NZ791470A

NZ791470A - Beta-lactamase inhibitor compounds

Info

Publication number: NZ791470A
Application number: NZ791470A
Authority: NZ
Inventors: Gregory S Basarab; Prevoir Janelle Comita; Reville Thomas Francois Durand; Lise Gauthier; Bill Moss; Donnell John O; Jan Romero; Ruben Tommasi; Jeroen Cunera Verheijen; Frank Wu
Original assignee: Entasis Therapeutics Limited
Priority date: 2016-09-16
Filing date: 2017-09-15
Publication date: 2022-08-26

Abstract

The present invention is directed to compounds which are beta-lactamase inhibitors. The compounds and their pharmaceutically acceptable salts are useful in combination with beta- lactam antibiotics, for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant organisms. The present invention includes compounds according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R2, R3, R4, R5 and R6 are described herein. ncluding multi-drug resistant organisms. The present invention includes compounds according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R2, R3, R4, R5 and R6 are described herein.

Description

WO 53215 Beta-Lactamase Inhibitor Compounds Related Applications This application claims priority to US. Provisional Application No. 62/395,464. filed September 16, 2616 and US. Provisional Application No. 62/456,423, filed February 8, 2i)? '7, the contents of each of which are incorporated herein by reference.

Field of the ion The present invention relates to novel oral beta—lactamase inhibitors, their pharmaceutical compositions and methods of use. In addition, the present invention relates to therapeutic methods for the treatment of ial infections, including overcoming bacterial otic resistance.

Background of the Invention The international microbiological and infectious disease community continues to express serious concern that the continuing evolution of antibacterial resistance could result in bacterial strains t which currently available antibacterial agents will be ineffective. The outcome of such an occurrence could have considerable morbidity and mortality. In general, bacterial pathogens may be classified as either Gram—positive or Gram—negative pathogens.

Antibiotic nds with effective activity against both Gram—positive and Gram—negative pathogens are typically regarded as having a broad spectrum of activity.

In the fight against bacterial infection, beta—lactam antibiotics are essential. Beta—lactams are a broad class of drugs which all have a actam in their core molecular structure, and lly show effectiveness against a broad spectrum of Gram—positive and Gram—negative bacteria by ting the cell wall synthesis of the bacterium. Because the drug target has no eukaryotic analog, their toxicity is low and they are generally well—tolerated. They remain among the most widely prescribed, safe and effective drugs ble to combat bacterial infection. However, their effectiveness is limited by highly resistant infectious s such as methicillin—resistant Staphylococcus aureus (MRSA) and multi—drug ant (MDR) strains of Pseudomonas aeruginosa, Acinetobacter baumannii, ichia coli, Klebsiella pneumoniae, and other Enterobacteriaceae. Such resistant bacteria are major causes of patient morbidity and mortality. Helfand, ,B-lactams t Emerging bugs’: Progress and Pitfalls, Expert Rev. Clin. Pharmacol. 1(4):559—571 (2008).

Beta—lactam antibiotics, alone and in combination with beta—lactamase inhibitors, continue to ent an ial portion of the antibacterial agents used to combat disease. Beta—lactam ance for Gram—negative infections is primarily driven by beta—lactamase activity; and the significant dependence on beta—lactam antibiotics has lead to the diversification and increased prevalence of beta—lactamases. These actamases are driving resistance to even the newest beta—lactam otics. Llarrull, et al., The Future ofBeta-Lactams, Current Opinion in Microbiology, 13 :55 1—557 (2010).

A major threat to the efficacy of these drugs is the increasing prevalence of extended— spectrum beta—lactamases (ESBLs). actamases are enzymes that are produced by some bacteria that ring open the beta—lactam portion of a beta—lactam antibiotic and thereby deactivate it. There are currently, four classes of beta—lactamases, denoted as Class A, Class B, Class C and Class D. Class A, Class C and Class D beta—lactamases are serine beta— lactamases, while Class B actamases are metallo—beta—lactamases . Bush & Jacoby, Updated Functional Classiﬁcation of,B-Lactamases, Antimicrobial Agents and Chemotherapy, 54(3):969—976 (Mar. 2010).

To help improve the effectiveness of beta—lactam antibiotics, some beta—lactamase inhibitors have been developed. However, the currently available beta—lactamase inhibitors in many instances are insufficient to counter the constantly increasing diversity of beta—lactamases.

The three most common serine beta—lactamase agents currently used — clavulanic acid, tazobactam and tam — have activity only against certain Class A enzymes, which severely limits their utility. Additionally, novel beta—lactamase inhibitors recently approved or currently in clinical trials, such as tam and 5, are only available for intravenous use and work primarily on Class A and C enzymes, with minimal effectiveness against Class D beta—lactamases. Bebrone, et al., Current Challenges in Antimicrobial Chemotherapy: Focus on ,B-Lactamase Inhibition, Drugs, 651—679 (2010). While these agents represent a considerable ement over the currently ble beta—lactamase inhibitors, agents which effectively hit all three classes of serine beta—lactamases, with the added benefit of an orally effective dose form for use outside of the hospital setting are desirable for combating the significant beta—lactam resistance seen today. Currently, there are no approved beta—lactamase inhibitors which are administered orally and effective against Class C or Class D beta—lactamases, yet resistance rates to conventional antibiotics are continuing to rise.

Compounds similar to the ones disclosed herein, also with broad beta—lactamase inhibition profiles (being effective t most Class A, Class C and Class D beta—lactamases), were described in following a: R1 R3 2*!“\ o OSOgH While the compounds of the improvement in the spectrum of beta—lactamase inhibitors presently on the market or in the clinic, the compounds described therein can only be administered intravenously (IV) e they are not orally bioavailable. Moreover, the compounds disclosed therein could not be made to be orally bioavailable by using a prodrug on the sulfate ting group on the molecule. Therefore, these potent beta—lactamase inhibitors are limited to intravenous or parenteral administration, which typically happens only in a al setting. ingly, there are limited treatment options for patients with serious, resistant ions but who are otherwise healthy and do not need to be admitted into the al, or patients who could be discharged from a hospital but who would benefit from antibacterial treatment in an outpatient setting (also known as “oral switch therapy”). The compounds of the W0 2013/150296 application have the potential to provide patients with more ive and broader actamase inhibition than anything yet identified, but the compounds currently require intravenous administration in a hospital setting.

There is a critical need for a new, broad spectrum, oral beta—lactamase inhibitor that would provide a significant benefit for patients infected with resistant pathogens who may be able to be treated outside of the hospital setting, or who are admitted to a hospital but may not have reliable venous access. Such patients may have s, complicated infections from pathogens which produce one or multiple beta—lactamases, but who may not require treatment in a hospital setting, or those recovering from infections which were lly successfully treated with an IV beta—lactam/beta—lactamase inhibitor combination in the hospital, but who would benefit from continued beta—lactam/beta—lactamase inhibitor combination therapy e of the hospital setting — which would be possible only with an orally active, broad— spectrum beta—lactamase inhibitor such as described herein.

Furthermore, for patients with resistant bacterial infections which require hospital admission for initial treatment, compounds according to the t invention, as described in Formulae (Ia), (Ila), (Illa), (IVa) and (Va), can be administered enously in the hospital setting until a patient is stable enough to be discharged into the community setting. Upon discharge, the patient can continue therapy with the same medication by administration of a nd according to one of Formulae (I), (II), (III), (IV), or (V), in a community g, while maintaining a consistent treatment until the bacterial infection is resolved. There are currently no Class A, C and D B—lactamase tors which can be stered initially by IV with the additional benefit of oral administration once a patient is well enough to be discharged from the hospital. The ability for a doctor to tailor the care to a t’ s needs would allow for earlier discharge of patients who require hospitalization, and significantly lessen the costs of treatment overall by avoiding prolonged hospital stays.

There is an urgent need for new, orally—active beta—lactamase inhibitors which are effective against more than one of Class A, C and D beta—lactamases.

Summary of the ion The present invention is directed to compounds which are orally available beta—lactamase inhibitors. The compounds, and their pharmaceutically able salts, are useful in combination with beta—lactam antibiotics for the treatment of bacterial infections, ing infections caused by drug resistant organisms, including multi—drug resistant organisms.

More particularly, the invention relates to compounds of formula (1): R1””, R3 0/ \ or a pharmaceutically acceptable salt thereof; wherein: R1 is —C(O)NR7R8, —CN, phenyl, a 5—7 membered heteroaryl, — C(O)NR’NR’C(O)R9, —C(O)NR’OR10, or a C1—C6 alkyl group, n the alkyl group is substituted with one to three groups ting of halo, C1—C3 alkoxy, —OH, —CN, —NR7R8, —NR7COR9, a 5—7 membered heteroaryl and a 5—7 membered heterocyclyl, and wherein the phenyl and heteroaryl represented by R1 are optionally and independently substituted with l— 3 groups selected from halo, —OH, C1—C3 alkoxy, —CN, —NR7R8, and —CONR7R8; R2 and R3 are independently selected from hydrogen, halo, C1—C3 alkyl, and C3— C6 cycloalkyl; R4 and R5 are ndently selected from hydrogen, halo, —CN, —COZR9, C1-C3 alkyl, and C1—C3 haloalkyl; R6 is hydrogen, C1—C12 alkyl, C1—C4alkyl—C1—C3alkoxy—(NR’C1—C6alkyl)—C1— C3alkoxy, C1—C4alkyl—C1—C3alkoxy—C1—C3alkoxy, C2—C12 alkenyl, C3—C10 cycloalkyl, a 5—7 membered heteroaryl and a 5—7 membered heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently tuted l—6 groups selected from a carboxyl, halo, C1—C6 alkoxy, C1—C6 alkyl and phenyl. Alternatively, R6 is C1-C12 alkyl, C1-C4alkyl-C1-C3alkoxy-(NR’C1-C6alkyl)-C1-C3alkoxy, C1-C4alkyl-C1- C3alkoxy—C1—C3alkoxy, C2—C12 alkenyl, C3—C10 cycloalkyl, a 5—7 ed heteroaryl and a —7 membered heterocyclyl, wherein the alkyl, l, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently substituted l—6 groups ed from a carboxyl, halo, C1—C6 alkoxy, C1—C6 alkyl and phenyl; each R7 and R8 are ndently hydrogen, C1—C3 alkyl, C1—C3 alkoxy, , C3—C6 cycloalkyl, 4—7 ed heterocyclyl, or 5—7 membered heteroaryl, wherein the alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or aryl represented by R7 or R8 is optionally and independently substituted with 1—6 groups selected from a 5—6 membered heterocyclyl optionally substituted with one or two —F atoms, carboxyl or —CO(OC1—6 alkyl), —6 membered aryl, —CN, —OH, C1—C3 alkyl ally substituted with —NH2 or —OH, C1—C3 kyl, C1—C3 haloalkoxy, C1—C3 alkoxy —NHCO(C1—C3alkyl), —NHCO(C1— C3alkoxy), —S(O)2NR’R”, -NHS(O)2NR’R”, -NHS(O)2(C1-C3alkyl), , and —C(O)NR’R’ ’; each R9 is C1—C6 alkyl, C1—C6 kyl, C1—C6 haloalkoxy or C1—C6 ; each R10 is a C1—C3 alkyl optionally substituted with 1—6 groups selected from a —6 membered heterocyclyl optionally substituted with one or two —F atoms, carboxyl or —CO(OC1—6 alkyl), a C3—C6 cycloalkyl, a 5—6 membered aryl, —CN, —OH, —NHCO(C1— C3alkyl), C1—C3alkoxy), —S(O)2NR’R”, -NHS(O)2NR’R”, -NHS(O)2(C1-C3alkyl), - NR’R”, or —C(O)NR’R”; and each R’ and R” is independently hydrogen, , ethyl or propyl; or R’ and R’’ are taken together with the nitrogen to which they are attached to form a 5—6 membered heterocyclyl; provided that at least one of R2 and R3 is other than hydrogen.

Detailed Description of the Invention In one aspect of the invention is an oral beta—lactamase inhibitor compound according to formula (I); as described above.

In another aspect of the ion, R1 in formula (I) is —C(O)NR7R8, —CN, phenyl, a 5—6 membered heteroaryl, —C(O)NR’NR’C(O)R9, —C(O)NR’OR10, or a C1—C6 alkyl group, wherein the alkyl group is substituted with one to three groups consisting of halo, C1—C3 alkoxy, —OH, —CN, —NR7R8, —NR7COR9, a 5—6 membered heteroaryl and a 5—7 membered cyclyl, and n the phenyl and heteroaryl represented by R1 are optionally and independently substituted with 1—3 groups selected from halo, —OH, C1—C3 alkoxy, —CN, -NR7R8, and —CONR7R8; R6 is hydrogen, C1-C12 alkyl, C1-C4alkyl-C1-C3alkoxy-(NR’C1-C6alkyl)-C1-C3alkoxy, C1- C4alkyl—C1—C3alkoxy—C1—C3alkoxy, C2—C12 alkenyl, C3—C10 lkyl, a 5—6 membered heteroaryl and a 5—7 membered heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently substituted l—6 groups selected from a carboxyl, halo, C1—C6 alkoxy, C1—C6 alkyl and phenyl (alternatively, R6 is C1—C12 alkyl, C1-C4alkyl-C1-C3alkoxy-(NR’C1-C6alkyl)-C1-C3alkoxy, C1-C4alkyl-C1-C3alkoxy-C1- C3alkoxy, C2—C12 alkenyl, C3—C10 cycloalkyl, a 5—6 membered heteroaryl and a 5—7 membered heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently substituted 1—6 groups selected from a carboxyl, halo, C1—C6 alkoxy, C1—C6 alkyl and phenyl); and each R7 and R8 are independently hydrogen, C1—C3 alkyl, C1—C3 alkoxy, phenyl, C3—C6 cycloalkyl, 4—7 membered heterocyclyl, or 5—6 membered aryl, wherein the alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl ented by R7 or R8 is ally and independently substituted with 1—6 groups selected from a 5—6 membered heterocyclyl ally substituted with one or two —F atoms, carboxyl or —CO(OC1—6 alkyl), 5—6 membered heteroaryl, —CN, —OH, C1—C3 alkyl optionally substituted with —NH2 or —OH, C1—C3 haloalkyl, C1—C3 haloalkoxy, C1—C3 alkoxy —NHCO(C1—C3alkyl), —NHCO(C1—C3alkoxy), —S(O)2NR’R”, —NHS(O)2NR’R”, -NHS(O)2(C1-C3alkyl), -NR’R”, and —C(O)NR’R’ ’; each R9 is C1—C6 alkyl, C1—C6 kyl, C1—C6 haloalkoxy or C1—C6 alkoxy; In r aspect of the ion is a compound according to Formula (11): R10,” \ 2 “\ or a pharmaceutically acceptable salt thereof, wherein the variables R1, R2, R4, R5 and R6 are as defined for formula (I).

In one aspect of the invention is a compound according to Formula (111): R30,” R3 (III) or a pharmaceutically acceptable salt thereof, wherein the variables R1, R3, R4, R5 and R6 are as defined for formula (I).

In a further aspect of the invention is a compound according to Formula (IV): HZNJLIII'“ \ or a pharmaceutically acceptable salt thereof, wherein the variables R4, R5 and R6 are as defined for formula (I).

In a further aspect of the invention is a compound according to a (V): HgNJL/Illl" \ or a pharmaceutically acceptable salt thereof, n the variables R4, R5 and R6 are as defined for formula (I).

In a further aspect of the invention is a compound according to Formula (Ia): or a pharmaceutically acceptable salt thereof; wherein: R1 is —C(O)NR7R8, —CN, , a 5—7 ed heteroaryl, —C(O)NR’NR’C(O)R9, —C(O)NR’OR10, or a C1—C6 alkyl group, wherein the alkyl group is substituted with one to three groups consisting of halo, C1—C3 alkoxy, —OH, —CN, —NR7R8, —NR7COR9, a 5—7 membered heteroaryl and a 5—7 membered heterocyclyl, and wherein the phenyl and heteroaryl represented by R1 are optionally and independently substituted with 1—3 groups selected from halo, —OH, C1—C3 alkoxy, —CN, —NR7R8, and —CONR7R8; R2 and R3 are independently selected from en, halo, C1—C3 alkyl, and C3—C6 cycloalkyl; R4 and R5 are independently selected from hydrogen, halo, —CN, —COZR9, C1—C3 alkyl, and C1—C3 haloalkyl; each R7 and R8 are independently en, C1—C3 alkyl, C1—C3 alkoxy, , C3—C6 cycloalkyl, 4—7 membered heterocyclyl, or 5—7 membered heteroaryl, wherein the alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl ented by R7 or R8 is optionally and independently substituted with 1—6 groups selected from a 5—6 membered heterocyclyl optionally substituted with one or two —F atoms, carboxyl or —CO(OC1—6 alkyl), 5—6 membered heteroaryl, —CN, —OH, C1—C3 alkyl optionally substituted with —NH2 or —OH, C1—C3 haloalkyl, C1—C3 haloalkoxy, C1—C3 alkoxy —NHCO(C1—C3alkyl), —NHCO(C1—C3alkoxy), —S(O)2NR’R”, )2NR’R”, -NHS(O)2(C1-C3alkyl), -NR’R”, and —C(O)NR’R’ ’; each R9 is C1—C6 alkyl, C1—C6 haloalkyl, C1—C6 koxy or C1—C6 alkoxy; each R10 is a C1—C3 alkyl optionally substituted with 1—6 groups selected from a 5—6 membered heterocyclyl optionally substituted with one or two —F atoms, carboxyl or — CO(OC1—6 alkyl), a C3—C6 cycloalkyl, a 5—6 membered heteroaryl, —CN, —OH, —NHCO(C1— C3alkyl), C1—C3alkoxy), —S(O)2NR’R”, -NHS(O)2NR’R”, -NHS(O)2(C1-C3alkyl), - NR’R’ ’, or R’R’ ’; and each R’ and R’’ is independently hydrogen, methyl, ethyl or propyl; or R’ and R’ ’ are taken together with the nitrogen to which they are attached to form a 5—6 membered heterocyclyl; ed that at least one of R2 and R3 is other than hydrogen.

In a further aspect of the ion is a compound according to Formula (Ia): or a pharmaceutically acceptable salt thereof; wherein: R1 is —C(O)NR7R8, —CN, phenyl, a 5—6 membered heteroaryl, —C(O)NR’NR’C(O)R9, —C(O)NR’OR10, or a C1—C6 alkyl group, wherein the alkyl group is substituted with one to three groups consisting of halo, C1—C3 alkoxy, —OH, —CN, —NR7R8, —NR7COR9, a 5—6 membered aryl and a 5—7 membered heterocyclyl, and wherein the phenyl and heteroaryl represented by R1 are optionally and independently substituted with 1—3 groups selected from halo, —OH, C1—C3 alkoxy, —CN, —NR7R8, and —CONR7R8; R2 and R3 are independently selected from hydrogen, halo, C1—C3 alkyl, and C3—C6 cycloalkyl; R4 and R5 are independently selected from hydrogen, halo, —CN, —C02R9, C1—C3 alkyl, and C1—C3 haloalkyl; each R7 and R8 are independently hydrogen, C1—C3 alkyl, C1—C3 , phenyl, C3—C6 cycloalkyl, 4—7 ed heterocyclyl, or 5—6 membered heteroaryl, wherein the alkyl, alkoxy, , cycloalkyl, heterocyclyl or heteroaryl represented by R7 or R8 is optionally and ndently substituted with 1—6 groups ed from a 5—6 membered heterocyclyl optionally substituted with one or two —F atoms, carboxyl or —CO(OC1—6 alkyl), 5—6 membered heteroaryl, —CN, —OH, C1—C3 alkyl optionally substituted with —NH2 or —OH, C1—C3 haloalkyl, C1—C3 haloalkoxy, C1—C3 alkoxy —NHCO(C1—C3alkyl), —NHCO(C1—C3alkoxy), —S(O)2NR’R”, —NHS(O)2NR’R”, -NHS(O)2(C1-C3alkyl), -NR’R”, and —C(O)NR’R’ ’; each R9 is C1—C6 alkyl, C1—C6 haloalkyl, C1—C6 haloalkoxy or C1—C6 ; each R10 is a C1—C3 alkyl optionally substituted with 1—6 groups selected from a 5—6 membered cyclyl optionally substituted with one or two —F atoms, yl or — CO(OC1—6 alkyl), a C3—C6 cycloalkyl, a 5—6 membered heteroaryl, —CN, —OH, —NHCO(C1— C3alkyl), —NHCO(C1—C3alkoxy), —S(O)2NR’R”, —NHS(O)2NR’R”, —NHS(O)2(C1—C3alkyl), — NR’R’ ’, or —C(O)NR’R’ ’; and each R’ and R’’ is independently hydrogen, methyl, ethyl or propyl; or R’ and R’ ’ are taken together with the nitrogen to which they are attached to form a 5—6 membered cyclyl; provided that at least one of R2 and R3 is other than en.

In another aspect of the invention is a compound according to Formula (Ila): R1////, \ (Ila) or a pharmaceutically acceptable salt thereof, wherein the variables R1, R2, R4 and R5 are as defined for formula (Ia).

In one aspect of the invention is a compound according to Formula (IIIa): R1/0,], R3 0/1 N (IIIa) or a ceutically acceptable salt thereof, wherein the variables R1, R3, R4 and R5 are as d for formula (Ia).

In a further aspect of the invention is a nd according to Formula (IVa): Jill/Ill H2N " \ 2 N\ (IVa) or a pharmaceutically acceptable salt thereof, wherein the variables R4 and R5 are as defined for formula (Ia).

In a further aspect of the invention is a compound according to Formula (Va): H2NJl”0"“ \ or a pharmaceutically acceptable salt thereof, wherein the variables R4 and R5 are as defined for formula (Ia).

In one aspect of the inventions, for Formulae (I), (Ia), (II), or (IIa), R2 is C1—C3 alkyl. In another aspect of the invention, for Formulae (I), (Ia), (II), or (IIa), R2 is methyl.

In one aspect of the invention, for a (I), (Ia), (III), and (IIIa), R3 is C1—C3 alkyl. In another aspect of the invention, for a (I), (Ia), (III), and (IIIa), R3 is methyl.

In one aspect of the invention, for Formula (I), (Ia), (II), (IIa), (III), and (IIIa), R1 is selected from an oxadiazole, —C(O)NHNHC(O)(C1—C3 alkyl), 2, —CH2NHCO(C1—C3 alkoxy), —CH2NHCO(C1—C3 , or —CH2NHCO(C1—C3 haloalkyl), wherein the oxadiazole of R1 is optionally substituted with —OH, C1—C3 alkoxy, —NR7R8, or —CONR7R8. In one aspect of the invention, for Formula (I), (Ia), (II), (Ila), (III), and (Illa), R1 is selected from —CH2NH2, Aﬁ/T‘i, FsCiH/tfé" kio ”/tfxi In a further aspect, for Formula (I), (la), (II), (IIa), (III), and (IIIa), R1 is —CN, l. HZN/\/O\”)erﬁ’ Hamif KZ)‘; or Yn\uiﬁ ; wherein R11 is hydrogen or —C(O)NH2. In one aspect of the invention, for a (I), (Ia), (II), (IIa), (III), and (IIIa), R1 is —CN or H2. In one aspect of the invention, for Formula (I), (Ia), (II), (IIa), (III), and , R1 is —CN. In one aspect of the invention, for Formula (I), (Ia), (II), (IIa), (III), and (IIIa), R1 is —C(O)NH2. In one aspect of the ion, for Formula (I), (Ia), (II), (IIa), (III), and (IIIa), R1 is —C(O)NR7R8. In one aspect of the invention, for Formula (I), (Ia), (II), (IIa), (III), and , when R1 is —C(O)NR7R8, R7 is hydrogen and R8 is l) a phenyl optionally substituted with a C1—C3 alkyl or C1—C3 alkyl—NHZ, 2) an C1—C3 alkyl or 3) C1—C3 alkoxy, wherein each alkyl or alkoxy of represented by R8 is optionally and independently substituted with a C3—C6 cycloalkyl, —CN, — OH, —NH2, 2, —NHSOzNH2, —C(O)NH2, -NHC(O)(C1-C3 alkyl), pyrazinyl, oxytanyl, oxazolyl, or a pyrrolidinyl optionally substituted with one or more carboxyl, fluoro, or —C(O)O(C1—C6 alkyl). In one aspect of the invention, for Formula (I), (Ia), (II), (IIa), (III), and (IIIa), when R1 is —C(O)NR7R8, R7 is hydrogen and R8 is selected from the group consisting ’3’ F /~ g 0 0 O 021; HZN if\N HZN/ \/\O:1L9 NH 9 9 £9 9 O/\o}i o o \S/ 0\ /0\s/ HN/\N/\;Z¢, A2 H N/ig H2N/\N/\\H H and —CHZOH.

, , , —CH2CN, In one aspect of the invention, for any one of Formulae (I), (II), (III), (IV) or (V), R6 is C1—C12 alkyl. In one aspect of the invention, for any one of Formulae (I), (II), (III), (IV) or (V), R6 is ethyl, isopropyl, l or isopentyl. In one aspect of the invention, for any one of Formulae (I), (II), (III), (IV) or (V), R6 is isopropyl. In one aspect of the invention, for any one of ae (I), (II), (III), (IV) or (V), R6 is C1—C4alkyl—OC(O)—(NHC1—C6alkyl)—C(O)C1— C3alkoxy, C1—C4alkyl—OC(O)—C1—C4alkyl or C1—C4alkyl—OC(O)—C1—C3alkoxy. In one aspect of the invention, for any one of Formulae (I), (II), (III), (IV) or (V), R6 is selected from the «TOY“YEA“ >6waO group consisting of: O 0 , , , {VOEKCAO, 29:9,FD,f23%, \ 5% 791A éf\/\O/, \ é n— 9 , 33A, methyl, n—propyl, n—butyl, n—pentyl, hexyl, n—septyl, n—octyl, or n—nonyl.

In one aspect of the invention, for any one of Formulae (I), (Ia), (II), (IIa), (III), , (IV), (IVa), (V) or (Va), R4 and R5 are ndently H, methyl or ﬂuoro. In another aspect of the invention, for any one of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), one of R4 and R5 is hydrogen and the other is fluoro. In another aspect of the invention, for any one of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), R4 is ﬂuoro and R5 is hydrogen. In another aspect of the invention, for any one of Formulae (I), (la), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), R4 is hydrogen and R5 is ﬂuoro. In r aspect of the invention, for any one of Formulae (I), (la), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), both R4 and R5 are hydrogen.

WO 53215 In r aspect of the invention, for any one of Formulae (I), (Ia), (II), (Ila), (III), (IIIa), (IV), (IVa), (V) or (Va), both R4 and R5 are fluoro.

Any embodiment described herein can be combined with any other suitable embodiment described herein to provide additional embodiments. For example, Where one embodiment individually or collectively describes possible groups for R1 and a separate embodiment bes possible groups for R2, it is understood that these embodiments can be combined to provide an additional embodiment utilizing any of the possible groups for R1 with any of the possible groups for R2. Analogously, the invention asses any ments called out individually for R1, R2, R3, R4, R5 and R6 in combination with any specific embodiments called out for each of the remaining variables. nds of ae (I), (II), (III), (IV) and (V), and pharmaceutically acceptable salts thereof, possess beneficial beta—lactamase inhibition spectrum and are suitable for oral administration. Compounds of ae (Ia), (Ila), (IIIa), (IVa) and (Va), and pharmaceutically acceptable salts thereof, possess beneficial beta—lactamase inhibition spectrum and are suitable for intravenous, intraperitoneal, intramuscular or subcutaneous administration, e.g., intravenous administration. As such, compounds of Formulae (Ia), (IIa), , (IVa) and (Va), and pharmaceutically acceptable salts thereof can be advantageously used when a patient is unable to take otics orally, such as in a hospital setting, urgent care setting or g home setting. Once the patient has improved sufficiently to take antibiotics orally, the treatment can be switched such that a compound of Formulae (I), (II), (III), (IV) and (V), or a pharmaceutically acceptable salt thereof can be administered orally to the patient. Additionally, compounds of Formulae (Ia), (IIa), , (IVa), (Va), (I), (II), (III), (IV) and (V), and pharmaceutically acceptable salts thereof, may possess beneficial efficacious, metabolic, toxicological and/or pharmacodynamic properties.

One aspect of the invention includes a compound according to one of the examples, or a pharmaceutically acceptable salt thereof, namely: Structure (R)-ethyl 2-((2S,5R) carbamoyl—3—methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yloxy)—2—flu0r0acetate (S)—ethyl 2—((2S,5R)—2—carbam0yl— 3—methyl—7-OXO- l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yloxy)—2—flu0r0acetate (2S)—{ [(2S ,5R)—2—carbam0yl—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy } (ﬂu0r0)ethan0ic acid lithium salt (2R)—{ [(2S,5R)—2—carbam0yl—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. 3—en—6— yl]0xy } (ﬂu0r0)ethan0ic acid m salt {[(2S,5R)—2—carbam0yl—3—methyl— 7-OXO- l ,6—diazabicyclo[3 .2. l]0ct— 3—en—6—yl]oxy } (ﬂu0r0)acetic acid m salt ethyl {[(2S,5R)—2—carbam0yl—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy } (ﬂu0r0)acetate ethyl {[(2S,5R)—2—carbam0yl—3— methyl—7—0X0— l ,6— icyclo[3 .2. l]0ct—3—en—6— yl]0xy } (diﬂu0r0)acetate 5R)—2—carbam0yl—3—methyl— 7-OXO- l ,6—diazabicyclo[3 .2. l]0ct— 3—en—6—yl]0xy } (diﬂu0r0)acetic acid lithium salt ethyl {[(2S,5R)—2—carbam0yl—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy } acetate {[(2S,5R)—2—carbam0yl—3—methyl— 7-OXO- l ,6—diazabicyclo[3 .2. l]0ct— —yl]0xy } acetic acid lithium 2—{ [(2S,5R)—2—carbam0yl—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy } —2—ﬂu0r0pr0pan0ic acid lithium salt propan—2—yl (2R)—{ [(2S,5R)—2— carbamoyl—3—methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy } (ﬂu0r0)ethan0ate propan—2—yl (2S)—{ [(2S ,5R)—2— carbamoyl—3—methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy } (ﬂu0r0)ethan0ate methylpentan—3 —yl (2S)— {[(2S,5R)—2—carbam0yl—3—methyl— 7-OXO- l ,6—diazabicyclo[3 .2. l]0ct— 3—en—6—yl]0xy } (ﬂu0r0)ethan0ate 2,4—dimethylpentan—3—yl (2R)— {[(2S,5R)—2—carbam0yl—3—methyl— 7-OXO- l ,6—diazabicyclo[3 .2. l]0ct— 3—en—6—yl]0xy } (ﬂu0r0)ethan0ate tetrahydr0—2H—pyran—4—yl { [(2S,5R)—2—carbam0y1—3—rnethy1— 7—0X0—1,6—diazabicyclo[3 .2. 1]oct— 3—en—6—yl]oxy } (ﬂu0r0)acetate 2—meth0xyethy1 {[(2S,5R)—2— carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl]0xy } (ﬂu0r0)acetate 2—meth0xyethy1 (2R)—{ [(2S,5R)— 2—carbam0y1—3—rnethy1—7—0X0— 1,6— diazabicyclo[3.2.1]oct—3—en—6— yl]0xy } (ﬂu0r0)ethan0ate 2-methoxyethyl (2S)-{ [(2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl]0xy } (ﬂu0r0)ethan0ate S)-sec-butyl 2-(((2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl)0xy)—2—ﬂu0r0acetate S)-sec-butyl 2-(((2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— icyclo[3.2.1]oct—3—en—6— )—2—ﬂu0r0acetate (2R)-(R)-sec-butyl 2-(((2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl)0xy)—2—ﬂu0r0acetate (2S)-(R)-sec-butyl 2-(((2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl)0xy)—2—ﬂu0r0acetate (R)—pentan—3—yl 2—((2S,5R)—2— carbamoyl—3—methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yloxy)—2—flu0r0acetate (S)—pentan—3—yl ,5R)—2— carbamoyl—3—methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yloxy)—2—flu0r0acetate ethyl 2-(((2S,5R)(2- hydrazinecarbonyl)—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl)0xy)—2—ﬂu0r0acetate 2-(((2S,5R)(2- acetylhydrazinecarbonyl)—3— methyl—7—0X0—l,6— icyclo[3 .2. l]0ct—3—en—6— yl)0xy)—2—ﬂu0r0acetic acid lithium salt (R)((2S,5R)(4- (aminomethyl)phenylcarbamoyl)— 3—methyl—7—0X0—l,6— diazabicyclo[3 .2. l]0ct—3—en—6— yloxy)—2—ﬂu0r0acetic acid TFA ethyl 2—ﬂu0r0—2—(((2S,5R)—3— methyl—7—0X0—2—((pyrazin—2— ylmethyl)carbam0yl)— l ,6— icyclo[3 .2. l]0ct—3—en—6— yl)0xy)acetate 2—flu0r0—2—(((2S,5R)—3—methyl—7— 0X0—2—((pyrazin—2— ylmethyl)carbam0yl)— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl)0xy)acetic acid lithium salt (2R)-ethy1 2-(((2S,5R) carbam0y1—4—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl)0xy)—2—ﬂu0r0acetate thy1 2-(((2S,5R) carbam0y1—4—methy1—7—0X0— 1 ,6— icyclo[3.2.1]oct—3—en—6— yl)0xy)—2—ﬂu0r0acetate (2R)—2—(((2S,5R)—2—carbam0y1—4— methyl—7—0X0—1,6— diazabicyclo[3.2.1]oct—3—en—6— yl)0xy)—2—ﬂu0r0acetic acid lithium salt (2S)—2—(((2S,5R)—2—carbam0yl—4— methyl—7—0X0—1,6— diazabicyclo[3.2.1]oct—3—en—6— yl)0xy)—2—ﬂu0r0acetic acid lithium salt (2R)—isopr0py1 2—(((2S,5R)—2— carbam0y1—4—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl)0xy)—2—ﬂu0r0acetate sopr0py1 2—(((2S,5R)—2— carbam0y1—4—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl)0xy)—2—ﬂu0r0acetate (2R)—isopr0py1 2—(((2S,5R)—2— carbam0y1—3—cyclopr0py1—7—0X0— 1,6—diazabicyclo[3.2.1]oct—3—en—6— yl)0xy)—2—ﬂu0r0acetate (2S)—isopr0pyl 2—(((2S,5R)—2— carbamoyl—3—cyclopr0pyl—7—0X0— l,6—diazabicyclo[3 .2. l]0ct—3—en—6— yl)0xy)—2—ﬂu0r0acetate (2R)-ethyl S,5R) carbamoyl—3—cyclopr0pyl—7—0X0— l,6—diazabicyclo[3 .2. l]0ct—3—en—6— yl)0xy)—2—ﬂu0r0acetate (2S)-ethyl 2-(((2S,5R) carbamoyl—3—cyclopr0pyl—7—0X0— l,6—diazabicyclo[3 .2. l]0ct—3—en—6— )—2—ﬂu0r0acetate (2R)—2—(((2S,5R)—2—carbam0yl—3— cyclopropyl—7—0X0—l,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl)0xy)—2—ﬂu0r0acetic acid lithium salt (2R)—2—(((2S,5R)—2—carbam0yl—3— cyclopropyl—7—0X0—l,6— icyclo[3 .2. l]0ct—3—en—6— yl)0xy)—2—ﬂu0r0acetic acid lithium salt 2—(((2S,5R)—2—carbam0yl—3— cyclopropyl—7—0X0—l,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl)0xy)—2—ﬂu0r0acetic acid lithium salt (l—isopropyl—2—methyl—pr0pyl) 2— [[(2S ,5R)—2—carbam0yl—3—methyl— 7-OXO- l ,6—diazabicyclo[3 .2. l]0ct— 3—en—6—yl]0xy] —2,2—diflu0r0— acetate octyl -[[(2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl] oxy] —2—ﬂu0r0—acetate methyl (2R)[[(2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl] oxy] —2—ﬂu0r0—acetate allyl -[[(2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl] oxy] —2—ﬂu0r0—acetate propyl (2R)—2—[[(2S,5R)—2— carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl] oxy] —2—ﬂu0r0—acetate isobutyl (2R)[[(2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl] oxy] —2—ﬂu0r0—acetate butyl (2R)[[(2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— diazabicyclo[3.2.1]oct—3—en—6— yl] oxy] —2—ﬂu0r0—acetate pentyl (2R)[[(2S,5R) carbamoyl—3—methy1—7—0X0— 1 ,6— icyclo[3.2.1]oct—3—en—6— yl] oxy] —2—ﬂu0r0—acetate hexyl (2R)[[(2S,5R) carbamoyl—3—methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl] oxy] —2—ﬂu0r0—acetate l—isopr0p0xycarbonyloxyethyl (2R)—2—[[(2S ,5R)—2—carbam0yl—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl] oxy] —2—ﬂu0r0—acetate (2R)-benzyl 2-(((2S,5R) carbamoyl—3—methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl)0xy)—2—ﬂu0r0acetate 2—[[(2S,5R)—2—(5—carbam0yl—l,3,4— oxadiazol—2—yl)—3—methyl—7—0X0— azabicyclo[3.2.l]0ct—3—en—6— yl]0xy] —2—ﬂu0r0—acetic acid lithium salt (2S)ﬂuoro[[(2S,5R)—3— methyl—7—0X0—2—(2— oylethoxycaIbamoyl)— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy] acetic acid lithium salt (2S)ﬂuoro[[(2S,5R)—3— methyl—7—0X0—2—(2— sulfamoylethylcarbamoyl)— 1,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy] acetic acid lithium salt ethyl 2-[[(2R)[[(2S,5R) oyl—3—methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— ] —2—ﬂu0r0— acetyl]0xymeth0xycarbonylamino ]—3—methyl—butan0ate tert-butyl -((((2S,5R)—6— ((S)—2—eth0xy— l —ﬂu0r0—2— oxoethoxy)—3—methyl—7—0X0— 1,6— diazabicyclo[3 .2. l]oct—3—ene—2— carboxamido)0xy)methyl)pyrrolid ine— l —carb0xylate ethyl -fluoro(((2S,5R)—3— methyl—7—0X0—2—((((S)—pyrrolidin— 2—yl)meth0xy)carbam0yl)— 1,6— diazabicyclo[3 .2. l]oct—3—en—6— yl)0xy)acetate TFA salt ethyl (2S)(((2S,5R)—2—((((S)— 4,4—diﬂu0r0pyrrolidin—2— yl)rneth0xy)carbam0yl)—3—methyl— 7-OXO- l ,6—diazabicyclo[3 .2. l]oct— 3—en—6—yl)0xy)—2—ﬂu0r0acetate TFA salt -ﬂuoro[[(2S,5R)—3— methyl—7—0X0—2—[[(2S)—pyrrolidin— 2—yl]meth0xycarbam0yl] — l ,6— diazabicyclo[3 .2. l]oct—3—en—6— yl]0xy] acetic acid TFA salt (2S)(((2S,5R)((((S)-4,4- diﬂuoropyrrolidin—2— yl)rneth0xy)carbam0yl)—3—methyl— 7-OXO- l ,6—diazabicyclo[3 .2. l]oct— 3—en—6—yl)0xy)—2—ﬂu0r0acetic acid TFA salt [(2R)—2—[[(2S, 5R)—2—carbam0yl— 3—methyl—7—0X0—l,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy]—2—ﬂu0r0— acetyl]0xymethyl 2,2— dimethylpropanoate indan-S-yl (2R)[[(2S,5R) oyl—3—methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl] oxy] —2—ﬂu0r0—acetate (2S)ﬂuoro[[(2S,5R)—3— methyl—2—(0xetan—3—ylcarbam0yl)— 7-OXO- l ,6—diazabicyclo[3 .2. l]0ct— 3—en—6—yl]oxy]acetic acid lithium (2S)ﬂuoro[[(2S,5R)[2- (methanesulfonamid0)ethylcaIba m0yl]—3—methyl—7—0X0—1,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy] acetic acid lithium salt (2S)ﬂuoro[[(2S,5R)—3— methyl—2—(0xazol—2— ylcarbamoyl)—7-OXO- 1,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy] acetic acid lithium salt (2S)ﬂuoro[[(2S,5R)—3— methyl—7—0X0—2—(pyrazin—2— ylmethylcarbamoyl)— l ,6— diazabicyclo[3 .2. 3—en—6— yl]0xy] acetic acid lithium salt (2S)[[(2S,5R) propylmethoxycarbamoyl)— 3—methyl—7—0X0—l,6— diazabicyclo[3 .2. l]0ct—3—en—6— ] —2—ﬂu0r0—acetic acid lithium salt —[[(2S,5R)—2—[(3—amin0—3— oxo—propyl)carbam0yl]—3—methyl— 7-OXO- l ,6—diazabicyclo[3 .2. l]0ct— 3—en—6—yl]oxy]—2—flu0r0—acetic acid lithium salt (2S)ﬂuoro[[(2S,5R)—3— methyl—7—0X0—2—[(5— oxopyrrolidin—2— yl)meth0xycarbam0yl] — l ,6— icyclo[3 .2. l]0ct—3—en—6— yl]0xy] acetic acid lithium salt (2S)ﬂuoro[[(2S,5R)—3— methyl—7—0X0—2—[2—(5— rolidin—2— yl)ethylcarbam0yl]—l,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy] acetic acid lithium salt (2S)ﬂuoro[[(2S,5R)—3— methyl—7—0X0—2—(3— sulfamoylpropylcarbamoyl)— 1,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy] acetic acid lithium salt (2S)ﬂuoro[[(2S,5R)—3— methyl—7—0X0—2—[2— (sulfamoylamin0)ethylcarbamoyl] — l ,6—diazabicyclo[3 .2. l]0ct—3—en— xy] acetic acid lithium salt (2S)[[(2S,5R)[(tert- butoxycarbonylamin0)methyl]—3— methyl—7—0X0—l,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy] —2—ﬂu0r0—acetic acid m salt (2S)[[(2S,5R) (aminomethyl)—3—methyl—7—0X0— l,6—diazabicyclo[3 .2. l]0ct—3—en—6 yl]0xy] —2—ﬂu0r0—acetic acid (2S)[[(2S,5R) (acetamidomethyl)—3—methyl—7— 0X0— 1 zabicyclo[3 .2. l]0ct—3— en—6—yl]0xy]—2—flu0r0—acetic acid lithium salt (2S)ﬂuoro[[(2S,5R)—3— methyl—7—0X0—2—[[(2,2,2— triﬂuoroacetyl)amin0]methyl]— l,6—diazabicyclo[3.2.l]0ct—3—en—6— yl]0xy] acetic acid lithium salt ethyl (2S)fluoro[[(2S,5R) (cyanomethylcarbamoyl)—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl] oxy] acetate ethyl (2R)—2—ﬂu0r0—2—[[(2S,5R)—2— (cyanomethylcarbamoyl)—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl] oxy] acetate (2S)ﬂuoro[[(2S,5R) (cyanomethylcarbamoyl)—3— —7—0X0—l,6— icyclo[3 .2. l]0ct—3—en—6— yl]0xy] acetic acid lithium salt ethyl (2S)fluoro[[(2S,5R) (cyanomethylcarbamoyl)—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl] oxy] acetate ethyl (2R)—2—ﬂu0r0—2—[[(2S,5R)—2— (cyanomethylcarbamoyl)—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. 3—en—6— yl] oxy] acetate ethyl -fluoro[[(2S,5R) (hydroxymethylcarbamoyl)—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl] oxy] e ethyl (2R)—2—ﬂu0r0—2—[[(2S,5R)—2 (hydroxymethylcarbamoyl)—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl] oxy] acetate (2S)ﬂuoro[[(2S,5R) (hydroxymethylcarbamoyl)—3— methyl—7—0X0—l,6— icyclo[3 .2. l]0ct—3—en—6— yl]0xy] acetic acid lithium salt (2S)ﬂuoro[[(2S,5R) (acetamidomethylcarbamoyl)—3— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl]0xy] acetic acid lithium salt (2S)ﬂuoro[[(2S,5R)—3— methyl—7—0X0—2— [(sulfamoylamin0)methylcarbamo yl]—l,6—diazabicyclo[3.2.l]0ct—3— en—6—yl]0xy] acetic acid lithium ethyl 2—(((2S,5R)—2—carbam0yl—4— methyl—7—0X0— l ,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl)0xy)—2,2—diflu0r0acetate S,5R)—2—carbam0yl—4— methyl—7—0X0—l,6— diazabicyclo[3 .2. l]0ct—3—en—6— yl)0xy)—2,2—diﬂu0r0acetic acid lithium salt ethyl 2—(((2S,5R)—2—carbamoyl—4— methyl—7—oxo— l ,6— diazabicyclo[3 .2. l]oct—3—en—6— yl)oxy)acetate S,5R)—2—carbamoyl—4— methyl—7—oxo—l,6— diazabicyclo[3 .2. l]oct—3—en—6— yl)oxy)acetic acid lithium salt ethyl (2R)—2—(((2S,5R)—2—cyano—4— —7—oxo— l ,6— diazabicyclo[3 .2. l]oct—3—en—6— yl)oxy)—2—fluoroacetate (2R)—2—(((2S,5R)—2—cyano—4— methyl—7—oxo—l,6— diazabicyclo[3 .2. l]oct—3—en—6— yl)oxy)—2—ﬂuoroacetic acid lithium salt isopropyl 2—(((2S,5R)—2— carbamoyl—4—methyl—7—oxo— l ,6— diazabicyclo[3 .2. l]oct—3—en—6— yl)oxy)acetate Compounds of the invention e those of formulae (I), (Ia), (II), (Ila), (III), (Illa), (IV), (IVa), (V), (Va) in free base (uncharged) state, as well as pharmaceutically acceptable salts thereof. £104 — As used herein the term “alkyl” refers to both straight and branched chain saturated arbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as “propyl” are specific for the straight chain n only and references to individual branched chain alkyl groups such as ‘isopropyl’ and “3 —pentyl” are specific for the branched chain version only. In one aspect, “alkyl” is methyl.

Halo — As used herein, the term “halo” is intended to include ﬂuoro, chloro, bromo and iodo.

In one aspect, the “halo” may refer fluoro, chloro, and bromo. In r aspect, “halo” may refer to ﬂuoro or chloro. In still another aspect, “halo” may refer to fluoro. In yet another , “halo” may refer to chloro.

Haloalkyl — As used herein is an ” moiety as d above substituted with one or more halogen atoms. In one aspect, a “haloalkyl” may be —CHF2, —CH2F or —CF3.

Cycloalkyl — In one aspect, alkyl” refers to a saturated monocyclic carbon ring, of which one or more —CH2— groups may be optionally replaced with a corresponding number of —C(O)— groups. Illustrative es of alkyl” include cyclopropyl, cyclobutyl, cyclopentyl, and cyclopentenyl. In one aspect, “3— to 5—membered carbocyclyl” may be cyclopropyl. —7 Membered Heterocyclyl — The term “5—7 membered heterocyclyl” refers to a saturated or partially saturated, non—aromatic monocyclic ring containing 5 to 7 ring atoms, of which at least one ring atom is selected from nitrogen, , and oxygen, and of which a —CH2— group may be ally replaced by a —C(O)— group. Analogously, “5—6 membered cyclyl” refers to a saturated or partially saturated, non—aromatic clic ring containing 5 to 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and , and of which a —CH2— group may be optionally replaced by a —C(O)— group. Unless otherwise specified, “5—7 ed heterocyclyl” and “5—6 membered heterocyclyl” groups may be carbon or nitrogen . Ring nitrogen atoms may be optionally oxidized to form an N—oxide. Ring sulfur atoms may be optionally oxidized to form S—oxides or sulphones.

Illustrative examples of “5—7 membered heterocyclyl” and “5—6 membered heterocyclyl” include, but are not limited to, azetidinyl, dioxidotetrahydrothiophenyl, 2,4—dioxoimidazolidinyl, 3,5—dioxopiperidinyl, furanyl, olyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxoimidazolidinyl, 3—oxo—l—piperazinyl, 2—oxopyrrolidinyl, 2—oxotetrahydrofuranyl, oxo—l,3—thiazolidinyl, piperazinyl, piperidyl, 2H—pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4—pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, lyl, l,3,4—thiadiazolyl, thiazolidinyl, thiomorpholinyl, thiophenyl, 4H—l,2,4—triazolyl, pyridine—N—oxidyl, tetrazolyl, oxadiazolyl, triazolyl, pyrazinyl, triazinyl, and homopiperidinyl. In one embodiment, the terms “5—7 membered heterocyclyl” and “5—6 membered heterocyclyl” includes siderophores of 5—7 or 5— 6 members which contain at least one heteroatom. — or 6—Membered Heteroaryl —The term “5—6 membered heteroaryl” refers to a monocyclic, aromatic heterocyclyl ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen. Unless otherwise specified, “5—6 membered WO 53215 heteroaryl” groups may be carbon or nitrogen linked. Ring nitrogen atoms may be ally oxidized to form an N—oxide. Ring sulfur atoms may be optionally oxidized to form S—oxides. rative examples of “5—6 membered heteroaryl” include furanyl, imidazolyl, isothiazolyl, isoxazole, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, dinyl, pyridinyl, pyrrolyl, tetrazolyl, azolyl, thiazolyl, enyl, and triazolyl.

Optionally substituted — As used herein, the phrase "optionally substituted" indicates that substitution is optional and therefore it is le for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, the appropriate number of hydrogens on the designated group may be replaced with a selection from the indicated tuents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound.

In one aspect, when a particular group is designated as being optionally tuted with one or more substituents, the particular group may be unsubstituted. In another , the particular group may bear one substituent. In another aspect, the particular substituent may bear two substituents. In still another aspect, the ular group may bear three substituents.

In yet another aspect, the particular group may bear four substituents. In a further aspect, the particular group may bear one or two substituents. In still a further aspect, the particular group may be unsubstituted, or may bear one or two substituents.

Pharmaceutically Acceptable — As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Mg— As used herein, the term “prodrug” refers to a chemically modified version of a cologically active agent that is transformed in vivo to e an active drug. (See Rautio, J., et al., Prodrngs: Design and Clinical Applications, Nature Rev., vol. 7, page 255 (March 2008)). In the present invention, prodrugs are used to make active beta—lactamase inhibitor compounds orally bioavailable following absorption from the gastrointestinal tract.

Effective Amount — As used , the phrase "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ient for use in a pharmaceutical ition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically—acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the ing physician.

Compounds of Formulae (I), (Ia), (II), (Ila), (III), (Illa), (IV), (IVa), (V), and (Va) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a nd as a salt may be appropriate. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, ate, lfate, 2—hydroxyethylsulfonate, oate, ate, hloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2—naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, e, tartrate, tosylate (p—toluenesulfonate), triﬂuoroacetate, and undecanoate. Examples of base salts include ammonium salts; alkali metal salts such as , lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N—methyl—D—glucamine; and salts with amino acids such as ne, lysine, omithine, and so forth. Also, basic nitrogen—containing groups may be quatemized with such agents as: lower alkyl halides, such as methyl, ethyl, , and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others.

Non—toxic physiologically—acceptable salts are preferred, although other salts may be useful, such as in isolating or ing the product.

The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a t or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion—exchange resin.

When a compound disclosed herein is depicted by name or structure and has one or more chiral centers, and where the name or ure encompasses more than one stereoisomer, e.g., does not indicate the chemistry at one or more chiral centers, it is to be understood that the name or structure encompasses all such stereoisomers and mixtures thereof.

The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Racemates may be separated into individual enantiomers using known ures (see, for example, Advanced c Chemistry: 3rd Edition: author J March, plO4—lO7). A le procedure involves formation of reomeric derivatives by reaction of the racemic material with a chiral auxiliary, followed by separation, for example by chromatography, of the diastereomers and then cleavage of the auxiliary species. Similarly, the above—mentioned activity may be evaluated using the standard tory techniques referred to after.

Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The enantiomers may be isolated by tion of a racemate for example by fractional crystallisation, resolution or HPLC. The diastereoisomers may be isolated by separation by virtue of the different physical properties of the diastereoisomers, for example, by fractional crystallisation, HPLC or flash chromatography. Alternatively particular stereoisomers may be made by chiral synthesis from chiral starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent.

When a specific isomer is designated, structurally or by name, it is favorably provided or ntially isolated from other stereoisomers of the same compound. In one aspect, a mixture containing a particular stereoisomer of a compound of Formulae (I), (Ia), (II), (Ila), (III), (Illa), (IV), (IVa), (V), or (Va) may contain less than 30%, particularly less than 20%, and more particularly less than 10% by weight of other stereoisomers of the same compound.

In another aspect, a e containing a particular stereoisomer of a compound of ae (I), (la), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) may contain less than 6%, particularly less than 3%, and more ularly less than 2% by weight of other stereoisomers of the compound. In another aspect, a mixture containing a particular stereoisomer of a compound of Formulae (I), (Ia), (II), (Ila), (III), , (IV), (IVa), (V), or (Va) may contain less than 1%, particularly less than 0.5%, and more particularly less than 0.3%, and still more particularly less 0.1% by weight of other stereoisomers of the compound.

In one aspect, the terms “infection” and “bacterial infection” may refer to a gynecological infection. In another aspect the terms “infection” and “bacterial infection” may refer to a respiratory tract infection (RTI). In still another, the terms “infection” and “bacterial infection” may refer to a sexually transmitted disease. In yet another aspect, the terms “infection” and “bacterial ion” may refer to an uncomplicated urinary tract infection (UTI). In yet another aspect, the terms tion” and “bacterial infection” may refer to a complicated urinary tract infection (cUTI). In a further aspect, the terms “infection” and “bacterial infection” may refer to acute exacerbation of chronic bronchitis (ACEB). In yet a further aspect, the terms tion” and “bacterial infection” may refer to acute otitis media.

In one aspect, the terms “infection” and “bacterial infection” may refer to acute sinusitis. In another aspect, the terms “infection” and “bacterial ion” may refer to an ion caused by drug resistant bacteria. In still another aspect, the terms “infection” and “bacterial infection” may refer to catheter—related sepsis. In yet another aspect, the terms “infection” and “bacterial infection” may refer to chancroid. In a r aspect, the terms “infection” and “bacterial infection” may refer to chlamydia. In still a further aspect, the terms “infection” and “bacterial infection” may refer to community—acquired pneumonia (CAP). In yet a further aspect, the terms “infection” and “bacterial ion” may refer to complicated skin and skin ure infection. In one aspect, the terms “infection” and “bacterial infection” may refer to uncomplicated skin and skin ure infection ($881). In another aspect, the terms “infection” and “bacterial infection” may refer to endocarditis. In still another aspect, the terms “infection” and “bacterial infection” may refer to e neutropenia. In yet another aspect, the terms “infection” and “bacterial infection” may refer to gonococcal cerVicitis. In a further aspect, the terms “infection” and “bacterial infection” may refer to ccal urethritis. In still a further aspect, the terms tion” and “bacterial infection” may refer to hospital—acquired pneumonia (HAP). In yet another , the terms “infection” and “bacterial infection” may refer to osteomyelitis. In a further aspect, the terms “infection” and “bacterial infection” may refer to sepsis. In still a further aspect, the terms “infection” and “bacterial infection” may refer to syphilis. In a further aspect, the terms “infection” and “bacterial infection” may refer to an abdominal infection (IAI).

In one aspect of the invention, the terms “infection” and “bacterial infection” may refer to an infection selected from the group ting of complicated y tract ion, uncomplicated urinary tract infection, kidney infection, lower respiratory tract infection, al—acquired bacterial pneumonia, pneumonia, acute bacterial prostatitis, acute bacterial skin and soft tissue infection, sepsis, intra—abdominal infection, and diabetic foot infection.

In one embodiment of the invention, the terms “infection” and “bacterial infection” refer to an infection caused by Gram—negative bacteria, also referred to as a “Gram—negative infection”. In one aspect of this ment, the Gram—negative infection is an infection resistant to one or more antibiotics. In one aspect of this embodiment, the Gram—negative infection is a multi—drug resistant infection. In one aspect of this embodiment, the Gram— negative ion is caused by one or more Enterobacteriaceae spp. pathogens. In one aspect of this embodiment, the one or more Enterobacteriaceae spp. pathogens includes one or more E. coli, K. pneumoniae, K. oxytoca, C. freundii, C. koseri, E. cloacae, P. mirabilis, M. morganii and/or S. marcescens. In one aspect of this ment, the one or more Enterobacteriaceae spp. ens includes one or more E. coli or K. pneumoniae en.

In another aspect of this embodiment, the Gram—negative ion is caused by one or more biothreat pathogens. In one aspect of this embodiment, the one or more biothreat pathogens is Burkholderia spp., Y. pestis, and/or F. nsis. In any of these aspects of the embodiment, the one or more egative pathogens may express one or more serine beta— lactamase enzymes. In one aspect of this embodiment, the one or more serine beta—lactamase enzymes includes one or more Class A, Class C and/or Class D beta—lactamase.

All the above mentioned infections can be caused by a variety of bacteria that potentially could be treatable with the claimed agents in combination with penicillin—binding protein inhibitors, or by itself. In one embodiment of the invention is a method of treating one or more of the infections listed above comprising administering to a subject suffering from a bacterial infection an effective amount of a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) or a pharmaceutically acceptable salt thereof, in combination with an additional antibiotic agent. In one aspect of this embodiment, the additional antibiotic agent is a actam antibiotic. In one aspect of this embodiment, the additional antibiotic agent is a penicillin—binding protein inhibitor.

In one , there is provided the use of a compound of Formulae (I), (la), (II), (Ila), (III), , (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the production of a bacterial peptidoglycan inhibitory effect, either alone or in combination with a penicillin—binding protein inhibitor, in a warm—blooded animal such as man.

In another aspect, there is provided the use of a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a bacterial infection in a warm—blooded animal such as man. In one , the compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, is administered in combination with an additional antibiotic agent, such as a beta—lactam antibiotic. In one aspect of this embodiment, the additional antibiotic agent is a penicillin—binding protein inhibitor. In one aspect of this embodiment, the additional antibiotic agent is a beta—lactam antibiotic. In one aspect of this embodiment, the beta—lactam antibiotic is selected from cefpodoxime, cefuroxime, tigemonam, loracarbef, cefixime, cephaleXin, cefadroxil, cefetamet, cefprozil, ceftibuten, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, oren, or a prodrug thereof. In one aspect of this embodiment, the beta—lactam antibiotic is cefpodoxime proxetil. In one aspect of this ment, the beta— lactam antibiotic is cefuroxime axetil. In one aspect of this embodiment, the beta—lactam antibiotic is cefpodoxime, or a prodrug thereof. In one aspect of this embodiment, the beta— lactam antibiotic is cefuroxime, or a prodrug f.

In still r , there is provided the use of a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, in the cture of a medicament for the treatment of complicated urinary tract infection, uncomplicated urinary tract infection, kidney infection, lower respiratory tract infection, hospital—acquired bacterial pneumonia, pneumonia, acute bacterial prostatitis, acute bacterial skin and soft tissue infection, sepsis, intra—abdominal infection, and diabetic foot infections, in a looded animal such as man. In one aspect of the ion, is the use of a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically able salt f, in the manufacture of a medicament for the treatment of complicated urinary tract infections. In one aspect of the preceding two embodiments, the nd of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) is stered in combination with an additional antibiotic agent. In one aspect of this embodiment, the additional antibiotic agent is a penicillin—binding protein inhibitor. In one aspect of this embodiment, the additional antibiotic agent is a beta—lactam antibiotic. In one aspect of this embodiment, the beta—lactam antibiotic is selected from oxime, cefuroxime, tigemonam, loracarbef, cefiXime, cephaleXin, cefadroxil, cefetamet, cefprozil, uten, cefditoren, nem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs f. In one aspect of this embodiment, the beta—lactam otic is cefpodoxime proxetil. In one aspect of this embodiment, the beta—lactam antibiotic is xime axetil. In one aspect of this embodiment, the beta—lactam otic is cefpodoxime, or a prodrug thereof. In one aspect of this embodiment, the actam antibiotic is cefuroxime, or a prodrug thereof.

In another aspect, there is provided a method for producing a bacterial peptidoglycan inhibitory effect, either alone or in combination with a penicillin—binding protein inhibitor, in a warm—blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt f.

In a further aspect, there is provided a method for treating a bacterial infection in a warm— blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof. In one aspect of this embodiment, the compound is as described for Formulae (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof. In one aspect of this embodiment, for a compound of Formulae (I), (II), (III), (IV) or (V), the compound is administered orally. In another aspect of this embodiment, the compound of Formulae (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, is administered in combination with an additional antibiotic agent. In one aspect of this ment, the additional otic agent is a penicillin—binding protein inhibitor. In one , the additional antibiotic agent is a beta—lactam antibiotic. In one aspect of this embodiment, the beta—lactam antibiotic is selected from cefpodoxime, cefuroxime, tigemonam, loracarbef, cefiXime, cephaleXin, cefadroxil, cefetamet, cefprozil, ceftibuten, cefditoren, nem, tebipenem, amoxicillin, carbenicillin, ir, ampicillin, cefditoren and prodrugs thereof. In one aspect of this embodiment, the beta—lactam antibiotic is cefpodoxime proxetil. In one aspect of this embodiment, the beta—lactam antibiotic is xime axetil. In one aspect of this ment, the beta—lactam antibiotic is oxime, or a prodrug thereof. In one aspect of this embodiment, the beta—lactam antibiotic is cefuroxime, or a prodrug thereof.

In a further embodiment, there is provided a method for treating a bacterial infection in a subject in need f, comprising administering to the subject an ive amount of a compound of Formulae (Ia), (IIa), (IIIa), (IVa) or (Va), or a pharmaceutically acceptable salt thereof enously, intraperitoneally, intramuscularly or subcutaneously, preferably intravenously. As such, a compound of Formulae (Ia), (IIa), (IIIa), (IVa) or (Va), or a pharmaceutically acceptable salt thereof are advantageously used when a patient is not able to take medication by mouth, e.g., in a hospital setting (e.g., in an intensive care unit, an ncy room setting, on a cardiology ﬂoor and the like), in an urgent care setting and a nursing home setting. In one aspect of this embodiment, the compound of Formulae (Ia), (IIa), (IIIa), (IVa) or (Va), or a pharmaceutically acceptable salt thereof, is stered intravenously (IV). In one apsect of this embodiment, the compound of Formulae (Ia), (IIa), (IIIa), (IVa) or (Va), or a pharmaceutically acceptable salt thereof, is administered until the patient is able to take medication orally, e.g.,for the duration of the al stay or urgent care stay, until such time the subject is able to be discharged from a hospital setting or urgent care setting or until such time until the t’s condition has improved so that the t can take medication orally, e.g., until the patient is able to orally take medication in a nursing home setting. In one aspect of this embodiment, the nd of Formulae (Ia), (IIa), (IIIa), (IVa) or (Va), or a ceutically acceptable salt thereof, is administered with a beta—lactam antibiotic. In one aspect of this embodiment, the beta—lactam antibiotic is selected from oxime, cefuroxime, tigemonam, loracarbef, cefixime, cephaleXin, cefadroxil, cefetamet, cefprozil, uten, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs thereof. In one aspect of this ment, the beta—lactam otic is cefpodoxime, or a prodrug thereof. In one aspect of this embodiment, the beta—lactam antibiotic is cefuroxime, or a prodrug thereof. In another aspect of this embodiment, the method further comprises administering an effective amount of a compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, to the subject in a community setting, after discharge from the hospital setting or urgent care setting or When the subject has improved sufficiently so that the subject is able to take medication orally, e.g., in a nursing home setting. In one aspect of this embodiment, the compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, is administered orally in a community setting. In one aspect of this embodiment, the compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, is administered in combination with the same beta—lactam otic that the compound of Formulae (Ia), (Ila), (Illa), (IVa) or (Va) is paired with in the hospital setting, urgent care setting or nursing home g. In one aspect of this embodiment, the administration of a compound of Formulae (Ia), (IIa), (IIIa), (IVa) or (Va) is followed by oral administration of a compound of a (I), (II), (III), (IV) or (V), or a pharmaceutically able salt thereof, once the t is able to take medication by mouth, e.g., once the patient has been discharged from the hospital setting or urgent care setting and is in a community setting or whose condition has sufficiently improved in a g home setting to orally take medication. Preferably, the switch from intravenous, intraperitoneal, intramuscular or subcutaneous (compound of Formulae (Ia), (IIa), (IIIa), (IVa) or (Va)) to oral administeration (compound of Formulae (I), (II), (III), (IV) or (V)) occurs without any gaps in the ent of the patient.

In still a further aspect, there is provided a method for treating complicated urinary tract infection, uncomplicated urinary tract infection, kidney infection, lower respiratory tract infection, hospital—acquired bacterial pneumonia (HAP), pneumonia, acute bacterial prostatitis, acute ial skin and soft tissue infection, , intra—abdominal infection, and diabetic foot infections, in a warm—blooded animal such as man, said method sing administering to said animal an effective amount of a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof. In still a further aspect, there is provided a method for treating complicated urinary tract infections, in a warm—blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof. In one aspect of either of the preceeding embodiment, the compound of Formulae(I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, is administered in combination with an additional antibiotic agent. In one aspect of this ment, the additional antibiotic agent is a penicillin—binding protein inhibitor. In one , the additional antibiotic agent is a beta—lactam antibiotic. In one aspect of this embodiment, the beta—lactam antibiotic is selected from cefpodoxime, cefuroxime, tigemonam, loracarbef, cefiXime, cephaleXin, cefadroxil, cefetamet, cefprozil, ceftibuten, cefditoren, faropenem, nem, illin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs thereof. In one aspect of this embodiment, the actam antibiotic is oxime proxetil. In one aspect of this embodiment, the beta—lactam otic is cefuroxime axetil. In one aspect of this embodiment, the beta—lactam antibiotic is cefpodoxime, or a prodrug f. In one aspect of this embodiment, the beta—lactam antibiotic is cefuroxime, or a prodrug thereof.

In yet a further aspect, there is provided a compound of Formulae (I), (la), (II), (Ila), (III), (IIIa), (IV), (IVa), (V), or (Va), or a ceutically acceptable salt thereof, for use in producing a bacterial peptidoglycan inhibitory effect, either alone or in combination with a penicillin—binding protein inhibitor, in a warm—blooded animal such as man. In one aspect, there is provided a nd of Formulae (I), (la), (II), (Ila), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, for use in treating egative bacterial infections, either alone or in combination with a beta—lactam antibiotic. In one aspect of this embodiment, the beta—lactam antibiotic is selected from cefpodoxime, cefuroxime, nam, loracarbef, cefiXime, cephaleXin, cefadroxil, cefetamet, cefprozil, ceftibuten, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs thereof. In one aspect of this embodiment, the actam antibiotic is cefpodoxime proxetil. In one aspect of this embodiment, the beta—lactam antibiotic is cefuroxime axetil. In one aspect of this embodiment, the beta—lactam antibiotic is cefpodoxime, or a prodrug thereof. In one aspect of this ment, the beta—lactam antibiotic is cefuroxime, or a prodrug thereof.

In one aspect of the invention, there is provided a method of inhibiting one or more beta— lactamase enzyme comprising administering a compound of Formulae (I), (la), (II), (Ila), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, to an animal in need thereof. In a further aspect, the one or more beta—lactamase enzyme is a serine beta—lactamase enzyme. In a further aspect, the one or more beta—lactamase enzyme is selected from the group ting of Class A, Class C and Class D. In a further asepct, the one or more beta—lactamase enzyme is a Class A enzyme. In a further aspect, the one or more beta—lactamase enzyme is a Class C enzyme. In a further asepct, the one or more beta— lactamase enzyme is a Class D enzyme. In a further aspect, the one or more beta—lactamase enzyme is a Class D enzyme and one or more of Class A and C s. In a further aspect, the one or more beta—lactamase enzyme is all three of Class A, C and D enzymes.

The beta—lactamase inhibitors of Formulae (I), (Ia), (II), (Ila), (III), (IIIa), (IV), (IVa), (V), or (Va) can be administered in combination with any beta—lactam antibiotic belonging, but not d to, the classes of clavams, carbapenems, monobactams, penems, penicillins, and or cephalosporins, or with any other compound susceptible to serine beta—lactamases. In one aspect of the invention, a nd of Formulae (I), (Ia), (II), (Ila), (III), (IIIa), (IV), (IVa), (V), or (Va) is combined with one or more of: penicillin, methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin, ﬂucloxacillin, temocillin, amoxicillin, ampicillin, co—amoxiclav, azlocillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, cephalexin, cephalothin, CXA— lOl, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan, cefoxitin, ceftriaxone, cefotaXime, oxime, cefiXime, ceftazidime, ceftobiprole medocaril, cefepime, cefpirome, ceftaroline, imipenem, meropenem, ertapenem, faropenem, sulopenem, nem, PZ—601 (Protez Pharmaceuticals), ME1036 (Forest Labs), BAL30072, MC—l, tomopenem, tebipenemn, aztreonam, nam, nocardicin A, or tabtoxinine—beta—lactam.

In one aspect of the invention, a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) is combined with cefpodoxime, cefuroxime, nam, cefixime or faropenem. In one aspect of the invention, a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) is combined with an antibacterial nd from the group consisting of penicillin V, illin, dicloxacillin, nafcillin, oxacillin, amoxicillin, ampicillin, bacampicillin, amoxicillin—clavulanate, carbenicillin, cefadroxil, cephaleXin, cephradine, or, cefprozil, cefuroxime , ir, loracabef, cefiXime, cefpodoxime, and ceftibuten, or a prodrug or salt thereof. In one aspect of the invention, a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) is combined with an antibacterial compound from the group consisting of cefpodoxime, xime, tigemonam, loracarbef, cefixime, cephalexin, cefadroxil, cefetamet, cefprozil, ceftibuten, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, oren and prodrugs thereof. In one aspect of the invention, a nd of Formulae (I), (Ia), (II), (IIa), (III), , (IV), (IVa), (V), or (Va) is combined with cefpodoxime, or a prodrug thereof, such as cefpodoxime proxetil. In one aspect of the invention, a nd of Formulae (I), (Ia), (II), (IIa), (III), , (IV), (IVa), (V), or (Va) is combined with cefuroxime or a g thereof, such as cefuroxime axetil.

In another aspect of the invention, the compound of Formulae (I), (II), (III) or (IV) is administered in combination with a beta—lactam antibiotic and an additional antibiotic and/or an additional beta—lactamase inhibitor. In one aspect of the invention, the additional antibiotic agent is selected from one of the classes of aminoglycosides, spectinomycins, macrolides, ketolides, streptogramins, oxazolidinones, tetracyclines, fluoroquinolones, quinolones, coumarin antibiotics, eptides, lipoglycopeptides, nitroimidazoles, ansamycins, phenicols, mupirocyn, ycin, ycin, linezolid, daptomycin, vancomycin, beta—lactams and the classes mentioned in ANTIMICROBIAL AGENTS (ASM Press, Ed: A. Bryskier (2005)).

In one aspect of the invention, the compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) is administered in combination with a beta—lactam antibiotic and a second agent which is designed to address beta—lactam resistance. In one aspect of the invention, the second agent ed to s beta—lactam resistance may be a o—beta— lactamase (MBL) inhibitor, also known as a Class B inhibitor.

In one aspect, there is provided a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt f, for use in treating a bacterial infection in a warm—blooded animal, such as man.

In another aspect, there is provided a nd of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically able salt thereof, for use in treating complicated urinary tract infection, uncomplicated y tract infection, kidney infection, lower respiratory tract infection, hospital—acquired bacterial pneumonia, pneumonia, acute bacterial prostatitis, acute bacterial skin and soft tissue infection, sepsis, abdominal infection, and diabetic foot infections, in a warm—blooded animal such as man. In another aspect, there is provided a compound of Formulae (I), (la), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, for use in treating cated urinary tract infections in a warm—blooded animal such as man.

In still another , there is provided a pharmaceutical composition comprising a compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one aspect of this embodiment, the pharmaceutical composition further comprises a beta—lactam antibiotic. In one apsect of this embodiment, the beta—lactam antibiotic is selected from cefpodoxime, xime, tigemonam, loracarbef, cefiXime, cephalexin, cefadroxil, cefetamet, cefprozil, ceftibuten, cefditoren , faropenem, tebipenem, illin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs thereof.

The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, s or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for e as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for enous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). In one aspect of the invention, the compound of Formulae (Ia), (Ila), , (IVa), or (Va), or a pharmaceutically acceptable salt thereof, is administered intravenously. In another aspect of the invention, the compound of Formulae (Ia), (IIa), (IIIa), (IVa), or (Va), or a ceutically acceptable salt thereof, is administered intravenously in combination with one or more other antibacterial agent. In one aspect of the invention, the compound of Formulae (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, is administered orally. In another aspect of the ion, the compound of Formulae (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, is stered orally in combination with one or more other antibacterial agent. In one aspect of any of these embodiments, the compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt f, is administered simultaneously with one or more other cterial agents. In another aspect of this embodiment, the compound of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va), or a pharmaceutically acceptable salt thereof, is administered consecutively with one or more other antibacterial agents, such as a beta—lactam antibiotic.

In one embodiment of the invention is a method of treating a bacterial infection in a person in need thereof, comprising administering to said person an effective amount of a compound of one of Formulae (Ia), (IIa), (IIIa), (IVa) or (Va) intravenously in combination with one or more additional antibacterial agent in a hospital setting, urgent care setting or nursing home setting ed by administering to said person an ive amount of a compound of one of Formulae (I), (II), (III), (IV) or (V) orally in combination with one or more additional antibacterial agent outside of, for example, a hospital setting, urgent care g or nursing home setting once the patient is again able to take medication by mouth.

In one embodiment of the invention is a method of treating a bacterial infection in a person in need thereof, comprising orally administering to said person an ive amount of a compound of one of Formulae (I), (II), (III), (IV) or (V) in combination with one or more additional antibacterial agent as an oral switch therapy following administering to said person an effective amount of one or more intravenously, intraperitoneally, intramuscularly or aneously —administered antibacterial agent, e.g., a compound of Formulae (Ia), (Ila), (Illa), (IVa) or (Va) or a pharmaceutically acceptable salt thereof. The , dose and duration of the antibiotic therapy and timing to switch from an intravenous, intraperitoneal, intramuscular or subcutaneous to oral medication are usually chosen by physician and can depend on the patient’ s health, his or her ability to receive an oral ent and the type of infections from which said person suffers. The patient may be switched from intravenous, intraperitoneal, intramuscular or subcutaneous to oral treatment when the patient becomes asymptomatic, has no fever or reduced fever (e.g., below 100.5O F, 1000 F, 99.50 F and the like), is removed from a ventilator or is no longer in need of intravenous fluids.

The compositions of the ion may be obtained by conventional procedures using tional pharmaceutical excipients well known in the art. Suitable pharmaceutically acceptable ents for a tablet formulation include, for example, inert ts such as lactose, sodium carbonate, calcium ate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; vative agents such as ethyl or propyl p—hydroxybenzoate; and anti—oxidants, such as ic acid. Tablet formulations may be ed or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 100 mg to WO 53215 2017/051692 about 4000 mg of an active ingredient. For oral administration, e.g., of compound of Formulae (I), (II), (III), (IV) or (V) or pharmaceutically acceptable salts thereof, 01 g to 10 g equiv of active ingredient per day are suitable; and for intravenous administration, e.g., of compound of Formulae (Ia), (Ila), (Illa), (IVa) or (Va) or pharmaceutically acceptable salts thereof, 0.5 to 8 g equiv of active ingredient per day are suitable.

In addition to the compounds of the present invention, the pharmaceutical composition of this invention may also n or be co—administered (simultaneously, sequentially or separately) with one or more known drugs selected from other ally useful classes of antibacterial agents (for example, macrolides, quinolones, beta—lactams or aminoglycosides) and/or other anti—infective agents (for example, an antifungal triazole or amphotericin). These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic iveness. Compounds of this invention may also contain or be inistered with bactericidal/permeability—increasing protein (BPI) products or efflux pump inhibitors to improve activity against Gram—negative bacteria and bacteria resistant to antimicrobial agents.

As stated above the size of the dose ed for the therapeutic or prophylactic treatment of a particular disease state will arily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient. nds of Formulae (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va) may be prepared in a variety of ways. The processes shown below illustrates a method for synthesizing compounds of Formula (I) (wherein R1, R2, and R3 unless otherwise defined, are as defined above). The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, on temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one d in the art of c synthesis that the functionality present on various ns of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods must then be used. The Schemes and Processes are not intended to present an exhaustive list of methods for preparing the compounds of Formulae (I), (Ia), (II), (Ila), (III), (Illa), (IV), (IVa), (V), or (Va); rather, additional techniques of which the skilled chemist is aware may be also be used for the compounds’ synthesis. The claims are not intended to be limited to the structures shown in the Schemes and Processes.

It will also be appreciated that in some of the reactions shown in the Schemes and ses mentioned herein, it may be necessary/desirable to protect any sensitive groups in nds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in ance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic sis, published by John Wiley and Sons, ) and as described hereinabove.

The skilled chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples and Scheme herein, to obtain necessary starting als and products.

If not cially available, the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are ous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples.

It is noted that many of the starting materials for synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of ses reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5th Edition, by Jerry March and Michael Smith, published by John Wiley & Sons (2001), for l guidance on reaction ions and reagents.

WO 53215 l Procedures and Schemes: In one aspect, compounds of Formulae (I) and (la), or pharmaceutically acceptable salts thereof, may be prepared by the s outlined in Scheme 1. From the Weinreb amide, introduction of substituents at the R3 position of Formulae (I) and (la) may be done Via a Grignard reaction. The ester moieties can be introduced by palladium—catalyzed deallylation followed by alkylation with cetates. Hydrolysis of the esters yield the acids. atively, other R1 groups could be obtained by modifying the primary alcohol.

SCHEME 1: [C3H5PdCI]2 9M9 H IIgand (RR) HO/V\ TBSCI N N \ O Oll‘hthallmlde TBSO/\i/\ h drazine B imidazole y r — N32C03 DCM O O N O MeOH’ 65C—,TBSO/\/\ DCM O Boc’ ;\ NH2 Boc20, DMF o N’O'V'e primary amine i Weinreb amide 2\ M /n, R3 //. R3 /n, R3 MgBr TBSO \ a-Grubbs TBSO GE TBSO '- \ AllONH-Ns, TBSO \ ' 2nd gen_ cat. CeCI3,NaBH4, PPh3,DIAD, THF, 0 C ,N N /N Boc’ -, /N ,OA“ Boc %% toluene 65C OMeOH,OC Boc ’OH toluene, RT Boo N ii i o HO/IIHCER3 R3 R3 HO \ R8R7N \ RsRvNJLu. R3 TBAF N ’OA” Cr03,H5|06 N [OAII HNR7R8,HATU N ,OA” ZnBr —» Boc’ [y — Boc’ 'i‘ _> Boc’ Ii] —2- HN N,OAII Ns Ns Ns NS primary alcohol 0 i 3 Jl, 1.PdPPh 3 , R 13l_dim:]{i1._,MeOH ii R3 i R3 R8R7N \ R8R7N , \ , R " '- LiOH, R8R7N '- \ R8R7N " \ ' - - y- PhSH trIphosgene N barbIturIc aCId N THFHO I 2 N HN OAII R4 R4 N! /J—N\ 2. base, DMF /J—N\ R5 /]—N\ R5 H o OAII RARS o 0 OR‘3 0 O OH BrJ$rOR6 O O An alternative means of synthesizing compounds with substitution at R3 is shown in Scheme 2, with the key steps being a Diels—Alder reaction and a nitroso ene reaction.

SCHEME 2 H2N\S"\E O (5) || j/RB(3'4 5C1) 0 O o EtOJk" / k )L,, R3 HCI J'n, R3 THF,'H20 Eto ’ EtO —> EtO , I N \\ 0 ~”-s TMSOTf l (Boc)2O l OQS’N Boc’N DielsAlder 4:\ )L, R3 CDI NH OAc j, R3 302%? JL R3 TBSCI imi HzNJL’“ \ HO 0/ ,_4_, H2N " _2—’ H2“ " \ —' ' N OTBS /N Boc /N nitroso ene ,N ,OH Boo Boo Boo N, I}! Boo R3 ‘i ZnBr2 HZNJI’“ \ triphosgene HZNJI'“ R3 HN N,OTBS N H N\ O OTBS The acetate and ester moieties can be introduced in one or two steps according to Scheme 3.

SCHEME 3 HF, Py O OH O O COZRs In another aspect, compounds with formulae (1) and (la) or pharmaceutically acceptable salts f, may be prepared by the process ed in Scheme 4, where substitution at R2 can be installed Via a Michael addition to enone 1, followed by oxidation to afford enone 2, from which the chemistry is r to that bed in Scheme 1.

SCHEME 4 R2 R2 1. R2Li, Cul T350 (1 W," W 2. TMSCI, DIEA TBSO Pd(0AC)2 TBSO \ /N N Boo 0 Bee” OTMS Boc’N o enone 1 enone 2 Alternatively, the R1 amide can be installed after urea cyclization according to Scheme 5.

SCHEME 5 R2 R2 R2 R2 /’h, ZnBrZ /’I., PhSH /’I., tnphosgene' /”I.

TBSO \ TBSO \ TBSO \ TBSO \ ,N ,OAII HN ,OAII HN ,OAII N Boc N N N I N Ns Ns 0/ ‘ R2 j R2 2 Crog, H5|05 HNR7R8v HATU’ )0 R TBAF HO/I' \ MHO L»R8R7N \ N\ N N‘ 0/ OAII 0/ OAII 0/ 0A” Compounds with tution at R2 can also be synthesized from ’s aldehyde as shown in Scheme 6. The route from the primary amine to compounds with formulae (1) or (la) is similar to Scheme 1.

SCHEME 6 O OH O/\—// O RZ-MgBrﬂ Dess- Martin 0/\—‘/<(|:W2WiLa.“ >LN1)TSOH0V2 TBSOAR2 AJL 2 ZnBr2 TBSO . R2 N‘ N‘ R _ —> : 2) BOCZO NH Boo Boo Boo NH2 3) TBSCI Additionally, compounds with substitution at R2 can be synthesized according to Scheme 7 below, Where the key step is a nitroso ene on. The amide can also be installed earlier in the synthesis from the carboxylic acid and carried through to the end.

SCHEME 7 0 0 HOJﬁ + || \‘ S‘NH2 H20 0 1 4A sueves, DCM rt ., = OH MeOH rt ('35 CH30H NH2 carboxylic acid 0 R2 0 F32 0 F32 JOL ' AIIyI-Br,LiOH \O)l,,,‘/\/ (Boc)20 \OJIII.,(:\/ RCM catalyst \OJLH Boo—NHOHVCUCI \o “d I—> /N ,Boc DMF,r1 HN\/\ tBuOH,requx Boc’NA DCM, rt Boo/N Py,02,DCM,rt Boc [i] nitroso ene OH R2 0 R2 o o R2 \O) IndL \ )L.

ZnBrz sgene O —> —’ N Boo/N BOC 'i" DCM,rt \OJLh'dHN N,OTBS DIEA,ACN,rt The alkyl bromoacetates for introduction of the carboxylic acid and ester moieties can be prepared by transesterification according to Scheme 8.

SCHEME 8 R4 R5 4 5 RBOH R R WW0“ —’ Brxir0R6 KOtBu o o Chiral bromofluoroacetates for introduction of the R and S fluorocarboxylic acid and ester es can be prepared by recrystallization of bromofluoroacetic acid with a chiral ethanamine followed by esterification according to Scheme 9.

SCHEME 9 F F F F CHCI - Br/SrOEt —>NaOH Br/KrfOH NH2 3 (R) o- (S) R OH, Meglel6 Br 3 —>Br (R) O o Recrystallization o EH43 o times in CHCI3 In any of the above—mentioned pharmaceutical compositions, processes, methods, uses, medicaments, and manufacturing features of the instant invention, any of the alternate embodiments of the compounds of the invention described herein also apply. For e, further details and method of ming the nitroso ene reaction on a variety of substrates are as described below in the example section. These details and methods include e.g., a first process for forming a compound of the formula VI: R1,," R3 N PG' OH (VI); or a salt thereof, n R1 is —C(O)NR7R8, —C(O)OR7, —CHZOR7, —CN, phenyl, a 5—6 membered heteroaryl, — C(O)NR’NR’C(O)R9, —C(O)NR’OR10, or a C1—C6 alkyl group, wherein the alkyl group is tuted with one to three groups consisting of halo, C1—C3 alkoxy, —OH, —CN, —NR7R8, —NR7COR9, a 5—6 membered heteroaryl and a 5—7 membered heterocyclyl, and wherein the phenyl and heteroaryl represented by R1 are optionally and independently substituted with l— 3 groups selected from halo, —OH, C1—C3 alkoxy, —CN, —NR7R8, and R8; R2 and R3 are each independently selected from hydrogen, halo, C1—C3 alkyl, and C3— C6 cycloalkyl, ed that at least one of R2 and R3 is other than hydrogen; each R7 and R8 are independently hydrogen, C1—C3 alkyl, C1—C3 alkoxy, phenyl, C3—C6 lkyl, 4—7 membered heterocyclyl, or 5—6 membered heteroaryl, wherein the alkyl, alkoxy, , cycloalkyl, heterocyclyl or aryl represented by R7 or R8 is optionally and independently substituted with 1—6 groups selected from a 5—6 membered heterocyclyl optionally substituted with one or two —F atoms, carboxyl or —CO(OC1—6 alkyl), 5—6 ed heteroaryl, —CN, —OH, C1—C3 alkyl optionally tuted with —NH2 or —OH, C1— C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy -NHCO(C1-C3alkyl), -NHCO(C1-C3alkoxy), —S(O)2NR’R”, —NHS(O)2NR’R”, —NHS(O)2(C1-C3alkyl), -NR’R”, and -C(O)NR’R”; each R9 is C1—C6 alkyl, C1—C6 haloalkyl, C1—C6 koxy or C1—C6 alkoxy; each R’ and R’’ is independently hydrogen, methyl, ethyl or propyl; or R’ and R’ ’ are taken together with the nitrogen to which they are attached to form a 5—6 membered heterocyclyl; and PG and PG’ are each independently an amine protecting group; the process comprising reacting a compound of the formula XI: PG (X1); or a salt thereof, with PG’NHOH in the presence of an oxidant to form the compound of the Formula VI; Also provided is a second s for forming a compound of the formula VI: R1,,“ R3 N PG' OH (VI); or a salt thereof, wherein R1 is —C(O)NR7R8, —C(O)OR7, —CHZOR7, —CN, phenyl, a 5—6 membered heteroaryl, — C(O)NR’NR’C(O)R9, R’OR10, or a C1—C6 alkyl group, wherein the alkyl group is substituted with one to three groups ting of halo, C1—C3 alkoxy, —OH, —CN, —NR7R8, —NR7COR9, a 5—6 membered heteroaryl and a 5—7 membered heterocyclyl, and wherein the phenyl and heteroaryl represented by R1 are optionally and independently tuted with l— 3 groups selected from halo, —OH, C1—C3 alkoxy, —CN, —NR7R8, and —CONR7R8; R2 and R3 are each ndently ed from hydrogen, halo, C1—C3 alkyl, and C3— C6 cycloalkyl, provided that at least one of R2 and R3 is other than hydrogen; each R7 and R8 are independently hydrogen, C1—C3 alkyl, C1—C3 alkoxy, phenyl, C3—C6 cycloalkyl, 4—7 membered heterocyclyl, or 5—6 membered heteroaryl, wherein the alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl represented by R7 or R8 is optionally and independently tuted with 1—6 groups selected from a 5—6 ed heterocyclyl optionally substituted with one or two —F atoms, yl or —CO(OC1—6 alkyl), 5—6 membered heteroaryl, —CN, —OH, C1—C3 alkyl optionally substituted with —NH2 or —OH, C1— C3 haloalkyl, C1—C3 haloalkoxy, C1—C3 alkoxy —NHCO(C1—C3alkyl), —NHCO(C1—C3alkoxy), —S(O)2NR’R”, —NHS(O)2NR’R”, —NHS(O)2(C1-C3alkyl), -NR’R”, and -C(O)NR’R”; each R9 is C1—C6 alkyl, C1—C6 haloalkyl, C1—C6 haloalkoxy or C1—C6 alkoxy; each R’ and R’’ is independently hydrogen, methyl, ethyl or ; or R’ and R’ ’ are taken together with the en to which they are attached to form a 5—6 membered heterocyclyl; and PG and PG’ are each independently an amine protecting group; the process comprising reacting a compound of the formula XI: PG (X1); or a salt thereof, with PG’NzO to form the compound of the Formula VI.

In a first aspect, the compound of formula XI in the first or second process is of the formula: R1,, ‘ R3 PG/O/ or a salt thereof.

In a second aspect, the compound of the formula VI in the first or second process is of the Formula VII: or a salt thereof.

In a third aspect, R2 in the first or second process, or formula VII is C1—C3 alkyl, wherein the remaining features are as described in the first or second process and the first or second aspect. Alternatively, R2 in the first or second s, or formula VII is methyl, wherein the remaining features are as described in the first or second process and the first or second aspect.

In a fourth apsect, the compound of the formula VI in the first or second process is of the Formula VIII: 0H (VIII); or a salt thereof, wherein the remaining features are as described in the first or second process and the first or second aspect.

In a fifth aspect, R3 in the first or second process, or formula VIII is C1—C3 alkyl, wherein the remaining features are as described in the first or second process and the first or second aspect. Alternatively, R3 in the first or second process, or a VIII is methyl, n the remaining features are as described in the first or second process and the first or second aspect.

In a sixth , R1 in the first or second process is selected from an oxadiazole, — C(O)NHNHC(O)(C1—C3 alkyl), —CH2NH2, -CH2NHCO(C1—C3 alkoxy), -CH2NHCO(C1—C3 alkyl), or —CH2NHCO(C1—C3 haloalkyl), n the oxadiazole of R1 is ally substituted with —OH, C1—C3 , —NR7R8, or —CONR7R8; and wherein the remaining features are as described in the first or second process and the first, second, third, fourth, or fifth aspect.

In a seventh aspect, R1 in the first or second process is selected from —CH2NH2, O o iu/Fi, min/>1, Kim/t;; and wherein the remaining es are as described in the first or second process and the first, second, third, fourth, fifth, or sixth aspect.

In an eighth aspect, R1 in the first or second process is: —CN, )1 HQ 0 HzN/V \MO )L Rﬂﬁ/Ol £2) >7;— H if N\N/ or Y \NN gi o . wherein R11 is hydrogen or —C(O)NH2; and wherein the remaining features are as described in the first or second process and the first, second, third, , fifth, sixth, or seventh aspect.

In a ninth aspect, R1 in the first or second process is R7R8, —C(O)OR7, or —CN; and n the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, or eighth aspect. Alternatively, R1 in the first or second process is —C(O)NH2, —C(O)OH, —CN, or —C(O)OC1—C6 alkyl; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, or eighth aspect. In another alternative, R1 in the first or second process is —CN or —C(O)NH2; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, or eighth aspect. In another ative, R1 in the first or second process is —CN; n the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, or eighth aspect. In another alternative, R1 in the first or second s is — 7R8; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, or eighth aspect.

In a tenth aspect, R7 and R8 in the first or second process are both hydrogen; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth aspect. atively, R7 in the first or second process is hydrogen and R8 is l) a phenyl optionally substituted with a C1—C3 alkyl or C1—C3 alkyl—NHZ, 2) an C1—C3 alkyl or 3) C1—C3 alkoxy, wherein each alkyl or alkoxy of ented by R8 is optionally and independently substituted with a C3—C6 cycloalkyl, —CN, —OH, —NH2, — SOzNHz, —NHSOzNH2, —C(O)NH2, —NHC(O)(C1—C3 alkyl), pyrazinyl, oxytanyl, oxazolyl, or a pyrrolidinyl optionally substituted with one or more yl, fluoro, or —C(O)O(C1—C6 alkyl); wherein the remaining features are as described in the first or second process and the first, , third, fourth, fifth, sixth, seventh, eighth, or ninth . In another alternative, R7 in the first or second s is hydrogen and R8 is selected from the group consisting of: ’3’ F if/~ g. 0 0 O 021; HZN \N HZN/ \/\O:1L9 NH 9 £9 9 9 H2N NH O O 0 ’ ’ ’ ’ O O); gA/i‘i AV o 0 g, 0 NH NH \/ O\ Mgi’ S / H N O HZN/N, , , O O O O \5/ \/ H2N/ \NM H2N/ \N/\ \ H HN/\é£ H and —CH20H; wherein.

, , , —CH2CN, the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth aspect.

In an eleventh aspect, the compound of the formula VI in the first or second process is of the Formula IX: jIII," H2N \ N PG' PG/ [11/ OH (IX); or a salt thereof.

In a twelfth aspect, the compound of the formula VI in the first or second process is of the Formula X: jIII!" H2N \ N PG' PG/ [\ll/ OH (X); or a salt thereof.

In a thirteenth , PG and PG’ in the first or second process taken together with the nitrogen atom of the amine which they are ting each independently form a carbamate, an amide, or a yl or N—aryl; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth aspect. Alternatively, PG and PG’ in the first or second process are each independently selected from t-butyloxycarbonyl (Boc), ybenzyl (Cbz),EilluorenylmethyloxycarbonyE (Fmoc), 2,2,2—trichloroethoxycarbonyl (Troc), CF3CO, acetyl (Ac), p—toluenesulfonamide (Ts), and methanesulfonyl (Ms); wherein the remaining features are as described in the first or second process and the first, , third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth aspect. In another ative, PG and PG’ in the first or second process are each the same; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth aspect. In another alternative, PG and PG’ in the first or second process are each a xycarbonyl; wherein the ing features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or h aspect.

In a fourteenth aspect, the first process futher comprises reacting the compound of formula XI with PG’NHOH in the presence of a metal catalyst; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth aspect. Alternatively, the metal catalyst is ed from CuCl, CuBr, CuI, CuCN, CuSCN, CuBr—Mezs, Cu(OAc)2, and CuOTf; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth aspect. In another alternative, the metal catalyst comprises a copper salt; wherein the ing features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, th, twelfth, or enth aspect.

In another alternative, the metal catalyst comprises a copper halide salt; wherein the remaining features are as bed in the first or second process and the first, second, third, fourth, fifth, sixth, h, eighth, ninth, tenth, eleventh, twelfth, or thirteenth aspect. In another alternative, the metal st is CuCl or CuBr—Mezs; n the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or enth aspect.

In a fifteenth aspect, the first process futher comprises reacting the compound of formula XI with PG’NHOH in the presence of an amine additive; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth . In one aspect, the amine additive process is pyridine, (lR,2R)—cyclohexane—l,2—diamine, N,N’— dimethylethane—l,2—diamine, 2,6—di—tert—butyl—4—methylpyridine, l,lO—phenanthroline, trans— exane— l ,2—diamine, Nl—(2—(diethylamino)ethyl)—N2,N2—diethylethane— l ,2—diamine, cis— cyclohexane—l,2—diamine, or Nl,Nl,N2,N2—tetramethylethane—l,2—diamine; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth aspect. atively, the amine is selected from pyridine, tidine, 4— dimethyiaminopyridine, picoiine, l,8—diazabicyclo[5.4.0]undec—7—ene, and N,N— diisopropylethylamine; wherein the remaining features are as bed in the first or second process and the first, , third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, h, thirteenth, or fourteenth aspect.In another alternative, the amine is pyridine; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth aspect.

In a nth apsect, the oxidant in the first or second process is 02, air, FCC13, MnO2, meta— peroxybenzoic acid (mCPBA), NaIO4, 2—iodoxybenzoic acid (IBX), (2,2,6,6— Tetramethylpiperidin—l—yl)oxyl (TEMPO), benzoyl peroxide (BPO), H103, urea—H202, I2, N— chlorosuccinimide (NCS), Dess—Martin inane (DMP), H2O2, or N—methylmorpholine N—oxide ; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth . Alternatively, the oxidant is urea—H202, H2O2 or 02; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth aspect.

In a seventeenth aspect, the reaction in the first or second process is carried out in a polar t; wherein the remaining features are as described in the first or second s and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, nth, or sixteenth aspect. Alternatively, the reaction is carried out in DCM, THF, MTBE, EtOAc, iPrOAc, MeCN, H2O, MeOH, EtOH, i-PrOH, , n- BuOH, 2—methyl—2—butanol, DMF, DMSO, ethylene glycol, hyleneglycol, sulfolane, sulfolane/H2O mixture, DMF/H2O, NMP/H2O, DCM/H2O, MeOH/H2O, EtOH/H2O, iPrOH/H2O, or n—BuOH/H2O; wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth aspect. In another alternative, the reaction is carried out in methylene de or sulfolane; n the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, th, twelfth, thirteenth, fourteenth, fifteenth, or nth aspect.

In an eighteenth aspect, the reaction in the first or second process r comprises the addition of water; wherein the remaining features are as described in the first or second WO 53215 process and the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth aspect.

Examples The invention will now be further described with nce to the following illustrative es in which, unless stated otherwise: (i) temperatures are given in degrees Celsius (°C); operations are carried out at room temperature or ambient temperature, that is, in a range of 18—25 0C; (ii) organic ons were dried over anhydrous magnesium e; evaporation of organic t was carried out using a rotary evaporator under reduced pressure (4.5 — 30 mmHg) with a bath temperature of up to 60 0C; (iii) chromatography means ﬂash chromatography on silica gel; thin layer tography (TLC) was carried out on silica gel plates; (W) in general, the course of reactions was followed by TLC or liquid chromatography/mass spectroscopy (LC/MS) and reaction times are given for ration only; (V) final products have satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectra data; (vi) yields are given for ration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in part per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHZ in DMSO—d6 unless otherwise stated; (viii) chemical symbols have their usual meanings; (iX) solvent ratio was given in volume : volume (v/v) terms; (X) an ISCO Combiﬂash refers to flash chromatography on silica gel using Isco Combiﬂash® separation : RediSep normal phase flash column, ﬂow rate, —40 ml/min; (Ki) the following abbreviations may have been used: ACN Acetonitrile BINAP 2,2’ —bis(diphenylphosphino)— l , l ’ —binapthyl BoczO tert-butyloxycarbonyl anhydride CDI rbonyldiimidazole DAST Diethylaminosulfur trifluoride DCM dichloromethane DIPEA/DIEA N, N—diisopropylethylamine DMAc N,N—dimethylacetamide DMF N,N—dimethylformamide DMAP thylaminopyridine DMSO dimethylsulfoxide ee enantiomeric excess EtOAc/EA ethyl acetate EtzO diethyl ether GC gas chromatography HATU O—(7—Azabenzotriazol— l—yl)—N,N,N‘,N‘—tetramethyluronium hexafluorophosphate Hex hexanes HPLC high—performance liquid chromatography hr/h hours KOtBu potassium utoxide LCMS liquid chromatography mass spectrometry LDA Lithium diisopropylamide MeCN acetonitrile MeOH methanol mins/min minutes MTBE methyl tert—butyl ether o/n overnight Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) PE petroleum ether iPrOH i—propanol rac. racemic TBAF n—butylammonium ﬂuoride TEA triethylamine TFA triﬂuoroacetic acid THF tetrahydrofuran TMS trimethyl silyl Tosyl, Ts para—toluenesulfonyl UPLC—MS ultra performance liquid chromatography mass spectrometry Nitroso ene conditions and trials In certain aspects, a nitroso ene reaction is used to install the requisite allylic hydroxylamine functionality. mar Adam and Oliver Krebs, Chem. Rev., 2003, 103, 4131—4146; Charles P. Frazier, Jarred R. Engelking, and Javier Read de Alaniz, J. Am. Chem.

Soc, 2011, 133 (27), 10430—10433; Leoni I. Palmer, Charles P. Frazier, Javier Read de Alaniz, Synthesis 2014, 46, 269—280). In the presence of an oxidant, hydroxylamines are oxidized to give highly reactive nitroso species, which react with an allylic substrate, as shown in Scheme 10. The oxidant can be an c oxidant or a combination of an oxidant, a metal st and optionally an amine additive. The nitroso species can be formed in situ (as in the reaction to form a nd of a VI) from the hydroxylamine or prepared separately and then added to the substrate, e.g., a compound of formula XI. For the l, 2, 3, 6— tetrahydropyridine scaffold with a N—carbamate functionality, it is believe that the A03) allylic strain exerted by the N—Boc functionality causes the R1 substituent to adopt a pseudo—axial orientation. It is ed to block the approach of the nitroso reactant from that face of the double bond. ore, the nitroso reactant reacts regio— and diastereoselectively from the opposite side of R1 to form the desired t in high diastereoselectivity and regioselectivity. The enantioselectivity is measured and has been demonstrated to be uniformly high, > 99% ee by chiral HPLC analysis.

SCHEME lO Oxidant, Solvent Catalyst, Addidive, Oxidant, t P62 i R2 PG _ [ 2 \NZO] ‘N=o R11, R3 PG1 \y R1’I. \ R3 H \N H I —> Nitroso r‘ /N ’OH N PG1 PG /1 Reactant R2 Ill H R3 PG2 Substrate R1 Product Reaction parameters, such as the oxidant, catalyst, ligand, solvent, reagent iometry, reaction temperature and on time can affect the reaction outcome and were screened and optimized. Some of the results are summarized in the following tables (ND 2 not determined).

Oxidant screen ate Reagents and Oxidant Conversion (by HPLC conditions area%) 02, 1 atm 5-9 FCClg, 1.2 eq. 43-2 MnO2, 1.2 eq. 10-28 Na104, 2.2 eq. 21-3 m—CPBA, 2.2 eq. 30-9 BPO, 1.0 eq.

TEMPO, 1.5 eq.

H103, 1.2 eq. 3-0 12, 1.2 eq. 24-6 BocNHOH (1.5 H202, 3.0 eq. 8-9 >—‘ PG1=PG2=BOC 6C1) MnO2, 1.2 eq.

R1=CONH2 CuCl (0.05 eq.) H202, 1 drop RZZMC, R3=H >—‘>—‘ Pyridine (0.013 IBX, 1.2 eq ND eq.) PhI(0Ac)2, 1.2 ND >—‘ (10V),17~25 0C, urea hydrogen 63.9 12.1 —60 h peroxide, 1.2 eq. r—‘r—‘r—‘H NCS, 1.0 eq. 59.9 12.5 DMP, 1.0 eq. ND 3% H202, 1.2 eq 70 3.1 1.5% H202, 1.2 64.4 4.1 [\)>—‘>—‘ 6% H202, 1.2 eq 73.6 5.5 NMMO, 1.0 eq. 37.8 38.6 PG1=PG2=BOC BocNHOH (1.5 36% isolated product R1=CO2Me eq.) R2=CH20PMB , CuCl (0.05 eq.) R3=H Pyridine (0.013 17~25 0C, —60 h N BocNHOH (1.5 46.08 10.28 eq.) FeC13 (1.2 eq.) 1.33 71.43 CuCl (0.05 eq.) Mn02 (1.2 eq.) 40.79 16.85 Pyridine (0.013 Na104 (1.2 eq.) 15.2 35.58 6C1) m-CPBA (1.2 3.04 89.1 PG1=PG2=BOC DCM eq.) [\DN R1=CONH2 (10V),20~30 0C, H104 (1.2 eq.) 0.52 46.47 RZZH, R3=MC 20 — 60 h 30% H202 (1.2 4.69 7.9 12 (1.2 eq.) 1.39 52.85 CaOz (1.2 eq.) 19.66 33.73 BOCNHOH (3.0 H202 (3%, 3 Cq.), 54.3 30.5 eq.), CuCl (0.05 16 h eq.), Sulfolane (5 V), H20 (5 V), H202 (3%, 3 Cq.), 38.8 0.24 Py (0.13 eq.), 96 h 0~5 OC, BOCNHOH (2.0 H202 (3%, 2 Cq.), 70.0 4.1 eq.), CuBr—Me2S 64 h (0.05 eq.), Sulfolane (5 V), H20 (0.5V), Py (0.13 eq.), 25~30 ts and Solvent, time sion (by conditions HPLC area%) Product SM % THF in DCM 77.6 5.0 (10 V), 90 h % THF in DCM 77.5 4.7 (10 V), 90 h % THF in DCM 68.8 19.4 (10 V), 90 h BOCNHOH (1.5 eq.) DCM (10 V), 68 h 65.8 20.4 CuCl (0.05 eq.) Pyridine (0.013 THF (10 V), 20 h 81.9 7.8 eq.), 15 OC, air EtOAc (10 V), 68 h 69.5 19.0 Acetone (10 V), 68 87.3 3.6 DCM (10 V) 35.2 20.6 DCM/H20 1:1 38.0 18.7 (10 V) MeOH (10 V) 50.0 21.8 MeOH/HzO 1:1 45.7 28.3 (10 V) EtOH (10 V) 47.5 15.9 i-PrOH (10 V) 43.3 10.0 PG1=PG2=BOC BOCNHOH (1.5 2—Methyl—2—butanol 48.0 16.6 eq.) (10 V) CuCl (0.05 eq.) Ethylene glycol (10 14.1 76.4 Pyridine (0.013 V) O’\ eq.), 20—30 0C, air, Polyethyleneglycol 9.3 96.9 60 h 2000/H20 (5 g/5 V) Sulfolane/HZO 1:1 57.0 14.7 (10 V) Sulfolane/HZO 9:1 55.58 17.5 (10 V) Sulfolane/HZO 3:7 23.3% 66.7 (10 V) Sulfolane/HZO 1:1 62.3 5.9 (5 V) BOCNHOH (1.5 DMF/HZO 58.11 1.71 eq.) 5V/5V CuCl (0.05 eq.) NMP/HZO 44.18 0.43 Pyridine (0.013 5V/5V eq.), 15—30 0C, 02 (1 atm), 48 h Catalyst screen l--Entry Substrate Reagents and Catalyst Conversion (by t SM .2 BocNHOH (1.5 Cu(OAc)2, 0.05 33.0 28.5 6(1) eq CuCl (005 69-) ane/HZO 58.49 1.30 Pyridine (0.013 5V/5V, 24 h n 69.) Sulfolane/HZO 38.83 0.24 DCM (10V), 5V/5V, 96 h -7 20~30 °C, 02 (1 HOAc/HZO 7.95 71.02 atm), 65 h 5V/5V, 96 h n CuCl, 0.05 eq., 24 58.49 1.30 nPGI=PG2=BOC CuCl, 0.05 eq., 96 38.83 0.24 R1=CONH2 h RFH’ R3=Me CuBr, 0.05 eq. 72 63.42 7.31 CuSCN 32.98 47.05 (0.05 eq.), 72 h BocNHOH (1.5 )2 59.69 15.94 69-), Pyridine (0.05 eq.), 72 h -14 (0.013 99.), CuBr—SMez 68.71 3.36 Sulfolane (5 V), (005 eq.), 72 h -15 H20 (5 V), 02, CuCN 5.60 5.32 ~30 °Ca (0.05 eq.), 84 h (0.05 eq.), 84 h Cu(OTf)-t01uene 66.24 9.31 (0.05 eq.), 84 h CuCl (0.05 eq.) 59.03 15.20 2—ethy10xazoline (0.05 eq.), 84 h CuCl . 26.26 (0.05 eq.) (0.05 eq.), 89 h Additive screen ate Reagents Conversion (by and HPLC area%) Pyridine (0.013 eq.) Ethane—1,2—diamine (0.013 eq.) (1R,2R)—cyclohexane—1,2—diamine (0.013 eq.) N] N]—dimethylethane—1,2—diamine (0.013 eq.) 2,6—di—tert—buty1—4—methy1pyridine 31.5 34.0 (0.013 eq.) 1,10—0—Phenanthroline ND (0.013 eq.) N0 ligand 24.8 47.4 H N2 «\NH2,0.013 37.73 27.4 eq, 72h 9 H2N\/\N/ 5.60 5.32 | 0.013 e., 72h 1,10—0—Phenanthroline (0.013 eq.), 72 h 64.45 5.14 BocNHO ”803- 0.013 eq. 96h H(1-5 Pyridine 58.49 1.30 eq-x CuCl (0.013 eq.), 24 h (005661), Pyridine 38.83 0.24 PG1=PG2=B Sulfolane (0,013 eq.), 96h 0C (5 V) P ' ' , 74.1 7.1 _ yridine R1—CONH2 H20 (5 (0.065 eq.), 84 h WO 53215 Pyridine (0.13 eq.), 24 h N) 64.43 9.24 PVNqN. 0.013 eq., 72 h HN/—\N_/—NH2 66.21 7.52 \—/ 0.013 eq., 72 h NH2 6.79 C'S'_ 0.013 eq., 72 h DMAP, 0.03 eq., 60 h 70.88 5.91 I 71.56 4.93 \N/\/N\ | 0.013 eq., 60h 0.013 eq., 89 h 18-Crown-6 (0.001 eq.), KCl (0.05 eq.), 36 h L—sodiurn ascorbate (0.1 eq.), 36 h 18-Crown-6 (0.001 eq.), KCl (0.05 eq.), Py (0.013 eq.), 86 h 0 O M0013 eq, wn—6 (0.001 eq.), KC1(0.05 eq.), 86 h O0.013 eq, 18—Crown—6 (0.001 eq.), KC1(0.05 eq.), 86 h BOCNHO Py (0.013 eq)., 85 h H (1.5 eq.), CuCl H H (0.05 eq.), HZN/\/N\/\M/\/N\/\NH2 Sulfolane 0.013 eq., 85 h (5 V), H20 (5 V), air, —30 0C Pyridine (0.013 eq.), 72 h DMAP (0.013 eq.), 86 h \N/\/N\ | 0.013 eq., 86 g Sulfolane NH2 (5 V), H20 (5 NH2 V), 02, 20— trans- 0.013 eq., 86 h OC BocNHO NH2 H (3 eq.), CuCl NHZ (0.05 eq.), trans- 0.013 eq, 66 h Sulfolane (5 V), H20 (5 V), H2O2 (3%, 3 After screening, the best ions for the ate with PG1=PG2=Boc, R1=CONH2, R2=Me, R3=H were: BocNHOH (1.5 eq), CuCl (0.05 eq), Py (0.013 eq), DCM (10V), 02 , 15—25 0C. For the substrate with PG1=PG2=Boc, R1=CONH2, R2=H, R3=Me, the best conditions were: BocNHOH (1.5 eq), CuCl (0.05 eq), Py (0.013 eq), Sulfolane (5 V), H20 (5 V), m), 15—25 0C or BocNHOH (2 eq), CuBr—Me2S (0.05 eq), Py (0.13 eq), Sulfolane (5 V), H2O (0.5 V), H2O2 (3% in water, 2—3 eq), 15—25 0C.

The following experimental procedures are for ration purposes.

BocNHOH (2 eq), CuBr-MeZS (0.05eq), i? Py(0.13eq), sulfolane j (5V), H2O (0.5V) H2N unfit H2N “.0/ /N ,OH Boo/N 800 I}! H202 (3% in water, 800 2eq), 15~25 0C, 29h To a mixture of starting material (1 eq), BocNHOH (2 eq), CuBr2—SMe2 (0.05 eq) was added sulfolane (5V) and H20 (0.5V), Pyridine (0.13 eq). The mixture was stirred 30—40 min at 15— °C. 3% H202 (2 eq) was added dropwise for 24—30 h. After the reaction is judged as complete, a solution of EDTA—2Na (0.31—0.32 eq. by weight) in water (3—3.2 x by weight) and MTBE (7.7 x by weight) were added. The resulting mixture was stirred for 20—30 min and settled for 20—30 min. The two phases were separated. The aqueous phase was extracted with MTBE (4x by weight) three times. The ed organic solution was dried with NaZSO4 and filtered, concentrated and ed by assay. 47.5% yield, 74.12% purity by HPLC % area. o o H (1.5 eq.) CuCl (0-05 eq-) HzN " \ H2N 0 Boc’N ,N ,Boc Py (0.013 eq.). 02 (9) 30° N DCM OH To the crude solution of substrate from previous step in DCM was added CuCl (0.05 eq.), BocNHOH (1.5 eq.) and Py (0.013 eq.). The e was stirred under 02 atmosphere at 20i5 °C until the starting material is 35% by HPLC %area. EDTA—2Na solution (5.0 vol) was d and the resulting mixture was stirred for at least 4 hours at 25i5 OC. The two phases were separated. The aqueous phase was extracted with DCM (3.0 vol) two times. The organic phases were combined and washed with water (5.0 vol) one time, concentrate under vacuum at <40 °C to ~ 3.0 vol. i—PrOAc (5.0 V) was charged to the reactor and the mixture was concentrated under vacuum at<40 °C to ~ 4.0 vol. This process was repeated one more time. n—Heptane (5.0 vol) was added to the reactor at 40i5 OC. The resulting mixture was gradually cooled to 20i5 0C. Solid was obtained by centrifuge and washed with i—PrOAc/n— Heptane (1:1, 2 vol) and dried under vacuum at 35i5 °C at least for 12 hours. 71.68% yield for 2 steps, 99.7% purity by HPLC %area. ediate 1: S 1-h drox buten l isoindoline-l 3-di0ne A 2—L reaction ﬂask containing a stir bar and sodium carbonate (1.981 g, 18.69 mmol) was placed under high vacuum and dried with a heating gun for ten minutes. Upon g, the ﬂask was backfilled with en. To it was added allylpalladium chloride dimer (0.553 g, 1.53 mmol), (1R,2R)—(+)—1,2—diaminocyclohexane—N,N'—bis(2—diphenylphosphino—1— naphthoyl) (CAS 174810—09—4)(3.36 g, 4.25 mmol), and phthalimide (50 g, 339.83 mmol).

The ﬂask was then purged with nitrogen for ten minutes. 1.4 L methylene chloride, previously degassed with a nitrogen line for ten minutes, was then added. This suspension was placed under an atmosphere of nitrogen; it was ately stirred and sonicated over a ten—minute period to facilitate solvation. At that time, it was a yellow or light orange solution containing white solid. To this mixture was added 2—vinyloxirane (24.06 g, 343.23 mmol).

The resulting mixture was d under a nitrogen atmosphere at ambient temperature for approximately 48 hours. is during that time by LCMS and TLC (1:1 hexanes:ethyl acetate) suggested progression of the reaction, and final analyses by those s suggested complete conversion of starting al to one major product. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The yellow, viscous ﬂuid was injected onto a 330—g silica column: a minimal volume of ene chloride was used to thin the crude material. Silica gel chromatography (15 —75% ethyl acetate in hexanes, 40 minutes, 330 g column) was used to isolate the desired product as a viscous yellow ﬂuid that became a pale yellowish white solid (69.6 g, 94%) over a period of hours under reduced pressure.

Optical Rotation : (2.02 g / 100 mL, methylene chloride) literature value = —72.2, obtained value = —71.

Intermediate 2: S 1- tert-but ldimeth lsil 10x buten l isoindoline-l 3-di0ne To a d solution of (S)—2—(1—hydroxybut—3—en—2—yl)isoindoline—1,3—dione (Intermediate 1, 69.4 g, 319.49 mmol) and imidazole (26.1 g, 383.39 mmol) in methylene chloride (160 mL), at ambient temperature under an atmosphere of nitrogen, was added tert— butyldimethylchlorosilane (55.4 g, 367.41 mmol) as a solid. This addition was performed over imately ten minutes. Warming of the mixture was observed during this addition.

After two hours stirring, the solution was poured into a saturated on of aqueous sodium bicarbonate (approximately 150 mL); this biphasic mixture was shaken, and the organic layer was separated. The aqueous layer was back—extracted three times with 200 mL methylene chloride each time. The organic layers were ed, dried over ium sulfate, filtered, and concentrated in vacuo. The d product was obtained as a pale yellow solid after drying overnight under high vacuum (107 g, 101%).

Intermediate 3: S tert-but ldimeth lsil 10x butenamine TBSOM To a stirred solution of (S)—2—(1—(tert—butyldimethylsilyloxy)but—3—en—2—yl)isoindoline—1,3— dione (Intermediate 2, 108.28 g, 326.65 mmol) in methanol (1 L), at ambient temperature under a nitrogen atmosphere, was added hydrazine (35.9 ml, ll43.29 mmol). The yellow on was heated to 65 OC. Within 30 minutes of reaching reaction temperature, a white precipitate was observed in the on mixture; this solid quickly became the bulk of the mixture, and at that time water (about 150 mL) was added to the reaction mixture. The reaction continued stirring without uption and within a few minutes the solid dissolved.

Upon complete conversion as indicated by LCMS analysis (both starting material and product give strong UV signals and are easily identified by LCMS), the heat was d and more water was added (a total water content of 600 mL). The mixture was allowed to come to ambient temperature.

The methanol was removed in vacuo at 35 °C (moderately reduced pressure); vacuum was d and the aqueous was warmed to about 50 °C and then extracted with 4 x 200 mL ene de. The organic extracts were combined, washed with saturated sodium bicarbonate (aq), washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo at not more than 30°C. The desired product was obtained as a yellow liquid (58.5 g, 94%).

Intermediate 4: 0-N-meth0x -N-meth mide A stirred solution of potassium carbonate (343 g, 2.48 mol) in water (about 800 mL) was prepared and cooled in an ice bath for 15 minutes under nitrogen. To it was added O,N— dimethylhydroxylamine hydrochloride (l 10 g, 1.13 mol) and diethyl ether (about 800 mL).

To this mixture was then added bromoacetyl bromide (273 g, 1.35 mol) by addition funnel over twenty minutes. The ice bath was removed and the mixture was stirred under nitrogen for two hours. The layers were separated and the aqueous layer was extracted with ether (about 350 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The desired product was obtained as a yellow liquid (143 g, 70%).

WO 53215 Intermediate 5: S -tert-but ll- tert-but h lsil 10x buten 12- 1 methoxyg methyl )amino 0ethyl )carbamate TBso/\;/\ Olly’OMe A suspension of (S)—1—(tert—butyldimethylsilyloxy)but—3—en—2—amine (Intermediate 3, 60.4 g, 300 mmol) and cesium carbonate (103 g, 315 mmol) in acetonitrile (about 700 mL) and water (about 120 mL) was prepared and stirred in an ice bath under nitrogen for 5 minutes. The mixture was biphasic and ed so for the duration of the reaction. To this e was then added 2—bromo—N—methoxy—N—methylacetamide (Intermediate 4, 57.0 g, 285 mmol) by addition funnel over 10 minutes. The mixture was stirred for two days, with the temperature maintained near 0°C. The mixture was kept in the freezer overnight. Another 0.05 eq of the electrophile was added. To the mixture was added di—tert—butyl dicarbonate (165 mL, 2M solution in THF). The organic layer was separated from the aqueous (TLC ted that no product remained in the aqueous), and the organic layer was concentrated in vacuo. Silica gel chromatography (5—55% ethyl acetate in hexanes), split into 3 batches, afforded the desired product as a pale yellow oil (80 g, 66%).

Intermediate 6: S -tert-but ll- tert-but ldimeth lsil 10x buten 12-0x0 ent enyl )carbamate To a solution of (S)—tert—butyl 1—(tert—butyldimethylsilyloxy)but—3—en—2—yl(2—(methoxy— (methyl)amino)—2—oxoethyl)carbamate (Intermediate 5, 32.5 g, 80.73 mmol) in THF (400 mL) under nitrogen at 0 °C was added prop—1—enylmagnesium bromide (323 ml, 161.45 mmol) dropwise. The on mixture was stirred at 0 °C for 1 hour, then quenched with 400 mL 10% citric acid, diluted further with 100 mL water and extracted with ether. The organics were trated and the resulting oil was dissolved in ether and washed with water and brine. The organics were dried over magnesium sulfate, filtered and concentrated.

Silica gel chromatography (5%—20% ethyl acetate/hexanes) afforded the d product as a colorless oil (27g, 87%).

M_S: 384 ES+ (C20H37NO4Si) WO 53215 1H NMR1300 MHz, CDCl;) 8: 0.05 (2, 6H); 0.88 (s, 9H); 1.39-1.47 (m, 9H); 1.90 (m, 3H); 3.80 (m, 2H); 4.05-4.18 (m, 2H); 4.43-4.76 (m, 1H); 5.22 (m, 2H); 5.86 (m, 1H); 6.21 (m, 1H); 6.91 (m, 1H).

Intermediate 7: S -tert-but 12- tert-but ldimeth lsil 10x meth l0x0-5 6- dih dr0 ridine-l 2H -carb0x late TBSO/h’ﬁOYN 0 (S)—tert—buty1 1—(tert—butyldimethylsilyloxy)but—3—en—2—yl(2—oxopent—3—enyl)carbamate (Intermediate 6, 27.0 g, 70.39 mmol) was dissolved in toluene (650 mL). The solution was purged with en for 15 minutes before the addition of Hoveyda—Grubbs Catalyst 2nd Generation (0.885 g, 1.41 mmol). The reaction mixture was heated under nitrogen at 65 °C.

The reaction mixture was concentrated under reduced pressure. Silica gel chromatography (10%—35% ethyl acetate/hexanes) afforded the desired product as a solid (17.0g, 70%).

Optical Rotation: 0.1 g/dL, methylene chloride 2 —175 Intermediate 8: 6S -tert-but l6- tert-but ldimeth lsil 10x meth lmeth l trimeth lsil 10x -5 6-dih dr0 ridine-l 2H -carb0x late To a suspension of copper(I) iodide (22.31 g, 117.12 mmol) in diethyl ether (250 mL) at 0°C was added lithium (1.6M in ether) (146 mL, 234.25 mmol) Via cannula. The suspension was d for 45 minutes at 0 °C. A on of (S)—tert—buty1 2—(((tert— butyldimethylsilyl)oxy)methy1)—5—oxo—5,6—dihydropyridine— 1 (2H)—carboxy1ate (Intermediate 7, 20 g, 58.56 mmol) in diethyl ether (50 mL) was added dropwise to the suspension at 0°C.

Once addition was complete, the reaction mixture was stirred for 45 minutes at 0°C. To the reaction mixture was then added trimethylsilane (1M in THF) (117 mL, 117.12 mmol) dropwise, followed by ylamine (16.28 mL, 117.12 mmol). The reaction mixture was d to warm to room temperature and stir for 2 hours. The reaction e was then diluted with ethyl acetate and washed with ice cold saturated sodium bicarbonate solution (added very carefully) three times, ed by brine. The organics were dried over sodium sulfate, filtered and concentrated to afford a brown oil.

Intermediate 9: S -tert-but 12- tert-but ldimeth lsil 10x meth lmeth l0x0- 6-dih dr0 ridine-l 2H -carb0x late To a solution of (6S)—tert—butyl 6—(((tert—butyldimethylsilyl)oxy)methyl)—5—methyl—3— ((trimethylsilyl)oxy)—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 8, 24.1 g, 56.08 mmol) in acetonitrile (280 mL) at room temperature was added palladium (II) acetate (12.59 g, 56.08 mmol). The on mixture was stirred at room temperature for ~40 hours, then diluted with ethyl acetate and filtered through celite. The filtrate was concentrated onto silica gel. Silica gel chromatography (0%—20% ethyl e/hexanes) afforded (S)—tert—butyl 2— (((tert—butyldimethylsilyl)oxy)methyl)—3—methyl—5—oxo—5,6—dihydropyridine—1(2H)— carboxylate (12.95 g, 65%) as a yellow solid.

Intermediate 10: 2S 5S -tert-but 12- tert-but ldimeth lsil 10x meth l-S-h drox meth l-5 6-dih dr0 ridine-l 2H -carb0x late TBso/“éN 'I Boc’ ’OH To a sion of cerium(III) de (8.98 g, 36.42 mmol) and (S)—tert—butyl 2—(((tert— butyldimethylsilyl)oxy)methyl)—3—methyl—5—oxo—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 9, 12.95 g, 36.42 mmol) in methanol (200 mL) at 0 °C was added sodium dride (1.378 g, 36.42 mmol), portionwise. After 15 minutes, the reaction mixture was diluted with saturated ammonium chloride (100 mL) and water (100 mL), then extracted twice with ether. The organic extracts were washed with brine, dried over magnesium e, filtered and concentrated. Silica gel chromatography (0%—20% ethyl e/hexanes) afforded (2S,5S)—tert—butyl 2—(((tert—butyldimethylsilyl)oxy)methyl)—5—hydroxy—3—methyl—5,6— dihydropyridine—1(2H)—carboxylate (9.79 g, 75%) as a colorless oil.

Intermediate 11: 2S 5R -tert-but 15- N- all 10x nitr0 hen lsulfonamido tert- but ldimeth lsil 10x meth lmeth l-5 6-dih dr0 ridine-1 2H x late TBSO/dN’ ,OAII Boc N To a solution of (2S,5S)—tert—butyl 2—(((tert—butyldimethylsilyl)oxy)methyl)—5—hydroxy—3— methyl—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 10, 9.79 g, 27.38 mmol) in toluene (100 mL) at room temperature was added triphenylphosphine (8.58 g, 32.86 mmol), N—(allyloxy)—2—nitrobenzenesulfonamide (7.07 g, 27.38 mmol) and diisopropyl azodicarboxylate (6.47 mL, 32.86 mmol). The reaction mixture was stirred overnight, then filtered and trated. The resulting oil was twice triturated with hexanes and filtered.

Silica gel chromatography (0%—20% ethyl acetate/hexanes) ed )—tert—butyl 5—(N— (allyloxy)—2—nitrophenylsulfonamido)—2—(((tert—butyldimethylsilyl)oxy)methyl)—3—methyl—5,6— dihydropyridine—1(2H)—carboxylate (10.75 g, 66%) as a light yellow foam.

Intermediate 12: 2S 5R -tert-but 15- N- all 10x nitr0 hen lsulfonamido h drox meth lmeth l-5 6-dih dr0 ridine-l 2H x late ’ ,OAII Boc N To a solution of (2S,5R)—tert—butyl 5—(N—(allyloxy)—2—nitrophenylsulfonamido)—2—(((tert— butyldimethylsilyl)oxy)methyl)—3 —methyl—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 11, 10.75 g, 17.98 mmol) in THF (100 mL) at 0 °C was added tetrabutylammonium ﬂuoride (1M in THF) (23.38 mL, 23.38 mmol). The reaction mixture turned from yellow to greenish brown. The reaction mixture was d for about 2 hours, then concentrated onto silica gel. Silica gel chromatography (0%—70% ethyl acetate/hexanes) afforded (2S,5R)—tert—butyl 5—(N—(allyloxy)—2—nitrophenylsulfonamido)—2—(hydroxymethyl)—3— methyl—5,6—dihydropyridine—1(2H)—carboxylate (7.72 g, 89%) as a tan foam.

Intermediate 13: 2S 5R N- all 10x nitr0 hen lsulfonamido tert- butox carbon lmeth l-1 2 5 6-tetrah dr0 ridinecarb0x lic acid HOJHHd(1 N ,OAll Boc/ N To a solution of periodic acid (1.588 g, 8.27 mmol) in wet acetonitrile (20 mL) (0.75% water by volume) at room ature was added chromium(VI) oxide (0.019 g, 0.19 mmol). The mixture was stirred until complete dissolution was achieved. To a solution of )—tert— butyl 5—(N—(a11yloxy)—2—nitropheny1su1fonamido)—2—(hydroxymethy1)—3—methy1—5 ,6— dihydropyridine—1(2H)—carboxy1ate (Intermediate 12, 2 g, 4.14 mmol) in wet acetonitrile (20 mL) (0.75% by volume) at 0°C was added dropwise the usly formed ic acid/chromium oxide solution (20 mL, 2 eq.), and stirred for 15 s. The reaction mixture was diluted with DCM (100 mL) and washed with 10% citric acid (50 mL) and twice with brine. The organics were dried over sodium sulfate, filtered and concentrated to afford a tan foam (1.9 g, 92%).

Intermediate 14: 2S 5R -tert-but 15- N- all 10x nitr0 hen lsulfonamido carbam0 lmeth l-5 6-dih dr0 ridine-l 2H -carb0x late W610LBoc,N N,OA|| To a solution of (2S,5R)—5—(N—(a11yloxy)—2—nitrophenylsulfonamido)—1—(tert—butoxycarbony1)— 3—methy1—1,2,5,6—tetrahydropyridine—2—carboxylic acid (Intermediate 13, 1.9 g, 3.82 mmol) in DMF (9.5 mL) at 0°C was added HATU (2.178 g, 5.73 mmol), ammonium chloride (0.613 g, 11.46 mmol) and DIEA (2.67 mL, 15.28 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 15 minutes. The reaction e was diluted with ethyl acetate and washed with saturated sodium bicarbonate and 1:1 brinezwater. Silica gel chromatography (0%—70% ethyl e/hexanes) afforded (2S,5R)—tert—buty1 5—(N— (allyloxy)—2—nitrophenylsulfonamido)—2—carbamoy1—3—methy1—5,6—dihydropyridine—1(2H)— carboxylate (1.270 g, 67%) as a light orange foam.

Intermediate 15: ZS 5R -tert-but lS- all 10x amino carbam0 lmeth l-5 6- dih dr0 ridine-1 2H -carb0x late HZNJI'“Cf \ , xOAII Boc N To a solution of (2S,5R)—tert—butyl 5—(N—(a11yloxy)—2—nitrophenylsulfonamido)—2—carbamoyl— 3—methy1—5,6—dihydropyridine—1(2H)—carboxy1ate (Intermediate 14, 3.63 g, 7.31 mmol) in acetonitrile (100 mL) at room temperature was added potassium carbonate (5.05 g, 36.55 mmol) and thiophenol (3.75 mL, 36.55 mmol). The on mixture was d overnight at room temperature. The reaction mixture was concentrated and the resulting e was triturated with DCM and filtered to remove solids. The filtrate was concentrated onto silica and purified. Silica gel chromatography (0%—90% ethyl acetate/hexanes) afforded (2S,5R)— tert—butyl 5—((allyloxy)amino)—2—carbamoy1—3—methy1—5,6—dihydropyridine— 1(2H)—carboxy1ate (1.49 g, 65%) as a yellow oil.

Intermediate 16: ZS 5R but lS- N- all 10x -1H-imidazolecarb0xamid0 carbam0 lmeth l-5 6-dih dr0 ridine-1 2H -carb0x late H2N “’6‘ Boc N,OA|| To a solution of (2S,5R)—tert—butyl 5—((a11yloxy)amino)—2—carbamoy1—3—methy1—5 ,6— opyridine—1(2H)—carboxy1ate (Intermediate 15, 1.49 g, 4.79 mmol) in THF (30 mL) at room temperature was added N,N—diisopropylethylamine (2.5 mL, 14.36 mmol) and N,N— carbonyldiimidazole (2.328 g, 14.36 mmol). The on mixture was stirred for ~2 hours at room temperature. Another equivalent of CD1 was added, and the reaction mixture stirred at room temperature for 1 hour, then another equivalent of CD1 was added and the reaction d for another hour. The reaction mixture was diluted with DCM, and washed four times with 1:1 brinezwater, then dried over magnesium sulfate, ed and concentrated to afford an off—white foam, 1.86 g. ediate 17: 2S 5R all 10x meth l0x0-1 abic clo 3.2.1 0ctene carboxamide To a solution of (2S,5R)—tert—butyl 5—(N—(allyloxy)—1H—imidazole—1—carboxamido)—2— carbamoyl—3—methyl—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 16, 1.86 g, 4.59 mmol) in DCM (20 mL) at 0 °C was added oroacetic acid (3.53 mL, 45.88 mmol). The reaction mixture was allowed to warm to room temperature slowly and stir overnight. The reaction mixture was concentrated. The oil was redissolved in DCM and washed with saturated sodium onate. The aqueous was extracted once with ~10% MeOH/DCM.

The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%—30% acetone/dichloromethane) afforded (2S,5R)—6—(allyloxy)—3— methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (0.83 g, 76%) as a light yellow oil.

Exam le 1: R -eth 12- 2S 5R bam0 lmeth l0x0-1 6-diazabic clo 3.2.1 oct- 3-en 10x ﬂu0r0acetate Exam le 2: S -eth 12- 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 oct- 3-en 10x ﬂu0r0acetate Exam le 3: ZS - ZS 5R -Z-carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0cten- 6- 1 0x ﬂu0r0 ethanoic acid lithium salt O O’SI/OH Exam le 4: ZR - ZS 5R -Z-carbam0 lmeth l0x0-1 6-diazabic clo 3.Z.1 0cten- 6- 1 0x ﬂu0r0 ethanoic acid lithium salt Hid/“6:? N OJ—N‘O’SrOHF Exam le 5: ZS 5R -Z-carbam0 lmeth l0x0-1 abic clo 3.Z.1 0cten yl|0xyﬂﬂu0r02acetic acid lithium salt (mixture of diastereomers) HZNJ’I'ﬁ(i N 02—N,O,$rOHF Examples 1-Z To a solution of )—6—(allyloxy)—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2— carboxamide (Intermediate 17, 100 mg, 0.42 mmol) in methanol (3 mL) at room temperature was added 1,3—dimethylbarbituric acid (132 mg, 0.84 mmol) and tetrakis(triphenylphosphine)palladium(0) (48.7 mg, 0.04 mmol). The reaction was stirred at room temperature for 2 hours. The reaction e was concentrated to afford an orange film. The orange film was dissolved in DMF (3 mL) and potassium carbonate (175 mg, 1.26 mmol) and ethyl bromoﬂuoroacetate (0.299 mL, 2.53 mmol) were added. The on mixture was stirred overnight at room temperature and was then diluted with ethyl acetate and filtered through a 0.45 n filter to remove solid potassium carbonate. The filtrate was washed twice with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography % ethyl acetate/hexanes) afforded ethyl 2—(((2S ,5R)—2—carbamoyl—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)—2— ﬂuoroacetate (97 mg, 76 %) as a mixture of diastereomers of Example 1 and Example 2 as an orange foam.

M_S: 198 ES+ (C3H11N303) Examples 3-5 To a solution of ethyl S,5R)—2—carbamoy1—3—methy1—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3— en—6—y1)oxy)—2—ﬂuoroacetate (Examples 1-2, 97 mg, 0.32 mmol) in THF (3 mL) and water (1 mL) at —5°C was added lithium hydroxide (9.25 mg, 0.39 mmol) as a solution in water (0.5 mL). The mixture was stirred at 0 °C for 60 minutes, allowed to warm to room ature and stirred for 15 minutes. The reaction mixture was adjusted to pH = 7 with 0.5M HCl. The THF was evaporated and the remaining aqueous phase was frozen and 1yophi1ized.

Purification of Examples 1-5 The mixture resulting from the reaction described in Examples 3—5 was ed by reversed phase HPLC (Synergi Polar RP 21.2 mm x 100 mm, 4 um d with YMC C30 20 mm x 150 mm, 5 um; 0% to 50% acetonitrile in water, 10 min; 20 mL/min) to obtain: Example 1: ethyl {[(2S,5R)—2—carbamoy1—3—methy1—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6— y1]oxy}(f1uoro)acetate (first e1uting ester): 4.4 mg, 4.5% M_S: 302 ES+ (C12H16FN305) 1H NMR 1300 MHz: DMSO-dg) 8: 1.21 (t, 3H); 1.62 (s, 3H); 3.05 (m, 1H); 3.75 (m, 1H); 4.03 (m, 1H); 4.20 (m, 3H); 6.01 (m, 1H); 6.13-6.31 (d, 1H); 7.36 (bs, 1H); 7.81 (bs, 1H).

Example 2: (S)—ethy1 2—((2S,5R)—2—carbamoy1—3—methy1—7—oxo—1,6—diazabicyclo[3.2. 1]oct— 3—en—6—yloxy)—2—f1uoroacetate (second e1uting ester): 4.2 mg, 4.3% M_S: 302 ES+ (C12H16FN305) 1H NMR 1300 MHz: g) 8: 1.26 (t, 3H); 1.63 (s, 3H); 3.08 (m, 1H); 3.75 (m, 1H); 3.94 (m, 1H); 4.20 (m, 1H); 4.27 (q, 2H); 6.03 (m, 1H); .50 (d, 1H); 7.37 (bs, 1H); 7.83 (bs, 1H).

Example 3: (2S)—{ [(2S,5R)—2—carbamoy1—3—methy1—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3—en—6— y1]oxy}(ﬂuoro)ethanoic acid (first e1uting acid): 7.7 mg, 8.8%.

M_S: 274 ES+ 2FN305) 1H NMR 1300 MHz, DMSO—dg) 5: 1.61 (s, 3H); 3.05 (m, 1H); 3.68 (m, 1H); 3.96 (m, 1H); 4.13 (m, 1H); 5.12-5.33 (d, 1H); 6.03 (m, 1H); 7.31 (bs, 1H); 7.80 (bs, 1H).

Example 4: (2R)—{ [(2S,5R)—2—carbamoyl—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6— yl]oxy}(ﬂuoro)ethanoic acid (second eluting acid): 9.9 mg, 11% M_S: 274 ES+ (C10H12FN305) 1H 0 MHz= g) 5: 1.61 (s, 3H); 3.05 (m, 1H); 3.70 (m, 1H); 4.00 (m, 1H); 4.13 (m, 1H); 5.15-5.37 (d, 1H); 6.01 (m, 1H); 7.31 (bs, 1H); 7.78 (bs, 1H). e 5: {[(2S,5R)—2—carbamoyl—3—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3—en—6— yl]oxy}(ﬂuoro)acetic acid (mixture of diastereomers): 20.4 mg, 23% M_S: 274 ES+ (C10H12FN305) 1H NMR1300 MHz, DMSO-dg) 8: 1.62 (s, 6H); 3.06 (m, 2H); 3.70 (m, 2H); 4.01 (m, 2H); 4.14 (m, 2H); 5.14-5.35 (d, 1H); 5.18-5.40 (d, 1H); 6.03 (m, 2H); 7.32 (bs, 2H); 7.80 (bs, The absolute stereochemistry for all compounds was determined by characterizing the co— l structure of example 4 complexed with AmpC. The absolute stereochemistry of the other diastereomer, example 3, was assigned as having the opposite stereochemistry at the ﬂuoroacetate carbon. The stereochemistry of each ester was assigned by hydrolysis of each ester to its corresponding acid and comparison of the UPLC retention times to those of examples 3 and 4.

Exam le 6: eth 1 2S 5R bam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0cten- 6-yl|0xyﬂﬂu0r0)acetate (mixture of diastereomers) According to the procedure given for examples 1 and 2, (2S,5R)—6—(allyloxy)—3—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 17, 0.506 g, 2.13 mmol) was converted into 70 mg of Example 6 after HPLC gi Polar RP 21.2 mm x 100 mm, 4 um coupled with YMC C30 20 mm x 150 mm, 5 um; 20% to 60% acetonitrile in water, 10 min; 20 ) and lyophilization.

M_S: 302 ES+ (C12H16FN305) 1H NMR1300 MHz= DMSO-dg) 8: 1.22 (t, 3H); 1.27 (t, 3H); 1.63 (s, 6H); 3.07 (m, 2H); 3.76 (m, 2H); 3.94 (m, 1H); 4.05 (m, 1H); 4.20 (m, 2H); 4.26 (m, 4H); 6.03 (m, 2H); 6.06—6.24 (d, 1H); 6.14-6.32 (d, 1H); 7.37 (bs, 1H); 7.83 (bs, 1H).

Exam le 7: eth 1 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0cten- 6- 1 0x diﬂuoro acetate (2S ,5R)—6—(allyloxy)—3 —methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 17, 204.2 mg, 0.86 mmol) was converted according to the procedure for examples 1 and 2 using ethyl ifluoroacetate (0.441 mL, 3.44 mmol) to give 130 mg (47%) of the title compound as an orange foam. e phase chromatography on 40 mg (Synergi Polar RP 21.2 mm x 100 mm, 4 um coupled with YMC C30 20 mm x 150 mm, 5 um; 20% to 40% acetonitrile in water, 10 min; 20 mL/min) ed the title compound as a white solid (21 mg).

M_S: 320 ES+ (C12H15F2N305) 1H NMR1300 MHz, DMSO-dg) 8: 1.30 (t, 3H); 1.65 (s, 3H); 3.19 (m, 1H); 3.84 (m, 1H); 4.06 (m, 1H); 4.26 (m, 1H); 4.39 (q, 2H); 6.05 (m, 1H); 7.42 (bs, 1H); 7.87 (bs, 1H).

Exam le 8: 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0cten 1 0x diﬂuoro acetic acid lithium salt Ethyl 2—(((2S ,5R)—2—carbamoyl—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)— 2,2—difluoroacetate (Example 7, 113.7 mg, 0.36 mmol) was converted according to the procedure for Examples 3—5. A white solid was ed after HPLC (Synergi Polar RP 21.2 mm x 100 mm, 4 um coupled with YMC C30 20 mm x 150 mm, 5 um; 100% water, 10 min; ) and lyophilization, 36.7 mg.

M_S: 292 ES+ (C10H11F2N305) WO 53215 1H NMR1300 MHz, g) 5: 1.63 (s, 3H); 3.13 (m, 1H); 3.75 (m, 1H); 3.95 (m, 1H); 4.18 (m, 1H); 6.04 (m, 1H); 7.34 (bs, 1H); 7.83 (bs, 1H).

Exam le 9: eth 1 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0ct enyl |0xy {acetate HZNJII" \ o‘ N‘O’yo\/ (2S ,5R)—6—(allyloxy)—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 17, 0.198 g, 0.83 mmol) was converted according to the procedure for Examples 1—2 using ethyl bromoacetate (0.592 mL) to give 147 mg (62%) as an orange solid.

Reverse phase chromatography on 41.5 mg (Synergi Polar RP 21.2 mm x 100 mm, 4 um coupled with YMC C30 20 mm x 150 mm, 5 um; 10% to 50% acetonitrile in water, 10 min; ) afforded the title compound as a White solid (32 mg).

M_S: 284 ES+ (C12H17N305) 1H NMR1300 MHz, DMSO-dg) 8: 1.22 (t, 3H); 1.61 (s, 3H); 3.00 (m, 1H); 3.68 (m, 1H); 4.05 (m, 1H); 4.13 (m, 1H); 4.16 (q, 2H); 4.37—4.65 (m, 2H); 6.05 (m, 1H); 7.33 (bs, 1H); 7.77 (bs, 1H).

Exam le 10: 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0cten 1 0x acetic acid lithium salt Ethyl 2—(((2S ,5R)—2—carbamoyl—3—methyl—7—oxo— 1 ,6—diazabicyclo[3 .2. 1]oct—3—en—6— yl)oxy)acetate (Example 9, 105.5 mg, 0.37 mmol) was hydrolyzed according to the procedure for Examples 3—5 to give 34 mg (37%) of the title nd after HPLC (Synergi Polar RP 21.2 mm x 100 mm, 4 um; 0% to 20% acetonitrile in water, 10 min; 20 ) and lyophilization.

M_S: 256 ES+ (C10H13N305) 1H NMR1300 MHz2 DMSO—dg) 5: 1.60 (s, 3H); 2.96 (m, 1H); 3.58 (m, 1H); 3.87 (m, 2H); 4.05 (m, 1H); 4.27 (m, 1H); 6.08 (m, 1H); 7.27 (bs, 1H); 7.74 (bs, 1H).

Exam le 11: 2- 2S 5R carbam0 lmeth l0x0-1 abic clo 3.2.1 0cten 1 0x ﬂu0r0 r0 anoic acid lithium salt mixture of diastere0mers (2S ,5R)—6—(allyloxy)—3 —methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 17, 0.101 g, 0.43 mmol) was converted according to the procedure for Examples 1—2 using methyl 2—bromo—2—f1uoropropanoate (0.315 g, 1.70 mmol) to give methyl 2—(((2S ,5R)—2—carbamoy1—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)—2— ﬂuoropropanoate (0.105 g, 82 %) as an orange foam. Reverse phase chromatography (Synergi Polar RP 21.2 mm x 100 mm, 4 pm coupled with YMC C30 20 mm x 150 mm, 5 pm; 100% water, 10 min; 20 mL/min) afforded the title compound as a White solid (19.1 mg, 19%).

M_S: 302 ES+ (C12H16FN305) 1H NMR1300 MHz2 DMSO-dg) 8: 1.67 (m, 6H); 3.04 (m, 1H); 3.72 (m, 4H); 3.80 (m, 1H); 4.17 (m, 1H); 6.02 (m, 1H); 7.36 (bs, 1H); 7.81 (bs, 1H).

Hydrolysis according to the procedure for Example 3—5 ed 19.1 mg of e 11 as a White solid after reverse phase purification (Synergi Polar RP 21.2 mm x 100 mm, 4 pm coupled with YMC C30 20 mm x 150 mm, 5 pm; 100% water, 10 min; 20 mL/min).

M_S: 288 ES+ (C11H14FN305) 1H NMR 300 MHz g) 5: 1.45 (m, 3H); 1.61 (s, 3H); 3.02 (m, 1H); 3.65 (m, 1H); 3.92—4.09 (m, 1H); 4.11 (m, 1H); 6.04 (m, 1H); 7.32 (m, 1H); 7.80 (m, 1H).

Intermediate 18: is0 r0 12-br0m0ﬂu0r0acetate ”)0? \/ iPrOH, tBuOK, hexane, O C O 32* YO O O To a solution of ethyl 2—bromo—2—ﬂuoroacetate (0.639 mL, 5.41 mmol) in hexanes (70 mL) and panol (7 mL) at 0°C was added potassium t—butoxide (0.091 g, 0.81 mmol) in two equal portions, 5 minutes apart. The reaction mixture was stirred for 1 hour at 0°C. The reaction was quenched with concentrated HCl (7 mL) and the layers were separated. The organics were washed twice with water, dried over magnesium sulfate, filtered and concentrated at 0°C to afford a colorles oil (0.88 g, 4.42 mmol, 82%). NMR confirmed the identity of the product, containing a trace of hexanes. The product was used as is in the next step. 1H 0 MHz, CDCléﬁ) 8: 1.34 (m, 6H); 5.18 (m, 1H); 6.45-6.62 (d, 1H).

Reference: Tet. Lett. (2000) 791.

Exam le 12: 1'0 an 1 2R - 2S 5R carbam0 lmeth l0X0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂu0r0 ethanoate Exam le 13: 1'0 an 1 2S - 2S 5R carbam0 lmeth l0X0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂu0r0 ethanoate HZNJJ/I'ﬁO N F O OJWO o 7’ Example 12-13 (2S ,5R)—6—(allyloxy)—3 —methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 17, 0.103 g, 0.43 mmol) was converted according to the ure for Examples 1—2 using isopropyl 2—bromo—2—ﬂuoroacetate (Intermediate 18, 0.518 g, 2.60 mmol). 34 mg of each diastereomer was ed after HPLC (Synergi Polar RP 21.2 mm x 100 mm, 4 um coupled with YMC C30 20 mm x 150 mm, 5 um; 25% to 50% acetonitrile in water, 10 min; 20 mL/min) and lyophilization. The chemistry of the ester was assigned by hydrolysis of each ester to its ponding acid and comparison of the UPLC retention time to those of examples 3 and 4.

Example 12: (first eluting ester) 33.4 mg, 24% M_S: 316 ES+ (C13H13FN305) 1H NMR 1300 MHz, DMSO—dg) 5: 1.22 (m, 6H); 1.63 (s, 3H); 3.03 (m, 1H); 3.75 (m, 1H); 4.01 (m, 1H); 4.19 (m, 1H); 5.00 (m, 1H); 6.01 (m, 1H); 6.11—6.29 (d, 1H); 7.37 (bs, 1H); 7.81 (bs, 1H).

Example 13: (second eluting ester) 33.6 mg, 25% M_S: 316 ES+ (C13H13FN305) 1H NMR 1300 MHz: DMSO-dg) 8: 1.27 (m, 6H); 1.63 (s, 3H); 3.07 (m, 1H); 3.75 (m, 1H); 3.94 (m, 1H); 4.20 (m, 1H); 5.05 (m, 1H); 6.03 (m, 1H); 6.02—6.21 (d, 1H); 7.37 (bs, 1H); 7.82 (bs, 1H).

Intermediate 19: 2 4-dimeth l entan 12-br0m0ﬂu0r0acetate ing the procedure for intermediate 18, using ethyl 2—bromo—2—ﬂuoroacetate (0.639 mL, 5.41 mmol) and 2,4—dimethyl—3—pentanol (7.05 mL, 50.27 mmol) the title compound was obtained as a colorles oil (0.988 g, 3.87 mmol, 71.6%). 1H NMR 1300 MHz, CDCléﬁ) 8: 0.94 (m, 12H); 2.01 (m, 2H); 4.73 (m, 1H); 6.52-6.69 (d, Exam le 14: 24-dimeth l entan 1 2S - 2S 5R carbam0 lmeth 0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂuoro ethanoate Exam le 15: 24-dimeth l entan 1 2R - 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂu0r0 ate HZNJII'ﬁ? N F o N‘o ”J140 Examples 14-15 (2S ,5R)—6—(allyloxy)—3 —methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 17, 0.097 g, 0.41 mmol) was converted according to the procedure for Examples 1—2 using 2,4—dimethylpentan—3—yl 2—bromo—2—ﬂuoroacetate (0.626 g, 2.45 mmol) to give 35 mg of each diastereomer (23% for each, 46% total) after HPLC gi Polar RP 21.2 mm x 100 mm, 4 um coupled with YMC C30 20 mm x 150 mm, 5 um; 40% to 70% acetonitrile in water, 10 min; 20 mL/min) and lyophilization. The stereochemistry of the esters was ed by hydrolysis of each ester to its corresponding acid and comparison of the UPLC retention time to those of examples 3 and 4.

Example 14: d eluting peak) 34.5 mg, 23% M_S: 372 ES+ (C17H26FN305) 1H NMR1300 MHz= DMSO-dg) 8: 0.86 (m, 12H); 1.63 (s, 3H); 1.94 (m, 2H); 3.07 (m, 1H); 3.78 (m, 1H); 3.98 (m, 1H); 4.23 (m, 1H); 4.62 (m, 1H); 6.04 (m, 1H); 6.15—6.34 (d, 1H); 7.38 (bs, 1H); 7.81 (bs, 1H).

Example 15: (first eluting peak) 35.2 mg, 23% M_S: 372 ES+ (C17H26FN305) 1H NMR1300 MHz= DMSO-dg) 8: 0.84 (m, 12H); 1.63 (s, 3H); 1.93 (m, 2H); 3.03 (m, 1H); 3.78 (m, 1H); 4.07 (m, 1H); 4.21 (m, 1H); 4.60 (m, 1H); 5.99 (m, 1H); 6.27—6.45 (d, 1H); 7.37 (bs, 1H); 7.83 (bs, 1H).

Intermediate 20: tetrah dr0-2H- ran 12-br0m0ﬂu0r0acetate Following the ure for Intermediate 18, using ethyl 2—bromo—2—fluoroacetate (0.319 mL, 2.70 mmol) and tetrahydro—2H—pyran—4—ol (2.333 mL, 24.33 mmol), the title compound was obtained as a colorless oil (0.15 g, 0.62 mmol, 29 %).

M_S: ES+ 241.2 for C7H10BrFO3 1H NMR 300 MHz CHLOROFORM-d 8 m: 1.47 - 1.81 (m, 2 H) 1.84 - 2.13 (m, 2 H) 3.39 — 3.68 (m, 2 H) 3.75 - 4.07 (m, 2 H) 4.37 (q, J=7.18 Hz, 1 H) 6.37 - 6.74 (m, 1 H) Exam le 16: tetrah dr0-2H- ran 1 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂu0r0 acetate mixture of diastereomers HzNJII.H\j? N )—N\ F O o#00 Following the procedure from Examples 1—2, using (2S,5R)—6—(allyloxy)—3—methyl—7—oxo—1,6— icyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 17, 40 mg, 0.17 mmol) and tetrahydro—2H—pyran—4—yl 2—bromo—2—fluoroacetate (Intermediate 20, 312 mg, 1.29 mmol), the title compound was ed after purification by reverse phase ISCO (15.5 g C18 Gold, 0%—80% acetonitrile/water), light orange solid as a mixture of diastereomers. (5.5 mg, 9%) M_S: ES+ 358.1 for C15H20FN306 1H NMR 300 MHz CHLOROFORM-d 8 m 1.15 - 1.42 (m, 2 H) 1.60 (br. s., 2 H) 1.92 (s, 3 H) 3.14 - 3.45 (m, 2 H) 3.56 (d, J=11.52 Hz, 1 H) 3.88 - 4.13 (m, 2 H) 4.20 - 4.50 (m, 2 H) 5.09 (br. s., 1 H) 5.35 - 5.58 (m, 1 H) 5.63 - 5.96 (m, 1 H) 6.09 (br. s., 1 H) Intermediate 21: 2-meth0x eth m0ﬂu0r0acetate Brwowo/ ing to the procedure for Intermediate 18, using ethyl 2—bromo—2—fluoroacetate (1.278 mL, 10.81 mmol) and 2—methoxyethanol (13.94 mL, 183.79 mmol) the title compound was obtained as a colorles oil (1.04 g, 4.84 mmol, 44.7%). NMR was tent with a 3:1 mixture of productzstarting material, which was used as is in the next step. 1H NMR1300 MHz, DMSO-dg) 8: 3.27 (s, 3H); 3.57 (m, 2H); 4.35 (m, 2H); 7.22-7.38 (d, WO 53215 Z Exam le 17: Z-meth0x eth 1 ZS 5R -Z-carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂuoro acetate (mixture of diastereomers) Exam le 18: Z-meth0x eth l ZR - ZS 5R -Z-carbam0 lmeth 0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂuoro ethan0ate HZNJ’I'ﬁ(i N )—N\ F 0 0V0\/\ O 0/ Exam le 19: Z-meth0x eth 1 ZS - ZS 5R -Z-carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂuoro ethan0ate 'ﬁ(iL .

O N‘OJVo\/\/ o 0 Example 17-19 According to the procedure for es 1—2, (2S,5R)—6—(allyloxy)—3—methyl—7—oxo—1,6— icyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 17, 0.101 g, 0.43 mmol) was converted into the title compound using 2—methoxyethyl 2—bromo—2—fluoroacetate (Intermediate 21, 0.549 g, 2.55 mmol). The following products were obtained after HPLC (Synergi Polar RP 21.2 mm x 100 mm, 4 um coupled with YMC C30 20 mm x 150 mm, 5 um; 30% to 50% acetonitrile in water, 10 min; 20 mL/min) and lization (wherein the stereochemistry of the esters was assigned by hydrolysis of each ester to its corresponding acid and comparison of the UPLC retention time to those of Examples 3 & 4): Example 17: mixture of diastereomers: 14.3 mg, 10.1% M_SZ 332 ES+ (C13H18FN305) 1H NMR1300 MHz, DMSO-dg) 8: 1.63 (s, 6H); 3.07 (m, 2H); 3.26 (s, 3H); 3.27 (s, 3H); 3.54 (m, 2H); 3.59 (m, 2H); 3.73 (m, 1H); 3.77 (m, 1H); 3.98 (m, 1H); 4.03 (m, 1H); 4.19 (m, 1H); 4.32 (m, 4H); 6.02 (m, 2H); 6.11-6.30 (d, 1H); 6.17-6.35 (d, 1H); 7.37 (bs, 2H); 7.81 (bs, 2H).

Example 18: (first eluting : 22 mg, 15.6%, M_S: 332 ES+ (C13H13FN305) 1H NMR1300 MHz= DMSO-dg) 5: 1.63 (s, 3H); 3.06 (m, 1H); 3.27 (s, 3H); 3.55 (m, 2H); 3.77 (m, 1H); 4.05 (m, 1H); 4.20 (m, 1H); 4.30 (m, 2H); 6.02 (m, 1H); 6.18—6.36 (d, 1H); 7.37 (bs, 1H); 7.82 (bs, 1H).

Example 19: (second eluting ester): 22.8 mg, 16.1% M_S: 332 ES+ (C13H13FN305) 1H NMR 300 MHz DMSO-dg) 8: 1.62 (s, 3H); 3.07 (m, 1H); 3.27 (s, 3H); 3.59 (m, 2H); 3.75 (m, 1H); 3.99 (m, 1H); 4.20 (m, 1H); 4.34 (m, 2H); 6.03 (m, 1H); 6.11—6.30 (d, 1H); 7.37 (bs, 1H); 7.83 (bs, 1H). ediate 22: S -sec-but lZ-bromo-Z-ﬂuoroacetate BrJYOf To a solution of ethyl o—2—ﬂuoroacetate (0.319 mL, 2.70 mmol) and (S)—butan—2—ol (3.72 mL, 40.54 mmol) in hexane (35 mL) at 0°C was added potassium t—butoxide (0.061 g, 0.54 mmol) in two equal portions 5 minutes apart. The reaction mixture was stirred for 2 hours at 0°C, then overnight at room temperature. The reaction was quenched with saturated ammonium chloride and the layers were separated. The organics were washed three times with water, dried over ium sulfate, filtered and trated at 0°C to afford a colorles oil, 0.550 g, 96%. 1H NMR1300 MHz, DMSO-dg) 8: 0.88 (m, 3H); 1.25 (m, 3H); 1.61 (m, 2H); 4.91 (m, 1H); 7.16-7.33 (m, 1H).

Intermediate 23: R -sec-but 12-br0m0ﬂu0r0acetate To a on of ethyl 2—bromo—2—ﬂuoroacetate (0.319 mL, 2.70 mmol) and (R)—butan—2—ol (3.72 mL, 40.54 mmol) in hexane (35 mL) at 0°C was added potassium t—butoxide (0.061 g, 0.54 mmol) in two equal portions 5 minutes apart. The reaction mixture was stirred for 2 hours at 0°C, then at room temperature for 2 hours. Then, more (R)—butan—2—ol (3.72 mL, 40.54 mmol) was added followed by another 0.1 eq of potassium xide. The reaction mixture was stirred at room temperature overnight. 0.1 eq of potasium t—butoxide was added every 2 hours for 6 hours. The reaction was quenched with ted ammonium chloride and the layers were separated. The organics were washed four times with water, dried over magnesium sulfate, filtered and concentrated at 0°C to afford a colorles oil, 422 mg, 73%. 1H NMR1300 MHz= DMSO-dg) 8: 0.88 (m, 3H); 1.25 (m, 3H); 1.61 (m, 2H); 4.91 (m, 1H); 7.16-7.33 (m, 1H).

Exam le 20: 2R - S -sec-but 12- 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0acetate Exam le 21: 2S - S -sec-but 12- 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0acetate Example 20-21 Prepared according to the procedure for Examples 1— 2. To a solution of )—6— (allyloxy)—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 17, 0.196 g, 0.83 mmol) in methanol (5 mL) at room temperature was added 1,3— dimethylbarbituric acid (0.258 g, 1.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.095 g, 0.08 mmol). The reaction was stirred at room temperature for 2 hours then concentrated to afford an orange film. The orange film was dissolved in DMF (5 mL), and potassium carbonate (0.343 g, 2.48 mmol) and (S)—sec—butyl 2—bromo—2—ﬂuoroacetate (Intermediate 22, 0.528 g, 2.48 mmol) were added. The on mixture was stirred for ~5 hours at room temperature then d with ethyl acetate and filtered through a 0.45 um filter to remove solid potassium carbonate. The filtrate was washed three times with 1:1 brine:water. The organics were dried over magnesium sulfate, ed and concentrated.

Silica gel chromatography (0%—65% ethyl acetate/hexanes) afforded (S)—sec—butyl 2— (((2S ,5R)—2—carbamoyl—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)—2— ﬂuoroacetate (0.218 g, 80 %) as a light yellow foam, ~1:1 mixture of diastereomers.

Separation of diastereomers was done on reverse phase HPLC (Atlantis T3 19 mm x 150 mm, —50% itrile in water, 20 mL/min, 15 min). The stereochemistry of the esters was ed by hydrolysis of each ester to its corresponding acid and comparison of the UPLC retention time to those of examples 3 and 4.

Example 20: (first eluting peak) 84 mg, 31% M_S: 330 ES+ (C14H20FN305) 1H NMR1300 MHz= DMSO-dg) 8: 0.84 (t, 3H); 1.22 (d, 3H); 1.55 (m, 2H); 1.63 (s, 3H); 3.03 (m, 1H); 3.76 (d, 1H); 4.04 (m, 1H); 4.19 (s, 1H); 4.86 (m, 1H); 6.01 (m, 1H); 6.13-6.31 (m, 1H); 7.37 (bs, 1H); 7.82 (bs, 1H).

Example 21: (second eluting peak) 85 mg, 31%.

M_S: 330 ES+ (C14H20FN305) 1H NMR1300 MHz= DMSO-dg) 8: 0.84 (t, 3H); 1.22 (d, 3H); 1.55 (m, 2H); 1.63 (s, 3H); 3.03 (m, 1H); 3.76 (d, 1H); 4.04 (m, 1H); 4.19 (s, 1H); 4.86 (m, 1H); 6.01 (m, 1H); 6.13-6.31 (m, 1H); 7.37 (bs, 1H); 7.82 (bs, 1H).

Exam le 22: 2R - R -sec-but 12- ZS 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x r0acetate diazabic clo 3.2.1 0cten 10x r0acetate ‘i \ O \O/Sro Example 22-23 Examples 22—23 were prepared according to the procedure for Examples 1—2. To a solution of (2S ,5R)—6—(a11yloxy)—3 —methy1—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 17, 0.202 g, 0.85 mmol) in methanol (5 mL) at room temperature was added 1,3—dimethy1barbituric acid (0.266 g, 1.70 mmol) and tetrakis(tripheny1phosphine)— palladium(0) (0.098 g, 0.09 mmol). The reaction was stirred at room temperature for 2 hours.

The reaction mixture was concentrated to afford an orange film. The orange film was dissolved in DMF (5 mL), and potassium carbonate (0.353 g, 2.55 mmol) and (R)—sec—buty1 2—bromo—2—ﬂuoroacetate (Intermediate 23, 0.421 g, 1.98 mmol) were added. The reaction mixture was stirred for 3 hours at room ature then diluted with ethyl acetate and ed through a 0.45 um filter to remove solid potassium carbonate. The filtrate was washed three times with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%—65% ethyl acetate/hexanes) afforded (R)—sec—buty1 2—(((2S,5R)—2—carbamoy1—3—methy1—7—oxo—1,6—diazabicyclo[3.2.1]oct— 3—en—6—y1)oxy)—2—ﬂuoroacetate (0.220 g, 78 %) as an orange foam, 1:1 e of diastereomers. Separation of diastereomers was done on reverse phase HPLC (Atlantis T3 19 mm x 150 mm, 30—50% itrile in water, 20 mL/min, 15 min). The stereochemistry of the WO 53215 esters was assigned by hydrolysis of each ester to its corresponding acid and comparison of the UPLC retention time to those of examples 3 and 4.

Example 22: (first eluting peak) 90 mg, 32% M_S: 330 ES+ (C14H20FN305) 1H NMR1300 MHz, DMSO-dg) 8: 0.87 (t, 3H); 1.17 (d, 3H); 1.59 (m, 2H); 1.63 (s, 3H); 3.03 (m, 1H); 3.76 (d, 1H); 4.02 (m, 1H); 4.19 (s, 1H); 4.86 (m, 1H); 6.02 (m, 1H); 6.16-6.34 (m, 1H); 7.37 (bs, 1H); 7.82 (bs, 1H).

Example 23: (second eluting peak) 87 mg, 31% M_S: 330 ES+ (C14H20FN305) 1H 0 MHz= DMSO-dg) 8: 0.88 (t, 3H); 1.24 (d, 3H); 1.61 (m, 2H); 1.63 (s, 3H); 3.08 (m, 1H); 3.76 (d, 1H); 3.94 (m, 1H); 4.21 (s, 1H); 4.89 (m, 1H); 6.04 (m, 1H); 6.03-6.22 (m, 1H); 7.38 (bs, 1H); 7.82 (bs, 1H).

Intermediate 24: entan 12-br0m0ﬂu0r0acetate Br Ear-#0 HO —> Ethyl 2—bromo—2—ﬂuoroacetate (0.639 ml, 5.41 mmol) was added to a mixture of dry pentan— 3—ol (4.68 ml, 43.25 mmol) and hexane (20 ml). The ing mixture was cooled to 0°C.

KOtBu (0.091 g, 0.81 mmol) was added and the mixture was allowed to stir for 16 h at 25°C.

The reaction was then quenched with 1N HCl (30 mL), washed with water (50 mL) and brine (50 mL), dried with NaZSO4, and concentrated. The crude material was purified by ﬂash chromatography (20 g silica gel, 0—100% EtzO in hexane, 25 min) to give pentan—3—yl 2— bromo—2—ﬂuoroacetate (0.754 g, 61.4 %) as a colorless oil. 1H NMR (300 MHz, FORM-d) 8 ppm 0.96 (td, J=7.46, 2.08 Hz, 6 H) 1.60 - 1.76 (m, 4 H) 4.93 (dt, J=12.28, 6.33 Hz, 1 H) 6.50 (s, 0.5 H) 6.67 (s, 0.5 H) Exam le 24: R - entan 12- 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0acetate HZNJI'“Cf \ Exam le 25: S - entan 12- 2S 5R carbam0 lmeth 0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0acetate H2NJ01.H\:(i o (Virob Example 24-25 Examples 24—25 were prepared according to the procedure for Examples l—2. To a solution of (2S ,5R)—6—(allyloxy)—3 —methyl—7 —oxo— l ,6—diazabicyclo[3 .2. l]oct—3—ene—2—carboxamide (Intermediate 17, 272 mg, 1.15 mmol) in methanol (5 mL) at room temperature was added l,3—dimethylbarbituric acid (358 mg, 2.29 mmol) and Pd(Ph3P)4 (132 mg, 0.11 mmol). The reaction was stirred at room temperature for 2 hours. The mass of the desired product was observed and no starting material was seen by LCMS. The reaction mixture was trated to afford an orange film. The orange film was dissolved in DMF (5 mL), and K2CO3 (475 mg, 3.44 mmol) and —3—yl 2—bromo—2—ﬂuoroacetate (Intermediate 24, 75 1 mg, 3.31 mmol) were added. The reaction mixture was stirred overnight at room ature then diluted with ethyl acetate and filtered through a 0.45 u filter to remove solid potassium carbonate. The filtrate was washed twice with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and trated. Silica gel chromatography (0%—70% ethyl acetate/hexanes) afforded —3—yl 2—(((2S,5R)—2—carbamoyl—3—methyl—7—oxo—1,6— diazabicyclo[3.2.l]oct—3—en—6—yl)oxy)—2—ﬂuoroacetate (320 mg, 81 %) as a light yellow foam.

LCMS and NMR m it is a 1:1 mixture of diastereomers. The diastereomers were separated on reverse phase HPLC (Atlantis T3 4.6mm x 50mm 5um column, from 30 to 50% ACN in water in 5 min, flow rate 1 ml/min).

Example 24 : 125 mg, 32% UPLC LCMS 2min_Acid_CV10 method acid condition retention time: 0.86 min, 344 (M+H)+ 1H NMR1300 MHz, CHLOROFORM-d) 8 ppm 0.92 (td, J=7.46, 3.21 Hz, 6 H) 1.61 - 1.75 (m, 4 H) 1.93 (s, 3 H) 3.21 - 3.35 (m, 2 H) 4.07 (dd, J=4.91, 2.64Hz, 1 H) 4.36 (s, 1 H) 4.91 (quin, J=6.18 Hz, 1 H) 5.47 (br. s., 1 H) 5.77 (s, 0.5 H) 5.94 (s, 0.5 H) 6.07 - 6.12 (m, 1 H) 6.59 (br. s., 1 H) Example 25: 125 mg, 32% UPLC LCMS 2min_Acid_CV10 method acid ion retention time: 0.91 min, 344 (M+H)+ 1H NMR (300 MHz, CHLOROFORM-d) 6 ppm 0.93 (t, J=7.46 Hz, 3 H) 0.95 (t, J=7.46 Hz, 3 H) 1.63 - 1.74 (m, 4 H) 1.93 (s, 3 H) 3.20 - 3.38 (m, 2 H) 4.02 (dd, J=5.00, 2.55 Hz, 1 H) 4.35 (s, 1 H) 4.92 (quin, J=6.18 Hz, 1 H) 5.56 (br. s., 1 H) 5.69 (s, 0.5 H) 5.89 (s, 0.5 H) 6.07 — 6.14 (m, 1 H) 6.64 (br. s., 1 H) Into a 250—mL round—bottom ﬂask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert—butyl (3R,6S)—6—[[(tert—butyldimethylsi1y1)— oxy]methyl] —5—methy1—3— [N—(prop—2—en— 1—yloxy)(2—nitrobenzene)sulfonamido] — 1 ,2,3 ,6— ydropyridine—1—carboxy1ate (Intermediate 11, 13.6 g, 22.75 mmol, 1 eq.) in dichloromethane (100 mL). This was followed by the addition of ZnBrz (10.2 g, 45.29 mmol, 2 eq.) in several batches. The resulting solution was d ght at room temperature.

The resulting solution was diluted with 500 mL of dichloromethane. The resulting mixture was washed with 2 x 200 mL of sodium bicarbonate (aq) and 2 x 200 mL of NH4C1 (aq). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 12 g (crude product) of the title compound as yellow oil.

M_SZ 498 ES+ (C22H35N3O6881) Intermediate 26: 3R 6S ut ldimeth lsil 10X meth l-S-meth l-N- r0 en 10X -1 2 3 6-tetrah dr0 ridinamine Into a 250—mL round—bottom ﬂask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N—[(3R,6S)—6—[[(tert—butyldimethylsilyl)oXy]methyl]—5— methyl— 1,2,3 ,6—tetrahydropyridin—3 —yl] —2—nitro—N—(prop—2—en— 1 )benzene— 1—sulfonamide (Intermediate 25, 12 g, 24.11 mmol, 1 eq.) in N,N—dimethylformamide (100 mL), 2— ylacetic acid (4.4 g, 47.77 mmol, 2 eq.). This was followed by the addition of LiOH (5.8 g, 242.17 mmol, 10 eq.), in portions. The resulting solution was stirred for 2 h at room temperature, then d with 500 mL of water, and extracted with 5 X 200 mL of ethyl acetate, and the organic layers combined. The organic mixture was washed with 3 X 200 mL of brine and 2 X 200 mL of sodium bicarbonate (aq.). The miXture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 8.4 g (crude product) of the title compound as yellow oil.

M_SZ 313 ES+ (C16H32N20281) Into a 2 L 3—necked round—bottom ﬂask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (3R,6S)—6—[[(tert—butyldimethylsilyl)0Xy]methyl]—5—methyl— N—(prop—2—en—1—y10Xy)—1,2,3,6—tetrahydropyridin—3—amine (Intermediate 26, 8.4 g, 26.88 mmol, 1 eq.) in acetonitrile (1.6 L) and N,N—diisopropylethylamine (14.2 g, 109.87 mmol, 4 eq.). This was followed by the addition of a solution of hloromethyl ate (2.9 g, 9.77 mmol, 0.4 eq.) in acetonitrile (100 mL) dropwise with stirring at —15°C over 3 hr. The ing solution was stirred overnight at room temperature. The resulting miXture was trated under vacuum. The crude product was diluted with 500 mL of ethyl acetate. The resulting miXture was washed with 2 X 400 mL of NH4Cl (aq.) and 2 X 400 mL of brine, then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 3.9 g (43%) of the title compound as yellow M_S: 339 ES+ (C17H30N203Sl) Intermediate 28: 2S 5R h dr0x meth lmeth [ r0 en 10x -1 6- diazabicyc10|3.2.1 |0cten0ne HO/I'“ \ Into a 100 mL round—bottom ﬂask was placed tetrahydrofuran (30 mL) and (2S,5R)—2—[[(tert— butyldimethylsilyl)oxy] methyl] —3—methyl—6—(prop—2—en— l—yloxy)— 1 ,6—diazabicyclo[3 .2. 1]oct— 3—en—7—one mediate 27, 3.2 g, 9.45 mmol, 1 eq.) and the solution was cooled to 0°C, then TBAF (14.2 mL 1N in THF, 1.5 eq.) was added dropwise. The reaction mixture was d for 1 h at 0°C in a ice bath. The resulting mixture was concentrated under . The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5—1:2). This resulted in 1.6 g (75%) of the title compound as a light yellow solid.

M_S: 225 ES+ (C11H16N203) 1H NMR1300 MHz, CDCl;) 8 1.63 (3H, d), 3.20 (2H, d), 3.62 - 3.84 (2H, m), 3.85 — 3.90 (2H, m), 4.35 - 4.48 (2H, m), 5.28 - 5.39 (2H, m), 5.95 - 6.08 (2H, m).

Intermediate 29: 2S 5R meth l0x0 r0 en 10x diazabic clo 3.2.1 0ctenecarb0x lic acid Ho)“-cf \ To a solution of H5IO6(12.93 g,56.71 mmol) in wet CH3CN(150 mL, 0.75% H20 v/v) at RT was added 28 mg, 1.28 mmol). The mixture was stirred until it was completely dissolved. Into a 100 mL round—bottom ﬂask, was placed wet acetonitrile (35 mL) and (2S ,5R)—2—(hydroxymethyl)—3—methyl—6—(prop—2—en— 1—yloxy)— 1 ,6—diazabicyclo[3 .2. 1]oct—3—en— 7—one (Intermediate 28, 740 mg, 3.30 mmol, 1 eq.) and it was cooled to 0°C. Then, the above oxidation solution (35 mL, 3 eq.) was added dropwise over the course of 30 min at 0°C. The ing solution was stirred for 1 h at 0°C in a water/ice bath. The reaction WO 53215 mixture was then diluted with 200 mL of chloroform and 50 mL of citric acid solution (25%).

The c layer was isolated and then washed by 3 x 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 0.70 g crude of the title compound as yellow oil.

M_S: 239 ES+ (C11H16N204) Intermediate 30: 2S 5R -N'-acet [ all 10x meth 0-1 6- ic clo 3.2.1 0ctenecarb0h drazide JII,,H ‘i O N x/L—N, To a solution of (2S,5R)—6—(allyloxy)—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2— carboxylic acid (Intermediate 29, 195.7 mg, 0.82 mmol) in DCM (10 mL) at room temperature was added 1—(3—dimethylaminopropyl)—3—ethylcarbodiimide hydrochloride (236 mg, 1.23 mmol), 1—hydroxybenzotriazole hydrate (219 mg, 1.23 mmol) and monoacetyl hydrazine (101 mg, 1.23 mmol). The mixture was cooled to 0°C and DIEA (0.715 mL, 4.11 mmol) was added. The reaction mixture was allowed to warm to rt and stirred at room temperature overnight, then diluted with ethyl acetate and washed twice with 1:1 brine:water.

The aqueous washes contained some product and were back extracted twice with ethyl acetate and once with ~5% methanol in dichloromethane. The combined organics were dried over magnesium sulfate, filtered and concentrated. Silica gel tography (0%—5% methanol/dichloromethane) afforded the title compound as a white foam (45.5 mg, 19%, ~50% purity).

M_S: 295 ES+ (C13H13N4O4) 1H NMR1300 MHz, DMSO—dg) 5: 1.62 (s, 3H); 1.86 (m, 3H); 2.88 (m, 1H); 3.40 (m, 1H); 3.81 (m, 1H); 3.95 (m, 1H); 4.38 (m, 2H); 5.32 (m, 2H); 5.94 (m, 1H); 6.11 (m, 1H); 9.86 (s, 1H); 10.24 (bs, 1H).

Exam le 26: eth 12- 2S 5R 2-acet lh drazinecarbon lmeth l0X0-1 6- diazabic clo 3.2.1 0cten 10X ﬂu0roacetate W0“... \ O N 02—N.09;fo\/ To a solution of (2S,5R)—N'—acetyl—6—(allyloxy)—3—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3— ene—2—carbohydrazide (Intermediate 30, 22.75 mg, 0.08 mmol, ) in methanol (3 mL) at room temperature was added 1,3—dimethylbarbituric acid (48.3 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (17.87 mg, 0.02 mmol). The reaction was stirred at room temperature for 2 hours then concentrated to afford an orange film. The orange film was dissolved in DMF (3 mL). Potassium carbonate (64.1 mg, 0.46 mmol) and ethyl 2— bromo—2—ﬂuoroacetate (0.055 mL, 0.46 mmol) were added. The reaction mixture was stirred for ~5 hours at room temperature then diluted with ethyl acetate and filtered h a 0.45 um filter to remove solid potassium carbonate. The filtrate was washed three times with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and trated.

Silica gel chromatography (0%—65% ethyl acetate/hexanes) afforded the title compound as an orange foam (25.9 mg, 94 %). The two diastereomers were present in a 1:1 ratio. The material was dissolved in ethyl acetate and washed three times with 1:1 brinezwater. The cs were dried over ium sulfate, filtered and concetrated. Another silica gel column was run (0%—30% e/dichloromethane) to afford pure title compound (16.6 mg, 60%).

M_S: 359 ES+ (C14H19FN4O6) 1H NMR1300 MHz= DMSO-dg) 5: 1.24 (m, 3H); 1.65 (s, 3H); 1.86 (m, 3H); 3.09 (m, 1H); 3.89 (d, 1H); 4.01 (m, 1H); 4.25 (m, 3H); 6.09 (m, 1H); 6.20 (m, 1H); 9.90 (s, 1H); 10.30 (d, Exam le 27: 2- 2S 5R 2-acet lh drazinecarbon lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂu0r0acetic acid lithium salt To a solution of ethyl S,5R)—2—(2—acetylhydrazinecarbonyl)—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)—2—ﬂuoroacetate (Example 26, 16.6 mg, 0.05 mmol) in THF (1 mL) and water (0.33 mL) at 0°C was added lithium hydroxide (1M) (0.05 mL, 0.05 mmol), and stirred for 10 minutes at 0°C. Another 0.2 eq of lithium hydroxide was added.

After 30 minutes another 0.2 equivalents of lithium hydroxide were added. The reaction mixture was stirred for an additional 30 minutes. HCl (0.5M) (0.046 mL, 0.02 mmol) was added to adjust the pH to ~4—5. The reaction e was extracted with ethyl acetate twice.

The aqueous layer was frozen and lyophilized. 15 mg of the title compound was obtained as an orange solid. The 2 diastereomers were t in a 1:1 ratio.

M_S: 331 ES+ (C12H15FN4O6) 1H NMR 300 MHz DMSO—dg) 5: 1.65 (s, 3H); 1.87 (m, 3H); 3.08 (m, 1H); 3.84 (m, 1H); 4.03 (m, 1H); 4.23 (s, 1H); 5.23 (m, 1H); 6.10 (m, 1H); 9.88 (s, 1H); 10.26 (bs, 1H).

Intermediate 31: tert-but 14- 2S 5R all 10x meth l0x0-1 6- diazabic clo 3.2.1 enecarb0xamid0 benz lcarbamate k0 ”noN)”i \ To a solution of (2S,5R)—6—(allyloxy)—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2— carboxylic acid (Intermediate 29, 130.5 mg, 0.55 mmol) in DMF (5 mL) at room temperature was added tert—butyl 4—aminobenzylcarbamate (146 mg, 0.66 mmol), s Base (0.287 mL, 1.64 mmol) and 1—propanephosphonic acid cyclic ide (50 wt% in DMF) (0.326 mL, 1.10 mmol). The mixture was stirred at room temperature for 1h. Water (10 mL) and 10% MeOH in DCM (20 mL) were added. The organic layer was separated, and concentrated to give the crude product. Purification by ﬂash chromatography (20g silica gel, 0%—10% MeOH in DCM, 20 min) afforded the title compound (178 mg, 73.4 % yield, ~50% purity) as a yellow oil.

M_S: 443 ES+ (C23H30N405) 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 1.47 (m, 12 H) 3.10 - 3.23 (m, 1 H) 3.25 - 3.39 (m, 1 H) 4.34 - 4.54 (m, 3 H) 4.36 - 4.49 (m, 3 H) 5.25 - 5.45 (m, 2 H) 6.03 (d, J=6.61 Hz, 1 H) 6.09 - 6.17 (m, 1 H) 7.24 - 7.29 (m, 2 H) 7.42 - 7.62 (m, 2 H) 8.64 (s, 1 H) Intermediate 32: R -eth 12- 2S 5R 4- tert-butox carbon lamino meth l hen [- carbamo th l0x0-1 6-diazabic clo 3.2.1 0cten 10x ﬂu0roacetate To a solution of tert—butyl 4—((2S,5R)—6—(allyloxy)—3—methyl—7—oxo—1,6—diazabicyclo— [3.2.1]oct—3—ene—2—carboxamido)benzylcarbamate (Intermediate 31, 178 mg, 0.40 mmol) in methanol (10 mL) at room temperature was added Pd(Ph3P)4 (465 mg, 0.40 mmol). The reaction was d at room temperature for 16 hours. The reaction mixture was concentrated to afford crude intermediate tert—butyl 4—((2S,5R)—6—hydroxy—3—methyl—7—oxo— 1,6—diazabicyclo[3.2.1]oct—3—enecarboxamido)benzylcarbamate as an orange film. The crude material was dissolved in DMF (1 mL). K2CO3 (167 mg, 1.21 mmol) and ethyl 2—bromo—2— ﬂuoroacetate (0.052 mL, 0.44 mmol) were added. The reaction mixture was stirred ght at room temperature. EtOAC (20 mL) was added, and the reaction mixture was washed with water (10 mL). The c layer was concentrated to give the crude product which was purified by ﬂash chromatography (12 g silca gel, 0—100% EtOAc in Hexane, 20 min; then 5% MeOH in DCM, 10 min) to afford the title compound (11 mg, 5.4% yield) as an orange solid.

M_S: 507 ES+ (C24H31FN4O7) 1H NMR1300 MHz= CHLOROFORM-d) 5 ppm 1.36 (t, 3 H) 1.48 (s, 9 H) 2.00 (s, 3 H) 3.21 - 3.27 (m, 1 H) 3.36 (d, J=1.70 Hz, 1 H) 4.08 (dd, J=5.00, 2.74 Hz, 1 H) 4.24 - 4.42 (m, 5 H) 4.47 (s, 1 H) 5.78 - 5.95 (m, 1 H) 6.12 - 6.17 (m, 1 H) 7.38 - 7.55 (m, 4 H) 8.47 (s, 1 H) Intermediate 33: R 2S 5R 4- tert-butox carbon lamin0 meth l hen l- carbam0 l meth l0x0-1 6-diazabic clo 3.2.1 0cten 10x ﬂu0r0acetic acid lithium salt “in0 ifI,“ To a solution of (2R)—ethyl S,5R)—2—((4—(((tert—butoxycarbonyl)amino)methyl)phenyl)— oyl)—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)—2—fluoroacetate (Intermediate 32, 11 mg, 0.02 mmol) in THF (1 mL) and water (0.5 mL) at 0°C was added m hydroxide (1M) (0.02 mL, 0.02 mmol). The mixture was stirred for 5 minutes at 0°C and DCM (10 mL) was added. Hydrochloric acid (0.5N) was carefully added to adjust the pH to ~5—6. The organic layer was separated and concentrated to give the title compound (8 mg, 77%) as a yellow solid.

UPLC acid condition retention time: 0.80 min, 479 (M+H)+ 1H NMR 300 MHz CHLOROFORM-d 5 m 1.47 (s, 9 H) 1.98 (s, 3 H) 3.19 - 3.44 (m, 1 H) 4.03 — 4.55 (m, 6 H) 5.68 - 6.05 (m, 1 H) 7.44 - 7.56 (m, 4 H) 8.49 (br. s., 1 H) Exam le 28: R 2S 5R 4- amin0meth l hen m0 l meth l0X0-1 6- To a solution of (2R)—2—(((2S,5R)—2—((4—(((tert—butoxycarbonyl)amino)methyl)phenyl)— carbamoyl)—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)—2—ﬂuoroacetic acid lithium salt (Intermediate 33, 8 mg, 0.02 mmol) in DCM (2 mL) at 0 °C was added TFA (0.128 mL, 1.67 mmol). The reaction mixuture was stirred at 0 °C for 6 hours and solvent was removed. Toluene (2 x 1 mL) was added and concentrated to remove excess TFA. EtzO (2 mL) was added and the precipitation formed was filtered, washed with EtzO and dried to give the title compound (8 mg, 97%) as a TFA salt.

WO 53215 M_S: 379 ES+ (C17H19FN405) 1H NMR {300 MHz: D20) 5 ppm 1.75 (s, 3 H) 3.23 — 3.61 (m, 2 H) 4.12 — 4.25 (m, 3 H) 4.51 - 4.60 (m, 1 H) 5.53 — 5.98 (m, 1 H) 6.29 (br. s., 1 H) 7.45 — 7.57 (m, 4 H) ediate 34: 2S 5R all 10X meth 0-N- razin lmeth l-1 6- diazabic clo 3.2.1 0ctenecarb0xamide N Oil—NOV To a solution of (2S,5R)—6—(allyloxy)—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2— carboxylic acid (Intermediate 29, 199 mg, 0.84 mmol) in DMF (5 mL) at 0°C was added pyrazin—Z—ylmethanamine (91 mg, 0.84 mmol), O—(7—azabenzotriazol—1—yl)—N,N,N',N'— tetramethyluronium hexaﬂuorophosphate (635 mg, 1.67 mmol) and DIEA (0.582 mL, 3.34 mmol). The reaction mixture was stirred for 30 minutes at room temperature, then diluted with ethyl acetate and washed with saturated sodium bicarbonate once and 1:1 brinezwater three times. The organics were dried over magnesium sulfate, filtered and trated.

Silica gel chromatography (0%—2.5% methanol/dichloromethane) afforded the title compound (147 mg, 53.5 %) as an orange oil.

M_S: 330 ES+ (C16H19N503) 1H NMR1300 MHz= DMSO-dg) 8: 1.60 (s, 3H); 3.14 (m, 2H); 3.64 (m, 1H); 3.94 (m, 1H); 4.35 (m, 2H); 4.46 (m, 2H); 5.29 (m, 2H); 5.96 (m, 1H); 6.07 (m, 1H); 8.56 (m, 3H); 9.05 (m, Exam le 29: eth lZ-ﬂu0r0 2S 5R meth l0X0 2- lmeth l carbam0 l -1 6-diazabic clo 3.2.1 0cten 1 0X acetate N\ NJ,“ E / \ N F O O/Sz/OV To a solution of (2S,5R)—6—(allyloxy)—3—methyl—7—oxo—N—(pyrazin—Z—ylmethyl)—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 34, 153.8 mg, 0.47 mmol) in methanol (3 mL) at room temperature was added 1,3—dimethylbarbituric acid (146 mg, 0.93 mmol) and tetrakis(triphenylphosphine)palladium(0) (54.0 mg, 0.05 mmol). The reaction was stirred at room temperature for 2 hours. More tetrakis(triphenylphosphine)palladium(0) (54.0 mg, 0.05 mmol) was added as well as 2 mL of methanol, and the mixture was stirred at room ature for another 2 hours. The reaction mixture was concentrated to afford an orange oil. The oil was dissolved in DMF (3 mL) and ium carbonate (194 mg, 1.40 mmol) and ethyl o—2—ﬂuoroacetate (0.166 mL, 1.40 mmol) were added. The on mixture was stirred overnight at room temperature then diluted with ethyl acetate and filtered through a 0.45 um filter to remove solid ium carbonate. The filtrate was washed three times with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%—100% ethyl acetate/hexanes) afforded the title compound (95 mg, 52%) as a light orange foam. The compound is a 1:1 mixture of diastereomers.

M_S: 394 ES+ (C17H20FN505) 1H NMR1300 MHz, DMSO—dg) 5: 1.22 (m, 3H); 1.63 (s, 3H); 2.71 (m, 1H); 3.10 (m, 1H); 3.98 (d, 1H); 4.02 (m, 1H); 4.26 (m, 2H); 4.47 (m, 2H); 6.05 (m, 1H); 6.20 (m, 1H); 8.56 (m, 3H); 9.10 (m, 1H).

To a solution of ethyl 2—fluoro—2—(((2S,5R)—3—methyl—7—oxo—2—((pyrazin—2—ylmethyl)— carbamoyl)—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)acetate (Example 29, 95.3 mg, 0.24 mmol) in THF (2 mL) and water (0.66 mL) at 0°C was added lithium hydroxide (1M) (0.254 mL, 0.25 mmol), and stirred for 25 minutes at 0°C. Another 0.1 eq of lithium hydroxide was added. After 15 minutes hydrochloric acid (0.5N) (0.242 mL, 0.12 mmol) was added to adjust the pH to ~5—6. The reaction mixture was frozen and lyophilized. 90 mg of a pale yellow solid were purified by reverse phase HPLC (YMC noid C30, 21.2mm x 150 mm, 4 um coupled with Synergi Polar RP, 21.2mm x 100mm, 4 um, 0%—30% acetonitrile in water, 20 mL/min, 15 min). 23.6 mg (27%) of the title compound was obtained as a white solid. The compound is a 1:1 mixture of diastereomers.

M_S: 366 ES+ 6FN505) 1H NMR1300 MHZ, DMSO-dg) 5: 1.63 (s, 3H); 3.09 (m, 1H); 3.68 (m, 1H); 4.02 (m, 1H); 4.29 (s, 1H); 4.48 (d, 2H); 5.22 (m, 1H); 6.05 (m, 1H); 8.57 (m, 3H); 9.07 (m, 1H).

Intermediate 35: S -tert-but ll- tert-but ldimeth lsil 10x buten l3-meth l 0x0butenyl )carbamate To a solution of (S)—tert—butyl 1—(tert—butyldimethylsilyloxy)but—3—en—2—yl(2— (methoxy(methyl)amino)—2—oxoethyl)carbamate (Intermediate 5, 30.79 g, 76.48 mmol) in THF (200 mL) at 0 °C was added prop—1—en—2—ylmagnesium bromide (0.5M in THF) (300 mL, 149.90 mmol), and stirred at 0 °C for 1 hour. The reaction mixture was quenched with 200 mL 10% citric acid, diluted r with 100 mL water and extracted with ether. The organics were concentrated and the ing oil was dissolved in ether and washed with water and brine. The organics were dried over magnesium sulfate, filtered and concentrated.

Silica gel chromatography (0%—20% ethyl acetate/hexanes) afforded the desired product (26.2 g, 89 %) as a colorless oil.

M_S: 384 ES+ (C20H37NO4Si) 1H 0 MHz= DMSO-dg) 8: 0.02 (d, 6H); 0.83 (s, 9H); 1.27-1.38 (m, 9H); 1.80 (m, 3H); 3.71 (m, 2H); 4.34 (m, 2H); 4.61 (m, 1H); 5.17 (m, 2H); 5.77 (m, 1H); 5.85 (m, 1H); 6.03 (m, 1H).

Intermediate 36: S -tert-but 12- tert-but ldimeth lsil 10x meth lmeth l0x0- 6-dih dr0 ridine-l 2H -carb0x late TBSO/I’I(:(boc’N O A on of rt—butyl t—butyldimethylsilyloxy)but—3—en—2—yl(3 —methyl—2—oxobut—3— enyl)carbamate (Intermediate 35, 26.18 g, 68.25 mmol) in toluene (600 mL) was purged with nitrogen for 15 minutes. (1,3—Bis—(2,4,6—trimethylphenyl)—2—imidazolidinylidene)— dichloro(0—isopropoxyphenylmethylene)ruthenium (0.987 g, 1.57 mmol) was then added.

The reaction mixture was heated at 65 °C for 1.5 hours. The reaction mixture was concentrated onto silica gel. Silica gel chromatography (0%—15% ethyl acetate/hexanes) afforded the desired product (21.18 g, 87 %) as a colorless oil.

M_S: 356 ES+ (C18H33NO4Si) 1H NMR1300 MHz= DMSO-dg) 8: 0.01 (d, 6H); 0.81 (s, 9H); 1.42 (s, 9H); 1.75 (m, 3H); 3.74-3.89 (m, 3H); 4.04-4.32 (m, 1H); 4.67 (m, 1H); 6.88 (m, 1H).

Intermediate 37: 2S 5S -tert-but 12- tert-but ldimeth lsil 10x meth l-S-h drox meth l-5 6-dih dr0 ridine-l 2H -carb0x late TBSO/",,(j/N 'I boc’ ’OH To a solution of (III) chloride (14.68 g, 59.57 mmol) and (S)—tert—butyl 2—((tert— butyldimethylsilyloxy)methyl)—4—methyl—5—oxo—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 36, 21.18 g, 59.57 mmol) in methanol (300 mL) at 0 °C was added sodium dride (2.254 g, 59.57 mmol) portionwise. After 15 minutes, the reaction mixture was diluted with saturated ammonium chloride (100 mL) and water (100 mL), then extracted twice with diethyl ether. The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography % ethyl acetate/hexanes) afforded the desired t (19.45 g, 91 %) as a colorless oil.

M_S: 358 ES+ (C13H35NO4Si) 1H NMR1300 MHz, g) 5: 0.02 (s, 6H); 0.86 (s, 9H); 1.39 (s, 9H); 1.69 (m, 3H); 2.63—2.72 (m, 1H); 3.59 (m, 2H); 3.82 (m, 1H); 4.03 (m, 1H); 4.21 (m, 1H); 5.04 (d, 1H); .38 (m, 1H).

Intermediate 38: N- all 10x nitrobenzenesulfonamide N02 0 ©/S\N’O\/\||/,OH To a stirred solution of O—allylhydroxylamine hydrochloride 5 g, 1341.59 mmol) in DCM (2.5 L) at 0 OC, pyridine (318 mL, 3948 mmol) was added followed by the addition of 2—nitrobenzene—1—sulfonyl de (250 g, 1128.05 mmol) portionwise as a solid. The reaction mixture was then stirred at the same temperature for 1 h. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with 1.5 N HCl (1 L). The organic layer was separated, washed with water (250 mL), brine (250 mL), dried over anhydrous NaZSO4, filtered and concentrated under vacuum to yield the residue. The crude was purified by crystallization using EtOAc:petroleum ether (1:3) (800 mL) and afforded 202 g of the title compound as a light brown solid. The mother liquor was concentrated and purified by silica gel column chromatography (mesh 60—120) using petroleum ether:EtOAc (7:3) to yield another 19.1 g of the title compound as a yellow solid. The total yield was 76%.

UPLC: 257 (M—l) for C9H10N205S 1HNMR1400 MHz, DMSO-dg): 5 4.36-4.38 (m, 2H), 5.22-5.32 (m, 2H), 5.84-5.91 (m, 1H), 7.92-7.96 (m, 2H), 8.02-8.05 (m, 2H), 11.07 (s, 1H).

Intermediate 39: 2S 5R -tert-but 15- N- all 10X nitr0 hen lsulfonamido tert- but ldimeth lsil 10X meth lmeth l-S 6-dih dr0 ridine-l 2H -carb0X late TBSO/Ill'ﬁ,N N’OW To a solution of (2S,5S)—tert—butyl 2—((tert—butyldimethylsilyloxy)methyl)—5—hydroxy—4— methyl—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 37, 19.45 g, 54.40 mmol) in toluene (300 mL) at room temperature was added triphenylphosphine (17.06 g, 65.28 mmol), N—(allyloXy)—2—nitrobenzenesulfonamide (Intermediate 38, 14.05 g, 54.40 mmol) and diisopropyl azodicarboxylate (12.85 mL, 65.28 mmol). After 2 hours, the reaction mixture was trated onto silica gel and purified. Silica gel chromatography (0%—50% ethyl e/hexanes) afforded the desired product (25.2 g, 78 %) as a yellow oil.

M_S: 598 ES+ (C27H43N308SSi) 1H NMR1300 MHz= g) 8: 0.00 (s, 6H); 0.83 (s, 9H); 1.31 (m, 9H); 1.34 (m, 3H); .25 (m, 1H); 3.59 (m, 2H); 3.99-4.41 (m, 5H); 5.17 (m, 2H); 5.72 (m, 2H); 7.93-8.16 (m, 4H). ediate 40: 2S 5R -tert-but 15- N- all 10X nitr0 hen lsulfonamido h drox meth lmeth l-5 6-dih dr0 ridine-l 2H -carb0X late To a solution of )—tert—butyl 5—(N—(allyloxy)—2—nitrophenylsulfonamido)—2—((tert— butyldimethylsilyloxy)methyl)—4—methyl—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 39, 1 g, 1.67 mmol) in THF (11 mL) at 0 °C was added tetrabutylammonium fluoride (1M in THF) (2.175 mL, 2.17 mmol). After 90 minutes, the on mixture was WO 53215 2017/051692 concentrated onto silica gel. Silica gel chromatography (0%—70% ethyl acetate/hexanes) ed the desired product (0.732 g, 90 %) as a tan foam.

M_S: 484 ES+ (C21H29N3OSS) 1H NMR1300 MHz= DMSO-dg) 8: 1.31 (m, 9H); 1.35 (m, 3H); 3.20 (m, 1H); 3.41 (m, 2H); 3.96-4.37 (m, 5H); 4.76 (m, 1H); 5.19 (m, 2H); 5.66-5.84 (m, 2H); 7.94-8.18 (m, 4H).

Intermediate 41: 2S 5R N- all 10x nitr0 hen lsulfonamido tert- butox carbon lmeth [-1 2 5 6-tetrah dr0 ridinecarb0x lic acid HO [Cf N ,O boc’ N A To a solution of periodic acid (6 g, 31.26 mmol) in wet itrile (60 mL) (0.75% water by volume) at room temperature was added um(VI) oxide (10 mg, 0.10 mmol). The mixture was stirred until complete dissolution was achieved. To a solution of (2S,5R)—tert— butyl 5—(N—(allyloxy)—2—nitrophenylsulfonamido)—2—(hydroxymethyl)—4—methyl—5,6— dihydropyridine—1(2H)—carboxylate (Intermediate 40, 5 g, 10.34 mmol) in wet acetonitrile (60 mL) (0.75% by volume) at 0 °C was added dropwise the previously formed ic acid/chromium oxide solution (60 mL, 3 eq). After 30 minutes, the reaction mixture was diluted with ether and washed with 10% citric acid, sat. sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated to afford an orange foam (4.16 g, 81%).

M_S: 498 ES+ (C21H27N309S) 1H NMR1300 MHz, DMSO-dg) 8: 1.26 (m, 9H); 1.31 (m, 3H); 3.02-3.25 (m, 1H); 3.90 (m, 1H); 4.17 (m, 3H); 4.65—4.77 (m, 1H); 5.12—5.21 (m, 2H); 5.68 (m, 1H); 5.88 (m, 1H); 7.92— 8.17 (m, 4H).

Intermediate 42: 2S 5R -tert-but 15- N- all 10x nitr0 hen lsulfonamido o lmeth l-S 6-dih dr0 ridine-l 2H -carb0X late H2N IMCC N ,O boc’ N A To a solution of (2S,5R)—5—(N—(allyloxy)—2—nitrophenylsulfonamido)—1—(tert—butoxycarbonyl)— yl—1,2,5,6—tetrahydropyridine—2—carboxylic acid mediate 41, 4.16 g, 8.36 mmol) in DMF (35 mL) at room temperature was added ammonium de (0.895 g, 16.72 mmol), HATU (4.77 g, 12.54 mmol) and DIEA (5.84 mL, 33.45 mmol). After 15 minutes, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and twice with 1:1 brine:water. The cs were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%—80% ethyl acetate/hexanes) was run twice to afforded the desired product (2.16 g, 52 %) as a yellow foam.

M_S: 497 ES+ 8N4OgS) 1H NMR1300 MHz, DMSO-dg) 8: 1.26 (m, 9H); 1.37 (m, 3H); 3.12-3.35 (m, 1H); 3.80 (m, 1H); 4.18 (m, 3H); 4.64-4.79 (m, 1H); 5.13-5.22 (m, 2H); 5.68 (m, 1H); 5.88 (m, 1H); 7.04 (m, 1H); 7.45 (bs, 1H);7.90—8.18(m, 4H).

Intermediate 43: 2S 5R N- all 10X nitr0 hen namido meth [-1 2 5 6- To a solution of (2S,5R)—tert—butyl 5—(N—(allyloxy)—2—nitrophenylsulfonamido)—2—carbamoyl— 4—methyl—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 42, 2.16 g, 4.35 mmol) in DCM (20 mL) at room temperature was added zinc bromide (0.700 mL, 13.05 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated to afford the desired product (1.450 g, 84 %) as a yellow foam.

M_S: 397 ES+ (C16H20N4O6S) 1H NMR1300 MHz, DMSO-dg) 8: 1.65 (m, 3H); 2.71 (m, 3H); 3.76 (m, 1H); 3.95 (m, 1H); 4.18—4.42 (m, 2H); 5.23 (m, 2H); 5.82 (m, 1H); 6.02 (m, 1H); 7.05 (bs, 1H); 7.30 (bs, 1H); 7.93-8.18 (m, 4H).

Intermediate 44: 2S 5R all 10X amin0 meth [-1 2 5 6-tetrah dr0 ridine carboxamide and 2R 5R all 10X amin0 meth [-1 2 5 6-tetrah dr0 ridine carboxamide To a solution of (2S,5R)—5—(N—(allyloxy)—2—nitrophenylsulfonamido)—4—methyl—1,2,5,6— tetrahydropyridine—2—carboxamide (Intermediate 43, 1.4 g, 3.53 mmol) and cesium carbonate (9.21 g, 28.25 mmol) in THF (100 mL) at room temperature was added PS— thiophenol (3—(3—mercaptophenyl)propanamidomethylpolystyrene) (1.55 mmol/g) (9.12 g, 14.13 mmol). After stirring overnight at room temperature, the reaction mixture was filtered through a fritted funnel and the resin was washed twice with DCM. The filtrate was concentrated to afford a yellow oil. Silica gel chromatography (0%—5% methanol/dichloromethane) afforded a 3 to 1 e of trans and cis isomers (0.473 g, 63.4%) as a light yellow oil. The mixture was taken d without separation.

M_S: 212 ES+ (C10H17N302) 1H NMR1300 MHz, g) 8: 1.73 (m, 3H); 2.63 (m, 1H); 2.97 (m, 1H); 3.01 (m, 1H); 3.60 (m, 1H); 4.12 (m, 2H); 5.11—5.26 (m, 2H); 5.92 (m, 1H); 6.45 (m, 1H); 7.00 (m, 1H); 7.33 (bs, 1H). ediate 45: 2S 5R all 10x meth l0x0-1 6-diazabic clo 3.2.1 0ctene carboxamide HZN \ 0 0V To a solution of )—5—(allyloxyamino)—4—methyl—1,2,5,6—tetrahydropyridine—2— carboxamide and (2R,5R)—5—(allyloxyamino)—4—methyl—1,2,5,6—tetrahydropyridine—2— carboxamide (Intermediate 44, 0.429 g, 2.03 mmol) and DIEA (1.415 mL, 8.12 mmol) in acetonitrile (170 mL) at 0 °C was added sgene (0.241 g, 0.81 mmol) as a solution in acetonitrile (1.5 mL) at a rate of 0.1 mL/min. Once addition was complete, the reaction was warmed to room temperature and d two days. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%—20% ethyl acetate/hexanes) afforded the product (0.312 g, 64.8%) as a light yellow oil.

M_S: 238 ES+ (C11H15N303) 1H NMR1300 MHZ, DMSO—dg) 5: 1.79 (m, 3H); 3.19 (m, 2H); 3.81 (m, 1H); 4.12 (m, 1H); 4.36 (m, 2H); 5.24—5.45 (m, 3H); 5.89—6.00 (m, 1H); 7.28 (bs, 1H); 7.49 (bs, 1H).

Exam le 31: ZR -eth lZ- ZS 5R -Z-carbam0 lmeth l0x0-1 6- ic clo 3.2.1 en 10x -Z-ﬂu0r0acetate Exam le 32: ZS -eth lZ- ZS 5R -Z-carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x -Z-ﬂu0r0acetate Examples 31-32 To a solution of (2S,5R)—6—(a11yloxy)—4—methy1—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2— carboxamide (Intermediate 45, 0.2972 g, 1.25 mmol) in methanol (6 mL) at room temperature was added 1,3—dimethy1barbituric acid (0.391 g, 2.51 mmol) and tetrakis(triphenylphosphine)pa11adium(0) (0.145 g, 0.13 mmol). The reaction was stirred at room temperature for 2 hours, then concentrated to afford an orange film. The orange film was dissolved in DMF (6 mL). Potassium carbonate (0.519 g, 3.76 mmol) and ethyl bromoﬂuoroacetate (0.592 mL, 5.01 mmol) were added. The reaction mixture was stirred overnight at room temperature, then diluted with ethyl acetate and ed through a 0.45 um filter to remove solid potassium carbonate. The filtrate was washed twice with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and concentrated.

Silica gel tography (0%—65% ethyl acetate/hexanes) afforded a 1:1 mixture of diastereomers, 372 mg, 99%. tion of diastereomers was done on reverse phase HPLC tis T3, 19 mm x 150 mm, 5 um, 20%—40% acetonitrile in water, 20 mL/min, 15 min).

Both diastereomers were obtained as white solids after 1yophi1ization.

The following products were obtained : Example 31: (first eluting diastereomer): 108.8 mg, 29% M_S: 302 ES+ (C12H16FN305) 1H NMR1300 MHz= DMSO-dg) 8: 1.23 (t, 3H); 1.82 (m, 3H); 3.19 (m, 1H); 3.29 (m, 1H); 3.96 (m, 1H); 4.23 (m, 1H); 4.24 (q, 2H); 5.52 (m, 1H); 6.28 (m, 1H); 7.32 (br s, 1H); 7.56 (br s, 1H).

Example 32: d eluting diastereomer): 103.3 mg, 27% M_S: 302 ES+ 6FN305) 1H NMR1300 MHz, DMSO-dg) 8: 1.27 (t, 3H); 1.81 (m, 3H); 3.21 (m, 1H); 3.31 (m, 1H); 3.82 (m, 1H); 4.24 (m, 1H); 4.28 (q, 2H); 5.52 (m, 1H); 6.17 (m, 1H); 7.32 (br s, 1H); 7.55 (br s, 1H).

The stereochemistry of the two diastereomers were assigned based on order of elution as well as based on the inhibitory activity of the corresponding carboxylic acids (examples 33 and 34): the more active acid, coming from the first eluting diastereomer, was assigned as the R— isomer.

Exam le 33: 2R 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0ct en 1 0x ﬂu0r0acetic acid lithium salt To a solution of (2R)—ethyl 2—(((2S,5R)—2—carbamoyl—4—methyl—7—oxo—1,6—diazabicyclo— [3.2.1]oct—3—en—6—yl)oxy)—2—fluoroacetate (Example 31, 96.6 mg, 0.32 mmol) in THF (3 mL) and water (1 mL) at 0 °C was added lithium ide (0.337 mL, 0.34 mmol). The reaction mixture was kept in ice bath and stirred for 15 s. Another 0.2 eq of lithium hydroxide was added. After 15 minutes, the reaction mixture was adjusted to pH = 7 with 0.5N HCl.

The THF was evaporated and the remaining aqueous was frozen and lyophilized to afford a pale yellow solid. Reverse phase HPLC (YMC noid C30, 19 mm x 150 mm, 5 um coupled with Synergi Polar RP 21.2 mm x 100 mm, 4 um, 0%—40% itrile in water, 20 mL/min, 15 min) afforded the title compound as a white solid after lyophilization, 34.8 mg, M_S: 274 ES+ (C10H12FN305) 1H NMR1300 MHz, g) 5: 1.83 (m, 3H); 3.21 (m, 2H); 3.91 (m, 1H); 4.16 (m, 1H); .33 (m, 1H); 5.44 (m, 1H); 7.27 (br s, 1H); 7.53 (br s, 1H).

Exam le 34: 2S 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0ct en 1 0x ﬂu0r0acetic acid lithium salt The title compound was prepared from (2S)—ethy1 2—(((2S,5R)—2—carbamoyl—4—methy1—7—oxo— 1,6—diazabicyclo[3.2.1]oct—3—en—6—y1)oxy)—2—ﬂuoroacetate (Example 32, 91.8 mg, 0.30 mmol) according to the procedure for Example 33. Purification ions were the same to afford an off—White solid after lyophilization, 11.7 mg, 14%.

M_S: 274 ES+ (C10H12FN305) 1H NMR1300 MHz= g) 5: 1.81 (m, 3H); 3.21 (m, 2H); 3.87 (m, 1H); 4.16 (m, 1H); .25 (m, 1H); 5.45 (m, 1H); 7.28 (br s, 1H); 7.54 (br s, 1H).

Exam le 35: 2R -is0 1'0 12- 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0acetate Exam le 36: 2S -is0 1'0 12- 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0acetate To a solution of (2S,5R)—6—(allyloxy)—4—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2— carboxamide (Intermediate 45, 0.15 g, 0.63 mmol) in methanol (3 mL) at room temperature was added 1,3—dimethylbarbituric acid (0.197 g, 1.26 mmol) and tetrakis(triphenyl— phosphine)palladium(0) (0.073 g, 0.06 mmol). The reaction was stirred at room temperature for 2 hours, then concentrated to afford an orange film. The orange film was dissolved in DMF (4 mL). Potassium carbonate (0.175 g, 1.26 mmol) and pyl 2—bromo—2— ﬂuoroacetate (Intermediate 18, 0.377 g, 1.90 mmol) were added. The reaction e was stirred at room temperature for 4.5 hours then diluted with ethyl acetate and filtered through a 0.45 um filter to remove solid potassium ate. The filtrate was washed twice with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and concentrated.

Silica gel chromatography (0%—65% ethyl acetate/hexanes) afforded a 1:1 mixture of diastereomers, 196 mg, 98%. Separation of diastereomers was done on reverse phase HPLC (Atlantis T3, 19 mm x 150 mm, 5 um, 20%—40% acetonitrile in water, 20 mL/min, 15 min).

Both diastereomers were obtained as white solids after lyophilization. e 35 : (first eluting diastereomer): 58.6 mg, 31%.

M_S: 316 ES+ (C13H13FN305) 1H NMR1300 MHz, DMSO—dg) 5: 1.22 (m, 6H); 1.81 (m, 3H); 3.17 (m, 1H); 3.34 (m, 1H); 3.93 (m, 1H); 4.22 (m, 1H); 5.01 (q, 2H); 5.51 (m, 1H); 6.23 (m, 1H); 7.31 (br s, 1H); 7.54 (br s, 1H).

Example 36: (2nd eluting diastereomer): 53.8 mg, 29%.

M_S: 316 ES+ (C13H18FN305) 1H 0 MHz, g) 5: 1.28 (m, 6H); 1.81 (m, 3H); 3.19 (m, 1H); 3.29 (m, 1H); 3.82 (m, 1H); 4.24 (m, 1H); 5.06 (m, 1H); 5.52 (m, 1H); 6.14 (m, 1H); 7.32 (br s, 1H); 7.55 (br s, 1H).

Intermediates 46-50 were intentionally omitted.

Intermediate 51: R -tert-but 14- e do r0 lh drox meth [-2 2- dimethyloxazolidinecarb0xylate To a solution of (R)—tert—butyl 4—formyl—2,2—dimethyloxazolidine—3—carboxylate (Aldrich, 12.44 g, 54.26 mmol) in THF (150 mL) at —78 °C was added cyclopropylmagnesium bromide (217 mL, 108.52 mmol), dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction was quenched with water and d with ethyl acetate and brine. The resulting emulsion was filtered through celite and the layers ted.

The organics were dried over magnesium sulfate, ed and concentrated. Silica gel chromatography (0%—20% ethyl acetate/hexanes) afforded the title compound as a light yellow oil (12.47 g, 85%). 1H NMR1300 MHz= DMSO-dg) 5: 0.16 (m, 2H); 0.37 (m, 2H); 0.82 (m, 1H); 1.45 (m, 15H); 2.87 (m, 1H); 3.86 (m, 2H); 3.97 (m, 1H); 4.74 (m, 1H).

Intermediate 52: R -tert-but 14- c clo r0 anecarbon l-2 th loxazolidine ylate To a solution of (R)—tert—butyl 4—(cyclopropyl(hydroxy)methyl)—2,2—dimethyloxazolidine—3— carboxylate mediate 51, 12.47 g, 45.95 mmol) in DCM (300 mL) at room temperature was added Dess—Martin periodinane (29.2 g, 68.93 mmol). The reaction mixture was stirred overnight then diluted with ethyl acetate and washed with saturated sodium bicarbonate. An emulsion formed and was filtered through celite. The layers were separated and the organics washed with brine. The organics were dried over magnesium sulfate, ed and concentrated. Silica gel chromatography (0%—20% ethyl acetate/hexanes) afforded the title compound as a colorless oil (11.15 g, 90%). 1H NMR1300 MHz, DMSO-dg) 8: 0.90 (m, 4H); 1.38 (m, 12H); 1.54 (m, 3H); 2.12 (m, 1H); 3.94 (m, 1H); 4.18 (m, 1H); 4.56 (m, 1H).

Intermediate 53: S -tert-but l4- l-c clo r0 lvin l-2 2-dimeth lidine carboxylate To a suspension of potassium tert—butoxide (9.29 g, 82.80 mmol) in ether (250 mL) at room temperature was added methyltriphenylphosphonium bromide (29.6 g, 82.80 mmol). The mixture turned bright yellow and was heated to 40 °C for 1 hour. The mixture was cooled to room temperature and a solution of (R)—tert—butyl 4—(cyclopropanecarbonyl)—2,2— dimethyloxazolidine—3—carboxylate (Intermediate 52, 11.15 g, 41.40 mmol) in ether (30 mL) was added and the reaction mixture was stirred for 2 hours. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous was extracted once with ether.

The combined organic ts were dried over magnesium sulfate, filtered and trated.

Silica gel chromatography % ethyl acetate/hexanes) afforded the title nd as a colorless oil (9.84 g, 89%). 1H 0 MHz= DMSO-dg) 5: 0.42 (m, 2H); 0.65 (m, 2H); 1.43 (m, 16H); 3.76 (m, 1H); 4.09 (m, 1H); 4.27 (m, 1H); 4.66 (m, 2H).

Intermediate 54: S -tert-but ll- tert-but ldimeth lsil 10x c clo r0 lbuten ylcarbamate To a solution of (S)—tert—butyl 4—(1—cyclopropylvinyl)—2,2—dimethyloxazolidine—3—carboxylate mediate 53, 8.25 g, 30.86 mmol) in methanol (100 mL) at room temperature was added enesulfonic acid monohydrate (1.174 g, 6.17 mmol). The reaction mixture was heated to 80 °C overnight. Another 0.2 eq of p—toluenesulfonic acid monohydrate was added and heated at 80 °C for another 2 hours. The reaction mixture was cooled to room temperature. Triethylamine (4.29 mL, 30.86 mmol) and di—tert—butyl dicarbonate (3.37 g, .43 mmol) were added. The reaction mixture was stirred two days then trated. The residue was dissolved in ethyl acetate and washed once with saturated sodium onate.

The combined organic extracts were dried over magnesium sulfate, filtered and concentrated.

The resulting oil was dissolved in DCM (100 mL). Imidazole (2.73 g, 40.11 mmol), 4— dimethylaminopyridine (0.754 g, 6.17 mmol) and tert—butyldimethylsilyl chloride (4.65 g, .86 mmol) were added and the reaction mixture was stirred overnight at room temperature.

The reaction mixture was filtered to remove solids and washed with brine twice. The organic layer was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%—10% ethyl acetate/hexanes) afforded the title compound as a colorless oil (6.77 g, 64%).

M_S: 342 ES+ (C18H35N03Si) 1H 0 MHz, DMSO—dg) 5: 0.04 (s, 6H); 0.39 (m, 2H); 0.63 (m, 2H); 0.85 (s, 9H); 1.32 (m, 1H); 1.37 (m, 9H); 3.55 (m, 1H); 3.67 (m, 1H); 3.99 (m, 1H); 4.63 (s, 1H); 4.78 (s, 1H); 6.80 (m, 1H).

Intermediate 55: S tert-but ldimeth lsil 10X c clo r0 lbutenamine TBSO/\\/ﬂ\\;7 To a solution of (S)—tert—butyl 1—(tert—butyldimethylsilyloxy)—3—cyclopropylbut—3—en—2— ylcarbamate (Intermediate 54, 6.77 g, 19.82 mmol) in DCM (100 mL) at room temperature was added zinc bromide (17.86 g, 79.28 mmol). The reaction mixture was d overnight at room temperature. r 1 eq of zinc e was added. After several hours the reaction mixture was filtered and washed with saturated sodium bicarbonate. The resulting emulsion was filtered through a nylon filter and the layers were separated. The organics were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a yellow oil (4.61 g, 96%). 1H NMR1300 MHz2 DMSO—dg) 5: 0.04 (s, 6H); 0.39 (m, 2H); 0.63 (m, 2H); 0.87 (s, 9H); 1.35 (m, 1H); 1.81 (m, 2H); 3.33 (m, 1H); 3.45 (m, 1H); 3.67 (m, 1H); 4.59 (s, 1H); 4.83 (m, Intermediate 56: S -tert-but ll- tert-but h lsil 10X c clo r0 lbuten l 2- meth0X meth 1 amino 0X0eth l carbamate TBso’“\{JL\§7 o ’O\~ The title compound was prepared from (S)—1—(tert—butyldimethylsilyloxy)—3—cyclopropylbut— 3—en—2—amine (Intermediate 55, 4.61 g, 19.09 mmol) and 2—bromo—N—methoxy—N— acetamide (Intermediate 4, 3.16 g, 17.36 mmol) following the procedure described for Intermediate 5. The desired product was obtained as a light yellow oil (4.94 g, 64%).

M_S: 443 ES+ (C22H42N205Si) 1H NMR1300 MHZ; DMSO-dg) 5: 0.03 (m, 6H); 0.35 (m, 1H); 0.48 (m, 1H); 0.61 (m, 2H); 0.83 (m, 9H); 1.35 (m, 9H); 3.07 (m, 3H); 3.65 (m, 3H); 3.84 (m, 2H); 4.02 (m, 2H); 4.54 (m, 1H); 4.83 (m, 2H).

A suspension of cerium (III) chloride (27.8 g, 112.95 mmol) in THF (100 mL) at room temperature was stirred usly for 2 hours. The suspension was cooled to —78°C and (E)— prop—1—enylmagnesium bromide (0.5 M in THF) (226 mL, 112.95 mmol) was added dropwise. The mixture was stirred at —78°C for 1.5 hours. (S)—tert—butyl 1—(tert— butyldimethylsilyloxy)—3—cyclopropylbut—3—en—2—yl(2—(methoxy(methyl)amino)—2— oxoethyl)carbamate (Intermediate 56, 5 g, 11.30 mmol) in THF (20 mL) was then added dropwise at —78°C. The reaction was stirred at —78 °C for 30 minutes and then warmed to 0°C for 15 minutes. The reaction was quenched with 10% citric acid, diluted further with water and extracted twice with ether. The organics were washed once with brine, dried over magnesium sulfate, filtered and trated. Silica gel chromatography (0%—20% ethyl e/hexanes) afforded the title compound as a light yellow oil (4.0 g, 84%).

M_S: 424 ES+ (C23H41NO4Si) 1H NMR1300 MHz, DMSO—dg) 5: 0.03 (m, 6H); 0.43 (m, 2H); 0.61 (m, 2H); 0.83 (m, 9H); 1.34 (m, 10H); 1.84 (m, 2H); 2.04 (m, 1H); 3.74 (m, 1H); 3.84 (m, 2H); 4.03 (m, 1H); 4.57 (m, 1H); 4.79 (m, 2H); 6.28 (m, 1H); 6.84 (m, 1H).

Intermediate 58: S -tert-but 12- ut ldimeth lsil 10x meth lc clo r0 [ 0x0-5,6-dihydropyridine-112H2-carb0xylate The title compound was prepared from (S)—tert—butyl t—butyldimethylsilyloxy)—3— cyclopropylbut—3—en—2—yl(2—oxopent—3—enyl)carbamate (Intermediate 57, 4 g, 9.44 mmol) following the procedure described for Intermediate 7, except the reaction e was heated at 110°C overnight. The desired product was obtained as a light brown oil (2.97 g, 82%).

M_S: 382 ES+ (C20H35NO4Si) 1H NMR1300 MHz2 DMSO—dg) 5: 0.01 (m, 6H); 0.62 (m, 1H); 0.80 (s, 9H); 1.00 (m, 3H); 1.42 (s, 9H); 1.61 (m, 1H); 3.80 (m, 1H); 3.95 (m, 2H); 4.19 (m, 1H); 4.75 (m, 1H); 5.72 (s, Intermediate 59: 2S SS but 12- tert-but ldimeth lsil l0X meth [ c clo r0 l-S-h dr0X -5 6-dih dr0 -l 2H -carb0X late TBSO/II" \ N '1 boc’ ’OH The title compound was prepared from (S)—tert—butyl 2—((tert—butyldimethylsilyloxy)methyl)— opropyl—5—oxo—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 58, 2.97 g, 7.78 mmol) ing the procedure described for Intermediate 10. The desired product was obtained as a tan oil (2.74 g, 92%).

M_S: 384 ES+ (C20H37NO4Si) 1H NMR1300 MHz2 DMSO-dg) 8: 0.02 (m, 6H); 0.34 (m, 1H); 0.47 (m, 1H); 0.64 (m, 2H); 0.85 (m, 9H); 1.26 (m, 1H); 1.39 (s, 9H); 2.65 (m, 1H); 3.89 (m, 3H); 4.05 (m, 1H); 4.95 (m, 1H); 5.34 (m, 1H).

Intermediate 60: 2S 5R -tert-but 15- N- all l0X nitr0 hen lsulfonamido tert- The title compound was prepared from (2S,5S)—tert—butyl 2—((tert—butyldimethylsilyloxy)— methyl)—3—cyclopropy1—5—hydroxy—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 59, 2.74 g, 7.14 mmol) and N—(allyloxy)—2—nitrobenzenesulfonamide (1.85 g, 7.14 mmol) following the procedure described for Intermediate 11. The desired product was obtained as a light yellow oil (3.19 g, 71%).

M_S: 624 ES+ (C29H45N308SSi) 1H NMR 300 MHz DMSO-dg) 5: 0.00 (m, 6H); 0.34 (m, 1H); 0.63 (m, 2H); 0.83 (m, 9H); 1.37 (m, 9H); 3.30 (m, 1H); 3.84 (m, 2H); 4.30 (m, 4H); 5.18 (m, 2H); 5.75 (m, 1H); 8.04 (m, Intermediate 61: 28 SR -tert-but 15- N- all l0X nitr0 hen lsulfonamido c clo r0 l h dr0X meth l-5 6-dih dr0 ridine-1 2H -carb0X late The title compound was prepared from )—tert—buty1 5—(N—(a11yloxy)—2— nitrophenylsulfonamido)—2—((tert—butyldimethylsilyloxy)methy1)—3—cyclopropy1—5,6— dihydropyridine—1(2H)—carboxy1ate (Intermediate 60, 3.19 g, 5.11 mmol) following the procedure bed for Intermediate 12. The desired product was obtained as a tan foam (2.35 g, 90%).

M_S: 510 ES+ (C23H31N30gS) 1H NMR1300 MHz2 g) 5: 0.32 (m, 2H); 0.62 (m, 2H); 1.35 (m, 9H); 3.30 (m, 1H); 3.67 (m, 2H); 4.27 (m, 4H); 4.71 (m, 1H); 5.19 (m, 2H); 5.71 (m, 1H); 8.04 (m, 4H). ediate 62: 28 SR N- all l0X nitr0 hen lsulfonamido tert- but0X carbon lc clo r0 l-1 2 5 ah dr0 ridinecarb0X lic acid HOJI'“CF \ , ,0 boc I}! A The title compound was prepared from (2S,5R)—tert—buty1 5—(N—(a11yloxy)—2— nitrophenylsulfonamido)—3—cyclopropy1—2—(hydroxymethy1)—5,6—dihydropyridine— 1(2H)— carboxylate (Intermediate 61, 2.35 g, 4.61 mmol) following the procedure described for Intermediate 13. The desired product was obtained as an orange foam (2.28 g, 94%).

M_S: 524 ES+ (C23H29N3098) Intermediate 63: 28 SR -tert-but 15- N- all l0X nitr0 hen lsulfonamido carbam0 lc clo r0 l-5 6-dih dr0 ridine-1 2H -carb0X late HZNJCl) \ ,N ,0 boc I}! A The title compound was prepared from (2S,5R)—5—(N—(allyloxy)—2—nitrophenylsulfonamido)— 1—(tert—butoxycarbonyl)—3—cyclopropyl—1,2,5,6—tetrahydropyridine—2—carboxylic acid mediate 62, 2.28 g, 4.35 mmol) following the procedure described for Intermediate 14. The desired product was obtained as an orange foam (1.07 g, 47%).

M_S: 523 ES+ (C23H30N40gS) 1H NMR1300 MHz2 DMSO—dg) 5: 0.23 (m, 2H); 0.59 (m, 2H); 1.35 (m, 9H); 3.58 (m, 1H); 4.23 (m, 3H); 4.72 (m, 1H); 5.19 (m, 2H); 5.71 (m, 1H); 7.18 (m, 1H); 7.59 (m, 1H); 8.04 (m, Intermediate 64: 2S 5R N- all 10X nitr0 hen lsulfonamido c clo r0 [- 6-tetrahydropyridinecarb0xamide HZN \ The title compound was prepared from (2S,5R)—tert—butyl 5—(N—(allyloxy)—2— nitrophenylsulfonamido)—2—carbamoyl—3—cyclopropyl—5,6—dihydropyridine—1(2H)—carboxylate (Intermediate 63, 0.932 g, 1.78 mmol) following the procedure described for Intermediate . The desired product was obtained as an orange foam (0.518 g, 68%).

M_S: 423 ES+ 2N4O6S) 1H NMR 300 MHz DMSO-dg) 8: 0.18 (m, 2H); 0.53 (m, 2H); 1.29 (m, 1H); 2.30 (m, 1H); 2.58 (m, 1H); 2.95 (m, 1H); 3.72 (m, 1H); 4.22 (m, 1H); 4.36 (m, 2H); 4.96 (m, 1H); 5.24 (m, 2H); 5.80 (m, 1H); 7.07 (bs, 1H); 7.39 (bs, 1H); 8.04 (m, 4H).

Intermediate 65: R all 10X amino c clo r0 [-1 2 5 6-tetrah dr0 ridine carboxamide The title compound was prepared from (2S,5R)—5—(N—(allyloxy)—2—nitrophenylsulfonamido)— opropyl—1,2,5,6—tetrahydropyridine—2—carboxamide (Intermediate 64, 0.518 g, 1.23 mmol) following the procedure described for Intermediate 26. The desired product was ed as a light yellow oil (0.171 g, 59%). The product is a mixture of diastereomers.

M_S: 238 ES+ 9N302) 1H NMR1300 MHz2 DMSO—dg) 5: 0.28 (m, 2H); 0.41 (m, 2H); 0.54 (m, 2H); 1.33 (m, 1H); 2.49 (m, 1H); 2.64 (m, 1H); 2.93 (m, 1H); 3.23 (m, 1H); 3.65 (m, 1H); 4.07 (m, 2H); 5.19 (m, 3H); 5.89 (m, 1H); 6.26 (m, 1H); 6.97 (bs, 1H); 7.34 (bs, 1H). ediate 66: 2S 5R all l0X c clo r0 l0X0-1 6-diazabic clo 3.2.1 0ct enecarb0xamide The title compound was prepared from (R)—5—(a11yloxyamino)—3—cyclopropy1—1,2,5,6— tetrahydropyridine—2—carboxamide (Intermediate 65, 0.316 g, 1.33 mmol) following the procedure described for Intermediate 27. The desired product was obtained as a colorless oil (0.261 g, 74%).

M_S: 264 ES+ (C13H17N303) 1H NMR1300 MHz= DMSO-dg) 8: 0.37 (m, 2H); 0.60 (m, 2H); 1.20 (m, 1H); 2.98 (m, 1H); 3.79 (m, 1H); 3.92 (m, 1H); 4.20 (m, 1H); 4.33 (m, 2H); 5.28 (m, 2H); 5.93 (m, 2H); 7.30 (bs, 1H); 7.86 (bs, 1H).

Exam le 37: 2R -is0 r0 12- 2S 5R carbam0 lc clo r0 0 diazabic clo 3.2.1 0cten l0X ﬂu0r0acetate Exam le 38: 2S -is0 r0 12- 2S 5R carbam0 lc clo r0 l0x0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0acetate H2N \ o 0&07/ To a solution of (2S,5R)—6—(allyloxy)—3—cyclopropyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene— oxamide (Intermediate 66, 0.15 g, 0.57 mmol) in methanol (3 mL) at room temperature was added 1,3—dimethylbarbituric acid (0.178 g, 1.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.066 g, 0.06 mmol). The reaction was stirred at room temperature for 2 hours, then concentrated to afford an orange film. The orange film was dissolved in DMF (4 mL). Potassium carbonate (0.157 g, 1.14 mmol) and isopropyl 2— bromo—2—ﬂuoroacetate (Intermediate 18, 0.340 g, 1.71 mmol) were added. The reaction e was stirred at room temperature ght then diluted with ethyl acetate and filtered through a 0.45 um filter to remove solid ium carbonate. The filtrate was washed twice with 1:1 brine:water. The organics were dried over ium sulfate, filtered and concentrated. Silica gel chromatography (0%—65% ethyl acetate/hexanes) afforded a 1:1 mixture of diastereomers, 166.3 mg, 86%. Separation of diastereomers was done on reverse phase HPLC (Atlantis T3, 19 mm x 150 mm, 5 um, 20%—40% itrile in water, 20 mL/min, 15 min). Both diastereomers were obtained as white solids after lyophilization.

Example 37: (first eluting diastereomer) : 47.3 mg, 24%.

M_S: 342 ES+ (C15H20FN305) 1H NMR1300 MHz, DMSO-dg) 8: 0.39 (m, 2H); 0.61 (m, 1H); 1.19 (d, 3H); 1.21 (m, 1H); 1.24 (d, 3H); 2.99 (m, 1H); 3.88 (m, 1H); 4.01 (m, 1H); 4.29 (m, 1H), 5.00 (m, 1H); 5.87 (m, 1H); 6.20 (m, 1H); 7.36 (br s, 1H); 7.90 (br s, 1H).

Example 38: d eluting diastereomer): 49.8 mg, 26%.

M_S: 342 ES+ (C15H20FN305) 1H NMR1300 MHz, DMSO-dg) 8: 0.41 (m, 2H); 0.62 (m, 1H); 1.22 (m, 1H); 1.27 (d, 3H); 1.29 (d, 3H); 3.03 (m, 1H); 3.91 (m, 1H); 3.94 (m, 1H); 4.31 (m, 1H), 5.05 (m, 1H); 5.91 (m, 1H); 6.12 (m, 1H); 7.37 (br s, 1H); 7.93 (br s, 1H).

Exam le 39: ZR -eth lZ- ZS 5R -Z-carbam0 lc clo r0 l0x0-1 6- diazabic clo 3.2.1 0cten 10x -Z-ﬂu0roacetate Exam le 40: ZS -eth lZ- ZS 5R -Z-carbam0 lc clo r0 l0x0-1 6- diazabic clo 3.Z.1 0cten 10x -Z-ﬂu0roacetate H2N \ 0 (TWOV To a solution of )—6—(allyloxy)—3—cyclopropyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene— oxamide (Intermediate 66, 0.2972 g, 1.13 mmol) in methanol (6 mL) at room temperature was added 1,3—dimethylbarbituric acid (0.352 g, 2.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.11 mmol). The reaction was stirred at room temperature for 2 hours, then concentrated to afford an orange film. The orange film was dissolved in DMF (6 mL). Potassium carbonate (0.468 g, 3.39 mmol) and ethyl luoroacetate (0.534 mL, 4.52 mmol) were added. The reaction mixture was stirred overnight at room temperature then diluted with ethyl acetate and ed through a 0.45 um filter to remove solid potassium carbonate. The filtrate was washed twice with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and concentrated.

Silica gel chromatography (0%—65% ethyl acetate/hexanes) afforded a 1:1 mixture of diastereomers, 303.7 mg, 82%. Separation of diastereomers was done on reverse phase HPLC (Atlantis T3, 19 mm x 150 mm, 5 um, % acetonitrile in water, 20 , 15 min). Both diastereomers were obtained as white solids after lyophilization.

Example 39: (first eluting diastereomer): 107 mg, 29% M_S: 328 ES+ (C14H13FN305) 1H NMR1300 MHz, DMSO-dg) 8: 0.39 (m, 2H); 0.61 (m, 2H); 1.21 (m, 4H); 3.01 (m, 1H); 3.89 (m, 1H); 4.02 (m, 1H); 4.19 (m, 2H); 4.29 (s, 1H); 5.88 (m, 1H); 6.22 (m, 1H); 7.36 (br s, 1H); 7.91 (br s, 1H).

Example 40: (second eluting diastereomer): 110.9 mg, 30%.

M_S: 328 ES+ (C14H18FN305) 1H NMR1300 MHz, DMSO-dg) 8: 0.40 (m, 2H); 0.61 (m, 2H); 1.26 (m, 4H); 3.04 (m, 1H); 3.90 (m, 1H); 3.94 (m, 1H); 4.26 (m, 3H); 5.90 (m, 1H); 6.24 (m, 1H); 7.36 (br s, 1H); 7.92 (br s, 1H).

Exam le 41: 2R 2S 5R carbam0 lc clo r0 l0x0-1 6- ic clo 3.2.1 0cten 1 0x ﬂu0r0acetic acid m salt To a solution of (2R)—ethyl 2—(((2S,5R)—2—carbamoyl—3—cyclopropyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)—2—ﬂuoroacetate (Example 39, 96.6 mg, 0.30 mmol) in THF (3 mL) and water (1 mL) at 0°C was added lithium ide (1M) (0.310 mL, 0.31 mmol). The reaction mixture was kept in an ice bath and stirred for 15 minutes. Another 0.2 eq of lithium hydroxide was added. After 15 minutes the reaction mixture was adjusted to pH = 7 with 0.5N HCl. The mixture was frozen and lyophilized to afford a pale yellow solid, 90.4 mg. Reverse phase HPLC (YMC Carotenoid 30, 19 mm x 150 mm, 5 pm coupled with Synergi Polar RP, 21.2 mm x 100 mm, 4 pm, 0%—25% acetonitrile in water, 20 , 5 min) afforded the title copound as awhite solid, 45.9 mg, 52%.

M_S: 300 ES+ (C12H14FN305) 1H NMR1300 MHz= DMSO-dg) 8: 0.38 (m, 2H); 0.59 (m, 2H); 1.20 (m, 1H); 3.02 (m, 1H); 3.83 (m, 1H); 4.00 (m, 1H); 4.25 (m, 1H); 5.24 (m, 1H); 5.89 (m, 1H); 7.30 (br s, 1H); 7.88 (br s, 1H).

Exam le 42: 2R ZS 5R carbam0 lc clo r0 l0x0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂu0r0acetic acid lithium salt I F O \O/SfOH To a solution of —(((2S,5R)—2—carbamoyl—3—cyclopropyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)—2—ﬂuoroacetic acid (Example 40, 96.6 mg, 0.30 mmol) in THF (3 mL) and water (1) at 0°C was added lithium hydroxide (1M) (0.310 mL, 0.31 mmol). The reaction mixture was kept in ice bath and stirred for 15 minutes. Another 0.2 eq of lithium hydroxide was added. After 15 minutes the reaction mixture was adjusted to pH = 7 with 0.5N HCl. The mixture was frozen and lized to afford a pale yellow solid, 90.6 mg. Reverse phase HPLC (YMC Carotenoid 30, 19 mm x 150 mm, 5 pm coupled with Synergi Polar RP, 21.2 mm x 100 mm, 4 pm, 0%—25% acetonitrile in water, 20 mL/min, 5 min) afforded the title copound as awhite solid, 41.2 mg, 45%.

M_S: 300 ES+ (C12H14FN305) 1H NMR1300 MHz= DMSO-dg) 8: 0.39 (m, 2H); 0.59 (m, 2H); 1.20 (m, 1H); 3.02 (m, 1H); 3.82 (m, 1H); 3.98 (m, 1H); 4.24 (m, 1H); 5.24 (m, 1H); 5.90 (m, 1H); 7.31 (br s, 1H); 7.90 (br s, 1H).

Exam le 43: 2- ZS 5R carbam0 lc clo r0 0-1 6-diazabic clo 3.2.1 0ct en 1 0x ﬂu0r0acetic acid lithium salt (2R)—2—(((2S ,5R)—2—carbamoyl—3—cyclopropyl—7—oxo—1,6—diazabicyclo[3.2. 3—en—6— )—2—ﬂuoroacetic acid (Example 41, 8 mg, 0.03 mmol) and (2S)—2—(((2S,5R)—2— carbamoyl—3—cyclopropyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)—2—ﬂuoroacetic acid (Example 42, 8 mg, 0.03 mmol) were combined in an amber Vial. Water (1.5 mL) was WO 53215 added. The mixture was frozen and lyophilized to afford a white solid, 16 mg.

M_S: 300 ES+ (C12H14FN305) 1H NMR 300 MHz DMSO-dg) 8: 0.39 (m, 2H); 0.58 (m, 2H); 1.19 (m, 1H); 3.00 (m, 1H); 3.81 (m, 1H); 3.98 (m, 1H); 4.24 (m, 1H); 5.19 (m, 1H); 5.89 (m, 1H); 7.29 (br s, 1H); 7.88 (br s, 1H).

Intermediate 67: 1-is0 r0 lmeth 1- r0 1 2-br0m0-2 2-diﬂu0r0-acetate To a solution of 2,4—dimethylpentan—3—ol (0.72 mL, 5.17 mmol) and N,N— diisopropylethylamine (1.81 mL, 10.34 mmol) in DCM (20 mL) at 0°C was added 2—bromo— 2,2—diﬂuoro—acetyl de (0.49 mL, 5.17 mmol) se. The reaction mixture was stirred at 35°C overnight. The reaction was quenched with 10 mL of 1N hydrochloric acid.

The layers were separated. The cs were washed twice with water, once with brine, then dried over magnesium sulfate, filtered and concentrated to afford the title compound as a dark orange oil, 1.95 g, quant. Crude used in next step. 1H NMR1300 MHZ, CDCl§ﬂ 5: 0.95 (m, 12H); 2.06 (m, 2H); 4.74 (m, 1H).

To a solution of (2S,5R)—6—hydroxy—3—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3—ene—2— carboxamide (Intermediate 193, 150 mg, 0.76 mmol) in DMF (5 mL) at room temperature was added potassium carbonate (210.27 mg, 1.52 mmol) and (1—isopropyl—2—methyl—propyl) 2—bromo—2,2—diﬂuoro—acetate (Intermediate 67, 623.28 mg, 2.28 mmol). The reaction mixture was d for 4 hours at room temperature. Another two equivalents of (1— isopropyl—2—methyl—propyl) 2—bromo—2,2—diﬂuoro—acetate were added, and the reaction e was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and filtered to remove the potassium carbonate. The filtrate was washed three WO 53215 times with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0% — 15% acetone/dichloromethane) afforded the title compound as a light orange sticky film after lyophilization, 44.6 mg, 13%.

M_S: 390 ES+ (C17H25FN305) 1H NMR1300 MHz, DMSO-dg) 8: 0.86 (m, 12H); 1.64 (s, 3H); 1.99 (m, 2H); 3.15 (m, 1H); 3.85 (m, 1H); 4.07 (m, 1H); 4.28 (s, 1H); 4.69 (m, 1H); 6.03 (m, 1H); 7.42 (s, 1H); 7.85 (s, Intermediate 68: oct 1 2R m0ﬂu0r0-acetate Br/'\H/O\/\/\/\/ To a suspension of (2R)—2—bromo—2—fluoro—acetic acid; (1S)—1—phenylethanamine (Intermediate 168, 642.8 mg, 2.31 mmol) and 1—octanol (554 mg, 5.78 mmol) in DCM (9 mL) at room temperature was added chlorotrimethylsilane (1.19 mL, 9.39 mmol) dropwise.

The suspension became a solution and was stirred overnight at room temperature. The reaction mixture was washed with water three times. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%—10% ethyl acetate/hexanes) afforded the title nd as a colorless liquid, 554.9 mg, 89%. 1H NMR 300 MHz CDCléﬁ) 8: 0.84 (m, 3H); 1.24 (m, 10H); 1.61 (m, 2H); 4.22 (m, 2H); 7.25 (d, 1H).

Exam le 45: oct 1 2R 2S 5R carbam0 lmeth l0X0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂu0r0-acetate H2N \ To a solution of (2S,5R)—6—hydroxy—3—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3—ene—2— carboxamide (Intermediate 193, 150 mg, 0.76 mmol) in 1,4—dioxane (4 mL) and DMF (0.5 mL) was added octyl —bromo—2—fluoro—acetate mediate 68, 0.09 mL, 2.06 mmol). The reaction mixture was cooled to 0°C and DBU (0.11 mL, 0.76 mmol) was added dropwise. The reaction e was stirred for 10 minutes, then diluted with ethyl acetate and washed three times with 1:1 water. The organics were dried over magnesium sulfate, filtered and concentrated to afford an orange oil. Silica gel chromatography (0%— 60% ethyl e/hexanes) afforded the title compound as a White solid, 247.9 mg, 84%.

M_S: 386 ES+ (ClgHZSFNSOS) 1H NMR1300 MHz, DMSO-dg) 8: 0.86 (m, 3H); 1.25 (m, 10H); 1.59 (m, 5H); 3.04 (m, 1H); 3.78 (m, 1H); 4.04 (m, 1H); 4.16 (m, 3H); 6.00 (m, 1H); 6.24 (d, 1H); 7.37 (s, 1H); 7.81 (s, Intermediate 69: oct 1 2R br0m0ﬂu0r0-acetate Br)\n/O\ The title compound was prepared from (2R)—2—bromo—2—fluoro—acetic acid; (1S)—1— phenylethanamine (Intermediate 168, 526.2 mg, 1.89 mmol) and methanol (260 mg, 5.68 mmol) according to the ure for Intermediate 68 to afford a White oily/solid, 260 mg, 1H NMR {300 MHz, CDCiﬂ) 5: 3.84 (s, 3H); 6.52 (d, 1H).

Exam le 46: meth 1 2R 2S 5R carbam0 lmeth l0X0-1 6- diazabic clo 3.2.1 0cten 10X ﬂu0r0-acetate I \ The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 193, 120 mg, 0.61 mmol) and methyl (2R)—2—bromo—2—fluoro—acetate (Intermediate 69, 0.09 mL, 1.52 mmol) according to the procedure for Example 45 to a White foam, 81.2 mg, 46%.

M_S: 288 ES+ (C11H14FN305) 1H NMR1300 MHz, DMSO-dg) 8: 1.63 (s, 3H); 3.07 (m, 1H); 3.75 (m, 1H); 3.78 (s, 3H); 4.05 (m, 1H); 4.19 (s, 1H); 6.02 (m, 1H); 6.24 (m, 1H); 7.37 (s, 1H); 7.81 (s, 1H). ediate 70: all 1 2R br0m0ﬂu0r0-acetate BrJWrOW The title compound was prepared from (2R)—2—bromo—2—fluoro—acetic acid; (1S)—1— phenylethanamine (Intermediate 168, 510 mg, 1.83 mmol) and allyl alcohol (0.37 mL, 5.5 mmol) according to the procedure for Intermediate 68 to afford a colorless liquid, 100 mg, 1H NMR1300 MHZ, ) 5: 4.71 (m, 2H); 5.31 (m, 2H); 5.86 (m, 1H); 6.55 (d, 1H).

Exam le 47: all 1 2R 2S 5R carbam0 lmeth l0X0-1 6- diazabic clo 3.2.1 0cten 10X ﬂu0r0-acetate HZNJl, \ The title compound was ed from )—6—hydroxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 193, 50 mg, 0.25 mmol) and allyl (2R)—2—bromo—2—fluoro—acetate (Intermediate 70, 100 mg, 0.51 mmol) according to the procedure for Example 45 to afford a white foam, 61.3 mg, 77%.

M_S: 314 ES+ (C13H16FN305) 1H NMR1300 MHz, DMSO-dg) 8: 1.63 (s, 3H); 3.55 (m, 1H); 3.76 (m, 1H); 4.05 (m, 1H); 4.19 (s, 1H); 4.70 (m, 2H); 5.36 (m, 2H); 5.90 (m, 1H); 6.01 (m, 1H); 6.28 (d, 1H); 7.37 (s, 1H); 7.82 (s, 1H).

Intermediate 71: r0 1 2R m0ﬂu0r0-acetate Brk{(O\/\ The title compound was prepared from (2R)—2—bromo—2—fluoro—acetic acid; (1S)—1— phenylethanamine mediate 168, 444.9 mg, 1.6 mmol) and l—propanol (0.3 mL, 4 mmol) according to the procedure for Intermediate 68 to afford a colorless liquid, 318 mg, 100%. 1H NMR1300 MHZ, CDCléﬁ) 5: 0.92 (t, 3H); 1.67 (m, 2H); 4.19 (m, 2H); 6.51 (d, 1H).

Exam le 48: r0 1 2R 2S 5R bam0 lmeth l0X0-1 6- diazabic clo 3.2.1 0cten 10X ﬂu0r0-acetate HZNJl, \ The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—l,6— diazabicyclo[3.2.l]oct—3—ene—2—carboxamide (Intermediate 193, 150 mg, 0.76 mmol) and propyl (2R)—2—bromo—2—fluoro—acetate (Intermediate 71, 302.78 mg, 1.52 mmol) according to the procedure for Example 45 to afford a white sticky foam, 156 mg, 65%.

M_S: 316 ES+ (C13H18FN305) 1H NMR1300 MHz= DMSO-dg) 8: 0.89 (t, 3H); 1.61 (m, 5H); 3.05 (m, 1H); 3.76 (m, 1H); 4.04 (m, 1H); 4.13 (m, 2H); 4.19 (m, 1H); 6.01 (m, 1H); 6.25 (d, 1H); 7.37 (s, 1H); 7.82 (s, Intermediate 72: isobut 1 2R br0m0ﬂu0r0-acetate The title compound was prepared from —bromo—2—fluoro—acetic acid; — phenylethanamine (Intermediate 168, 487.5 mg, 1.75 mmol) and 2—methyl—l—propanol (0.4 mL, 4.38 mmol) according to the ure for Intermediate 68 to afford a colorless liquid, 373 mg, 100%. 1H NMR {300 MHZ, CDCiﬂ) 5: 0.91 (d, 6H); 1.97 (m, 1H); 4.00 (m, 2H); 6.51 (d, 1H).

Exam le 49: isobut 1 2R 2S 5R carbam0 lmeth l0X0-1 6- diazabic clo 3.2.1 0cten 10X ﬂu0r0-acetate HZNJl, \ N\ .: O 0’07’0\/< The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—l,6— diazabicyclo[3.2.l]oct—3—ene—2—carboxamide (Intermediate 193, 150 mg, 0.76 mmol) and WO 53215 2017/051692 isobutyl —bromo—2—fluoro—acetate (Intermediate 72, 372.73 mg, 1.75 mmol) according to the procedure for Example 45 to afford a sticky White foam, 161 mg, 64%.

M_S: 330 ES+ (C14H20FN305) 1H NMR1300 MHz= DMSO-dg) 8: 0.90 (d, 6H); 1.63 (s, 3H); 1.90 (m, 1H); 3.05 (m, 1H); 3.76 (m, 1H); 3.97 (m, 2H); 4.04 (m, 1H); 4.20 (s, 1H); 6.00 (m, 1H); 6.27 (d, 1H); 7.37 (s, 1H); 7.82 (s, 1H).

Intermediate 73: but 1 2R br0m0ﬂu0r0-acetate Br/vwrow The title compound was prepared from (2R)—2—bromo—2—ﬂuoro—acetic acid; (1S)—1— phenylethanamine (Intermediate 168, 400 mg, 1.44 mmol) and 1—butanol (0.33 mL, 3.6 mmol) according to the procedure for Intermediate 68 to afford a colorless liquid, 322 mg, quant. 1H NMR1300 MHZ, ) 8: 0.88 (t, 3H); 1.33 (m, 2H); 1.65 (m, 2H); 4.23 (m, 2H); 6.50 (d, 1H).

Exam le 50: but 1 2R 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0-acetate HZNJ’“? \ The title compound was prepared from (2S,5R)—6—hydroxy—3—methy1—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 193, 150 mg, 0.76 mmol) and butyl (2R)—2—bromo—2—ﬂuoro—acetate (Intermediate 73, 322.49 mg, 1.51 mmol) according to the procedure for Example 45 to afford a sticky White foam, 198 mg, 79%.

M_S: 330 ES+ (C14H20FN305) 1H NMR1300 MHz, DMSO-dg) 8: 0.88 (t, 3H); 1.35 (m, 2H); 1.59 (m, 2H); 1.63 (s, 3H); 3.06 (m, 1H); 3.77 (m, 1H); 4.04 (m, 1H); 4.20 (m, 2H); 4.21 (s, 1H); 6.00 (m, 1H); 6.24 (d, 1H); 7.37 (s, 1H); 7.82 (s, 1H).

WO 53215 Intermediate 74: ent 1 2R m0ﬂu0r0-acetate Br/'\H/0\/\/\ The title compound was prepared from (2R)—2—bromo—2—fluoro—acetic acid; (1S)—1— phenylethanamine (Intermediate 168, 474.2 mg, 1.71 mmol) and 1—pentanol (0.46 mL, 4.26 mmol) according to the procedure for Intermediate 68 to afford a colorless , 363 mg, 1H NMR 300 MHZ CDCléﬁl 5: 0.88 (m, 3H); 1.28 (m, 4H); 1.60 (m, 2H); 4.17 (m, 2H); 6.45 (d, 1H).

Exam le 51: ent 1 2R 2S 5R carbam0 lmeth l0X0-1 6- diazabic clo 3.2.1 0cten 10X ﬂu0r0-acetate HZNJII"? \ The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—1,6— icyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 193, 150 mg, 0.76 mmol) and pentyl (2R)—2—bromo—2—fluoro—acetate (Intermediate 74, 362.73 mg, 1.6 mmol) according to the procedure for Example 45 to afford a sticky white foam, 225 mg, 86%.

M_S: 344 ES+ (C15H22FN305) 1H NMR1300 MHz= g) 5: 0.87 (m, 3H); 1.30 (m, 4H); 1.58 (m, 2H); 1.63 (s, 3H); 3.04 (m, 1H); 3.77 (m, 1H); 4.04 (m, 1H); 4.20 (m, 2H); 4.21 (s, 1H); 6.00 (m, 1H); 6.24 (d, 1H); 7.37 (s, 1H); 7.82 (s, 1H).

Intermediate 75: heX 1 2R br0m0ﬂu0r0-acetate Br/'\n/OV\/\/ The title compound was prepared from (2R)—2—bromo—2—fluoro—acetic acid; (1S)—1— phenylethanamine (Intermediate 168, 400 mg, 1.44 mmol) and hexyl alcohol (0.45 mL, 3.6 mmol) according to the procedure for Intermediate 68 to afford a colorless liquid, 313 mg, 1H NMR1300 MHz, CDCléﬁ) 5: 0.86 (m, 3H); 1.22 (m, 6H); 1.59 (m, 2H); 4.17 (m, 2H); 6.45 (d, 1H).

Exam le 52: hex 1 2R 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0-acetate HZNJII“‘i \ The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 193, 150 mg, 0.76 mmol) and hexyl (2R)—2—bromo—2—fluoro—acetate (Intermediate 75, 313.62 mg, 1.3 mmol) according to the procedure for e 45 to afford a sticky white foam, 224 mg, 82%.

M_S: 358 ES+ (C16H24FN305) 1H NMR1300 MHz= DMSO-dg) 5: 0.87 (m, 3H); 1.30 (m, 6H); 1.57 (m, 2H); 1.62 (s, 3H); 3.04 (m, 1H); 3.77 (m, 1H); 4.04 (m, 1H); 4.19 (m, 2H); 4.20 (s, 1H); 6.00 (m, 1H); 6.24 (d, 1H); 7.37 (s, 1H); 7.82 (s, 1H).

Intermediate 76: l-chloroeth liso r0 [carbonate CITOTOY To a solution of 2—propanol (0.64 mL, 8.39 mmol) and pyridine (0.79 mL, 9.79 mmol) at — 78°C was added 1—chloroethyl formate (0.76 mL, 6.99 mmol) dropwise. The reaction mixture was d to slowly warm to room temperature and stir overnight. The reaction e became a solid white clump and was ted in dichloromethane. The resulting suspension was concentrated and the white solid was dissolved in ethyl acetate and washed with water and brine. The organics were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a colorless liquid, 1.29 g, 99%. 1H NMR {300 MHz, CDCiﬂ) 5: 1.35 (m, 6H); 1.84 (d, 3H); 4.96 (m, 1H); 4.44 (m, 1H).

Exam le53:1-iso r0 0x carbon 10x eth 1 2R 2S 5R carbam0 lmeth l 0x0-1 6-diazabic clo 3.2.1 0cten 1 0x ﬂu0r0-acetate O 0’27/07/0 O o 7/ To a solution of (2R)—2—[[(2S,5R)—2—carbamoyl—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3— en—6—yl]oxy]—2—fluoro—acetic acid le 4, 194.46 mg, 0.71 mmol), N,N— ropylethylamine (0.12 mL, 0.71 mmol) and 1—chloroethyl pyl carbonate (Intermediate 76, 237.15 mg, 1.42 mmol) in DMF (5 mL) at room temperature was added tetrabutylammonium chloride (162.22 mg, 0.71 mmol). The reaction mixture was heated at 40°C for ~4 hours, then d with ethyl acetate and washed twice with 1:1 water.

The organics were dried over magnesium sulfate, filtered and concentrated to afford an orange oil. Silica gel chromatography (0%—50% ethyl acetate/hexanes) afforded the title compound as a 1:1 mixture of diastereomers, white foam, 33.2 mg, 11%.

M_S: 404 ES+ (C16H22FN308) 1H NMR1300 MHz, DMSO—dg) 5: 1.23 (m, 6H); 1.46 (m, 3H); 1.62 (m, 3H); 3.05 (m, 1H); 3.79 (m, 1H); 4.00 (m, 1H); 4.19 (s, 1H); 4.80 (m, 1H); 6.00 (m, 1H); 6.33 (dd, 1H); 7.37 (s, 1H); 7.80 (d, 1H).

Exam le 54: 2R -benz 12- 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 en 10x ﬂu0r0acetate HZNJI'“OI \ DBU (8.83 mL, 58.57 mmol) in DMF (30 mL) was added dropwise to a solution of (2S,5R)— 6—hydroxy—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 193, 10.5 g, 53.25 mmol) and (R)—benzyl 2—bromo—2—ﬂuoroacetate (Intermediate 171, 14.47 g, 58.57 mmol) in DMF (100 mL) at —40°C over a period of 30 minutes under nitrogen. The resulting on was stirred at —40°C for 30 minutes, then quenched with water (15 mL).

The reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organics were washed with brine (3 X 20 mL), dried over sodium sulfate, filtered and trated.

Silica chromatography (0% to 40% ethyl acetate/petroleum ether) afforded the title compound as a white solid, 8.8 g, 45%.

M_S: 364 ES+ (C17H18FN305) 1H NMR1400 MHz, DMSO-dg) 8: 1.62 (s, 3H); 2.92 (d, 1H); 3.75 (d, 1H); 3.99 (m, 1H); 4.02 (s, 1H); 5.25 (s, 2H); 5.76 (s, 1H); 6.33 (d, 1H); 7.38 (m, 5H); 7.39 (s, 1H); 7.85 (s, 1H). ediate 77: 2S 5R tert-but l dimeth 1 Si] 1 0X meth l0X0-1 6- diazabic clo 3.2.1 0ctenecarb0X lic acid Ho)“-3 \ 0 \OTBS To a solution of methyl (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—l,6— diazabicyclo[3.2.l]oct—3—ene—2—carboxylate mediate 185, 538.5 mg, 1.65 mmol) in DCE (3 mL) in a 20 mL microwave vial was added trimethyltin hydroxide (477.l7 mg, 2.64 mmol). The reaction was run in the microwave for 2 hours at 80°C. The solvent was removed and the resulting residue was ved in ethyl acetate and washed three times with 0.01N potassium bisulfate and once with brine. The organics were dried over sodium sulfate, filtered and concentrated to afford an orange foam, 649 mg, 100%.

M_S: 3l3 ES+ (C14H24N204Si) 1H NMR1300 MHZ, DMSO—dg) 5: 0.00 (s, 6H); 0.78 (s, 9H); 1.50 (s, 3H); 2.92 (m, 1H); 3.47 (m, 1H); 3.53 (m, 1H); 3.77 (m, 1H); 5.85 (m, 1H). o \OTBS To a solution of )—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—l,6— diazabicyclo[3.2.l]oct—3—ene—2—carboxylic acid (Intermediate 77, 397.5 mg, 1.02 mmol) in DMF (6 mL) at 0°C was added oxamic hydrazide (209.83 mg, 2.04 mmol), HATU (387 mg, 1.02 mmol) and N,N—diisopropylethylamine (0.57 mL, 3.26 mmol). The reaction mixture was stirred for 1 hour, then diluted with ethyl acetate and washed once with saturated sodium bicarbonate. The aqueous contained some product and was extracted once with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated to afford a yellow oil. Silica gel chromatography (0%—5% methanol) afforded the title compound as a light yellow solid, 142 mg, 35%.

M_S: 398 ES+ (C16H27N505Si) 1H NMR1300 MHz, DMSO—dg) 5: 0.00 (s, 6H); 0.78 (s, 9H); 1.53 (s, 3H); 2.95 (m, 1H); 3.60 (m, 1H); 3.67 (m, 1H); 4.04 (s, 1H); 5.98 (m, 1H); 7.75 (s, 1H); 8.07 (s, 1H); 10.30 (s, 1H); 10.48 (s, 1H).

Intermediate 79: 5- 2S 5R tert-but l dimeth 1 Si] 1 0X meth l0X0-1 6- diazabic clo 3.2.1 0cten l -1 3 4-oxadiazole-Z-carboxamide o \OTBS To a on of 2—[2—[(2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carbonyl]hydrazino]—2—oxo—acetamide (Intermediate 78, 142 mg, 0.36 mmol) in DCM (6 mL) at room ature was added 4—nitrobenzenesulfonyl chloride (79.17 mg, 0.36 mmol) and N,N—diisopropylethylamine (0.19 mL, 1.07 mmol). The reaction e became yellow and was stirred for 30 minutes, then was diluted with dichloromethane and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated to afford an orange oil. Silica gel tography (0%—5% methanol/dichloromethane) afforded the title compound as an orange foam, 93.8 mg, 69%.

M_S: 380 ES+ (C16H25N504Si) 1H NMR 300 MHz DMSO-dg) 8: 0.00 (s, 6H); 0.77 (s, 9H); 1.53 (s, 3H); 3.02 (m, 2H); 3.70 (m, 1H); 5.01 (s, 1H); 6.14 (m, 1H); 8.13 (s, 1H); 8.53 (s, 1H).

Intermediate 80: 5- 2S 5R h dr0x meth l0x0-1 6-diazabic clo 3.2.1 0cten- 2- l -1 3 4-0xadiaz01ecarb0xamide To a solution of 5—[(2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—en—2—yl]—1,3,4—oxadiazole—2—carboxamide (Intermediate 79, 267.6 mg, 0.71 mmol) in ethyl acetate (6 mL) was added HF—pyridine (0.04 mL, 1.41 mmol). The reaction mixture was stirred for 2.5 hours, then r 2 eq of HF—pyridine was added and the reaction stirred for another hour. The reaction e was concentrated to afford the title nd as a tan solid, 245 mg, 99%.

M_S: 266 ES+ 1N504) 1H NMR1300 MHz= DMSO-dg) 5: 1.52 (s, 3H); 3.01 (m, 2H); 3.66 (m, 1H); 4.95 (s, 1H); 6.18 (m, 1H); 8.09 (s, 1H); 8.45 (m, 1H).

To a solution of 5—[(2S,5R)—6—hydroxy—3—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3—en—2—yl]— 1,3,4—oxadiazole—2—carboxamide (Intermediate 80, 176.8 mg, 0.67 mmol) in DMF (5 mL) was added ethyl (2S)—2—bromo—2—ﬂuoro—acetate (0.16 mL, 1.33 mmol) and potassium carbonate (276.39 mg, 2 mmol). The reaction mixture was stirred for 2 hours, then diluted with ethyl acetate, filtered and washed three times with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and concentrated to afford a yellow oil. Silica gel chromatography (0%—70% ethyl acetate/hexanes) afforded the title compound as a light yellow film, 66.8 mg, 27%. The compound is a 7:3 mixture of diastereomers.

M_S: 370 ES+ (C14H16FN506) WO 53215 1H NMR1300 MHz, DMSO—dg) 5: 1.25 (m, 3H); 1.72 (s, 3H); 3.20 (m, 2H); 4.19 (m, 1H); .30 (m, 1H); 6.25 (m, 1H); 6.26 (m, 1H); 8.26 (s, 1H); 8.65 (s, 1H).

Exam le 55: 2- 2S 5R S-carbamo l-1 3 4-0xadiazol l meth 0-1 6- diazabic clo 3.2.1 0cten 1 0x ﬂu0r0-acetic acid lithium salt To a solution of ethyl —[[(2S,5R)—2—(5—carbamoyl—1,3,4—oxadiazol—2—yl)—3—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl]oxy]—2—fluoro—acetate (Intermediate 81, 66.8 mg, 0.18 mmol) in THF (1 mL) and water (0.5 mL) at 0 °C was added lithium hydroxide (0.18 mL, 0.18 mmol). The reaction mixture was stirred for 10 minutes. Another 0.5 lents of lithium hydroxide added. After 10 minutes, the reaction mixture was treated with an additional 0.5 equivalents of lithium hydroxide. The reaction mixture was stirred for 20 minutes, neutralized with 0.5N HCl, frozen and lyophilized to afford a yellow solid. Reverse phase ISCO (50 g RediSep Gold C18, 100% water, 4 min; then 0%—50% acetonitrile/water) ed the title compound as an off—white solid, 26 mg, 36%. The compound is a 7:3 mixture of diastereomers.

M_S: 342 ES+ (C12H12FN506) 1H NMR 300 MHz DMSO—dg) 5: 1.70 (s, 3H); 3.20 (m, 2H); 4.15 (m, 1H); 5.20 (s, 1H); .28 (m, 1H); 6.27 (m, 1H); 8.25 (s, 1H); 8.65 (s, 1H).

Intermediate 82: 2- 1 3-di0x0is0indolin 1 0x ethanesulfonamide To a suspension of 2—hydroxyethanesulfonamide (Enamine, 1.92 mL, 7.19 mmol), N— hydroxyphthalimide (1.41 g, 8.63 mmol) and triphenylphosphine (2.26 g, 8.63 mmol) at 0 °C was added diisopropylazodicarboxylate (1.7 mL, 8.63 mmol) dropwise. The reaction mixture became dark orange then turned pale yellow. After ng for ~3 hours the reaction mixture was concentrated to afford a sticky pale yellow oil, which was triturated with ethyl acetate/hexanes. The white solid was collected by filtration and is the title compound, 1.8 g, M_S: 271 ES+ (C10H10N205S) 1H NMR 300 MHz DMSO-dg) 8: 3.52 (m, 2H); 4.50 (m, 2H); 6.96 (s, 2H); 7.87 (s, 4H).

Intermediate 83: 2-aminooxyethanesulfonamide H2 N\|lS/\/0 NH2\ To a solution of 2—(1,3—dioxoisoindolin—2—yl)oxyethanesulfonamide (Intermediate 82, 740 mg, 2.05 mmol) in DCM (20 mL) at room ature was added methylhydrazine (0.11 mL, 2.05 mmol). A precipitate immediately formed. The suspension was stirred at room temperature for ~2 hours, then concentrated. The solid was triturated with DCM and collected by tion. The solid was triturated with methanol and the resulting white solid was filtered off. NMR of the solid indicates byproduct. The filtrate was concentrated to afford the title compound as an off—white solid, 228.2 mg, 58%. NMR indicates 73% desired product. 1H NMR1300 MHz= DMSO-dg) 8: 3.27 (m, 2H); 3.85 (m, 2H); 6.11 (bs, 2H); 6.79 (s, 2H).

H ifI, O N % N\ O OTBS To a solution of (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—1,6— icyclo[3.2.1]oct—3—ene—2—carboxylic acid (Intermediate 77, 465.74 mg, 1.19 mmol) in DMF (8 mL) at 0°C was added 2—aminooxyethanesulfonamide (Intermediate 83, 228.96 mg, 1.19 mmol), HATU (453.43 mg, 1.19 mmol) and N,N—diisopropylethylamine (0.57 mL, 3.26 mmol). The reaction mixture was then stirred for 1 hour at 0 0C, then diluted with ethyl e and washed twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated to afford a yellow oil. Silica gel chromatography (0%—80% ethyl acetate/hexanes) ed the title compound as a colorless oil, 343 mg, 66%.

M_S: 435 ES+ (C16H30N4O6SiS) 1H NMR1300 MHz= DMSO-dg) 8: 0.00 (s, 6H); 0.78 (s, 9H); 1.45 (s, 3H); 2.97 (m, 1H); 3.20 (m, 2H); 3.57 (m, 2H); 3.84 (m, 1H); 4.02 (m, 2H); 6.01 (m, 1H); 6.80 (s, 2H); 11.74 (s, To a solution of (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—N—(2— sulfamoylethoxy)—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 84, 343 mg, 0.79 mmol) in ethyl acetate (4 mL) was added HF—pyridine (0.04 mL, 1.58 mmol). The reaction mixture was stirred for 30 minutes. Another 2 eq. of HF—pyridine were added and the on stirred for another hour. After 6 hours, and a total of 7 eq of HF—pyridine, the reaction was complete. The reaction e was filtered to collect an ite solid. The solid became gummy and stuck in the filter. Ethyl acetate and a small amount of methanol was used to rinse the filter and transfer the solid to a ﬂask. The solvent was removed under vacuum to afford the title compound as an off—white solid, 337 mg, 100%.

M_S: 321 ES+ (C10H16N4O6S) H2N\§/\/O\HJO|| | O N I; N\ O O O The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—N—(2— oylethoxy)—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 85, 279.32 mg, 0.65 mmol) and ethyl (2S)—2—bromo—2—ﬂuoro—acetate (Intermediate 174, 0.08 mL, 0.65 mmol) according to the procedure for Example 45 to afford a light yellow oil, 26.7 mg, 10%.

M_S: 425 ES+ (C14H21FN40gS) 1H NMR1300 MHz, DMSO—dg) 5: 1.25 (m, 3H); 1.60 (m, 3H); 3.15 (m, 1H); 3.36 (m, 1H); 3.78 (m, 1H); 4.02 (m, 3H); 4.07 (m, 2H); 4.28 (m, 2H); 6.13 (m, 1H); 6.16 (d, 1H); 6.95 (s, 2H); 11.91 (s, 1H).

WO 53215 Z Exam le 56: ZS -Z-ﬂu0r0-Z- ZS 5R meth l0x0-Z- Z-sulfam0 leth0x carbam0 l- 1 6-diazabic clo 3.2.1 0cten 1 0x acetic acid lithium salt To a on of ethyl (2S)—2—ﬂuoro—2—[[(2S,5R)—3—methyl—7—oxo—2—(2—sulfamoylethoxy— carbamoyl)—1,6—diazabicyclo[3.2.1]oct—3—en—6—y1]oxy] acetate (Intermediate 86, 26.7 mg, 0.06 mmol) in THF (1 mL) and water (0.5 mL) at 0 °C was added LiOH (0.06 mL, 0.06 mmol). The reaction mixture was stirred for 15 minutes, and another 0.5 equivalents of lithium hydroxide was added. After 15 minutes, another 0.5 eq of lithium hydroxide was added. After 30 minutes, and warming the temperature slightly, the reaction was complete.

The reaction mixture was neutralized with 0.5N HCl, frozen and lyophilized to afford a yellow oil. The compound was purified by reverse phase ISCO (5.5 g RediSep Gold C18, 100% water). The title compound was obtained as an ite solid, 11.3 mg, 29%.

M_S: 397 ES+ (C12H17FN4OgS) 1H NMR1300 MHz, DMSO—dg) 5: 1.56 (s, 3H); 3.02 (m, 1H); 3.26 (m, 1H); 3.98 (m, 5H); .20 (d, 1H); 6.03 (m, 1H); 7.06 (s, 2H).

Intermediate 87: ZS 5R all 10x meth l0x0-N- amo leth l -1 6- diazabicycloI 3.Z.1 |0ctene-Z-carb0xamide O O goo J, HZN/ \/\H I,‘ \ é N\ The title nd was prepared from (2S,5R)—6—allyloxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxylic acid (Intermediate Z9, 208.5 mg, 0.88 mmol) and o—ethanesulfonamide hydrochloride (281.1 mg, 1.75 mmol) according to the procedure for Intermediate 84 to afford a pale yellow oil, 86.6, 29%.

M_S: 345 ES+ (C13H20N405S) 1H NMR1300 MHz, DMSO-dg) 8: 1.63 (s, 3H); 3.04 (m, 1H); 3.14 (m, 2H); 3.26 (m, 1H); 3.51 (m, 2H); 3.94 (m, 1H); 4.09 (m, 1H); 4.36 (m, 2H); 5.27 (m, 2H); 5.95 (m, 1H); 6.07 (m, 1H); 6.89 (s, 2H); 8.52 (m, 1H).

Intermediate 88: 2S 5R h dr0x meth 0-N- 2-sulfam0 leth l -1 6- diazabicyc10|3.2.1 |0ctenecarb0xamide O O /S/ I H2N WMJ/ \ To a solution of (2S,5R)—6—allyloxy—3—methyl—7—oxo—N—(2—sulfamoylethyl)—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 87, 86.6 mg, 0.25 mmol) in ol (3 mL) at room temperature was added methylbarbituric acid (78.53 mg, 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (58.12 mg, 0.05 mmol). The on mixture was stirred for 1 hour at room temperature, then concentrated to afford a dark orange oil, 76.5 mg, 100%.

M_S: 305 ES+ (C10H16N405S) Intermediate 89: eth 1 2S ﬂu0r0 2S 5R meth l0x0 2- sulfamo leth lcarbamo l-1 6-diazabic clo 3.2.1 0cten 10x acetate 0 O 540 JL HZN/ w” 1,, \ )—w F 0 00%)\/ To a solution of (2S,5R)—6—hydroxy—3—methyl—7—oxo—N—(2—sulfamoylethyl)—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 88, 76.5 mg, 0.25 mmol) in 1,4— dioxane (2 mL) and DMF (0.25 mL) was added ethyl (2S)—2—bromo—2—ﬂuoro—acetate (Intermediate 174, 0.09 mL, 0.75 mmol). The reaction mixture was cooled to 0 °C and DBU (0.04 mL, 0.25 mmol) was added se. More ethyl (2S)—2—bromo—2—fluoro—acetate (0.09 mL, 0.75 mmol) was added. Then, more DBU (0.04 mL, 0.25 mmol) was added. After another 15 minutes at 0 °C with occasional warming, another 0.5 eq. of DBU was added.

The on mixture was stirred for another 15 minutes at room temperature. The on mixture was diluted with ethyl acetate and washed three times with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and concentrated to afford an orange oil. Silica gel chromatography (0%—25% acetone/dichloromethane) afforded the title compound and with some triphenylphosphine oxide as an orange film, 77.3 mg, 75%.

M_S: 409 ES+ (C14H21FN4O7S) Exam le 57: 2S ﬂu0r0 2S 5R meth l0x0 2-sulfam0 leth lcarbam0 l- 1 6-diazabic clo 3.2.1 0cten 1 0x acetic acid lithium salt o 0 £40 JL HZN’ \/\N ’ \ 2— F O O/SZ/OH T a solution of ethyl (2S)—2—ﬂuoro—2—[[(2S,5R)—3—methyl—7—oxo—2—(2—sulfamoylethyl— carbamoyl)—1,6—diazabicyclo[3.2.1]oct—3—en—6—y1]oxy] e (Intermediate 89, 72.3 mg, 0.18 mmol) in THF (2 mL) and water (1 mL) at 0°C was added 1M lithium hydroxide (0.18 mL, 0.18 mmol). The reaction e was stirred for 10 minutes at 0 0C, then neutralized with 0.5N hydrochloric acid, frozen and lyophilized to afford a yellow solid. Reverse phase ISCO (100% water) ed the title compound as a pale yellow solid, 14.3 mg, 21%.

M_S: 381 ES+ (C12H17FN4O7S) 1H NMR1300 MHz= DMSO-dg) 5: 1.64 (s, 3H); 3.13 (m, 3H); 3.52 (m, 3H); 3.99 (m, 1H); 4.14 (m, 1H); 5.24 (d, 1H); 6.04 (m, 1H); 6.90 (m, 2H); 8.57 (m, 1H).

E - \O/2]’ vow/EffO o 0/\ To a solution of (2R)—2—[[(2S,5R)—2—carbamoyl—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3— en—6—yl]oxy]—2—fluoro—acetic acid (Example 4, 100 mg, 0.37 mmol), Hunig's base (0.06 mL, 0.37 mmol) and ethyl 2—(chloromethoxycarbonylamino)—3—methyl—butanoate (0.05 mL, 0.73 mmol) in DMF (1.5 mL) at room temperature was added tetrabutylammonium chloride (83.42 mg, 0.37 mmol). The reaction mixture was stirred at 40 °C for 2 hours. It was then diluted with ethyl acetate and washed twice with brine/water (1:1). The organics were dried over anhydrous magnesium sulfate, filtered and trated to afford an orange oil. Silica gel chromatography (0%—80% ethyl acetate/hexanes) afforded the title compound (7 mg, 3.63%) as a white solid.

M_S: 475 ES+ (C19H27FN409) 1H NMR1300 MHz= DMSO-dgﬁ 0.90 (m, 6H); 1.21 (m, 3H); 1.61 (s, 3H); 2.15 (m, 1H); 3.78 (m, 1H); 3.95 (m, 1H); 4.01 (m, 1H); 4.15 (m, 2H); 4.22 (m, 1H); 5.80 (m, 2H); 5.95 (m, 1H); 6.30 (d, 1H); 7.40 (s, 1H); 7.80 (s, 1H); 8.10 (d, 1H).

Intermediate 90: tert-but 1 2S 1 3-di0X0is0indolin 10X meth l rrolidine-l- carboxylate To a solution of diethylazodicarboxylate (14.21mL, 12.48 mmol) in THF (10 mL) at —10°C was added dropwise a solution of triphenylphosphine (3273.22 mg, 12.48 mmol) in THF (20 mL). The suspension was d at —10 0C. After 20 minutes the suspension became a solid and another 40 mL of THF was added. After 1 hour, a solution of Boc—L—prolinol (448.18 mL, 5.94 mmol) in THF (10 mL) was added, followed by a solution of N— Hydroxyphthalimide (969.41 mg, 5.94 mmol) in THF (10 mL). The on mixture was allowed to warm to room temperature and stir overnight. It was concentrated and the resulting oil was triturated with ethyl acetate/hexanes. The precipitate was d by filtration and the filtrate was concentrated onto silica gel. Silica gel chromatography (0%— 40% EtOAc/Hexanes) afforded the title compound (2.37 g, quant.) as a pale yellow solid.

M_S: 347 ES+ (ClgszNzos) Intermediate 91: ut 1 2S amin00X meth l rrolidine-l-carbox late Q40-NH2 To a solution of utyl (2S)—2—[(1,3—dioXoisoindolin—2—yl)oxymethyl]pyrrolidine—1— carboxylate (Intermediate 90, 2.06 g, 5.95 mmol) in DCM (20 mL) at room temperature was added hydrazine monohydrate (2.14 mL, 17.84 mmol). A white precipitate immediately formed. The suspension was stirred at room temperature for 1 hour, then filtered through . The filtrate was washed twice with brine/water (1:1), dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound (1.35 g, quant.) as a sticky oil. 1H NMR1300 MHz: CDCl;) 8: 1.50 (s, 9H); 1.85 (m, 4H); 3.32 (m, 2H); 3.63 (m, 1H); 4.25 (m, 2H). ylate The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxylic acid (Intermediate 77, 1.85 g, 5 .92 mmol) and tert—butyl —(aminooxymethyl)pyrrolidine—1—carboxylate mediate 91, 1.28 g, 5.92 mmol) according to the ure for Intermediate 84 to afford (585 mg, 19%) a white sticky foam.

M_SZ 511 ES+ (C24H42N4O6SI) To a solution of tert—butyl (2S)—2—[[[(2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo— 1,6—diazabicyclo[3.2. 1]oct—3—ene—2—carbonyl]amino]oxymethyl]pyrrolidine—1—carboxylate (Intermediate 92, 401 mg, 0.79 mmol) in ethyl acetate (20 mL) at 0 °C under nitrogen atmosphere was added HF‘Pyridine (24 uL, 0.94 mmol). The reaction mixture was stirred at room temperature for 3 hours, then concentrated. The crude material was partitioned between DCM (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated to give the title compound (309 mg, 84%) as a white sticky solid.

M_S: 396 ES+ (C18H28N406) carboxylate To a suspension of tert—butyl (2S)—2—[[[(2S,5R)—6—hydroxy—3—methyl—7—oxo—1,6— diazabicyclo [3 .2. 1]oct—3 —ene—2—carbonyl] amino]oxymethyl]pyrrolidine— 1 xylate (Intermediate 93, 309 mg, 0.78 mmol) and cesium carbonate (304.75 mg, 0.94 mmol) in THF (15 mL) at 0 °C was added ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.14 mL, 1.17 mmol). The reaction was stirred at 0 °C for 8 hours. Water (50 mL) and EtOAc (100 mL) were added. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by ﬂash chromatography (20 g silica gel, 0—100% EtOAc/Hexanes) to afford the title compound (164 mg, 40%) as a sticky solid.

M_S: 501 ES+ 3FN408) 1H NMR 300 MHz CDCl;) 8: 1.38 (m, 3H); 1.45 (s, 9H); 1.80 (s, 3H); 1.95 (m, 4H); 3.35 (m, 3H); 3.60 (m, 2H); 3.95 (m 4.01 (m, 1H); 4.28 (m, 2H); 4.35 (m, 2H); 5.75 (d, 1H); , 1H); 6.10 (s, 1H).

Exam le 60: eth 1 2S ﬂu0r0 2S 5R meth l0X0 S - rrolidin-Z- l meth0X carbamo l -1 6-diazabic clo 3.2.1 en 1 0X acetate TFA salt O‘N 1.. \ L F N\ O 0#0V To a soluiton of tert—butyl —((((2S,5R)—6—((S)—2—ethoxy—l—ﬂuoro—2—oxoethoxy)—3— methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamido)oxy)methyl)pyrrolidine—1— carboxylate (Example 59, 76 mg, 0.15 mmol) in DCM (10 mL) at 0 °C was added TFA (0.58 WO 53215 mL, 7.59 mmol) dropwise. The reaction mixture was stirred at 0 °C for 2 hours then concentrated. The residue was triturated with diethyl ether to afford the title compound (53 mg, 83%) as a TFA salt.

M_S: 401 ES+ 5FN4O6) 1H NMR1300 MHz: CDCl;) 5: 1.45 (m, 3H); 1.86 (m, 4H); 2.15 (m, 3H); 3.55(m, 4H); 4.01 (m, 2H); 4.32 (m, 5H); 5.85 (d, 1H); 6.13 (s, 1H).

Intermediate 94: tert-but l S 1 3-di0X0is0indolin 1 0X meth l -4 4- diﬂuoropyrrolidine-l-carboxylate FWOAIWF N O The title nd was prepared from tert—butyl (S)—4,4—diﬂuoro—2—(hydroxymethyl)— pyrrolidine—l—carboxylate (2.8 g, 11.8 mmol) according to the procedure for Intermediate 90 to afford (4.3 g, 95%) a pale yellow sticky solid.

M_S: 383 ES+ (ClgHzonNzos) Intermediate 95: tert-but l S aminoox meth l-4 4-diﬂu0r0 rrolidine-l- carboxylate The title nd was ed from tert—butyl (S)—2—(((1,3—dioxoisoindolin—2— yl)oxy)methyl)—4,4—diﬂuoropyrrolidine—1—carboxylate (Intermediate 94, 1.9 g, 4.97 mmol) according to the procedure for Intermediate 91 to afford (1.25 g, 99%) an orange sticky oil. 1H NMR1300 MHz: CDCl;) 8: 1.51 (s, 9H); 2.42 (m, 2H); 3.63 (m, 2H); 3.85 (m, 2H); 4.97 (m, 1H).

Intermediate 96: tert-but 1 2S 2S 5R tert-but ldimeth lsil 10X meth [- 7-0X0-1 6-diazabic clo 3.2.1 0ctenecarb0xamid0 0X meth l -4 4- diﬂuoropyrrolidine-l-carboxylate The title compound was prepared from (2S,5R)—6—[tert—buty1(dimethy1)si1y1]oxy—3—methy1—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxy1ic acid (Intermediate 77, 1.3 g, 4.16 mmol) and tert—butyl (S)—2—((aminooxy)methy1)—4,4—difluoropyrrolidine—1—carboxy1ate (Intermediate 95, 1.26 g, 4.99 mmol) according to the procedure for Intermediate 84 to afford (489 mg, 18%) a sticky White foam.

M_SZ 547 ES+ (C24H40F2N4O6SI) The title compound was prepared from tert—butyl —((((2S,5R)—6—((tert— butyldimethylsi1y1)oxy)—3—methy1—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2— carboxamido)oxy)methy1)—4,4—diﬂuoropyrrolidine—1—carboxy1ate mediate 96, 489 mg, 0.89 mmol) according to the procedure for Intermediate 93 to afford (330 mg, 72%) as a White sticky solid.

MS: 433 ES+ (C18H26F2N4O6) Intermediate 98: tert-but 1 2S 2S 5R S eth0X ﬂu0r00X0eth0X meth 0-1 6-diazabic clo 3.2.1 0ctenecarb0xamid0 0X meth l -4 4- diﬂuoropyrrolidine-l-carboxylate (DJ—ijgro\/ To a sion of tert—butyl (2S)—4,4—difluoro—2—((((2S,5R)—6—hydroxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxamido)oxy)methyl)pyrrolidine—1—carboxylate (Intermediate 97, 300 mg, 0.69 mmol) and cesium carbonate (339 mg, 1.04 mmol) in ethyl e (15 mL) at 0°C was added ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.1 mL, 0.83 mmol). The reaction was stirred at 10 °C for 1 hour. Water (50 mL) and EtOAc (100 mL) were added. The organic layer was separated, concentrated and purified by silica gel flash chromatography (0—100%, EtOAc/Hexane) to afford the title compound (70 mg, 18%) as a sticky white foam.

MS: 537 ES+ (C22H31F3N40g) H C? O\” I] L F N\ O 0#0V The title compound was ed from tert—butyl (2S)—2—((((2S,5R)—6—((S)—2—ethoxy—1—ﬂuoro— 2—oxoethoxy)—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamido)oxy)methyl)— 4,4—diﬂuoropyrrolidine—1—carboxylate (Intermediate 98, 26 mg, 0.05 mmol) according to the procedure for Example 60 to afford (20 mg, 85%) as a TFA salt.

M_S: 437 ES+ (C17H23F3N4O6) 1H NMR1300 MHz, CDCl;) 8: 1.42 (m, 3H); 1.80 (s, 3H); 2.65 (m, 2H); 3.45 (m, 2H); 3.82 (m, 2H); 4.10 (m, 1H); 4.38 (m, 6H); 5.80 (d, 1H); 6.18 (s, 1H).

To a solution of tert—butyl (2S)—2—((((2S,5R)—6—((S)—2—ethoxy—l—ﬂuoro—2—oxoethoxy)—3— methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamido)oxy)methyl)pyrrolidine—1— carboxylate (Example 59, 81 mg, 0.16 mmol) in THF (1 mL) and water (0.50 mL) at 0 °C was added lithium hydroxide (1N, 0.01 mL, 0.40 mmol). The reaction mixture was d for 30 min. Dilute HCl solution (0.5N) was added to adjust the pH to 2. The reaction mixture was extracted with EtOAc (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to afford the title compound (50 mg, 65%) as a gum.

M_33 471 133- (C20H29FN408) The title compound was prepared from (2S)—2—[[(2S,5R)—2—[[(2S)—1—tert—butoxycarbonyl— pyrrolidin—2—yl]methoxycarbamoyl]—3—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3—en—6— ]—2—fluoro—acetic acid (Intermediate 99, 65 mg, 0.14 mmol) according to the procedure for Example 60 to afford (40 mg, 70%) as a TFA salt.

MS: 473 ES+ (C20H29FN4Og) 1H NMR1300 MHz, mg) 5: 1.65 (s, 3H); 1.82 (m, 1H); 2.23 (m, 2H); 2.35 (m, 1H); 3.40 (m, 3H); 3.58 (m, 1H); 3.82 (m, 1H); 4.02 (m, 1H); 4.18 (m, 1H); 4.33 (m, 2H); 5.70 (d, 1H); 6.28 (s, 1H). - 1 0X ﬂu0r0acetic acid kN O 0&0 O‘N L’ 2* F 0 O/S]/OH The title compound was prepared from tert—butyl (2S)—2—((((2S,5R)—6—((S)—2—ethoxy—l—ﬂuoro— 2—oxoethoxy)—3—methyl—7—oxo— l ,6—diazabicyclo[3 .2. l]oct—3—ene—2—carboxamido)oxy)methyl)— 4,4—diﬂuoropyrrolidine—l—carboxylate mediate 98, 37 mg, 0.07 mmol) according to the procedure for Intermediate 99 to afford (35 mg, 90%) as a gum.

M_S: 507 133- (C20H27F3N408) The title compound was prepared from (2S)—2—(((2S,5R)—2—((((S)—l—(tert—butoxycarbonyl)—4,4— diﬂuoropyrrolidin—2—yl)methoxy)carbamoyl)—3—methyl—7—oxo— l ,6—diazabicyclo[3 .2. l]oct—3— en—6—yl)oxy)—2—ﬂuoroacetic acid (Intermediate 100, 35 mg, 0.07 mmol) according to the ure for Example 60 to afford (22 mg, 70%) as a TFA salt.

M_S: 409 ES+ (C15H19F3N4O6) 1H NMR1300 MHz= D;@ 5: 1.78 (s, 3H); 2.62 (m, 1H); 2.95 (m, 1H); 3.13 (m, 1H); 3.42 (m, 1H); 3.58 (m, 1H); 3.96 (m, 2H); 4.61 (m, 1H); 4.40 (m, 3H); 5.82 (d, 1H); 6.33 (s, 1H).

WO 53215 Exam le 64: 2R 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 oct- 3-en 10x ﬂu0r0-acet 10x meth meth 1 r0 anoate HZNJ'Cl) \ The title nd was prepared from (2R)—2—[[(2S,5R)—2—carbamoyl—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—en—6—yl]oxy]—2—ﬂuoro—acetic acid (Example 4, 47 mg, 0.17 mmol) and methyl pivalate (0.05 mL, 0.34 mmol) according to the procedure for Example 53 to afford (33.2 mg, 49.8%) as a white solid.

M_S: 388 ES+ (C16H22FN3O7) 1H NMR1300 MHz, DMSO—dg) 5: 1.12 (s, 9H); 1.62 (s, 3H); 3.01 (m, 1H); 3.82 (m, 1H); 4.02 (m, 1H); 4.19 (m, 1H); 5.76 (m, 1H); 5.87 (m, 1H); 5.91 (m, 1H); 6.25—6.43 (d, 1H); 7.41 (bs,1 H); 7.86 (bs,1H).

Exam le 65: indan-S- 1 2R 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0-acetate HZNJ”‘? \ To a solution of (2R)—2—[[(2S,5R)—2—carbamoyl—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3— en—6—yl]oxy]—2—fluoro—acetic acid (Example 4, 100 mg, 0.37 mmol) and 5—indanol (58.9 mg, 0.44 mmol) in DCM (3 mL) and THF (3 mL) at 0 °C was added N,N'—dicyclohexyl— carbodiimide (113.3 mg, 0.55 mmol) and DMAP (5.0 mg). The reaction mixture was stirred at RT for 1 hour. The reaction was concentrated, then dissolved in EtOAC. The white solid formed was filtered off. The filtrate was concentrated. Silica gel chromatography (0—80% ethyl acetate/hexanes) afforded the title compound (72 mg, 48%) as a white solid.

M_S: 390 ES+ (C19H20FN305) 1H NMR1300 MHz= DMSO-dg) 5: 1.64 (s, 3H); 2.05 (m, 2H); 2.85 (m, 4H); 3.10 (m, 1 H); 3.79 (m, 1H); 4.06 (m, 1H); 4.22 (m, 1H); 6.06 (m, 1H); 6.44—6.51 (d, 1H); 6.86 (m, 1H); 6.97 (m, 1H); 7.28 (m, 1H); 7.43 (bs, 1H); 7.87 (bs, 1H).

Intermediate 101: 2S 5R tert-but l dimeth l sil 1 0X meth l-N- oxetan l 0X0-1 6-diazabic clo 3.2.1 0ctenecarb0xamide ‘ﬂNJL.O \ o ‘O,Si\ To a solution of (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxylic acid (Intermediate 77, 100 mg, 0.32 mmol) in DMF (1.5 mL) at 0 °C was added HATU (35 mg, 0.48 mmol) and N,N'— diisopropylethylamine (0.167 mL, 0.96 mmol). The reaction mixture was stirred for 30 minutes at room temperature, then diluted with ethyl acetate and washed with saturated sodium bicarbonate once and 1:1 brinezwater three times. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel tography % methanol/dichloromethane) afforded the title compound (80 mg, 68%) as a yellow oil.

M_SZ 368 ES+ (C17H29N3O4Sl) Intermediate 102: 2S 5R h dr0X meth l-N- oxetan l0X0-1 6- diazabicyc10|3.2.1 |0ctenecarb0xamide O\lNJh, ’6 N\ O OH A 25 mL round bottom ﬂask was charged with (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3— methyl—N—(oxetan—3—yl)—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 101, 0.10 g, 0.22 mmol) in ethyl acetate (0.5 mL) at room temperature under nitrogen. HF.Pyridine (0.015 mL, 0.33 mmol) was added and the reaction e was stirred at room temperature for 1 hour. The solvent was d.

M_33 254 133+ (C11H15N3O4) Intermediate 103: eth 1 2S ﬂu0r0 2S 5R meth l 0xetan lcarbamo l 0x0-1 6-diazabic clo 3.2.1 0cten 1 0x acetate OQNJL.0 \ O 00%)\/ To a solution of (2S,5R)—6—hydroxy—3—methyl—N—(oxetan—3—yl)—7—oxo—l,6— diazabicyclo[3.2. l]oct—3—ene—2—carboxamide (Intermediate 102, 50 mg, 0.20 mmol) in 1,4— dioxane (2 mL) and DMF (0.25 mL) was added ethyl (2S)—2—bromo—2—ﬂuoro—acetate (Intermediate 174, 0.047 mL, 0.39 mmol). The reaction mixture was cooled to 0 °C and DBU (0.089 mL, 0.59 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 15 minutes, then diluted with ethyl acetate and washed three times with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and concentrated.

Silica gel chromatography (0—80% Hexane) afforded the title compound (58 mg, 82.2%) as colorless oil. The compound is a 2:8 mixture of diastereomers.

M_SI 358 ES+ (C15H20FN3O6) Exam le 66: 2S ﬂu0r0 2S 5R meth l 0xetan lcarbam0 l 0x0-1 6- diazabic clo 3.2.1 0cten 1 0x acetic acid lithium salt To a on of ethyl (2S)—2—ﬂuoro—2—[[(2S,5R)—3—methyl—2—(oxetan—3—ylcarbamoyl)—7—oxo— l,6—diazabicyclo[3.2.l]oct—3—en—6—yl]oxy]acetate (Intermediate 103, 56.3 mg, 0.16 mmol) in THF (10 mL) and water (0.5 mL) at 0 °C was added lithium hydroxide (1M) (0.50 mL, 0.50 mmol). The reaction e was stirred for 1 hour. HCl (lN) solution was added to adjust pH to ~5—6. The t was removed. A sepabead column (saturated with water first, then ACN, then washed with water) eluting with water (0%—5% ACN/water) afforded the title compound (10 mg, 17.3%) as a white solid after lyophilization.

M_SZ 330 ES+ (C13H16FN3O6) 1H NMR1300 MHz, mg) 5: 1.63 (s, 3H); 3.22 (m, 1H); 3.37 (m, 1H); 4.04 (m, 1H); 4.30 (s, 1H); 4.58 (m, 2H); 4.86 (m, 3H); 5.15-5.56 (d, 1H); 6.15 (m, 1H).

Intermediate 104: 2S 5R tert-but l dimeth 1 Si] 1 0X -N- 2- methanesulfonamido eth l meth l0X0-1 6-diazabic clo 3.2.1 0ctene carboxamide Ofs’N\/\NJ”H | H H O N 7|— / o N‘O’S' The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxylic acid (Intermediate 77, 300 mg, 0.96 mmol) in DMF (1.5 mL) and mino—ethyl)—methanesulfonamide hydrochloride salt (251.5 mg, 1.44 mmol) according to the procedure for Intermediate 101 to afford (220 mg, 53%) as a White solid.

M_SZ 433 ES+ 2N4OsSlS) The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—N—[2— (methanesulfonamido)ethyl]—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2— carboxamide (Intermediate 104, 0.12 g, 0.28 mmol) according to the procedure for Intermediate 102 to afford a tan residue.

M_SZ 319 ES+ (C11H13N4053) H Cl) Ojs’NwN " \ H H o N )— F o o#Ox/ The title compound was prepared from (2S,5R)—6—hydroxy—N—[2—(methanesulfonamido)— ethyl]—3—methyl—7—oxo—1,6—diazabicyclo[3.2.l]oct—3—ene—2—carboxamide (Intermediate 105, 80 mg, 0.25 mmol) and ethyl (2S)—2—bromo—2—ﬂuoro—acetate (Intermediate 174, 0.089 mL, 0.75 mmol) ing to the procedure for Intermediate 103 to afford (25 mg, 18.8%) as a white solid. The compound is a 1:4 mixture of diastereomers.

M_S: 423 ES+ (C15H23FN4O7S) 0\ [N j \/\N I] )S \ H ! F O O/SZ/OH The title compound was prepared from ethyl —ﬂuoro—2—[[(2S,5R)—3—methyl—2—(3— methylsulfonylpropylcarbamoyl)—7—oxo— 1 ,6—diazabicyclo[3 .2. 1]oct—3—en—6—yl]oxy] acetate (Intermediate 106, 25 mg, 0.06 mmol) ing to the procedure for Example 66 to afford (4.0 mg, 15.4%) as a white solid after lyophilization.

M_S: 395 ES+ (C13H19FN4O7S) 1H NMR1300 MHz= D;@ 8: 1.63 (s, 3H); 2.95 (s, 3H); 3.18-3.38 (m, 6H); 4.02 (m, 1H); 4.27 (s, 1H); 5.56-5.74 (d, 1H); 6.13 (m, 1H).

Intermediate 107: 2S 5R tert-but l dimeth 1 Si] 1 0X h l-N- oxazol-Z- The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxylic acid (Intermediate 77, 400 mg, 1.28 mmol) and oxazol—2—yl—methylamine hydrochloride (258.4 mg, 1.92 mmol) according to the procedure for Intermediate 101 to afford (120 mg, 23.9%) as a white solid.

M_S: 393 ES+ (C13H23N4O4Si) The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—N— (oxazol—2—ylmethyl)—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 107, 0.12 g, 0.31 mmol) according to the procedure for Intermediate 102 to afford a residue.

MS: 279 ES+ (C12H14N404) N! F o 0/87/0\/ The title nd was prepared from (2S,5R)—6—hydroxy—3—methyl—N—(oxazol—2—ylmethyl)— 7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 108, 80 mg, 0.29 mmol) and ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.10 mL, 0.86 mmol) according to the procedure for ediate 103 to afford (15 mg, 13.6%) a colorless oil.

The compound is a 15:85 mixture of diastereomers.

M_SZ 383 ES+ (C16H19FN4O6) @0N\ NJ’I, \ 0%Nxo/SZ/OHF The title compound was prepared from ethyl —fluoro—2—[[(2S,5R)—3—methyl—2—(oxazol— 2—ylmethylcarbamoyl)—7—oxo— 1 ,6—diazabicyclo[3 .2. 1]oct—3—en—6—yl]oxy] acetate mediate 109, 15 mg, 0.039 mmol) according to the procedure for Example 66 to afford (4.0 mg, .9%) as a white solid after lization.

M_S: 355 ES+ (C14H15FN4O6) 1H 0 MHz= D;@ 5: 1.62 (s, 3H); 3.28 (m, 2H); 4.03 (m, 1H); 4.36 (s, 1H); 4.47 (m, 2H); 5.56-5.74 (d, 1H); 6.13 (m, 1H); 7.01 (d, 1H); 7.71 (d, 1H).

Intermediate 110: 28 SR tert-but l dimeth 1 Si] 1 0X meth l0X0-N- razin- The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxylic acid (Intermediate 77, 200 mg, 0.64 mmol) and pyrazin—2—yl—methylamine oxalate (191.2 mg, 0.96 mmol) according to the procedure for Intermediate 101 to afforded (120 mg, 46.4%) a white solid.

M_S: 404 ES+ (C19H29N5038i) Intermediate 111: 28 SR h dr0X meth l0X0-N- razin lmeth [-1 6- diazabic clo 3.2.1 enecarb0xamide rm /I,'Ci \ The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—N—(pyrazin—2—ylmethyl)—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 110, 0.10 g, 0.26 mmol) according to the procedure for Intermediate 102 to afford a residue.

MS: 290 ES+ (C13H15N503) Intermediate 112: eth 1 2S ﬂu0r0 28 SR h l0X0 razin lmeth lcarbamo l -1 6-diazabic clo 3.2.1 0cten 1 0X acetate N\ NJ,“ E/ \ N )—N\ F o OJWOV The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—N—(pyrazin—2— ylmethyl)—l,6—diazabicyclo[3.2. 3—ene—2—carboxamide (Intermediate 111, 70 mg, 0.24 mmol) and ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.086 mL, 0.73 mmol) according to the ure for Intermediate 103 to afford (50 mg, 52.5%) a colorless oil.

The compound is a 15:85 mixture of diastereomers.

M_S: 394 ES+ (C17H20FN505) Exam le 69: 2S ﬂu0r0 2S 5R meth l0x0 razin lmeth [- carbam0 l -1 6-diazabic clo 3.2.1 0cten 1 0x acetic acid lithium salt E /N\ NJI'“ \ N F O \OJYO“ The title compound was prepared from ethyl (2S)—2—ﬂuoro—2—[[(2S,5R)—3—methyl—7—oxo—2— (pyrazin—2—ylmethylcarbamoyl)— l ,6—diazabicyclo[3 .2. l]oct—3—en—6—yl] oxy] acetate (Intermediate 112, 50 mg, 0.13 mmol) ing to the procedure for Example 66 to afford (4.0 mg, 8.2%) a White solid after lyophilization.

M_S: 366 ES+ (C15H16FN505) 1H NMR1300 MHz= D;@ 5: 1.62 (s, 3H); 3.28 (m, 2H); 4.03 (m, 1H); 4.36 (s, 1H); 4.53 (m, 2H); 5.56-5.75 (d, 1H); 6.13 (m, 1H); 8.49 (m, 3H).

The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—l,6—diazabicyclo[3.2. l]oct—3—ene—2—carboxylic acid (Intermediate 77, 200 mg, 0.64 mmol) and lopropylmethyl) hydroxylamine (83.6 mg, 0.96 mmol) according to the ure for Intermediate 101 to afford (100 mg, 40.9%) a colorless oil.

M_S: 382 ES+ (C18H31N304Si) Intermediate 114: ZS 5R -N- e do r0 lmeth0X h dr0X meth l0X0-1 6- diazabicyc10|3.Z.1 |0ctene-Z-carb0xamide A/O\ JV“,‘i N \ //'—N.

O OH The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—N— (cyclopropylmethoxy)—3—methyl—7—oxo— l ,6—diazabicyclo[3 .2. l]oct—3—ene—2—carboxamide (Intermediate 113, 0. lg, 0.26 mmol) ing to the procedure for Intermediate 102 to afford a residue.

M_33 268 133+ (C12H17N3O4) Intermediate 115: eth 1 ZS -Z- ZS 5R -Z- e do r0 lmeth0X carbam0 lmeth l 0X0-1 6-diazabic clo 3.Z.1 0cten 1 0X -Z-ﬂu0r0-acetate The title compound was prepared from (2S,5R)—N—(cyclopropylmethoxy)—6—hydroxy—3— methyl—7—oxo—l,6—diazabicyclo[3.2. l]oct—3—ene—2—carboxamide (Intermediate 114, 60 mg, 0.22 mmol) and ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.08 mL, 0.67 mmol) ing to the procedure for Intermediate 103 to afford (15 mg, 18%) a colorless oil. The nd is a 1:9 mixture of diastereomers.

M_SZ 372 ES+ (C16H22FN3O6) Exam le 70: ZS -Z- ZS 5R -Z- e do r0 lmethox 0 lmeth l0X0-1 6- diazabic clo 3.Z.1 0cten 1 0X -Z-ﬂu0r0-acetic acid lithium salt The title compound was prepared from ethyl (2S)—2—[[(2S,5R)—2—(cyclopropylmethoxy— oyl)—3—methyl—7—oxo— l ,6—diazabicyclo[3 .2. l]oct—3—en—6—yl]oxy] —2—fluoro—acetate (Intermediate 115, 15 mg, 0.04 mmol) according to the ure for Example 66 to afford (4.5 mg, 32.5%) as a White solid after 1yophi1ization.

M_S: 344 ES+ (C14H18FN306) 1H NMR1300 MHz= D;@ 8: 0.00 (m, 2H); 0.28 (m, 2H); 0.81 (m, 1H); 1.38 (s, 3H); 3.02 (m, 1H); 3.35 (m, 1H); 3.42 (m, 2H); 3.82 (m, 1H); 3.92 (s, 1H); 5.37—5.55 (d, 1H); 5.95 (m, The title compound was prepared from (2S,5R)—6—[tert—buty1(dimethy1)si1y1]oxy—3—methy1—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxy1ic acid (Intermediate 77, 200 mg, 0.64 mmol) and alaninamide hydrochloride (119.6 mg, 0.96 mmol) according to the procedure for Intermediate 101 to afford (140 mg, 57.2%) as a White solid.

M_S: 383 ES+ (C17H30N4O4Si) The title compound was prepared from (2S,5R)—N—(3—amino—3—oxo—propy1)—6—[tert— dimethy1)si1y1]oxy—3—methy1—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 116, 140 mg, 0.37 mmol) according to the procedure for ediate 102 to afford a residue.

M_S: 269 ES+ (C11H16N4O4) The title compound was prepared from (2S,5R)—N—(3—amino—3—oxo—propyl)—6—hydroxy—3— —7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 117, 90 mg, 0.34 mmol), K2CO3 (139.1 mg, 1.01 mmol) and ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.12 mL, 1.01 mmol) ing to the procedure for Intermediate 103 to afford (26.0 mg, 20.8%) as a White solid. The compound is a 1:9 mixture of diastereomers.

M_S: 373 ES+ (C15H21FN4O6) The title compound was prepared from ethyl (2S)—2—[[(2S,5R)—2—[(3—amino—3—oxo— propyl)carbamoyl]—3—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3—en—6—yl]oxy]—2—fluoro— acetate (Intermediate 118, 25 mg, 0.07 mmol) according to the procedure for Example 66 to afford (8 mg, 34.6%) a White solid after lization.

M_S: 345 ES+ (C13H17FN4O6). 1H NMR1300 MHz, D29 8: 1.62 (s, 3H); 2.49 (m, 2H); 3.29 (M, 1H); 3.42 (m, 1H); 3.50 (m, 2H); 4.10 (m, 1H); 4.30 (s, 1H); 5.65-5.82 (d, 1H); 6.22 (m, 1H).

Intermediate 119: 2- ZS 0X0 rr01idin l meth0X isoindoline-l 3-di0ne To a solution of diethylazodicarboxylate (16.6 mL, 14.6 mmol, 40% wt) in THF (10 mL) at —10°C was added dropwise a solution of triphenylphosphine (3.83 g, 14.6 mmol) in THF (20 mL). The suspension was stirred at —10 0C. After 1 hour, a solution of (S)—(+)—5— (hydroxymethyl)—2—pyrrolidinone) (0.80 g, 6.95 mmol) in THF (10 mL) was added dropwise, followed by a solution of N—hydroxyphthalimide (1.13 g, 6.95 mmol) in THF (10 mL). The reaction mixture was allowed to warm to room temperature and stir for 2 days. The reaction mixture was concentrated. Silica gel chromatography (0—100 % EtOAc/Hexane, then 10% MeOH/DCM) afforded the title compound (1.5 g, 83% ) as a pale yelllow solid.

M_S: 261 ES+ 2N204) Intermediate 120: SS aminoox meth l rrolidin-Z-one p40_NH2N To a solution of 2—[[(2S)—5—oxopyrrolidin—2—yl]methoxy]isoindoline—1,3—dione (Intermediate 119, 1.5 g, 5.76 mmol) in DCM (70 mL) at room temperature was added hydrazine drate (0.84 mL, 17.3 mmol). The reaction mixture was stirred at room ature for 1 hour, then washed with water (3 x 20 mL). The aqueous layer was concentrated. A sepabead column afforded the title compound (0.60 g, 79.9%) as a white solid.

MS: 163 ES+ (C3H6N202) The title nd was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— 6—diazabicyclo[3.2.1]oct—3—ene—2—carboxylic acid (Intermediate 77, 250 mg, 0.80 mmol) and 5—(aminooxymethyl) pyrrolidin—2—one (Intermediate 120, 156.2 mg, 1.2 mmol) ing to the procedure for Intermediate 101 to afford (55 mg, 16.2%) as a white solid.

M_S: 425 ES+ (C19H32N405Si) Intermediate 122: 28 SR h dr0X meth l0X0-N- 5-0X0 in l meth0X -1 6-diazabic clo 3.2.1 0ctenecarb0xamide The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—N—[[(2S)—5—oxopyrrolidin—2—yl]methoxy] — 1 ,6—diazabicyclo[3 .2. 1]oct—3—ene—2— carboxamide (Intermediate 121, 55 mg, 0.13 mmol) according to the procedure for Intermediate 102 to afford a light yellow gum.

MS: 311 ES+ 3N405) Intermediate 123: eth 1 2S ﬂu0r0 28 SR meth l0X0 5-0X0 rrolidin l meth0X o l -1 6-diazabic clo 3.2.1 0cten 1 0X acetate 04%NH o.NJL,,, \ )—N\ F 0 (TWO\/ The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—N—[(5— oxopyrrolidin—2—yl)methoxy] — 1 ,6—diazabicyclo[3 .2. 1]oct—3—ene—2—carboxamide (Intermediate 122, 35 mg, 0.11 mmol) and ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.04 mL, 0.34 mmol) according to the ure for Intermediate 103 to afford (15 mg, 32.1%) as a sticky solid. The compound is a 1:4 mixture of diastereomers.

M_SZ 415 ES+ (C17H23FN4O7) The title compound was prepared from ethyl (2S)—2—ﬂuoro—2—[[(2S,5R)—3—methyl—7—oxo—2— [(5—oxopyrrolidin—2—yl)methoxycarbamoyl] — 1 zabicyclo[3 .2. 1]oct—3—en—6—yl]oxy] acetate (Intermediate 123, 15 mg, 0.036 mmol) ing to the ure for Example 66 to afford (7.0 mg, 40%) a white solid after lyophilization.

M_S: 387 ES+ 9FN4O7). 1H NMR1300 MHz= D;@ 8: 1.64 (s, 3H); 1.82 (m, 1H); 2.25 (m, 1H); 2.38 (m, 2H); 3.24 (m, 1H); 3.76 (m, 2H); 3.96 (m, 2H); 4.09 (m, 2H); 5.63—5.82 (d, 1H); 6.17 (m, 1H).

Intermediate 124: 2S 0x0 rr01idin lmeth l4-meth lbenzenesulfonate O-ﬁ@9 To a stirred solution of (S)—(+)—5—(hydroxymethyl)—2—pyrrolinone (2.0 g, 17.4 mmol) and P— toluenesulfonyl chloride (4.17 g, 21.9 mmol) in CHzClz (50 mL) at 0 °C were added dimethylaminopyridine (111.4 mg, 0.91 mmol) and triethylamine (3.05 mL, 21.9 mmol).

The resulting mixture was allowed to warm to RT and stir for 12 hours. The reaction was then quenched with water, and the aqueous layer was extracted with CHzClz. The combined organic extracts were washed with 1N HCl solution and dried over anhydrous NaZSO4.

Removal of solvent under reduced pressure followed by ﬂash chromatography (2.5% MeOH in DCM) afforded the title compound (4.58 g, 93.2%) as a white solid.

M_S: 270 ES+ (C12H15NO4S).

Intermediate 125: 2- 2S 0x0 in lacetonitrile To a solution of [(2S)—5—oxopyrrolidin—2—yl]methyl 4—methylbenzenesulfonate (Intermediate 124, 4.5 g, 16.7 mmol) in acetonitrile (50 mL) was added KCN (2.76 g, 41.8 mmol). The solution was heated at 85 °C for 18 hours. The solution was then diluted with itrile (200 mL), filtered through celite, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (9:1 DCM/MeOH) to afford the title compound (1.8 g, 86.8%) as a white solid.

M_S: 125 ES+ ZO).

Intermediate 126: tert-but lN- 2- 2S 0X0 rrolidin-Z- l eth l carbamate To a stirred solution of )—5—oxopyrrolidin—2—yl]acetonitrile (Intermediate 125, 300 mg, 2.42 mmol) in methanol (l5mL) at 0°C was added di—tert—butyl dicarbonate (1.05 g, 4.83 mmol) and NiClz‘6 H20 (57.4 mg, 0.24 mmol). Then NaBH4 (0.64 g, 16.9 mmol) was added over 30 minutes. The reaction mixture was warmed up to RT and stirred for 1 hour. Hunig's base (0.42 mL, 2.42 mmol) was added, then stirred for 30 minutes. The t was removed. The residue was dissolved in EtOAc and washed with sat. NaHC03 solution, brine, dried over MgSO4, filtered and concentrated to afford the title compound (0.50 g, 90.6%) as a white solid.

M_S: 229 ES+ (C11H20N203) Intermediate 127: SS 2-amin0eth l rrolidin-Z-one To a solution of tert—butyl N—[2—[(2S)—5—oxopyrrolidin—2—yl]ethyl]carbamate (Intermediate 126, 500 mg, 2.19 mmol) in DCM (2.5 mL) was added trifluoroacetic acid (1.15 g, 10.9 mmol). The reaction was then d at RT for 2 hours. The solvent was removed to afford the title compound as a TFA salt.

M_S: 129 ES+ (C6H12N20) Intermediate 128: 28 SR tert-but l dimeth 1 Si] 1 0X meth l0X0-N- 2- 5- The title compound was prepared from )—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—l,6—diazabicyclo[3.2. l]oct—3—ene—2—carboxylic acid (Intermediate 77, 300 mg, 0.96 mmol) and 5—(2—aminoethyl)pyrrolidin—2—one TFA salt (Intermediate 127, 0.35 g, 1.44 mmol) according to the procedure for Intermediate 101 to afford (120 mg, 29.6%) as a White solid.

M_SZ 423 ES+ (C20H34N404Sl) I2 0 The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— [2—(5—oxopyrrolidin—2—yl)ethyl] — l ,6—diazabicyclo[3 .2. l]oct—3—ene—2—carboxamide (Intermediate 128, 120 mg, 0.28 mmol) according to the procedure for Intermediate 102 to afford a White gum.

M_33 309 133+ (C14H20N4O4) I2 0 The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—N—[2—(5— oxopyrrolidin—2—yl)ethyl]—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 129, 80 mg, 0.26 mmol), K2CO3 (179.3 mg, 1.3 mmol) and ethyl (2S)—2—bromo—2—fluoro— acetate (Intermediate 174, 0.12 mL, 0.78 mmol) according to the ure for Intermediate 103 to afford (30 mg, 28%) as a White solid. The compound is a 1:4 mixture of diastereomers.

M_S: 413 ES+ (C13H25FN4O6) The title compound was prepared from ethyl (2S)—2—fluoro—2—[[(2S,5R)—3—methyl—7—oxo—2—[2— pyrrolidin—2—yl)ethylcarbamoyl] — 1 ,6—diazabicyclo[3 .2. 1]oct—3—en—6—yl] oxy] acetate (Intermediate 130, 30 mg, 0.07 mmol) according to the ure for Example 66 to afford (8.0 mg, 25.8%) as a White solid after lyophilization.

M_S: 385 ES+ (C16H21FN4O6) 1H NMR1300 MHz, mg) 5: 1.69 (s, 3H); 1.77 (m, 3H); 2.36 (m, 2H); 3.30 (m, 3H); 3.44 (m, 1H); 3.76 (m, 2H); 4.11 (m, 1H); 4.31 (m, 1H); 5.63—5.82 (d, 1H); 6.23 (m, 1H).

The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—l,6—diazabicyclo[3.2. l]oct—3—ene—2—carboxylic acid (Intermediate 174, 300 mg, 0.96 mmol) and 3—aminopropane—l—sulfonamide hloride (251 mg, 1.44 mmol) according to the procedure for Intermediate 101 to afford (198 mg, 47.7%) as a White solid.

M_S: 433 ES+ (C17H32N4058iS) The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—N—(3—sulfamoylpropyl)— l ,6—diazabicyclo[3 .2. l]oct—3—ene—2—carboxamide (Intermediate 131, 200 mg, 0.46 mmol) according to the procedure for Intermediate 102 to afford a White M_S: 319 ES+ (C11H13N4053) Intermediate 133: eth 1 2S ﬂu0r0 28 SR h l0X0 3- sulfamo 1 r0 mo l-1 6-diazabic clo 3.2.1 0cten 10X acetate H2N II H O N! F O O The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—N—(3— sulfamoylpropyl)—l,6—diazabicyclo[3.2.l]oct—3—ene—2—carboxamide (Intermediate 132, 100 mg, 0.31 mmol) and ethyl (2S)—2—bromo—2—ﬂuoro—acetate (Intermediate 174, 0.11 mL, 0.94 mmol) according to the ure for Intermediate 103 to afford (22 mg, 16.7%) as a White solid. The nd is a 1:4 mixture of diastereomers.

M_S: 423 ES+ (C15H23FN4O7S) HEESMNJ’“L \ 2 H o N SrOHF The title compound was prepared from ethyl (2S)—2—fluoro—2—[[(2S,5R)—3—methyl—7—oxo—2—(3— sulfamoylpropylcarbamoyl)— 1 ,6—diazabicyclo[3 .2. 1]oct—3—en—6—yl]oxy] acetate (Intermediate 133, 22 mg, 0.05 mmol) according to the procedure for Example 66 to afford (8.0 mg, 37%) a white solid after lyophilization.

M_S: 395 ES+ 9FN4O7S) 1H NMR1300 MHz= D;@ 8: 1.69 (s, 3H); 2.04 (m, 2H); 3.35 (m, 6H); 4.11 (m, 1H); 4.34 (m, 1H); 5.65-5.83 (d, 1H); 6.22 (m, 1H).

Intermediate 134: tert-butyl N-|2-1sulfamoylamin02ethyl |carbamate o,\S/ N\/\ A0)< , N HN||2 H A solution of tert—butyl N—(2—aminoethyl) carbamate (2.0 g, 12.5 mmol) and sulfamide (2.0 g, 24.9 mmol) in dioxane (10 mL) was stirred at 90 °C for 5 hours. The mixture was then ed to remove the insoluble material and the filtrate was concentrated under reduced pressure. The residue was then dissolved in EtOAc, washed with dilute HCl solution three times, then brine, dried over MgSO4, filtered and concentrated to afford the title compound (1.2 g, 40.2%) as a yellow oil. 1H NMR1300 MHz= DMSO-dg) 5: 1.39 (s, 9H); 2.92 (m, 2H); 3.04 (m, 6H); 6.50 (m, 3H); 6.75 (m, 1H).

Intermediate 135: 1-amin0 sulfamo lamino ethane TFA salt \ H 28’ H2 To a solution of tert—butyl N—[2—(sulfamoylamino)ethyl]carbamate (Intermediate 134, 1.2 g, .01 mmol) in DCM (5 mL) was added trifluoroacetic acid (5.72 g, 50.1 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed to afford the title compound as a yellow TFA salt.

M_SZ 140 ES+ (C2H9N30zS) Intermediate 136: ZS 5R ut l dimeth 1 Si] 1 0X meth l0X0-N- 2- sulfamo lamino eth l -1 6-diazabic clo 3.2.1 enecarb0xamide The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxylic acid (Intermediate 77, 300 mg, 0.96 mmol) and 1—amino—2—(sulfamoylamino) ethane TFA salt (Intermediate 135, 365 mg, 1.44 mmol) according to the procedure for Intermediate 101 to afford (117 mg, 28.1%) a white solid.

M_SI 434 ES+ 1N505818) O\\ ,“\/\ l/I Hm? M " \ o N O OH The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—N—[2—(sulfamoylamino)ethyl]—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 136, 117 mg, 0.27 mmol) according to the procedure for Intermediate 102 to afford the title compound as a white gum.

M_SZ 320 ES+ (C10H17N5058) WO 53215 The title compound was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—N—[2— (sulfamoylamino)ethyl]—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 137, 80 mg, 0.25 mmol) and ethyl (2S)—2—bromo—2—ﬂuoro—acetate (Intermediate 174, 0.089 mL, 0.75 mmol) according to the procedure for Intermediate 103 to afford (22.0 mg, 16.5%) as a White solid. The compound is a 3:7 mixture of diastereomers.

M_S: 424 ES+ (C14H22FN507) The title compound was ed from ethyl (2S)—2—fluoro—2—[[(2S,5R)—3—methyl—7—oxo—2—[2— (sulfamoylamino)ethylcarbamoyl] — 1 ,6—diazabicyclo[3 .2. 1]oct—3—en—6—yl]oxy] acetate (Intermediate 138, 30 mg, 0.071 mmol) according to the procedure for Example 66 to afford (13.0 mg, 44.1%) as a White solid.

M_S: 396 ES+ (ClelgFN507S) 1H NMR1300 MHz= D;@ 5: 1.71 (s, 3H); 3.21—3.47 (m, 6H); 4.11 (m, 1H); 4.35 (m, 1H); .64-5.84 (d, 1H); 6.22 (m, 1H).

Intermediate 139: ZS 5R tert-but l dimeth 1 Si] 1 0X meth l0X0-1 6- ic clo 3.2.1 0ctenecarb0nitrile To a solution of (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.l]oct—3—ene—2—carboxamide (Intermediate 192, 3.0 g, 9.63 mmol) in DCM (50 mL) at room temperature was added Burgess Reagent (3.44 g, 14.4 mmol) portionwise over 2 hours. The on mixture was stirred for an additional 16 hours, then washed with 1:1 water twice. The organics were dried over magnesium e, filtered and concentrated. Silica gel chromatography (0—25% ethyl acetate/hexanes) afforded the title compound (2.3 g, 81.3%) as a white solid.

M_S: 294 ES+ 3N302Si) Intermediate 140: tert-but lN- 2S tert-but ldimeth lsil 10X meth l0X0- 1 6-diazabic clo 3.2.1 0cten l meth l carbamate k 0CAM/0,, \ O o»Sl\ To a stirred solution of (2S)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carbonitrile (Intermediate 139, 1.2 g, 4.09 mmol) in methanol (100 mL) at 0 °C was added di—tert—butyl dicarbonate (1.78 g, 8.18 mmol) and NiClz‘6 H20 (97.2 mg, 0.41 mmol). Then NaBH4 (1.08 g, 28.6 mmol) was added over 30 minutes. The reaction mixture was then warmed to RT and stirred for 1 hour. s base (0.71 mL, 4.09 mmol) was added, then stirred for 30 minutes. The solvent was removed. The residue was dissolved in EtOAc and washed with sat. NaHC03 solution, brine, dried over MgSO4, filtered and concentrated. The e was purified with silica gel chromatography (40 g, 0%—35% EtOAc/Hexane) to afford the title compound (0.58 g, 35.7%) as a white solid.

M_S: 398 ES+ (C19H35N304Sl) Intermediate 141: tert-but lN- 2S 5R h dr0X meth l0X0-1 6- diazabic clo 3.2.1 0cten l meth l carbamate )(OJLN/n.0 \ O OH The title compound was prepared from tert—butyl N—[[(2S,5R)—6—[tert—butyl(dimethyl)— silyl]oxy—3—methyl—7—oxo— 1 ,6—diazabicyclo[3 .2. 1]oct—3—en—2—yl]methyl]carbamate (Intermediate 140, 80 mg, 0.20 mmol) according to the procedure for Intermediate 102 to afford a White gum.

M_S: 284 ES+ 1N3O4) ediate 142: eth 1 2S 28 SR tert-but0X carbon 1 amino meth l meth l0X0-1 6-diazabic clo 3.2.1 0cten 1 0X ﬂu0r0acetate )(OJLM/h.O \ O O/Sfov The title compound was prepared from tert—butyl N—[[(2S,5R)—6—hydroxy—3—methyl—7—oxo— 1,6—diazabicyclo[3.2.1]oct—3—en—2—yl]methyl]carbamate (Intermediate 141, 50 mg, 0.18 mmol) and ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.063 mL, 0.53 mmol) according to the ure for Intermediate 103 to afford (50 mg, 73.1%) a White solid. The compound is a 1:9 mixture of diastereomers.

M_S: 388 ES+ (C17H26FN3O6) The title compound was prepared from ethyl (2S)—2—(((2S,5R)—2—(((tert—butoxycarbonyl)— amino)methyl)—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl)oxy)—2—fluoroacetate (Intermediate 142, 50 mg, 0.13 mmol) according to the procedure for Example 66 to afford (35 mg, 67.9%) as a White solid after lyophilization.

M_S: 360 ES+ (C15H22FN306) 1H NMR1300 MHz= D;@ 5: 1.43 (s, 9H); 1.65 (s, 3H); 3.17—3.36 (m, 3H); 3.49 (m, 1H); 3.74 (m, 1H); 4.05 (m, 1H); 5.62-5.81 (d, 1H); 6.08 (m, 1H).

WO 53215 To a solution of (2S)—2—[[(2S,5R)—2—[(tert—butoxycarbonylamino)methyl]—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—en—6—yl]oxy]—2—ﬂuoro—acetic acid (Example 76, 25 mg, 0.07 mmol) in DCM (1 mL) at 0 °C was added trifluoroacetic acid (0.79 g, 6.96 mmol). The reaction mixture was stirred for 2 hours, then concentrated. The residue was ved in pH 7 buffer, then loaded on a sepabead column (saturated with water first, then ACN, then washed with water) eluting with (0%—2.5% CAN/water) to afford the title compound (8 mg, 37.7%) as a white solid after lization.

M_S: 260 ES+ (C10H14FN304) 1H NMR1300 MHz= ngl 8: 1.64 (s, 3H); 3.19-3.30 (m, 3H); 3.44 (m, 1H); 3.96 (m, 1H); 4.09 (m, 1H); 5.64-5.84 (d, 1H); 6.16 (m, 1H).

Intermediate 143: ZS 5R aminometh l tert-but l dimeth 1 Si] 1 0x meth [- 1,6-diazabicyclo| 3.2.1 -en0ne 0%“! / ‘0»Si\ To a solution of tert—butyl N—[[(2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—en—2—yl]methyl]carbamate (Intermediate 140, 100 mg, 0.25 mmol) in DCM (5 mL) at 0 °C was added ZnBrz (170 mg, 0.75 mmol). The reaction mixture was stirred at RT for 16 hours, then concentrated and used in the next step without purification.

M_S: 298 ES+ (C14H27N3Ole) To a solution of )—2—(aminomethyl)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—1,6— diazabicyclo[3.2.1]oct—3—en—7—one (Intermediate 143, 74 mg, 0.25 mmol) in pyridine (1 mL) at 0 °C was added AczO (168 mg, 0.75 mmol). The reaction mixture was stirred at RT for 30 minutes, then washed with water, sat. NaHCOg, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel tography (0%— 100% Hexane) to afford the title compound (70 mg, 78.7%) as a white solid.

M_S: 340 ES+ (C16H29N303Si).

The title compound was prepared from of N—[[(2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3— methyl—7—oxo—1,6—diazabicyclo[3.2.l]oct—3—en—2—yl]methyl]acetamide (Intermediate 144, 70 mg, 0.21 mmol) according to the procedure for Intermediate 102 to afford a white gum.

M_S: 226 ES+ (C10H15N303) Intermediate 146: eth 1 2S 2S 5R acetamidometh l meth l0X0-1 6- diazabic clo 3.2.1 0cten 10X ﬂu0r0-acetate A//I,‘ u \ L F N\ O O#0v The title compound was prepared from of N—[[(2S,5R)—6—hydroxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2. l]oct—3—en—2—yl]methyl]acetamide (Intermediate 145, 40 mg, 0.18 mmol) and ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.063 mL, 0.53 mmol) WO 53215 according to the procedure for Intermediate 103 to afford (15 mg, 25.6%) as a white solid after lyophilization. The compound is a 15:85 mixture of diastereomers.

M_S: 330 ES+ (C14H20FN305) The title compound was prepared from ethyl —[[(2S,5R)—2—(acetamidomethyl)—3— methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl]oxy]—2—fluoro—acetate (Intermediate 146, mg, 0.05 mmol) according to the procedure for Example 66 to afford (10 mg, 65.6%) a white solid after lyophilization.

M_S: 302 ES+ (C12H16FN305) 1H 0 MHz, mg) 5: 1.64 (s, 3H); 1.99 (s, 3H); 3.19 (m, 1H); 3.34 (m, 2H); 3.64 (m, 1H); 3.79 (m, 1H); 4.05 (m, 1H); 5.63-5.81 (d, 1H); 6.09 (m, 1H).

Intermediate 147: eth 1 ZS ZS 5R aminometh l meth l0x0-1 6- diazabic clo 3.2.1 en 1 0x ﬂu0r0-acetate TFA salt % F N\ O O#0v To a solution of ethyl (2S)—2—[[(2S,5R)—2—[(tert—butoxycarbonylamino)methyl]—3—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—en—6—yl]oxy]—2—fluoro—acetate (Intermediate 142, 97.4 mg, 0.25 mmol) in DCM (2 mL) at 0 °C was added trifluoroacetic acid (2.87 g, 25.2 mmol). The reaction mixture was stirred at 0 °C for 2 hours, then concentrated to afford the title compound as TFA salt.

MS: 288 ES+ (C12H13FN304) Intermediate 148: tert-but lN-chlorosulfon lcarbamate k 0 9 OJLWEEI To a stirred solution of tert—butanol (1.9 mL, 20 mmol) in CHzClz (12 mL) at 0°C was added chlorosulfonyl isocyanate (1.4 mL, 15 mmol) dropwise over the course of 10 s. After ng at 0 °C for 5 minutes, the on mixture was warmed to RT and stirred for 20 minutes. The reaction mixture was trated in vacuo to one—third volume. The ﬂask was placed back into the 0 °C bath, and the product crystallized out of solution. After 50 minutes, the product was collected by tion and washed with hexanes to afford the title compound (2.8 g, 80.7%) as a white solid.

To a solution of ethyl (2S)—2—[[(2S,5R)—2—(aminomethyl)—3—methyl—7—oxo—1,6—diazabicyclo— [3.2. l]oct—3—en—6—yl]oxy]—2—fluoro—acetate TFA salt (Intermediate 147, 72 mg, 0.25 mmol) in DCM (2 mL) at 0 °C was added tert—butyl N—chlorosulfonylcarbamate (Intermediate 148, 54.0 mg, 0.25 mmol) and triethylamine (63.4 mg, 0.63 mmol). The reaction mixture was stirred at RT for 30 minutes, then diluted with DCM, washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by ﬂash chromatography (0%— 100% EtOAc/Hexane) to afford the title compound (38 mg, 39.6%) as a white solid.

M_S: 384 ES+ (C14H17F4N305) The title compound was prepared from ethyl (2S)—2—ﬂuoro—2—[[(2S,5R)—3—methyl—7—oxo—2— [[(2,2,2—triﬂuoroacety1)amino]methyl] — 1 zabicyclo[3 .2. 3—en—6—y1]oxy] acetate (Intermediate 149, 38 mg, 0.10 mmol) according to the procedure for Example 66 to afford (25 mg, 60.3%) a White solid after lyophilization.

M_S: 356 ES+ (C12H13FN305) 1H NMR1300 MHz= D;@ 5: 1.66 (s, 3H); 3.22 (m, 1H); 3.36 (m, 1H); 3.59 (m, 1H); 3.73 (m, 1H); 3.86 (m, 1H); 4.08 (m, 1H); 5.62-5.83 (d, 1H); 6.11 (m, 1H).

Intermediate 150: 2S 5R tert-but l dimeth l sil 1 0X -N- c anometh l meth l 0X0-1 6-diazabic clo 3.2.1 0ctenecarb0xamide N§/\NJl,I \ )—N / 0 ‘0’3'\ The title compound was prepared from (2S,5R)—6—[tert—buty1(dimethy1)si1y1]oxy—3—methy1—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxy1ic acid (Intermediate 77, 700 mg, 2.24 mmol) and aminoacetonitrile hydrochloride (207 mg, 2.24 mmol) according to the ure for ediate 101 to afford (302 mg, 38.4%) a White solid.

M_S: 351 ES+ (C16H26N403Si) Intermediate 151: 2S 5R -N- c anometh l h dr0X meth l0X0-1 6- diazabicycloI 3.2.1 |0ctenecarb0xamide Nj/\MJl,1., \ l; N\ O OH The title compound was prepared from (2S,5R)—6—[tert—buty1(dimethy1)si1y1]oxy—N— (cyanomethy1)—3 1—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 150, 300 mg, 0.86 mmol) according to the procedure for Intermediate 102 to afford a residue.

M_S: 237 ES+ (C10H12N4O3) Oil—Nb/FSWO\/ To a solution of )—N—(cyanomethyl)—6—hydroxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 151, 239 mg, 1.01 mmol) in THF (3 mL) and DMF (0.3 mL) at —40 °C was added DBU (0.18 mL, 1.22 mmol) and ethyl (2S)—2— bromo—2—ﬂuoro—acetate (Intermediate 174, 0.18 mL, 1.52 mmol). The reaction mixture was stirred at —40°C for 30 minutes, then d with ethyl acetate and washed three times with 1:1 brinezwater. The organics were dried over magnesium sulfate, filtered and concentrated.

The residue was purified by ﬂash tography 0% EtOAc/Hexane) to give a 1:4 e of diastereomers. The diastereomers were separated by reverse phase HPLC (T3 column, 20%—50% ACN/water, 10 minutes) to afford Example 80 (64 mg, 18.2%) and Example 81 (8 mg, 2.3%) as white solids.

M_S: 341 ES+ (C14H17FN405) 1H NMR1300 MHz= DMSO-dg) 5: 1.27 (m, 3H); 1.64 (s, 3H); 3.13 (m, 1H); 3.61 (m, 1H); 3.98 (m, 1H); 4.21 (m, 5H); 6.06-6.26 (m, 1H); 6.10 (m, 1H); 9.18 (m, 1H).

Exam le 81: eth 1 2R ﬂu0r0 2S 5R c anometh lcarbamo lmeth l0x0- 1 6-diazabic clo 3.2.1 0cten 1 0x acetate f”)|,1,, \ M_S: 341 ES+ (C14H17FN405) 1H NMR1300 MHz, DMSO—dg) 5: 1.21 (m, 3H); 1.65 (s, 3H); 3.12 (m, 1H); 3.60 (m, 1H); 4.07 (m, 1H); 4.22 (m, 5H); 6.08 (m, 1H); 6.15—6.33 (m, 1H); 9.16 (m, 1H).

WO 53215 Exam le 82: 2S ﬂu0r0 2S 5R c anometh lcarbamo l meth l0x0-1 6- diazabic clo 3.2.1 0cten 1 0x acetic acid lithium salt The title compound was prepared from ethyl (2S)—2—ﬂuoro—2—[[(2S,5R)—2—(cyanomethyl— carbamoyl)—3—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3—en—6—yl]oxy] acetate (Example 80, 50 mg, 0.15 mmol) according to the procedure for Example 66 to afford (32 mg, 66.3%) as a White solid after lyophilization.

M_S: 313 ES+ 3FN405) 1H NMR1300 MHz, mg) 5: 1.74 (s, 3H); 3.35 (m, 2H); 4.12 (m, 1H); 4.25 (m, 2H); 4.42 (m, 1H); 5.63-5.83 (d, 1H); 6.23 (m, 1H).

Intermediate 138 (230 mg) was separated by reverse phase preparative HPLC (T3 column, ACN/Water 20—50% for 10 mins) to afford Example 83 (104 mg) and Example 84 (7 mg) as White solids.

M_S: 424 ES+ (C14H22FN507S) 1H 0 MHz= DMSO-dg) 8: 1.27 (m, 3H); 1.63 (s, 3H); 2.97 (m, 2H); 3.10 (m, 1H); 3.26 (m, 2H); 3.73 (m, 1H); 3.96 (m, 1H); 4.21 (m, 3H); 6.06—6.26 (m, 2H); 6.56 (m, 3H); 8.45 (m, 1H).

Exam le 84: eth l ZR -Z-ﬂu0r0-Z- ZS 5R -Z- c h lcarbamo lmeth l0X0- M_S: 424 ES+ (C14H22FN507S) 1H 0 MHz2 DMSO—dg) 5: 1.21 (m, 3H); 1.62 (s, 3H); 2.95 (m, 2H); 3.07 (m, 1H); 3.24 (m, 2H); 3.71 (m, 1H); 4.06 (m, 1H); 4.21 (m, 3H); 6.03 (m, 1H); 6.14—6.31 (m, 1H); 6.55 (m, 3H); 8.42 (m, 1H).

To a solution of (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—1,6— diazabicyclo[3.2.1]oct—3—ene—2—carboxamide mediate 19Z,1.0 g, 3.21 mmol) was added paraformaldehyde (1.45 g, 16.1 mmol) in 1,4—dioxane (10 mL). The reaction mixture was heated to 90 °C for 16 hours under microwave. The solvent was removed. Silica gel chromatography (0%—80% EtOAc/Hexane) afforded the title compound (0.62 g, 56.5%) as a white solid.

M_S: 342 ES+ (C15H27N3O4Sl) Intermediate 153: eth 1 ZS -Z-ﬂu0r0-Z- ZS 5R -Z- h dr0X meth lcarbamo l meth l0X0-1 abic clo 3.Z.1 0cten 1 0X acetate /\ JI’I, HO N ‘\ L . N\ O 0#0V To a solution of (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—N—(hydroxymethyl)—3—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 152, 230 mg, 0.67 mmol) and cerium(III) chloride (166 mg, 0.67 mmol) in THF (3 mL) at —78 °C was added TBAF (0.67 mL, 0.67 mmol) (1M in THF). The e was stirred for about 10 minutes. To the reaction mixture was added ethyl (2S)—2—bromo—2—fluoro—acetate mediate 174, 24.4 mg, 0.67 mmol). After 5 minutes, the reaction mixture was partitioned between water and EtOAc. The organic layer was collected, washed with water, brine, dried over MgSO4, filtered and trated. Silica gel chromatography (0%—80% EtOAc/Hexane) afforded a mixture of two diastereomers in a ratio of 1:3, 180 mg.

Exam le 85: eth 1 2S ﬂu0r0 2S 5R h drox meth mo lmeth l 0x0-1 6-diazabic clo 3.2.1 0cten 1 0x acetate Ho/\NJ|, \ 3— F O O#O\/ Intermediate 153 (180 mg) was separated by reverse phase preparative HPLC (T3 , ACN/water 20—50% for 10 mins) to afford Example 85 (43 mg) and Example 86 (2.6 mg) as white solids.

MS: 332 ES+ (C13H13FN3O6) 1H NMR1300 MHz, DMSO—dg) 5: 1.28 (m, 3H); 1.61 (s, 3H); 3.09 (m, 1H); 3.79 (m, 1H); 3.96 (m, 1H); 4.25 (m, 3H); 4.54 (m, 2H); 5.68 (m, 1H); 6.06—6.24 (m, 2H); 8.99 (m, 1H).

Exam le 86: eth 1 2R ﬂu0r0 2S 5R h drox meth lcarbamo lmeth l 0x0-1 6-diazabic clo 3.2.1 0cten 1 0x acetate HOAN \ M_S: 332 ES+ (C13H18FN306) 1H NMR1300 MHz= DMSO-dg) 5: 1.24 (m, 3H); 1.61 (s, 3H); 2.97 (m, 1H); 3.35 (m, 1H); 4.06 (m, 1H); 4.26 (m, 3H); 4.59 (m, 2H); 5.52 (m, 1H); 6.03 (m, 1H); 6.06—6.24 (m, 1H); 8.99 (m, 1H).

The title compound was prepared from ethyl (2S)—2—fluoro—2—[[(2S,5R)—2— (hydroxymethylcarbamoyl)—3—methyl—7—oxo— 1 ,6—diazabicyclo[3 .2. 1]oct—3—en—6—yl]oxy] acetate (Example 85, 15 mg, 0.05 mmol) according to the procedure for Example 66 to afford (8 mg, 55.3%) a white solid after lyophilization.

M_S: 304 ES+ (C11H14FN306) 1H NMR1300 MHz, D29 8: 1.77 (s, 3H); 3.42 (m, 2H); 4.17 (m, 1H); 4.41 (m, 1H); 4.79 (m, 2H); 5.70-5.89 (d, 1H); 6.28 (m, 1H).

Intermediate 154: tert-but lN- isoc anatometh lcarbamate kJOL /\ O N N H \o To a stirred solution of Y—OH (10 g, 57.08 mmol) in THF (200 mL) at 0°C was added methyl chloroformate (5.29 mL, 68.5 mmol) dropwise, followed by triethylamine (9.55 mL, 68.5 mmol) dropwise. A white itate formed immediately. The mixture was stirred for 45 minutes before the on of NaN3 (5.58 g, 85.6 mmol) in water (10 mL) at 0 OC.

The resulting mixture was stirred at 0 °C for 1 hour, then diluted with water. The acyl azide was extracted four times with toluene (4 x 25 mL) and the combined organic extracts were successively washed with saturated sodium bicarbonate (2 x 30 mL) and water (50 mL). The organics were dried over MgSO4 at 0 OC, filtered and then heated slowly with stirring until nitrogen gas evolution was observed, which ed at 59 °C for 20 minutes. The temperature was increased and ined at 64 °C for 1.5 hours, then increased slowly to 70 °C for 20 minutes. The solution was concentrated under reduced pressure to afford the title nd (8.6 g, 87.5%) as a colorless oil.

Intermediate 155: tert-but lN- benz 10x carbon lamin0meth lcarbamate )(OJLNAMAOAQO O To a solution of tert—butyl N—(isocyanatomethyl)carbamate (Intermediate 154, 8.3 g, 48.2 mmol) in DCE (5 mL) at 0 °C was added benzyl alcohol (7.48 mL, 72.3 mmol) and triethylamine (0.67 mL, 4.82 mmol), se. The reaction mixture was warmed to RT and d for 30 s. The white solid formed was collected by filtration and washed with hexane to afford the title compound (5.2 g, 38.5%) as a white solid.

M_SZ 303 ES+Na (C14H20N204).

Intermediate 156: tert-but lN- amin0meth l ate o N/\NH2 A solution of tert—butyl zyloxycarbonylaminomethyl)carbamate (Intermediate 155, 1.5 g, 5.35 mmol) in methanol (20 mL) was bubbled with nitrogen gas. Pd/C (10%) (150 mg) was added. The reaction mixture was degassed and then put under hydrogen balloon for minutes. The reaction mixture was ed through . The filtrate was concentrated to afford the title compound as colorless oil.

M_SI 147 ES+ (C6H14N202) Intermediate 157: tert-but lN- 2S 5R tert-but l dimeth 1 Si] 1 0x meth l 0x0-1 6-diazabic clo 3.2.1 0ctenecarb0n 1 amino meth l carbamate Kay”)...0 0 O//‘—N‘o>/Si/% The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—l,6—diazabicyclo[3.2. l]oct—3—ene—2—carboxylic acid (Intermediate 77, 350 mg, 1.12 mmol) and tert—butyl N—(aminomethyl)carbamate (Intermediate 156, 246 mg, 1.68 mmol) according to the procedure for Intermediate 101 to afford (170 mg, 34.4%) a white solid.

MS: 441 ES+ (C20H36N405SI) Intermediate 158: 2S 5R -N- amin0meth l tert-but l dimeth 1 Si] 1 0X h [- oHg‘0'? To a solution of utyl N—[[[(2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—l,6— diazabicyclo[3.2. l]oct—3—ene—2—carbonyl]amino]methyl]carbamate (Intermediate 157, 170 mg, 0.39 mmol) in DCM (3 mL) at 0 °C was added ZnBrz (261 mg, 1.16 mmol). The reaction mixture was stirred at RT for 16 hours, then concentrated to afford the title compound.

M_S: 341 ES+ 8N403SI) To a solution of (2S,5R)—N—(aminomethyl)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7—oxo— l,6—diazabicyclo[3.2.l]oct—3—ene—2—carboxamide (Intermediate 158, 131 mg, 0.39 mmol) in pyridine (3 mL) at 0 °C was added acetic anhydride (394 mg, 3.86 mmol). The reaction e was stirred at RT for 30 minutes, then partitioned between EtOAc and water. The organic layer washed with water, sat. NaHCOg, brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography (0%—80% EtOAc/Hexane) afforded the title compound (75 mg, 50.8%) as a white solid.

M_S: 383 ES+ 0N4O4Si) Intermediate 160: 2S 5R -N- acetamid0meth l h dr0X meth l0X0-1 6- diazabicyc10|3.2.1 |0ctenecarb0xamide o o )LNAN I/I \ H H 0’ N‘OH The title compound was prepared from (2S,5R)—N—(acetamidomethyl)—6—[tert— butyl(dimethyl)silyl]oxy—3—methyl—7—oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 159, 75 mg, 0.20 mmol) according to the ure for Intermediate 102 to afford a White gum.

M_S: 269 ES+ (C11H16N4O4) Intermediate 161: eth 1 2S ﬂu0r0 28 SR acetamidometh lcarbamo l meth l0X0-1 6-diazabic clo 3.2.1 0cten 1 0X e O O MAMJLII‘ \ 04—”?ng\/ The title compound was prepared from (2S,5R)—N—(acetamidomethyl)—6—hydroxy—3—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 160, 50 mg, 0.19 mmol) and ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.067 mL, 0.56 mmol) according to the procedure for ediate 103 to afford a White solid after sepabead column (saturated with water first, then ACN, then eluting with water) eluting with (0%—15% ter) and lyophilization, 21 mg, 27%. The compound is a 1:4 mixture of diastereomers.

M_S: 373 ES+ (C15H21FN4O6) The title compound was prepared from ethyl (2S)—2—ﬂuoro—2—[[(2S,5R)—2—(acetamido— methylcarbamoyl)—3 —methyl—7—oxo— 1 ,6—diazabicyclo[3 .2. 1]oct—3—en—6—yl] oxy] acetate (Intermediate 161, 21 mg, 0.056 mmol) in water (1 mL) according to the ure for Example 66 to afford (6.0 mg, 29.3%) a White solid after lyophilization.

M_S: 345 ES+ (C13H17FN4O6) 1H NMR1300 MHz= D;@ 5: 1.75 (s, 3H); 2.02 (s, 3H); 3.42 (m, 2H); 4.15 (m, 1H); 4.37 (m, 1H); 4.64 (m, 2H); 5.70-5.89 (d, 1H); 6.27 (m, 1H).

Intermediate 162: tert-but lN- tert-but0X carbon lamin0 meth lsulfamo [- carbamate )OOL Q’Oik o NAN’S‘N 0 To a solution of tert—butyl N—(aminomethyl)carbamate (Intermediate 156, 700 mg, 4.79 mmol) in DCM (20 mL) at 0°C was added ylamine (0.67 mL, 4.79 mmol). Then tert— butyl N—chlorosulfonylcarbamate (Intermediate 148, 1.03 g, 4.79 mmol) in DCM (5 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 30 minutes, then diluted with DCM, washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was triturated with DCM/Hexane to afford the title compound (650 mg, 41.7%) as a white solid.

M_S: 324 ES- 3N3O6S) Intermediate 163: amino- sulfamo lamin0 e TFA salt To a solution of tert—butyl N—[(tert—butoxycarbonylamino)methylsulfamoyl]carbamate (Intermediate 162, 650 mg, 2 mmol) in DCM (5 mL) at 0 °C was added triﬂuoroacetic acid (2.28 g, 19.9 mmol). The reaction mixture was stirred at RT for 30 minutes, then concentrated to afford the title compound as light yellow gum.

Intermediate 164: ZS 5R tert-but l dimeth l sil 1 0X meth l0X0-N- sulfamo lamin0 meth l-1 6-diazabic clo 3.2.1 0ctenecarb0xamide The title compound was ed from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— oxo—l,6—diazabicyclo[3.2. l]oct—3—ene—2—carboxylic acid (Intermediate 77, 350 mg, 1.12 mmol) according to the procedure for Intermediate 101 to afford (125 mg, 26.6%) a white solid.

M_S: 420 ES+ (C15H29N5058iS) Intermediate 165: ZS 5R h dr0X h l0X0-N- sulfamo lamin0 meth [-1 6- diazabicyc10|3.Z.1 |0ctene-Z-carb0xamide \\ ’/ | /S\N/\ JIM, H2N N \ H H O OH The title compound was prepared from (2S,5R)—6—[tert—butyl(dimethyl)silyl]oxy—3—methyl—7— [(sulfamoylamino)methyl] — l ,6—diazabicyclo[3 .2. l]oct—3—ene—2—carboxamide mediate 164, 125 mg, 0.30 mmol) according to the procedure for Intermediate 102 to afford a light yellow gum.

M_SZ 306 ES+ (C9H15N5058) Intermediate 166: eth 1 ZS -Z-ﬂu0r0-Z- ZS 5R meth l0X0-Z- sulfamo lamin0 meth lcarbam0 l -1 6-diazabic clo 3.Z.1 0cten 1 0X acetate 0‘0 0 /S\ I H2N NAN) ' \ H H L . N\ O O#O\/ The title nd was prepared from (2S,5R)—6—hydroxy—3—methyl—7—oxo—N— [(sulfamoylamino)methyl] — l ,6—diazabicyclo[3 .2. l]oct—3—ene—2—carboxamide (Intermediate 165, 88 mg, 0.29 mmol) and ethyl (2S)—2—bromo—2—fluoro—acetate (Intermediate 174, 0.10 mL, 0.86 mmol) according to the procedure for Intermediate 103 to afford (18 mg, 12.2%) a white solid. The compound is a 17:83 mixture of diastereomers.

M_S: 410 ES+ (C13H20FN507S) Exam le 89: ZS -Z-ﬂu0r0-Z- ZS 5R meth l0X0-Z- sulfamo lamin0 - meth lcarbam0 l -1 6-diazabic clo 3.Z.1 0cten 1 0X acetic acid lithium salt The title compound was prepared from ethyl (2S)—2—ﬂuoro—2—[[(2S,5R)—3—methyl—7—oxo—2— WO 53215 [(su1famoy1amino)methy1carbamoy1] — 1 ,6—diazabicyclo[3 .2. 1]oct—3—en—6—y1] oxy] acetate (Intermediate 166, 18 mg, 0.040 mmol) according to the procedure for Example 66 to afford (5.0 mg, 25.3%) a white solid after 1yophi1ization.

M_S: 382 ES+ (C11H16F54O7S) 1H NMR1300 MHz, mg) 5: 1.76 (s, 3H); 3.40 (m, 2H); 4.16 (m, 1H); 4.41 (m, 1H); 4.63 (m, 2H); 5.70-5.89 (d, 1H); 6.28 (m, 1H).

Intermediate 167: racemic 2-br0m0ﬂu0r0acetic acid Br/SfOH To a 50 L reactor at 0—5 °C was d a solution of ethyl 2—bromo—2—ﬂuoroacetate (3.5 kg) in tetrahydrofuran (7L, 2V) and a on of sodium hydroxide (830 g) in water (7L, 2V) dropwise over 1 hour. The resulting solution was stirred at 0—5 °C for 1 hour. HC1 (160 mL) was added dropwise at 0—5 OC. Water and tetrahydrofuran were removed by concentration under vacuum. The residue was suspended in tetrahydrofuran (35 L, 10V) and conc. HC1 (1.57 L, 1.0 eq.) was added dropwise. Anhydrous sodium sulfate was added and the resulting mixture was stirred for 2 hours. The solid was filtered off, and washed with THF (1L x 2).

The filtrate was concentrated under vacuum to give 2—bromo—2—ﬂuoroacetic acid (2.2 kg) as a yellow oil, which was combined with a previous batch made by the same method (940 g, : 72%) and distilled in vacuum (65—70°C 100 Pa) to give 2—bromo—2—ﬂuoroacetic acid (2.55 kg, total yield 67%) as a colorless oi1. 1H NMR {400 MHz,CDC1;L 5 11.15 (s, 1H), 6.66 (d, 1H, J = 68 Hz).

Intermediate 168: S hen lethan-l-amine R br0m0ﬂu0r0acetate To a 10 L reactor at 0—5 °C was charged a solution of 2—bromo—2—ﬂuoroacetic acid (Intermediate 167, 2.0 kg) in 1 L of form (1V), to which, a solution of (S)—1— phenylethanamine (1.39 kg) in 1 L of chloroform (1V) was added se. The mixture was stirred at room temperature overnight and the resulting white solid was collected by filtration to give a salt of (S)—1—pheny1ethanamine 2—bromo—2—ﬂuoroacetate (2.5 kg; ee: 6%), which was charged into a 10 L reactor, followed by addition of chloroform (5L, 2V). The resulting mixture was stirred for 2 hours at 50°C (solid was partially ved in chloroform), cooled to 0 OC, and was allowed to stand for 2 hours. Solid was collected by filtration, and washed with cooled chloroform (500 mL, 0.2V). The recrystallization procedure was repeated 4 times to afford 1.09 kg (97 %ee) of the title compound as a white solid with an overall yield of 31% (2 steps).

Intermediate 169: entan l R m0ﬂu0r0acetate Br/SfOY To a 2 L reactor at room temperature was d (S)—1—phenylethanamine (R)—2—bromo—2— ﬂuoroacetate mediate 168, 450 g), dichloromethane (900 mL, 2V) and iPrOH (2.0 eq.). trimethylsilane (1.12 L) was added slowly, and a white precipitate was formed. The resulting mixture was stirred at room temperature overnight. White precipitate was filtered off, and the filter cake was washed with hexane (450 mL, 1V). The combined filtrate was washed with water (3x100 mL). Organic solution was dried with anhydrous sodium sulfate, filtered, concentrated under vacuum. Residue was distilled (54—60°C, 100 Pa) to give the title compound as a colorless oil (290 g, 79% yield, 95% purity). 1H NMR 1CDCl§= 400 MHz): 6 6.53 (d, J: 51.2 Hz, 1H), 5.17 (m, 1H), 1.32 (m, 6H).

Intermediate 170: eth l R br0m0ﬂu0r0acetate Br/vwl/OV Into a 50 mL 3—necked round—bottom ﬂask, purged and maintained with an inert atmosphere of nitrogen, was placed (1R)—1—phenylethan—l—amine; (2S)—2—bromo—2—ﬂuoroacetic acid (Intermediate 168, 30 g, 107.9 mmol) and ethanol (34.7 g, 755.3 mmol). This was ed by the addition of chlorotrimethylsilane (82 g, 755.3 mmol) dropwise with stirring at room temperature. The resulting solution was stirred for 4 h at room temperature, then ed by the addition of 10 mL of water/ice. The resulting solution was extracted with 3,x,20 mL of petroleum ether (30—60 degree) and the organic layers combined. The resulting mixture was washed with 2,x,20 mL of brine. The mixture was dried over ous sodium sulfate, filtered and concentrated. The residue was applied onto a silica gel column with eum ether (30—60 degree). This resulted in 10 g (50%) of the title compound as a colorless oil. 1H NMR1300 MHz= CDCl§L 5 6.58 (d, 1H, J = 51 Hz), 4.38 (q, 2H, J = 6 Hz), 1.38 (t, 3H, J = 6 Hz).

Intermediate 171: R -benz 12-br0m0ﬂu0r0acetate 81893 Chlorotrimethylsilane (60 mL, 719.12 mmol) was added portionwise to (S)—l— phenylethanamine bromo—2—ﬂuoroacetate (Intermediate 168, 20 g, 71.91 mmol) and phenylmethanol (60 mL, 71.91 mmol) at 25 °C over a period of 3 minutes under nitrogen.

The resulting solution was stirred at 25 °C for 4 hours. The reaction e was diluted with heptane (500 mL), then washed with water and brine. The organics were dried over sodium sulfate, filtered and concentrated. Silica gel chromatography (0% to 10% ethyl acetate/petroleum ether) afforded the title compound as a yellow oil, 17.5 g, 98%. 1H 0 MHZ, CDCli—d, 30 °C) 5: 5.30 (s, 2H); 6.60 (d, 1H); 7.40 (m, 5H).

Intermediate 172: IR hen lethan-l-amine' 2S br0m0ﬂu0r0acetic acid OH ©45NH2 Into a 100—mL round—bottom ﬂask was placed a solution of —phenylethan—1—amine (107.7 g, 0.89 mol) in methanol (325 mL). This was followed by the addition of a solution of 2—bromo—2—fluoroacetic acid (Intermediate 167, 140 g, 0.89 mol) in methanol (420 mL) dropwise with stirring at 0 °C over 30 min. The resulting solution was stirred overnight at room ature, then concentrated under vacuum. The residue was diluted with CHC13 (3V). The solids were collected by filtration. The solid was dried under , then suspended in CHC13 and heated to 60 °C for 2 hours. The mixture was then was cooled to 0°C and the solid was filtered. The process was repeated 6 times. This resulted in 80 g (32%) of title compound as a white solid. 1H NMR1300 MHZ, d6—DMSO): 5 8.56 (brs, 3H), 7.49—7.46 (m, 2H), 7.42—7.38 (m, 2H), 7.36—7.34 (m, 1H), 6.48 (d, 1H, J = 56 HZ), .34 (m, 1H), 1.48 (d, 3H, J = 6.8 HZ).

Intermediate 173: S -iso r0 12-br0m0ﬂu0r0acetate Br/Kg/OY Into a 250—mL 3—necked round—bottom ﬂask, purged and maintained with an inert atmosphere of en, was placed (R)—1—phenylethanamine (S)—2—bromo—2—fluoroacetate (Intermediate 172, 32.0 g, 116 mmol), and isopropanol (13.9 g, 232 mmol) in DCM (64 mL). This was followed by the dropwise addition of chlorotrimethylsilane (56.4 g, 519 mmol) with ng at room temperature. The resulting on was d overnight at room temperature, then quenched by the addition of 100 mL of ice. The resulting solution was ted with 3 x 100 mL of eum ether (30—60 degree), and the c layers combined. The resulting mixture was washed with 3 x 70 mL of brine. The e was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with petroleum ether (30—60 degree). This resulted in 19 g (83%) of title compound as colorless oil. 1H NMR 1CDC15, 400 MHz): 8 6.53 (d, J: 50.8 Hz, 1H), 5.17 (m, 1H), 1.32 (m, 6H).

Intermediate 174: ethyl 12S 2br0m0ﬂu0r0acetate Br/\n/0v Into a 50 mL 3—necked round—bottom ﬂask, purged and maintained with an inert atmosphere of nitrogen, was placed (1R)—l—phenylethan—l—amine (2S)—2—bromo—2—ﬂuoroacetic acid (Intermediate 172, 20 g, 72 mmol) and ethanol (23.2 g, 504 mmol). This was followed by the dropwise addition of chlorotrimethylsilane (54.8 g, 504 mmol) with stirring at room temperature. The resulting solution was stirred for 4 h at room temperature, then quenched by the addition of 10 mL of water/ice. The resulting solution was ted with 3 x 20 mL of petroleum ether (30—60 degree) and the organic layers combined. The resulting mixture was washed with 2 x 20 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was applied onto a silica gel column with petroleum ether (30—60 degree). This resulted in 6 g (45%) of title compound as colorless oil. 1H NMR1300 MHz= d6-DMSO): 5 6.57 (d, 1H, J = 56 Hz), 4.37 (q, J = 7.2 Hz, 2H), 1.33 (t, 3H, J = 7.2 Hz).

Intermediate 175: E -buten lb0r0nic acid \ZL [OH To a solution of (E)—but—2—en—1—ol (59.5 g, 826 mmol) in MeOH (360 mL) at room temperature was added HdeCl4 (2.06 g, 8.34 mmol), then to the mixture was added B2(OH)4 (81.8 g, 919 mmol) by n at 30—40 0C. The resulting solution was stirred at 30—40 °C for minutes, then filtered through celite. 1H—NMR gDMSO—dg, 400 MHz): 5 5.39—5.49 (m, 1H), 5.16—5.26 (m, 1H), 3.38 (s, 2H), 1.38— 1.58 (m, 5H) Intermediate 176: S E tert-but lsulfin limino acetic acid HowN‘lsl"\‘< To molecular sieves type 4104 (500 g) in DCM (600 mL) at room ature was added (S)— 2—methylpropane—2—sulfinamide (100 g, 819mmol) and 2—oxoacetic acid e (91.2 g, 991 mmol). The resulting solution was stirred at room temperature for overnight, then filtered through celite. 1H-NMR {DMSO-dg, 400 MHz): 8 7.77 (s, 1H), 5.74 (s, 1H), 1.13 (s, 9H) Intermediate 177: 2S 3R S -1 l-dimeth leth lsulfinamido meth l enten0ic To a solution of the crude product (S,E)—2—(tert—butylsulfinylimino)acetic acid (Intermediate 176) in DCM (600 mL) at 0—15 °C was added dropwise a solution of the (E)—but—2— enylboronic acid (Intermediate 175) in MeOH (360 mL). The resulting on was stirred at 0—15 °C for 1 hour. The molecular sieves were removed through filtration, and washed with DCM. The te was removed by distillation under vacuum to get crude product. To the crude product was added H20 (600 mL), petroleum ether (240 mL) and methyl tert—butyl ether (120 mL), stirred at room temperature for 1 hour, then filtered and collected the solid and dried under vacuum at 25 °C to afford the product (110 g, 58%) as a white solid. 1H—NMR (DMSO—dg, 400 MHz): 6 5.71—5.80 (m, 1H), 5.01—5.07 (m, 2H), 4.94 (d, J: 8 Hz, 1H), 3.58—3.62 (m, 1H), 2.56—2.61 (m, 1H), 1.15 (s, 9H), 0.975 (d, J = 4 Hz, 3H) Intermediate 178: 12S= thyl 2-amin0methylpenten0ate \OJLII'N3 To a solution of )—2—((S)—1,1—dimethylethylsulfinamido)—3—methylpent—4—enoic acid (Intermediate 177, 44 g, 189 mmol) in MeOH (200 mL) was added dropwised SOClz (68.6 mL, 944 mmol) at 0 OC. The reaction mixture was stirred at 0 °C for 1 hour, then warmed up to 70 °C and stirred overnight. The t was removed and the residue diluted with water.

To the water phase was added NaHC03 to lize pH to ~8, and extracted with DCM, dried over NaZSO4, ed and concentrated to give 23 g crude t as a yellow liquid. 1H—NMR gDMSO—dg, 400 MHz): 5 5.71—5.82 (m, 1H), 4.97—5.05 (m, 2H), 3.61 (s, 3H), 3.27 (d, J: 8 Hz, 1H), 2.33—2.45(m, 1H), 1.79 (s, 2H), 0.96 (d, J: 8 Hz, 3H) LCMS: tR=0.682, [M+H]+ 144.2 Intermediate 179: 12S33R 2-methyl 2-1allylamino2methylpenten0ate 0 E \OJ'I/(k/ HN\/\ To a solution of (2S, 3R)—methyl 2—amino—3—methylpent—4—enoate (Intermediate 178, 23 g, 161mmol) in DMF (90 mL) at 0 °C was added LiOH (4.248 g, 177 mmol). The mixture was stirred at 0°C for 30 minutes. Then a solution of 4—bromobut—1—ene (17.5 g, 145 mmol) in DMF (15 mL) was added dropwised. The reaction was stirred at —7 °C for 20 mins, then warmed to room temperature slowly, and stirred overnight. The reaction was quenched with water, extracted with EtOAc. The organic layer was washed with water, brine, dried over NaZSO4, filtered and concentrated to give 28 g crude product as yellow liquid. 1H—NMR (DMSO—dg, 400 MHz): 5 5.65—5.83 (m, 2H), 4.93—5.16 (m, 4H), 3.60 (s, 3H), 3.14— 3.22011, 1H), 3.06 (d, J = 8 Hz, 1H), 2.93—3.01(m, 1H), 2.34—2.41 (m, 1H), 0.99 (d, J = 8 Hz, LCMS: tR=0.461, m/z: 184[M+H] Intermediate 180: 12S13R z-methyl 2-1allylg tert-butoxycarbonyl [amino 2methylpent en0ate 0 E \OJL.N Boc/ A To a solution of (2S,3R)—methyl ylamino)—3—methylpent—4—enoate mediate 179, 28g, 153 mmol) in t—BuOH (150 mL) was added (Boc)20 (33.4 g, 153 mmol). The reaction was stirred at room temperature for 10 minutes, then warmed up to 90 °C and d ght. The reaction mixture was concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% EtOAc in eum ether. Pure fractions were evaporated to afford the product (24 g, 56 %) as a light yellow liquid. 1H—NMR gDMSO—dg, 400 MHz}: 6 5.71—5.84 (m, 2H), 5.00—5.11 (m, 4H), 3.66—4.43 (m, 3H), 3.58 (s, 3H), 2.81 (s, 1H), 1.39 (s, 9H), 0.93 (d, J = 8 Hz, 3H) LCMS: tR=1.096, 184[M—Boc+H] Intermediate 181: 2S 3R tert-but l2-meth l3-meth l-2 3-dih dr0 ridine-l 2 6H - dicarboxylate \OJL.,0 To a solution of )—methyl 2—(allyl(tert—butoxycarbonyl)amino)—3—methylpent—4—enoate (Intermediate 180, 24 g, 84.8 mmol) in DCM (250 mL) was added Grubbs catalyst, 1St generation (886 mg 1.06 mmol) at 0 °C in three batches and stirred for 4 hours. More Grubbs catalyst, 1St generation was added (886 mg 1.06 mmol) at 0 °C in three batches, then warmed up to 25 OC. The resulting solution was stirred at room temperature overnight.

LCMS: tR=0.987, 156.2 [M—Boc+H], 295[M+K] Intermediate 182: 2S 5R tert-but l2-meth 15- tert- but0X carbon lh dr0X amin0 meth l-5 6-dih dr0 ridine-l 2 2H -dicarb0X late \OJL, \ To a solution of (2S,3R)—1—tert—butyl 2—methyl yl—2,3—dihydropyridine—1,2(6H)— dicarboxylate (Intermediate 181, 21.6 g, 84.8 mmol) in DCM (250 mL) was added BocNHOH (16.9 g, 127 mmol), CuCl (0.419 g, 4.24 mmol) and pyridine (87 mg, 1.1 mmol) and degassed with oxygen. The resulting solution was stirred at room temperature for 44 hours under oxygen. The solid was removed by tion. The filtrate was washed with water (3 X 200 mL) and brine, dried over NaZSO4, filtered and concentrated. The crude t was purified by flash silica chromatography, eluting with 0 to 50% DCM in petroleum ether to give the product (29 g, 88%) as brown oil. 1H—NMR 1CDC13, 400 MHz): 8 5.66 (d, J: 16 Hz, 1H), 5.31 (s, 1H), 4.90 (d, 1H), 4.51 (d, 1H), 4.11 (t, J: 20 Hz, 1H), 3.75 (s, 3H), 3.50-3.61 (m, 1H ), 1.90 (d, J: 8 Hz, 3H), 1.43- 1.51 (m, 18H ) LCMS: tR=0.713, 279 [M—Boc+Na] Intermediate 183: 2S 5R tert-but lZ-meth 15- tert-butox carbon ltert- but ldimeth lsil 10X amino meth l-S 6-dih dro -l 2 2H -dicarb0X late To a solution of (2S,5R)—1—tert—butyl 2—methyl 5—(tert—butoxycarbonyl(hydroxy)amino)—3— methyl—5,6—dihydropyridine—1,2(2H)—dicarboxylate (Intermediate 182, 23 g 59.5 mmol) in DCM (180 mL) was added imidazole (8.09 g 119 mmol). The resulting solution was stirred at room temperature for 10 s, then a solution of TBS—Cl (11.6 g, 77.4 mmol) in DCM (20 mL) was added dropwise at 0—5 OC. The reaction was stirred at 0 °C for additional 18 hours. The c phase was washed with water and brine, dried over , filtered and concentrated. The crude product was purified by flash silica chromatography, eluting with petroleum ether and DCM to give product (20 g, 67%) as a brown oil. 1H—NMR(CDC1;, 400 MHz): 5 5.7(s, 1H), 4.45—4.85 (m, 2H), 4.09 (d, J = 20 Hz, 1H), 3.76 (s, 3H), 3.53—3.58 (m, 1H), 1.9 (s, 3H), 1.45—1.54 (m, 18H), 0.92 (d, J = 16 Hz, 9H), 0.10 (d, J = Hz, 6H).

LCMS: tR=1.467, 523 .55[M+Na] Intermediate 184: 2S 5R -meth 15- tert-but ldimeth lsil 10X amino h [-1 2 5 6- tetrahydropyridine-Z-carboxylate HN NO,TB8 To a solution of (2S, 5R)—l—tert—butyl 2—methyl 5—(tert—butoxycarbonyl(tert— butyldimethylsilyloxy)amino)—3—methyl—5,6—dihydropyridine— l ,2(2H)—dicarboxylate (Intermediate 183, 20 g, 40 mmol) in DCM (200 mL) was added ZnBrz (35.5 g 160 mmol) at 0 OC. The resulting solution was stirred at room temperature overnight. The solid was removed through filtration. The filtrate was washed with ted NaHC03 to neutralize pH to ~8, ted with DCM, dried over NaZSO4, filtered and concentrated. The crude product was purified by ﬂash silica chromatography, eluting with 0 to l% MeOH in DCM to give product (8.4 g, 70%) as a brown oil. 1H—NMR(CDC1;, 400 MHz): 5 5.59—5.62 (m, 1H), 3.82 (s, 1H), 3.75 (s, 3H), 3.14—3.23 (m, 2H), 2.92—2.97 (m, 1H), 1.79 (s, 3H), 0.90 (s, 9H), 0.10 (s, 6H).

LCMS: tR=l.O73, 301.2[M+H] ediate 185: meth 1 2S 5R tert-but l dimeth 1 Si] 1 0X meth l0X0-1 6- diazabic clo 3.2.1 0ctenecarb0X late \o I. \ o \OTBS To a solution of (2S,5R)—methyl 5—(tert—butyldimethylsilyloxyamino)—3—methyl—l,2,5,6— tetrahydropyridine—2—carboxylate (Intermediate 184, 42 g, 140 mmol) in MeCN (840 mL) was added DIEA (72.2 g 560 mmol) and degassed with nitrogen, then a solution of triphosgene (16.408 g, 56 mmol) in MeCN (120 mL) was added dropwised at 0 i 5 °C under nitrogen. The resulting solution was stirred at room ature under nitrogen overnight.

The reaction e was concentrated, then added EtOAc and washed with lN citric acid, ted NaHC03 and brine, dried over NaZSO4, filtered and concentrated. The crude product was purified by flash C—lS chromatography, eluting with 0 to 38% MeCN in H20 to give product (22 g, 49%) as an orange solid.

(CDC1;, 400 MHz): 5 6.15 (t, J = 1.6 Hz, 1H), 4.412 (s, 1H), 3.807 (s, 3H), 3.610— 3.629 (m, 1H), 3.506 (d, J: lle, 1H), 3290-3322011, 1H), 1.722 (s, 3H), 0.962 (s, 9H), 0.195 (s, 3H) 0.172 (s, 3H) LCMS: tR=l.585, 327.35[M+H] ediate 186: 2S 3R amin0meth l entenamide h dr0ch10ride HZNJI’“N NHZHCI To a solution of (Intermediate 177, 75.2 kg, 322.8 mol, 1.0 eq.) in THF (600 L) was added CDI (61.9 kg, 382.1 mol, 1.2 eq.) in batches at 20i10 OC. The mixture was stirred for 2 h at 20i10 OC. The mixture was cooled to —40i5 OC. NH3‘HZO (43.55 kg, 640.4 mol, 2.0 eq., 25 wt.%) was added dropwise at —40i5 OC. The e was stirred for 10 min at —40i5 0C.

After completion of the reaction, it was warmed to —10~0 0C, then concentrated under vacuum to ~ 3.0 vol. THF (2.0 vol) was added and concentrated under vacuum to ~ 3.0 vol.

THF was swapped with EtOAc (2.0 vol) two times. EtOAc (6.0 vol) was added to the solution, and cooled to 5i5 OC. MCSO3H (148.3 kg, l543.0 mol, 2.4 eq.) was added dropwise at <10 OC, and stirred for l h at 5i5 OC. The mixture was centrifuged, and the resultant solid cake was washed with EtOAc (1.0 vol) two times. The mother liquor was collected to afford the compound in EtOAc solution, which was used directly in the next step. HCl (gas) was bubbled into the solution at 0i5 °C for 17 h (~4 kg/h). After completion of the reaction, the mixture was centrifuged and the resultant solid cake was washed with EtOAc (1.0 vol) two times. The cake was dried over under vacuum at 25i5 °C for at least 12 h to afford the title nd as a light yellow solid (98 kg, 90% overall yield from 2 . 1H NMR1400 MHz= DMSO): 6 8.24 (s, 2H), 8.00 (s, 1H), 7.56 (s, 1H), 5.84-5.76 (m, 1H), .17-5.09 (m, 2H), 3.70-3.68 (m, 1H), 2.77-2.72 (m, 1H), 1.04 (d, J: 6.8 Hz, 3H).

Intermediates 187 and 188: all 1 2S 3R amin0meth l0x0 enten l and tert-but lall 1 2S 3R amin0meth l0x0 enten lcarbamate O : O : L, 3 4'“ E HN\/\ BOO/NA To a solution of LiOH (27.55 kg, ll47.9 mol, 2.0 eq.) in DMF (285 L) was added Intermediate 186 (95 kg, 564.67 mol, l.0 eq.) in batches at 0i5 OC. The mixture was stirred for 0.5 h. Allyl bromide (76.76 kg, 634.5 mol, l.l eq.) was added dropwise for 9 h at 0i5 0C.

The reaction mixture was warmed to 20i5 °C and stirred for at least 8 h. The reaction mixture was cooled to 10i5 °C and soft water was added (3.0 vol). The mixture was extracted with DCM (3.0 vol) three times. The combined organics were washed with brine (2.0 vol). The brine layer was extracted with DCM (3.0 vol). The combined organic layers were concentrated under atmospheric re at < 60 °C to ~ 5.0 vol. t—Butyl alcohol (2.0 vol) was added to the solution and concentrated under vacuum at < 60 °C to ~ 5.0 vol. The concentration with t—butyl alcohol (2.0 vol) was repeated once more until the water content .2% to afford Intermediate 187. t—Butyl l (8.0 vol) was added to the concentrated solution. BoczO (138.07 kg, 633.3 mol, 1.1 eq.) was added at 20i5 OC. The mixture was warmed to 70i5 °C and stirred for at least 15 h. After tion of the reaction, the mixture was cooled to 40i5 0C, then concentrated under vacuum at < 60 °C to ~ 5 vol. The concentrated mixture was cooled to 25i5 OC, and soft water (5.0 vol) was added. The e was extracted with methyl t—butyl ether (4.0 vol) two times. The combined organics were washed with 0.5 M HCl solution (2.0 vol) once, brine (1.0 vol) three times and concentrated under vacuum at <50 °C to ~ 2.0 vol. ane (1.0 vol) was added to the reactor and concentrate under vacuum at <50 °C to ~20 vol. This was repeated once more. n—Heptane (1.0 vol) was added to the concentrated solution, cooled to —10i5 °C and stirred for at least 2 h. The mixture was centrifuged and the resultant solid cake washed with cooled n—heptane (0.5 vol). The cake was dried at 25i5 °C under vacuum for at least 12 h to afford Intermediate 188 as a white solid (84.2 kg, 100% purity, 54.4% overall yield from 2 steps). 1H NMR1400 MHz= DMSO): 6 7.42 (s, 1H), 6.95 (s, 1H), 5.78-5.70 (m, 2H), 5.11-4.98 (m, 4H), 4.33 (d, J = 10.8 Hz, 1H), 3.92-3.78 (m, 2H), 2.70 (br, 1H), 1.41 (s, 9H), 0.88 (d, J = 6.4 Hz, 3H). LC/MS (ES+) m/z 169.2 (M + H) Intermediates 189: 2S 5R -tert-but 15- tert-butox carbon 1 h dr0x amino carbamo lmeth l-5 6-dih dr0 ridine-l 2H -carb0x late I N Md N ,B To a solution of ediate 188 (81.0 kg, 301.8 mol, 1.0 eq.) in DCM (810 L) was added Grubb’s catalyst, 1St generation (1.215 kg, 1.5 mol, 0.005 eq.) in 3 batches at 0i5 OC. The reaction e was stirred for 1 h at 0i5 0C, then warmed to 25i5 °C and d for 1 h.

The mixture was cooled to 0i5 °C and more catalyst (1.215 kg, 1.5 mol, 0.005 eq.) was added in 3 batches at 0i5 OC. The mixture was warmed to 25i5 °C and stirred for at least 8 h.

After completion of the reaction, CuCl (1.46 kg, 14.8 mol, 0.05 eq.), BocNHOH (59.94 kg, 450.7 mol, 1.5 eq.) and pyridine (0.31 kg, 3.9 mol, 0.013 eq.) were added to the solution at 25i5 OC. The e was stirred for at least 43 h at 25i5 °C under oxygen atmosphere.

Once the reaction was complete, EDTAzNa solution (5.0 vol) was added to the reactor and stirred for at least 4 h at 25i5 OC. The layers were separated and the aqueous extracted with DCM (3.0 vol) two times. The organics were combined and concentrate under vacuum at <40 °C to ~30 vol. Methyl t—butyl ether (MTBE) (2.0 vol) was added to the reactor and concentrated under vacuum at <40 °C to ~30 vol. This was repeated once more. MTBE (2.5 vol), n—heptane (2.5 vol) and soft water (5.0 vol) were added to the concentrated solution and the mixture was slurried at 20i5 °C for at least 2 h. The mixture was centrifuged and the cake was washed with MTBE/n—heptane (0.5 vol, 1:1). The cake was dried under vacuum at 35i5 °C for at least 12 h until the water content 31% to afford the title compound as a light—brown solid (70.3 kg, 98% purity, 61.3% l yield from 2 steps). 1H NMR1400 MHz= DMSO): 6 8.93-8.78 (m, 1H), 7.49 (s, 1H), 7.07 (s, 1H), 5.57(s, 1H), 4.62-4.41 (m, 2H), .50 (m, 2H), 1.79 (s, 3H), 1.43 (s, 1H), 1.40 (s, 9H). LC/MS (ES+) m/z 272.2 (M + H) Intermediates 190 and 191: tert-but 1 3R 6S tert-butox carbon 1 tert- but ldimeth lsil 10x amino carbam0 l-S-meth l-3 6-dih dr0 ridine-l 2H - carbox late and 2S 5R tert-but ldimeth lsil 10x amino meth [-1 2 5 6- tetrah dr0 ridinecarb0xamide JlI, I H2N ['6‘ \ and HzNJII" /N ,B00 HN 800 N N,OTBS OTBS H To a solution of Intermediate 189 (50 kg, 134.6 mol, 1.0 eq.) and imidazole (18.5 kg, 268.1 mol, 2.0 eq.) in DCM (500 L) was added TBS—Cl (30.5 kg, 202.0 mol, 1.5 eq.) in DCM on (1.5 vol) se at 0i5 °C over 4.5 h. The mixture was warmed to 20i5 °C and stirred for at least 5 h. After completion of the on, soft water (250 L, 5.0 vol) was added. The layers were separated and the aqueous extracted with DCM (3.0 vol). The combined organic layers were washed with soft water (3.0 vol) two times, then concentrated under atmospheric distillation at <50 °C to ~20 vol. DCM (200 L, 4.0 vol) was added to the solution and concentrated under atmospheric distillation at <50 °C to ~20 vol, until the water t was 31%, affording Intermediate 190. DCM (750 L, 15.0 vol) was added to the solution with stirring at 20i5 0C under nitrogen atmosphere. ZnBrz (60.5 kg, 268.9 mol, 2.0 eq.) was added to the solution and stirred for 6 h at 20i5 0C. More ZnBrz (30.5 kg, 135.6 mol, 1.0 eq.) was added to the reaction mixture ever 6—8 hours until the reaction was complete (~5 eq total of ZnBrz). The reaction was ed with NaHC03 (113.0 kg, 1345.2 mol, 10.0 eq.) solution (18.0 vol) by addition below 20 OC. The mixture was stirred for at least 1 hour at 20i5 0C, then centrifuged, and the liquor collected. The ant solid cake was slurried with dichloromethane (5.0 vol) at 20i5 °C for 1 h, then centrifuged. The liquor was combined with the previous liquor and the layers ted. The aqueous was extracted with DCM (3.0 vol) two times. The combined organics were washed with soft water (4.0 vol) four times, then concentrated the under normal re at <50 °C to ~20 vol. CH3CN (2.0 vol) was added to the solution and concentrate under vacuum at <50 °C to ~40 vol to afford Intermediate 191 in solution.

LC/MS: (ES+) m/z 282.2 (M + H) Intermediate 192: 2S 5R tert-but ldimeth lsil 10x meth l0x0-1 6-diaza- bicyc10|3.2.1 -enecarb0xamide o \OTBS To a solution of Intermediate 191 (38.43 kg in theory, 134.6 mol, 1.0 eq.) in CH3CN (1036 L, 27 vol) was added DIEA (69.56 kg, 539.2 mol, 4.0 eq.) at 20i5 OC. The e was cooled to 0i5 OC, and triphosgene (13.07 kg, 44.0 mol, 0.33 eq.) in CH3CN (115.2 L, 3.0 vol) was added dropwise. The mixture was warmed to 25i5 °C and stirred for at least 8 h, then cooled to 10i5 OC, and quenched with soft water (24.19 kg, 1343.9 mol, 10.0 eq.). The mixture was stirred for at least 1 h, then concentrated under vacuum at <40 °C to ~50 vol.

The solution was cooled to 10i5 °C and MTBE (3 84 L, 10 vol) and brine (4.0 vol) were added. The layers were separated, and the organics washed with brine (4.0 vol), and concentrated under vacuum at <40 °C to ~20 vol. The MTBE was swapped with n—heptane (1.0 vol) and the solid slurried for 1 h at 20i5 OC. The mixture was centrifuged and the cake washed with n—heptane (0.5 vol) two times. The cake was slurried in MTBE (67.5 L) for at least 3 h at 20i5 0C, then n—heptane (336 L) was added with stirring for at least 1 h. The mixture was centrifuged and the resultant solid cake washed with n—heptane (1.0 vol). The cake was dried under vacuum at 30i5 °C for 12 h to afford the title compound as a light— brown solid (21.1 kg, 99.6% purity, 49.6% l yield from 3 steps). 1H NMR {400 MHz, DMSO): 5 7.80 (s, 1H), 7.33 (s, 1H), 6.06 (t, J = 2 Hz, 1H), 4.10 (s, 1H), 3.71—3.69 (m, 1H), 3.65 (d, J: 10.8 Hz, 1H), 3.10 (dd, J: 10.8 Hz, 2.0 Hz, 1H),1.63 (s, 3H), 0.92 (s, 9H), 0.14 (d, J = 0.8 Hz, 1H). LC/MS (ES+) m/z 312.2 (M + H) Intermediate 193: 2S 5R -tert-but 15- tert-but0x carbon 1 h dr0x amino carbam0 l meth l-5 6-dih dr0 -1 2H -carb0x late HZNJI, \ To a solution of Intermediate 192 (18.5 kg, 59.4 mol, 1.0 eq.) in EtOAc (92.5 L, 5 vol) was added HF‘Py (2.04 kg, 71.4 mol, 1.2 eq., 70 wt.%) at 0i5 OC. The mixture was stirred for at least 10 h at 20i5 0C, then cooled to 0i5 °C and additional HF‘Py (0.33 kg, 11.6 mol, 0.2 eq., 70 wt.%) was added. The e was d for at least 3 h at 20i5 0C, then MTBE (27.8 L, 1.5 vol) was added and stirred for 3 h at 10i5 OC. The mixture was centrifuged and the cake washed with EtOAc (0.5 vol). The cake was slurried with EtOAc (2.0 V) for at least 1 h at 20i5 0C, then centrifuged. The cake was slurried with EtOAc (0.5 vol), then dried under vacuum at 25i5 °C for 12 h to afford the title compound as a yellow solid (11.0 kg, 99.5% purity, 91% yield). 1H NMR1400 MHz, DMSO): 6 9.56 (s, 1H), 7.79 (s, 1H), 7.32 (s, 1H), 6.10 (d, J: 3.2 Hz, 1H), 4.06 (s, 1H), 3.68-3.62 (m, 2H), 3.07 (d, J: 8.4 Hz, 1H), 1.61 (s, 3H). LC/MS (ES+) m/z 198.1 (M + H) Intermediate 194: eth l S E tert-but lsulfin l imin0 acetate N \ “k To a solution of ethyl 2—oxoacetate (66 mL, 321 mmol, 50% in toluene) in DCM (1 L) at 0°C was added (S)—2—methylpropane—2—sulfinamide (30 g, 248 mmol) and molecular sieves (4,51, 500 g). The resulting solution was stirred at room temperature for 18 hours. Molecular sieves were removed by filtration; filtrate was concentrated by distillation under vacuum to give a crude t, which was purified by flash silica chromatography (0% to 5% EtOAc in eum ether) to give a colorless oil, 45 g, 88%. 1HNMR1400MHZ,CDC13): 81.28 (s, 9H), 1.39 (t, J = 12 Hz, 3H), 4.38 (q, J = 12 Hz, 2H), 8.01 (s, 1H).

Intermediate 195: eth l S S -tert-but lsulfin l meth [-1 2 3 6- tetrahydropyridine-Z-carboxylate Eto/l’mg/CiO¢$,N To a solution of (S,E)—ethyl 2—(tert—butylsulfinylimino)acetate (Intermediate 194, 50 g, 244 mmol) in DCM (600 mL), at —78°C was added isoprene (97.21 mL, 971.91 mmol), followed by addition of TMSOTf (97.42 mL, 416.54 mmol). The resulting on was stirred at —78°C for 3 hours and quenched slowly at —78°C with phosphate buffer solution (pH=7.4, 1 L). After warming to room temperature, the mixture was extracted with DCM (3 x 500 mL).

The combined organic extracts were washed with water (2 x 500 mL) and brine. The organic layer was dried over Na2S04, filtered and evaporated to afford 60 g of crude product as a brown oil. The product was used in the next step without further cation. 1HNMR z, d6-DMSO): 51.08(s, 9H), 1.18 (t, J = 12 Hz, 3H), 1.64 (q, J = 4 Hz, 3H), 3.59 (m, 2H), 4.11 (dq, J = 12, 4 Hz, 2H), 4.30 (dd, J: 8,4 Hz, 1H), 5.39 (ddd, J: 4,8 4 Hz, LCMS: (ES+) [M+H]+ = 274; HPLC tR=1.78 min.

Intermediate 196: 1- ut l 2-eth l S meth l-3 6-dih dr0 ridine-1 2 2H - dicarboxylate Eto/l’“‘? Boc/0/ To a on of the crude hyl 1—((S)—tert—butylsulfinyl)—4—methyl—1,2,3,6— tetrahydropyridine—2—carboxylate (Intermediate 195, 100 g) in MeOH (1 L) at 0°C was added hydrogen chloride (100 mL, 4M in dioxane). The resulting solution was stirred at room temperature for 18 hours. MeOH and HCl/dioxane were d by distillation under vacuum to give a crude product, which was dissolved in water (1 L) and extracted with EtOAc (3 x 500 mL). The pH of the aqueous solution was adjusted to 7 with solid NaHCOg.

The aqueous was extracted with EtOAc until LCMS showed no product detected. The c phases were combined and dried over NaZSO4, filtered and concentrated to afford crude product (30 g, 177 mmol) as a light yellow oil. The oil was dissolved in THF (500 mL) and cooled by ice—water bath. To the cooled solution was added a solution of sodium bicarbonate (22.3 g, 265.5 mmol) in water (500 mL), followed by di—tert—butyl dicarbonate (57.8 g, 265.5 mmol). The resulting solution was stirred at room ature for 18 hours.

The two layers were separated. The s layer was extracted with ethyl acetate. The combined organic layers were dried over NaZSO4, filtered and evaporated. Crude product was purified by ﬂash silica chromatography (0%—30% EtOAc in PE) to afford the title compound 47.5 g, 43% yield from Intermediate 194. 1HNMR1400MHZ, CDCl3 ): 8 1.24 (t, 3H), 1.50 (m, 9H), 1.71 (s, 3H), 2.46 (m, 2H), 3.73 (m, 1H), 4.10 (m, 3H), 4.95 (m, 1H); LC—MS: (ES+) [M+Na]+ = 292; HPLC tR=1.71 min. ediate 197: tert-but l S carbam0 lmeth l-3 6-dih dr0 ridine-l 2H - carboxylate HO/l"‘? To a solution of 1—(tert—butyl) l (S)—4—methyl—3,6—dihydropyridine—1,2(2H)— dicarboxylate (Intermediate 196, 47.5 g, 176 mmol) in THF (1000 mL) and water (500 mL) at 0°C was added dropwise lithium hydroxide (1 M, 440 mL, 440 mmol). The reaction mixture was warmed to room temperature and d for 16 hours. Solvent was removed; residue was diluted with water. The pH of the solution was adjusted to ~3 with HCl (1N) solution. The mixture was extracted with EtOAc (3 x 300 mL). c layers were combined, washed with water and brine, dried over MgSO4, filtered and concentrated to give a colorless oil, 40.3 g. 1HNMR1300MHZ, d6-DMSO): 8 1.38 (m, 9H), 1.64 (s, 3H), 2.53(m, 2H), 3.68 (m, 3H), 4.73 (m, 1H), 5.35 (dd, J=3, 15Hz, 1H), 12.45(s, 1H); LCMS: (ES+) [M+Na]+ =264; HPLC tR=1.01 min.

Intermediate 198: ut l S carbam0 lmeth l-3 6-dih dr0 -1 2H - carboxylate To a solution of (tert—butoxycarbonyl)—4—methyl—l,2,3,6—tetrahydropyridine—2— carboxylic acid (Intermediate 197, 40.3 g, 167.2 mmol) in THF (500 mL) at 0°C was added N,N’—carbonyldiimidazole (32.5 g, 200.6 mmol) in portions. The crude was stirred at 0°C for hours. Then ammonium acetate (38.2 g, 502.9 mmol) was added. The reaction was stirred at room temperature for an additional 18 hours, quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over NaZSO4, filtered and concentrated. Crude product was purified by ﬂash silica chromatography (0%— % EtOAc in PE) to give a white solid, 25 g, 62%. 1HNMR (400MHz, d6-DMSO): 5 1.41 (s, 9H), 1.66 (s, 3H), 2.35 (s, 2H), 3.84 (m, 2H), 4.66 (m, 1H), 5.35 (m, 1H) 6.96 (s, 1H), 7.19 (s, 1H); LCMS: (ES+) [M+Na]+ = 263; HPLC tR=0.86 min. ediate 199: tert-but 1 3R 6S tert-but0X carbon 1 h dr0X amino carbam0 lmeth l-3 6-dih dr0 ridine-1 2H -carb0X late HZNJI"‘1 BOC CCN/OH To a solution of tert—butyl (S)—2—carbamoyl—4—methyl—3,6—dihydropyridine—l(2H)—carboxylate (Intermediate 198, 25g, 104.1 mmol) in DCM (250 mL) was added BocNHOH (70.6 g, 530.9 mmol), CuCl (6.1 g, 62.5 mmol) and pyridine (106.9 mg, 1.3 mmol). The resulting solution was stirred at room temperature for 44 hours under oxygen. The solids were removed by filtration. The filtrate was washed with water (6 X 500 mL) and brine, dried over , filtered and concentrated. The crude product was purified by ﬂash silica tography (0%—50% EtOAc in PE) to give the title compound as a white solid, 40% yield. Starting material was recovered (10 g). The same procedure was ed three times to afford 15 g of product in total.

LCMSZ (ES+) [M+Na]+ = 394 (C17H29N3O6) Intermediate 200: tert-but 1 3R 6S tert-butox carbon 1 tert- but ldimeth lsil 10x amino carbam0 lmeth 1-3 6-dih dr0 ridine-1 2H - carboxylate To a solution of tert—butyl (3R,6S)—3—((tert—butoxycarbonyl)(hydroxy)amino)—6—carbamoyl—4— methyl—3,6—dihydropyridine—1(2H)—carboxylate (Intermediate 199, 12 g, 32.3 mmol) in DCM (96 mL) at 0 iSOC was added imidazole (4.4 g 64.6 mmol). The resulting solution was stirred at room temperature for 10 mins, then TBS—Cl (4.8 g, 32.3 mmol) in DCM (10 mL) was added dropwise. The reaction mixture was stirred at 0°C for an additional 18 hours, washed with water and brine, dried over , filtered and concentrated. The crude product was ed by flash silica tography (0%—20% EtOAc in PE) to afford the title compound as a white solid, 10 g, 63%.

LCMSZ (ES+) 486 (C23H43N3O6SI) To a solution of utyl (3R,6S)—3—[tert—butoxycarbonyl—[tert—butyl(dimethyl)silyl]oxy— —6—carbamoyl—4—methyl—3,6—dihydro—2H—pyridine—1—carboxylate (Intermediate 200, 21.7 g, 44.68 mmol) in DCM (250 mL) at 0°C was added zinc bromide (40.24 g, 178.71 mmol). The ing suspension was allowed to warm to room temperature and stir ~ 66 hours. The reaction mixture was cooled by ice—water bath, to which a slurry of NaHC03 (38.23 g, 10 equivalent) in water (300 mL) was added. The resulting mixture was stirred for 1 hr. Solid was removed by filtration and washed 3—4 times with DCM until no product was detected from the rinsing solution. The two layers from the filtrate were separated. The aqueous layer was extracted with DCM three times (until no product was detected from s layer). The combined DCM solution was concentrated to remove most of the solvent. The residue was partially dissolved in 10% MeOH in DCM and was loaded onto a short silica gel pad and eluted with 10% MeOH in DCM. The filtrate was evaporated and dried under vacuum to give a yellow foam solid (crude 9.9 g, 77%).

M_SZ 286 ES+ (C13H27N3Ole) Intermediate 202: 2S 5R tert-but ldimeth lsil 10x meth l0x0-1 6- diazabic clo 3.2.1 0ctenecarb0xamide 0 OTBS To a clear solution of (3R,6S)—3—[[tert—butyl(dimethyl)silyl]oxyamino]—4—methyl—1,2,3,6— tetrahydropyridine—6—carboxamide (Intermediate 201, 7.66 g, 26.83 mmol) in MeCN (150 mL) and DCM (200 mL) at 0°C was added N,N’—diisopropylethylamine (19.11 mL, 107.34 mmol) followed by a solution of triphosgene (2.71 g, 9.12 mmol) in MeCN (50 mL) dropwise (2 mL/hour by a syringe pump). After addition, the solution was allowed to warm to room ature and stirred overnight. The reaction mixture was concentrated to dryness.

The resulting residue was diluted with EtOAc and washed with brine. The aqueous layer was extracted with EtOAc. The combined c ts were dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography (0%—100% EtOAc/ ) to give the title compound as a white solid 4.36 g, 52%.

M_SZ 312 ES+ (C14H25N303Sl) Intermediate 203: 28 SR h dr0x meth l0x0-1 6-diazabic clo 3.2.1 0ctene carboxamide o N‘OH To a solution of (ZS,5R)—5—(((tert—butyldimethylsilyl)oxy)amino)—4—methyl—1,2,5,6— tetrahydropyridine—2—carboxamide (Intermediate 202, 165.mg, 0.53 mmol) in ethyl acetate (4 mL) at 0 °C was added HF—pyridine (0.02 mL, 0.64 mmol). The on mixture was warmed to room ature and stirred for 1 hr. Only a small amount of product was observed. r equivalent of HF—pyridine was added and the reaction mixture was stirred for 3 hrs. The reaction mixture was concentrated to afford an orange solid.

M_S: 198 ES+ (C8H11N3O3) Exam le 35: 2R -iso r0 12- 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x ﬂu0r0acetate To a solution of (2S,5R)—6—hydroxy—4—methyl—7—oxo—l,6—diazabicyclo[3.2. l]oct—3—ene—2— carboxamide mediate 203, 582 mg, 2.95 mmol) in l,4—dioxane (16 mL) and DMF (2 mL) was added isopropyl (2R)—2—bromo—2—ﬂuoro—acetate (Intermediate 169, 881.1 mg, 4.43 mmol). The reaction mixture was cooled to 0 °C and DBU (0.44 mL, 2.95 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes, then diluted with ethyl acetate and washed with 1:1 brine water twice. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%—90% ethyl acetate/hexanes) afforded a white foam. The foam was ved in 1:1 acetonitrilezwater, frozen and lized to afford a white solid, 614 mg, 66%. There is 6% of the S—diastereomer present.

M_SZ 316 ES+ (C13H18FN305) 1H NMR1300 MHz, DMSO—dg) 5: 1.22 (m, 6H); 1.81 (m, 3H); 3.17 (m, 1H); 3.34 (m, 1H); 3.93 (m, 1H); 4.22 (m, 1H); 5.01 (m, 2H); 5.51 (m, 1H); 6.23 (m, 1H); 7.31 (s, 1H); 7.55 (s, Exam le 90: eth 12- 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0ct enyl[oxyzdiﬂu0r0acetate H2N "13/N F }—N\ F O V To a solution of (2S,5R)—6—hydroxy—4—methyl—7—oxo—l,6—diazabicyclo[3.2. l]oct—3—ene—2— carboxamide mediate 203, 64.5 mg, 0.33 mmol) and ethyl iﬂuoroacetate (0.13 mL, 0.98 mmol) in DMF (3 mL) at room temperature was added potassium carbonate (135.62 mg, 0.98 mmol). The mixture was stirred for ~3 hours, then diluted with ethyl acetate and filtered. The filtrate was combined with a previous small batch, washed twice with 1:1 brinezwater, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%—80% ethyl acetate/hexanes) afforded the title nd (52.1 mg, 34%) as an orange solid after lyophilization.

M_S: 320 ES+ (C12H15F2N305) 1H NMR1300 MHz, DMSO—dg) 5: 1.29 (t, 3H); 1.82 (m, 3H); 3.36 (m, 2H); 3.94 (m, 1H); 4.31 (m, 1H); 4.39 (m, 2H); 5.57 (m, 1H); 7.36 (s, 1H); 7.59 (s, 1H).

Exam le 91: 2- 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0cten 1 0x -2 2-diﬂu0r0acetic acid lithium salt HZN \ O}— ,OJerHFN To a solution of ethyl 2—(((2S,5R)—2—carbamoyl—4—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3— en—6—yl)oxy)—2,2—diﬂuoroacetate (Example 90, 46 mg, 0.14 mmol) in THF (2 mL) and water (0.50 mL) at 0 °C was added 1M m hydroxide (0.14 mL, 0.14 mmol). The reaction e was stirred at 0 °C for 10 minutes. Another 0.2 eq. of lithium hydroxide was added, and after 5 minutes the reaction mixture was neutralized with 0.5N hydrochloric acid, and the THF evaporated. The resulting on was frozen and lyophilized. Gilson purification (Synergi Polar RP 21.2 mm x 100 mm, 4 um coupled with YMC C30 20 mm x 150 mm, 5 um, 0%—16% acetonitrile/water, 6 min) afforded the title compound (27.2 mg, 64.8%) as an off—white solid.

M_S: 292 ES+ (C10H11F2N305) 1H NMR 300 MHz DMSO-dg) 8: 1.81 (m, 3H); 3.30 (m, 2H); 3.84 (m, 1H); 4.20 (m, 1H); .48 (m, 1H); 7.29 (s, 1H); 7.55 (s, 1H).

Exam le 92: eth 12- 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0ct enyl 20x! [acetate Oko/W/OV To a solution of (ZS,5R)—6—((tert—butyldimethylsilyl)oxy)—4—methyl—7—oxo—1,6—diazabicyclo— ]oct—3—ene—2—carboxamide (Intermediate 202, 152 mg, 0.49 mmol) in THF (4mL) at 0 °C was added TBAF (0.49mL, 0.49 mmol). The mixture was stirred for ~10 minutes. To the reaction mixture was added ethyl bromoacetate (0.05 mL, 0.49 mmol) and stirred for 10 minutes. More ethyl bromoacetate (0.05 mL, 0.49 mmol) was added and stirred 30 s.

Additional ethyl cetate (0.05 mL, 0.49 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The on mixture was concentrated onto silica gel and purified (0%—90% ethyl acetate/hexanes) to afford a colorless oil. The oil was dissolved in 1:1 acetonitrilezwater, frozen and lized to afford the title compound as a white solid, 78.5 mg, 56%.

M_S: 284 ES+ (C12H17N305) 1H NMR1300 MHz= DMSO-dg) 8: 1.23 (t, 3H); 1.84 (m, 3H); 3.19 (m, 2H); 3.97 (m, 1H); 4.17 (m, 3H); 4.53 (m, 2H); 5.46 (m, 1H); 7.29 (s, 1H); 7.50 (s, 1H).

Exam le 93: 2- 2S 5R carbam0 lmeth l0x0-1 6-diazabic clo 3.2.1 0cten 1 0x acetic acid m salt HZN \ O o/\n/OH To a solution of ethyl 2—(((2S,5R)—2—carbamoyl—4—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3— en—6—yl)oxy)acetate (Example 92, 57.4 mg, 0.2 mmol) in THF (2 mL) and water (1 mL) at 0 0C was added 1M lithium hydroxide (0.66 mL, 0.66 mmol). The reaction mixture was stirred at 0 0C for 10 minutes. Another 0.2 equivalents of lithium ide was added and after 10 minutes the reaction is complete. The on mixture was neutralized with 0.5N hydrochloric acid and 1 eq of sodium bicarbonate in water was added at 0 OC. The resulting solution was frozen and lyophilized. Gilson purification (0%—16%, 6 min) afforded the title compound as a white solid, 18.3 mg, 35%.

M_S: 256 ES+ (C10H13N305) 1H NMR1300 MHZ, DMSO-dg) 5: 1.85 (m, 3H); 3.11 (m, 2H); 3.88 (m, 2H); 4.07 (m, 1H); 4.24 (m, 1H); 5.39 (m, 1H); 7.24 (s, 1H); 7.48 (s, 1H).

Intermediate 204: 2S 5R ut ldimeth lsil 10x h l0x0-1 6- diazabic clo 3.2.1 0ctenecarb0nitrile The title compound was prepared from (ZS,5R)—6—((tert—butyldimethylsilyl)oxy)—4—methyl—7— oxo—1,6—diazabicyclo[3.2.1]oct—3—ene—2—carboxamide (Intermediate 202, 0.205 g, 0.66 mmol) according to the procedure for Intermediate 139 to afford the title compound (159 mg, 82%) as a white solid.

M_S: 294 ES+ (C14H23N302Si) Exam le 94: eth 1 2R 2S 5R c an0meth l0x0-1 6-diazabic clo 3.2.1 oct- 3-en 10x ﬂu0r0acetate The title compound was ed from (2S,5R)—6—((tert—butyldimethylsilyl)oxy)—4—methyl—7— 6—diazabicyclo[3.2.1]oct—3—ene—2—carbonitrile (Intermediate 204, 152 mg, 0.49 mmol) according to the alternate procedure for Example 35 to afford (26.9 mg, 19%) a colorless oil.

There was approximately 9% S—diastereomer present.

M_S: 284 ES+ (C12H14FN304) 1H NMR1300 MHZ, DMSO-dg) 5: 1.09 (t, 3H); 1.72 (m, 3H); 3.26 (m, 2H); 3.97 (m, 1H); 4.11 (m, 2H); 4.94 (m, 1H); 5.30 (m, 1H); 6.16 (m, 1H).

Exam le 95: 2R 2S 5R c an0meth l0x0-1 6-diazabic clo 3.2.1 0cten- 6- 1 0x ﬂu0r0acetic acid lithium salt ,,Cf\ The title compound was prepared from ethyl (2R)—2—(((2S,5R)—2—cyano—4—methyl—7—oxo—1,6— diazabicyclo[3.2. 1]oct—3—en—6—y1)oxy)—2—ﬂuoroacetate (Example 94, 22 mg, 0.08 mmol) ing to the procedure for Example 91 to afford (3.8 mg, 15%) a light yellow solid.

M_S: 256 ES+ (C10H10FN304) 1H NMR1300 MHz, DMSO-dg) 8: 1.81 (m, 3H); 3.30 (m, 2H); 4.00 (m, 1H); 4.92 (m, 1H); .27 (m, 1H); 5.28 (m, 1H).

Exam le 96: is0 1'0 12- 2S 5R carbam0 lmeth l0x0-1 6- diazabic clo 3.2.1 0cten 10x acetate 4—N\ o o 0/731/ T To a solution of (2S,5R)—6—hydroxy—4—methyl—7—oxo—1,6—diazabicyclo[3.2. 1]oct—3—ene—2— carboxamide (Intermediate 203, 93.38 mg, 0.47 mmol) and isopropyl bromoacetate (0.18 mL, 1.42 mmol) in DMF (4 mL) at room ature was added potassium carbonate (196.35 mg, 1.42 mmol). The reaction mixture was stirred for ~3 hours, then diluted with ethyl acetate and filtered. The filtrate was washed twice with 1:1 water, dried over ium sulfate, filtered and concentrated. Silica gel chromatography % ethyl acetate/hexanes) afforded the title compound as an ite solid after lyophilization in acetonitrile, 106.6 mg, 72%.

M_S: 298 ES+ (C13H19N305) 1H NMR1300 MHz= DMSO-dg) 5: 1.23 (m, 6H); 1.84 (m, 3H); 3.19 (m, 2H); 3.97 (m, 1H); 4.16 (m, 1H); 4.35 (m, 1H); 4.62 (m, 1H); 5.00 (m, 1H); 5.46 (m, 1H); 7.29 (s, 1H); 7.50 (s, BIOLOGICAL EXAMPLES Example 102: Inhibition of beta-lactamase Enzymes A buffer consisting of 0.1 M sodium phosphate (pH 7.0), 10 mM NaHCOg, and 0.005% Triton X— 100 was used for all enzymes. The chromogenic substrate nitrocefin (SynGene, Bangalore, India) was used at 100 MM. Enzyme activity was monitored by the 490 nm absorbance increase upon efin hydrolysis. Assays were performed in clear polystyrene 384—well plates (Greiner e, Monroe, NC). Absorbance was measured for 1 hour at 30— s als using a Spectramax absorbance plate reader (Molecular Devices, Sunnyvale, CA).

Measurement of beta—lactamase inhibition by INHIBITOR employed serial 3—fold dilutions of the inhibitor in assay buffer, ranging from 100 uM to 62.7 pM. A background absorbance progress curve for a control lacking enzyme and inhibitor was subtracted from each progress curve.

The te set of progress curves for one enzyme with all inhibitor concentrations was ted to numerical integration with the program Kintek Global Kinetic Explorer (Kintek Corp, oe PA) to obtain a best—fit to the ism shown in Scheme 10. k k E+S<;—1'ES<;—2’E+P k k -1 -2 E+I.—+_3>EI Scheme 10 where E, S, ES, P, I, and EI are the concentrations of the enzyme, nitrocefin, the enzyme— nitrocefin complex, the nitrocefin hydrolysis product, INHIBITOR, and the enzyme— INHIBITOR complex respectively. The ed value of Km(nitrocefin) was used to define the fixed values of k+1, k_1, and 19,2, where k+1 = k_1 = 1 and k+2 = Km—l. The values of 19,2, k+3, and k_3 were fit. Concentration series s of the absorbance measurements were used to correct for slight absorbance baseline differences between wells. The parameter k+3 is equivalent to the second order rate constant kinact/Ki. In some cases, the inhibition was in rapid equilibrium on the experimental time scale, so that only the ratio k_3/k+3 = K could be determined. Although k_3 represents reversal of tor binding in Scheme 10, hydrolysis of the enzyme—inhibitor complex could not be ed based on kinetic measurements.

Best—fit absorbance values from the above ure at each time point for each compound concentration were exported to Excel. To calculate the 60—min IC50, the % WO 53215 tion at each inhibitor concentration at 60 min was calculated based on the best—fit absorbance values at that time, using the equation % inhibition 2 100 x (1 — Ainhib/Amax) where A is the best—fit ance without inhibitor and Ainhib is the best—fit absorbance in the presence of the inhibitor. IC50 was calculated from the set of % inhibition values by nonlinear least—squares regression using the equation % inhibition = 100 [I]“/(IC50 + [1]“) where [I] is the inhibitor concentration and n is the Hill coefficient. The Excel add—in XLfit (ID Business Solutions) was used for nonlinear regression.

Table 1 lists IC50s of exemplar compounds (uM) Table 1 Class A Class C Class D Example TEM-l AmpC OXA-48 60 min IC50 (HM) 60 min IC50 (HM) 60 min IC50 (HM) 0.019 0.071 0.015 0.00135 0.011 0.015 0.0044 0.02 0.017 00 0.0015 0.012 0.014 >—‘>—‘ r—‘O 0.43 0% #N 0.051 0.23 l\)l\) l\)\l 0.047 0.018 93030) #030 0.081 0.14 0.0032 0.077 0.026 0 DJ 0.019 4k4> [\)>—‘ 0.0035 0.0064 0.024 0.0052 0.024 0.0073 0.093 0.22 0.057 0.41 O’\O’\ UJN 0.21 0.87 0.11 0.23 O\ O\ 0.66 0.012 O’\O\ OO\] 0.064 0.34 0.31 0.078 \]\]O\ r—‘OO 0.18 0.11 0.026 0.087 0.11 0.075 \]\] DJN 0.077 0.11 0.73 0.53 \l 4; 0.28 0.59 \]\l O’\Ul 0.083 0.42 0.94 0.22 0.085 0.054 0.033 0.00047 0.035 okN‘oﬁrm_E Comparator 98 Comparator 99 Exam le 103: Restoration of t of cef odoxime in resence of fixed concentration of 4 umeL of BLI The minimal inhibitory concentration (MIC) values against each organism and drug combination were determined using the Clinical and Laboratory Standards Institute guidelines (CLSI) broth microdilution methodology (CLSI M07—AlO). The ended quality l (QC) bacterial strains E. coli ATCC 25922, E. coli ATCC 35218 and Klebsiella pneumoniae ATCC 700603 were incorporated into each test according to the CLSI guidelines to assure that there was no variation between test dates (CLSI MlOO—S25). The MICs of these QC strains were within QC range on all test occasions. Drug containing plates were made using the master plate method. A cefpodoxime solution was prepared to 20X concentration and 2—fold serial dilutions were made in cation adjusted Mueller—Hinton Broth.

Equal volumes of 20X ar compounds at a fixed concentration were added to the master plate. lOuL was stamped into daughter plates using a Tecan EVO robot. Organism suspensions were ed to a 0.5 McFarland standard and further diluted to yield a final inoculum between 3x105 and 7x105 colony—forming units (CFU)/mL. Bacterial inocula were made in sterile, cation ed Mueller—Hinton Broth (Beckton son). An inoculum volume of l.lX concentration of 90 uL was added to wells (using a Tecan EVO robot). All inoculated microdilution plates were incubated in ambient air at 35 ° C for 18—24 hours.

Following incubation, the lowest concentration of the drug that prevented Visible growth as read at OD600 nm was recorded as the MIC (Table 2, all MICs are in ug/mL and all beta— lactamase inhibitors were tested at a fixed concentration of ).

Table 2 C. Klebsiella pneumoniae frezmdii SHV-18, AmpC, WT OXA-2, OXA-l, Beta-lactarnase content: (ATCC OKP-6 CTX-M- 25922) (ATCC , TEM-l 700603) Cefpodoxirne alone >64 1 >64 HNo >64 + 3 51 50.5 ,_1 0 U1 + 4 50.125 50.06 0.06 0.06 25 2 MN .PH + 27 <0.03125 <0.03125 <0.03125 25 4; >—* N 0-5 N p—A +33 <0.03125 50.03125 <0.03125 50.0625 <0.03125 <0-03125 50.125 50.0625 000024 0.25 0.01117 2 p—A 00039 l—‘N 0.063 +55 >32 0.0625 2 N U.) N <0-03125 0.125 0.0625 <0-0625 >—* 0.0625 <0-03125 50.0625 <0.03125 32 >32 +66 16 0.5 >32 #00 00 <0-03125 >32 #-l> OCH + 69 >32 0.25 16 4; 00 +71 0.25 0.5 N 4 #N-P 32 ND EGOH + 74 0.5 <0.03125 <0.03125 N 0.03125 <0-03125 0.125 <0.03125 >32 ._1 O\ >32 <0-03125 <0.03125 <0.03125 >32 >32 >32 p—A000 >32 <0-03125 <0.03125 <0-03125 25 <0-03125 <0.03125 <0-03125 <0.03125 + 91 50.03 50.03 50.03 50.03 + 93 50.03 50.03 50.03 50.03 + 95 32 0.25 p—A N N 0 Nbﬁw Comparator 97 ator 99 Exam le 104: Restoration of activit of various oral beta-lactams in resence of fixed concentration of 4 u mL of BL] Following the procedure from Example 103, MICs were determined for several beta—lactams in presence of a fixed concentration (4 ug/mL) of exemplar compounds (Table 3) against 3 Enterobacteriaceae strains.

Table 3 Compound C. frezmdii E. coli ella pneumomae AmpC, WT SHV— 18, OXA—2, TEM— 1 , (ATCC OKP—6 (ATCC CMY65 25922) 700603) Cefpodoxime >64 16 Ex. 3 (4ug/ml) 0.5 0.125 Cefpodoxime + Ex. 4 (4ug/ml) 30.125 £0.06 Cefpodoxime + Ex. 33 (4ug/ml) <0.03125 30.03125 oxime + Ex. 34 (4ug/ml) 25 30.03125 Cefpodoxime + Ex. 93 (4ug/ml) £0.06 £0.06 Ex. 3 (4ug/ml) 1 0.02 Ex. 4 (4ug/ml) 0.02 0.02 Cefuroxime + EX. 33 (4pg/ml) <0.03125 <0.03125 Cefuroxime + EX. 34 (4pg/ml) <0.03125 <0.03125 Tigemonam + 0.125 1 EX. 3 (4pg/ml) Tigemonam + £0.06 £0.06 .0 L11 EX. 4 (4pg/ml) Tigemonam + £0.06 £0.06 .o L11 EX. 33 (4pg/ml) Tigemonam + £0.06 £0.06 .0 LII EX. 34 (4pg/ml) Tigemonam + 0.125 0.125 >—‘ EX. 93 (4pg/ml) Tebipenem 0. 125 £0.06 Tebipenem + £0.06 £0.06 EX. 3 (4pg/ml) Tebipenem + £0.06 £0.06 EX. 4 (4pg/ml) nem + £0.06 £0.06 EX. 33 (4pg/ml) Tebipenem + £0.06 £0.06 EX. 34 l) Tebipenem + £0.06 £0.06 EX. 93 (4pg/ml) 0 (J1 Faropenem + 0.25 0.2 N00 EX. 3 (4pg/ml) Faropenem + £0.06 £0.06 *—‘ EX. 4 (4pg/ml) Faropenem + £0.06 £0.06 .0 LII EX. 33 (4pg/ml) Faropenem + £0.06 £0.06 .0 LII EX. 34 (4pg/ml) Faropenem + £0.06 £0.06 EX. 93 (4pg/ml) Cefixime >64 ll 0.5 Cefixime + EX. 3 1 0.125 .0 LII Cefixime + £0.06 £0.06 EX. 4 (4pg/ml) Cefixime + £0.06 £0.06 EX. 33 (4pg/ml) Cefixime + £0.06 £0.06 EX. 34 (4pg/ml) Cefixime + £0.06 £0.06 EX. 93 l) Loracarbef >64 N 03 l\) EX. 3 (4ug/ml) rbef + £0.06 £0.06 EX. 4 (4ug/ml) Loracarbef + £0.06 £0.06 EX. 33 (4ug/ml) Loracarbef + £0.06 £0.06 EX. 34 (4ug/ml) Loracarbef + £0.06 £0.06 EX. 93 (4ug/ml) Example 105: Stability/conversion in the absence or presence of metabolizing enzymes The human intestinal S9 with the absence of PMSF, human liver S9, rat intestinal S9, and rat liver S9 preparations were obtained from Xenotech (Lenexa, ).

The 500—uL incubation solution contained 0.8 mg/mL of enzyme (or no enzyme for buffer stability), 10uM of test compounds in 100mM of HEPES buffer, pH 7.4. The hydrolysis reactions were conducted in a l—mL glass insert (Analytical Sales, Pompton Plains, New Jersey) in a shake water bath at 37 0C. At 0, 2, 5, 10, 15, 30 and 60 min, the reaction was terminated by pipetting 50uL incubate to a 96 DeepWell plate (Thermo Fisher Scientific, Rochester, New York) containing 100uL of acetonitrile with mL of Carbutamide (Sigma—Aldrich, St. Louis, ri) as the internal standard. The crashed solutions were then vortexed well followed by centrifuge at 4000rpm for 15min at 4 OC. The extract was transferred to a new 96 DeepWell plate for MS analysis.

LC—MS/MS analysis was done using an AB Sciex QTrap 6500 mass spectrometer under positive ionization mode, coupled to a Schimadzu Nexera LC system.

A Waters Atlantis T3 (3pm, 3.0 X 50mm) column was used for separation. The mobile phase consisted 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B) with a ﬂow rate set at 1.2 mL/min. For the prodrug analysis, the Multiple Reaction Monitoring (MRM) specific for each compound was set up so that both prodrug and its hydrolyzed active can be monitored simultaneously.

Table 4 lists the first—order ives of the exemplar compounds (Tl/2 in minutes). Half— lives listed are based on disappearance of starting ester. As can be seen from Table 4, there is a good correlation between the rat and human s. The data in Table 4 tes that there is generally more rapid conversion of ester into the active compound by rat and human liver S9 enzymes, while the esters are inantly stable in the presence of buffer and intestinal S9.

Table 4 pH 7.4 Rat Intestinal Rat Liver Human Human Liver E”mp e1 Buffer s9 s9 Intestinal s9 s9 4-4 38 6-5 1-4 21 1-9 0-5 2-4 0-8 “——1-4 17 -8 2-9 14 132 16 ND 44 1 ——m- 1-5 >100 12-4 7 15 9-2 6-1 40 5-1 9-2 43 4-6 ND 34 9 35 27 2-4 6-9 2-4 240 32 163 39 _—-i- 3 36 8-5 0-22 2 0-39 1-8 8-2 2-3 3 42 6-1 ——m- 1-8 32 6-9 2-8 73 3-5 1-7 1-5 6-4 0-45 5-7 0-84 2 <1-0 1-7 0-9 5 1-9 “——10 22 9-9 <1-0 <1-0 <1-0 <1-0 <1-0 <1-0 3-8 20 3-5 “——23 36 24 “——0-7 1 0-7 160-9 11 193-1 24-8 1-3 10-6 0 “——10-3 1475-6 57 ND = not determined Example 106: Rat PK Intravenous rat cokinetics of exemplar compounds were ined in jugular vein cannulated e—Dawley rats (n23) (Harlan Laboratories, Indianapolis, IN) at a dose of 10 mg/kg. Compounds were dissolved and administered intravenously in 0.9% saline, pH 6.5 at a dose volume of 2 mL/kg. Blood samples (~100 uL) were obtained via the jugular vein catheter prior to dosing and at 0.08, 0.17, 0.25, 0.5, 1, 2, 4, and 8 hpd and prepared for plasma in KZEDTA microtainers. Oral pharmacokinetic studies were conducted with exemplar compounds at 10 mg/kg equivalents of carboxylic acids. Doses were dissolved and administered orally in 25:75 PEG400: water for injection, pH 4.5 at a dose volume of 10 mL/kg. Blood samples were ed via the jugular vein catheter prior to dosing and at 0.25, 0.5, l, 2, 4, 8, and 24 hpd and prepared for plasma in KZEDTA microtainers. Plasma samples were stored at —80°C prior to bioanalysis.

Sample preparation for LC/MS/MS analysis Plasma samples were thawed on ice prior to processing. Samples (30 uL) were diluted and proteins precipitated with 180 uL of acetonitrile containing 0.1% formic acid and 250 ng/mL of carbutamide (Nl—(butylcarbanoyl)—sulfanilamide, Sigma—Aldrich Catalog# $385433) as an internal standard. Samples were vortexed for 30 seconds, centrifuged at 3400g for 10 minutes and the supernatant transferred to injection vials.

LC/MS/MS conditions Rapid hydrolysis precluded satisfactory analysis of circulating concentrations of Examples 12 and 35. LC/MS/MS analysis was completed on an AB Sciex QTrap 6500 mass ometer in positive tion mode, coupled to a dzu Nexera LC system.

A Waters Atlantis T3 (3um, 3.0 x 50mm) column was used for chromatographic separation.

Injection volume was 1 uL. The mobile phase consisted 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B), with a gradient of 2—98% B:A over two minutes.

Pharmacokinetic analysis Plasma concentration vs. time es following intravenous (IV) stration and oral (PO) administration of ar compounds were analyzed by non—compartment analysis using WinNonLin 6.4. Mean AUC and F% are summarized in Table 5. Absolute oral bioavailability (F%) of es following stration of their respective esters was determined as: F% = 100 * (AUCpO*DoseiV)/(AUCiV*Dosepo).

In general, the exemplar compounds exhibit increased AUC upon oral dosing as compared with sulfate—derived beta—lactamase inhibitors, resulting in favorable F%.

TableS Example admmlstered AUC uM*h — ————— —-IV_————— —-I_——— —-I_——— “-F————— 34 IV 34 16.1 36 P0 34 13.5 84 P0 33 25.8 98 32 P0 34 11.5 71 31 P0 33 19.8 75 53 PO 4 2.2 1 1 65 PO 4 2.8 15 H2N \ N PO ETX2514 0.44 o ‘osogH ETX2514 N PO Relebactam 0.29 o ‘osogH Relebactam q PO WCK 4234 0.45 o ‘osogH WCK 4234 Exam le 106: In Vivo oral efficac of cef odoxime roxetil in combination with Example 35 vs. E. coli 1beta-lactamase content: AmpC= CTX-M-14) The oral in viva cy of Example 35 was evaluated in combination with cefpodoxime il in a mouse neutropenic thigh infection model versus a relevant clinical isolate. The isolate, E. coli ARC2687, ses the beta—lactamases AmpC and CTX—M—14, both of which can readily hydrolyze cefpodoxime resulting in non—susceptible MICs in excess of 512 ug/mL. In combination with Example 33 (4 ug/mL), the cefpodoxime MIC is reduced to <0.03 ug/mL. Dose setting for the study was based upon targeting cefpodoxime exposure above an MIC of 0.03 ug/mL for at least 50% of the dosing interval for all treatment arms while titrating increasing doses of the nd from Example 35. CD—1 mice (Charles River, Wilmington US) were housed in shoebox type cages with contact bedding and ated to the facility for a minimum of 2 days prior to use. The animal room was maintained at 700 F, with 50 +/— 10% relative humidity and a 12—hour light/dark cycle. The study was conducted using an IACUC—approved protocol in accordance with Title 9 of the Code of Federal Regulations. Animals were ed neutropenic with two intraperitoneal doses of cyclophosphamide (150 mg/kg —4 days and 100 mg/kg —1 day prior to infection (Gerber er al. (1983) JInfect Dis 147(5); 7)). s were infected via an intramuscular challenge of ~1 x 106 CFU administered within 100 uL of 0.9% saline. The um was prepared from a 25 mL overnight culture of E. coli ARC 2687 in tryptic soy broth media. Following an OD600 determination, the inoculum was diluted in 0.9% saline to a concentration of ~10 x 106 CFU/mL prior to inoculation into the left and right thigh. Oral therapy with cefpodoxime proxetil alone and in combination with Example 35 was initiated 2 hours post bacterial challenge. Doses were suspended in 0.5%HPMC/0.l% Tween 80 and stered by oral gavage at a dose volume of 10 mL/kg. A terminal endpoint was ed at 24 hr to determine bacterial counts in thigh tissue (CFU/gm). Animals were ethically ized, thighs were asceptically removed, weighed and homogenized in 1 mL of saline. Bacterial burden ation of tissue homogenate was performed by serial on on tryptic soy agar plates which were incubated overnight at 37 °C prior to colony (CFU) counting. The lower limit of detection was ~2.6 log10 CFU/gm of tissue.

As summarized in Table 6, bacterial burden in the thighs of mice receiving cefpodoxime proxetil alone at 50 mg/kg q6h or Example 35 at 10 mg/kg q6h demonstrated r than 3 logo CFU/gm of growth after 24 hours of therapy. In combination with cefpodoxime proxetil, increasing dose of the nd from Example 35 resulted in dose dependent reduction of bacterial burden with maximal kill of —0.75 log10 CFU/gm (relative to initiation of therapy) achieved at 50 mg/kg oxime proxetil +100 mg/kg Example 35 q6h.

Meropenem used as a positive control achieved just over l—log10 ion in CFU relative to initiation of therapy at 600 mg/kg q6h administered subcutaneously.

Table 6 Group Dose Route/Regimen logloCFU/gm . CFU (mg/kg) thigh Change from 26 26 hr Growth vehicle PO/q6h 10.86 —— Cefpodoxime 50 PO/q6h 10.24 . —0.62 proxetil alone.- ---_Example 35 10 PO/q6h 9.56 0.29 +3 .29 — l .30 Example 35 + 10+50 PO/q6h . . —5.09 cefpodoxime .- WO 53215 Example 35 + 25+50 PO/q6h . . —5 .27 cefpodoxime proxetil Example 35 + 100+50 PO/q6h . . -5 .34 cefpodoxime proxetil _mSC/q6h 5.17 0.27 —1.10 —5.69 WE

Claims

CLAIM :

1. A compound according to a (I): or a pharmaceutically acceptable salt thereof; wherein: R1 is –C(O)NR7R8, -CN, phenyl, a 5-6 membered heteroaryl, -C(O)NR’NR’C(O)R9, R’OR10, or a C1-C6 alkyl group, wherein the alkyl group is substituted with one to three groups selected from halo, C1-C3 alkoxy, -OH, -CN, – NR7R8, -NR7COR9, a 5-6 membered heteroaryl and a 5-7 membered heterocyclyl, and wherein the phenyl and heteroaryl represented by R1 are optionally and independently substituted with 1- 3 groups selected from halo, -OH, C1-C3 alkoxy, -CN, –NR7R8, and -CONR7R8; R2 and R3 are independently selected from hydrogen, halo, C1-C3 alkyl, and C3-C6 cycloalkyl; R4 and R5 are ndently selected from en, halo, -CN, -CO2R9, C1-C3 alkyl, and C1-C3 haloalkyl; R6 is hydrogen, C1-C12 alkyl, C1-C4 alkyl-C1-C3 alkoxy-(NR’C1-C6 alkyl)-C1-C3 alkoxy, C1-C4 alkyl-C1-C3 alkoxy-C1-C3 alkoxy, C2-C12 l, C3-C10 cycloalkyl, a 5-6 membered heteroaryl and a 5-7 membered heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently tuted with 1-6 groups selected from a carboxyl, halo, C1-C6 alkoxy, C1-C6 alkyl and phenyl; each R7 and R8 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, , C3-C6 cycloalkyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, n the alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl represented by R7 or R8 is optionally and ndently substituted with 1-6 groups selected from a 5-6 membered heterocyclyl optionally substituted with one or two –F atoms, carboxyl or –CO(OC1-6 alkyl), 5-6 membered heteroaryl, -CN, -OH, C1-C3 alkyl optionally substituted with –NH2 or –OH, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy -NHCO(C1-C3alkyl), -NHCO(C1- C3alkoxy), NR’R’’, -NHS(O)2NR’R’’, -NHS(O)2(C1-C3alkyl), -NR’R’’, and -C(O)NR’R’’; each R9 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy or C1-C6 alkoxy; each R10 is a C1-C3 alkyl ally tuted with 1-6 groups selected from a 5-6 membered heterocyclyl optionally substituted with one or two –F atoms, carboxyl or –CO(OC1-6 alkyl), a C3-C6 cycloalkyl, a 5-6 membered heteroaryl, -CN, -OH, -NHCO(C1-C3 alkyl), C1-C3 alkoxy), NR’R’’, -NHS(O)2NR’R’’, -NHS(O)2(C1-C3 alkyl), - NR’R’’, or -C(O)NR’R’’; and each R’ and R’’ is independently hydrogen, methyl, ethyl or propyl; or R’ and R’’ are taken together with the nitrogen to which they are attached to form a 5-6 membered heterocyclyl; provided that at least one of R2 and R3 is other than hydrogen.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 is C1- C12 alkyl, C1-C4 alkyl-C1-C3 alkoxy-(NR’C1-C6 alkyl)-C1-C3 alkoxy, C1-C4 alkyl-C1-C3 - C1-C3 , C2-C12 alkenyl, C3-C10 cycloalkyl, a 5-6 membered heteroaryl and a 5-7 membered heterocyclyl, wherein the alkyl, l, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently substituted with 1-6 groups selected from a carboxyl, halo, C1-C6 alkoxy, C1- C6 alkyl and phenyl.

3. The compound of claim 1 or 2, according to formula (III): or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R3 is C1-C3 alkyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, n R3 is methyl.

6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R1 is –C(O)NR7R8.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are both hydrogen.

8. The compound of claim 3, according to formula (V): or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1-8 or a pharmaceutically able salt f, wherein R6 is C1-C12 alkyl.

10. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt f, wherein R4 and R5 are independently H, methyl or .

11. The compound ing to claim 10 or a pharmaceutically acceptable salt thereof, wherein one of R4 and R5 is hydrogen, and the other is .

12. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R4 is fluoro and R5 is hydrogen.

13. The compound of Claim 1, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof.

14. The compound of Claim 1, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-14, and at least one pharmaceutically acceptable carrier, t or excipient.

16. Use of the compound according to any one of Claims 1-14, or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic in the manufacture of a medicament in treating a bacterial ion.

17. The use of claim 16, wherein said beta-lactam antibiotic is cefpodoxime proxetil.

18. The use of claim 16 or 17, wherein the bacterial infection is selected from the group consisting of complicated urinary tract infection, uncomplicated urinary tract infection, kidney infection, lower respiratory tract infection, hospital-acquired bacterial pneumonia (HAP), pneumonia, acute bacterial prostatitis, acute bacterial skin and soft tissue infection, , intraabdominal infection, and ic foot infection.

19. A process for forming a compound of the formula VI: (VI); or a salt thereof, wherein R1 is –C(O)NR7R8, –C(O)OR7, –CH2OR7, -CN, phenyl, a 5-6 ed aryl, - C(O)NR’NR’C(O)R9, -C(O)NR’OR10, or a C1-C6 alkyl group, wherein the alkyl group is substituted with one to three groups selected from halo, C1-C3 alkoxy, -OH, -CN, – NR7R8, -NR7COR9, a 5-6 membered aryl and a 5-7 membered heterocyclyl, and wherein the phenyl and aryl represented by R1 are optionally and independently substituted with 1- 3 groups ed from halo, -OH, C1-C3 alkoxy, -CN, -NR7R8, and R8; R2 and R3 are each independently selected from hydrogen, halo, C1-C3 alkyl, and C3-C6 cycloalkyl, provided that at least one of R2 and R3 is other than hydrogen; each R7 and R8 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, phenyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, or 5-6 ed heteroaryl, wherein the alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl represented by R7 or R8 is optionally and independently substituted with 1-6 groups selected from a 5-6 membered heterocyclyl optionally substituted with one or two –F atoms, carboxyl or –CO(OC1-6 alkyl), 5-6 membered heteroaryl, -CN, -OH, C1-C3 alkyl optionally substituted with –NH2 or –OH, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy -NHCO(C1-C3alkyl), -NHCO(C1- C3alkoxy), -S(O)2NR’R’’, -NHS(O)2NR’R’’, -NHS(O)2(C1-C3alkyl), -NR’R’’, and -C(O)NR’R’’; each R9 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy or C1-C6 alkoxy; each R’ and R’’ is independently hydrogen, methyl, ethyl or propyl; or R’ and R’’ are taken er with the nitrogen to which they are attached to form a 5-6 membered heterocyclyl; PG and PG’ are each independently an amine protecting group; the process comprising reacting a compound of the formula XI: (XI); or a salt thereof, with PG’NHOH in the presence of an oxidant to form the nd of the Formula VI.

20. A process for forming a compound of the a VI: (VI); or a salt thereof, wherein R1 is –C(O)NR7R8, –C(O)OR7, –CH2OR7, -CN, phenyl, a 5-6 membered heteroaryl, - ’NR’C(O)R9, -C(O)NR’OR10, or a C1-C6 alkyl group, wherein the alkyl group is substituted with one to three groups selected from halo, C1-C3 alkoxy, -OH, -CN, – NR7R8, -NR7COR9, a 5-6 membered heteroaryl and a 5-7 membered heterocyclyl, and wherein the phenyl and aryl represented by R1 are ally and independently substituted with 1- 3 groups ed from halo, -OH, C1-C3 alkoxy, -CN, -NR7R8, and -CONR7R8; R2 and R3 are each ndently selected from hydrogen, halo, C1-C3 alkyl, and C3-C6 cycloalkyl, provided that at least one of R2 and R3 is other than hydrogen; each R7 and R8 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, phenyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, n the alkyl, alkoxy, phenyl, lkyl, heterocyclyl or heteroaryl represented by R7 or R8 is optionally and independently substituted with 1-6 groups selected from a 5-6 membered cyclyl optionally substituted with one or two –F atoms, carboxyl or –CO(OC1-6 alkyl), 5-6 membered heteroaryl, -CN, -OH, C1-C3 alkyl optionally substituted with –NH2 or –OH, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy -NHCO(C1-C3alkyl), -NHCO(C1- C3alkoxy), -S(O)2NR’R’’, -NHS(O)2NR’R’’, -NHS(O)2(C1-C3alkyl), -NR’R’’, and -C(O)NR’R’’; each R9 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy or C1-C6 alkoxy; each R’ and R’’ is independently hydrogen, methyl, ethyl or propyl; or R’ and R’’ are taken together with the nitrogen to which they are attached to form a 5-6 membered cyclyl; PG and PG’ are each independently an amine protecting group; the process comprising reacting a compound of the formula XI: (XI); or a salt thereof, with PG’N=O to form the compound of the Formula VI.