The filtrate was purified on RP-HPLC (Gilson) (C-18 column), eluting with 20-100% ACN/water containing 0.05% TFA (12 min) to afford the title compound. LC-MS [M+1]: m/z 1109.52.

[00470] Step H: (S )-3-((Z)-2-(((S)-2-(4-(1-((S)-3-Amino-2-hydroxypropyl)-2 sulfate -(azetidin-3-ylmethyl)-1H-pyrazol-2-yl-4-yl)phenoxy)- 1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2- dimethyl-4- oxoazetidin-1-yl 2TFA To a solution of (S)-3-((Z)-2-((((S)-1- (tert-Butoxy)-3-(4-() sulfate 1-((S)-3-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)- 2-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-2-yl-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2- (2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl (140 mg, 0.13 mmol) in CH2Cl2 (0.5 mL) , TFA (1 mL, 13 mmol) was added. The reaction was stirred at room temperature for 1 h, then the solvent was removed. The resulting residue was washed with Et2O (3 times) and then dried under vacuum to afford a solid. The solid was dissolved in DMSO and purified on RP-HPLC (Gilson) (C-18 column), eluting with ACN/water containing 0.05% TFA (0-40%, 12 min) to afford the title compound. LC-MS [M+1]: m/z 750.71. 1H NMR (500 MHz, D2O) δH 8.59 (1H, s), 8.53 (1H, s), 7.49 (1H, d), 7.00 (1H, s), 6.97 (2H, d, J = 10.8 Hz), 5.05 (1H, d), 4.83 (2H, d), 4.50 (2H, t), 4.41 (1H, m), 4.29-4.18(2H, m), 4.04 (2H, t), 3.61 (1H, m), 3.26 (1H, m), 2.99 (1H, m), 1.32 (3H, s), 0.91 (3H, s). EXAMPLE 53 (S)-3-((Z)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-(((R)-pyrrolidin-3-yl sulfate )methyl)-1H-pyrazol-2-iso-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)- 2,2-dimethyl-4-oxoazetidin- 1 -ila

[00471] Step A: 3-(4-(1-(3-(( tert -butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin- (S )-tert-butyl 2-yl)oxy)propanoate A solution of 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)- 1H-pyrazol-4-yl)phenoxy (R)-tert-butyl)-2-hydroxypropanoate (1.77 g, 3.83 mmol) in THF (20 mL), 2-hydroxyisoindoline-1,3-dione (0.69 g) was added , 4.2 mmol), triphenylphosphine (1.5 g, 5.8 mmol) and DEAD (0.91 mL, 5.8 mmol). The reaction was stirred at rt for 3 h and then concentrated. The resulting residue was purified on silica gel using EtOAc/hexane as eluting solvents to afford the title compound. LC/MS: [M+1]+ m/z 607.58.

[00472] Step B: 4-(4-((S)-3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-((tere-butoxycarbonyl)amino)propyl)-2-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-1H-pyrazol-2-ium To a solution of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidin-1-carboxylate (0.60 g, 3.0 mmol) and Hunig's base (1.03 mL, 5.9 mmol) in CH2Cl2 (15 mL) at -78°C was added trifluoromethanesulfonic anhydride (0.61 mL, 3.6 mmol) over 5 min. The reaction was stirred at -78 °C for 1 h, then quenched with saturated NaHCO 3 . The reaction was allowed to warm to 0 °C. The organic layer was separated and washed with brine. The aqueous layers were combined and back extracted with DCM. The organic layers were combined, dried over Na 2 SO 4 , and concentrated in vacuo to afford (R)-tert-butyl 3-((((trifluoromethyl)sulfonyl)oxy)methyl)pyrrolidine-1-carboxylate. 1H NMR(500MHz, D2O): δ 4.51-4.48(m, 2H), 3.71-3.57(m, 2H), 3.21-3.11(m, 2H), 2.76-2.69(m, 1H), 2.14-2.08(m, 1H), 1.81-1.74(m, 1H). To a solution of (S)-tert-butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (0.90 g, 1.5 mmol) and R)-tert-butyl (3-((((trifluoromethyl)sulfonyl)oxy)methyl) pyrrolidine-1-carboxylate (0.99 g, 3.0 mmol) in acetonitrile (15 mL) was added sodium bicarbonate (1.2 g, 15 mmol). The reaction mixture was heated at 60 °C overnight and then filtered. The filtrate was concentrated to afford the title compound. LC/MS: (M)+ m/z 790.75.

[00473] Step C: 4-(4-((S)-2-(amino-oxy)-3-(tert-butoxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl) amino)propyl)-2-(((R )-1-( tert -butoxycarbonyl)pyrrolidin-3-yl)methyl)-1 H-pyrazol-2-io A a solution of 4- (4-((S) -3-(tert-butyl)butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl) -2-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-1H-pyrazol-2-io (1.2 g, 1.5 mmol) in CH2Cl2 (10 mL) and ethanol (10 mL) at 0 °C was added hydrazine (0.056 mL, 1.8 mmol). The reaction was stirred at rt for 1 h and then concentrated. The resulting residue was suspended in DCM (20 mL), stirred at rt for 10 min and then filtered. The filtrate was concentrated to afford the title compound. LC/MS: (M)+ m/z 660.72.

[00474] Step D: 4-(4-(( S )-3-( tert -butoxy)-2-(((Z)-((2-(( tert -butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-(( tert -butoxycarbonyl)-amino)propyl)-2-(((R )-1-(tert -butoxycarbonyl)pyrrolidin-3-yl)methyl)-1H-pyrazol-2-ium A solution of 4-(4-((S)-2-(amino-oxy)-3-(tert -butoxy)-3-oxopropoxy)phenyl)-1-(3-((tert -butoxycarbonyl)amino)propyl)-2-(((R)-1-(tert -butoxycarbonyl)pyrrolidin-3- To the reaction mixture (2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (520 mg, 1.9 mmol) was added 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (520 mg, 1.9 mmol). The reaction was stirred at rt for 3 h, then concentrated. The resulting residue was purified on reversed-phase MPLC using acetonitrile (0.1% formic acid)/water (0.1% formic acid) as eluting solvents to afford the title compound. LC/MS: (M)+ m/z 914.84.

[00475] Step E: 4-(4-(( 5 )-3-( tert -butoxy)-2-(((Z)-(1-(2-(( tert -butoxycarbonyl)amino)thiazol-4- il)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy) phenyl)-1- (3-((tert-butoxycarbonyl)amino)propyl)-2-((( R )-1-( tert -butoxycarbonyl)pyrrolidin-3-yl)methyl)-1 H-pyrazol-2- io To a solution of 4- (4-((S)-3-(tert-butoxy)-2-(((Z)-((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)-amino) oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-((((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl) -1H-pyrazol-2-ium (660 mg, 0.72 mmol) in acetonitrile (10 mL) at -5°C, added pyridine (0.23 mL, 2.9 mmol), hydrogen sulfate (S) - 3-amino-2,2-dimethyl-4-oxoazetidin-1-yl (300 mg, 1.4 mmol) and EDC (300 mg, 1.6 mmol). The reaction was stirred at -5°C for 2 h and then concentrated. The resulting residue was purified on reversed-phase MPLC using acetonitrile (0.1% formic acid)/water (0.1% formic acid) as eluent solvents to afford the title compound. LC/MS: (M)+ m/z 1107.25.

[00476] Step F: (S )-3-((Z)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-((R)-pyrrolidin-sulfate 3-ylmethyl)-1H-pyrazol-2-iso-4-yl)phenoxy)-1 - carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4- oxoazetidin-1-yl A a solution of 4-(4-((S)-3-(tert-butoxy)-2-(((Z)-(1-(2- ((tert-butoxycarbonyl)-amino) thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1- (sulfo-oxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)-oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2- (((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-1H-pyrazol-2-ium (610 mg, 0.55 mmol) in CH2Cl2 (3 mL), TFA (6 mL, 78 mmol). The reaction was stirred at rt for 55 min and then concentrated. The resulting residue was treated with Et2O (20 mL), and the resulting precipitate was collected and dried under vacuum. The precipitate was dissolved in NH4OAc solution (300 mM, 2x70 mL) and stirred for 5 min, then purified on a C18 column using acetonitrile (0.1% formic acid)/water (0.1% formic acid) as solvents eluted to afford the crude product. The crude product was repurified by reversed-phase HPLC using acetonitrile (0.1% formic acid)/water (0.1% formic acid) to afford the title compound. LC/MS : (M+1)+ m/z 750.5. 1H NMR (500MHz, D2O): δ 8.64-8.63(d, J=5.7Hz, 2H), 8.41(s, 1H), 7.53-7.51(d, J=8.6Hz, 2H), 7.02-7.00(d, J=9.2Hz, 2H), 6.91(s, 1H), 4.92-4.90(m, 1H), 4.66-4.63(m, 1H), 4.62-4.59(t, J=6.8Hz, 2H), 4.48-4.39 (m, 3H), 3.61- 3.56(m, 1H), 3.54-3.49(m, 1H). 3.37-3.32(m, 1H). 3.18-3.12(m, 3H), 3.08- 3.01(m, 1H), 2.40-2.34(m, 2H), 2.32-2.25(m, 1H), 1.91-1.83(m, 1H), 1.37(s, 3H) ), 1.01(s, 3H). EXAMPLE 54 (S )-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((S)-2-(4-(1,2-bis(3-aminopropyl) sulfate )-1H-pyrazol-2-yl-4-yl)phenoxy)-1-carboxyethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00477] Step A: 3-Azidopropyl trifluoromethanesulfonate To a solution of 3-azidopropan-1-ol (2.7 g, 26 mmol) and Hunig's base (9.2 mL, 52 mmol) in CH2Cl2 (60 mL) at -78 °C was added trifluoromethanesulfonic anhydride (5.4 mL, 32 mmol) over 5 min. The reaction was stirred at -78 °C for 1 h, quenched with saturated NaHCO3, and allowed to warm to 0 °C. The organic layer was separated and washed with brine. The aqueous layers were combined, back extracted with DCM. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to afford the title compound. 1H NMR (500MHz, D2O): δ 4.67-4.64(t, J=5.8Hz, 2H), 3.56-3.54(t, J=5.8Hz, 2H).

[00478] Step B: (5)-2-(3-azidopropyl)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3 -oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-2-io The mixture of 3-(4-(1-(3-((tert)-butoxycarbonyl (5)-tert-butyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (6.4 g, 11 mmol ), 3-azidopropyl trifluoromethanesulfonate (5.0 g, 21 mmol), and sodium bicarbonate (8.9 g, 110 mmol) was heated to 60 °C for 3 h. Then, the reaction mixture was filtered, and the filtrate was concentrated to afford the title compound. LC/MS: [M]+ m/z 690.6.

[00479] Step C: (5)-4-(4-(2-(amino-oxy)-3-(tert-butoxy)-3-oxopropoxy)phenyl)-2-(3-azidopropyl)-1-( 3-((tert)-butoxycarbonyl)amino)propyl)-1H-pyrazol-2-io

[00480] To a solution of (5)-2-(3-azidopropyl)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-2-ium (7.3 g, 11 mmol) in CH2Cl2 (30 mL) and EtOH (30.0 mL) at 0°C was added hydrazine (0.40 mL, 13 mmol). The reaction was stirred at room temperature for 1 h, then concentrated. The resulting residue was treated with DCM (30 mL). The reaction was stirred at rt for 30 min, then filtered, and the filtrate was concentrated to afford the title compound. LC/MS: [M]+ m/z 560.6

[00481] Step D: (S,Z)-2-(3-azidopropyl)-4-(4-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl)-amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-( (tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-2-ium To a solution of (S)-4-(4-(2-(amino-oxy)-3-( tert-butoxy)-3-oxopropoxy)phenyl)-2-(3-azidopropyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-2-ium (6.0 g, 11 mmol) in MeOH (25 mL) and CH2Cl2 (25 mL), was added ether 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (3.8 g, 14 mmol). The reaction was stirred at room temperature overnight and concentrated. The residue was purified by reversed-phase HPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as eluting solvents to afford the title compound. LC/MS: [M]+ m/z 814.7.

[00482] Step E: (S,Z)-2-(3-aminopropyl)-4-(4-(3-(tert-butoxy)-2- ((((2-((tert-butoxycarbonyl)amino) -thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1 H-pyrazol-2-io In solution of (S,Z)-2-(3-azidopropyl)-4-(4-(3-(tert-butoxy)-2- ((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl )(carboxy)methylene)-amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)-amino)propyl)- 1H-pyrazol-2-ium (7.8 g, 9.6 mmol) in MeOH (200 mL) was added with 10% Pd/C (1.5 g, 1.4 mmol). The reaction was hydrogenated at rt for 40 min. The reaction was filtered through Celite™ and the filtrate was concentrated to afford the title compound. LC/MS: [M]+ m/z 788.8

[00483] Step F: (S,Z)-4-(4-(3-( tert-butoxy)-2-((((2-(( tert -butoxycarbonyl)amino)thiazol-4-yl)(carboxy )methylene)amino)oxy)-3-oxopropoxy)phenyl)-1,2-bis(3-(( tert-butoxycarbonyl)amino)propyl)-1 H- pyrazol-2-io To solution of (S,Z) -2-(3-aminopropyl)-4-(4-(3-(tert-butoxy)-2- ((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene) amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-2-io (7.6 g, 9.6 mmol) in CH2Cl2 (200 mL), Boc2O (2.7 mL, 12 mmol) and TEA (1.3 mL, 9.6 mmol) were added. The reaction was stirred at rt for 1 h and then concentrated. The resulting residue was purified on reversed-phase MPLC (C18) using acetonitrile (0.05% TFA) as elution solvents to afford the title compound. LC/MS: [M]+ m/z 888.8

[00484] Step G: 4-(4-((5)-3-(tert-butoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4- il)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy) phenyl)-1, 2-bis(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-2-io A a solution of (S,Z)-4-(4-(3-(tert -butoxy)-2-(((((2-((tert-butoxycarbonyl)amino)thiazol- 4-yl(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1,2-bis(3-((tert-butoxycarbonyl))amino)propyl)-1H-pyrazol-2-ium (2 .5 g, 2.8 mmol) in acetonitrile (30 ml) at 0°C, (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogensulfate (1.2 g, 5.5 mmol), pyridine (0.90 ml, 11 mmol) and EDC (1.3 g, 6.9 mmol). The reaction was stirred at 0 °C for 1 h and then concentrated in vacuo at rt. The resulting residue was purified on reversed-phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as elution solvents. to afford the title compound. LC/MS: [M]+ m/z 1081.1.

[00485] Step H: (S)-3-((Z)-2-(2-aminothiazol-4-yl)-2-(((S)-2-(4-(1,2-bis) sulfate (3-aminopropyl)-1H-pyrazol-2-yl-4-yl)phenoxy)-1-carboxyethoxy)imino)-acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl To a solution of 4 -(4-((S)-3-(tert-butoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)-amino)thiazol-4-yl)-2-( ((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3- (2-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)phenyl)-1,2-bis(3-((tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-2-ium (400 mg, 0.37 mmol) in DCM (3 mL), TFA (6.0 mL, 78 mmol) was added. The reaction was stirred at rt for 50 min and then concentrated. The resulting residue was washed with Et2O (3x10 mL ), dried under vacuum and dissolved in ammonium acetate (200 mM, 80 mL, 16 mmol). The resulting solution was stirred at rt for 10 min, and then purified on reversed-phase MPLC using acetonitrile (0.1% acetonitrile formic acid)/water (0.1% formic acid) as solvents eluted to provide a residue and a small amount of TFA. The residue was redissolved in 80 mL of NH4OAc (200 mM, 80 mL) and the reaction was stirred at rt for 10 min, and then purified on reversed-phase MPLC using acetonitrile (0.1% formic acid)/water (0 ,1% formic acid) as elution solvents to afford the title compound as free base. LC/MS: [M]+ m/z 724.6. 1H NMR (500MHz, D2O): δ 8.57(s, 2H), 8.41(s, 1H), 7.49-7.48(d, J=8.8Hz, 2H), 6.99-6.98(d, J=8.8Hz, 2H) , 6.90(s, 1H), 4.91-4.89(m, 1H), 4.59-4.56(t, J=8.0Hz, 4H), 4.46- 4.40(m, 4H), 3.16-3.12(m, 4H), 2.39 -2.33(m, 4H), 1.37(s, 3H), 1.01(s, 3H). EXAMPLE 55 (S)-3-(4-(1-(3-amino-2-(aminomethyl)propyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-4- acid yl)phenoxy)-2-(( ((Z)-1 -(2-aminothiazol-4-yl)-2-( ((S )-2,2-dimethyl-4-oxo-1-(sulfo-oxy )azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[00486] Step A: 3-((tert-Butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)amino)methyl)propyl methanesulfonate To a solution of di-tert-butyl (2-(hydroxymethyl)propane-1,3-diyl)dicarbamate (1.4 g, 4.6 mmol) in DCM (anhydrous, 20 mL) at 0 °C were added TEA (1.3 mL, 9.1 mmol) and MsCl (0.43 mL, 5.5 mmol). The reaction was stirred at 0 °C for 1 h, then partitioned between DCM (100 mL) and 0.1 M HCl (ice-cooled). The organic layer was washed with 0.1 M HCl (ice-cooled), dried over Na2SO4, and concentrated to afford the title compound. LC/MS: [M+1]+ m/z 383.4.

[00487] Step B: Di-tert-butyl (2-((4-bromo-1H-imidazol-1-yl)methyl)propane-1,3-diyl)dicarbamate To a solution of 3-((tert-butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)amino)methyl)-propyl methanesulfonate (1.8 g, 4.7 mmol) in DMF (25 mL) were added 4-bromo-1H-imidazole (0.69 g, 4.7 mmol) and Cs2CO3 (3.1 g, 9.4 mmol). The reaction was heated at 60 °C overnight, then partitioned between EtOAc (200 mL) and saturated NaHCO3 (200 mL). The organic layer was separated, washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated. The resulting residue was purified on silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: [M+1]+ m/z 433.3; 435.3.

[00488] Step C: 4-Bromo-1-(3-(( tert -butoxycarbonyl)ammo)-2-((( tert -butoxycarbonyl)-amino)methyl)propyl)-3-methyl-1H-imidazol-3-ium To a solution of di-tert -butyl (2-((4-bromo-1H-imidazol-1-yl)methyl)propane-1,3-diyl)dicarbamate (1.5 g, 3.5 mmol) in acetonitrile (10 mL) was added MeI (1.08 mL, 17 mmol). The reaction was heated at 60 °C overnight and then concentrated. The resulting residue was purified on a silica gel column using MeOH/DCM as eluting solvents to afford the title compound. LC/MS: [M]+ m/z 447.4; 449.4

[00489] Step D: Di-tert-butyl (2-((4-bromo-2-(( tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)propane-1,3-diyl)dicarbamate To a solution of tert-butyl carbamate (0.87 g, 7.4 mmol) in CH2Cl2 (10 mL) was added tert-butyl hypochlorite (0.97 mL, 8.4 mmol). The reaction was stirred at rt. for 30 min, then cooled to 0 °C and DBU (1.52 mL, 10 mmol) was added, followed by 4-bromo-1-(3-((tert-butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)amino)methyl)propyl)-3-methyl-1H-imidazole-3-ium (1.5 g, 3.4 mmol) in CH2Cl2 (16 mL). The reaction was stirred at rt for 30 min and then concentrated. The resulting residue was purified on a silica gel column using MeOH/DCM as eluting solvents to afford the title compound. LC/MS: [M+1]+ m/z 562.4; 564.4.

[00490] Step E: 3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)-amino)methyl)propyl)-2-((tert-butoxycarbonyl (R)-tert-butyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate A mixture of tribasic potassium phosphate (3,6 ml, 3.6 mmol), (R)-tert-propanoate 2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy) butyl (0.53 g, 1.5 mmol), and (4-bromo-1-(3-((tert- tert-butyl)-2-((tert-butoxycarbonyl)amino)methyl)propyl)-3-methyl-1H-imidazol-2(3H)-ylidene)carbamate (0.68 g, 1.2 mmol ) in dioxane (12 ml) was degassed by bubbling N2 for 30 min, then 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.079 g , 0.12 mmol) was added. The reaction mixture was further degassed by bubbling N2 for 20 min and then heated at 60°C overnight. The reaction mixture was filtered through Celite™ and the filtrate was concentrated. The resulting residue was purified on a silica gel column using MeOH/DCM as eluent solvents to provide the title compound. LC/MS: [M+1]+ m/z 720.7.

[00491] Step F: (S)-tert-butyl 3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)-amino)methyl)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate To a solution of 3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-((tert-butoxycarbonyl)amino)methyl)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate (R)-tert-Butyl (0.64 g, 0.89 mmol) in THF (15 mL) were added 2-hydroxyisoindoline-1,3-dione (0.17 g, 1.1 mmol), triphenylphosphine (0.35 g, 1.3 mmol), and DEAD (0.21 mL, 1.3 mmol). The reaction was stirred at rt for 2 h and then concentrated. The resulting residue was purified on a silica gel column using MeOH/DCM to afford the title compound. LC/MS: [M+1]+ m/z 865.8.

[00492] Step G: 2-(amino-oxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)amino)methyl)propyl)- 2-(( tert -butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy) (S)-tert-butyl propanoate A solution of 3-( 4-(1-(3-((tert-butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)amino)methyl)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2, 3-dihydro-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxo-isoindolin-2-yl)oxy)propanoate (S)-tert-butyl (0.77 g, 0.89 mmol) in CH2Cl2 (5 mL) and ethanol (5 mL) at 0°C was followed by addition of hydrazine (0.033 mL, 1.1 mmol). The reaction mixture was stirred at rt for 1 h and then concentrated. The resulting residue was treated with DCM (10 mL), stirred at rt for 10 min and then filtered. The filtrate was concentrated to afford the title compound. LC/MS: [M +1]+ m/z 735.7

[00493] Step H: (2Z)-2-((((S)-1-(tert-butoxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)amino)methyl)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid A solution of 2-(aminooxy)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)amino)-methyl) To (S)-tert-butyl (((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)propanoate (0.65 g, 0.89 mmol) in CH2Cl2 (10 mL) and MeOH (10 mL) was added 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (0.29 g, 1.1 mmol). The reaction was stirred at RT for 2 h and then concentrated. The resulting residue was purified on reversed-phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as eluting solvents to afford the title compound. LC/MS: [M+1]+ m/z 989.8.

[00494] Step I: 3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)-amino)methyl)propyl)-2-((tert-butoxycarbonyl )imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-(((Z)-(1-(2-(( tert -butoxycarbonyl)amino) thiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate of (S)-tert-butyl To a solution of acid (2Z)-2-((((S)-1-(tert-butoxy)-3-(4-(1-(3- ((tert-butoxycarbonyl)amino)-2-(((tert-butoxycarbonyl)amino)methyl)propyl)- 2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H- imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (550 mg, 0.55 mmol ) in acetonitrile (8 mL) at 0°C, (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogensulfate (230 mg, 1.1 mmol), pyridine (0 .18 mL, 2.2 mmol) and EDC (260 mg, 1.4 mmol). The reaction was stirred at 0 °C for 2 h and then concentrated. The resulting residue was purified on reversed-phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as elution solvents to afford the compound of the title. LC/MS: [M+1]+ m/z 1182.0.

[00495] Step J: (S )-3-(4-(1-(3-amino-2-(aminomethyl)propyl)-2-imino-3-methyl-2,3-dihydro-1H acid -imidazol-4-yl)phenoxy)-2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1 -(sulfo-oxy)azetidin-3 - yl)amino)-2-oxoethylidene)amino)oxy)propanoic A a solution of 3-(4-(1- (3-((tert-butoxycarbonyl)amino)-2- (((tert-butoxycarbonyl)-amino)-methyl)propyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4- yl)phenoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4- (S)-tert-butyl oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate (420 mg, 0.36 mmol) in CH2Cl2 (2 mL) , TFA (4 mL, 52 mmol) was added. The reaction was stirred at rt for 50 min and then concentrated at rt. The resulting residue was treated with Et2O (10 mL) to provide a precipitate, which was washed with Et2O three times times, concentrated and purified by reverse HPLC using acetonitrile (0.1% formic acid)/water (0.1% formic acid) as eluting solvents to afford the title compound. LC/MS: [M+1]+ m/z 725.7. 1H NMR (500MHz, D2O): δ 7.35-7.33(d, J=8.1Hz, 2H), 7.04- 7.02(d, J=8.1Hz, 2H), 6.99(s, 1H), 6.89(s, 1H) , 4.98-4.96(m, 1H), 4.66(s, 1H), 4.47-4.41(m, 2H), 4.08-4.06(d, J=6.1Hz, 2H), 3.35(s, 3H), 3.25- 3.19 (m, 2H), 3.14-3.09(m, 2H), 2.73-2.67(m, 2H), 1.42(s, 3H), 1.03(s, 3H). EXAMPLE 56(2S)-3-(4-(1-(3-amino-2-hydroxypropyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy acid )-2-(( ((Z)-1 -(2-aminothiazol-4-yl)-2-( ((S )-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin- 3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[00496] Step A: tert-Butyl (3-(4-bromo-1H-imidazol-1-yl)-2-(( tert-butyldimethylsilyl)oxy)-propyl)carbamate To a solution of 5-bromo-1H-imidazole (2.8 g, 19 mmol) and tert-butyl (3-bromo-2-(( tert-butyldimethylsilyl)oxy)propyl)carbamate (7.4 g, 20 mmol) in DMF (20 mL) was added cesium carbonate (12 g, 38 mmol)). The reaction mixture was heated at 60 °C overnight and then partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was washed with saturated NaHCO3 twice, dried over Na2SO4, and concentrated. The resulting residue was purified on silica gel column using EtOAc/hexane as elution solvents to afford the title compound. LC/MS: (M+1)+ m/z 434.2; 436.2.

[00497] Step B: 4-Bromo-1-(3-(( tert -butoxycarbonyl)amino)-2-(( tert -butyldimethylsilyl)oxy)propyl)-3-methyl-1H-imidazol-3-ium To a solution of tert -butyl (3-(4-bromo-1H-imidazol-1-yl)-2-(( tert -butyldimethylsilyl)oxy)propyl)carbamate (2.7 g, 6.2 mmol) in acetonitrile (10 mL) was added methyl iodide (1.9 mL, 31 mmol). The reaction was heated at 60 °C overnight, then concentrated to afford the title compound. LC/MS: [M]+ m/z 448.2; 450.2.

[00498] Step C: (3-(4-bromo-2-(( tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)-2-(( tert-butyldimethylsilyl)oxy)propyl) tert-butyl carbamate A solution of tert-butyl carbamate (1.6 g, 14 mmol) in CH2Cl2 (20 mL) was added to tert-butyl hypochlorite (1.8 mL, 16 mmol) and stirred at room temperature for 30 min. Then, the reaction was cooled to 0 °C and DBU (2.8 mL, 19 mmol) was added, followed by the addition of 4-bromo-1-(3-((tert-butoxycarbonyl)-amino)-2-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-imidazole-3-ium (2.8 g, 6.2 mmol) in CH2Cl2 (16 mL). The reaction was stirred at rt for 30 min and then concentrated. The resulting residue was purified by silica gel column using MeOH/EtOAc as elution solvents to afford the title compound. LC/MS: [M+1]+ m/z 563.5; 565.5.

[00499] Step D: 3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propyl)-2-((tert)-butoxycarbonyl)imino) (2R)-tert-Butyl-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate (Peak A) A mixture of tribasic potassium phosphate (11 ml , 11 mmol), (R)-tert-butyl 2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate (1 .6 g, 4.4 mmol) and (4-bromo-1-(3-((tert-butoxycarbonyl) tert-Butylamino)-2-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-1H-imidazol-2(3H)-ylidene)carbamate was degassed (2.1 g, 3.7 mmol) in dioxane (24 mL) with bubbling N2 for 30 min and then 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.24 g, 0.37 mmol) was added. The reaction mixture was further degassed with bubbling N2 for 20 min and then heated at 75°C for 3 h. The reaction mixture was filtered through Celite™ and the filtrate was concentrated. The resulting residue was purified on a silica gel column using MeOH/DCM as elution solvents to afford the title compound as a mixture of diastereoisomers. LC/MS: (M+1)+ m/z 721.5. The diastereoisomers were separated in chiral SFC (Whelk-01, 4.6x250 mm, IPA + 0.1DIPA) to afford the two separated diastereomers. The fast eluting diastereomer was carried forward to the next step.

[00500] Step H: (Z)-2-((((2S)-1-(tert-butoxy)-3-(4-((Z)-1-(3-((tert-butoxycarbonyl)amino acid) )-2-(hydroxypropyl)-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl )oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid To a solution of (2Z)-2-((((2S)-1-(tert-butoxy )-3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propyl)-2-((tert- (butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert- To (1.2 g, 1.2 mmol, prepared following steps F-H as described in Example 55) in THF (20 mL) was added TBAF (1.13 g, 4. 3 mmol). The reaction was stirred at rt for 2 h and then concentrated. The resulting residue was purified on reversed-phase MPLC using acetonitrile (0.05% TFA)/water (0.05% TFA) as eluting solvents to afford the title compound. LC/MS: (M+1)+ m/z 876.5.

[00501] Step IJ: (2S)-3-(4-(1-(3-amino-2-hydroxypropyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid The title compound was prepared from (Z)-2-((((2S)-1-(tert-butoxy)-3-(4-((Z)-1-(3-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)-2-((tert-butoxycarbonyl) imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid following the procedure of Example 55 Steps IJ. LC/MS: (M+1)+ m/z 712.4. 1H NMR (500MHz, D2O): δ 7.34-7.32(d, J=8.8Hz, 2H), 7.04-7.02(d, J=8.8Hz, 2H), 6.94(s, 1H), 6.84(s, 1H), 4.94-4.92(m, 1H), 4.66(s, 1H), 4. 45-4.39(m, 2H), 4.24-4.21(m, 1H), 4.05-4.02(d, J=4.8Hz, 1H), 3.92- 3.88(m, 1H), 3.34(s, 3H), 3.25-3.22(d, J=4.8Hz, 1H), 3.00-2.95(t, J=10.5Hz, 1H), 1.41(s, 3H), 1.06(s, 3H). EXAMPLE 57 Acid (S)-3-(4-((Z)-2-((2-aminoethyl)imino)-1-(3-aminopropyl)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-(( ((Z)- 1-(2-aminothiazol-4-yl)-2-( ((S )- sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[00502] Step A: 3-(4-bromo-2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)propan-1-amine To a solution of (Z)-tert-butyl (3-(4-Bromo-2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)propyl)carbamate (1.1 g, 2.5 mmol) in CH2Cl2 (2 mL) was added TFA (6.0 mL, 78 mmol). The reaction was stirred at rt for 1 h and then concentrated to afford the title compound. LC/MS: (M+1)+ m/z 233.1; 235.1

[00503] Step B: tert-Butyl (3-(4-bromo-2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)propyl)-carbamate To a 3-(4-bromo-2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)propan-1-amine (0.59 g, 2.5 mmol) in CH2Cl2 (40 mL) was added TEA (1.8 mL, 13 mmol) and Boc2O (0.59 mL, 2.5 mmol). The reaction was stirred at rt for 1 h, then concentrated. The resulting residue was purified on a silica gel column using MeOH/DCM as eluting solvents to afford the title compound. LC/MS: (M+1)+ m/z 333.1; 335.1.

[00504] Step C: (Z)-(3-(4-bromo-2-((2-(( tert-butoxycarbonyl)amino)ethyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)propyl)carbamate To a solution of tert-butyl (3-(4-bromo-2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)propyl)carbamate (1.0 g, 3.0 mmol) and tert-butyl (2-bromoethyl)carbamate (1.3 g, 6.0 mmol) in acetonitrile (10 mL) was added Cs2CO3 (2.9 g, 9.0 mmol). The reaction was stirred at 50 °C for 6 h, then concentrated. The resulting residue was dissolved in DCM (50 mL) and filtered. The filtrate was purified on a silica gel column using MeOH/DCM as elution solvents to afford the title compound. LC/MS: (M+1)+ m/z 476.0; 478.0.

[00505] Step D: (5)-3-(4-((Z)-2-((2-aminoethyl)imino)-1-(3-aminopropyl)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-(( (Z)-( 1-(2-aminothiazol-4-yl)-2-(((5 )-2,2-dimethyl-4-oxo-1-(sulfo-oxyl)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid The title compound was prepared from (Z)-(3-(4-bromo-2-((2-((tert-butoxycarbonyl)amino)ethyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)propyl)carbamate tert-butyl according to the procedure of Example 55, Steps E- J. LC/MS: (M+1)+ m/z 739.4 . 1H NMR (500MHz, D2O): δ 7.37-7.35(d, J=8.6Hz, 2H), 7.15(s, 1H), 7.06-7.04(d, J=8.6Hz, 2H), 6.93(s, 1H), 4.94- 4.93(m, 1H), 4.63(s, 1H), 4 .47-4.39(m, 2H), 4.11-4.09(m, 2H), 3.63- 3.61(m, 2H), 3.52(s, 3H), 3.29-3.27(m, 2H), 3.07-3.04(m, 2H), 2.21- 2.16(m, 2H), 1.41(s, 3H), 1.02(s, 3H). EXAMPLES 58 and 59 Acid (S )-3-(4-(( S )-2-((2-aminoethyl)amino)-4,5-dihydro-1 H-imidazol-4-yl)phenoxy)-2-(((Z)-1 -(2-Aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1 - (sulfo-oxy)azetidin-3 -yl)amino)-2-oxoethylidene)amino(oxy)propanoic acid (58) (R)-3-(4-((S)-1-amino-2-((4,5-dihydro-1H-imidazol-2-yl)amino)ethyl) phenoxy)-2-(((Z)-1-(2-aminothiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (59)

[00506] Step A: (R)-tert-Butyl 2-hydroxy-3-(4-vinylphenoxy)propanoate To a solution of (R)-tert-butyl 3-(4-bromophenoxy)-2-hydroxypropanoate (2400 mg, 7.6 mmol) in EtOH (60 mL) were added potassium vinyltrifluoroborate (1520 mg, 11 mmol), Et3N (1.58 mL, 11 mmol), and PdCl2(dppf)-CH2Cl2 adduct (310 mg, 0.38 mmol). The reaction mixture was exchanged into N2/vacuum (3 times) and heated at reflux overnight, then cooled to room temperature and filtered through a short Celite™ pad washing with CH2Cl2. The filtrate was concentrated and purified by ISCO column (40 g, gold), eluting with 0-50% EtOAc/hexane gradient to afford the title compound. LC-MS [M + Na]+: m/z 287.2.

[00507] Step B: (R)-tert-Butyl 2-(( tert-butyldimethylsilyl)oxy)-3-(4-vinylphenoxy)propanoate To a solution of (R)-tert-butyl 2-hydroxy-3-(4-vinylphenoxy))propanoate (1580 mg, 6.0 mmol), imidazole (980 mg, 14 mmol), and TBDMS-Cl (1.1 g, 7.2 mmol) in acetonitrile (25 mL), was added DMAP (73 mg, 0.60 mmol). The resulting solution was stirred at room temperature overnight. Then the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by ISCO Redi-Sep column (gold, 40 g) eluting with 0-30% EtOAc/hexane gradient to afford the title compound.

[00508] Step C: (2R)-tert-Butyl 2-(( tert -butyldimethylsilyl)oxy)-3-(4-(1,2-diazidoethyl)phenoxy)propanoate (R)-tert-Butyl 2-((tert -butyl)butyldimethylsilyl)oxy)-3-(4-vinyl-phenoxy)propanoate (1.9 g, 5.0 mmol) was added to a stirred mixture of sodium periodate (1.1 g, 5.0 mmol) and sodium azide (1.0 g, 15 mmol) in DMSO (15 mL) and acetic acid (5 mL). The reaction mixture was stirred at 75 °C for 2 h and then cooled, diluted with ethyl acetate, washed with water (4x) and brine, dried (MgSO4 ), and filtered. The filtrate was evaporated under reduced pressure. The resulting residue was purified by column chromatography on an ISCO silica gel column (40 g gold) eluting with a 0-20% EtOAc/hexane gradient to afford the title compound.

[00509] Step D: tert-Butyl (2R)-2-(( tert-butyldimethylsilyl)oxy)-3-(4-(1,2-diaminoethyl)-phenoxy)propanoate Palladium on carbon (300 mg, 2.8 mmol) was added to a stirred mixture of (2R)-tert-butyl 2-(( tert-butyldimethylsilyl)oxy)-3-(4-(1,2-diazidoethyl)-phenoxy)propanoate (1500 mg, 3.2 mmol) in methanol (30 mL) under a balloon of H2. The reaction mixture was vacuum/H2 exchanged 3 times and then stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and filtered through a short Celite™ pad. The filtrate was concentrated under reduced pressure to afford the title compound. LC-MS [M + H]+: m/z 411.6.

[00510] Step E: (2R)-2-(( tert-butyldimethylsilyl)oxy)-3-(4-(2-thioxoimidazolidin-4-yl)phenoxy)propanoate tert-Butyl 1,1-terticarbonyldiimidazole (360 mg, 2.0 mmol) in DCM (8 mL) was added slowly dropwise over 20 min to a stirred mixture of (2R)-tert-butyl 2-(( tert-butyldimethylsilyl)oxy)-3-(4-(1,2-diaminoethyl)phenoxy))propanoate (800 mg, 1.9 mmol) in DCM (16 mL). The reaction mixture was stirred at room temperature for 15 min, then concentrated under reduced pressure. The resulting residue was purified on a silica gel column (gold, 80 g) using a 0–60% EtOAc/hexane gradient to afford the title compound as a racemic mixture. This racemic mixture was separated with chiral resolution by SFC (IC (2 × 15 cm + 3 × 15 cm); 35% isopropanol/CO2, 100 bar (10 MPa); 50 mL/min, 220 nm; inj. vol.: 1.5 mL, 15 mg/mL ethanol:DCM) to afford the title compound as two enantiomerically pure isomers. The second isomer (longer retention time) was used in the next step. LC-MS [M + H]+: m/z 453.3.

[00511] Step F: (R )-2-(( tert-butyldimethylsilyl)oxy)-3-(4-(( 5 )-2-(methylthio)-4,5-dihydro-1H-imidazol-4-yl)phenoxy)propanoate tert-butyl Iodomethane (0.967 mL, 15.46 mmol) was added to a stirred mixture of (R)-tert-butyl 2-(( tert-butyldimethylsilyl)oxy)-3-(4-(2-thioxoimidazolidin-4-yl))phenoxy)propanoate (1400 mg, 3.1 mmol) in MeCN (12 mL). The reaction mixture was stirred at 70 °C for 2 h, then cooled and concentrated under reduced pressure to afford the title compound. LC-MS [M + H]+: m/z 467.3.

[00512] Step G: (5 )-4-(4-((R )-3-( tert-butoxy)-2-(( tert-butyldimethylsilyl)oxy)-3-oxo-propoxy)phenyl)-2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate DMAP (190 mg, 1.5 mmol) was added to a stirred mixture of Boc-anhydride (1.4 mL, 6.2 mmol), (R)-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-3-(4-((5)-2-(methylthio)-4,5-dihydro-1H-imidazol-4-yl)phenoxy)propanoate (1400 mg, 3.1 mmol), and triethylamine (1.3 mL, 9.3 mmol) in CH2Cl2 (14 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated. The resulting residue was purified by column chromatography on silica gel (ISCO 80 g gold) eluting with a 0-100% EtOAc/hexane gradient to afford the title compound as a mixture of Boc regioisomers. LC-MS [M + H]+: m/z 567.4.

[00513] Step H: (5 )-4-(4-((R )-3-( tert-butoxy)-2-(( tert-butyldimethylsilyl)oxy)-3-oxopropoxy)phenyl)-2-( (2-(( tert-butoxycarbonyl)amino)ethyl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate Acetic acid (0.94 mL) was added to a stirred mixture of N-Boc-ethylenediamine (420 mg, 2.6 mmol) and the mixture of Boc regioisomers from Step G (750 mg, 1.3 mmol) in EtOH (7.5 mL). The reaction mixture was stirred at 55 °C overnight, then cooled and concentrated under reduced pressure. The resulting residue was dissolved in DCM and washed with 2N aqueous NaHCO3/NaOH solution (final aqueous wash pH~10). The aqueous layer was separated and extracted with DCM 3 times. The combined organic layers were washed with brine, dried (MgSO4), and filtered. The filtrate was removed under reduced pressure to afford the title compound. LC-MS [M + H]+: m/z 679.5.

[00514] Step I: (5 )-4-(4-(( R )-3-( tert-butoxy)-2-(( tert-butyldimethylsilyl)oxy)-3-oxopropoxy)phenyl)-2-(( tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)-4,5-dihydro-1H-imidazole-1-tert-butyl carboxylate Boc anhydride (4.6 mL, 20 mmol) was added to (5)-4-(4-((R)-3-(tert-butoxy)-2-((tert-butyldimethylsilyl)oxy)-3-oxopropoxy)phenyl)-2-((2-((tert)-butoxycarbonyl)amino)ethyl)amino)-4,5-di- tert-Butyl hydro-1H-imidazole-1-carboxylate (900 mg, 1.3 mmol) was added, and the mixture was stirred at 100 °C for 1.5 h. Then, the reaction mixture was cooled and loaded directly onto an ISCO column (80 g gold), eluting with a 0-100% EtOAc/Hexane gradient to afford the title compound as a mixture of regioisomers. LC-MS [M + H]+: m/z 780.5.

[00515] Step J: (5)-4-(4-((R)-3-(tert-butoxy)-2-hydroxy-3-oxopropoxy)phenyl)-2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate TBAF (1.7 mL, 1.7 mmol) was added to a stirred mixture of (5)-4-(4-((R)-3-(tert-butoxy)-2-((tert-butyldimethylsilyl)oxy)-3-oxopropoxy)phenyl)-2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate tert-Butyl group (900 mg, 1.155 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The resulting residue was purified with an ISCO silica gel column (40 g gold) eluting with 0-100% EtOAc/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 665.4.

[00516] Step K: (5)-4-(4-(( 5)-3-( tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-2-(( tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate (5)-tert-butyl (460 mg of English:To the mixture, 0.69 mmol) in THF (5 mL) were added 2-hydroxyisoindoline-1,3-dione (135 mg, 0.83 mmol) and triphenylphosphine (254 mg, 0.97 mmol), followed by dropwise addition of DIAD (0.19 mL, 0.97 mmol). The reaction was stirred at rt for 1 h and then concentrated. The resulting residue was purified on a silica gel column (ISCO gold 40 g) using 0-100% EtOAc/hexane gradient to afford the title compound as a mixture of isomers. LC-MS [M + H]+: m/z 810.7.

[00517] Step L: 2-((((5)-1-(tert-butoxy)-3-(4-((5)-1-(tert-butoxycarbonyl)-2-(( tert-butoxycarbonyl)(2-(( tert-butoxycarbonyl)amino)ethyl)amino)-4,5-dihydro-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid To a solution of 4-(4-((S)-3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino) (S)-tert-Butyl (ethyl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate (350 mg, 0.432 mmol) in CH2Cl2 (2 mL) at rt was added, hydrazine (0.016 mL, 0.52 mmol) in ethanol (2 mL). The reaction was stirred at rt for 30 min, then 2-(2-((tert-butoxycarbonyl)amino) acid was added

[00518] thiazol-4-yl)-2-oxoacetic acid (190 mg, 0.69 mmol). The reaction mixture was stirred at rt for 1.5 h, then concentrated to afford the title compound, which was used as in the next step. LC-MS [M + H]+: m/z 934.5.

[00519] Step M: 4-(4-((5)-3-(tert-butoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)-amino)thiazol-4 -yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy )phenyl)-2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate of (S )-tert -butyl

[00520] To a solution of 2-((((S)-1-(tert-butoxy)-3-(4-((S)-1-(tert-butoxycarbonyl)-2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)-4,5-dihydro-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (400 mg, 0.43 mmol) in DMF (3.5 mL) was added DCC (260 mg, 1.3 mmol) and HOBt (200 mg, 1.3 mmol). The resulting solution was stirred at rt overnight. for 30 min, then (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (220 mg, 1.1 mmol) and sodium bicarbonate (220 mg, 2.6 mmol) were added. The reaction was stirred at room temperature overnight, then filtered through a sintered syringe and washed with DMF (1.5 mL). The filtrate was purified on the ISCO system with a reversed-phase C-18 column (80 g) eluting with 10-100% ACN/water with 0.05% TFA to afford the title compound as a mixture of isomers. LC-MS [M + H]+: m/z 1126.7.

[00521] Step N: (R)-3-(4-((S)-1-amino-2-((4,5-dihydro-1H-imidazol-2-yl)amino)ethyl) acid phenoxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)- 2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin -3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (59) and (S)-3-(4-((S)-2-((2-aminoethyl)-amino)-4 acid, 5-dihydro-1H-imidazol-4-yl)phenoxy)-2-(( ((Z)-1 -(2-aminothiazol-4-yl)-2-( ((S )-2,2- dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (58)

[00522] TFA (5 mL) was added to a solution of (S)-tert-butyl 4-(4-((S)-3-(tert-butoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)-amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)phenyl)-2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)-4,5-dihydro-1H-imidazole-1-carboxylate (200 mg, 0.18 mmol, as a mixture of isomers) in CH2Cl2 (4 mL). The mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure. Ether was added to the resulting residue, and the solvent was then removed under reduced pressure. To the resulting residue, ether was added to remove a solid, and then the solvent was removed. The resulting residue was dried under vacuum, dissolved in DMSO (5 mL), and purified via Gilson reverse-phase separation (5–25% MeCN/water, 0.05% TFA gradient) to afford (2S)-3-(4-(1-amino)-2-((4,5-dihydro-1H-imidazol-2-yl)amino)ethyl)phenoxy)-2-((((Z)-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 ); and (S)-3-(4-((S)-2-((2-aminoethyl)amino)-4,5-dihydro-1H-imidazol-4-yl)phenoxy)-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 (58). Example 58: LC-MS [M + H]+: m/z 670.4. 1H NMR (500MHz, D2O, ppm) 3.66 (dd, J = 10.5 Hz, 1 H), 3.55 (dd, J = 10.5 Hz, 1 H), 3.48 (s, 3 H), 1.37 (s, 3 H), 1.04 (s, 3 H). Example 59: LC-MS [M + H]+: m/z 670.0. 1H NMR (500MHz, D2O, ppm) Hz, 1 H), 3.47 (m, 3 H), 3.12 (t, J = 5 Hz, 2 H), 1.34 (s, 3 H), 0.97 (s, 3 H). EXAMPLES 60 and 61(2S)-3-(4-(2-((2-aminoethyl)amino)-4,5-dihydro-1H-imidazol-5-yl)phenoxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino acid )-2-oxoethylidene)amino)oxy)propanoic acid (60) (2S)-3-(4-(1-amino-2-((4,5-dihydro-1H-imidazol-2-yl)amino)ethyl) phenoxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid (61)

[00523] The title compounds were prepared according to the procedure of Examples 58 and 59 starting from the first isomer (shortest retention time) from Step E. Example 60: LC-MS [M + H]+ : m/z 670.4. Example 61: LC-MS [M + H]+ : m/z 670.0. EXAMPLE 62 (S)-3-((Z)-2-((( S )-2-(4-(2-((2-aminoethyl)amino)-1-methylpyridin-1-io-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00524] Step A: tert-Butyl (2-((4-bromopyridin-2-yl)amino)ethyl)carbamate A mixture of 4-bromopyridin-2-amine (500 mg, 2.9 mmol), 125 mg of 4 Å molecular sieves, and tert-butyl (2-oxoethyl)carbamate (510 mg, 3.2 mmol) in 1,2-dichloroethane (10 mL) was stirred at RT for 60 min, followed by the addition of sodium triacetoxyborohydride (1200 mg, 5.8 mmol). The mixture was stirred overnight, then diluted with EtOAc and washed with aqueous NaHCO3 solution (3 times). The organic layer was separated, washed with water and brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified on a silica gel cartridge (ISCO gold 40 g) eluting with a 0-100% EtOAc/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 316.2.

[00525] Step B: (R)-tert-butyl 3-(4-(2-((2-(( tert-butoxycarbonyl)amino)ethyl)amino)pyridin-4-yl)phenoxy)-2-hydroxypropanoate To a solution of PdCl2(dppf)-CH2Cl2 (180 mg, 0.22 mmol), tert-butyl (2-((4-bromopyridin-2-yl)amino)ethyl)carbamate (870 mg, 2.8 mmol), and (R)-tert-butyl 2-hydroxy-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-propanoate (800 mg, 2.2 mmol) in dioxane (7.5 mL), was added Na2CO3 (0.70 g, 6.6 mmol) in water (2.5 mL). The reaction mixture was exchanged with N2/vacuum (3 times) and then heated at 100 °C under microwave reaction conditions for 1 h. Then, the mixture was purified on a silica gel column (ISCO gold, 40 g) eluting with 0-100% EtOAc/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 474.5.

[00526] Step C: (S)-3-((Z)-2-((( S )-2-(4-(2-((2-aminoethyl)amino)-1-methylpyridin-1-io-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl ((R )-3-(4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)-amino)pyridin-4-yl)phenoxy)-2-hydroxypropanoate) sulfate was converted to the title compound using a procedure similar to the procedure in Example 1, Step C to Step H. LC-MS [M + H] + : m/z 694.0. 1H NMR (500MHz, D2O, ppm): δ 7.83 (d, J = 5 Hz, 1 H), 7.64 (d, J = 5 Hz, 2H), 7.13 (d, J = 5 Hz, 1 H), 7.07 (s, 1 H), 6.99 (d, J = 5 Hz, 2H), 6.96 (s, 1 H), 5 .01 (m, 1 H), 4.49 (s, 1 H), 4.43 (m, 2 H), 3.75 (t, J = 5 Hz, 2 H), 3.72 (s, 3 H), 3.22 (t, J = 5 Hz, 2 H), 1.28 (s, 3 H), 0.96 (s, 3 H). Table 4. Examples 63-83 were prepared according to the procedure of Example 62. EXAMPLES 84 and 85 (3S)-3-(2-((2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenoxy)-2-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate (84) and of (3S)-3-(2-((2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenoxy)-2-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)-acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl (85)

[00527] Step A: Methyl 2-(4-bromophenoxy)-3-methoxypropanoate A solution of 4-bromophenol (1.8 g, 10 mmol), methyl 2-bromo-3-methoxypropanoate (1.4 mL, 10 mmol), and lithium hydroxide (0.29 g, 12 mmol) in DMF (25.4 mL) was stirred at room temperature for 3 h. This reaction was partitioned between EtOAc and water. The separated organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by ISCO silica gel column (24 g) eluting with 0-20% EA/hexane gradient to afford the title compound. LC-MS [M + Na]+: m/z 311.2.

[00528] Step B: Methyl 2-(4-bromophenoxy)-3-hydroxypropanoate To a stirred solution of methyl 2-(4-bromophenoxy)-3-methoxypropanoate (1.0 g, 3.6 mmol) in CHCl3 (18 mL) was added TMS-I. (3.0 mL, 22 mmol). This mixture was stirred at room temperature over the weekend. The reaction was then quenched with MeOH and the volatiles were removed in vacuo. The resulting residue was then taken up in EtOAc and washed sequentially with 1 N aqueous NaOH and brine, dried over MgSO4, filtered, and the filtrate was concentrated. The resulting residue was purified using an ISCO silica gel column (24 g) by gradient elution of 0-30% EA/hexane to afford the title compound. LC-MS [M + H]+: m/z 275.1.

[00529] Step C: 2-(4-(1-(3-(( tert-Butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-3-hydroxypropanoic acid To a solution of methyl 2-(4-bromophenoxy)-3-hydroxypropanoate (0.14 g, 0.51 mmol)), tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl)carbamate (0.18 g, 0.51 mmol)), and 1,1'-bis(di-tert-butylphosphino)-ferrocenepalladium dichloride (0.033 g, 0.051 mmol)) in dioxane (2.5 mL), the aqueous solution was added at 1 M potassium phosphate (1.5 mL, 1.5 mmol). The microwave vial was sealed, degassed, backfilled with N2, and stirred at 70 °C for 1 h in a microwave reactor. The mixture was filtered, and the filtrate was diluted with water and extracted with EtOAc. The aqueous layer was acidified with 1 N HCl and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound. LC-MS [M + H]+: m/z 406.5.

[00530] Step D: Benzhydryl 2-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-3-hydroxypropanoate To a solution of 2-(4-(1-(3-(( tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-4-yl)phenoxy)-3-hydroxypropanoic acid (0.21 g, 0.51 mmol) in MeOH (5.1 mL) was added diphenyl diazomethane (0.50 g, 2.6 mmol). The resulting solution was stirred at RT for 1 h and then concentrated. The resulting residue was purified on ISCO (12 g of gold) using 0-100% EtOAc/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 572.6.

[00531] Step E: 2-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-3-((1,3-dioxoisoindolin- Benzhydryl 2-yl)oxy)propanoate A solution of 2-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-3-hydroxypropanoate benzhydryl (0.41 g, 0.72 mmol) in THF (7.2 mL), added 2-hydroxyisoindoline-1,3-dione (0.35 g, 2.2 mmol), triphenylphosphine (0.23 g, 0.86 mmol) and DIAD (0.17 mL, 0.86 mmol) at RT. The reaction was stirred for 2 h and then concentrated. The resulting residue was purified by ISCO silica gel column (40 g) eluting with 0-50% EtOAc in Hexanes to afford the title compound. LC-MS [M + H ]+: m/z 717.7.

[00532] Step F: 4-(4-((1-(Benzhydryloxy)-3-((1,3-dioxoisoindolin-2-yl)oxy)-1-oxopropan-2-yl)oxy)-phenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide To a solution of benzhydryl 2-(4-(1-(3-((tert -butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-3-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (0.12 g, 0.17 mmol) in acetonitrile (1.7 mL) was added Mel (0.087 mL, 1.4 mmol). The reaction was stirred at 70 °C overnight. The mixture was then cooled and concentrated to afford the title compound. LC-MS [M]+: m/z 731.4.

[00533] Step G: 4-(4-((1-(benzhydryloxy)-3-((((2-((tert - butoxycarbonyl)-amino)thiazol-4-yl)(carboxy)methylene)amino)oxy )-1 - oxopropan-2-yl)oxy)phenyl)-1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-methyl- 1H-pyrazol-2-io To 4-( iodide solution 4-((1-(benzhydryloxy)-3-((1,3-dioxoisoindolin-2-yl)oxy)-1-oxopropan-2-yl)oxy)phenyl)-1-(3-((tert-butoxycarbonyl )amino)propyl)2-methyl-1H-pyrazol-2-ium (0.15 g, 0.17 mmol) in CH2Cl2 (1.2 mL) at RT, hydrazine (6.6, 0.21 mmol) in ethanol (1.2 mL) was added. The resulting solution was stirred at RT for 1.5 h. To this mixture was added 2-(2-( (tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (0.085 g, 0.31 mmol), and the reaction was stirred at room temperature for 2 h. The mixture was then concentrated to afford compound of the title. LC-MS [M]+: m/z 855.7.

[00534] Step H: 4-(4-((1-(benzhydryloxy)-3-(((1-(2-(( tert - butoxycarbonyl)amino)thiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-1-oxopropan-2-yl)oxy)phenyl)- 1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-io In solution of 4-(4-((1-(benzhydryloxy)-3-(((( 2-((tert-butoxycarbonyl)-amino) thiazol-4-yl)(carboxy)methylene)amino)oxy)-1-oxopropan-2-yl)oxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H -pyrazol-2-ium (0.15 g, 0.17 mmol) in DMF (3.5 mL) was added DCC (0.090 g, 0.44 mmol) and HOBt (0.067 g, 0.44 mmol). The reaction mixture was stirred at rt for 30 min, then (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (0.073 g, 0.35 mmol) and sodium hydrogen carbonate (0.073 g, 0.87 mmol) were added. The resulting mixture was stirred at room temperature overnight, then filtered through a sintered syringe and washed with DMF (1.5 mL). The solution was purified on an ISCO system with a reversed-phase C-18 column (43 g ) eluted with 10-100% ACN/water with 0.05% TFA (25 min) to afford the title compound. LC-MS [M]+: m/z 1048.1.

[00535] Step I: (3S)-3-(2-((2-(4-(1-(3-ammopropyl)-2-methyl-1H-pyrazol-2-io-4-yl) sulfate phenoxy)-2-carboxyethoxy(imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl (84) To a solution of (3S)- 3-(2-((3-(benzhydryloxy)-2-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-yl-4-yl )phenoxy)-3sulfoxy)-imino)-2-(2- ((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4- oxoazetidin-1-yl (0.10 g, 0.095 mmol) in CH2Cl2 (3.2 mL), TFA (3.2 mL) was added. The reaction solution was stirred at room temperature for 1.5 h, then the solvent was removed under reduced pressure. Ether was added to the resulting residue and the solvent was again removed under reduced pressure. The resulting residue was dried under vacuum and then dissolved in 4 mL of DMSO and purified on a Gilson reverse phase (525% MeCN/ water gradient of 0.05% TFA) to afford the title compounds. Example 84: LC-MS [M + H]+: m/z 681.5. 1H NMR (500MHz, D2O, ppm): δ 8.43 (s, 1 H), 8.36 (s, 1 H), 7.43 (d, J = 10 Hz, 2 H), 6.97 (s, 1 H), 6.99 (d, J = 10 Hz, 2H), 4.89 (br dd, 1 H), 4.63 (m, 1 H), 4.59 (s, 1 H), 4.55 (m, 1 H), 4.47 (t, J = 10 Hz, 2 H), 4.03 (s, 3 H), 3.03 (t, J = 5 Hz, 2 H), 2.24 (m, 2 H), 1.34 (s, 3 H), 0.98 (s, 3 H). Example 85: LC-MS [M + H]+: m/z 681.5. EXAMPLE 86 (S)-3-(2-(2-aminothiazol-4-yl)-2-((2-(4-(4,5,6,7-tetrahydro-3H-imidazo[4) hydrogen sulfate ,5-c]pyridin-2-yl)phenoxy)ethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00536] Step A: (3S,4R)-tert-Butyl 3-azido-4-(((benzyloxycarbonyl)amino)piperidine-1-carboxylate To a solution of (3R,4R)-tert-butyl 4-(((benzyloxycarbonyl)amino)-3-hydroxypiperidine-1-carboxylate (2.0 g, 5.7 mmol) in CH2Cl2 (28 mL) were added TEA (1.6 mL, 11 mmol) and methanesulfonyl chloride (0.53 mL, 6.8 mmol) dropwise at 0 °C. The reaction was stirred for 0.5 h, then diluted with CH2Cl2, washed with 1 N HCl, saturated NaHCO3, and brine, dried over MgSO4, filtered, and concentrated. The resulting residue was dissolved in DMF (28.5 mL), followed by addition of sodium azide (1.1 g, 17 mmol). The reaction mixture was stirred overnight at 80 °C. Then, the reaction mixture was cooled, diluted with EtOAc, washed with water and brine, dried over MgSO 4 , filtered and concentrated. The resulting residue was purified using an ISCO silica gel column (40 g) eluting with a 0-30% EA/hexane gradient to afford the title compound.

[00537] Step B: (3S,4R)-tert-Butyl 3,4-diaminopiperidine-1-carboxylate To a solution of (3S,4R)-tert-butyl 3-azido-4-(((benzyloxycarbonyl)amino)piperidine-1-carboxylate (1.5 g, 4.1 mmol) in MeOH (20 mL) was added Pd-C (0.15 g, 0.14 mmol). The reaction was stirred over the weekend at room temperature under a balloon of H2. Then, the reaction mixture was filtered through Celite™ using CH2Cl2 and concentrated to afford the title compound.

[00538] Step C: (3aS,7aR)-tert-Butyl 2-(4-(benzyloxy)phenyl)-3a,4,7,7a-tetrahydro-3H-imidazo[4,5-c]pyridin-5(6H)-carboxylate To a solution of 4-(benzyloxy)benzaldehyde (0.25 g, 1.2 mmol) in t-BuOH (12 mL) was added (3S,4R)-tert-butyl 3,4-diaminopiperidine-1-carboxylate (0.30 g 1.4 mmol) at room temperature. The reaction was stirred for 30 min. Then potassium carbonate (0.48 g, 3.5 mmol) and iodine (0.37 g, 1.45 mmol) were added, and the reaction mixture was stirred at 70 °C for 3 h. The reaction mixture was cooled, then EtOAc was added and the mixture was washed with water and brine, dried over MgSO4, filtered and concentrated to afford the title compound. LC-MS [M + H]+: m/z 408.5.

[00539] Step D: tert-Butyl 2-(4-(benzyloxy)phenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-carboxylate To a 2M solution of oxalyl chloride (0.28 mL, 0.55 mmol) in CH2Cl2 under N2 at -78°C was added dropwise a solution of DMSO (0.073 mL, 1.03 mmol) in CH2Cl2 (0.2 mL). The reaction was stirred for 5 min, then a solution of 2-(4-(benzyloxy)phenyl)-3a,4,7,7a-tetrahydro-3H-imidazo[4,5-c]pyridin-5(6H)-(3aS,7aR)-tert-butyl carboxylate (0.10 g, 0.24 mmol) in CH2Cl2 (0.5 mL) was added dropwise. The reaction was stirred for 1 h, then TEA (0.37 mL, 2.6 mmol) was added dropwise. Then the reaction mixture was allowed to warm to RT and stirred for 2 h. Water was added, and the mixture was extracted with DCM. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated in vacuo to afford the title compound. LC-MS [M + H]+: m/z 406.4.

[00540] Step E: 2-(4-(benzyloxy)phenyl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-1,5 (4H)-di-tert dicarboxylate -butyl and di-tert-butyl 2-(4-(benzyloxy)phenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-3,5(4H)-dicarboxylate A mixture of tert-butyl 2-(4-(benzyloxy)phenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-carboxylate (0.2 g, 0. 49 mmol), BOC-Anhydride (0.23 ml, 0.97 mmol), and DMAP (0.060 g, 0.49 mmol) was stirred at RT for 1.5 h. Then, the mixture was concentrated and purified by ISCO silica gel column (12 g) eluting with 0-30% EA/hexane gradient to afford the title compound . LC-MS [M + H]+: m/z 506.5.

[00541] Step F: Di-tert-butyl 2-(4-hydroxyphenyl)-6,7-dihydro-3H-imidazo[4,5- c ]pyridin-3,5(4H)-dicarboxylate A mixture of 2-(4-(benzyloxy)phenyl)-6,7-dihydro-3H-imidazo[4,5- c ]pyridin-3,(4H)-di-tert-butyl dicarboxylate (0.17 g, 0.34 mmol), Pd/C (0.36 g, 0.34 mmol), and ammonium formate (0.10 g, 1.6 mmol) in MeOH (7 mL) was refluxed for 2 h. Then, the mixture was filtered through Celite™ using CH2Cl2 and concentrated to afford the title compound. LC-MS [M + H]+: m/z 416.3.

[00542] Step G: Di-tert-butyl 2-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)phenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-3,5(4H)-dicarboxylate To a solution of di-tert-butyl 2-(4-hydroxyphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-3,5(4H)-dicarboxylate, 2-(2-hydroxyethoxy)isoindoline-1,3-dione (0.061 g, 0.29 mmol), and PPh3 (0.085 g, 0.32 mmol), was added DEAD (0.15 mL, 0.32 mmol, 40% solution) in toluene at room temperature. The reaction was stirred at room temperature overnight. Then, the mixture was concentrated and purified by ISCO silica gel column (12 g) eluting with 0-100% EA/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 605.4.

[00543] Step H: 2-(4-(2-(amino-oxy)ethoxy)phenyl)-3a,4,7,7a-tetrahydro-3H-imidazo[4,5-c]pyridin-3, (3aS,7aR)-di-tert-butyl 5(6H)-dicarboxylate To solution of 2-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)ethoxy)phenyl)- 6, Di-tert-butyl 7-dihydro-3H-imidazo[4,5-c]pyridin-3,5(4H)-dicarboxylate (0.18 g) in CH2Cl2 (1.5 mL) at RT was Hydrazine (11) in EtOH (1.5 mL) was added. The resulting solution was stirred at RT for 0.5 h, then diluted with DCM and washed with saturated NaHCO3 solution 3 times. The aqueous phase was extracted with DCM once. The combined organic layers were washed with saturated aqueous sodium chloride solution. sodium, dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound, which was used directly in the next step. LC-MS [M + H]+: m/z 477.5.

[00544] Step I: 2-((2-(4-(3,5-bis( tert -butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)phenoxy)ethoxy)imino)-2-(2-((tert -butoxycarbonyl)amino)thiazol-4-yl)acetic acid A solution of 2-(4-(2-(amino-oxy)ethoxy)phenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-3,5(4H)-di-tert -butyl dicarboxylate (0.10 g, 0.22 mmol) and 2-(2-((tert -butoxycarbonyl)-amino)thiazol-4-yl)-2-oxoacetic acid (0.072 g, 0.27 mmol) in EtOH (1.5 mL) and CHCl3 (0.74 mL) was stirred at RT for 1.5 h. Then, the mixture was concentrated to afford the title compound, which was used as is in the next step. LC-MS [M + H]+: m/z 729.5.

[00545] Step J: 2-(4-(2-(((1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-((2,2-dimethyl-4-oxo -1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)ethoxy)-phenyl)-6,7-dihydro-3H-imidazo[4,5-c1pyridin-3 (S)-di-tert-butyl ,5(4H)-dicarboxylate To a solution of acid 2-((2-(4-(3,5-bis(tert-butoxycarbonyl)-4,5,6,7 -tetrahydro-3H-imidazo [4,5-(1pyridin-2-yl)phenoxy)ethoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (0.16 g, 0.22 mmol) in DMF (2.2 ml), DCC (0.11 g, 0.55 mmol) and HOBt (0.085 g, 0.55 mmol) were added. The resulting solution was stirred at rt for 30 min, then hydrogen sulfate (S )-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl (0.093 g, 0.44 mmol) and sodium hydrogencarbonate (0.093 g, 1.1 mmol) were added. The resulting mixture was stirred at room temperature overnight, then filtered through a sintered syringe and washed with DMF (1.5 mL). The solution was purified using an ISCO system with a reversed-phase C-18 column (86 g) eluting with 10-100% ACN/water with 0.05% TFA to afford the title compound. LC-MS [M - Boc]+: m/z 821.6.

[00546] Step K: (S)-3-(2-(2-aminothiazol-4-yl)-2-((2-(4-(4,5,6,7-tetrahydro-3H) hydrogen sulfate -imidazo[4,5-c]pyridin-2-yl)phenoxy)ethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl To a solution of 2-(4- (2-( ((1-(2-((tert-butoxycarbonyl)amino)-thiazol-4-yl)-2-((2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl) amino)-2-oxoethylidene)-amino)oxy)ethoxy)phenyl)- (S)-Di-tert-butyl 6,7-dihydro-3H-imidazo[4,5-c]pyridin-3,5(4H)-dicarboxylate (0.075 g, 0.081 mmol) in CH2Cl2 (1.357 mL ), TFA (1.4 mL) was added. The reaction mixture was stirred at rt for 1.5 h, then the solvent was removed under reduced pressure. The resulting residue was dried in vacuo, then dissolved in 4 mL of DMSO and purified by Gilson reversed phase separation (gradient 5-25% MeCN/water to 0.05% TFA) to afford the title compound. LC-MS [M + H]+: m/z 621.4. 1H NMR (500MHz, D2O, ppm): δ 7.66 (d, J = 10 Hz, 2 H), 7.05 (d, J = 10 Hz, 2H), 6.91 (s, 1 H), 4.63 (s, 1 H ), 4.50 (m, 2 H), 4.35 (s, 2 H), 4.33 (m, 2 H), 3.55 (t, J = 5 Hz, 2 H), 3.00 (t, J = 5 Hz, 2 H ), 2.24 (m, 2 H), 1.34 (s, 3 H), 0.98 (s, 3 H). EXAMPLE 87 (S)-3-((Z)-2-((((S)-1-(4-(6-((2-aminoethyl)amino)-1-methylpyridin-1-io-3 sulfate -yl)phenoxy-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00547] Step A: (S)-tert-Butyl 2-(aminooxy)-3-(4-(6-((2-((tert-butoxycarbonyl)amino)ethyl)amino)pyridin-3-yl)phenoxy)-2-methylpropanoate A mixture of (S)-tert-butyl 2-(amino)-3-(4-bromophenoxy)-2-methylpropanoate (0.5 g, 1.4 mmol), bis(pinacolato)diboron (0.38 g, 1.5 mmol), potassium acetate (0.42 g, 4.3 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.14 g, 0.22 mmol) in dioxane (7.2 mL) was degassed three times via vacuum/N2 recharges. The reaction was heated at 70 °C overnight. Then, the reaction mixture was cooled and 1,1´-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.094 g, 0.1 eq), tert-butyl (2-((5-bromopyridin-2-yl)amino)ethyl)-carbamate (first eluent from chiral SFC separation of intermediate 10 using OD-H, 4.6 × 250 mm, 20% MeOH/CO2, 2.5 mL/min, 100 bar (10 MPa), 35 °C) (0.50 g, 1.6 mmol), and 1 M potassium phosphate tribasic solution (4.3 mL, 4.3 mmol) in water were added. The mixture was degassed three times by vacuum/N2 recharges, then heated at 70 °C for 5 h. Then, the reaction mixture was filtered through Celite™ and the filtrate was concentrated. The resulting residue was purified by ISCO (40 g) using 0-100% EA/hex to afford the product, which was further purified by ISCO (40 g) using 0-30% 3:1 EA; EtOH/hex to afford the title compound. LC-MS [M + H]+: m/z 503.6.

[00548] Step B: (S)-tert-Butyl 3-(4-(6-((2-(( tert-butoxycarbonyl)amino)ethyl)amino)pyridin-3-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate A mixture of (S)-tert-butyl 2-(aminooxy)-3-(4-(6-((2-((tert-butoxycarbonyl)amino)ethyl)amino)pyridin-3-yl)phenoxy)-2-methylpropanoate (0.25 g, 0.50 mmol), isobenzofuran-1,3-dione (0.074 g, 0.50 mmol), and TEA (0.069 mL, 0.50 mmol) in toluene (4.97 mL) was heated to 120 °C for 1.5 h. Then, the mixture was cooled to rt and concentrated. The resulting residue was purified by ISCO silica gel column (24 g) eluting with 0-100% EA/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 633.4.

[00549] Step C: (S)-5-(4-(3-( tert -Butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methyl-3-oxo-propoxy)phenyl)-2-((2-(( tert -butoxycarbonyl)amino)ethyl)amino)-1-methylpyridin-1-ium iodide To a solution of (S)-tert -butyl 3-(4-(6-((2-((tert -butoxycarbonyl)amino)ethyl)-amino)pyridin-3-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate (0.13 g, 0.20 mmol) in acetonitrile (2.0 mL), was added MeI (0.102 mL, 1.6 mmol). The reaction was stirred at 75 °C for 3 h, then concentrated to afford the title compound. LC-MS [M]+: m/z 648.4.

[00550] Step D: (S)-3-((Z)-2-(((( S )-1-(4-(6-((2-aminoethyl)amino)-1-methylpyridin-1-io-3-yl)phenoxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl iodide (S)-5-(4-(3-(tert-Butoxy)-2-((1,3-dioxo-2-isoindolinyl)oxy)-2-methyl-3-oxopropoxy)phenyl)-2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-1-methylpyridin-1-ium was converted to the title compound following a procedure similar to the procedure of Example 1, Step And up to Step H. 1H NMR (500MHz, D2O, ppm): δ 8.15 (d, J = 10 Hz, 1 H), 8.11 (s, 1 H), 7.40 (d, J = 10 Hz, 2H), 7.15 (d, J = 10 Hz, 1H), 6.97 (d, J = 10 Hz, 2 H), 6. 90 (s, 1 H), 4.50 (s, 1 H), 4.44 (d, J = 15 Hz, 1 H), 4.30 (d, J = 15 Hz, 1 H), 3.80 (s, 3 H), 3.73 (t, J = 5 Hz, 2 H), 3.20 (t, J = 5 Hz, 2 H), 1.54 (s, 3 H), 1.31 (s, 3 H), 1.10 (s, 3 H). LC-MS [M + H]+: m/z 707.4. EXAMPLE 88 (S )-3-((Z)-2-((( S )-2-(4-(6-(3-aminopropyl)-1-methylpyridin-1-io-3-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00551] Step A: (3-(5-bromopyridin-2-yl)prop-2-yn-1-yl) tert-butyl carbamate A mixture of 2,5-dibromopyridine (0.76 g, 3.2 mmol), tert-butyl prop-2-yn-1-ylcarbamate (0.5 g, 3.2 mmol), diphenylphosphine palladium dichloride (0.045 g, 0.064 mmol), and copper(I) iodide (0.012 g, 0.064 mmol) in TEA (10 mL, 72 mmol) was cooled in an ice bath for 1 h. Then, the reaction was stirred at rt for 1 h. The reaction mixture was diluted with Et2O, washed with water (4x), brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by ISCO 40 g (0-30% AE/hex) to afford the title compound.

[00552] Step B 3-(4-(6-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)pyridin-3-yl)phenoxy)-2-hydroxypropanoate (R) -tert-butyl A solution of (R)-tert- butyl (0.4 g, 1.1 mmol), tert-butyl (3-(5-bromopyridin-2-yl)prop-2-yn-1-yl)carbamate (0.38 g) and 1 ,1'-bis(di-tert-butylphosphine)-ferrocene palladium (0.072 g, 0.11 mmol) in THF (5.5 ml) In a microwave vial, 1 M aqueous potassium phosphate solution (3.3 mL, 3.3 mmol) was added. The microwave vial was sealed, degassed (3x), recharged with N2, and shaken at 70°C for 3 h. Then, the reaction mixture was diluted with saturated NH4Cl solution and extracted with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated to dryness. The resulting residue was purified by gel column of ISCO silica (24 g) eluted with gradient (0-60%) of EtOAc/Hexane to afford the title compound. LC-MS [M - Boc]+: m/z 413.3.

[00553] Step C: (R)-tert-Butyl 3-(4-(6-(3-((tert-butoxycarbonyl)amino)propyl)pyridin-3-yl)phenoxy)-2-hydroxypropanoate A mixture of tert-butyl (R)-3-(4-(6-(3-((tert-butoxycarbonyl)-amino)prop-1-yn-1-yl)pyridin-3-yl)phenoxy)-2-hydroxypropanoate (0.33 g, 0.71 mmol) and Pd-C (0.067 g, 0.63 mmol) in MeOH (3.6 mL) was stirred at room temperature under a balloon of H2 overnight. The reaction mixture was filtered through Celite™ using CH2Cl2 and the filtrate was concentrated to afford the title compound. LC-MS [M + H]+: m/z 473.0.

[00554] Step D: (S )-3-((Z)-2-(((S)-2-(4-(6-(3-aminopropyl)-1-methylpyridin-1-io-3 sulfate -yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl 3-(4-(6-(3 - (R)-tert-butyl ((tert-Butoxycarbonyl)amino)propyl)pyridin-3-yl)phenoxy)-2-hydroxypropanoate was converted into the title compound following a procedure similar to the procedure of Example 1, Step C to Step H. 1H NMR (500MHz, D2O, ppm): δ 8.85 (s, 1 H), 8.49 (d, J = 5 Hz, 1 H), 7.82 (d, J = 5 Hz, 1H), 7.56 (d, J = 10 Hz, 2 H), 7.02 (d, J = 10 Hz, 2 H), 6.98 (s, 1 H ), 5.01 (s, 1 H), 4.47 (m, 3 H), 4.19 (s, 3 H), 3.10 (m, 4 H), 2.09 (m, 2 H), 1.31 (s, 3 H), 0.92 (s, 3H). LC-MS [M + H]+: m/z 692.5. EXAMPLE 89 (S)-3-((Z)-2-((((R)-1-(4-(6-((2-aminoethyl)amino)-1-methylpyridin-1-io-3 sulfate -yl)phenoxy-3-hydroxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00555] Step A: (R)-4-((4-bromophenoxy)methyl)-2,2-dimethyl-1,3-dioxolane To a solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (5.0 g, 38 mmol), triphenylphosphine (13 g, 49 mmol), and 4-bromophenol (15 g, 87 mmol) in toluene (200 mL) was added DEAD (6.0 mL, 38 mmol). The reaction was heated to 70 °C and stirred for 18 h. Then, the reaction mixture was evaporated and purified by silica gel chromatography (SiO2, EA: PE = 0% to 5%) to afford the title compound.

[00556] Step B: (S)-3-(4-bromophenoxy)propane-1,2-diol To a solution of (R)-4-((4-bromophenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (9 g, 31 mmol) in MeOH (150 mL) was added Amberlyst-15 (660 mg). The reaction was stirred for 24 h at 25 °C, then Amberlyst-15 was removed by filtration and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (SiO2, EtOAc/hexane 2:1 to 4:1) to afford the title compound.

[00557] Step C: (R)-1-(4-bromophenoxy)-3-(trityloxy)propan-2-ol To a solution of (S)-3-(4-bromophenoxy)propane-1,2-diol (5 g, 20 mmol) and TBAI (2.2 g, 6.1 mmol) in CH2Cl2 (100 mL), DIPEA (11 mL, 61 mmol) was added. Then, (chloromethanetriyl)tribenzene (6.2 g, 22 mmol) was added at 25 °C, and the reaction mixture was stirred for 18 h at 25 °C. The reaction was quenched by the addition of 3 M aqueous HCl (50 mL). The organic layer was separated, washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (SiO2, EtOAc/PE 1:10 to 1:4) to afford the title compound.

[00558] Step D: (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3-(trityloxy)propan-2-ol To a solution of (R )-1-(4-bromophenoxy)-3-(trityloxy)propan-2-ol (3 g, 6.1 mmol) in DMF (50 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.7 g, 6.7 mmol), potassium acetate (1.8 g, 18 mmol, 3 eq.), and PdCl2 (dppf) (0.31 g, 0.43 mmol). The reaction was purged with nitrogen and heated for 10 h at 90 °C. Then the reaction mixture was diluted with 500 mL of EtOAc and filtered. The filtrate was washed with 2 x 300 mL of water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (SiO2, EA: PE = 0% to 20%) to afford the title compound. LC-MS [M + H]+: m/z 359.2.

[00559] Step E: (R)-tert-Butyl (2-((5-(4-(2-hydroxy-3-(trityloxy)propoxy)phenyl)pyridin-2-yl)amino)ethyl)carbamate To a solution of PdCl2(dppf)-CH2Cl2 (78 mg, 0.095 mmol), tert-butyl (2-((5-bromopyridin-2-yl)amino)ethyl)carbamate (300 mg), and (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-3-(trityloxy)propan-2-ol (510 mg, 0.95 mmol) in dioxane (4.5 mL), was added Na2CO3 (300 mg, 2.8 mmol) in water (1.5 mL). The resulting mixture was exchanged with N2/vacuum 3 times, then heated at 100 °C under microwave reaction conditions for 1 h. Then, the reaction mixture was cooled and diluted with EtOAc, dried (MgSO4), filtered, and concentrated. The resulting residue was purified on a silica gel column (ISCO Gold, 80 g) using 0–100% EtOAc/hexane to afford the title compound. LC-MS [M + H]+: m/z 646.6.

[00560] Step F: (S)-3-((Z)-2-(((( R )-1-(4-(6-((2-aminoethyl)amino)-1-methylpyridin-1-io-3-(yl)phenoxy)-3-hydroxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl (2-((5-(4-(2-hydroxy-3-(trityloxy)-propoxy)phenyl)pyridin-2-yl)amino)ethyl) carbamate sulfate (R)-tert-butyl was converted to the title compound as a TFA salt following a procedure similar to the procedure in Example 1, Step C to Step H. LC-MS [M + H] + : m/z 679.6. 1H NMR (500MHz, D2O, ppm): δ 8.15 (d, J = 10 Hz, 1 H), 8.11 (s, 1 H), 7.41 (d, J = 10 Hz, 2 H), 7.14 (d, J = 10 Hz, 1 H), 6.96 (d, J = 10 Hz, 2 H), 6.82 (s, 1 H), 4 3.19 3H), 0.95 (s, 3H). EXAMPLE 90 (S)-3-((Z)-2-((((S)-1-(4-(6-((2-aminoethyl)amino)-1-methylpyridin-1-io-3-yl)phenoxy)propan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00561] Step A: (R)-1-(4-bromophenoxy)propan-2-ol To a solution of 4-bromophenol (1.8 g, 11 mmol) in DMF (25 mL) was added K2CO3 (2.9 g, 21 mmol) and (R)-1-chloropropan-2-ol (2.0 g, 21 mmol). The reaction was stirred and heated at 140 °C for 48 h. TLC showed a new spot formed. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo . The resulting residue was purified by column chromatography (SiO2, EtOAc/PE = 0% to 15%) to afford the title compound

[00562] Step B: (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (R)-1-(4-bromophenoxy)propan-2-ol was converted to (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol following the same procedure as the procedure in Example 89, Step D.

[00563] Step C: (R)-tert-Butyl (2-((5-(4-(2-hydroxypropoxy)phenyl)pyridin-2-yl)amino)ethyl)-carbamate To a solution of PdCl2(dppf)-CH2Cl2 adduct (88 mg, 0.11 mmol), tert-butyl (2-((5-bromopyridin-2-yl)amino)ethyl)carbamate (340 mg), and (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (300 mg, 1.1 mmol) in dioxane (4.5 mL), was added Na2CO3 (340 mg, 3.2 mmol) in water (1.5 mL). The resulting mixture was exchanged with N2/vacuum 3 times, then heated at 100 °C under microwave reaction conditions for 1 h. Then, the reaction was cooled and diluted with EtOAc, dried (MgSO4), filtered, and concentrated. The resulting residue was purified on a silica gel column (ISCO Gold, 80 g) using 0-100% EtOAc/hexane to afford the title compound. LC-MS [M + H]+: m/z 388.4.

[00564] Step D: (S)-tert-Butyl (2-((5-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)propoxy)phenyl)pyridin-2-yl)amino)ethyl)carbamate To a solution of (R)-tert-butyl (2-((5-(4-(2-hydroxypropoxy))pyridin-2-yl)amino)ethyl)carbamate (210 mg, 0.54 mmol) in THF (4 mL), were added 2-hydroxyisoindoline-1,3-dione (106 mg, 0.65 mmol), triphenylphosphine (200 mg, 0.76 mmol), followed by dropwise addition of DIAD (0.15 mL, 0.76 mmol). The resulting solution was stirred at rt for 1 h, then concentrated. The resulting residue was purified on silica gel column (ISCO gold 80 g) using 0-100% EtOAc/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 533.3.

[00565] Step E: (S )-3-((Z)-2-((((S)-1-(4-(6-((2-aminoethyl)amino)-1-methylpyridin-1 sulfate -io-3-yl)phenoxy)propan-2-yl)oxy)imino)-2- (2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1 -yl (2- ((5-(4-(2-((1,3-dioxoisoindolin-2-yl)oxy)-propoxy)phenyl)pyridin-2-yl)amino)ethyl) (S)-tert-butyl carbamate was converted in the compound a salt of formic acid following a process similar to the procedure in Example 1, Step D to Step H. 1H NMR (500MHz, D2O, ppm): δ 8.06 (d, J = 10 Hz, 1 H), 8.00 (s, 1 H), 7.33 (d, J = 10 Hz, 2 H), 7.06 (d, J = 10 Hz, 1H), 6.95 (d, J = 10 Hz, 2 H), 6.67 (s, 1 H), 4.51 (m, 1 H), 4.47 (s, 1 H), 4.08 (d, J = 10 Hz, 1 H), 3.95 (dd, J = 10.5 Hz, 1 H), 3.73 (s, 3 H), 3.68 (t, J = 5 Hz, 2 H), 3.17 (t, J = 5 Hz, 2 H), 1.21 (s, 3 H ), 1.18 (d, J = 5 Hz, 3 H), 0.92 (s, 3H). LC-MS [M + H]+: m/z 663.6. EXAMPLE 91 (3S)-3-(2-((2-((4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenyl)amino sulfate )-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00566] Step A: tert-Butyl oxirane-2-carboxylate To a mixture of tert-butyl acrylate (10 g, 78 mmol) in DCM (100 mL) was added 80% m-CPBA (30 g, 140 mmol) in DCM (140 mL). The reaction mixture was stirred at 40 °C for 48 h. Then, the reaction was cooled to 0 °C and saturated aqueous Na2SO3 solution (300 mL) was added dropwise. The organic layer was separated, washed with saturated aqueous NaHCO3 (2 x 200 mL) and saturated brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound, which was used directly in the next step without purification.

[00567] Step B: tert-Butyl 3-((4-bromophenyl)amino)-2-hydroxypropanoate To a mixture of 4-bromoaniline (4.0 g, 23 mmol) in acetonitrile (80 mL) was added tert-butyl oxirane-2-carboxylate (5.0 g, 35 mmol) and lithium trifluoromethanesulfonate (5.4 g, 35 mmol). The reaction mixture was stirred at 60 °C under N2 for 15 h, then the reaction was diluted with EtOAc (100 mL) and water (120 mL). The aqueous layer was separated and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, PE: EtOAc = 100:1 to 5:1) to afford the title compound. LC-MS [M + H]+: m/z 316.2.

[00568] Step C: tert-Butyl 3-((4-bromophenyl)amino)-2-((tert-butyldimethylsilyl)oxy)propanoate To a solution of tert-butyl 3-((4-bromophenyl)amino)-tert-butyl 2-hydroxypropanoate (3.3 g, 10 mmol) and DBU (3.2 mL, 21 mmol) in CH3CN (50 mL) was added tert-butylchlorodimethylsilane (2.4 g, 16 mmol). The reaction mixture was stirred at 25 °C for 2 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, PE:EtOAc = 100:1 to 10:1) to afford the title compound. LC-MS [M + H]+: m/z 430.0.

[00569] Step D: tert-Butyl 3-((4-bromophenyl)(tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propanoate A solution of tert-butyl 3-((4-bromophenyl)amino)-2-((tert-butyldimethylsilyl)oxy)propanoate (4.4 g, 10 mmol) in (Boc)2O (50 mL) was stirred at 125 °C for 1 h. The reaction mixture was cooled and the solvent was removed. The resulting residue was purified by column chromatography (SiO2, PE:EtOAc = 100:1 to 10:1) to afford the title compound. LC-MS [M + H]+: m/z 554.1.

[00570] Step E:3-((tert-butoxycarbonyl) (4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1 H-pyrazol-4-yl)-phenyl)amino)-2 -((tert-butyldimethylsilyl)oxy)tert-butylpropanoate To a solution of 3-((4-bromophenyl)(tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)-oxy)tert-butylpropanoate (0.50 g, 0.94 mmol)), (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl )propyl) tert-butyl carbamate (0.33 g, 0.94 mmol)) and tert-butyl dichloride 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium (0.061 g, 0.094 mmol) in dioxane (4.71 ml) in a microwave vial was added to 1 M aqueous potassium phosphate solution (2.8 ml, 2.8 mmol). The microwave vial was sealed, degassed, filled with N2, and stirred at 70°C overnight. The reaction mixture was then filtered, and the filtrate was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified by ISCO silica gel column (12 g) eluting with 0-100% EA/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 675.9.

[00571] Step F: 3-(( tert-butoxycarbonyl)(4-( 1 -(3-(( tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)-phenyl)amino)-2- tert-butyl hydroxypropanoate To a solution of 3-(( tert-butoxycarbonyl)(4-( 1-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenyl)amino)-2-(( tert-butyldimethylsilyl)oxy)propanoate (0.57 g, 0.85 mmol) in THF (4.25 mL), 1 M TBAF (0.85 mL, 0.85 mmol, THF solution) was added. The reaction was stirred at RT for 1 h and then concentrated. The resulting residue was purified by ISCO silica gel column (12 g) eluting with 0-100% EA/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 561.5.

[00572] Step G:3-((tert-butoxycarbonyl)(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1 H-pyrazol-4-yl)phenyl)amino)-2- tert-butyl (1,3-dioxoisoindolin-2-yl)oxy)propanoate A solution of 3-((tert-butoxycarbonyl)(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)- tert-butyl 1H-pyrazol-4-yl)phenyl)amino)-2-hydroxypropanoate (0.36 g, 0.65 mmol) in THF (6.5 ml), 2-hydroxyisoindoline-1,3 was added -dione (0.12 g, 0.71 mmol), triphenylphosphine (0.20 g, 0.78 mmol) and DIAD (0.15 mL, 0.78 mmol). The reaction was stirred at RT for 2 h, then concentrated and purified by ISCO silica gel column (12 g) eluting with 0-100% EtOAc in Hexanes to afford the title compound. LC-MS [M + H]+: m/z 706.6.

[00573] Step H: (3S)-3-(2-((2-((4-(1-(3-Aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenyl)amino)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate 3-(( tert -butoxycarbonyl)(4-(1-(3-((tert -butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenyl)amino)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate tert-butyl was converted to the title compound as a TFA salt following a procedure similar to the procedure in Example 1, Step D to Step H. 1H NMR (500 MHz, D2O, ppm) Hz, 2 H), 4.03 (s, 3 H), 3.61 (m, 2 H), 3.03 (t, J = 5 Hz, 2 H), 2.24 (m, 2 H), 1.28 (s, 3 H), 1.05 (s, 3 H). LC-MS [M + H]+: m/z 680.6. EXAMPLE 92 (3S)-3-(2-((2-((4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenyl)(methyl)amino)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00574] Step A: 4-Bromo-N-methylaniline To a mixture of 4-bromoaniline (5.0 g, 29 mmol) and Cs2CO3 (9.5 g, 29 mmol) in DMF (60 mL) was added CH3I (2.7 mL, 44 mmol). The reaction mixture was stirred at 25 °C for 2 h, then diluted with EtOAc (100 mL) and water (200 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, PE:EtOAc = 100:1 to 10:1) to afford the title compound. LC-MS [M + H]+: m/z 186.0.

[00575] Step B: tert-Butyl 3-((4-bromophenyl)(methyl)amino)-2-hydroxypropanoate To a mixture of 4-bromo-N-methylaniline (2.2 g, 12 mmol) in CH3CN (50 mL) was added tert-butyl oxirane-2-carboxylate (2.6 g, 18 mmol) and lithium trifluoromethanesulfonate (2.8 g, 18 mmol). The reaction mixture was stirred at 65 °C under N2 for 15 h, then diluted with EtOAc (30 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, PE:EtOAc = 100:1 to 5:1) to afford the title compound. LC-MS [M + H]+: m/z 330.0.

[00576] Step C: tert-Butyl 3-((4-Bromophenyl)(methyl)amino)-2-(( tert-butyldimethylsilyl)oxy)-propanoate To a solution of tert-butyl 3-((4-bromophenyl)(methyl)amino)-2-hydroxy-propanoate (3.8 g, 11.51 mmol) and DBU (2.081 mL, 13.81 mmol) in CH3CN (50 mL) was added tert-butylchlorodimethylsilane (2.60 g, 17.26 mmol). The reaction mixture was stirred at 25 °C for 2 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, PE:EtOAc = 100:1 to 10:1) to afford the title compound. LC-MS [M + H]+: m/z 444.1.

[00577] Step D: (3S)-3-(2-((2-((4-(1-(3-Aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenyl)(methyl)amino)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate tert-Butyl 3-((4-bromophenyl)(methyl)amino)-2-((tert-butyldimethylsilyl)oxy)-propanoate was converted to the title compound as a TFA salt following a procedure similar to the procedure in Example 91. 1H NMR (500MHz, D2O, ppm): δ 8.44 (s, 1 H), 8.40 (s, 1 H), 7.42 (d, J = 10 Hz, 2 H), 6.92 (d, J = 10 Hz, 2 H), 6.80 (s, 1 H), 4.86 (m, 1 H), 4.48 (t, J = 5 Hz, 2 H), 4.04 (s, 3 H), 4.02 (dd, J = 10.5 Hz, 1 H), 3.83 (s, 1 H), 3. 72 (d, J = 10 Hz, 1 H), 3.05 (t, J = 5 Hz, 2 H), 2.89 (s, 3 H), 2.26 (m, 2 H), 1.28 (s, 3 H), 1.05 (s, 3 H). LC-MS [M + H]+: m/z 694.5. EXAMPLE 93 (3S)-3-(2-((3-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenyl)-1-carboxypropoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00578] Step A: 4-(4-Bromophenyl)-2-hydroxybutanoic acid A mixture of (4-bromophenyl)-methanol (10 g, 54 mmol), 2-hydroxypropanoic acid (5.8 g, 64 mmol), KOH (5.4 g, 96 mmol), nickel(II) acetate tetrahydrate (6.6 g, 27 mmol), and triphenylphosphine (14 g, 54 mmol) was stirred at 160 °C for 7.5 h under N 2 . Then, the mixture was cooled to 25 °C and H 2 O (40 mL) and 1 N HCl were added until the pH of the mixture was pH < 3. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, PE:EtOAC = 28:72) to afford the title compound.

[00579] Step B: Benzhydryl 4-(4-bromophenyl)-2-hydroxybutanoate To a mixture of 4-(4-bromophenyl)-2-hydroxybutanoic acid (3.5 g, 6.8 mmol) in THF (40 mL) was added 3,3-diphenyl-3H-diazirine (1.3 g, 6.8 mmol). The reaction mixture was stirred at 25 °C for 16 h, then concentrated in vacuo. The resulting residue was purified by preparative HPLC to afford the title compound.

[00580] Step C: Benzhydryl 4-(4-bromophenyl)-2-hydroxybutanoate Benzhydryl 4-(4-bromophenyl)-2-hydroxybutanoate (4.5 g, 11 mmol) was separated by SFC (Column: OJ (250mm*50mm, 10um)

[00581] Mobile phase: A: CO2 B: 0.1% NH3H2O EtOH Gradient: from 40% to 40% B Flow rate: 200 mL/min Wavelength: 220 nm) to produce the first isomer 4-(4-bromophenyl)-2-benzhydryl hydroxybutanoate, and the 2nd isomer 4-(4-bromophenyl)-2-benzhydryl hydroxybutanoate.

[00582] Step D: Benzhydryl 4-(4-bromophenyl)-2-((tert-butyldimethylsilyl)oxy)butanoate To a mixture of benzhydryl 4-(4-bromophenyl)-2-hydroxybutanoate (2° isomer from Step 3, 2.2 g, 5.2 mmol) in DMF (15 mL) were added 1H-imidazole (0.70 g, 10 mmol) and tert-butylchlorodimethylsilane (1.9 g, 13 mmol). The reaction mixture was stirred at 25 °C for 16 h under N 2 . Then the solvent was removed in vacuo and the resulting residue was purified by column chromatography (SiO 2 , PE : EtOAc = 20:1~5:1) to afford the title compound.

[00583] Step E: 4-(4-(1-(3-((tert-butoxycarbonyl)-amino)propyl)- 1 H-pyrazol-4-yl)phenyl)-2-((tert-butyldimethylsilyl)oxy )benzyl butanoate

[00584] To a solution of benzhydryl 4-(4-bromophenyl)-2-((tert-butyldimethylsilyl)oxy)butanoate, peak 2 (0.68 g, 1.3 mmol)), tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propyl) carbamate (0.45 g, 1.3 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.082 g, 0.13 mmol) in dioxane (6.3 mL) was added 1 M aqueous potassium phosphate solution (3.8 mL, 3.8 mmol). The microwave vial was sealed, degassed and refilled with N2 and stirred at 70 °C overnight. Then the mixture was filtered and the filtrate was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The resulting crude product was purified using an ISCO silica gel column (24 g) eluting with 0-50% EA/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 684.7.

[00585] Step F: Benzhydryl 4-(4-(1-(3-(( tert -butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenyl)-2-hydroxybutanoate To a solution of benzhydryl 4-(4-(1-(3-(( tert -butoxycarbonyl)amino)-propyl)-1H-pyrazol-4-yl)phenyl)-2-(( tert -butyldimethylsilyl)oxy)butanoate (0.70 g, 1.03 mmol) in THF (5.1 mL) was added 1 M TBA solution (1.03 mL, 1.03 mmol) of THF. The reaction was stirred at RT for 1 h, then concentrated and purified by ISCO silica gel column (24 g) eluting with 0-100% EA/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 570.6.

[00586] Step G: 4-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenyl)-2-((1,3-dioxoisoindolin- Benzhydryl 2-yl)oxy)butanoate A solution of 4-(4-(1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenyl)-2-hydroxybutanoate benzhydryl (0.41 g, 0.72 mmol) in THF (7.2 mL), added 2-hydroxyisoindoline-1,3-dione (0.13 g, 0.79 mmol), triphenylphosphine (0.23 g, 0.86 mmol) and DIAD (0.17 mL, 0.86 mmol) at RT. The reaction was stirred for 1 h, then the mixture was concentrated and purified by ISCO silica gel column (24 g) eluting with 0-100% EA/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 715.5.

[00587] Step H: 4-(4-(4-(Benzhydryloxy)-3-((1,3-dioxoisoindolin-2-yl)oxy)-4-oxobutyl)phenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazol-2-ium iodide To a solution of benzhydryl 4-(4-(1-(3-(( tert -butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenyl)-2-((1,3-dioxoisoindolin-2-yl)oxy)butanoate (0.51 g, 0.71 mmol) in acetonitrile (7.1 mL) was added Mel (0.36 mL, 5.7 mmol). The reaction was stirred at 70 °C overnight. The mixture was then cooled and concentrated to afford the title compound. LC-MS [M + H]+: m/z 730.4.

[00588] Step I: (3S)-3-(2-((3-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl) sulfate phenyl)-1-carboxypropoxy(imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl 4-(4-(4-(benzhydryloxy)) iodide -3-((1,3-dioxoisoindolin-2-yl)oxy)-4-oxobutyl)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-methyl-1H-pyrazole-2 -io was converted to the title compound as a TFA salt following a procedure similar to the procedure from Step E to Step H in Example 1. 1H NMR (500MHz, D2O, ppm): δ 8.52 (s, 1 H), 8.47 (s, 1 H), 7.44 (d, J = 10 Hz, 2 H), 7.26 (d, J = 10 Hz, 2 H), 6.95 (s, 1 H), 4.70 (m, 2 H), 4.49 (t, J = 5 Hz, 2 H), 4.08 (s, 3 H), 3.06 (t, J = 5 Hz, 2 H), 2.73-2.60 ( m, 2 H), 2.27 (t, J = 5 Hz, 2 H), 2.27-2.15 (m, 2 H) 1.43 (s, 3 H), 1.22 (s, 3 H). LC-MS [M + H]+: m/z 679.5. EXAMPLE 94 (2S)-3-(4-(2-((2-aminoethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy acid)-2-((((Z) -1-(2-aminothiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene )amino)oxy)propanoic

[00589] Step A: 4-(1,3-dinitropropan-2-yl)phenol To a solution of 4-hydroxybenzaldehyde (5 g, 41 mmol), bis(triphenylphosphine)nickel(II) bromide (6.1 g, 8.2 mmol), K2CO3 (23 g, 164 mmol), and triphenylphosphine (13 g, 49 mmol) in CH3NO2 (500 mL) was added zinc (11 g, 164 mmol). The mixture was stirred at 80 °C for 20 h, then the mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, PE:EtOAc = 45:55) to afford the title compound.

[00590] Step B: (R)-tert-Butyl 3-(4-( 1,3-dinitropropan-2-yl)phenoxy)-2-hydroxypropanoate To the mixture of 4-(1,3-dinitropropan-2-yl)phenol (4 g, 18 mmol) and molecular sieves (4Â, 4 g) in tert-butyl oxirane-2-carboxylate (10 g, 71 mmol), was added co-catalyst (CAS: 240489-45-6) (1.2 g 1.4 mmol) under N2. The resulting suspension was stirred at 25 °C under N2 for 48 h, then the mixture was filtered, and the filtrate was purified by column chromatography (SiO2, PE:EtOAc = 45:55) to afford the title compound.

[00591] Step C: (R)-tert-Butyl 2-(( tert-Butyldimethylsilyl)oxy)-3-(4-(1,3-dinitropropan-2-yl)phenoxy)propanoate To a solution of (R)-tert-butyl 3-(4-(1,3-dinitropropan-2-yl)phenoxy)-2-hydroxypropanoate (4 g, 11 mmol) in DMF (30 mL) were added imidazole (2.2 g, 32 mmol) and tert-butylchlorodimethylsilane (3.3 g, 22 mmol) at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 3 h. Then the mixture was added to EtOAc (50 mL) and washed with water (3 × 50 mL) and brine (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound, which was used in the next step without further purification.

[00592] Step D: tert-Butyl 3-(4-( 1,3-diaminopropan-2-yl)phenoxy)-2-hydroxypropanoate To a solution of (R)-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-3-(4-(1,3-dinitropropan-2-yl)phenoxy)propanoate (4 g, 8.25 mmol) in EtOH (150 mL) was added platinum(II) oxide (0.35 g, 1.7 mmol). The mixture was stirred under H2 (50 psi) at 25 °C for 16 h. Then, the mixture was filtered and concentrated under reduced pressure to afford crude (R)-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-3-(4-(1,3-dinitropropan-2-yl)phenoxy)propanoate which was desilylated during the freeze-drying process after pre-purification by acidic HPLC.

[00593] Step E: (R)-tert-butyl 2-hydroxy-3-(4-(2--thioxo-hexahydropyrimidin-5-yl)phenoxy)-propanoate

[00594] 1,1’-Thiocarbonyldiimidazole (362 mg, 2.03 mmol) was added in 5 portions over 10 min to a stirred mixture of (R)-tert-butyl 3-(4-(1,3-diaminopropan-2-yl)phenoxy)-2-hydroxypropanoate (600 mg, 1.93 mmol) in DCM (30 mL). The mixture was stirred at room temperature for 2 h, then the solvent was removed under reduced pressure. The resulting residue was purified on a silica gel column (80 g) using 060% EtOAc/Hexane to afford the title compound. LC-MS [M + H]+: m/z 353.5.

[00595] Step F: (R)-tert-Butyl 2-((tert-butyldimethylsilyl)oxy)-3-(4-(2-thioxo-hexahydropyrimidin-5-yl)phenoxy)propanoate To a solution of (R)-tert-butyl 2-hydroxy-3-(4-(2-thioxo-hexahydropyrimidin-5-yl)phenoxy)propanoate (200 mg, 0.57 mmol), imidazole (93 mg, 1.36 mmol), and TBDMS-Cl (100 mg, 0.68 mmol) in acetonitrile (4 mL) was added DMAP (6.9 mg, 0.057 mmol). The resulting mixture was stirred at rt overnight. Then the reaction mixture was concentrated. The resulting residue was purified by ISCO Combi-flash on 40 g gold column, eluting with 0-100% EtOAc/hexane to afford the title compound. LC-MS [M + H]+: m/z 467.5.

[00596] Step G: (2R)-tert-Butyl 2-((tert-butyldimethylsilyl)oxy)-3-(4-(2-(methylthio)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)propanoate Iodomethane (0.17 mL, 2.8 mmol) was added to a stirred mixture of (R)-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-3-(4-(2-thioxo-hexahydropyrimidin-5-yl)phenoxy)propanoate (260 mg, 0.55 mmol) in MeCN (3 mL). The mixture was stirred at 70 °C for 2 h, then cooled and the solvent was evaporated under reduced pressure to afford the title compound. LC-MS [M + H]+: m/z 481.0.

[00597] Step H: (2R)-3-(4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)tert-butyl propanoate Hunig's base (0.19 mL, 1.1 mmol) was added to a stirred mixture of N-Boc-ethylenediamine (130 mg, 0.83 mmol) and (2R)-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-3-(4-(2-(methylthio)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)propanoate (260 mg, 0.55 mmol) in dioxane (3 mL). The mixture was stirred at 70 °C for 24 h, then the solvent was removed under reduced pressure to afford the title compound, which was used directly in the next step. LC-MS [M + H]+: m/z 593.5.

[00598] Step I: 5-(4-((R )-3-( tert-butoxy)-2-(( tert-butyldimethylsilyl)oxy)-3-oxopropoxy)-phenyl)-2-(( tert-butoxycarbonyl)(2-(( tert-butoxycarbonyl)amino)ethyl)amino)-5,6-dihydropyrimidine-1(4H)-tert-butyl carboxylate Boc anhydride (2100, 9.3 mmol) was added to (2R)-tert-butyl 3-(4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)-2-((tert-butyldimethylsilyl))oxy)propanoate (275 mg, 0.46 mmol), and the mixture was stirred at 100 °C for 6 h. Then, the reaction mixture was cooled and loaded directly onto an ISCO column (40 g gold) eluting with a 0-100% EtOAc/Hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 793.6.

[00599] Step J: 5-(4-((R)-3-(tert-butoxy)-2-hydroxy-3-oxopropoxy) phenyl)-2-(( tert-butoxycarbonyl)(2-(( tert - tert-butyl butoxycarbonyl)butoxycarbonyl)amino)ethyl)amino)-5,6-dihydropyrimidine-1(4H)-carboxylate TBAF (0.79 ml, 0.79 mmol) was added to a stirred mixture of 5 -(4- (R)-3-(tert-butoxy)-2-((tert-butyldimethylsilyl)oxy)-3-oxopropoxy)phenyl)-2- ((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl) )amino)ethyl)amino)-5,6-dihydropyrimidine-1 (4H)-carboxylate tert-butyl (420 mg, 0.53 mmol) in THF (5 ml). The mixture was stirred at room temperature for 1 h, then the solvent was removed. The resulting residue was purified using an ISCO silica gel column ( 40 g of gold) eluting with a 0-100% EtOAc/hexane gradient to afford the title compound. LC-MS [M + H]+: m/z 679.5.

[00600] Step K: 5-(4-((S)-3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-2- ((tert-butoxycarbonyl)(2-(( tert -butoxycarbonyl)amino)ethyl)amino)-5,6-dihydropyrimidine-1(4H)-tert-butyl carboxylate A solution of 5-(4-( (R))-3-(tert-butoxy)-2-hydroxy-3-oxopropoxy)phenyl)-2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino) ethyl)amino)-5, tert-butyl 6-dihydropyrimidine-1(4H)-carboxylate (360 mg, 0.53 mmol) in THF (5 mL), 2-hydroxyisoindoline-1,3-dione (104 mg, 0.64 mmol), triphenylphosphine (195 mg, 0.74 mmol) were added, followed by dropwise addition of DIAD (0.144 ml, 0.74 mmol). The resulting solution was stirred at rt for 1 h, then concentrated. The resulting residue was purified on a silica gel column (ISCO gold 40 g) using a 0-100% EtOAc/hexane gradient to afford the compound of the title. LC-MS [M + H]+: m/z 824.8.

[00601] Step L: (2S)-3-(4-(2-((2-aminoethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)-2-( (((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfo-oxy)azetidin-3-yl)amino )-2-oxoethylidene)amino) oxy)propanoic acid 5-(4-((S)-3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)- 3-oxopropoxy) phenyl)-2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl) tert-butyl amino)ethyl)amino)-5,6-dihydropyrimidine-1(4H)-carboxylate was converted to the title compound as a formic acid salt following a procedure similar to the procedure in Step E through Step H of Example 1. 1H NMR (500MHz, D2O, ppm): δ 7.13 (d, J = 10 Hz, 2 H), 7.02 (s, 1 H), 6.85 (d, J = 10 Hz, 2 H), 5.05 (m , 1H), 4.68 (s, 1 H), 4.36 (m, 2 H), 3.45 (dd, J = 15.5 Hz, 2 H), 3.38 (t, J = 5 Hz, 2 H), 3.32 ( dd, J = 10.5 Hz, 2 H), 3.11 (m, 1 H), 3.06 (t, J = 5 Hz, 2 H), 1.34 (s, 3 H), 0.95 (s, 3 H). LC-MS [M + H]+: m/z 684.4. EXAMPLE 95 (2S)-3-(4-(2-((2-aminoethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy acid)-2-((((Z )-1-(2-aminothiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1- (sulfo-oxy)azetidin-3-yl)amino)-2- oxoethylidene)amino)oxy)-2-methylpropanoic acid

[00602] Step A: tert-butyl (2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)ethyl)carbamate To a solution of tert-butyl (2-((5-bromopyrimidin-2-yl)-amino)ethyl)carbamate (700 mg, 2.2 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (840 mg, 3.3 mmol), and 1,1’-bis(diphenylphosphino)ferrocene palladium(II) dichloride-dichloromethane complex (180 mg, 0.22 mmol) in 1,4-dioxane (10 mL), was added potassium acetate (650 mg, 6.6 mmol). The mixture was degassed and recharged with nitrogen and heated at 85 °C for 4 h. The mixture was then filtered and concentrated to dryness under vacuum and purified through an ISCO column (40 g gold, 0-100% EtOAc/hexane gradient) to afford the title compound.

[00603] Step B: (S)-tert-Butyl 3-(4-bromophenoxy)-2-((( tert-butoxycarbonyl)amino)oxy)-2-methylpropanoate Boc-anhydride (8.38 mL, 36.1 mmol) was added to a mixture of (S)-tert-butyl 2-(amino-oxy)-3-(4-bromophenoxy)-2-methylpropanoate (5 g, 14.44 mmol) in DCM (10 mL), and the mixture was stirred at 50 °C overnight. Then, the mixture was cooled and purified directly by ISCO (120 g gold), eluting with a 0-30% EtOAc/isohexane gradient, to afford the title compound. LC-MS [M + Na]+: m/z 468.2.

[00604] Step C: (S)-tert-butyl 3-(4-(2-((2-(( tert-butoxycarbonyl)amino)ethyl)amino)pyrimidin-5-yl)phenoxy)-2-(((tert-butoxycarbonyl)amino)oxy)-2-methylpropanoate To a solution of PdCl2(dppf)-CH2Cl2 (75 mg, 0.092 mmol), tert-butyl (2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)amino)ethyl)carbamate (350 mg, 0.96 mmol) and (S)-tert-butyl 3-(4-bromophenoxy)-2-((((tert-butoxycarbonyl)amino)oxy)-2-methylpropanoate (410 mg, 0.92 mmol) in dioxane (4.5 mL) was added Na2CO3 (290 mg, 2.8 mmol) in water (1.5 mL). The resulting mixture was exchanged with N2/vacuum for 3 times before being heated at 100 °C under microwave reaction conditions for 1 h. Then the mixture was cooled and diluted with EtOAc, dried (MgSO4), filtered, and concentrated. The resulting residue was purified on a silica gel column (ISCO Gold, 80 g) using 0-100% EtOAc/hexane to afford the title compound. LC-MS [M + H]+: m/z 604.5.

[00605] Step D: (2S)-tert-Butyl 3-(4-(2-((2-(( tert-butoxycarbonyl)amino)ethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)-2-((( tert-butoxycarbonyl)amino)oxy)-2-methylpropanoate Palladium on carbon (20 mg, 0.19 mmol) was added to a stirred mixture of (S)-tert-butyl 3-(4-(2)-((2-(( tert-butoxycarbonyl)amino)ethyl)amino)pyrimidin-5-yl)-phenoxy)-2-((( tert-butoxycarbonyl)amino)oxy)-2-methylpropanoate (100 mg, 0.17 mmol) in MeOH (5 mL) and hydrochloric acid (0.83 mL, 0.83 mmol). The mixture was vacuum/H2 exchanged 3 times and stirred under a hydrogen balloon at room temperature for 2.5 h. Then, the mixture was diluted with DCM and filtered through a sintered funnel. The filtrate was diluted with DCM and washed with 1 N aqueous NaOH solution (~5 mL). The aqueous phase was extracted with DCM (2x). The combined organic phases were washed with brine, dried (MgSO4), filtered, and concentrated to afford the title compound. LC-MS [M + H]+: m/z 608.5.

[00606] Step E (2S)-tert-butyl 3-(4-(2-((2-aminoethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)-2-(aminooxy)-methylpropanoate TFA (1 mL) was added to a solution of (2S)-tert-butyl 3-(4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)-2-(((tert-butoxycarbonyl)amino)oxy)-2-methylpropanoate (120 mg, 0.20 mmol) in CH2Cl2 (1 mL) and the mixture was stirred at room temperature for 40 min. Then, the reaction was quenched by removing the solvent under reduced pressure. Ether was added to the residue and the solvent was removed under reduced pressure. To the resulting residue was added ether to remove a solid, then the solvent was removed via pipette. The solid residue was dried under vacuum to afford the title compound. LC-MS [M + H]+: m/z 408.4.

[00607] Step F: (2S)-tert-butyl 3-(4-(2-((2-aminoethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)-phenoxy)-2-(((Z)-(1-(2-(( tert-butoxycarbonyl)amino)thiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate To a solution of (2S)-tert-butyl 3-(4-(2-((2-aminoethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)-2-(aminooxy)-2-methylpropanoate (148 mg, 0.20 mmol) in methanol (2.5 mL) at rt, (S)-3-(2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetamido)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate (110 mg, 0.24 mmol) was added. The resulting solution was stirred at rt for 4 h, then concentrated to afford the title compound. LC-MS [M + H]+: m/z 854.5.

[00608] Step G: (2S)-3-(4-(2-((2-aminoethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)-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-methylpropanoic acid TFA (2 mL) was added to a solution of 3-(4-(2-((2-aminoethyl)amino)-1,4,5,6-tetrahydropyrimidin-5-yl)phenoxy)-2-(((Z)-(1- English:(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (2S)-tert-butyl (160 mg, 0.19 mmol) in CH2Cl2 (1 mL) and the mixture was stirred at room temperature for 45 min. Then, the reaction was stopped by removing the solvent under reduced pressure. Ether was added to the residue, and the solvent was removed under reduced pressure again. To the resulting residue was added ether to form a solid, and the solvent was removed with a pipette. The solid residue was dried under vacuum and then dissolved in 5 mL of DMSO for purification of HTP with standard formic acid conditions to afford the title compound as the formic acid salt. 1H NMR (500MHz, D2O, ppm) Hz, 1 H), 3.42 (dd, J = 10.5 Hz, 2 H), 3.37 (t, J = 5 Hz, 2 H), 3.27 (dd, J = 15.5 Hz, 2 H), 3.06 (t, J = 5 Hz, 2 H), 1.53 (s, 3 H), 1.36 (s, 3 H), 1.12 (s, 3H). LC-MS [M + H]+: m/z 698.7. EXAMPLE 96 Acid(S)-3-(4-(1-(3-aminopropyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-4-yl)-3-fluorophenoxy)-2-(((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2- -yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[00609] The title compound was prepared following the same procedure as Example 32 using the appropriate starting material. LC-MS [M + H]+ : m/z 714.4 EXAMPLE 97 (S)-3-((Z)-2-((( S )-2-(4-(1-(3-Aminopropyl)-2-(azetidin-3-ylmethyl)- 1H-pyrazol-2-io-4-yl)phenoxy)-1-carboxyethoxy)immo)-2-(2-ammothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00610] Step A: tert-Butyl 3-(((((trifluoromethyl)sulfonyl)oxy)methyl)azetidin-1-carboxylate To a solution of tert-butyl 3-(hydroxymethyl)azetidin-1-carboxylate (1.32 g, 7.1 mmol, Example 1, Step C) and Hunig's base (3.1 mL, 18 mmol) in CH2Cl2 (35.4 mL) at -78 °C was added trifluoromethanesulfonic anhydride (1.8 mL, 11 mmol) over 5 min. The internal temperature was maintained between -75 °C and -65 °C during the addition of Tf2O. After 30 min, the reaction was quenched with saturated NaHCO3 solution (30 mL) and allowed to warm to 0 °C. The resulting mixture was partitioned, and the organic layer was washed with brine (10 mL). The aqueous layers were evaporated and evaporated. were re-extracted with CH2Cl2 (15 mL), and the organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound, which was used immediately without further purification.

[00611] Step B: (5)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxo-2-isoindolinyl)oxy)-3-oxopropoxy)phenyl)-1- (3-((tert-butoxycarbonyl)amino)propyl)-2-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-2-ium To a vial containing 3-(( tert-butyl ((trifluoromethyl)sulfonyl)oxy)methyl)azetidin-1-carboxylate (2.3 g, 7.1 mmol), a solution of (5)-3-(4-(1-(3) -((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)- tert-Butyl 2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (3.03 g, 4.30 mmol) from Example 1, Step C in anhydrous CH3CN (43 mL), followed by the addition of solid sodium bicarbonate (3.6 g, 43 mmol). The resulting mixture was heated at 60°C for 2.5 h. Then, solid NaHCO3 was removed by filtration and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography on SiO2 and eluted with hexanes/(EtOAc/EtOH 3:1) 0-100% to obtain the title compound. LC-MS [M + H]: m/z 776.6

[00612] Step C: (S)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1- (3- ((tert-butoxycarbonyl)amino)propyl)-2- ((1 -(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1 H-pyrazol-2-io A a solution of (S)- 4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolino-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino )propyl)-2-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-2-io (1.24 g, 1.6 mmol) in anhydrous MeOH (6.4 mL), 7 N ammonia solution in MeOH (1.8 mL, 12.8 mmol) was added at room temperature. The reaction was stirred for 23 h and then concentrated in vacuo to afford the title compound, which was used immediately in the following reaction. LC-MS [M + H]: m/z 647.5

[00613] Step D: 4-(4-(( 5 )-3-( tert -butoxy)-2-(((Z)-(1-(2-(( tert -butoxycarbonyl)amino)thiazol-4- yl)-2-(((R )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy) phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-((1-(tert-butoxycarbonyl)-azetidin-3-yl)methyl)-1H-pyrazol-2-ium A mixture of (5)-4-(4-(3-(tert-butoxy)-2- ((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-((1-(tert-butoxycarbonyl)azetidin -3-yl)methyl)-1H-pyrazol-2-io (0.12 g, 0.085 mmol) and (5)-3-(2-(2)-((tert-butoxycarbonyl)amino)thiazol-hydrogensulfate 4-yl)-2-oxoacetamido)-2,2-dimethyl-4-oxoazetidin-1-yl (Intermediate 22, 0.071 g, 0.13 mmol) in anhydrous DCE (0.36 mL) and anhydrous MeOH (0. 36 mL), benzenesulfonic acid (4.0 mg, 0.025 mmol) was added. The resulting mixture was stirred at room temperature. After 3 h, the reaction was concentrated in vacuo. The resulting residue was purified by reversed-phase ISCO C18 column (130 g) and eluted with H2O/AcCN (0-100%). fractions were collected and lyophilized to afford the title compound. LC-MS [M + H]: m/z 1093. 1H NMR (500 MHz, DMSO-d6) δ 9.49 (d, J = 7.9 Hz, 1H), 9.01 (s, 1H), 8.90 (s, 1H) , 7.78 - 7.62 (m, 2H), 7.34 (s, 1H), 7.10 - 7.03 (m, 2H), 6.99 (s, 1H), 4.96 (dd, J = 4.6, 3.0 Hz, 1H), 4.71 (d , J = 7.7 Hz, 2H), 4.62 (dd, J = 8.1, 2.3 Hz, 1H), 4.46 (t, J = 7.1 Hz, 2H), 4.41 (dd, J = 10.8, 4.7 Hz, 1H), 4.33 (dd, J = 10.7, 3.0 Hz, 1H), 4.02 (bs, 2H), 3.71 (bs, 2H), 3.29 - 3.12 (m, 1H) , 3.06 (d, J = 6.5 Hz, 2H), 2.06 (dd, J = 12.3, 5.4 Hz, 2H), 1.38-1.48 (multiple s, 35 H), 1.14 (s, 3H).

[00614] Step E: (5 )-3-((Z)-2-(((5 )-2-(4-(1-(3-aminopropyl)-2-(azetidin-3-ylmethyl) sulfate -1H-pyrazol-2-io-4-yl)phenoxy)-1 - carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl To a solution of 4-(4-((S)-3-(tert-butoxy)-2-(((Z)-(1-(2- ((tert-butoxycarbonyl)-amino)thiazol-4-yl )-2-(((R)-2,2-dimethyl-4-oxo-1- (sulfo-oxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-(( 1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-pyrazol-2-ium (1.51 g, 1.4 mmol) in anhydrous CH2Cl2 (3.5 mL) at an internal temperature of 10° C (dry ice/dioxane bath) trifluoroacetic acid (5.3 mL, 69 mmol) was added dropwise over 5 min. The internal temperature was maintained below 11°C during the addition. The bath was removed and the reaction was stirred at room temperature. After 2 h, the reaction was cooled to 0 °C and pipetted dropwise into a cold MTBE solution (-5 °C, 35 mL) under stirring. The resulting solid was collected by vacuum filtration and washed with 35 mL of MTBE divided into 3 portions. The solids were dried under a stream of N2 for 1.5 h. Then, the crude solid was purified 2x by reversed-phase chromatography using a Waters CSH column (50X250 mm, 5 microns, flow rate = 100 mL/ min., eluted with H2O + 8% formic acid/AcCN + 8% formic acid (0%-8% gradient)). The desired fractions were lyophilized to afford the title compound. 1H NMR (500 MHz, deuterium oxide) δ 8.62 (s, 1H), 8.51 (s, 1H), 8.40 (d, J = 1.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 1.1 Hz, 1H), 4.90 (dd, J = 6.3, 2.2 Hz, 1H), 4.82 (d, J = 7.6 Hz, 2H), 4.56 (t, J = 7.5 Hz, 2H), 4.47 (dd, J = 11.7, 2.3 Hz, 1H), 4.44 - 4.36 (m, 2H), 4.29 (dd, J = 9.6, 5.8 Hz, 2H), 4.11 (ddd, J = 10.9, 7.3, 2.3 Hz, 2H), 3.64 (p, J = 8.0 Hz, 1H), 3.17 - 3.06 (m, 2H) , 2.35 (p, J = 7.6 Hz, 2H), 1.36 (s, 3H), 0.99 (s, 3H). EXAMPLE 98 (S)-3-((Z)-2-(((S)-2-(4-(6-((2-aminoethyl)amino)-1-(azetidin-3-ylmethyl)pyridin sulfate -1-io -3-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00615] The title compound was prepared following the same procedure as in Example 97. LC-MS [M + H]: m/z 748.7 EXAMPLE 99 (S)-3-((Z)-2-((( S )-2-(4-(2-((2-aminoethyl)amino)-1-(azetidin-3-ylmethyl)pyrimidin-1-io-5-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00616] The title compound was prepared following the same procedure as in Example 97. LC-MS [M + H]: m/z 749.7 EXAMPLE 100 (S)-3-((Z)-2-(((S)-2-(4-(2-(2-Aminoethyl)-1-(3-aminopropyl)-1H-pyrazol-2-io-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00617] Step A: 2-Bromoethyl trifluoromethanesulfonate Using the procedure described in Example 97, Step A, 2-bromoethanol (0.41 g, 3.3 mmol) was converted to the corresponding triphthlate, which was used without further purification.

[00618] Step B: (5)-2-(2-bromoethyl)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3 -oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-2-io Using the procedure described in Example 97, Step B, (5)-3-(4- tert-Butyl (1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate ( 0.43 g, 0.61 mmol) from Example 1, Step C, was alkylated with 2-bromoethyl trifluoromethanesulfonate to provide the title compound. LC-MS [M + H]: m/z 715.04

[00619] Step C: (5)-2-(2-azidoethyl)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3 -oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-2-io A flask equipped with a stirrer was charged with (5)-2-(2-bromoethyl) -4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl) amino)propyl)-1H-pyrazol-2-io (0.47 g, 0.66 mmol), sodium azide (0.15 g, 2.4 mmol) and DMF anhydrous (3.3 mL). The reaction was heated conventionally on a heating block at 50 °C for 1 h. The reaction was then quenched with the addition of brine and extracted with EtOAc (2x). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by reversed-phase ISCO C18 column (86 g) eluted with H2O/MeCN (0-100%). The desired fractions were collected and partitioned between EtOAc and brine. The aqueous layer was back-extracted with EtOAc (2x). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound. LC-MS [M + H]: m/z 677.3. 1H NMR (500 MHz, Chloroform-d) δ 8.71 (s, 1H), 8.55 (s, 1H), 7.88 (dd, J = 5.4, 3.1 Hz, 2H), 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 7.55 - 7.49 (m, 2H), 6.96 (d, J = 8.6 Hz, 2H), 5.38 (s, 1H), 5.08 (dd, J = 5.4, 3.5 Hz, 1H), 4.77 (t, J = 5.2 Hz, 2H), 4.63 (t, J = 6.9 Hz, 2H), 4.60 - 4.45 (m, 2H), 4.00 (t, J = 5.2 Hz, 2H), 3.29 (s, 2H), 2.21 (q, J = 6.5 Hz, 2H), 1.53 (s, 9H), 1.44 (s, 9H).

[00620] Step D: (S )-4-(4-(2-(amino-oxy)-3-(tert-butoxy)-3-oxopropoxy)feml)-2-(2-azidoethyl)-1-( 3-((tert)-butoxycarboml)amino)propyl)- 1H-pyrazol-2-io The title compound was prepared from (S)-2-(2-azidoethyl)- 4-(4-(3-(tert -butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)-phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-2 -io (0.31 g, 0.45 mmol) using the procedure described in Example 97, Step C. LC-MS [M + H]: m/z 547.2

[00621] Step E: (S,Z)-2-(2-azidoethyl)-4-(4-(3-(tert-butoxy)-2-((((2- ((tert-butoxycarbonyl)-amino )thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1 H-pyrazol-2-ium A solution of (S)-4-(4-(2-(amino-oxy)-3-(tert-butoxy)-3-oxo-propoxy)phenyl)-2-(2-azidoethyl)-1-(3- ((tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-2-ium (0.25 g, 0.45 mmol) in anhydrous DCE (1.8 ml) and anhydrous MeOH (1.8 ml), 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (0.25 g, 0.90 mmol, Intermediate 5) was added. The reaction was stirred at room temperature for 21 h. Then, the reaction was concentrated in vacuo and purified by reversed-phase ISCO C18 column (130 g), eluting with H2O/MeCN (0-100%). The desired fractions were collected and lyophilized to afford the title compound. LC-MS [M + H]: m/z 800.4

[00622] Step F: (S,Z)-4-(4-(3-( tert -butoxy)-2-((((2-(( tert -butoxycarbonyl)amino)thiazol-4-yl)(carboxy )methylene)amino)oxy)-3-oxopropoxy)phenyl)-2-(2-((tert-butoxycarbonyl)-amino)ethyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H- pyrazol-2-io To a solution of (S,Z)-2-(2-azidoethyl)-4-(4-(3-(tert-butoxy)-2-((((2-((tert-butoxycarbonyl )amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-1-(3-((tert- (1H-pyrazol-2-yl) (0.19 g, 0.24 mmol) and BOC2O (0.052 g, 0.24 mmol) in THF (2.4 mL) were added 10 % Pd/C (0.038 g). The mixture was hydrogenated under atmospheric H2 for 1 h. Then, the catalyst was removed by filtration through Celite™ and the Celite™ plug was washed well with EtOAc. The filtrate was concentrated in vacuum to afford the title compound, which was used in the next step without further purification. LC-MS [M + H]: m/z 875.5

[00623] Step G: 4-(4-(( 5 )-3-( tert -butoxy)-2-(((Z)-(1-(2-(( tert -butoxycarbonyl)amino)thiazol-4- il)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfoxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy) phenyl)-2- (2-((tert-butoxycarbonyl)amino)ethyl)-1-(3-((tert-butoxycarbonyl)-amino)propyl)-1 H-pyrazol-2-io A a mixture of (S ,Z)-4-(4-(3-(terc- butoxy)-2-((((2-((tert-butoxycarbonyl)amino)thiazol-4-yl)(carboxy)methylene)amino)oxy)-3-oxopropoxy)phenyl)-2-(2-((tert -butoxycarbonyl)amino)ethyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-2-io (0.21 g, 0.24 mmol) in anhydrous MeCN (2.1 ml ), (S)-3-amino-2,2-dimethyl-4-oxoazetidin-1-yl hydrogensulfate (0.093 g, 0.36 mmol, commercial sources CAS: 102507-49-3) and pyridine ( 0.048 ml, 0.59 mmol) under N2 at room temperature. The reaction mixture was cooled to 0 °C, and EDC-HCl (0.091 g, 0.47 mmol) was added in one portion. After 1 h, the reaction was partitioned between EtOAc and a 1:1 mixture of aqueous 0.5 M citric acid and brine. The aqueous layer was back-extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by reversed-phase ISCO C18 column (86 g) and eluted with H2O/MeCN (0-100%). The desired fractions were collected and concentrated in vacuo. The resulting wet residue was partitioned between EtOAc/AcCN (4:1) and brine containing solid NaCl. The aqueous layer was back-extracted with EtOAc . The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound. LC-MS [M + H]: m/z 1066.9

[00624] Step H: 2-(2-aminoethyl)-1-(3-aminopropyl)-4-(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-carboxyethoxy)phenyl)-1H-pyrazole-2-ium Using the procedure described in Example 97, Step E, a 1:2 mixture of DCM/TFA (1.66 mL) was used, and the reaction mixture was stirred for 1 h at room temperature. 4-(4-((S)-3-(tert-butoxy)-2-(((Z)-(1-(2-((tert-butoxycarbonyl)-amino)thiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-3-oxopropoxy)phenyl)-2-(2-((tert-butoxycarbonyl)amino)ethyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-2-ium (0.179 g, 0.168 mmol) was worked up to the final product, followed by purification using reversed phase chromatography using Waters CSH column (50X250 mm, 5 micrometer, flow rate = 100 mL/min., eluting with H2O + 8% formic acid/AcCN + 8% formic acid (gradient 0%-10%)) to afford the title compound. LC-MS [M+1]: m/z 710.2 1H NMR (500 MHz, Deuterium Oxide) δ 8.67 (dd, J = 14.9, 1.2 Hz, 2H), 8.38 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 6.91 (s, 1H), 4.88 (dt, J = 13.2, 5.9 Hz, 3H), 4.60 (t, J = 7.5 Hz, 2H), 4.50 - 4.31 (m, 3H), 3.61 (t, J = 6.5 Hz, 2H), 3.22 - 3.06 (m, 2H), 2.39 (p, J = 7.6 Hz, 2H), 1.38 (s, 3H), 1.00 (s, 3H). EXAMPLE 101 (S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((S)-1-carboxy-2-(4-(1-(3- ((S)-2,3-dihydroxypropyl)amino)propyl)-2-methyl-1H-pyrazol-2-io-4- sulfate) 4-oxoazetidin-1-yl HQ or

[00625] To a solution of (S)-3-((E)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfonate (50 mg, 0.073 mmol, Example 1) in DMSO (1 mL) was added (R)-2,3-dihydroxypropanal (9.9 mg, 0.11 mmol). The mixture was stirred at room temperature for 1 h and then sodium triacetoxyborohydride (23 mg, 0.11 mmol) was added. The mixture was stirred at room temperature overnight. The DMSO solution was then injected directly into preparative HPLC for separation (Gilson, water/MeCN/0.05% TFA, 0-40% in 10 min). The first collected peak was combined and lyophilized to afford the title compound. LC-MS [M+H]: m/z 755.10. 1H NMR (500 MHz, D2O) δ 8.52 (s, 1H); 8.48 (s, 1H); 7.48 (d, J=6.8 Hz, 2H); 6.98 (s, 1H); 6.94 (d, J=6.8, 2H); 5.01 (s, 1H); 4.48 (m, 2H); 4.38 (m, 2H);4.02 (s, 3H); 3.06-3.65 (m, 7H); 2.39 (m, 2H); 1.25 (s, 3H); 0.98 (s, 3H). EXAMPLE 102 (S)-3-((E)-2-(((S)-2-(4-(1-(3-((2-aminoethyl)amino)propyl)-2-methyl-1H-pyrazol-2-yn-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoa zetidin-1-yl

[00626] To a solution of Example 1 (50 mg, 0.073 mmol) in DMSO (1 mL), tert-butyl (2-oxoethyl)carbamate (18 mg, 0.11 mmol) and TFA (0.1 mL) were added. The mixture was stirred at rt for 1 h, then sodium triacetoxyborohydride (17 mg, 0.081 mmol) was added. The resulting mixture was stirred at rt overnight. The DMSO solution was then injected directly into the prep HPLC for separation (Gilson, water/MeCN/0.05% TFA, 0-40% in 10 min). The first collected peak was lyophilized to afford a crude product, which was dissolved in DCM (1 mL) with 0.2 mL of TFA. The resulting mixture was stirred at room temperature for 30 min and then concentrated to dryness. The resulting residue was redissolved in 0.5 mL of DMSO and injected into Prep HPLC for separation (Gilson, water/MeCN/0.05% TFA, 0–40% in 10 min). The product peak was collected and lyophilized to afford the title compound as a TFA salt. LC-MS [M + H]: m/z 724.08. 1H NMR (500 MHz, D2O) δ 8.55 (s, 1 H); 8.52 (s, 1 H); 7.42 (d, J=8, 2H); 7.07 (s, 2H); 7.00 (d, J=8, 2H); 5.15 (s, 1H); 4.56 (m, 4H); 4.19 (s, 3H); 3.46 (m, 6H); 2.46 (m, 2 H); 1.53 (s, 3H); 1.29 (s, 3H). Table 5. Examples 103 and 104 were prepared according to the procedure for Example 101. Example Name Structure LCMS [M+H] 103 (S )-3-((E)-2-(2-aminothiazol-4-yl)-2-((( S )-2-(4-(1-(3-((azetidin-3-ylmethyl)amino)propyl)-2-methyl-1 H-pyrazol-2-io-4-yl)phenoxy)-1-carboxyethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate, 3TFA r—NH EXAMPLE 105 (S)-3-((Z)-2-((((S)-1-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)-3-fluorophenoxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoa sulfate zetidin-1 -yl

[00627] The title compound was prepared following procedures similar to those described in Example 39 starting from Intermediate 14. LC-MS [M+H]: m/z 713.5. EXAMPLE 106 (S)-3-((Z)-2-(((S)-2-((6-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)pyridazin-3-yl)oxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00628] The title compound was prepared following procedures similar to those described in Example 1 starting from Intermediate 12. LC-MS [M + H]: m/z 683.3. EXAMPLE 107 (S)-3-((Z)-2-(((( S )-1-(4-(1-(3-aminopropyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-carboxy-propan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00629] The title compound was prepared following procedures similar to those described in Example 39 starting from Intermediate 10. LC-MS [M+H]: m/z 728.3. EXAMPLE 108 (S)-3-((Z)-2-(2-Aminothiazol-4-yl)-2-(((S)-2-((6-((1-(azetidin-3-ylmethyl)pyridin-1-io-4-yl)amino)pyridin-3-yl)oxy)-1-carboxyethoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00630] The title compound was prepared following procedures similar to Example 33. LC-MS [M + H]: m/z 706.6. Table 6. Examples 109-112 were prepared using procedures similar to the procedures used for the synthesis of EXAMPLE 113 (5 )-3-((Z)-2-(((( 5 )-1-((6-(3-(3-aminopropyl)-1H-imidazol-3-yl-1-yl)pyridin-3-yl)oxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-sulfate oxoazetidin-1-yl

[00631 ] Step A: (5 )-3-((6-bromopyridin-3-yl)oxy)-2-hydroxy-2-methylpropanoate tert-Butyl N,N’-diisopropylcarbamidate (380 μL, 1.63 mmol) was added to a stirred solution of (5 )-3-((6-bromopyridin-3-yl)oxy)-2-hydroxy-2-methylpropanoic acid (180 mg, 0.65 mmol) in THF (6.5 mL). The resulting mixture was heated at 60 °C for 1 h, then the reaction was cooled to rt and concentrated in vacuo. Purification of the resulting crude residue by column chromatography on silica gel (0-50% EtOAc in hexanes as eluent) afforded the title compound. LC-MS [M + H]: m/z 332.1.

[00632] Step B: tert-Butyl (5 )-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-hydroxy-2-methylpropanoate The title compound was prepared following similar procedures as in Example 36, Step E. LC-MS [M + H]: m/z 320.2.

[00633] Step C: tert-Butyl (5)-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-(aminooxy)-2-methylpropanoate To a stirred solution of tert-butyl (5)-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-hydroxy-2-methylpropanoate (100 mg, 0.313 mmol) in THF (3.1 mL) at 0 °C, was added NaH (22.5 mg of a 60% dispersion in mineral oil, 0.56 mmol) in one portion. The resulting mixture was allowed to stir at 0 °C for 15 min, at which time, O-(mesitylsulfonyl)-hydroxylamine (74 mg, 0.344 mmol) was added, and the mixture was stirred at 0 °C for 1 h. Then, the reaction mixture was partitioned between EtOAc and water. The layers were separated, and the organic layer was washed with water and brine. The organic layers were further dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to afford a crude residue that was purified by column chromatography on silica gel (0–10% CH 3 OH in DCM as eluent) to afford the title compound. LC-MS [M + H]: m/z 335.2.

[00634] Step D: tert-Butyl (5)-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((1,3-dioxoisoindolin-2-yl)oxy-2-methylpropanoate To a stirred solution of tert-butyl (5)-3-((6-(1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-(aminooxy)-2-methylpropanoate (62 mg, 0.185 mmol) in toluene (1.9 mL) was added phthalic anhydride (33 mg, 0.223 mmol), followed by a small amount of 3 Å molecular sieves. p-Toluenesulfonic acid polymer (16 mg of 2-3 mmol/g beads, 0.032-0.048 mmol) was added, and the The resulting mixture was heated to 100 °C. After 2 h, the reaction mixture was cooled to rt and concentrated in vacuo to afford a suspension that was purified by column chromatography on silica gel (0-10% CH3OH in DCM as eluent) to afford the title compound. LC-MS [M + H]: m/z 465.3.

[00635] Step E: (5 )-1-(5-(3-( tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methyl-3-oxo-propoxy)pyridin-2-yl)-3-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-imidazole-3-ium The title compound was prepared following similar procedures as in Example 35, Step F. LC-MS [M + H]: m/z 509.2.

[00636] Step F: (5)-3-((Z)-2-((((5)-1-((6-(3-(3-aminopropyl)-1H-imidazol-3-ium sulfate -1-yl)pyridin-3-yl)oxy)-2-carboxypropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin - 1-yl, was prepared from (5)-1-(5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methyl-3 -oxopropoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-3-ium following procedures similar to those described in Example 36, GJ steps. LC-MS [M + H]: m/z 682.2. EXAMPLE 114 (S)-3-((Z)-2-((((S)-1-amino-3-(4-(1-(3-aminopropyl)-2-imino-3-methyl-sulfate 2,3-dihydro-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)- 2-(2-aminothiazol-4-yl)acetamido)-2,2- dimethyl-4-oxoazetidin-1-yl

[00637] Step A: Ethyl (R,E)-3-(4-(1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-(( tert -butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-hydroxypropanoate The title compound was prepared following similar procedures to those described in Example 1, Step B. LC-MS [M + H]: m/z 563.6.

[00638] Step B: Ethyl (S,Z)-3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-2-(( tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate The title compound was prepared following similar procedures to those described in Example 1, Step C. LC-MS [M + H]: m/z 708.4.

[00639] Step C: (S,Z)-(4-(4-(3-amino-2-(aminooxy)-3-oxopropoxy)phenyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-3-methyl-1,3-dihydro-2H-tert -butyl imidazol-2-ylidene)carbamate Ammonia (0.65 mL of a 7.0 M CH 3 OH solution, 4.54 mmol) was added to a stirred solution of (S,Z)-3-(4-(1-(3-(( tert -butoxycarbonyl)amino)propyl)-2-(( tert -butoxycarbonyl)-imino)-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)ethyl propanoate (107 mg, 0.151 mmol) in CH3OH (2.0 mL). The reaction was sealed and allowed to stir at rt overnight. Then, the reaction mixture was concentrated in vacuo and the resulting crude residue was purified by reverse-phase chromatography on C-18 silica (0-100% CH3CN in water as eluent) to afford the title compound. LC-MS [M + H]: m/z 549.3.

[00640] Step D: (5 )-3-((Z)-2-(((( 5 )-1-amino-3-(4-(1-(3-aminopropyl)-2-imino-sulfate 3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)-acetamido) -2,2-dimethyl-4-oxoazetidin-1-yl The title compound was prepared from (S,Z)-(4- (4-(3-amino-2-(amino-oxy)-3- oxopropoxyl)phenyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate tert-butyl following the procedures described in Example 1, Steps FH. LC-MS [M + H]: m/z 695.7. EXAMPLE 115 (5)-3-((Z)-2-((((5)-3-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-ium sulfate -4-yl)phenoxy)-1-ethoxy-1-oxopropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1 -ila

[00641] The title compound was prepared from intermediate 11 following the procedures described in Example 1, Steps BH. LC-MS [M + H]: m/z 709.5. EXAMPLE 116 Ethyl (S)-3-(4-(1-(3-aminopropyl)-2-imino-3-methyl-2,3-dihydro-1H-imidazol-4-yl)phenoxy)-2-(( (Z)-1-(2-aminothiazol-4-yl)-2-( ((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoate

[00642] The title compound was prepared from intermediate 13 following procedures similar to those described in Example 114, Steps AB and Example 1, Steps FH. LC-MS [M + H]: m/z 724.6. EXAMPLE 117 (S)-3-((Z)-2-((((S)-3-(4-(1-(3-aminopropyl)-2-methyl-1H-pyrazol-2-io-4-yl)phenoxy)-1-methoxy-1-oxopropan-2-yl)oxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate

[00643] The title compound was prepared from Intermediate 15 following the procedures described in Example 1, Steps BH. LC-MS [M + H]: m/z 695.4. EXAMPLE 118 (S)-3-((6-(3-(3-aminopropyl)-2-imino-2,3-dihydro-1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((( S )-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid

[00644] Step A: (S,E)-tert-butyl 3-((6-(3-(3-(( tert -butoxycarbonyl)amino)propyl)-2-(( tert -butoxycarbonyl)imino)-2,3-dihydro-1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate tert-Butyl hypochlorite (250 μL, 2.22 mmol) was added to a mixture of tert-butyl carbamate (229 mg, 1.95 mmol) in DCM (6.0 mL). The resulting mixture was stirred at rt for 30 min, then the mixture was cooled to 0 °C and DBU (402 μL, 2.66 mmol) was added. To this stirred mixture was added a solution of (S)-1-(5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)-3-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazole-3-ium (541 mg, 0.888 mmol from Example 36, step F) in DCM (6.0 mL). The reaction mixture was stirred at 0 °C for 1 h, then the mixture was suspended in benzene. The resulting mixture was loaded onto a silica column and purified by column chromatography (0-7% CH3OH in DCM as eluent) to afford the title compound. LC-MS [M + H]: m/z 723.6.

[00645] Steps BE: (S)-3-((6-(3-(3-Aminopropyl)-2-imino-2,3-dihydro-1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-(( ((Z)-1-(2-aminothiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid The title compound was prepared following procedures similar to those described in Example 36, Steps GJ. LC-MS [M + H]: m/z 683.4. EXAMPLE 119 (S)-3-((Z)-2-(((S)-2-(4-(1-(3-aminopropyl)-2-((3-fluoroazetidin-3-yl)methyl)-1H-pyrazol-2-yl-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4 sulfate -oxoazetidin-1 -il

[00646] Step A: (R )-3-((4-(4-(3-(tert-butoxy)-2-hydroxy-3-oxopropoxy)phenyl)-1H-pyrazol-1-yl)methyl)- tert-butyl 3-fluoroazetidin-1-carboxylate

[00647] The title compound was prepared from Intermediate 4 following procedures similar to those described in Example 1, Step B, substituting Intermediate 13 with tert-butyl (3-(4-bromo-1H-pyrazol-1-yl))propyl)carbamate. Intermediate 16. LC-MS [M + H]: m/z 492.5.

[00648] Step B: (S )-3-((4-(4-(3-( tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-1H-pyrazol-1-yl)methyl)-3- tert-butyl fluoroazetidin-1-carboxylate The title compound was prepared following similar procedures to those described in Example 1, Step C. LC-MS [M + H]: m/z 637.6.

[00649] Step C: (S )-2-(3-azidopropyl)-4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3 -oxopropoxy)phenyl)-1-((1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl)-1H-pyrazol-2-io Intermediate 17 (406 mg, 1.74 mmol) was added to a stirred solution of (S)-3-((4-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)- tert-butyl 1H-pyrazol-1-yl)methyl)-3-fluoroazetidin-1-carboxylate (300 mg, 0.471 mmol) and sodium bicarbonate (396 mg, 4.71 mmol) in acetonitrile (5.0 mL). The resulting suspension was heated to 60 °C, and after 30 min, the reaction mixture was filtered through a Celite™ pad . The column was washed with acetonitrile and the combined organic layers were concentrated in vacuo. The resulting crude residue was triturated with DCM and ether, and purified by column chromatography on silica gel (0-100% (EtOAc:EtOH 3:1 ) in hexanes as eluent) to afford the title compound.

[00650] Steps D-F: (S)-3-((Z)-2-(((( S )-3-(4-(1-(3-azidopropyl)-2-((1-( tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl)-1H-pyrazol-2-yl-4-yl)phenoxy)-1-( tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate The title compound was prepared following the procedures described in Example 1, Steps EG.

[00651] Step G: (S )-3-((Z)-2-((((S)-3-(4-(1-(3-aminopropyl)-2-((1-(terc) sulfate -butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl)-1H-pyrazol-2-yl-4-yl)phenoxy)-1-(tert-butoxy)-1-oxopropan-2-yl)oxy)imino )-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl A stirred solution of (S)-3-( (Z)-2-((((S)-3- (4-(1-(3-azidopropyl)-2-((1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl)-1H-pyrazol-2-io-4-yl)phenoxy)- 1-(tert-butoxy)-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2,2-dimethyl-4 -oxoazetidin-1-yl (50 mg, 0.048 mmol) in 2,2,2-trifluoroethanol (2.0 mL) was degassed three times under house vacuum, backfilling with nitrogen gas in each iteration. To this mixture was added 10% of palladium on carbon (5.0 mg, 4.70 mmol), and the resulting mixture was degassed as described above, filling with hydrogen gas. After 2 h, the reaction mixture was filtered through a Celite™ pad, washing the column with CH3OH. The combined organic layers were concentrated in vacuo to afford the title compound, which was carried on without purification.

[00652] Step H: (S)-3-((Z)-2-((( S )-2-(4-(1-(3-aminopropyl)-2-( (3-fluoroazetidin-3-yl)methyl)-1H-pyrazol-2-yl-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate The title compound was prepared following the procedures described in Example 1, Step H. LC-MS [M + H]: m/z 755.2 EXAMPLE 120 (S )-3-((Z)-2-((( S )-2-(4-(2-(3-amino-2-fluoro-2,3-propyl)-1-(3-aminopropyl)-1 H-pyrazol-2-io-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl

[00653] Step A: tert-Butyl (2R)-3-(4-(1-(3-(( tert-butoxycarbonyl)amino)-2-fluoropropyl)-1H-pyrazol-4-yl)phenoxy)-2-hydroxypropanoate The title compound was prepared as a mixture of stereoisomers of Intermediate 4 following procedures similar to those described in Example 1, Step B, substituting Intermediate 15 with tert-butyl (3-(4-bromo-1H-pyrazol-1-yl)propyl)carbamate. Step B: Separation of stereoisomers of (2R)-3-(4-(1-(3-(( tert -butoxycarbonyl)amino)-2-fluoropropyl)-1H-pyrazol-4-yl)phenoxy)2-hydroxypropanoate tert -butyl The stereoisomers of (2R)-3-(4-(1-(3-(( tert -butoxycarbonyl)amino)-2-fluoropropyl)-1H-pyrazol-4-yl)phenoxy)-2-hydroxypropanoate tert -butyl were separated using preparative supercritical fluid chromatography. A solution of tert-butyl (2R)-3-(4-(1-(3-((tert-butoxycarbonyl)amino)-2-fluoropropyl)-1H-pyrazol-4-yl)phenoxy)-2-hydroxypropanoate (260 mg) in methanol (20 mL) was injected (40 × 0.5 mL) onto a Chiralpak® AD-H (available from Chiral Technologies, Inc., Exton, Pa.) semi-preparative HPLC column (250 × 21 mm) (eluting with 40% (EtOH + 0.2% diisopropylamine)/CO2 at 70 mL/min, 120 bar (12 MPa) outlet pressure with UV detection at 215 nm) to afford a faster eluting enantiomer B-1 (retention time = 2.4 min) and a faster eluting enantiomer B-2 slower (retention time = 3.1 min) using analytical chiral HPLC conditions: Chiralpak® AD-H (available from Chiral Technologies, Inc., Exton, Pa.) semi-preparative HPLC column (250 x 4.6 mm) (eluting with 40% (EtOH + 0.1% diisopropylamine)/CO2 at 120 bar (12 MPa) outlet pressure with UV detection at 254 nm).

[00654] Step C: (S)-3-((Z)-2-(((S)-2-(4-(2-(3-amino-2-fluoro-2'-3-propyl)-1-(3-aminopropyl)-1H-pyrazol-2-yl-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate The title compound was prepared from intermediate B-2 of Step B following procedures similar to those described in Example 1, Steps CH. (S )-3-((Z)-2-(((S)-2-(4-(2-(3-amino-2-fluoro-2X3-propyl)-1-(azetidin-3-ylmethyl)-1H-pyrazol-2-yl-4-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2- zetidin-1 -yl

[00655] The title compound was prepared from Intermediate 20 following procedures similar to those described in Example 119, Steps B-HEXAMPLES 122 and 123 (S )-3-((Z)-2-( ((S )-2-(4-(3-((3-aminopropyl)amino)-1-methylpyridazin-1-io-6-yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl sulfate (122) and (S )-3-((Z)-2-(((S )-2-(4-(6-((3-aminopropyl)amino)-1-methylpyridazin-1-io-3-yl)phenoxy)- 1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl (123)

[00656] Step A: tert-Butyl (R)-3-(4-(6-((3-(( tert-butoxycarbonyl)amino)propyl)amino)pyridazin-3-yl)phenoxy)-2-hydroxypropanoate The title compound was prepared from Intermediate 4 following similar procedures as described in Example 1, Step B. Step B: tert-Butyl (R)-3-(4-(6-((3-(( tert-butoxycarbonyl)amino)propyl)amino)pyridazin-3-yl)phenoxy)-2-(( 1,3-dioxoisoindolin-2-yl)oxy)propanoate The title compound was prepared from tert-Butyl (R)-3-(4-(6-((3-(( tert-butoxycarbonyl)amino)propyl)amino)pyridazin-3-yl)phenoxy)-2-hydroxypropanoate tert-butyl following procedures similar to those described in Example 1, Step C. Step C: (R)-6-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-3-((3-((tert-butoxycarbonyl)amino)propyl)amino)-1-methylpyridazin-1-ium (C-1); and (R)-3-(4-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)phenyl)-6-((3-(tert-butoxycarbonyl)amino)propyl)amino)-1-methylpyridazin-1-ium (C-2)

[00657] The title compounds were prepared as a mixture of regioisomers of (R)-3-(4-(6-((3-((tert-butoxycarbonyl)amino)propyl)amino)pyridazin-3-yl)phenoxy)-2-((1,3-dioxo-isoindolin-2-yl)oxy)propanoate tert-butyl, following procedures similar to those described in Example 1, Step D. The crude mixture of regioisomers was separated by column chromatography on silica gel (0-5% CH3OH in DCM as eluent) to afford intermediates H1 and H2. H1:

[00658] (S )-3-((Z)-2-(((S)-2-(4-(3-((3-aminopropyl) amino)-i-methylpyridazin-i-io-6 sulfate -yl)phenoxy)-( í -carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-yl (í 22) The title compound was prepared from compound Hí, following procedures described in Example í, Steps E-H.

[00659] (S )-3-((Z)-2-(((S)-2-(4-(6-((3-aminopropyl) amino)-i-methylpyridazin-i-io-3 sulfate -yl)phenoxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-yl (23) The title compound was prepared from compound H2, following procedures described in Example 1, Steps EH. EXAMPLE 124 (S )-3-((Z)-2-(((S )-2-((6-(4-(3-aminopropyl)-3-((3-fluoroazetidin-3-yl) sulfate methyl)-1H-imidazol-3-io-1-yl)pyridin-3-yl)oxy)-1-carboxyethoxy)imino)-2-(2-aminothiazol-4-yl)acetamido)-2,2-dimethyl -4-oxoazetidin-1-yl

[00660] Step A: (R )-3-((6-(4-(3-(( tert-butoxycarbonyl)amino)propyl)-1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy) tert-butyl propanoate The title compound was prepared from tert-butyl (R)-3-((6-bromopyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (Example 36, step D) following procedures similar to those described in Example 35, step C. Steps BC: (S )-3-((6(4-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-1-yl)pyridin-3- The title compound was prepared from (R)-3-((6-(4-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((tert-butyldimethylsilyl)oxy)propanoate following procedures similar to those described in Example 36, Steps F and G. Step D: (S)-1-(5(3-( tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)-3-((1-( tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl)-4-(3-(( tert - The title compound was prepared from (S)-3-((6-(4-(3-((tert-butoxycarbonyl)amino)propyl)-1H-imidazol-1-yl)pyridin-3-yl)oxy)-2-((1,3-dioxoisoindolin-2-yl)oxy) tert-butyl propanoate following procedures similar to those described in Example 36, Step H. 4-(3-Aminopropyl)-1-(5-(( S )-2-((((Z)-1-(2-aminothiazol-4-yl)-2-((( S )-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3- The title compound was prepared from (S)-1-(5-(3-(tert-butoxy)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-oxopropoxy)pyridin-2-yl)-3-((1-(tert-butoxycarbonyl)-3-fluoroazetidin-3-yl)methyl)-4-(3-((1-tert-butoxycarbonyl)amino)propyl)-1H-imidazole-3-ium following procedures similar to those described in Example 1, Steps EH. LC-MS [M+]: m/z 755.5. example amino)-2-oxoethylidene)amino)oxy)propanoic

[00661] Step A: (R)-4-(3-( tert-butoxy)-2-hydroxy-3-oxopropoxy) methyl benzoate A mixture of tert-butyl oxirane-2-carboxylate (2.1 g, 14.5 mmol), methyl 4-hydroxybenzoate (1 g, 6.6 mmol), molecular sieves (0.1 g), and (R,R) co-catalyst (0.28 g, 0.33 mmol) in t-BuOMe (2.2 mL) was stirred at rt for 4 days. Then the reaction mixture was filtered through Celite™, the filtrate was concentrated, and the resulting residue was purified on a silica gel column (220 g) using 0-30% EtOAc/hexane to afford the title compound. LC/MS: m/e 319.34 [M+Na]+.

[00662] Step B: Methyl (R)-4-(3-(tert-butoxy)-2-((tert-butyldimethylsilyl)oxy)-3-oxopropoxy)-benzoate To a solution of (R)-methyl 4-(3-(tert-butoxy)-2-hydroxy-3-oxopropoxy)benzoate (1.38 g, 4.7 mmol) and imidazole (0.79 g, 11.6 mmol) in DCM (47 mL) was added TBDMS-Cl (0.84 g, 5.6 mmol) at RT. The reaction was stirred at room temperature overnight and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified on a silica gel column (220 g) using 0-10% EtOAc/hexane to afford the title compound. LC/MS: m/e 433.21 [M+Na]+.

[00663] Step C: tert-Butyl (R)-2-(( tert-butyldimethylsilyl)oxy)-3-(4-(methoxy(methyl)carbamoyl)phenoxy)propanoate To a 0 °C solution of (R)-methyl 4-(3-(tert-butoxy)-2-((tert-butyldimethylsilyl)oxy)-3-oxopropoxy)benzoate (1.9 g, 4.7 mmol) and Weinreb amide (0.96 g, 9.9 mmol) in THF (47 mL) was added dropwise iPrMgCl solution (6.5 mL, 19 mmol, 2.9 M) while maintaining the internal temperature below 5 °C. The reaction mixture was stirred at 0 °C for 3 h and then quenched with aqueous NH 4 Cl. The reaction mixture was extracted with EtOAc (3x), dried over MgSO4, filtered, and concentrated. The resulting residue was purified on a silica gel column (80 g) using 0-30% EtOAc/hexane to afford the title compound. LC/MS: m/e 440.23 [M+H]+.

[00664] Step D: (R )-3-(4-(4-(benzyloxy)but-2-ynoyl)phenoxy)-2-(( tert -butyldimethylsilyl)oxy)propanoate To a solution of ((prop-2-yn-1-yloxy)methyl)benzene (1.87 g, 12.8 mmol) in THF (12 mL) at -78°C was added butyllithium (4.26 mL, 10.6 mmol)(2.5M/hexane). The reaction mixture was stirred at -78 °C for 1 h, then added dropwise via syringe to a solution of (R)-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-3-(4-(methoxy-(methyl)carbamoyl)phenoxy)propanoate (1.56 g, 3.6 mmol) in THF (5 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min and at 0 °C for 30 min. Then, the reaction was quenched with saturated NH4Cl solution and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The resulting residue was purified on a silica gel column (40 g) using 0-30% EtOAc/hexane to afford the title compound. LC/MS: m/e 525.23 [M+H]+.

[00665] Step E: (R)-3-(4-(5-((benzyloxy)methyl)-1H-pyrazol-3-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate A solution of (R)-tert-butyl 3-(4-(4-(benzyloxy)-but-2-ynno)-phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (1.16 g, 2.2 mmol) and hydrazine (0.35 mL, 11 mmol) in EtOH (22 mL) was heated at 80 °C for 1 h. Then, the reaction mixture was concentrated to dryness and purified on a silica gel column (80 g) using 0-30% EtOAc/hexane to afford the title compound. LC/MS: m/e 539.25 [M+H]+.

[00666] Step F: (R )-3-(4-(5-((benzyloxy)methyl)-1-(3-(( tert -butoxycarbonyl)amino)-propyl)-1H-pyrazol-3-yl) tert-butyl phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate A solution of 3-(4-(5-((benzyloxy)methyl)-1H-pyrazol-3-yl)phenoxy)-2- (R)-tert-Butyl((tert-butyldimethylsilyl)oxy)propanoate (1.11 g, 2.1 mmol), tert-butyl(3-bromopropyl)carbamate (0.49 g, 2.1 mmol) and Cs2CO3 (1.0 g, 3.1 mmol) in DMF (4.12 mL) was stirred at room temperature overnight. Then the reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine (3x), dried over MgSO4 and concentrated. The resulting residue was purified on a silica gel column (120 g) using 0-30% EtOAc/hexane to afford the title compound. LC/MS: m/e 696.37 [M+H]+.

[00667] Step G: (R)-3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-5-(hydroxymethyl)-1H-pyrazol-3-yl)phenoxy)-2-(( tert-butyldimethylsilyl)oxy)propanoate A mixture of (R)-tert-butyl 3-(4-(5-((benzyloxy)methyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-3-yl)phenoxy)-2-(( tert-butyldimethylsilyl)oxy)propanoate (810 mg, 1.16 mmol) and Pd/C (82 mg, 0.077 mmol) in MeOH (5.8 mL) was stirred under balloon H2 at rt overnight. TLC showed complete reaction. It was filtered through a Celite™ pad and concentrated to dryness to afford the title compound. LC/MS: m/e 606.32 [M+H]+.

[00668] Step H: (R )-3-(4-(1-(3-(( tert-butoxycarbonyl)amino) propyl)-5-formyl-1 H-pyrazol-3-yl)phenoxy)-2- (tert-butyl)(tert-butyldimethylsilyl)oxy)propanoate tert-butyl A a solution of 3-(4-(1- (3-((tert-butoxycarbonyl)amino)propyl)-5-(hydroxymethyl)-1H (R)-tert-Butyl-pyrazol-3-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (590 mg, 0.97 mmol) in DCM (9.7 mL) at 0°C Dess-martin periodinane (434 mg, 1.02 mmol) was added. After addition, the reaction mixture was warmed to RT and stirred for approx. 2 hours. The reaction mixture was quenched with 5% Na2S2O3 solution. The mixture was extracted with EtOAc (3x), and the combined organic layers were washed with saturated NaHCO3 and brine, dried over MgSO4, concentrated in vacuo and purified on a silica gel column (40 g) using 0-30% EtOAc/hexane to afford the title compound. LC/MS: m/e 604.30 [M+H]+.

[00669] Step I: (R )-3-(4-(5-(((2-(( tert-butoxycarbonyl)amino) ethyl)amino)methyl)-1 -(3-(( tert-butoxycarbonyl)amino tert-butyl)propyl)-1H-pyrazol-3 - yl)phenoxy)-2-((tert-butyldimethylsilyl)-oxy)propanoate A solution of 3-(4-(1-(3-(tert-butoxycarbonyl (R)-tert-butyl)amino)-propyl)-5-formyl-1H-pyrazol-3-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)propanoate (203 mg, 0.34 mmol) and N-boc-ethylenediamine hydrochloride (99 mg, 0.50 mmol) in THF (1.7 mL) at temperature At room temperature, triethylamine (70 μL, 0.50 mmol) and MgSO4 were added. The reaction was stirred at rt for 16 h, filtered, and concentrated. The resulting residue was redissolved in MeOH (1.7 mL), then boron was added -sodium hydride (12.7 mg, 0.34 mmol) and the reaction was stirred at rt for 2 h. The reaction mixture was partitioned between EtOAc and H2O. Then the aqueous layer was extracted with EtOAc (3x), washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified on a silica gel column (24 g) using 0-100% EtOAc/hexane to afford the title compound. LC/MS: m/e 748.46 [M+H]+.

[00670] Step J: (R )-3-(4-(5-(( tert-butoxycarbonyl)(2-(( tert -butoxycarbonyl)amino)-ethyl)amino)methyl)-1-(3-( ( tert-biyloxycarbonibamino)propyl)-1H-pyrazol-3-yl)phenoxy)-2-((tert-butyldimethylsilyl)oxy)tert-butylpropanoate The solution of 3-(4-(5-(((2- ((tert-buloxycarbonyl)amino)helyl)amino)methyl)-1-(3-((tert-bitoxycarbonyl)amino)propyl)-1H-pyrazol-3-yl)phenoxy)-2-((tert-butyldimethylsilyl) (R)-tert-butyl oxy)propanoate (290 mg, 0.39 mmol), BOC2O (0.18 ml, 0.78 mmol) and TEA (0.16 ml, 1.16 mmol) in THF (10 ml) was stirred at rt overnight, diluted with H2O, extracted with EtOAc (3x), washed with brine, dried in MgSO4, filtered, concentrated and purified on a silica gel column (40 g) using 0-80% EtOAc/hexane to afford the title compound. LC/MS: m/e 848.47 [M+H]+.

[00671] Step K: (R )-3-(4-(5-(((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino-ethyl)-amino)methyl)-1-(3-( tert-butyl (tert-butoxycarbonyl)amino)propyl)-1 H-pyrazol-3-yl)phenoxy)-2-hydroxypropanoate A a solution of 3-(4-(5-((tert-butoxycarbonyl)(2- ((tert-butoxycarbonyl)amino)ethyl)amino)methyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-3-yl)phenoxy)-2-((tert-butyldimethylsilyl) (R)-tert-butyl oxy)propanoate (305 mg, 0.36 mmol) in THF (3.6 ml) at RT was added TBAF (430μL, 0.43 mmol). The reaction was stirred at rt for 3 h and then concentrated and purified on a silica gel column (40 g) using 0-75% EtOAc/hexane to afford the title compound. LC/ MS: m/e 734.42(M+H)+.

[00672] Step L: (S)-3-(4-(5-(((2-Aminoethyl)amino)methyl)-1-(3-aminopropyl)-1H-pyrazol-3-yl)phenoxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)-azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid The title compound was prepared according to the procedure of Example 1, Step C to Step H starting from (R)-3-(4-(5-((tert-butoxycarbonyl))(2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)-1- tert-butyl (3-((tert-butoxycarbonyl)-amino)propyl)-1H-pyrazol-3-yl)phenoxy)-2-hydroxypropanoate. LC/MS: m/e 739.18 [M+H]+. 1H NMR (500 MHz, Deuterium oxide) δ (ppm) 7.59 (d, J = 8.4 Hz, 2H), 7.02 - 6.86 (m, 3H), 6.74 (s, 1H), 5.07 - 4.92 (m, 1H), 4.54 - 4.28 (m, 5H), 4.22 (t, J = 6.9 Hz, 2H), 3.43 (t, J = 6.9 Hz, 2H), 3.32 (t, J = 7.0 Hz, 2H), 2.93 (t, J = 7.9 Hz, 2H), 2.10 (p, J = 6.8 Hz, 2H), 1.23 (s, 3H), 0.96 (s, 3H). EXAMPLE 126 Acid (S )-3-(4-(5-(Aminomethyl)-1-(3-aminopropyl)-1H-pyrazol-3-yl)phenoxy)- 2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy) deno)amino)oxy)propanoic acid

[00673] Step A: Potassium bis(tert-butoxycarbonyl) amide To a solution of di-tert-butyl iminodicarboxylate (20 g, 92 mmol) in EtOH (20 mL) was added KOH (5.4 g, 97 mmol) in EtOH (20 mL). The reaction was stirred at rt for 40 min and then Et2O was added. The mixture was filtered and washed with Et2O to afford the title compound, which was used in the next step without further purification.

[00674] Step B: (R)-tert-butyl 3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-5-(chloromethyl)-1H-pyrazol-3-yl)phenoxy)-2-(( tert-butyldimethylsilyl)oxy)propanoate To a solution of (R)-tert-butyl 3-(4-(1-(3-(( tert-butoxycarbonyl)amino)propyl)-5-(hydroxymethyl)-1H-pyrazol-3-yl)phenoxy)-2-(( tert-butyldimethylsilyl)oxy)propanoate (100 mg, 0.16 mmol) in DCM (825 μL) at 0°C, TEA (23 μL, 0.16 mmol) was added along with methanesulfonyl (13, 0.16 mmol) and sodium chloride (12, 0.16 mmol). mmol). The reaction mixture was stirred at 0 °C for 1 h, then additional TEA (23.01, 0.165 mmol) and methanesulfonyl chloride (12.86, 0.165 mmol) were added. The reaction mixture was heated for 2 h, then partitioned between DCM and water. The organic layer was separated, dried over MgSO4, concentrated, and purified on a gel column (40 g) using 0-30-60% EtOAc/hexane to afford the title compound. LC/MS: m/e 624.74 [M+H]+.

[00675] Step C: (R )-3-(4-(5-((bis(tert-butoxycarbonyl)amino)methyl)- 1-(3-((tert-butoxycarbonyl)amino)propyl)-1 H- tert-butyl pyrazol-3-yl)phenoxy)-2-((tert-butyldimethylsilyl)-oxy)propanoate A solution of 3-(4-(1- (3-((tert-butoxycarbonyl)amino)-propyl (R)-tert-Butyl )-5-(chloromethyl)-1H-pyrazol-3-yl)phenoxy)-2-((tert-butyldimethylsilyl)-oxy)-propanoate (70 mg, 0.112 mmol) in DMF ( 1 ml) at RT, potassium bis(tert-butoxycarbonyl)amide (32 mg, 0.123 mmol) was added. The reaction mixture was stirred at room temperature overnight. Additional potassium bis(tert-butoxycarbonyl)amide (10 mg) was added and the reaction was stirred at room temperature for 1 h, then diluted with H2O, extracted with EtOAc (3x ). The combined organic layers were washed with brine (3x), dried over MgSO4, filtered, and concentrated. The resulting residue was purified on a silica gel column (24 g) using 0.30% EtOAc/hexane to afford the title compound . LC/MS: m/e 805.45 [M+H]+.

[00676] Step D: (R)-3-(4-(5-((bis( tert -butoxycarbonyl)amino)methyl)-1-(3-(( tert -butoxycarbonyl)amino)propyl)-1H-pyrazol-3-yl)phenoxy)-2-tert-butyl hydroxypropanoate To a solution of (R)-tert-butyl 3-(4-(5-((bis( tert -butoxycarbonyl)amino)methyl)-1-(3-(( tert -butoxycarbonyl)-amino)propyl)-1H-pyrazol-3-yl)phenoxy)-2-(( tert -butyldimethylsilyl)oxy)propanoate (76 mg, 0.094 mmol) in THF (944 μL) at RT, TBAF was added (113, 0.113 mmol). The reaction mixture was stirred at rt overnight. for 30 min and then concentrated. The resulting residue was purified by ISCO (12 g, 0-60% EtOAc/hexanes) to afford the title compound. LC/MS: m/e 691.39 [M+H]+.

[00677] Step F: (5 )-3-(4-(5-(Aminomethyl)-1-(3-aminopropyl)-1H-pyrazol-3-yl)phenoxy)-2-((((Z)-1-(2-aminothiazol-4-yl)-2-(((S)-2,2-dimethyl-4-oxo-1-(sulfooxy)azetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)propanoic acid The title compound was prepared according to the procedure for Example 1 Step C-Step H starting from (R)-tert-butyl 3-(4-(5-((bis(tert-butoxycarbonyl)amino)methyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-3-yl)phenoxy)-2-hydroxypropanoate. LC/MS: m/e 696.27 [M+H]+. 1H NMR (500 MHz, D2O): δ (ppm) 7.58 (d, J = 8.4 Hz, 2 H); 6.93 (d, J = 8.3 Hz, 2 H); 6.81 (s, 1H); 6.65 (s, 1H); 4.81 (s, 1H); 4.40 (s, 1 H); 4.35-4.36 (m, 2H); 4.23 (s, 2 H); 4.18 (t, J = 6.9 Hz, 2 H); 2.94 (t, J = 7.8 Hz, 2 H); 2.10 (t, J = 7.8 Hz, 2 H); 1.25 (s, 3H); 1.02 (s, 3 H). BIOLOGICAL ASSESSMENTS Antibiotic Activity: Determination of Growth Inhibitory Concentration

[00678] The concentrations of compounds required to inhibit the growth of various strains of bacteria were determined in an assay that assessed bacterial growth by measuring optical density at 600 nm (OD600). Bacterial strains tested included clinical strains of Escherichia coli expressing NDM-1 (CLB30016), Klebsiella pneumoniae expressing KPC-1 (CL6569), Acinetobacter baumannii expressing TEM-1, AmpC and Oxa-24/40 (CL6188) and Pseudomonas aeruginosa expressing AmpC (CL5701). All compounds were tested in the presence of a Lactamase inhibitor (BLi, Relebactam) in 384-well microplates.

[00679] Clinical strains were stored as single-use frozen stocks, thawed, and diluted in 1.1X cation-adjusted Mueller-Hinton II broth to achieve approximately 2 x 105 CFU/mL. Test compounds were dissolved in DMSO and diluted 1:50 in the assay, resulting in a final concentration range of 100 μM to 0.098 μM. On the day of the assay, 1 μL of test compound was added to the plate followed by 4 μL of 50 μg/mL BLi in MOPS buffer and 45 μL of diluted bacteria. Plates were centrifuged at 1000 rpm for 30 seconds, shaken at approximately 800 rpm for 1 minute, and incubated at 35°C2 for 22 hours. The concentration of BLi used in the assay was 4 μg/mL. At the end of the incubation, the absorbance at 600 nm was determined using a spectrophotometer. Inhibition was quantified by identifying the lowest concentration of test compound that was required to inhibit 95% of bacterial growth. The results for Examples 1–126 are presented in Table I, expressed as the concentration of compound that inhibited 95% of bacterial growth (Minimum Inhibitory Threshold Concentration; MITC95).

[00680] Representative compounds of the present invention exhibit a growth inhibitory effect. For example, representative compounds of Examples 1-126 were determined to inhibit growth at concentrations of 100 μM or less. Table I. Antibacterial Activity of Examples 1-126

Claims (19)

1. Compound, characterized by the fact that it is of Formula I: or a pharmaceutically acceptable salt thereof, wherein: W is a bond or O; Rx and Rz are independently hydrogen, -SC1-C3 alkyl, C1-C3 alkyl, -(C1-C3 alkylene)nOC1-C3 alkyl, or -(C1-C3 alkylene)nNC1-C3 alkyl, wherein the -SC1-C3 alkyl, C1-C3 alkyl, -(C1-C3 alkylene)nOC1-C3 alkyl, and (C1-C3 alkylene)nNC1-C3 alkyl are optionally substituted with one to seven fluorines; or, alternatively, Rx and Rz, together with the carbon to which they are attached, form a monocyclic C4-C7 cycloalkyl or a monocyclic C4-C7 heterocycloalkyl having 1, 2, or 3 heteroatom ring atom(s) independently selected from N, O, and S, wherein said C4-C7 cycloalkyl and said C4-C7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from -F, -OH, and -OC1-C3 alkyl; X is N or CR1; R1 is hydrogen, C1-C3 alkyl, or halogen; wherein said C1-C3 alkyl is optionally substituted with one to three Ra; each occurrence of Ra is independently hydrogen, halogen, C1-C3 alkyl, -NRcRd, or -ORe; Z is C2-C3 alkylene, optionally substituted with one to three Rb; each occurrence of Rb is independently -C1-C8 alkyl, -C3-C7 cycloalkyl, -C(O)ORe, -C(O)NRcRd, tetrazolyl, oxadiazolonyl, HetA, AriA, S(O)mRe, -S(O)mNRcRd, or -P(O)(Re)p, wherein said -C1-C8 alkyl and said -C3-C7 cycloalkyl are optionally substituted with one to three Ra; HetA is a 4- to 6-membered saturated or monounsaturated monocyclic ring having 1, 2, or 3 heteroatom ring atom(s) independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; AriA is a 5- to 6-membered monocyclic aromatic ring having 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; Y is a bond, O, NR2, S, or CH2; R2 is hydrogen, -C1-C3 alkyl, -C(O)Re, -C(O)NRcRd, -S(O)mRe, or -S(O)mNRcRd, wherein said -C1-C3 alkyl is optionally substituted with one to three Ra; A1 is AriA; where * indicates bond to Q and ** indicates bond to M; each occurrence of R4 is independently: -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, halogen, -ORe, -S(O)mRe, -S(O)mNRcRd, - eee cd cd cd C(O)R , —OC(O)R , -C(O)OR , -CN, -C(O)NR R , —NR R , -(CH2)nNR R , -NRcC(O)Re, -NRcC(O)ORe, -NRcC(O)NRcRd, -NRcS(O)mRe, =NH, -CF3, - OCF3, -OCHF2, -C3-C6 cycloalkyl, -O-C3-C6 cycloalkyl, -C1-C10 alkylene-C3-C6 cycloalkyl, -O-C1-C10-alkylene-C3-C6-cycloalkyl, HetB, -O-HetB, -C1-C10-alkylene-HetB, -O-C1-C10-alkylene-HetB, AriA, -O-AriA, -C1-C10-alkylene-AriA, or -O-C1-C10-alkylene-AriA, wherein each R4 is unsubstituted or substituted with one to four substituents selected from halogen, -C1-C6-alkyl, and -(CH2)nNRcRd, or wherein R4 and M, together with the atoms to which they are attached, form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S, and -NRg; HetB is a 3- to 6-membered saturated or monounsaturated monocyclic ring having 1, 2, or 3 heteroatom ring atom(s) independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to three Ra; Q is a bond, CH2, O, S, -(CH2)nNR3-, or -NR3(CH2)n-, wherein each CH2 is unsubstituted or substituted with one to two substituents selected from halogen, -C1-C6 alkyl, ORe, and -(CH2)nNRcRd; R3 is hydrogen or -C1-C3 alkyl, wherein said -C1-C3 alkyl is optionally substituted with one to three Ra; M 5 55 5 5 5 is R , -NHR , -N(R ) 2 , -OR , -(CH 2) nR , -C(O) R , - CH(NH) R 5 , or -S(O) mR 5 ; R 5 is H, C 2 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl-C 3 -C 7 cycloalkyl, HetB, AriB or -NH(C 1 -C 6 alkyl), wherein said C 1 -C 6 alkyl, said C 2 -C 10 alkyl and said C 3 -C 7 cycloalkyl are optionally substituted with one to four R 6 ; AriB is a 5- to 6-membered monocyclic aromatic ring having 0, 1, 2 or 3 ring atoms independently selected from N, O and S, optionally substituted with one to four R 4 ; each occurrence of R6 is independently selected from the group consisting of: halogen, -ORe, -S(O)mRe, -S(O)mNRcRd, -C(O)Re, ee cd cd cd -OC(O)R, -C(O)OR , -CN, -C(O)NRR, -C(NH)NRR, -NR R , - (CHi^NRcRd, -N(Rc)(C(O)Re), -N(Rc)(C(O)ORe), -N(Rc)(C(O)NRcRd), - N(Rc)(S(O)mRe) and HetB; each occurrence of Rc and Rd is independently: hydrogen, - C1-C10 alkyl, -C2-C10 alkenyl, -C3-C6 cycloalkyl, -C1-C10 alkylene-C3-C6 cycloalkyl, HetA, -C1-C10 alkylene-HetB, AriB, -C1-C10 alkylene-AriB, and -C1-C10 alkylene-HetB, or, alternatively, Rc and Rd together with the nitrogen atom to which they are attached, form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S, and -NRg, and wherein each Rc and Rd is optionally substituted with one to three Rf; each occurrence of Re is independently: hydrogen, -C1-C10 alkyl, -C2-C10 alkenyl, -OH, -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C1 alkylenylene-C3-C6 cycloalkyl, HetB, -C1-C10 alkylene-HetB, AriB, -C1-C10 alkylene-AriB, or -C1-C10 alkylene -HetB; wherein each Re is optionally substituted with one to three Rh; each occurrence of Rf is independently: halogen, -C1-C10 alkyl, -OH, -OC1-C4 alkyl, -S(O)C1-C4 alkyl, -CN, -CF3, -OCHF2, -OCF3 or NH2, wherein said -C1-C10 alkyl is optionally substituted with one to three substituents independently selected from: -OH, halogen, cyano and -S(O)2CH3; each occurrence of Rg is independently: hydrogen, -C(O)Re, and -C1-C10 alkyl, wherein said -C1-C10 alkyl is optionally substituted with one to five fluorine atoms; each occurrence of Rh is independently: halogen, -C1-C10alkyl, -OH, -OC1-C4alkyl, -S(O)m-C1-C4alkyl, -CN, -CF3, -OCHF2, or -OCF3; wherein said -C1-C10alkyl is optionally substituted with one to three substituents independently selected from: -OH, halogen, cyano, or -S(O)2CH3; each n is independently 0, 1, 2, 3, or 4; each m is independently 0, 1, or 2, and each p is independently 1 or 2. 2. Compound of formula (I) according to claim 1, characterized in that it is or a pharmaceutically acceptable salt thereof, wherein: W is a bond or O; Rx and Rz are independently hydrogen, -SC1-C3 alkyl, C1-C3 alkyl, -(C1-C3 alkylene)nOC1-C3 alkyl, or -(C1-C3 alkylene)nNC1-C3 alkyl, wherein the -SC1-C3 alkyl, C1-C3 alkyl, -(C1-C3 alkylene)nOC1-C3 alkyl and (C1-C3 alkylene)nNC1-C3 alkyl are optionally substituted with one to seven fluorines; or, alternatively, Rx and Rz, together with the carbon to which they are attached, form a monocyclic C4-C7 cycloalkyl or a monocyclic C4-C7 heterocycloalkyl having 1, 2, or 3 heteroatom ring atom(s) independently selected from N, O, and S, wherein said C4-C7 cycloalkyl and said C4-C7 heterocycloalkyl are optionally substituted with one to three substituents independently selected from -F, -OH, and -OC1-C3 alkyl; X is N or CR1; R1 is hydrogen, C1-C3 alkyl, or halogen; wherein said C1-C3 alkyl is optionally substituted with one to three Ra; each occurrence of Ra is independently hydrogen, halogen, C1-C3 alkyl, -NRcRd, or -ORe; Z is C2-C3 alkylene, optionally substituted with one to three Rb; each occurrence of Rb is independently -C1-C8 alkyl, -C3-C7 cycloalkyl, -C(O)ORe, -C(O)NRcRd, tetrazolyl, oxadiazolonyl, HetA, AriA, -S(O)mRe, -S(O)mNRcRd or P(O)(Re)p wherein said -C1-C8 alkyl and said C3-C7 cycloalkyl are optionally substituted with one to three Ra; AriA is a 5- to 6-membered monocyclic aromatic ring having 0, 1, 2 or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R4; HetA is a 4- to 6-membered saturated or monounsaturated monocyclic ring having 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O, and S, optionally substituted with one to four R4; Y is a bond, O, NR2, S, or CH2; R2 is hydrogen, -C1-C3 alkyl, -C(O)Re, -C(O)NRcRd, -S(O)mRe, or -S(O)mNRcRd, wherein said -C1-C3 alkyl is optionally substituted with one to three Ra; A1 is AriA; A2 is: where * indicates binding to Q and ** indicates binding to M; each occurrence of R4 is independently: -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, halogen, -ORe, -S(O)mRe, -S(O)mNRcRd, - eee cd cd ce C(O)R , -OC(O)R , -C(O)OR , -CN, -C(O)NR R , -NR R , -NR C(O) R , — NRcC(O)ORe, -NRcC(O)NRcRd, - NRcS(O)mRe, = NH, -CF3, -OCF3, - )CHF2, -C3-C6 cycloalkyl, -)-C3-C6 cycloalkyl, -C1-C10 alkylene- C3-C6 cycloalkyl, -)-C1-C10 alkylene-C3-C6 cycloalkyl, HetB, -)-HetB, -C1-C10 alkylene-HetB, -)-C1-C10 alkylene-HetB, AriA, -)-AriA, -C1-C10 alkylene-AriA, or -)-C1-C10 alkylene-AriA; HetB is a 3- to 6-membered saturated or monounsaturated monocyclic ring having 1, 2 or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, ) and S, optionally substituted with one to three Ra; Q is a bond, CH2, ), S, -(CH2)nNR3- or -NR3(CH2)n-; R3 is hydrogen or -C1-C3 alkyl, wherein said -C1-C3 alkyl is optionally substituted with one to three Ra; M 5 55 5 5 5 is R , -NHR , -N(R ) 2 , -)R , -(CH 2 )nR , -C())R , - CH(NH)R 5 , or -S())mR 5 ; R 5 is C 2 -C 10 alkyl, C 3 -C 7 cycloalkyl, HetB or AriB, wherein said C 2 -C 10 alkyl and said C 3 -C 7 cycloalkyl are optionally substituted with one to four R 6 ; AriB is a 5- to 6-membered monocyclic aromatic ring having 0, 1, 2 or 3 ring atoms independently selected from N, ) and S, optionally substituted with one to four R 4 ; each occurrence of R6 is independently selected from the group consisting of: halogen, -)Re, -S())mRe, -S())mNRcRd, -C())Re, ee cd cd cd -)C())R , -C()))R , -CN, -C())NR R , -C(NH)NR R , -NR R , - cecec cd ce N(R )(C())R ), -N(R )(C()))R ), - N(R )(C())NR R ) and -N(R )(S())mR ); each occurrence of Rc and Rd is independently: hydrogen, -C1-C10 alkyl, -C2-C10 alkenyl, -C3-C6 cycloalkyl, -C1-C10 alkylene-C3-C6 cycloalkyl, HetA, -C1-C10 alkylene-HetB, AriB, -C1-C10 alkylene-AriB, and -C1-C10 alkylene-HetB, or, alternatively, Rc and Rd together with the nitrogen atom to which they are attached form a 4- to 7-membered cycloheteroalkyl optionally containing one to two additional heteroatoms independently selected from O, S, and -NRg, and wherein each of Rc and Rd is optionally substituted with one to three Rf; each occurrence of Re is independently: hydrogen, -C1-C10 alkyl, -C2-C10 alkenyl, -OH, -C1-C4 alkyl, -C3-C6 cycloalkyl, -C1-C1 alkylenylene-C3-C6 cycloalkyl, HetB, -C1-C10 alkylene-HetB, AriB, -C1-C10 alkylene-AriB, or -C1-C10 alkylene-HetB; wherein each Re is optionally substituted with one to three Rh; each occurrence of Rf is independently: halogen, -C1-C10 alkyl, -OH, -Oalkyl, -S(O)m-C1-C4 alkyl, -CN, -CF3, -OCHF2, or -OCF3; wherein said -C1-C10 alkyl is optionally substituted with one to three substituents independently selected from: -OH, halogen, cyano, and -S(O)2CH3; each occurrence of Rg is independently: hydrogen, -C(O)Re, and -C1-C10 alkyl, wherein said -C1-C10 alkyl is optionally substituted with one to five fluorines; each occurrence of Rh is independently: halogen, -C1-C10alkyl, -OH, -OC1-C4 alkyl, -S(O)m-C1-C4 alkyl, -CN, -CF3, -OCHF2, or -OCF3; wherein said -C1-C10 alkyl is optionally substituted with one to three substituents independently selected from: -OH, halogen, cyano, or -S(O)2CH3; each n is independently 0, 1, 2, 3, or 4; each m is independently 0, 1, or 2, and each p is either 1 or 2. 3. Compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized by having formulas II-1, II-2, II-3, III-1, III-2 or III-3: are independently hydrogen, C1-C8 alkyl, C3-C7 cycloalkyl, -C(O)ORe, -C(O)NRcRd, tetrazolyl, oxadiazolonyl, HetA, AriA, -S(O)mRe, -S(O)mNRcRd or -P(O)(Re)p, wherein said C1-C8 alkyl and said C3-C7 cycloalkyl are optionally substituted with one to three Ra. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein Rb1 and Rb2 are independently hydrogen, C1-C3 alkyl, tetrazolyl, oxadiazolonyl, or -C(O)ORe; and Rb3 is hydrogen. 5. A compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, characterized in that X is N. 6. A compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, characterized in that X is CR1. 7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein A1 is: where it indicates the connection points to the rest of the compound. 8. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein A2 is a 5- to 6-membered monocyclic aromatic ring having 1, 2 or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with one to four R4. 9. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein M is - (CH2)nR5 or R5. 10. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein M is C2-C10 alkyl substituted with -NRcRd. 11. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Rx and Rz are methyl, or Rx is methyl and Rz is hydrogen. 12. Compound according to claim 2, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof. 13. Trifluoroacetic acid salt, characterized by the fact that it is the compound as defined in claim 12. 14. Trifluoroacetic acid salt, characterized by the fact that it is the compound as defined in claim 2. 15. Pharmaceutical composition, characterized by the fact that it comprises a therapeutically effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 16. Pharmaceutical composition according to claim 15, characterized in that it further comprises a therapeutically effective amount of a beta-lactamase inhibiting compound. 17. Pharmaceutical composition according to claim 16, characterized in that the beta-lactamase inhibitor compound is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam and avibactam. 18. Use of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is in the manufacture of a medicament for treating a bacterial infection. 19. Use according to claim 18, characterized in that the bacterial infection is due to Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichia spp., Morganella spp., Citrobacter spp., Serratia spp. or Acintetobacter spp.