β-lactamase inhibitor compounds

Abstract

The present invention relates to compounds that are beta-lactamase inhibitors. The combination of the compounds and their pharmaceutically acceptable salts with beta-lactam antibiotics can be used to treat bacterial infections, including infections caused by resistant organisms (including multi-drug resistant organisms). The present invention includes compounds according to formula (I) or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 The values ​​of are as described in this article.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 201780057302.4, filed on September 15, 2017, and invention name “β-lactamase inhibitor compounds”.

[0002] Related Applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 395,464, filed on September 16, 2016, and U.S. Provisional Application No. 62 / 456,423, filed on February 8, 2017, the contents of each of which are incorporated herein by reference. Technical Field

[0004] The present invention relates to novel oral β-lactamase inhibitors, pharmaceutical compositions and methods of use thereof. In addition, the present invention relates to therapeutic methods for treating bacterial infections, including overcoming bacterial antibiotic resistance. Background Art

[0005] The international microbiology and infectious disease community continues to express serious concern that the continued evolution of antimicrobial resistance may produce bacterial strains for which existing antimicrobial agents will be ineffective. The consequences of such a situation may have considerable morbidity and mortality. In general, bacterial pathogens can be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds that are effectively active against both Gram-positive and Gram-negative pathogens are generally considered to have broad-spectrum activity.

[0006] In the fight against bacterial infection, beta-lactam antibiotics are indispensable. Beta-lactams are a wide range of drug classes, and their core molecular structures all have beta-lactams, and usually show effectiveness against a wide spectrum of Gram-positive and Gram-negative bacteria by inhibiting bacterial cell wall synthesis. Because the drug target does not have eukaryotic analogs, their toxicity is low and they are usually well tolerated. They are the most widely formulated, safe and effective drugs against bacterial infection. However, their effectiveness is subject to the limitation of highly resistant infectious strains such as methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant (MDR) strains of Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and other Enterobacteriaceae. Such resistant bacteria are the main causes of morbidity and death in patients. Helfand, β-lactams Against Emerging 'Superbugs': Progress and Pitfalls, Expert Rev. Clin. Pharmacol. 1(4): 559-571 (2008).

[0007] β-lactam antibiotics alone and in combination with β-lactamase inhibitors still represent an essential part of the antimicrobial arsenal used to combat disease. β-lactam resistance in Gram-negative infections is driven primarily by β-lactamase activity; and the apparent reliance on β-lactam antibiotics has led to a diversification and increased prevalence of β-lactamases. These β-lactamases drive resistance to even the newest β-lactam antibiotics. Llarrull et al., The Future of Beta-Lactams, Current Opinion in Microbiology, 13:551-557 (2010).

[0008] A major threat to the efficacy of these drugs is the increasing prevalence of extended-spectrum β-lactamases (ESBLs). β-lactamases are enzymes produced by some bacteria that ring-open the β-lactam portion of β-lactam antibiotics, thereby inactivating them. There are currently four classes of β-lactamases, denoted Class A, Class B, Class C, and Class D. Class A, Class C, and Class D β-lactamases are serine β-lactamases, while Class B β-lactamases are metallo-β-lactamases (MBLs). Bush and Jacoby, Updated Functional Classification of β-Lactamases, Antimicrobial Agents and Chemotherapy, 54(3):969-976 (March 2010).

[0009] To help improve the effectiveness of β-lactam antibiotics, several β-lactamase inhibitors have been developed. However, currently available β-lactamase inhibitors are in many cases insufficient to combat the increasing diversity of β-lactamases. The three most common serine β-lactamase agents currently in use—clavulanic acid, tazobactam, and sulbactam—are active only against certain class A enzymes, which severely limits their utility. Furthermore, new β-lactamase inhibitors that have been recently approved or are currently in clinical trials, such as avibactam and MK-7655, are only available for intravenous use and act primarily against class A and C enzymes, with little effectiveness against class D β-lactamases. Bebrone et al., Current Challenges in Antimicrobial Chemotherapy: Focus on β-Lactamase Inhibition, Drugs, 70(6): 651-679 (2010). While these drugs represent a significant improvement over currently available β-lactamase inhibitors, an agent that is effective against all three classes of serine β-lactamases, and the added benefit of an orally effective dosage form for use outside of the hospital, is desirable to combat the significant β-lactam resistance seen today. Currently, no β-lactamase inhibitors are approved that are orally administered and effective against class C or D β-lactamases, and resistance rates to conventional antibiotics continue to rise.

[0010] Compounds similar to those disclosed herein are described in WO 2013 / 150296, which have a broad β-lactamase inhibition spectrum (effective against most class A, C and D β-lactamases). This patent application features compounds according to the following formula:

[0011]

[0012] Although the compounds of WO 2013 / 150296 application show a significant improvement in the spectrum of β-lactamase inhibitors currently on the market or in the clinic, the compounds described therein can only be administered intravenously (IV) because they are not orally bioavailable. Moreover, the compounds disclosed therein cannot be made orally bioavailable by using prodrugs on the sulfate activated groups of the molecules. Therefore, these potent β-lactamase inhibitors are limited to intravenous or parenteral administration, which can usually only occur in a hospital setting. Therefore, for patients with severe drug-resistant infections but otherwise healthy and do not need hospitalization, or patients who can be discharged but will benefit from antimicrobial treatment in an outpatient setting (also known as "oral conversion therapy"), there are limited treatment options. The compounds of WO 2013 / 150296 application have the potential to provide patients with more effective and more extensive β-lactamase inhibition than any compound identified, but the compounds currently need to be administered intravenously in a hospital setting.

[0013] There is an urgent need for a new broad-spectrum oral β-lactamase inhibitor that would provide significant benefit to patients infected with resistant pathogens who may be able to be treated outside of a hospital setting, or who are hospitalized but may not have reliable intravenous access. Such patients may have severe and complicated infections from pathogens that produce one or more β-lactamases but may not require treatment in a hospital setting, or those who have recovered from an infection that was initially successfully treated in a hospital with an IV β-lactam / β-lactamase inhibitor combination but would benefit from continuous β-lactam / β-lactamase inhibitor combination therapy outside of a hospital setting—and such treatment is only possible with an orally active broad-spectrum β-lactamase inhibitor such as described herein.

[0014] In addition, for patients with resistant bacterial infections who require hospitalization for initial treatment, compounds of the invention as described in Formula (Ia), (IIa), (IIIa), (IVa) and (Va) can be administered intravenously in a hospital setting until the patient is sufficiently stable to be discharged to a community setting. After discharge, the patient can continue treatment with the same medication by administering a compound of one of Formula (I), (II), (III), (IV) or (V) in a community setting, while maintaining consistent treatment until the bacterial infection resolves. Once the patient is well enough to be discharged, there are currently no Class A, C and D β-lactamase inhibitors that can be administered by IV with the added benefit of oral administration. The ability for physicians to tailor care to the needs of the patient will allow patients who require hospitalization to be discharged earlier and significantly reduce overall treatment costs by avoiding long-term hospitalizations.

[0015] There is an urgent need for new orally active β-lactamase inhibitors that are active against more than one of the class A, C and D β-lactamases. Summary of the invention

[0016] The present invention relates to compounds that are orally available beta-lactamase inhibitors. The compounds and pharmaceutically acceptable salts thereof are useful in combination with beta-lactam antibiotics for the treatment of bacterial infections, including infections caused by drug-resistant organisms, including multidrug-resistant organisms.

[0017] More specifically, the present invention relates to compounds of formula (I):

[0018]

[0019] or a pharmaceutically acceptable salt thereof; wherein:

[0020] R 1 Yes-C(O)NR 7 R 8 , -CN, phenyl, 5-7 membered heteroaryl, -C(O)NR'NR'C(O)R 9 、-C(O)NR'OR 10 or C 1 -C 6 Alkyl groups, wherein the alkyl groups are substituted by halogen, C 1 -C 3 Alkoxy, -OH, -CN, -NR 7 R 8 、-NR 7 COR 9 , 5-7 membered heteroaryl and 5-7 membered heterocyclic group, and wherein R 1 The phenyl and heteroaryl groups represented by 1 -C 3 Alkoxy, -CN, -NR 7 R 8 and-CONR 7 R 8 1-3 groups are substituted;

[0021] R 2 and R 3 are independently selected from hydrogen, halogen, C 1 -C 3 Alkyl and C 3 -C 6 Cycloalkyl;

[0022] R 4 and R 5 are independently selected from hydrogen, halogen, -CN, -CO 2 R9 , C 1 -C 3 Alkyl and C 1 -C 3 Haloalkyl;

[0023] R 6 It is hydrogen, C 1 -C 12 Alkyl, C 1 -C 4 Alkyl-C 1 -C 3 Alkoxy-(NR'C 1 -C 6 Alkyl)-C 1 -C 3 Alkoxy, C 1 -C 4 Alkyl-C 1 -C 3 Alkoxy-C 1 -C 3 Alkoxy, C 2 -C 12 Alkenyl, C 3 -C 10 Cycloalkyl, 5-7 membered heteroaryl and 5-7 membered heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently selected from carboxyl, halogen, C 1 -C 6 Alkoxy, C 1 -C 6 1 to 6 groups in the alkyl and phenyl groups are substituted. Alternatively, R 6 It is C 1 -C 12 Alkyl, C 1 -C 4 Alkyl-C 1 -C 3 Alkoxy-(NR'C 1 -C 6 Alkyl)-C 1 -C 3 Alkoxy, C 1 -C 4 Alkyl-C 1 -C 3 Alkoxy-C 1 -C 3 Alkoxy, C 2 -C 12 Alkenyl, C 3 -C 10 Cycloalkyl, 5-7 membered heteroaryl and 5-7 membered heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently selected from carboxyl, halogen, C 1 -C6 Alkoxy, C 1 -C 6 1-6 groups are substituted in alkyl and phenyl groups;

[0024] Each R 7 and R 8 are independently hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, phenyl, C 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl or 5-7 membered heteroaryl, wherein R 7 or R 8 The alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl groups represented by the present invention are optionally and independently selected from the group consisting of: optionally substituted by one or two -F atoms, carboxyl or -CO(OC 1-6 alkyl) substituted 5-6 membered heterocyclic group, 5-6 membered heteroaryl, -CN, -OH, optionally substituted with -NH 2 or -OH substituted C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Alkoxy-NHCO(C 1 -C 3 Alkyl), -NHCO(C 1 -C 3 Alkoxy), -S(O) 2 NR'R", -NHS(O) 2 NR'R", -NHS(O) 2 (C 1 -C 3 alkyl), -NR'R" and -C(O)NR'R"; each R 9 It is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy or C 1 -C 6 Alkoxy;

[0025] Each R 10 It is C 1 -C 3 Alkyl, which is optionally selected from optionally substituted by one or two -F atoms, carboxyl or -CO(OC1-6 alkyl) substituted 5-6 membered heterocyclic group, C 3 -C 6 Cycloalkyl, 5-6 membered heteroaryl, -CN, -OH, -NHCO(C 1 -C 3 Alkyl), -NHCO(C 1 -C 3 Alkoxy), -S(O) 2 NR'R", -NHS(O) 2 NR'R", -NHS(O) 2 (C 1 -C 3 alkyl), -NR'R" or -C(O)NR'R"; and

[0026] Each R' and R" is independently hydrogen, methyl, ethyl or propyl; or R' and R" together with the nitrogen to which they are attached form a 5-6 membered heterocyclic group; provided that R 2 and R 3 At least one of them is not hydrogen. DETAILED DESCRIPTION

[0027] One aspect of the present invention is an oral β-lactamase inhibitor compound according to formula (I); as described above.

[0028] In another aspect of the present invention, R in formula (I) 1 Yes-C(O)NR 7 R 8 , -CN, phenyl, 5-6 membered heteroaryl, -C(O)NR'NR'C(O)R 9 、-C(O)NR'OR 10 or C 1 -C 6 Alkyl groups, wherein the alkyl groups are substituted by halogen, C 1 -C 3 Alkoxy, -OH, -CN, -NR 7 R 8 、-NR 7 COR 9 , 5-6 membered heteroaryl and 5-7 membered heterocyclic group, and wherein R 1 The phenyl and heteroaryl groups represented by 1 -C 3 Alkoxy, -CN, -NR 7 R 8 and-CONR 7 R 8 1-3 groups are substituted;

[0029] R 6 It is hydrogen, C 1 -C 12 Alkyl, C 1 -C 4 Alkyl-C 1 -C 3 Alkoxy-(NR'C 1 -C 6 Alkyl)-C 1 -C 3 Alkoxy, C 1 -C 4 Alkyl-C 1 -C 3 Alkoxy-C 1 -C 3 Alkoxy, C 2 -C 12 Alkenyl, C 3 -C 10 Cycloalkyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently selected from carboxyl, halogen, C 1 -C 6 Alkoxy, C 1 -C 6 1-6 groups in the alkyl and phenyl groups are substituted (or, R 6 It is C 1 -C 12 Alkyl, C 1 -C 4 Alkyl-C 1 -C 3 Alkoxy-(NR'C 1 -C 6 Alkyl)-C 1 -C 3 Alkoxy, C 1 -C 4 Alkyl-C 1 -C 3 Alkoxy-C 1 -C 3 Alkoxy, C 2 -C 12 Alkenyl, C 3 -C 10 Cycloalkyl, 5-6 membered heteroaryl and 5-7 membered heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently selected from carboxyl, halogen, C 1 -C 6 Alkoxy, C 1 -C 6 alkyl and phenyl) substituted with 1 to 6 groups; and each R 7 and R 8are independently hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, phenyl, C 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein R 7 or R 8 The alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl groups represented by the present invention are optionally and independently selected from the group consisting of: optionally substituted by one or two -F atoms, carboxyl or -CO(OC 1-6 alkyl) substituted 5-6 membered heterocyclic group, 5-6 membered heteroaryl, -CN, -OH, optionally substituted with -NH 2 or -OH substituted C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Alkoxy-NHCO(C 1 -C 3 Alkyl), -NHCO(C 1 -C 3 Alkoxy), -S(O) 2 NR'R", -NHS(O) 2 NR'R", -NHS(O) 2 (C 1 -C 3 alkyl), -NR'R" and -C(O)NR'R"; each R 9 It is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy or C 1 -C 6 Alkoxy;

[0030] Another aspect of the present invention is a compound according to formula (II):

[0031]

[0032] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 2 , R 4 , R 5 and R 6As defined for formula (I). One aspect of the present invention is a compound according to formula (III):

[0033]

[0034] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 3 , R 4 , R 5 and R 6 As defined for formula (I). A further aspect of the invention is a compound according to formula (IV):

[0035]

[0036] or a pharmaceutically acceptable salt thereof, wherein the variable R 4 , R 5 and R 6 As defined for formula (I).

[0037] A further aspect of the invention are compounds according to formula (V):

[0038]

[0039] or a pharmaceutically acceptable salt thereof, wherein the variable R 4 , R 5 and R 6 As defined for formula (I).

[0040] A further aspect of the invention are compounds according to formula (Ia):

[0041]

[0042] or a pharmaceutically acceptable salt thereof; wherein: R 1 Yes-C(O)NR 7 R 8 , -CN, phenyl, 5-7 membered heteroaryl, -C(O)NR'NR'C(O)R 9 、-C(O)NR'OR 10 or C 1 -C 6 Alkyl groups, wherein the alkyl groups are substituted by halogen, C 1 -C 3 Alkoxy, -OH, -CN, -NR 7 R 8 、-NR 7 COR 9 , 5-7 membered heteroaryl and 5-7 membered heterocyclic group, and wherein R 1The phenyl and heteroaryl groups represented by 1 -C 3 Alkoxy, -CN, -NR 7 R 8 and-CONR 7 R 8 1-3 groups in R are substituted; 2 and R 3 are independently selected from hydrogen, halogen, C 1 -C 3 Alkyl and C 3 -C 6 Cycloalkyl; R 4 and R 5 are independently selected from hydrogen, halogen, -CN, -CO 2 R 9 , C 1 -C 3 Alkyl and C 1 -C 3 haloalkyl; each R 7 and R 8 are independently hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, phenyl, C 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl or 5-7 membered heteroaryl, wherein R 7 or R 8 The alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl groups represented by the present invention are optionally and independently selected from the group consisting of: optionally substituted by one or two -F atoms, carboxyl or -CO(OC 1-6 alkyl) substituted 5-6 membered heterocyclic group, 5-6 membered heteroaryl, -CN, -OH, optionally substituted with -NH 2 or -OH substituted C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Alkoxy-NHCO(C 1 -C 3 Alkyl), -NHCO(C 1 -C 3 Alkoxy), -S(O) 2 NR'R", -NHS(O) 2 NR'R", -NHS(O) 2 (C 1 -C3 alkyl), -NR'R" and -C(O)NR'R"; each R 9 It is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy or C 1 -C 6 Alkoxy; each R 10 It is C 1 -C 3 Alkyl, which is optionally selected from optionally substituted by one or two -F atoms, carboxyl or -CO(OC 1-6 alkyl) substituted 5-6 membered heterocyclic group, C 3 -C 6 Cycloalkyl, 5-6 membered heteroaryl, -CN, -OH, -NHCO(C 1 -C 3 Alkyl), -NHCO(C 1 -C 3 Alkoxy), -S(O) 2 NR'R", -NHS(O) 2 NR'R", -NHS(O) 2 (C 1 -C 3 alkyl), -NR'R" or -C(O)NR'R"; and each R' and R" are independently hydrogen, methyl, ethyl or propyl; or R' and R" together with the nitrogen to which they are attached form a 5-6 membered heterocyclic group; provided that R 2 and R 3 At least one of them is not hydrogen.

[0043] A further aspect of the invention are compounds according to formula (Ia):

[0044]

[0045] or a pharmaceutically acceptable salt thereof; wherein: R 1 Yes-C(O)NR 7 R 8 , -CN, phenyl, 5-6 membered heteroaryl, -C(O)NR'NR'C(O)R 9 、-C(O)NR'OR 10 or C 1 -C 6 Alkyl groups, wherein the alkyl groups are substituted by halogen, C 1 -C 3 Alkoxy, -OH, -CN, -NR 7R 8 、-NR 7 COR 9 , 5-6 membered heteroaryl and 5-7 membered heterocyclic group, and wherein R 1 The phenyl and heteroaryl groups represented by 1 -C 3 Alkoxy, -CN, -NR 7 R 8 and-CONR 7 R 8 1-3 groups in R are substituted; 2 and R 3 are independently selected from hydrogen, halogen, C 1 -C 3 Alkyl and C 3 -C 6 Cycloalkyl; R 4 and R 5 are independently selected from hydrogen, halogen, -CN, -CO 2 R 9 , C 1 -C 3 Alkyl and C 1 -C 3 haloalkyl; each R 7 and R 8 are independently hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, phenyl, C 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein R 7 or R 8 The alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl groups represented by the present invention are optionally and independently selected from the group consisting of: optionally substituted by one or two -F atoms, carboxyl or -CO(OC 1-6 alkyl) substituted 5-6 membered heterocyclic group, 5-6 membered heteroaryl, -CN, -OH, optionally substituted with -NH 2 or -OH substituted C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Alkoxy-NHCO(C 1 -C 3 Alkyl), -NHCO(C 1 -C 3Alkoxy), -S(O) 2 NR'R", -NHS(O) 2 NR'R", -NHS(O) 2 (C 1 -C 3 alkyl), -NR'R" and -C(O)NR'R"; each R 9 It is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy or C 1 -C 6 Alkoxy; each R 10 It is C 1 -C 3 Alkyl, which is optionally selected from optionally substituted by one or two -F atoms, carboxyl or -CO(OC 1-6 alkyl) substituted 5-6 membered heterocyclic group, C 3 -C 6 Cycloalkyl, 5-6 membered heteroaryl, -CN, -OH, -NHCO(C 1 -C 3 Alkyl), -NHCO(C 1 -C 3 Alkoxy), -S(O) 2 NR'R", -NHS(O) 2 NR'R", -NHS(O) 2 (C 1 -C 3 alkyl), -NR'R" or -C(O)NR'R"; and each R' and R" are independently hydrogen, methyl, ethyl or propyl; or R' and R" together with the nitrogen to which they are attached form a 5-6 membered heterocyclic group; provided that R 2 and R 3 At least one of them is not hydrogen.

[0046] Another aspect of the present invention is a compound according to formula (IIa):

[0047]

[0048] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 2 , R 4 and R 5 As defined for formula (Ia).

[0049] One aspect of the present invention is a compound according to formula (IIIa):

[0050]

[0051] or a pharmaceutically acceptable salt thereof, wherein the variable R 1 , R 3 , R 4 and R 5 As defined for formula (Ia).

[0052] A further aspect of the invention are compounds according to formula (IVa):

[0053]

[0054] or a pharmaceutically acceptable salt thereof, wherein the variable R 4 and R 5 As defined for formula (Ia).

[0055] A further aspect of the invention are compounds according to formula (Va):

[0056]

[0057] or a pharmaceutically acceptable salt thereof, wherein the variable R 4 and R 5 As defined for formula (Ia).

[0058] In one aspect of the present invention, for Formula (I), (Ia), (II) or (IIa), R 2 It is C 1 -C 3 In another aspect of the present invention, for Formula (I), (Ia), (II) or (IIa), R 2 It's methyl.

[0059] In one aspect of the present invention, for Formula (I), (Ia), (III) and (IIIa), R 3 It is C 1 -C 3 In another aspect of the present invention, for formula (I), (Ia), (III) and (IIIa), R 3 It's methyl.

[0060] In one aspect of the present invention, for Formula (I), (Ia), (II), (IIa), (III) and (IIIa), R 1 Selected from oxadiazole, -C(O)NHNHC(O)(C 1 -C 3 Alkyl), -CH 2 NH 2 、-CH 2 NHCO(C1 -C 3 Alkoxy), -CH 2 NHCO(C 1 -C 3 alkyl) or -CH 2 NHCO(C 1 -C 3 haloalkyl), wherein R 1 The oxadiazole is optionally substituted with -OH, C 1 -C 3 Alkoxy, -NR 7 R 8 or-CONR 7 R 8 In one aspect of the present invention, for Formula (I), (Ia), (II), (IIa), (III) and (IIIa), R 1 Selected from -CH 2 NH 2 ,

[0061] In yet another aspect, for Formula (I), (Ia), (II), (IIa), (III) and (IIIa), R 1 Yes-CN,

[0062] 1.

[0063] Where R 11 is hydrogen or -C(O)NH 2 In one aspect of the present invention, for Formula (I), (Ia), (II), (IIa), (III) and (IIIa), R 1 Is -CN or -C(O)NH 2 In one aspect of the present invention, for Formula (I), (Ia), (II), (IIa), (III) and (IIIa), R 1 In one aspect of the present invention, for Formula (I), (Ia), (II), (IIa), (III) and (IIIa), R 1 Yes -C(O)NH 2 In one aspect of the present invention, for Formula (I), (Ia), (II), (IIa), (III) and (IIIa), R 1 Yes-C(O)NR 7 R 8 In one aspect of the present invention, for Formula (I), (Ia), (II), (IIa), (III) and (IIIa), when R 1 Yes-C(O)NR7 R 8 When R 7 is hydrogen and R 8 Yes 1) optionally C 1 -C 3 Alkyl or C 1 -C 3 Alkyl-NH 2 Substituted phenyl, 2)C 1 -C 3 Alkyl or 3)C 1 -C 3 Alkoxy, wherein R 8 Each alkyl or alkoxy group represented by 3 -C 6 Cycloalkyl, -CN, -OH, -NH 2 、-SO 2 NH 2 、-NHSO 2 NH 2 ,

[0064] -C(O)NH 2 、-NHC(O)(C 1 -C 3 alkyl), pyrazinyl, oxytanyl, oxazolyl, or optionally substituted by one or more carboxyl, fluorine or -C(O)O(C 1 -C 6 In one aspect of the present invention, for formula (I), (Ia), (II), (IIa), (III) and (IIIa), when R 1

[0065] Yes-C(O)NR 7 R 8 When R 7 is hydrogen and R 8 Selected from the group consisting of:

[0066]

[0067]

[0068] -CH 2 CN and -CH 2 OH.

[0069] In one aspect of the present invention, for any of Formula (I), (II), (III), (IV) or (V), R 6 It is C 1 -C 12In one aspect of the present invention, for any of Formula (I), (II), (III), (IV) or (V), R 6 is ethyl, isopropyl, 2-butyl or isopentyl. In one aspect of the present invention, for any one of formula (I), (II), (III), (IV) or (V), R 6 In one aspect of the present invention, for any one of formula (I), (II), (III), (IV) or (V), R 6 It is C 1 -C 4 Alkyl-OC(O)-(NHC 1 -C 6 Alkyl)-C(O)C 1 -C 3 Alkoxy, C 1 -C 4 Alkyl-OC(O)-C 1 -C 4 Alkyl or C 1 -C 4 Alkyl-OC(O)-C 1 -C 3 In one aspect of the present invention, for any of Formula (I), (II), (III), (IV) or (V), R 6 Selected from the group consisting of:

[0070] methyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl or n-nonyl.

[0071] In one aspect of the invention, for any of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), R 4 and R 5 In another aspect of the invention, for any of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), R 4 and R 5 In another aspect of the present invention, for any of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), R 4 is fluorine and R 5In another aspect of the present invention, for any of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), R 4 is hydrogen and R 5 In another aspect of the present invention, for any of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), R 4 and R 5 Both are hydrogen.

[0072] In another aspect of the present invention, for any of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), R 4 and R 5 Both are fluorine.

[0073] Any embodiment described herein can be combined with any other suitable embodiment described herein to provide additional embodiments. 1 and another embodiment describes R 2 In the case of possible groups, it should be understood that these embodiments can be combined to provide a method utilizing R 1 Any possible group with R 2 Similarly, the present invention includes any additional embodiments for any possible groups of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Any implementation called out individually may be combined with any specific implementation called out for each of the remaining variables.

[0074] Compounds of formula (I), (II), (III), (IV) and (V), and pharmaceutically acceptable salts thereof, have beneficial β-lactamase inhibition profiles and are suitable for oral administration. Compounds of formula (Ia), (IIa), (IIIa), (IVa) and (Va), and pharmaceutically acceptable salts thereof, have beneficial β-lactamase inhibition profiles and are suitable for intravenous, intraperitoneal, intramuscular or subcutaneous administration, such as intravenous administration. Thus, compounds of formula (Ia), (IIa), (IIIa), (IVa) and (Va) and pharmaceutically acceptable salts thereof may be advantageously used when the patient is unable to take antibiotics orally, such as in a hospital setting, an emergency care setting or a nursing home setting. Once the patient has improved sufficiently to be able to take antibiotics orally, treatment may be switched so that the patient may be orally administered a compound of formula (I), (II), (III), (IV) and (V) or a pharmaceutically acceptable salt thereof. In addition, compounds of Formula (Ia), (IIa), (IIIa), (IVa), (Va), (I), (II), (III), (IV) and (V), and pharmaceutically acceptable salts thereof, may have beneficial efficacy, metabolism, toxicology and / or pharmacodynamic properties.

[0075] One aspect of the present invention includes a compound according to one of the following examples, or a pharmaceutically acceptable salt thereof, namely:

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090] The compounds of the present invention include compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va) in the free base (uncharged) state, and pharmaceutically acceptable salts thereof.

[0091] Alkyl - As used herein, the term "alkyl" refers to both straight and branched chain saturated hydrocarbon groups having the specified number of carbon atoms. References to individual alkyl groups such as "propyl" are specific for the straight chain form only, and references to individual branched chain alkyl groups such as "isopropyl" and "3-pentyl" are specific for the branched chain form only. In one aspect, "alkyl" is methyl.

[0092] Halogen - As used herein, the term "halogen" is intended to include fluorine, chlorine, bromine, and iodine. In one aspect, "halogen" may refer to fluorine, chlorine, and bromine. In another aspect, "halogen" may refer to fluorine or chlorine. In yet another aspect, "halogen" may refer to fluorine. In yet another aspect, "halogen" may refer to chlorine.

[0093] Haloalkyl - as used herein is an "alkyl" moiety as defined above substituted with one or more halogen atoms. In one aspect, "haloalkyl" can be -CHF 2 、-CH 2 F or -CF 3 .

[0094] Cycloalkyl - In one aspect, "cycloalkyl" refers to a saturated monocyclic carbocyclic ring wherein one or more -CH 2 The -group may be optionally replaced by a corresponding number of -C(O)-groups. Illustrative examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl and cyclopentenyl. In one aspect, the "3- to 5-membered carbocyclyl" may be cyclopropyl.

[0095] 5-7 membered heterocyclic group -The term "5-7 membered heterocyclyl" refers to a saturated or partially saturated non-aromatic monocyclic ring containing 5 to 7 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen, and wherein -CH 2 -group may be optionally replaced by a -C(O)-group. Similarly, "5-6 membered heterocyclyl" refers to a saturated or partially saturated non-aromatic monocyclic ring containing 5 to 6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen, and wherein -CH 2-groups may be optionally replaced by -C(O)-groups. Unless otherwise specified, "5-7 membered heterocyclyl" and "5-6 membered heterocyclyl" groups may be carbon or nitrogen-linked. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Ring sulfur atoms may be optionally oxidized to form S-oxides or sulfones. Illustrative examples of "5-7 membered heterocyclyl" and "5-6 membered heterocyclyl" include, but are not limited to, azetidinyl, dioxytetrahydrothienyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxobutyl, oxoimidazolidinyl, 3-oxo-1-piperazinyl, 2-oxopyrrolidinyl, 2-oxotetrahydrofuranyl, oxo-1,3-thiazole alkyl, piperazinyl, piperidinyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, 1,3,4-thiadiazolyl, thiazolidinyl, thiomorpholinyl, thienyl, 4H-1,2,4-triazolyl, pyridine-N-oxide, tetrazolyl, oxadiazolyl, triazolyl, pyrazinyl, triazinyl and homopiperidinyl. In one embodiment, the terms "5-7 membered heterocyclyl" and "5-6 membered heterocyclyl" include 5-7 or 5-6 membered siderophores containing at least one heteroatom.

[0096] 5- or 6-membered heteroaryl -The term "5-6 membered heteroaryl" refers to a monocyclic aromatic heterocyclyl ring containing 5 or 6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen. Unless otherwise indicated, a "5-6 membered heteroaryl" group can be carbon or nitrogen attached. The ring nitrogen atom can be optionally oxidized to form an N-oxide. The ring sulfur atom can be optionally oxidized to form an S-oxide or sulfone. Illustrative examples of "5-6 membered heteroaryl" include furanyl, imidazolyl, isothiazolyl, isoxazole, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyridyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl and triazolyl.

[0097] Optional Substituted - As used herein, the phrase "optionally substituted" indicates that the substitution is optional, and thus the designated group may be substituted or unsubstituted. Where substitution is desired, an appropriate number of hydrogens on the designated group may be replaced by a selection from the indicated substituents, provided that the normal valence of the atom on the particular substituent is not exceeded and that the substitution results in a stable compound.

[0098] In one aspect, when a particular group is designated as optionally substituted with one or more substituents, the particular group may be unsubstituted. In another aspect, the particular group may carry one substituent. In another aspect, the particular substituent may carry two substituents. In yet another aspect, the particular group may carry three substituents. In yet another aspect, the particular group may carry four substituents. In yet another aspect, the particular group may carry one or two substituents. In yet another aspect, the particular group may be unsubstituted, or may carry one or two substituents.

[0099] Pharmaceutically acceptable - As used herein, the term "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.

[0100] Prodrug - As used herein, the term "prodrug" refers to a chemically modified form of a pharmacologically active agent that is converted in vivo to release the active drug. (See Rautio, J., et al., Prodrugs: Design and Clinical Applications, Nature Rev., vol. 7, pp. 255 (March 2008)). In the present invention, the prodrug is used to produce an orally bioavailable active β-lactamase inhibitor compound after absorption from the gastrointestinal tract.

[0101] Effective amount - As used herein, the phrase "effective amount" refers to an amount of a compound or composition sufficient to significantly and positively alter the symptoms and / or condition to be treated (e.g., provide a positive clinical response). The effective amount of the active ingredient used in the pharmaceutical composition will vary with the specific condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific active ingredient employed, the specific pharmaceutically acceptable excipient / carrier utilized, and similar factors within the knowledge and expertise of the attending physician.

[0102] The compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) and (Va) may form stable pharmaceutically acceptable acid or base salts, and in such cases, administration of the compound as a salt may be appropriate. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, 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, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate and undecanoate. Examples of base salts include ammonium salts; alkali metal salts such as sodium, 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 arginine, lysine, ornithine, etc. In addition, basic nitrogen-containing groups can be quaternized with agents such as: lower alkyl halides, such as methyl, ethyl, propyl and butyl halides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide, etc. Nontoxic physiologically acceptable salts are preferred, but other salts may also be used, for example, in product isolation or purification.

[0103] The salts may be formed by conventional means, for example by reacting the free base form of the product with one or more equivalents of an appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, the latter solvent being removed in vacuo or by freeze drying or by exchanging the anion of the existing salt for another anion on a suitable ion exchange resin.

[0104] When a compound disclosed herein is described by name or structure and has one or more chiral centers, and wherein the name or structure encompasses more than one stereoisomer, e.g., the stereochemistry at the one or more chiral centers is not indicated, it is understood that the name or structure includes all such stereoisomers and mixtures thereof.

[0105] The synthesis of optically active forms can be carried out by standard techniques of organic chemistry known in the art, for example, by synthesis from optically active starting materials or by splitting racemic forms. Racemates can be separated into single enantiomers using known procedures (see, for example, Advanced Organic Chemistry: 3rd Edition: author JMarch, pp. 104-107). Suitable procedures include forming diastereomeric derivatives by reaction of racemic materials with chiral auxiliary agents, then separating diastereomers, for example, by chromatography, and then cleaving auxiliary species. Similarly, the above-mentioned activity can be evaluated using standard laboratory techniques mentioned below.

[0106] Stereoisomers can be separated using conventional techniques, such as chromatography or fractional crystallization. Enantiomers can be separated by separation of racemates, such as by fractional crystallization, resolution or HPLC. Diastereomers can be separated by separation by means of the different physical properties of the diastereomers, for example, by fractional crystallization, HPLC or flash chromatography. Alternatively, specific stereoisomers can be prepared by chiral synthesis from chiral starting materials under conditions that will not cause racemization or epimerization, or by derivatization with chiral reagents.

[0107] When a specific stereoisomer is indicated by structure or name, it is advantageous to provide that same compound or that same compound is substantially separated from other stereoisomers. In one aspect, a mixture containing a specific stereoisomer of a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) may contain less than 30% by weight, particularly less than 20% by weight, and more particularly less than 10% by weight of other stereoisomers of the same compound. In another aspect, a mixture containing a specific stereoisomer of a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) may contain less than 6% by weight, particularly less than 3% by weight, and more particularly less than 2% by weight of other stereoisomers of the compound. In another aspect, a mixture containing a specific stereoisomer of a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) may contain less than 1% by weight, particularly less than 0.5% by weight, more particularly less than 0.3% by weight, and even more particularly less than 0.1% by weight of other stereoisomers of the compound.

[0108] In one aspect, the terms "infection" and "bacterial infection" may refer to gynecological infections. In another aspect, the terms "infection" and "bacterial infection" may refer to respiratory tract infections (RTI). In yet another aspect, the terms "infection" and "bacterial infection" may refer to sexually transmitted diseases. In yet another aspect, the terms "infection" and "bacterial infection" may refer to simple urinary tract infections (UTI). In yet another aspect, the terms "infection" and "bacterial infection" may refer to complicated urinary tract infections (cUTI). In yet another aspect, the terms "infection" and "bacterial infection" may refer to acute exacerbation of chronic bronchitis (ACEB). In yet another aspect, the terms "infection" 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 infection" may refer to infections caused by resistant bacteria. In yet another aspect, the terms "infection" and "bacterial infection" may refer to tube-related sepsis. In another aspect, the terms "infection" and "bacterial infection" may refer to chancroid. In yet another aspect, the terms "infection" and "bacterial infection" may refer to Chlamydia. In yet another aspect, the terms "infection" and "bacterial infection" may refer to community-acquired pneumonia (CAP). In yet another aspect, the terms "infection" and "bacterial infection" may refer to complicated skin and skin structure infections. In one aspect, the terms "infection" and "bacterial infection" may refer to simple skin and skin structure infections (SSSI). In another aspect, the terms "infection" and "bacterial infection" may refer to endocarditis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to febrile neutropenia. In yet another aspect, the terms "infection" and "bacterial infection" may refer to gonococcal cervicitis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to gonococcal urethritis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to hospital-acquired pneumonia (HAP). In another good aspect, the terms "infection" and "bacterial infection" may refer to osteomyelitis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to sepsis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to syphilis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to intra-abdominal infection (IAI). In one aspect of the invention, the terms "infection" and "bacterial infection" may refer to an infection selected from the group consisting of complicated urinary tract infection, simple 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 infection.

[0109] In one embodiment of the invention, the terms "infection" and "bacterial infection" refer to infections caused by gram-negative bacteria, also referred to as "gram-negative infections". In one aspect of this embodiment, gram-negative infections are infections resistant to one or more antibiotics. In one aspect of this embodiment, gram-negative infections are multidrug-resistant infections. In one aspect of this embodiment, gram-negative infections are caused by one or more Enterobacteriaceae (Enterobacteriaceaespp.) pathogens. In one aspect of this embodiment, the one or more Enterobacteriaceae pathogens include one or more Escherichia coli (E.coli), Klebsiella pneumoniae (K.pneumoniae), Klebsiella oxytoca (K.oxytoca), Citrobacter freundii (C.freundii), Citrobacter koseri (C.koseri), Enterobacter cloacae (E.cloacae), Proteus mirabilis (P.mirabilis), Morganella morganii (M.morganii) and / or Serratia marcescens (S.marcescens). In one aspect of this embodiment, the one or more Enterobacteriaceae pathogens include one or more Escherichia coli or Klebsiella pneumoniae pathogens. In another aspect of this embodiment, Gram-negative infections are caused by one or more biological threat pathogens. In one aspect of this embodiment, the one or more biological threat pathogens are Burkholderia spp., Yersinia pestis and / or F. tularensis. In any of these aspects of this embodiment, the one or more Gram-negative pathogens can express one or more serine beta-lactamases. In one aspect of this embodiment, the one or more serine beta-lactamases include one or more Class A, Class C and / or Class D beta-lactamases.

[0110] All of the above infections can be caused by various bacteria that may be treatable with the claimed agents in combination with penicillin binding protein inhibitors or by themselves. In one embodiment of the invention is a method for treating one or more of the above infections, the method comprising administering to a subject suffering from a bacterial infection an effective amount of a compound of formula (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 beta-lactam antibiotic. In one aspect of this embodiment, the additional antibiotic agent is a penicillin binding protein inhibitor.

[0111] In one aspect, provided is the use of a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) or a pharmaceutically acceptable salt thereof, alone or in combination with a penicillin binding protein inhibitor, in the manufacture of a medicament for producing an inhibitory effect on bacterial peptidoglycan in a warm-blooded animal, such as a human.

[0112] In another aspect, there is provided a use of a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a bacterial infection in a warm-blooded animal, such as a human. In one aspect, a compound of Formula (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 β-lactam antibiotic is selected from cefpodoxime, cefuroxime, tigemonam, loracarpa, cefixime, cephalexin, cefadroxil, cefmet, cefprozil, cefbutan, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren, or a prodrug thereof. In one aspect of this embodiment, the β-lactam antibiotic is cefpodoxime axetil. In one aspect of this embodiment, the β-lactam antibiotic is cefuroxime axetil. In one aspect of this embodiment, the β-lactam antibiotic is cefpodoxime or a prodrug thereof. In one aspect of this embodiment, the β-lactam antibiotic is cefuroxime or a prodrug thereof.

[0113] In yet another aspect, there is provided a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating complicated urinary tract infections, simple urinary tract infections, kidney infections, lower respiratory tract infections, hospital-acquired bacterial pneumonia, pneumonia, acute bacterial prostatitis, acute bacterial skin and soft tissue infections, sepsis, intra-abdominal infections and diabetic foot infections in warm-blooded animals such as humans. In one aspect of the invention, is a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating complicated urinary tract infections. In one aspect of the first two embodiments, a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) is administered in combination with another 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 β-lactam antibiotic. In one aspect of this embodiment, the β-lactam antibiotic is selected from cefpodoxime, cefuroxime, tigemonam, loracarpa, cefixime, cephalexin, cefadroxil, cefmet, cefprozil, cefbutan, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren and its prodrug. In one aspect of this embodiment, the β-lactam antibiotic is cefpodoxime axetil. In one aspect of this embodiment, the β-lactam antibiotic is cefuroxime axetil. In one aspect of this embodiment, the β-lactam antibiotic is cefpodoxime or its prodrug. In one aspect of this embodiment, the β-lactam antibiotic is cefuroxime or its prodrug. In one aspect of this embodiment, the β-lactam antibiotic is cefuroxime or its prodrug.

[0114] In another aspect, a method for producing a bacterial peptidoglycan inhibitory effect in a warm-blooded animal, such as a human, alone or in combination with a penicillin binding protein inhibitor is provided, the method comprising administering to the animal an effective amount of a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) or a pharmaceutically acceptable salt thereof.

[0115] In yet another aspect, a method of treating a bacterial infection in a warm-blooded animal, such as a human, is provided, the method comprising administering to the animal an effective amount of a compound of Formula (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 Formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof. In one aspect of this embodiment, for a compound of Formula (I), (II), (III), (IV) or (V), the compound is administered orally. In another aspect of this embodiment, a compound of Formula (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 embodiment, the additional antibiotic agent is a penicillin binding protein inhibitor. In one aspect, the additional antibiotic agent is a β-lactam antibiotic. In one aspect of this embodiment, the β-lactam antibiotic is selected from cefpodoxime, cefuroxime, tigemonam, loracarpa, cefixime, cephalexin, cefadroxil, cefmet, cefprozil, cefbutan, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs thereof. In one aspect of this embodiment, the β-lactam antibiotic is cefpodoxime axetil. In one aspect of this embodiment, the β-lactam antibiotic is cefuroxime axetil. In one aspect of this embodiment, the β-lactam antibiotic is cefpodoxime or a prodrug thereof. In one aspect of this embodiment, the β-lactam antibiotic is cefuroxime or a prodrug thereof.

[0116] In yet another embodiment, a method for treating a bacterial infection in a subject in need thereof is provided, the method comprising administering to the subject intravenously, intraperitoneally, intramuscularly or subcutaneously, preferably intravenously, an effective amount of a compound of Formula (Ia), (IIa), (IIIa), (IVa) or (Va) or a pharmaceutically acceptable salt thereof. Thus, compounds of Formula (Ia), (IIa), (IIIa), (IVa) or (Va) or a pharmaceutically acceptable salt thereof are advantageously used when the patient is unable to take medication by mouth, such as in a hospital setting (e.g., in an intensive care unit, an emergency room setting, on a cardiology floor, etc.), in an emergency care setting, and in a nursing home setting. In one aspect of this embodiment, the compound of Formula (Ia), (IIa), (IIIa), (IVa) or (Va), or a pharmaceutically acceptable salt thereof, is administered intravenously (IV). In one aspect of this embodiment, the compound of Formula (Ia), (IIa), (IIIa), (IVa) or (Va), or a pharmaceutically acceptable salt thereof, is administered until the patient is able to take oral medications, e.g., during a hospital stay or acute care stay, until the subject is able to be discharged from the hospital setting or acute care setting, or until the patient's condition has improved such that the patient can take oral medications, e.g., until the patient is able to take oral medications in a nursing home setting. In one aspect of this embodiment, the compound of Formula (Ia), (IIa), (IIIa), (IVa) or (Va), or a pharmaceutically acceptable salt thereof, is administered with a beta-lactam antibiotic. In one aspect of this embodiment, the β-lactam antibiotic is selected from cefpodoxime, cefuroxime, tigemonam, loracarbef, cefixime, cephalexin, cefadroxil, cefmet, cefprozil, cefbuten, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs thereof. In one aspect of this embodiment, the β-lactam antibiotic is cefpodoxime or a prodrug thereof. In one aspect of this embodiment, the β-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 a hospital setting or an emergency care setting, or when the subject has improved sufficiently to allow the subject to take oral medication, for example, 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 orally administered in a community setting.In one aspect of this embodiment, a compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, is administered in combination with a compound of Formula (Ia), (IIa), (IIIa), (IVa) or (Va) in a hospital setting, an acute care setting, or a nursing home setting, with the same β-lactam antibiotic with which it is paired. In one aspect of this embodiment, administration of a compound of Formula (Ia), (IIa), (IIIa), (IVa) or (Va) is followed by administration of a compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, once the patient is able to take medications orally, e.g., once the patient has been discharged from a hospital setting or an acute care setting and is in a community setting or their condition has improved sufficiently to allow oral medications in a nursing home setting. Preferably, the switch from intravenous, intraperitoneal, intramuscular or subcutaneous (compound of Formula (Ia), (IIa), (IIIa), (IVa) or (Va)) to oral administration (compound of Formula (I), (II), (III), (IV) or (V)) occurs without any gaps in the patient's treatment.

[0117] In yet another aspect, a method for treating complicated urinary tract infections, simple urinary tract infections, kidney infections, lower respiratory tract infections, hospital-acquired bacterial pneumonia (HAP), pneumonia, acute bacterial prostatitis, acute bacterial skin and soft tissue infections, sepsis, intra-abdominal infections, and diabetic foot infections in warm-blooded animals, such as humans, is provided, the method comprising administering to the animal an effective amount of a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) or a pharmaceutically acceptable salt thereof. In yet another aspect, a method for treating complicated urinary tract infections in warm-blooded animals, such as humans, is provided, the method comprising administering to the animal an effective amount of a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) or a pharmaceutically acceptable salt thereof. In one aspect of any of the foregoing embodiments, a compound of Formula (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 embodiment, the additional antibiotic agent is a penicillin binding protein inhibitor. In one aspect, the additional antibiotic agent is a β-lactam antibiotic. In one aspect of this embodiment, the β-lactam antibiotic is selected from cefpodoxime, cefuroxime, tigemonam, loracarb, cefixime, cephalexin, cefdroxil, cefazil, cefprozil, cefprozil, cefbuten, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs thereof. In one aspect of this embodiment, the β-lactam antibiotic is cefpodoxime axetil. In one aspect of this embodiment, the β-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 thereof.

[0118] In yet another aspect, a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) or a pharmaceutically acceptable salt thereof is provided for use alone or in combination with a penicillin binding protein inhibitor to produce a bacterial peptidoglycan inhibitory effect in a warm-blooded animal, such as a human. In one aspect, a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) or a pharmaceutically acceptable salt thereof is provided, alone or in combination with a β-lactam antibiotic, for use in treating gram-negative bacterial infections. In one aspect of this embodiment, the β-lactam antibiotic is selected from cefpodoxime, cefuroxime, tigemonam, loracarpa, cefixime, cephalexin, cefadroxil, cefmet, cefprozil, cefbutan, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs thereof. In one aspect of this embodiment, the β-lactam antibiotic is cefpodoxime axetil. In one aspect of this embodiment, the β-lactam antibiotic is cefuroxime axetil. In one aspect of this embodiment, the β-lactam antibiotic is cefpodoxime or a prodrug thereof. In one aspect of this embodiment, the β-lactam antibiotic is cefuroxime or a prodrug thereof.

[0119] In one aspect of the invention, a method of inhibiting one or more beta-lactamases is provided, the method comprising administering a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) or a pharmaceutically acceptable salt thereof to an animal in need thereof. In another aspect, the one or more beta-lactamases are serine beta-lactamases. In another aspect, the one or more beta-lactamases are selected from the group consisting of Class A, Class C and Class D. In yet another aspect, the one or more beta-lactamases are Class A enzymes. In yet another aspect, the one or more beta-lactamases are Class C enzymes. In yet another aspect, the one or more beta-lactamases are Class D enzymes. In yet another aspect, the one or more beta-lactamases are one or more of Class D enzymes and Class A and Class C enzymes. In yet another aspect, the one or more beta-lactamases are all three of Class A, C and D enzymes.

[0120] The β-lactamase inhibitors of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) may be used in combination with any β-lactam antibiotic belonging to, but not limited to, clavams, carbapenems, monobactams, penicillins and / or cephalosporins, or with any other compound susceptible to serine β-lactamase. In one aspect of the invention, the compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) are combined with one or more of the following: penicillin, methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin, temocillin, amoxicillin, ampicillin, combined amoxicillin-clavulanic acid, azlocillin, carbenicillin, temocillin Carcillin, mezlocillin, piperacillin, cephalexin, cephalothin, CXA-101, cefazolin, cefaclor, cefuroxime, cefmandole, cefotetan, cefoxitin, ceftriaxone, cefotaxime, cefpodoxime, cefixime, ceftazidime, ceftoroxil, cefepime, cefpirome, ceftaroline, imipenem, meropenem, ertapenem, faropenem, sulfapenem, doripenem, PZ-601 (Protez Pharmaceuticals), ME1036 (Forest Labs), BAL30072, MC-1, tomopenem, tebipenem, aztreonam, tigemonam, nocardiacin A, or tabtoxinine-β-lactam. In one aspect of the invention, a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) is combined with cefpodoxime, cefuroxime, tigemonam, cefixime or faropenem. In one aspect of the invention, a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) is combined with an antibacterial compound from the group consisting of penicillin V, cloxacillin, dicloxacillin, nafcillin, oxacillin, amoxicillin, ampicillin, bacampicillin, amoxicillin-clavulanic acid, carbenicillin, cefadroxil, cephalexin, cephradine, cefaclor, cefprozil, cefuroxime axetil, cefdinir, loracabef, cefixime, cefpodoxime and ceftibuten, or a prodrug or salt thereof.In one aspect of the invention, a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) is combined with an antibacterial compound from the group consisting of cefpodoxime, cefuroxime, tigemonam, loracarbef, cefixime, cephalexin, cefadroxil, cefetamet, cefprozil, cefbuten, cefditoren, faropenem, tebipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs thereof. In one aspect of the invention, a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) is combined with cefpodoxime or a prodrug thereof, such as cefpodoxime axetil. In one aspect of the invention, a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) is combined with cefuroxime or a prodrug thereof, such as cefuroxime axetil.

[0121] In another aspect of the invention, the compound of formula (I), (II), (III) or (IV) is administered in combination with a β-lactam antibiotic and an additional antibiotic and / or an additional β-lactamase inhibitor. In one aspect of the invention, the additional antibiotic agent is selected from one of the following classes: aminoglycosides, spectinomycins, macrolides, ketolides, streptogramins, oxazolidinones, tetracyclines, fluoroquinolones, quinolones, coumarin antibiotics, glycopeptides, lipoglycopeptides, nitroimidazoles, ansamycins, phenicols, mupirocyn, fosfomycin, tobramycin, linezolid, daptomycin, vancomycin, β-lactams, and the classes mentioned in ANTIMICROBIAL AGENTS (ASM Press, Editor: A. Bryskier (2005)).

[0122] In one aspect of the invention, a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) is administered in combination with a β-lactam antibiotic and a second agent intended to address β-lactam resistance. In one aspect of the invention, the second agent intended to address β-lactam resistance can be a metallo-β-lactamase (MBL) inhibitor, also known as a class B inhibitor.

[0123] In one aspect, a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), or a pharmaceutically acceptable salt thereof, is provided for use in treating a bacterial infection in a warm-blooded animal, such as a human.

[0124] In another aspect, a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), or a pharmaceutically acceptable salt thereof, is provided for use in treating complicated urinary tract infections, simple urinary tract infections, kidney infections, lower respiratory tract infections, hospital-acquired bacterial pneumonia, pneumonia, acute bacterial prostatitis, acute bacterial skin and soft tissue infections, sepsis, intra-abdominal infections and diabetic foot infections in warm-blooded animals such as humans. In another aspect, a compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), or a pharmaceutically acceptable salt thereof, is provided for use in treating complicated urinary tract infections in warm-blooded animals such as humans.

[0125] In yet another aspect, a pharmaceutical composition is provided, comprising a compound of formula (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 β-lactam antibiotic. In one aspect of this embodiment, the β-lactam antibiotic is selected from cefpodoxime, cefuroxime, tigemonam, loracarb, cefixime, cephalexin, cefadroxil, cefmetamido, cefprozil, cefbuten, cefditoren, faropenem, tibipenem, amoxicillin, carbenicillin, cefdinir, ampicillin, cefditoren and prodrugs thereof.

[0126] The compositions of the invention may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by insufflation (e.g., as finely divided powders) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular administration, or as suppositories for rectal administration). In one aspect of the invention, the compound of Formula (Ia), (IIa), (IIIa), (IVa) or (Va), or a pharmaceutically acceptable salt thereof, is administered intravenously. In another aspect of the invention, the compound of Formula (Ia), (IIa), (IIIa), (IVa) or (Va), or a pharmaceutically acceptable salt thereof, is administered intravenously in combination with one or more other antibacterial agents. In one aspect of the invention, the compound of formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, is administered orally. In another aspect of the invention, the compound of formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof, is administered orally in combination with one or more other antibacterial agents. In one aspect of any of these embodiments, the compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), or a pharmaceutically acceptable salt thereof, is administered simultaneously with one or more other antibacterial agents. In another aspect of this embodiment, the compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va), or a pharmaceutically acceptable salt thereof, is administered sequentially with one or more other antibacterial agents, such as β-lactam antibiotics.

[0127] One embodiment of the invention is a method of treating a bacterial infection in a human in need thereof, comprising administering to said human intravenously an effective amount of a compound of one of Formula (Ia), (IIa), (IIIa), (IVa) or (Va) in combination with one or more additional antibacterial agents in a hospital setting, an acute care setting, or a nursing home setting, and then orally administering to said human an effective amount of a compound of one of Formula (I), (II), (III), (IV) or (V) in combination with one or more additional antibacterial agents outside of, for example, a hospital setting, an acute care setting, or a nursing home setting, once the patient is again able to take medications by mouth.

[0128] One embodiment of the invention is a method of treating a bacterial infection in a human in need thereof, the method comprising administering to the human an effective amount of one or more intravenous, intraperitoneal, intramuscular or subcutaneous antibacterial agents, such as a compound of Formula (Ia), (IIa), (IIIa), (IVa) or (Va) or a pharmaceutically acceptable salt thereof, followed by oral administration to the human of an effective amount of a compound of one of Formula (I), (II), (III), (IV) or (V) in combination with one or more additional antibacterial agents. The nature, dosage and duration of the antibiotic therapy and the timing of switching from intravenous, intraperitoneal, intramuscular or subcutaneous administration to oral administration are generally selected by the physician and may depend on the patient's health, his or her ability to accept oral therapy, and the type of infection the person has. The patient may be switched from intravenous, intraperitoneal, intramuscular or subcutaneous therapy to oral therapy when the patient becomes asymptomatic, afebrile or has a reduced fever (e.g., below 100.5°F, 100°F, 99.5°F, etc.), is removed from the ventilator, or no longer requires intravenous fluids.

[0129] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients known in the art. Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrants such as corn starch or algenic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl paraben; and antioxidants such as ascorbic acid. Tablet formulations can be uncoated or coated, the coating being either to modify their disintegration in the gastrointestinal tract and subsequent absorption of the active ingredient, or to improve their stability and / or appearance, in both cases using conventional coating agents and methods known in the art.

[0130] The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host being treated and the specific route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, an active agent mixed with an appropriate and convenient excipient dosage, the amount of which may vary from about 5% by weight to about 98% by weight of the total composition. The dosage unit form generally contains from about 100 mg to about 4000 mg of active ingredient. For oral administration of, for example, a compound of formula (I), (II), (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, 0.1 g to 10 g of active ingredient per day is suitable; and for intravenous administration of, for example, a compound of formula (Ia), (IIa), (IIIa), (IVa) or (Va) or a pharmaceutically acceptable salt thereof, 0.5 to 8 g of active ingredient per day is suitable.

[0131] In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain or co-administer (simultaneously, sequentially or separately) one or more known drugs selected from other clinically useful antibacterial agents (e.g., macrolides, quinolones, β-lactams or aminoglycosides) and / or other anti-infective agents (e.g., antifungal triazoles or amphotericin). These may include carbapenems, such as meropenem or imipenem, to extend the therapeutic effect. The compounds of the present invention may also contain or co-administer bactericidal / permeability increasing protein (BPI) products or efflux pump inhibitors to improve activity against Gram-negative bacteria and antimicrobial resistant bacteria.

[0132] As mentioned above, the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily vary depending on the host being treated, the route of administration and the severity of the condition being treated. Thus, the optimum dose can be determined by the practitioner treating any particular patient.

[0133] Compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va) may be prepared in a variety of ways. The process shown below illustrates a method for synthesizing a compound of formula (I) (wherein R 1 , R 2 and R 3 Unless otherwise indicated, as defined above). The reactions are carried out in a solvent suitable for the reagents and materials used and suitable for the transformations being performed. In addition, in the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and post-processing procedures, should be selected as standard conditions for the reaction, which should be readily recognized by those skilled in the art. It should be understood by those skilled in the art of organic synthesis that the functional groups present on the various parts of the molecule must be compatible with the proposed reagents and reactions. Such restrictions on substituents that are compatible with the reaction conditions are obvious to those skilled in the art, and alternative methods must then be used. The schemes and methods are not intended to provide an exhaustive list of methods for preparing compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V) or (Va); on the contrary, other techniques known to skilled chemists may also be used for the synthesis of the compounds. The claims are not intended to be limited to the structures shown in the schemes and processes.

[0134] It will also be appreciated that in some of the reactions shown in the schemes and processes mentioned herein, it may be necessary / desirable to protect any sensitive groups in the compounds. The situations where it is necessary or desirable to protect are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups can be used according to standard operating procedures (illustration see TW Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, (1991)) and as described above.

[0135] A skilled chemist will be able to use and adapt the information contained and cited in the above-mentioned references, as well as the exemplifications appended therein and the examples and schemes herein, to obtain the necessary starting materials and products.

[0136] If not commercially available, the necessary starting materials for use in, for example, the procedures described herein may be made by techniques selected from standard organic chemistry techniques, techniques analogous to the synthesis of known structurally similar compounds, or techniques analogous to the procedures described in the described procedures or examples.

[0137] It should be noted that many of the starting materials for the synthetic methods described herein are commercially available and / or widely reported in the scientific literature, or can be made from commercially available compounds using adaptations of processes reported in the scientific literature. For general guidance on reaction conditions and reagents, the reader is further referred to Advanced Organic Chemistry by Jerry March and Michael Smith, 5th edition, published by John Wiley and Sons (2001).

[0138] General procedures and protocols:

[0139] In one aspect, compounds of formula (I) and (Ia), or pharmaceutically acceptable salts thereof, can be prepared by the process outlined in Scheme 1. Starting from the Weinreb amide, the reaction of R in formula (I) and (Ia) can be carried out via a Grignard reaction. 3 The ester moiety can be introduced by palladium-catalyzed deallylation followed by alkylation with bromoacetate. Ester hydrolysis produces the acid. Alternatively, other R 1 Group.

[0140] Scenario 1:

[0141]

[0142] Synthesis in R 3An alternative method for the preparation of substituted compounds is shown in Scheme 2, with the key steps being the Diels-Alder reaction and the nitrosoene reaction.

[0143] Solution 2

[0144]

[0145] Acetate and ester moieties can be introduced according to Scheme 3 in one or two steps.

[0146] Solution 3

[0147]

[0148] In another aspect, compounds of formula (I) and (Ia) or pharmaceutically acceptable salts thereof can be prepared by the process outlined in Scheme 4, wherein R 2 The substitution at can be installed onto enone 1 via Michael addition followed by oxidation to afford enone 2, with the chemistry being similar to that described in Scheme 1.

[0149] Solution 4

[0150]

[0151] Alternatively, R can be installed after urea cyclization according to Scheme 5 1 Amide.

[0152] Solution 5

[0153]

[0154] In R 2 Substituted compounds can also be synthesized from Garner aldehydes as shown in Scheme 6. The route from primary amines to compounds of formula (I) or (Ia) is similar to Scheme 1.

[0155] Solution 6

[0156]

[0157] In addition, in R 2 Compounds with substitution at can be synthesized according to Scheme 7 below, where the key step is the nitrosoene reaction. Amides can also be installed from carboxylic acids early in the synthesis and maintained to the end.

[0158] Solution 7

[0159]

[0160] Alkyl bromoacetates used to introduce carboxylic acid and ester moieties can be prepared by transesterification according to Scheme 8.

[0161] Solution 8

[0162]

[0163] Chiral bromofluoroacetates for introduction of R and S fluorocarboxylic acid and ester moieties can be prepared by recrystallization of bromofluoroacetic acid with chiral phenylethylamine according to Scheme 9 followed by esterification.

[0164] Solution 9

[0165]

[0166] In any of the above pharmaceutical compositions, processes, methods, uses, medicaments and manufacturing features of the present invention, any of the alternative embodiments of the compounds of the present invention described herein also apply. For example, further details and methods of performing nitrosoalkene reactions on various substrates are described in the Examples section below. These details and methods include, for example, a first process for forming a compound of Formula VI or a salt thereof:

[0167]

[0168] in,

[0169] R 1 Yes-C(O)NR 7 R 8 、-C(O)OR 7 、-CH 2 OR 7 , -CN, phenyl, 5-6 membered heteroaryl, -C(O)NR'NR'C(O)R 9 、-C(O)NR'OR 10 or C 1 -C 6 Alkyl groups, wherein the alkyl groups are substituted by halogen, C 1 -C 3 Alkoxy, -OH, -CN, -NR 7 R 8 、-NR 7 COR 9 , 5-6 membered heteroaryl and 5-7 membered heterocyclic group, and wherein R 1 The phenyl and heteroaryl groups represented by 1 -C 3 Alkoxy, -CN, -NR 7 R 8 and-CONR 7 R 8 1-3 groups are substituted;

[0170] R 2 and R 3are each independently selected from hydrogen, halogen, C 1 -C 3 Alkyl and C 3 -C 6 Cycloalkyl, provided that R 2 and R 3 At least one of them is not hydrogen;

[0171] Each R 7 and R 8 are independently hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, phenyl, C 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein R 7 or R 8 The alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl groups represented by the present invention are optionally and independently selected from the group consisting of: optionally substituted by one or two -F atoms, carboxyl or -CO(OC 1-6 alkyl) substituted 5-6 membered heterocyclic group, 5-6 membered heteroaryl, -CN, -OH, optionally substituted with -NH 2 or -OH substituted C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Alkoxy-NHCO(C 1 -C 3 Alkyl), -NHCO(C 1 -C 3 Alkoxy), -S(O) 2 NR'R", -NHS(O) 2 NR'R", -NHS(O) 2 (C 1 -C 3 alkyl), -NR'R" and -C(O)NR'R";

[0172] Each R 9 It is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy or C 1 -C 6 Alkoxy;

[0173] Each R' and R" is independently hydrogen, methyl, ethyl or propyl; or R' and R" together with the nitrogen to which they are attached form a 5-6 membered heterocyclic group; and

[0174] PG and PG' are each independently an amine protecting group;

[0175] The process comprises:

[0176] The compound of formula XI:

[0177]

[0178] or a salt thereof, reacted with PG'NHOH in the presence of an oxidizing agent to form a compound of formula VI;

[0179] Also provided is a second process for forming a compound of formula VI or a salt thereof:

[0180]

[0181] in,

[0182] R 1 Yes-C(O)NR 7 R 8 、-C(O)OR 7 、-CH 2 OR 7 , -CN, phenyl, 5-6 membered heteroaryl, -C(O)NR'NR'C(O)R 9 、-C(O)NR'OR 10 or C 1 -C 6 Alkyl groups, wherein the alkyl groups are substituted by halogen, C 1 -C 3 Alkoxy, -OH, -CN, -NR 7 R 8 、-NR 7 COR 9 , 5-6 membered heteroaryl and 5-7 membered heterocyclic group, and wherein R 1 The phenyl and heteroaryl groups represented by 1 -C 3 Alkoxy, -CN, -NR 7 R 8 and-CONR 7 R 8 1-3 groups are substituted;

[0183] R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-C 3 Alkyl and C 3 -C 6 Cycloalkyl, provided that R 2 and R 3 At least one of them is not hydrogen;

[0184] Each R 7 and R 8 are independently hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, phenyl, C 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl, wherein R 7 or R 8 The alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl groups represented by the present invention are optionally and independently selected from the group consisting of: optionally substituted by one or two -F atoms, carboxyl or -CO(OC 1-6 alkyl) substituted 5-6 membered heterocyclic group, 5-6 membered heteroaryl, -CN, -OH, optionally substituted with -NH 2 or -OH substituted C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Halogenated alkoxy, C 1 -C 3 Alkoxy-NHCO(C 1 -C 3 Alkyl), -NHCO(C 1 -C 3 Alkoxy), -S(O) 2 NR'R", -NHS(O) 2 NR'R", -NHS(O) 2 (C 1 -C 3 alkyl), -NR'R" and -C(O)NR'R";

[0185] Each R 9 It is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy or C 1 -C 6 Alkoxy;

[0186] Each R' and R" is independently hydrogen, methyl, ethyl or propyl; or R' and R" together with the nitrogen to which they are attached form a 5-6 membered heterocyclic group; and

[0187] PG and PG' are each independently an amine protecting group;

[0188] The process comprises:

[0189] The compound of formula XI:

[0190]

[0191] or a salt thereof, and reacted with PG'N=O to form a compound of formula VI.

[0192] In the first aspect, the compound of formula XI in the first or second process is a compound of the formula:

[0193]

[0194] or a salt thereof.

[0195] In a second aspect, the compound of formula VI in the first or second process is a compound of formula VII:

[0196]

[0197] or a salt thereof.

[0198] In a third aspect, R in the first or second process 2 , or Formula VII is C 1 -C 3 Alkyl, wherein the remaining features are as described in the first or second process and the first or second aspect. Alternatively, R in the first or second process 2 , or formula VII is methyl, wherein the remaining features are as described in the first or second process and the first or second aspect.

[0199] In a fourth aspect, the compound of formula VI in the first or second process is a compound of formula VIII:

[0200]

[0201] or a salt thereof, wherein the remaining features are as described in the first or second process and the first or second aspect.

[0202] In the fifth aspect, R in the first or second process 3 , or formula VIII is C 1 -C 3 Alkyl, wherein the remaining features are as described in the first or second process and the first or second aspect. Alternatively, R in the first or second process 3, or formula VIII is methyl, wherein the remaining features are as described in the first or second process and the first or second aspect.

[0203] In the sixth aspect, R in the first or second process 1 Selected from oxadiazole, -C(O)NHNHC(O)(C 1 -C 3 Alkyl), -CH 2 NH 2 、-CH 2 NHCO(C 1 -C 3 Alkoxy), -CH 2 NHCO(C 1 -C 3 alkyl) or -CH 2 NHCO(C 1 -C 3 haloalkyl), wherein R 1 The oxadiazole is optionally substituted with -OH, C 1 -C 3 Alkoxy, -NR 7 R 8 or-CONR 7 R 8 Replaced; and wherein the remaining features are as described in the first or second process and the first, second, third, fourth or fifth aspect.

[0204] In the seventh aspect, R in the first or second process 1 Selected from -CH 2 NH 2 , And wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth or sixth aspect.

[0205] In the eighth aspect, R in the first or second process 1 Yes: -CN,

[0206]

[0207]

[0208] Where R 11 is hydrogen or -C(O)NH 2 ; and wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth or seventh aspect.

[0209] In the ninth aspect, R in the first or second process 1 Yes-C(O)NR 7 R8 、-C(O)OR 7 or -CN; and 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, R in the first or second process 1 Yes -C(O)NH 2 , -C(O)OH, -CN or -C(O)OC 1 -C 6 wherein the remaining features are as described in the first or second process and the first, second, third, fourth, fifth, sixth, seventh or eighth aspects. In another alternative, R in the first or second process 1 Is -CN or -C(O)NH 2 ; 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, R in the first or second process 1 is -CN; 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, R in the first or second process 1 Yes-C(O)NR 7 R 8 ; 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.

[0210] In the tenth aspect, R in the first or second process 7 and R 8 Both are 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. Alternatively, R in the first or second process 7 is hydrogen and R 8 Yes: 1) optionally C 1 -C 3 Alkyl or C 1 -C 3 Alkyl-NH 2 Substituted phenyl, 2) C 1 -C 3 Alkyl or 3)C 1 -C 3 Alkoxy, wherein R 8 Each alkyl or alkoxy group represented by 3 -C 6 Cycloalkyl, -CN, -OH, -NH 2 、-SO 2 NH 2 、-NHSO 2 NH2 、-C(O)NH 2 、-NHC(O)(C 1 -C 3 alkyl), pyrazinyl, oxetanyl, oxazolyl, or optionally substituted by one or more carboxyl, fluorine or -C(O)O(C 1 -C 6 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. In another alternative, R in the first or second process 7 is hydrogen and R 8 Selected from the group consisting of:

[0211]

[0212]

[0213] -CH 2 CN and -CH 2 OH; 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.

[0214] In the eleventh aspect, the compound of formula VI in the first or second process is a compound of formula IX:

[0215]

[0216] or a salt thereof.

[0217] In the twelfth aspect, the compound of formula VI in the first or second process is a compound of formula X:

[0218]

[0219] or a salt thereof.

[0220] In the thirteenth aspect, PG and PG' in the first or second process, together with the nitrogen atom of the amine they protect, independently form a carbamate, an amide, or an N-benzyl or N-aryl group; 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 independently selected from tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), 2,2,2-trifluoroethoxycarbonyl (Troc), CF 3CO, acetyl (Ac), p-toluenesulfonamide (Ts) and methanesulfonyl (Ms); 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 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 tert-butyloxycarbonyl; 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.

[0221] In the fourteenth aspect, the first process further 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 selected from CuCl, CuBr, CuI, CuCN, CuSCN, CuBr-Me 2 S, 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 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 halide salt; 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 is CuCl or CuBr-Me 2 S; 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.

[0222] In the fifteenth aspect, the first process further 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 aspect. In one aspect, the amine additive process is pyridine, (1R,2R)-cyclohexane-1,2-diamine, N,N'-dimethylethane-1,2-diamine, 2,6-di-tert-butyl-4-methylpyridine, 1,10-phenanthroline, trans-cyclohexane-1,2-diamine, N1-(2-(diethylamino)ethyl)-N2,N2-diethylethane-1,2-diamine, cis-cyclohexane-1,2-diamine or N1,N1,N2,N2-tetramethylethane-1,2-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. Alternatively, the amine is selected from pyridine, 2,6-lutidine, 4-dimethylaminopyridine, picoline, 1,8-diazabicyclo[5.4.0]undec-7-ene and N,N-diisopropylethylamine; 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 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.

[0223] In the sixteenth aspect, the oxidant in the first or second process is O 2 , air, FeCl 3 、MnO 2 , m-chloroperbenzoic acid (mCPBA), NaIO 4 , 2-iodobenzoic acid (IBX), (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO), benzoyl peroxide (BPO), HIO 3 , Urea-H 2 O 2 ,I 2 , N-chlorosuccinimide (NCS), Dess-Martin periodinane (DMP), H 2 O 2 or N-methylmorpholine N-oxide (NMMO); 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. Alternatively, the oxidant is urea-H 2 O 2 , H2 O 2 or 2 ; 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.

[0224] In the seventeenth aspect, the reaction in the first or second process is carried out in a polar solvent; 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. Alternatively, the reaction is carried out in DCM, THF, MTBE, EtOAc, iPrOAc, MeCN, H 2 O, MeOH, EtOH, i-PrOH, t-BuOH, n-BuOH, 2-methyl-2-butanol, DMF, DMSO, ethylene glycol, polyethylene glycol, sulfolane, sulfolane / H 2 O mixture, DMF / H 2 O、NMP / H 2 O、DCM / H 2 O, MeOH / H 2 O, EtOH / H 2 O、iPrOH / H 2 O or n-BuOH / H 2 O; 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 dichloromethane or sulfolane; 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.

[0225] In the eighteenth aspect, the reaction in the first or second process further comprises adding water; 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, sixteenth or seventeenth aspect.

[0226] Example

[0227] The invention will now be further described with reference to the following illustrative examples, in which, unless otherwise stated:

[0228] (i) Temperatures are given in degrees Celsius (°C); operations are carried out at room or ambient temperature, i.e. in the range of 18-25°C;

[0229] (ii) drying the organic solution over anhydrous magnesium sulfate; evaporation of the organic solvent was performed using a rotary evaporator under reduced pressure (4.5-30 mmHg) with a maximum bath temperature of 60°C;

[0230] (iii) Chromatography refers to flash chromatography on silica gel; thin layer chromatography (TLC) is performed on silica gel plates;

[0231] (iv) Generally, the reaction progress was followed by TLC or liquid chromatography / mass spectrometry (LC / MS), and the reaction times given are for illustration only;

[0232] (v) the final product has satisfactory proton nuclear magnetic resonance (NMR) spectrum and / or mass spectrum data;

[0233] (vi) Yields given are for illustration only and are not necessarily obtainable through diligent process development; preparations were repeated if more material was required;

[0234] (vii) When given, NMR data are given as delta values ​​of major diagnostic protons in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard in DMSO-d 6 Measured at 300 MHz unless otherwise stated;

[0235] (viii) Chemical symbols have their usual meanings;

[0236] (ix) Solvent ratios are given in volume:volume (v / v) terms;

[0237] (x) ISCO Combiflash refers to the use of ISCO Separation system Flash chromatography on silica gel: RediSep normal phase flash column, flow rate, 30-40 ml / min;

[0238] (xi) The following abbreviations may be used:

[0239] ACN Acetonitrile

[0240] BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[0241] Boc 2 O tert-Butyloxycarbonyl anhydride

[0242] CDI N,N-Carbonyldiimidazole

[0243] DAST Diethylaminosulfur trifluoride

[0244] DCM Dichloromethane

[0245] DIPEA / DIEA N,N-Diisopropylethylamine

[0246] DMAc N,N-Dimethylacetamide

[0247] DMF N,N-Dimethylformamide

[0248] DMAP 4-dimethylaminopyridine

[0249] DMSO Dimethyl sulfoxide

[0250] ee enantiomeric excess

[0251] EtOAc / EA Ethyl acetate

[0252] Et 2 O Diethyl ether

[0253] GC Gas Chromatography

[0254] HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0255] Hex

[0256] HPLC High Performance Liquid Chromatography

[0257] hr / h hour

[0258] KO t Bu Potassium tert-butoxide

[0259] LCMS Liquid chromatography mass spectrometry

[0260] LDA Lithium diisopropylamide

[0261] MeCN Acetonitrile

[0262] MeOH Methanol

[0263] mins / min minutes

[0264] MTBE Methyl tert-butyl ether

[0265] o / n Overnight

[0266] Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0)

[0267] PE Petroleum Ether

[0268] iPrOH Isopropyl alcohol

[0269] rac. racemic

[0270] TBAF Tetra-n-butylammonium fluoride

[0271] TEA Triethylamine

[0272] TFA Trifluoroacetic acid

[0273] THF Tetrahydrofuran

[0274] TMS Trimethylsilyl

[0275] Tosyl, Ts p-toluenesulfonyl

[0276] UPLC-MS Ultra-Performance Liquid Chromatography-Mass Spectrometry

[0277] Nitrosolene Conditions and Tests

[0278] In certain aspects, the nitrosoene reaction is used to install the necessary allylic hydroxylamine functionality. (Waldemar 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, the hydroxylamine is oxidized to produce a highly reactive nitroso species, which reacts with an allylic substrate as shown in Scheme 10. The oxidant can be an organic oxidant, or a combination of an oxidant, a metal catalyst, and an optional amine additive. The nitroso species can be formed in situ from the hydroxylamine (e.g., in the reaction to form the compound of formula VI), or prepared separately and then added to a substrate, such as a compound of formula XI. For 1,2,3,6-tetrahydropyridine scaffolds with N-carbamate functional groups, it is believed that the A imposed by the N-Boc functional group (1,3) Allyl strain leads to R 1 The substituent adopts a pseudo-axial orientation. It is believed that this blocks access to the nitroso reactant from the double bond side. 1 The opposite side of the amine reacts regio- and diastereoselectively to form the desired product with high diastereo- and regio-selectivity. The enantioselectivity is measured by chiral HPLC analysis and has been shown to be consistently high, >99% ee.

[0279] Solution 10

[0280]

[0281] Reaction parameters such as oxidant, catalyst, ligand, solvent, reagent stoichiometry, reaction temperature and reaction time can affect the reaction outcome and are screened and optimized. Some results are summarized in the table below (ND = not determined).

[0282] Oxidant screening

[0283]

[0284]

[0285] Solvent screening

[0286]

[0287]

[0288] Catalyst screening

[0289]

[0290]

[0291] Additive screening

[0292]

[0293]

[0294]

[0295] After screening, for those with PG 1 =PG 2 =Boc, R 1 =CONH 2 , R 2 =Me, R 3 The optimal conditions for the substrate with =H were: BocNHOH (1.5 equiv), CuCl (0.05 equiv), Py (0.013 equiv), DCM (10 V), O 2 (1 atmosphere), 15-25°C. For PG 1 =PG 2 =Boc, R 1 =CONH 2 , R 2 =H, R 3 The optimal conditions for the substrate of =Me were: BocNHOH (1.5 equiv), CuCl (0.05 equiv), Py (0.013 equiv), sulfolane (5 V), H 2 O(5V),O2 (1 atm), 15-25°C or BocNHOH (2 equivalents), CuBr-Me 2 S (0.05 eq.), Py (0.13 eq.), sulfolane (5 V), H 2 O(0.5V), H 2 O 2 (3% aqueous solution, 2-3 eq.), 15-25°C.

[0296] The following experimental procedure is provided for illustrative purposes.

[0297]

[0298] To the starting material (1 eq.), BocNHOH (2 eq.), CuBr 2 -SMe 2 To the mixture of sulfolane (5 V) and H2O (0.5 V), pyridine (0.13 eq.) (0.05 eq.) was added. The mixture was stirred at 15-25 °C for 30-40 min. 3% H 2 O 2 (2 equivalents) for 24-30 hours. After the reaction is judged to be complete, a solution of EDTA-2Na (0.31-0.32 equivalents by weight) in water (3-3.2x by weight) and MTBE (7.7x by weight) are added. The resulting mixture is stirred for 20-30 minutes and allowed to settle for 20-30 minutes. The two phases are separated. The aqueous phase is extracted three times with MTBE (4x by weight). The combined organic solution is washed with Na 2 SO 4 Dried and filtered, concentrated and analyzed by assay. 47.5% yield, 74.12% area purity by HPLC.

[0299]

[0300] To the crude solution of the substrate from the previous step in DCM were added CuCl (0.05 eq), BocNHOH (1.5 eq) and Py (0.013 eq). The mixture was heated at 20 ± 5 °C and O 2Stir under atmosphere until the starting material is ≤5% according to HPLC% area. EDTA-2Na solution (5.0 vol) is added and the resulting mixture is stirred at 25±5°C for at least 4 hours. The two phases are separated. The aqueous phase DCM (3.0 vol) is extracted twice. The organic phases are combined, washed once with water (5.0 vol), and concentrated in vacuo to ~3.0 vol at <40°C. i-PrOAc (5.0V) is added to the reactor and the mixture is concentrated in vacuo to ~4.0 vol at <40°C. The process is repeated once more. n-heptane (5.0 vol) is added to the reactor at 40±5°C. The resulting mixture is gradually cooled to 20±5°C. The solid is obtained by centrifugation and washed with i-PrOAc / n-heptane (1:1, 2 vol) and dried in vacuo at 35±5°C for at least 12 hours. The 2-step yield is 71.68%, and the purity according to HPLC% area is 99.7%

[0301] Intermediate 1: (S)-2-(1-hydroxybut-3-en-2-yl)isoindoline-1,3-dione

[0302]

[0303] A 2-L reaction flask containing a stirring bar and sodium carbonate (1.981 g, 18.69 mmol) was placed under high vacuum and dried with a heat gun for 10 minutes. After cooling, the flask was backfilled with nitrogen. Allyl palladium chloride dimer (0.553 g, 1.53 mmol), (1R, 2R)-(+)-1,2-diaminocyclohexane-N,N'-bis(2-diphenylphosphino-1-naphthoyl) (CAS174810-09-4) (3.36 g, 4.25 mmol) and phthalimide (50 g, 339.83 mmol) were added thereto. The flask was then purged with nitrogen for ten minutes. 1.4 L of dichloromethane, which had been degassed with a nitrogen line for ten minutes, was then added. The suspension was placed under a nitrogen atmosphere; it was alternately stirred and sonicated within 10 minutes to promote solvation. At that time, it was a yellow or light orange solution containing a white solid. 2-vinyl oxirane (24.06g, 343.23mmol) is added to the mixture. The resulting mixture is stirred for about 48 hours at ambient temperature and under a nitrogen atmosphere. During this period, the progress of the reaction is analyzed by LCMS and TLC (1:1 hexane: ethyl acetate), and the final analysis of those methods indicates that the starting material is completely converted into a major product. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The yellow viscous fluid is injected into a 330g silica gel column: the raw material is diluted with dichloromethane of a minimum volume. The target product is separated using silica gel chromatography (hexane solution of 15-75% ethyl acetate, 40 minutes, 330g column), which is a viscous yellow fluid that becomes a light yellowish white solid (69.6g, 94%) under reduced pressure through several hours.

[0304] Optical rotation : (2.02 g / 100 mL, dichloromethane) Literature value = -72.2, obtained value = -71.

[0305] Intermediate 2: (S)-2-(1-(tert-butyldimethylsilyloxy)but-3-en-2-yl)isoindoline-1,3-diol ketone

[0306]

[0307] To a stirred 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 dichloromethane (160 mL) was added tert-butyldimethylsilyl chloride (55.4 g, 367.41 mmol) as a solid at ambient temperature under a nitrogen atmosphere. The addition took about ten minutes. Warming of the mixture was observed during the addition. After stirring for 2 hours, the solution was poured into saturated aqueous sodium bicarbonate solution (about 150 mL); the biphasic mixture was shaken, and the organic layer was separated. The aqueous layer was back-extracted three times with 200 mL of dichloromethane each time. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. After drying under high vacuum overnight, the desired product was obtained as a light yellow solid (107 g, 101%).

[0308] Intermediate 3: (S)-1-(tert-butyldimethylsilyloxy)but-3-en-2-amine

[0309]

[0310] 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) was added hydrazine (35.9 mL, 1143.29 mmol) at ambient temperature and under a nitrogen atmosphere. The yellow solution was heated to 65°C. Within 30 minutes of reaching the reaction temperature, a white precipitate was observed in the reaction mixture; the solid quickly became the bulk of the mixture, at which point water (approximately 150 mL) was added to the reaction mixture. The reaction was continued to stir uninterrupted, and within a few minutes the solid dissolved. After analysis by LCMS indicated complete conversion (both the starting material and the product produced strong UV signals and were easily identified by LCMS), the heat was removed and more water was added (total water content was 600 mL). The mixture was allowed to reach ambient temperature.

[0311] Methanol was removed under vacuum (moderate reduced pressure) at 35°C; the vacuum was removed, the aqueous solution was warmed to about 50°C, and then extracted with 4x200 mL of dichloromethane. The organic extracts were combined, washed with saturated sodium bicarbonate (aqueous), washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum at no more than 30°C. The desired product was obtained as a yellow liquid (58.5 g, 94%).

[0312] Intermediate 4: 2-Bromo-N-methoxy-N-methylacetamide

[0313]

[0314] Prepare a stirred solution of potassium carbonate (343 g, 2.48 mol) in water (about 800 mL) and cool it in an ice bath under nitrogen for 15 minutes. Add O, N-dimethylhydroxylamine hydrochloride (110 g, 1.13 mol) and diethyl ether (about 800 mL) to it. Then add bromoacetyl bromide (273 g, 1.35 mol) to the mixture through an addition funnel over 20 minutes. Remove the ice bath and stir the mixture under nitrogen for 2 hours. Separate the layers and extract the aqueous layer with diethyl ether (about 350 mL). Combine the organic layers, dry over magnesium sulfate, filter, and concentrate in vacuo. Obtain the target product as a yellow liquid (143 g, 70%).

[0315] Intermediate 5: (S)-1-(tert-butyldimethylsilyloxy)but-3-en-2-yl (2-(methoxy(methyl)amino tert-Butyl)-2-oxoethyl)carbamate

[0316]

[0317] Prepare (S)-1-(tert-butyldimethylsilyloxy)but-3-ene-2-amine (intermediate 3, 60.4g, 300mmol) and cesium carbonate (103g, 315mmol) in acetonitrile (about 700mL) and water (about 120mL) suspension and stir in ice bath under nitrogen for 5 minutes. The mixture is biphasic and remains like this during the reaction. Then add 2-bromo-N-methoxy-N-methylacetamide (intermediate 4, 57.0g, 285mmol) to the mixture through a charging funnel in 10 minutes. The mixture is stirred for two days, and the temperature is maintained near 0°C. The mixture is left in a refrigerator overnight. Add 0.05 equivalent of the described electrophilic reagent. Di-tert-butyl dicarbonate (165mL, 2M THF solution) is added to the mixture. The organic layer is separated from the aqueous solution (TLC shows that no product remains in the aqueous solution), and the organic layer is concentrated in vacuo. Silica gel chromatography (5-55% ethyl acetate in hexanes) gave the desired product in three batches as a light yellow oil (80 g, 66%).

[0318] Intermediate 6: (S)-1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-oxopent-3-enyl)amine tert-Butyl formate

[0319]

[0320] 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) was added prop-1-enylmagnesium bromide (323 mL, 161.45 mmol) dropwise under nitrogen at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then quenched with 400 mL of 10% citric acid, diluted with 100 mL of water and extracted with diethyl ether. The organics were concentrated and the resulting oil was dissolved in diethyl 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 desired product as a colorless oil (27 g, 87%).

[0321] MS :384ES+(C 20 H 37 NO 4 Si)

[0322] 1 HNMR(300MHz,CDCl 3 )δ: 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).

[0323] Intermediate 7: (S)-2-((tert-butyldimethylsilyloxy)methyl)-5-oxo-5,6-dihydropyridine-1 (2H)-tert-Butyl carboxylate

[0324]

[0325] (S)-1-(tert-butyldimethylsilyloxy)but-3-ene-2-yl(2-oxopent-3-enyl)carbamic acid tert-butyl ester (Intermediate 6, 27.0 g, 70.39 mmol) was dissolved in toluene (650 mL). The solution was purged with nitrogen for 15 minutes, and then the second generation Hoveyda-Grubbs catalyst (0.885 g, 1.41 mmol) was added. The reaction mixture was heated at 65 ° C under nitrogen. The reaction mixture was concentrated under reduced pressure. Silica gel chromatography (10%-35% ethyl acetate / hexane) obtained the target product as a solid (17.0 g, 70%).

[0326] Optical rotation :0.1g / dL, dichloromethane=-175

[0327] Intermediate 8: (6S)-6-((tert-butyldimethylsilyloxy)methyl)-5-methyl-3-(trimethylsilyl) Oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0328]

[0329] Methyl lithium (1.6M in diethyl ether) (146mL, 234.25mmol) was added to a suspension of copper (I) iodide (22.31g, 117.12mmol) in diethyl ether (250mL) via cannula at 0°C. The suspension was stirred at 0°C for 45 minutes. A solution of (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (intermediate 7, 20g, 58.56mmol) in diethyl ether (50mL) was added dropwise to the suspension at 0°C. Once the addition was completed, the reaction mixture was stirred at 0°C for 45 minutes. Trimethylchlorosilane (1M in THF) (117mL, 117.12mmol) was then added dropwise to the reaction mixture, followed by triethylamine (16.28mL, 117.12mmol). The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with ethyl acetate and washed three times with ice cold saturated sodium bicarbonate solution (added very carefully) and then with brine. The organics were dried over sodium sulfate, filtered and concentrated to give a brown oil.

[0330] Intermediate 9: (S)-2-((tert-butyldimethylsilyloxy)methyl)-3-methyl-5-oxo-5,6-dihydropyrrolidone tert-Butylpyridine-1(2H)-carboxylate

[0331]

[0332] 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) was added palladium(II) acetate (12.59 g, 56.08 mmol) at room temperature. The reaction 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 acetate / 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.

[0333] Intermediate 10: (2S,5S)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-3-methyl-5,6- Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0334]

[0335] To a suspension of cesium (III) chloride (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) was added sodium borohydride (1.378 g, 36.42 mmol) in portions at 0°C. 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 extract was washed with brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate / hexanes) afforded tert-butyl (2S,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-hydroxy-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate (9.79 g, 75%) as a colorless oil.

[0336] Intermediate 11: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethyl tert-Butyl (((((((((((((((- ...

[0337]

[0338] To a solution of (2S,5S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-hydroxy-3-methyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Intermediate 10, 9.79 g, 27.38 mmol) in toluene (100 mL) 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) at room temperature. The reaction mixture was stirred overnight, then filtered and concentrated. The resulting oil was triturated twice with hexanes and filtered. Silica gel chromatography (0%-20% ethyl acetate / hexanes) afforded tert-butyl (2S,5R)-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.

[0339] Intermediate 12: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-3-methyl tert-Butyl-5,6-dihydropyridine-1(2H)-carboxylate

[0340]

[0341] To a solution of tert-butyl (2S,5R)-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 (1 M in THF) (23.38 mL, 23.38 mmol). The reaction mixture turned from yellow to green-brown. The reaction mixture was stirred for about 2 hours and then concentrated onto silica gel. Silica gel chromatography (0%-70% ethyl acetate / hexanes) afforded tert-butyl (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate (7.72 g, 89%) as a tan foam.

[0342] Intermediate 13: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonylamino)-1-(tert-butyloxycarbonyl) 1,2,5,6-tetrahydropyridine-2-carboxylic acid

[0343]

[0344] Chromium oxide (VI) (0.019 g, 0.19 mmol) was added to a solution of periodic acid (1.588 g, 8.27 mmol) in wet acetonitrile (20 mL) (0.75% by volume of water) at room temperature. The mixture was stirred until complete dissolution was achieved. The periodic acid / chromium oxide solution (20 mL, 2 equivalents) formed previously was added dropwise to a solution of (2S, 5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (intermediate 12, 2 g, 4.14 mmol) in wet acetonitrile (20 mL) (0.75% by volume) at 0°C and stirred for 15 minutes. The reaction mixture was diluted with DCM (100 mL), washed with 10% citric acid (50 mL), and washed twice with brine. The organics were dried over sodium sulfate, filtered and concentrated to give a tan foam (1.9 g, 92%).

[0345] Intermediate 14: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3-carboxylic acid tert-Butyl-5,6-dihydropyridine-1(2H)-carboxylate

[0346]

[0347] To a solution of (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3-methyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 13, 1.9 g, 3.82 mmol) in DMF (9.5 mL) 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 at 0°C. The reaction mixture was warmed to room temperature and stirred for 15 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and 1:1 brine:water. Silica gel chromatography (0%-70% ethyl acetate / hexanes) afforded tert-butyl (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate (1.270 g, 67%) as a light orange foam.

[0348] Intermediate 15: (2S,5R)-5-((allyloxy)amino)-2-carbamoyl-3-methyl-5,6-dihydropyridine-1 (2H)-tert-Butyl carboxylate

[0349]

[0350] To a solution of (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3-methyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (intermediate 14, 3.63 g, 7.31 mmol) in acetonitrile (100 mL) was added potassium carbonate (5.05 g, 36.55 mmol) and thiophenol (3.75 mL, 36.55 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, the resulting residue was ground with DCM and filtered to remove the solid. The filtrate was concentrated onto silica gel and purified. Silica gel chromatography (0%-90% ethyl acetate / hexane) obtained (2S,5R)-5-((allyloxy)amino)-2-carbamoyl-3-methyl-5,6-dihydropyridine-1(2H)-carboxylic tert-butyrate (1.49 g, 65%) as a yellow oil.

[0351] Intermediate 16: (2S,5R)-5-(N-(allyloxy)-1H-imidazole-1-carboxamido)-2-carbamoyl-3-carboxamido tert-Butyl-5,6-dihydropyridine-1(2H)-carboxylate

[0352]

[0353] To a solution of (2S,5R)-5-((allyloxy)amino)-2-carbamoyl-3-methyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Intermediate 15, 1.49 g, 4.79 mmol) in THF (30 mL) was added N,N-diisopropylethylamine (2.5 mL, 14.36 mmol) and N,N-carbonyldiimidazole (2.328 g, 14.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for ~2 hours. Another equivalent of CDI was added and the reaction mixture was stirred at room temperature for 1 hour, then one equivalent of CDI was added and the reaction was stirred for an additional hour. The reaction mixture was diluted with DCM and washed four times with 1:1 brine:water, then dried over magnesium sulfate, filtered and concentrated to give an off-white foam, 1.86 g.

[0354] Intermediate 17: (2S,5R)-6-(allyloxy)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane- 3-ene-2-carboxamide

[0355]

[0356] To a solution of (2S,5R)-5-(N-(allyloxy)-1H-imidazole-1-carboxamido)-2-carbamoyl-3-methyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (Intermediate 16, 1.86 g, 4.59 mmol) in DCM (20 mL) at 0°C was added trifluoroacetic acid (3.53 mL, 45.88 mmol). The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated. The oil was redissolved in DCM and washed with saturated sodium bicarbonate. The aqueous solution was extracted 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.

[0357] Example 1: (R)-2-((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1] Ethyl oct-3-en-6-yloxy)-2-fluoroacetate

[0358]

[0359] Example 2: (S)-2-((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1] Ethyl oct-3-en-6-yloxy)-2-fluoroacetate

[0360]

[0361] Example 3: (2S)-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1] Oct-3-en-6-yl]oxy}(fluoro)acetic acid lithium salt

[0362]

[0363] Example 4: (2R)-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1] Oct-3-en-6-yl]oxy}(fluoro)acetic acid lithium salt

[0364]

[0365] Example 5: {[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-3- [6-Alkenyl]oxy}(fluoro)acetic acid lithium salt (mixture of diastereomers)

[0366]

[0367] Example 1-2

[0368] To a solution of (2S, 5R)-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) was added 1,3-dimethylbarbituric acid (132 mg, 0.84 mmol) and tetrakis(triphenylphosphine)palladium(0) (48.7 mg, 0.04 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 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 reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate and filtered through a 0.45 μ filter to remove solid potassium carbonate. The filtrate was washed twice with 1:1 brine: water. The organic matter was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-70% ethyl acetate / hexanes) gave 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.

[0369] MS :198ES+(C 8 H 11 N 3 O 3 )

[0370] Embodiment 3-5

[0371] To a solution of ethyl 2-(((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-6-yl)oxy)-2-fluoroacetate (Example 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 temperature and stirred for 15 minutes. The reaction mixture was adjusted to pH = 7 with 0.5M HCl. THF was evaporated and the remaining aqueous phase was frozen and lyophilized.

[0372] Purification of Examples 1-5

[0373] The mixture obtained from the reaction described in Examples 3-5 was purified by reverse phase HPLC (Synergi Polar RP2 1.2 mm x 100 mm, 4 μm coupled with YMC C30 20 mm x 150 mm, 5 μm; 0% to 50% acetonitrile in water, 10 min; 20 mL / min) to obtain:

[0374] Example 1: Ethyl {[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy}(fluoro)acetate (first eluting ester): 4.4 mg, 4.5%

[0375] MS :302ES+(C 12 H 16 FN 3 O 5 )

[0376] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0377] Example 2: (S)-ethyl 2-((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yloxy)-2-fluoroacetate (second eluting ester): 4.2 mg, 4.3%

[0378] MS :302ES+(C 12 H 16 FN 3 O5 )

[0379] 1 H NMR(300MHz,DMSO-d 6 )δ: 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); 6.24-6.50 (d, 1H); 7.37 (bs, 1H); 7.83 (bs, 1H).

[0380] Example 3: (2S)-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy}(fluoro)acetic acid (first eluting ester): 7.7 mg, 8.8%.

[0381] MS :274ES+(C 10 H 12 FN 3 O 5 )

[0382] 1 H NMR(300MHz,DMSO-d 6 )δ: 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).

[0383] Example 4: (2R)-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy}(fluoro)acetic acid (first eluting acid): 9.9 mg, 11%

[0384] MS :274ES+(C 10 H 12 FN 3 O 5 )

[0385] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0386] Example 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%

[0387] MS :274ES+(C 10 H 12 FN 3 O 5 )

[0388] 1 HNMR(300MHz,DMSO-d 6 )δ: 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,2H).

[0389] The absolute stereochemistry of all compounds was determined by characterizing the cocrystal structure of Example 4 complexed with AmpC. The absolute stereochemistry of the other diastereomer of Example 3 was assigned to have the opposite stereochemistry at the fluoroacetate carbon. The stereochemistry of each ester was assigned by hydrolyzing each ester to its corresponding acid and comparing the UPLC retention time with the retention times of Examples 3 and 4.

[0390] Example 6: {[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-3- Ethyl 6-enyl]oxy}(fluoro)acetate (mixture of diastereomers)

[0391]

[0392] According to the procedure given in 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 (Synergi PolarRP 21.2 mm x 100 mm, 4 μm coupled to YMC C30 20 mm x 150 mm, 5 μm; 20% to 60% acetonitrile in water, 10 min; 20 mL / min) and lyophilized.

[0393] MS :302ES+(C 12 H 16 FN 3 O 5 )

[0394] 1 H NMR(300MHz,DMSO-d 6 )δ: 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).

[0395] Example 7: {[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-3- Ethyl 6-enyl]oxy}(difluoro)acetate

[0396]

[0397] (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 procedures of Examples 1 and 2 using ethyl bromodifluoroacetate (0.441 mL, 3.44 mmol) to give 130 mg (47%) of the title compound as an orange foam. 40 mg was subjected to reverse phase chromatography (Synergi Polar RP 21.2 mm x 100 mm, 4 μm coupled to YMC C30 20 mm x 150 mm, 5 μm; 20% to 40% acetonitrile in water, 10 min; 20 mL / min) to afford the title compound as a white solid (21 mg).

[0398] MS :320ES+(C 12 H 15 F 2 N 3 O 5 )

[0399] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0400] Example 8: {[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-3- [6-Alkenyl]oxy}(difluoro)acetic acid lithium salt

[0401]

[0402] 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 of Example 3-5. A white solid was obtained after HPLC (Synergi Polar RP 21.2 mm x 100 mm, 4 μm coupled with YMC C30 20 mm x 150 mm, 5 μm; 100% water, 10 min; 20 mL / min) and lyophilized, 36.7 mg.

[0403] MS :292ES+(C 10 H 11 F 2 N 3 O 5 )

[0404] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0405] Example 9: {[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-3- Ethyl 6-enyl]oxy}acetate

[0406]

[0407] (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 of Example 1-2 using ethyl bromoacetate (0.592 mL) to yield 147 mg (62%) as an orange solid. 41.5 mg was subjected to reverse phase chromatography (Synergi Polar RP 21.2 mm x 100 mm, 4 μm coupled to YMC C30 20 mm x 150 mm, 5 μm; 10% to 50% acetonitrile in water, 10 min; 20 mL / min) to afford the title compound as a white solid (32 mg).

[0408] MS :284ES+(C 12 H 17 N 3 O 5 )

[0409] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0410] Example 10: {[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane- 3-en-6-yl]oxy}acetic acid lithium salt

[0411]

[0412] 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 of Examples 3-5 to yield 34 mg (37%) of the title compound after HPLC (Synergi Polar RP 21.2 mm x 100 mm, 4 μm; 0% to 20% acetonitrile in water, 10 min; 20 mL / min) and lyophilized.

[0413] MS :256ES+(C 10 H 13 N 3 O 5 )

[0414] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0415] Example 11: 2-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1] Oct-3-en-6-yl]oxy}-2-fluoropropionic acid lithium salt (mixture of diastereomers)

[0416]

[0417] (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 of Example 1-2 using methyl 2-bromo-2-fluoropropanoate (0.315 g, 1.70 mmol) to give methyl 2-(((2S,5R)-2-carbamoyl-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 (SynergiPolar RP 21.2 mm x 100 mm, 4 μm coupled to YMC C30 20 mm x 150 mm, 5 μm; 100% water, 10 min; 20 mL / min) afforded the title compound as a white solid (19.1 mg, 19%).

[0418] MS :302ES+(C 12 H 16 FN 3 O 5 )

[0419] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0420] Hydrolysis according to the procedure of Example 3-5 afforded 19.1 mg of Example 11 as a white solid after reverse phase purification (Synergi Polar RP 21.2 mm x 100 mm, 4 μm coupled with YMC C30 20 mm x 150 mm, 5 μm; 100% water, 10 min; 20 mL / min).

[0421] MS :288ES+(C 11 H 14 FN 3 O 5 )

[0422] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0423] Intermediate 18: Isopropyl 2-bromo-2-fluoroacetate

[0424]

[0425] To a solution of ethyl 2-bromo-2-fluoroacetate (0.639 mL, 5.41 mmol) in hexane (70 mL) and isopropanol 1 (7 mL) at 0°C was added potassium tert-butoxide (0.091 g, 0.81 mmol) in two equal portions 5 minutes apart. The reaction mixture was stirred at 0°C for 1 hour. 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 give a colorless oil (0.88 g, 4.42 mmol, 82%). NMR confirmed the identification of the product, which contained trace amounts of hexane. The product was used as is in the next step.

[0426] 1 HNMR(300MHz,CDCl 3 -d) δ: 1.34 (m, 6H); 5.18 (m, 1H); 6.45-6.62 (d, 1H).

[0427] Reference: Tet. Lett. (2000) 791.

[0428] Example 12: (2R)-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl]oxy}(fluoro)acetic acid propan-2-yl ester

[0429]

[0430] Example 13: (2S)-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl]oxy}(fluoro)acetic acid propan-2-yl ester

[0431]

[0432] Examples 12-13

[0433] (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 procedure of Example 1-2 using isopropyl 2-bromo-2-fluoroacetate (Intermediate 18, 0.518 g, 2.60 mmol). HPLC (Synergi Polar RP 21.2 mm x 100 mm, 4 μm coupled with YMC C30 20 mm x 150 mm, 5 μm; 25% to 50% acetonitrile in water, 10 min; 20 mL / min) gave 34 mg of each diastereomer and lyophilized. The stereochemistry of each ester was assigned by hydrolyzing each ester to its corresponding acid and comparing the UPLC retention time with that of Examples 3 and 4.

[0434] Example 12: (first eluting ester) 33.4 mg, 24%

[0435] MS :316ES+(C 13 H 18 FN 3 O 5 )

[0436] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0437] Example 13: (Second eluting ester) 33.6 mg, 25%

[0438] MS :316ES+(C 13 H 18 FN 3 O 5 )

[0439] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0440] Intermediate 19: 2,4-dimethylpentan-3-yl 2-bromo-2-fluoroacetate

[0441]

[0442] Following the procedure of 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) gave the title compound as a colored oil (0.988 g, 3.87 mmol, 71.6%).

[0443] 1 HNMR(300MHz,CDCl 3 -d) δ: 0.94 (m, 12H); 2.01 (m, 2H); 4.73 (m, 1H); 6.52-6.69 (d, 1H).

[0444] Example 14: (2S)-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] 2,4-dimethylpentan-3-yl [3.2.1] oct-3-en-6-yl]oxy} (fluoro)acetate

[0445]

[0446] Example 15: (2R)-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] 2,4-dimethylpentan-3-yl [3.2.1] oct-3-en-6-yl]oxy} (fluoro)acetate

[0447]

[0448] Examples 14-15

[0449] (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 of Example 1-2 using 2-bromo-2-fluoroacetic acid 2,4-dimethylpentan-3-yl ester (0.626 g, 2.45 mmol) to give 35 mg of each diastereomer (23% each, 46% total) after HPLC (Synergi Polar RP 21.2 mm x 100 mm, 4 μm coupled with YMCC30 20 mm x 150 mm, 5 μm; 40% to 70% acetonitrile in water, 10 min; 20 mL / min) and lyophilized. The stereochemistry of the esters was assigned by hydrolysis of each ester to its corresponding acid and comparison of the UPLC retention time with that of Examples 3 and 4.

[0450] Example 14: (second elution peak) 34.5 mg, 23%

[0451] MS :372ES+(C 17 H 26 FN 3 O 5 )

[0452] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0453] Example 15: (first elution peak) 35.2 mg, 23%

[0454] MS :372ES+(C 17 H 26 FN 3 O 5 )

[0455] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0456] Intermediate 20: 2-Bromo-2-fluoroacetic acid tetrahydro-2H-pyran-4-yl ester

[0457]

[0458] Following the procedure of 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) gave the title compound as a colorless oil (0.15 g, 0.62 mmol, 29%).

[0459] MS: C7H10BrFO3 is ES+241.2

[0460] 1HNMR (300MHz, chloroform-d) δppm: 1.47-1.81 (m, 2H) 1.84-2.13 (m, 2H) 3.39-3.68 (m, 2H) 3.75-4.07 (m, 2H) 4.37 (q, J=7.18Hz, 1H) 6.37-6.74 (m, 1H)

[0461] Example 16: {[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane- Tetrahydro-2H-pyran-4-yl 3-en-6-yl]oxy}(fluoro)acetate (mixture of diastereomers)

[0462]

[0463] Following the procedure of Example 1-2, using (2S,5R)-6-(allyloxy)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 17, 40 mg, 0.17 mmol) and 2-bromo-2-fluoroacetic acid tetrahydro-2H-pyran-4-yl ester (Intermediate 20, 312 mg, 1.29 mmol), the title compound was obtained after purification by reverse phase ISCO (15.5 g C18 Gold, 0%-80% acetonitrile / water) as a light orange solid as a mixture of diastereomers (5.5 mg, 9%).

[0464] MS: C15H20FN3O6 is ES+358.1

[0465] 1H NMR (300MHz, chloroform-d) δppm1.15-1.42 (m, 2H) 1.60 (br.s., 2H) 1.92 (s, 3H) 3.14-3.45 (m, 2H) 3.56 (d, J=11.52Hz, 1H) 3.88-4. 13(m,2H)4.20-4.50(m,2H)5.09(br.s.,1H)5.35-5.58(m,1H)5.63-5.96(m,1H)6.09(br.s.,1H)

[0466] Intermediate 21: 2-Methoxyethyl 2-bromo-2-fluoroacetate

[0467]

[0468] Following the procedure of Intermediate 18, ethyl 2-bromo-2-fluoroacetate (1.278 mL, 10.81 mmol) and 2-methoxyethanol (13.94 mL, 183.79 mmol) afforded the title compound as a colorless oil (1.04 g, 4.84 mmol, 44.7%). NMR was consistent with a 3:1 mixture of product: starting material, which was used as is in the next step.

[0469] 1 HNMR(300MHz,DMSO-d 6 )δ: 3.27 (s, 3H); 3.57 (m, 2H); 4.35 (m, 2H); 7.22-7.38 (d, 1H).

[0470] Example 17: {[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane- 2-Methoxyethyl 3-en-6-yl]oxy}(fluoro)acetate (mixture of diastereomers)

[0471]

[0472] Example 18: (2R)-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] 2-methoxyethyl [3-oct-6-en-3-yl]oxy}(fluoro)acetate

[0473]

[0474] Example 19: (2S)-{[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] 2-methoxyethyl [3-oct-6-en-3-yl]oxy}(fluoro)acetate

[0475]

[0476] Examples 17-19

[0477] According to the procedure of Example 1-2, (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 to the title compound using 2-bromo-2-fluoroethyl 2-methoxyacetate (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 μm coupled with YMC C30 20 mm x 150 mm, 5 μm; 30% to 50% acetonitrile in water, 10 min; 20 mL / min) and lyophilized (where the stereochemistry of the esters was assigned by hydrolyzing each ester to its corresponding acid and comparing the UPLC retention time with that of Examples 3 and 4):

[0478] Example 17: Mixture of diastereomers: 14.3 mg, 10.1%

[0479] MS :332ES+(C 13 H 18 FN 3 O 5 )

[0480] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0481] Example 18: (first eluting ester): 22 mg, 15.6%,

[0482] MS :332ES+(C 13 H 18 FN 3 O 5 )

[0483] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0484] Example 19: (Second eluting ester): 22.8 mg, 16.1%

[0485] MS :332ES+(C 13 H 18 FN 3 O 5 )

[0486] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0487] Intermediate 22: (S)-2-bromo-2-fluoroacetic acid sec-butyl ester

[0488]

[0489] To a solution of ethyl 2-bromo-2-fluoroacetate (0.319 mL, 2.70 mmol) and (S)-butan-2-ol (3.72 mL, 40.54 mmol) in hexane (35 mL) was added potassium tert-butoxide (0.061 g, 0.54 mmol) in two equal portions at 0°C, 5 minutes apart. The reaction mixture was stirred at 0°C for 2 hours, then stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride, and the layers were separated. The organics were washed three times with water, dried over magnesium sulfate, filtered and concentrated at 0°C to give a colorless oil, 0.550 g, 96%.

[0490] 1 HNMR(300MHz,DMSO-d 6 )δ: 0.88 (m, 3H); 1.25 (m, 3H); 1.61 (m, 2H); 4.91 (m, 1H); 7.16-7.33 (m, 1H).

[0491] Intermediate 23: (R)-Sec-butyl bromo-2-fluoroacetate

[0492]

[0493] Potassium tert-butoxide (0.061 g, 0.54 mmol) was added to a solution 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) in two equal portions 5 minutes apart. The reaction mixture was stirred at 0 ° C for 2 hours and then at room temperature for 2 hours. Then, (R)-butan-2-ol (3.72 mL, 40.54 mmol) was added, followed by another 0.1 equivalent of potassium tert-butoxide. The reaction mixture was stirred at room temperature overnight. 0.1 equivalent of potassium tert-butoxide was added every 2 hours for 6 hours. The reaction was quenched with saturated ammonium chloride and the layers were separated. The organic matter was washed with water four times, dried over magnesium sulfate, filtered at 0 ° C and concentrated to give a colorless oil, 422 mg, 73%.

[0494] 1 HNMR(300MHz,DMSO-d 6 )δ: 0.88 (m, 3H); 1.25 (m, 3H); 1.61 (m, 2H); 4.91 (m, 1H); 7.16-7.33 (m, 1H).

[0495] Example 20: (2R)-(S)-2-(((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] sec-butyl oct-3-en-6-yl)oxy)-2-fluoroacetate

[0496]

[0497] Example 21: (2S)-(S)-2-(((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] sec-butyl oct-3-en-6-yl)oxy)-2-fluoroacetate

[0498]

[0499] Examples 20-21

[0500] Prepared according to the procedure of Example 1-2. To a solution of (2S, 5R)-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) was added 1,3-dimethylbarbituric acid (0.258 g, 1.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.095 g, 0.08 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours and then concentrated to give an orange film. The orange film was dissolved in DMF (5 mL) and potassium carbonate (0.343 g, 2.48 mmol) and (S)-2-bromo-2-fluoroacetic acid sec-butyl ester (intermediate 22, 0.528 g, 2.48 mmol) were added. The reaction mixture was stirred at room temperature for ~5 hours, then diluted with ethyl acetate and filtered through a 0.45 μm filter to remove solid potassium 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%-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-ene-6-yl)oxy)-2-fluoroacetate (0.218 g, 80%) as a light yellow foam, a ~1:1 mixture of diastereomers. Separation of diastereomers was performed on reverse phase HPLC (Atlantis T3 19 mm x 150 mm, 30-50% acetonitrile in water, 20 mL / min, 15 min). The stereochemistry of the esters was assigned by hydrolyzing each ester to its corresponding acid and comparing the UPLC retention time with that of Examples 3 and 4.

[0501] Example 20: (first elution peak) 84 mg, 31%

[0502] MS :330ES+(C 14 H 20 FN 3 O 5 )

[0503] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0504] Example 21: (Second elution peak) 85 mg, 31%.

[0505] MS :330ES+(C 14 H 20 FN 3 O 5 )

[0506] 1 HNMR(300MHz,DMSO-d 6 )δ: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)。

[0507] Example 22: (2R)-(R)-2-(((2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] sec-butyl oct-3-en-6-yl)oxy)-2-fluoroacetate

[0508]

[0509] Example 23: (2S)-(R)-2-(((2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] sec-butyl oct-3-en-6-yl)oxy)-2-fluoroacetate

[0510]

[0511] Examples 22-23

[0512] Embodiment 22-23 is prepared according to the procedure of embodiment 1-2.To (2S, 5R)-6-(allyloxy)-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-ene-2-carboxamide (intermediate 17, 0.202g, 0.85mmol) in methanol (5mL) solution, 1,3-dimethylbarbituric acid (0.266g, 1.70mmol) and tetrakis (triphenylphosphine) palladium (0) (0.098g, 0.09mmol) are added at room temperature. The reaction is stirred at room temperature for 2 hours. The reaction mixture is concentrated to obtain an orange film. The orange film is dissolved in DMF (5mL), and potassium carbonate (0.353g, 2.55mmol) and (R)-2-bromo-2-fluoroacetic acid sec-butyl ester (intermediate 23, 0.421g, 1.98mmol) are added. The reaction mixture was stirred at room temperature for 3 hours, then diluted with ethyl acetate and filtered through a 0.45 μm filter to remove solid potassium carbonate. The filtrate was washed three times with 1:1 brine: water. The organic matter was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-65% ethyl acetate / hexane) obtained (R)-2-(((2S, 5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-ene-6-yl) oxygen)-2-fluoroacetic acid sec-butyl ester (0.220g, 78%), as an orange foam, a 1:1 mixture of diastereomers. The separation of diastereomers was carried out on reverse phase HPLC (Atlantis T3 19mm x 150mm, 30-50% acetonitrile in water, 20mL / min, 15min). The stereochemistry of the esters was assigned by hydrolyzing each ester to its corresponding acid and comparing the UPLC retention times with those of Examples 3 and 4.

[0513] Example 22: (first elution peak) 90 mg, 32%

[0514] MS :330ES+(C 14 H 20 FN 3 O 5 )

[0515] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0516] Example 23: (second elution peak) 87 mg, 31%

[0517] MS :330ES+(C 14 H 20 FN 3 O 5 )

[0518] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0519] Intermediate 24: 2-Bromo-2-fluoroacetic acid pent-3-yl ester

[0520]

[0521] Ethyl 2-bromo-2-fluoroacetate (0.639 mL, 5.41 mmol) was added to a mixture of anhydrous pentan-3-ol (4.68 mL, 43.25 mmol) and hexane (20 mL). The resulting mixture was cooled to 0°C. KOtBu (0.091 g, 0.81 mmol) was added and the mixture was stirred at 25°C for 16 h. The reaction was then quenched with 1N HCl (30 mL), washed with water (50 mL) and brine (50 mL), and washed with Na 2 SO 4 Dry and concentrate. The crude material was purified by flash chromatography (20 g silica gel, 0-100% Et 2 D in hexanes, 25 min) to give pentan-3-yl 2-bromo-2-fluoroacetate (0.754 g, 61.4%) as a colorless oil.

[0522] 1 H NMR (300 MHz, chloroform-d) δ ppm 0.96 (td, J = 7.46, 2.08 Hz, 6H) 1.60-1.76 (m, 4H) 4.93 (dt, J = 12.28, 6.33 Hz, 1H) 6.50 (s, 0.5H) 6.67 (s, 0.5H)

[0523] Example 24: (R)-2-((2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yloxy)-2-fluoroacetic acid pent-3-yl ester

[0524]

[0525] Example 25: (S)-2-((2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yloxy)-2-fluoroacetic acid pent-3-yl ester

[0526]

[0527] Examples 24-25

[0528] Examples 24-25 were prepared according to the procedure of Examples 1-2. To a solution of (2S,5R)-6-(allyloxy)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 17, 272 mg, 1.15 mmol) in methanol (5 mL) were added 1,3-dimethylbarbituric acid (358 mg, 2.29 mmol) and Pd(Ph 3 P) 4 (132 mg, 0.11 mmol). The reaction was stirred at room temperature for 2 hours. The mass of the target product was observed and no starting material was found by LCMS. The reaction mixture was concentrated to give an orange film. The orange film was dissolved in DMF (5 mL) and K was added. 2 CO 3 (475mg, 3.44mmol) and 2-bromo-2-fluoroacetic acid pentan-3-yl ester (intermediate 24, 751mg, 3.31mmol). The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate and filtered through a 0.45μm filter to remove solid potassium carbonate. The filtrate was washed twice with 1:1 brine: water. The organic matter was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-70% ethyl acetate / hexane) gave 2-(((2S, 5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-ene-6-yl) oxygen)-2-fluoroacetic acid pentan-3-yl ester (320mg, 81%) as a light yellow foam. LCMS and NMR confirmed that it was a 1:1 mixture of diastereomers. Diastereoisomers were separated on reverse phase HPLC (Atlantis T3 4.6 mm x 50 mm 5 μm column, 30 to 50% ACN in water in 5 min, flow rate 1 mL / min).

[0529] Example 24: 125 mg, 32%

[0530] UPLC LCMS 2min_Acid_CV10 method acid condition retention time: 0.86min, 344 (M+H) +

[0531] 1 HNMR (300 MHz, chloroform-d) δ ppm0.92 (td, J=7.46, 3.21Hz, 6H) 1.61-1.75 (m, 4H) 1.93 (s, 3H) 3.21-3.35 (m, 2H) 4.07 (dd, J=4.91, 2.64Hz, 1H) 4.36 (s, 1H) 4.91 (quin, J = 6.18Hz, 1H) 5.47 (br.s., 1H) 5.77 (s, 0.5H) 5.94 (s, 0.5H) 6.07-6.12 (m, 1H) 6.59 (br.s., 1H)

[0532] Example 25: 125 mg, 32%

[0533] UPLCLCMS 2min_Acid_CV10 method acid condition retention time: 0.91min, 344(M+H)+

[0534] 1 HNMR (300 MHz, chloroform-d) δ ppm 0.93 (t, J=7.46Hz, 3H) 0.95 (t, J=7.46Hz, 3H) 1.63-1.74 (m, 4H) 1.93 (s, 3H) 3.20-3.38 (m, 2H) 4.02 (dd, J=5.00, 2.55Hz, 1 H) 4.35 (s, 1H) 4.92 (quin, J = 6.18Hz, 1H) 5.56 (br.s., 1H) 5.69 (s, 0.5H) 5.89 (s, 0.5H) 6.07-6.14 (m, 1H) 6.64 (br.s., 1H)

[0535] Intermediate 25: N-[(3R,6S)-6-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methyl-1,2, 3,6-Tetrahydropyridin-3-yl]-2-nitro-N-(prop-2-en-1-yloxy)benzene-1-sulfonamide

[0536]

[0537] In a 250 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere, a solution of (3R,6S)-6-[[(tert-butyldimethylsilyl)-oxy]methyl]-5-methyl-3-[N-(prop-2-en-1-yloxy)(2-nitrobenzene)sulfonamido]-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (Intermediate 11, 13.6 g, 22.75 mmol, 1 equivalent) in dichloromethane (100 mL) was placed. This was followed by the addition of ZnBr in several batches. 2 (10.2 g, 45.29 mmol, 2 eq.). The resulting solution was stirred at room temperature overnight. The resulting solution was diluted with 500 mL of dichloromethane. The resulting mixture was washed with 2 x 200 mL of sodium bicarbonate (aqueous solution) and 2 x 200 mL of NH 4The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 12 g (crude) of the title compound as a yellow oil.

[0538] MS :498ES+(C 22 H 35 N 3 O 6 SSi)

[0539] Intermediate 26: (3R,6S)-6-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methyl-N-(propan-2- (1-enyloxy)-1,2,3,6-tetrahydropyridin-3-amine

[0540]

[0541] In a 250 mL round bottom flask purged and maintained with an inert nitrogen atmosphere, 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-yloxy)benzene-1-sulfonamide (Intermediate 25, 12 g, 24.11 mmol, 1 eq) in N,N-dimethylformamide (100 mL), 2-sulfanylacetic 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 at room temperature for 2 h, then diluted with 500 mL of water, extracted with 5x200 mL of ethyl acetate, and the organic layers combined. The organic mixture was washed with 3x200 mL of brine and 2x200 mL of sodium bicarbonate (aq.). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This yielded 8.4 g (crude) of the title compound as a yellow oil.

[0542] MS :313ES+(C 16 H 32 N 2 O 2 Si)

[0543] Intermediate 27: (2S,5R)-2-[[(tert-butyldimethylsilyl)oxy]methyl]-3-methyl-6-(propane-2- 1,6-diazabicyclo[3.2.1]oct-3-en-7-one

[0544]

[0545] In a 2L 3-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere, a solution of (3R, 6S)-6-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methyl-N-(prop-2-en-1-yloxy)-1,2,3,6-tetrahydropyridine-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) were placed. This was followed by a solution of dichlorotrimethyl carbonate (2.9 g, 9.77 mmol, 0.4 eq) in acetonitrile (100 mL) added dropwise at -15 °C with stirring for 3 h. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The crude product was diluted with 500 mL of ethyl acetate. The resulting mixture was washed with 2x400 mL of NH 4 The mixture was washed with Cl(aq) and 2x400 mL of brine, then concentrated in vacuo. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1:10). This yielded 3.9 g (43%) of the title compound as a yellow oil.

[0546] MS :339ES+(C 17 H 30 N 2 O 3 Si)

[0547] Intermediate 28: (2S,5R)-2-(Hydroxymethyl)-3-methyl-6-(prop-2-en-1-yloxy)-1,6-diazabi Cyclo[3.2.1]oct-3-en-7-one

[0548]

[0549] In 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-1-yloxy)-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (Intermediate 27, 3.2 g, 9.45 mmol, 1 eq) and the solution was cooled to 0 ° C, and then TBAF (14.2 mL 1N in THF, 1.5 eq) was added dropwise. The reaction mixture was stirred at 0 ° C for 1 h in a water / ice bath. The resulting mixture was concentrated in vacuo. The residue was added to a silica gel column with ethyl acetate / petroleum ether (1:5-1:2). This produced 1.6 g (75%) of the title compound as a light yellow solid.

[0550] MS :225ES+(C 11 H 16 N 2 O 3 )

[0551] 1 HNMR(300MHz,CDCl 3 )δ1.63(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).

[0552] Intermediate 29: 2S,5R)-3-methyl-7-oxo-6-(prop-2-en-1-yloxy)-1,6-diazabicyclo [3.2.1] Oct-3-ene-2-carboxylic acid

[0553]

[0554] At room temperature, H 5 IO 6 (12.93 g, 56.71 mmol) in wet CH 3 CN (150 mL, 0.75% H 2 O v / v) solution was added with CrO 3 (128 mg, 1.28 mmol). The mixture was stirred until it was completely dissolved. In a 100 mL round-bottom flask, wet acetonitrile (35 mL) and (2S, 5R)-2-(hydroxymethyl)-3-methyl-6-(prop-2-ene-1-yloxy)-1,6-diazabicyclo[3.2.1]oct-3-ene-7-one (intermediate 28, 740 mg, 3.30 mmol, 1 eq.) were placed and cooled to 0 ° C. Then, the above oxidation solution (35 mL, 3 eq.) was added dropwise at 0 ° C over the course of 30 minutes. The resulting solution was stirred at 0 ° C for 1 h in a water / ice bath. The reaction mixture was then diluted with 200 mL of chloroform and 50 mL of citric acid solution (25%). The organic layer was separated, then washed with 3x50 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. This produced 0.70 g of the crude title compound as a yellow oil.

[0555] MS :239ES+(C 11 H 16 N 2 O 4 )

[0556] Intermediate 30: (2S,5R)-N'-acetyl-6-(allyloxy)-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] Oct-3-ene-2-carbohydrazide

[0557]

[0558] 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) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (236 mg, 1.23 mmol), 1-hydroxybenzotriazole hydrate (219 mg, 1.23 mmol) and monoacetylhydrazine (101 mg, 1.23 mmol) at room temperature. The mixture was cooled to 0 °C and DIEA (0.715 mL, 4.11 mmol) was added. The reaction mixture was warmed to room temperature 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 chromatography (0% to 5% methanol / dichloromethane) provided the title compound as a white foam (45.5 mg, 19%, -50% purity).

[0559] MS :295ES+(C 13 H 18 N 4 O 4 )

[0560] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0561] Example 26: 2-(((2S,5R)-2-(2-acetylhydrazinecarbonyl)-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] Ethyl 2-fluoroacetate (oct-3-en-6-yl)oxy)

[0562]

[0563] 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) was added 1,3-dimethylbarbituric acid (48.3 mg, 0.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (17.87 mg, 0.02 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours and then concentrated to give 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 at room temperature for ~5 hours and then diluted with ethyl acetate and filtered through a 0.45 μm filter to remove solid potassium carbonate. The filtrate was washed three times with 1:1 brine:water. The organic matter was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-65% ethyl acetate / hexane) obtained the title compound as an orange foam (25.9 mg, 94%). Two diastereoisomers exist in a 1:1 ratio. The material was dissolved in ethyl acetate and washed three times with 1:1 brine: water. The organic matter was dried over magnesium sulfate, filtered and concentrated. Another silica gel column (0%-30% acetone / dichloromethane) was run to obtain the pure title compound (16.6 mg, 60%).

[0564] MS :359ES+(C 14 H 19 FN 4 O 6 )

[0565] 1 HNMR(300MHz,DMSO-d 6 )δ: 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, 1H).

[0566] Example 27: 2-(((2S,5R)-2-(2-acetylhydrazinecarbonyl)-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl)oxy)-2-fluoroacetic acid lithium salt

[0567]

[0568] To a solution of ethyl 2-(((2S,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) was added lithium hydroxide (1 M) (0.05 mL, 0.05 mmol) at 0°C and stirred at 0°C for 10 minutes. An additional 0.2 equivalents of lithium hydroxide were added. After 30 minutes, an additional 0.2 equivalents of lithium hydroxide were added. The reaction mixture was stirred for an additional 30 minutes. HCl (0.5 M) (0.046 mL, 0.02 mmol) was added to adjust the pH to ~4-5. The reaction mixture was extracted twice with ethyl acetate. The aqueous layer was frozen and lyophilized. 15 mg of the title compound was obtained as an orange solid. The two diastereomers were present in a 1:1 ratio.

[0569] MS :331ES+(C 12 H 15 FN 4 O 6 )

[0570] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0571] Intermediate 31: 4-((2S,5R)-6-(allyloxy)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1] tert-Butyl Oct-3-enecarboxamido)benzylcarbamate

[0572]

[0573] 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) was added tert-butyl 4-aminobenzylcarbamate (146 mg, 0.66 mmol), Hunig base (0.287 mL, 1.64 mmol) and 1-propanephosphonic acid cyclic anhydride (50 wt% DMF solution) (0.326 mL, 1.10 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. Water (10 mL) and 10% MeOH in DCM (20 mL) were added. The organic layer was separated and concentrated to give a crude product. Purification by flash chromatography (20 g silica gel, 0%-10% MeOH in DCM, 20 min) afforded the title compound (178 mg, 73.4% yield, -50% purity) as a yellow oil.

[0574] MS :443ES+(C 23 H 30 N 4 O 5 )

[0575] 1 H NMR (300 MHz, chloroform-d) δ ppm 1.47 (m, 12H) 3.10-3.23 (m, 1H) 3.25-3.39 (m, 1H) 4.34-4.54 (m, 3H) 4.36-4.49 (m, 3H) 5.25-5.45 (m, 2H) 6.03 (d, J = 6.61 Hz, 1H) 6.09-6.17 (m, 1H) 7.24-7.29 (m, 2H) 7.42-7.62 (m, 2H) 8.64 (s, 1H)

[0576] Intermediate 32: (R)-2-((2S,5R)-2-(4-((tert-butoxycarbonylamino)methyl)phenyl-carbamoyl)- Ethyl 3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yloxy)-2-fluoroacetate

[0577]

[0578] 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) was added Pd(Ph 3 P) 4(465 mg, 0.40 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give the 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). K 2 CO 3 To 4- bromo-2-fluoroacetic acid ester (167mg, 1.21mmol) and ethyl 2-bromo-2-fluoroacetate (0.052mL, 0.44mmol). The reaction mixture was stirred at room temperature overnight. EtOAC (20mL) was added, and the reaction mixture was washed with water (10mL). The organic layer was concentrated to give the product, which was purified by flash chromatography (12g silica gel, 0-100% EtOAc in hexane, 20min; then 5% MeOH in DCM, 10min) to obtain the title compound (11mg, 5.4% yield), as an orange solid.

[0579] MS :507ES+(C 24 H 31 FN 4 O 7 )

[0580] 1 HNMR (300 MHz, chloroform-d) δ ppm 1.36 (t, 3H) 1.48 (s, 9H) 2.00 (s, 3H) 3.21-3.27 (m, 1H) 3.36 (d, J = 1.70Hz, 1H) 4.08 (dd, J = 5.00, 2.74H z, 1H) 4.24-4.42 (m, 5H) 4.47 (s, 1H) 5.78-5.95 (m, 1H) 6.12-6.17 (m, 1H) 7.38-7.55 (m, 4H) 8.47 (s, 1H)

[0581] Intermediate 33: (R)-2-((2S,5R)-2-(4-((tert-butoxycarbonylamino)methyl)phenyl-carbamoyl)- 3-Methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yloxy)-2-fluoroacetic acid lithium salt

[0582]

[0583] 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)-ethyl 2-fluoroacetate (Intermediate 32, 11 mg, 0.02 mmol) in THF (1 mL) and water (0.5 mL) at 0°C was added lithium hydroxide (1 M) (0.02 mL, 0.02 mmol). The mixture was stirred at 0°C for 5 minutes and DCM (10 mL) was added. Hydrochloric acid (0.5 N) 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.

[0584] UPLC acid condition retention time :0.80min,479(M+H)+

[0585] 1 HNMR (300 MHz, chloroform-d) δ ppm 1.47 (s, 9H) 1.98 (s, 3H) 3.19-3.44 (m, 1H) 4.03-4.55 (m, 6H) 5.68-6.05 (m, 1H) 7.44-7.56 (m, 4H) 8.49 (br.s., 1H)

[0586] Example 28: (R)-2-((2S,5R)-2-(4-(aminomethyl)phenylcarbamoyl)-3-methyl-7-oxo-1,6- Diazabicyclo[3.2.1]oct-3-en-6-yloxy)-2-fluoroacetic acid TFA salt

[0587]

[0588] 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 mixture was stirred at 0°C for 6 hours and the solvent was removed. Toluene (2x1 mL) was added and concentrated to remove excess TFA. Et 2 O (2 mL) was added and the formed precipitate was filtered and washed with Et 2 O and dried to obtain the title compound (8 mg, 97%) as a TFA salt.

[0589] MS :379ES+(C 17 H 19 FN 4 O 5 )

[0590] 1 HNMR(300MHz,D2O)δppm1.75 (s, 3H) 3.23-3.61 (m, 2H) 4.12-4.25 (m, 3H) 4.51-4.60 (m, 1H) 5.53-5.98 (m, 1H) 6.29 (br.s., 1H) 7.45-7.57 (m, 4H)

[0591] Intermediate 34: (2S,5R)-6-(allyloxy)-3-methyl-7-oxo-N-(pyrazin-2-ylmethyl)-1,6-diol Azabicyclo[3.2.1]oct-3-ene-2-carboxamide

[0592]

[0593] 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) was added pyrazin-2-ylmethylamine (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) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes, then diluted with ethyl acetate, washed once with saturated sodium bicarbonate and three times with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0% to 2.5% methanol / dichloromethane) provided the title compound (147 mg, 53.5%) as an orange oil.

[0594] MS :330ES+(C 16 H 19 N 5 O 3 )

[0595] 1 HNMR(300MHz,DMSO-d 6 )δ: 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, 1H).

[0596] Example 29: 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)ethyl acetate

[0597]

[0598] To a solution of (2S,5R)-6-(allyloxy)-3-methyl-7-oxo-N-(pyrazine-2-ylmethyl)-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (intermediate 34, 153.8 mg, 0.47 mmol) in methanol (3 mL) was added 1,3-dimethylbarbituric acid (146 mg, 0.93 mmol) and tetrakis(triphenylphosphine)palladium(0) (54.0 mg, 0.05 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. Tetrakis(triphenylphosphine)palladium(0) (54.0 mg, 0.05 mmol) and 2 mL of methanol were added, and the mixture was stirred at room temperature for another 2 hours. The reaction mixture was concentrated to give an orange oil. The oil was dissolved in DMF (3 mL) and potassium carbonate (194 mg, 1.40 mmol) and ethyl 2-bromo-2-fluoroacetate (0.166 mL, 1.40 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate and filtered through a 0.45 μm filter to remove solid potassium carbonate. The filtrate was washed three times with 1:1 brine: water. The organic matter was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-100% ethyl acetate / hexane) obtained the title compound (95 mg, 52%) as a light orange foam. The compound is a 1:1 mixture of diastereomers.

[0599] MS :394ES+(C 17 H 20 FN 5 O 5 )

[0600] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0601] Example 30: 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)acetic acid lithium salt

[0602]

[0603] 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) was added lithium hydroxide (1 M) (0.254 mL, 0.25 mmol) at 0°C and stirred at 0°C for 25 minutes. An additional 0.1 equivalent of lithium hydroxide was added. After 15 minutes, hydrochloric acid (0.5 N) (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 light yellow solid was purified by reverse phase HPLC (YMC Carotenoid C30, 21.2 mm x 150 mm, 4 μm combined with Synergi Polar RP, 21.2 mm x 100 mm, 4 μm, 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 was a 1:1 mixture of diastereomers.

[0604] MS :366ES+(C 15 H 16 FN 5 O 5 )

[0605] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0606] Intermediate 35: (S)-1-(tert-butyldimethylsilyloxy)but-3-en-2-yl (3-methyl-2-oxobut-3 tert-Butyl)carbamate

[0607]

[0608] 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) was added prop-1-en-2-ylmagnesium bromide (0.5 M in THF) (300 mL, 149.90 mmol) at 0°C and stirred at 0°C for 1 hour. The reaction mixture was quenched with 200 mL of 10% citric acid, further diluted with 100 mL of water and extracted with ether. The organics were concentrated 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 (0%-20% ethyl acetate / hexanes) afforded the desired product (26.2 g, 89%) as a colorless oil.

[0609] MS :384ES+(C 20 H 37 NO 4 Si)

[0610] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0611] Intermediate 36: (S)-2-((tert-butyldimethylsilyloxy)methyl)-4-methyl-5-oxo-5,6-dihydro Pyridine-1(2H)-carboxylic acid tert-butyl ester

[0612]

[0613] A solution of (S)-1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(3-methyl-2-oxobut-3enyl)carbamate (Intermediate 35, 26.18 g, 68.25 mmol) in toluene (600 mL) was purged with nitrogen for 15 minutes. Then (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinyl)-dichloro(o-isopropoxyphenylmethylene)ruthenium (0.987 g, 1.57 mmol) was 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 / hexane) obtained the desired product (21.18 g, 87%) as a colorless oil.

[0614] MS :356ES+(C 18 H 33 NO 4 Si)

[0615] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0616] Intermediate 37: (2S,5S)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-4-methyl-5,6- Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0617]

[0618] To a solution of cesium (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) was added sodium borohydride (2.254 g, 59.57 mmol) in portions at 0°C. After 15 minutes, the reaction mixture was diluted with saturated ammonium chloride (100 mL) and water (100 mL) and then extracted twice with diethyl ether. The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate / hexanes) afforded the desired product (19.45 g, 91%) as a colorless oil.

[0619] MS :358ES+(C 18 H 35 NO 4 Si)

[0620] 1 H NMR(300MHz,DMSO-d 6 )δ: 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); 5.38 (m, 1H).

[0621] Intermediate 38: N-(allyloxy)-2-nitrobenzenesulfonamide

[0622]

[0623] To a stirred solution of O-allylhydroxylamine hydrochloride (147.05 g, 1341.59 mmol) in DCM (2.5 L) at 0 °C was added pyridine (318 mL, 3948 mmol) followed by addition of 2-nitrobenzene-1-sulfonyl chloride (250 g, 1128.05 mmol) as a solid in portions. 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), and purified by anhydrous Na 2 SO 4 The crude product was purified by crystallization using EtOAc: petroleum ether (1: 3) (800 mL) to obtain 202 g of the title compound as a light brown solid. The mother liquor was concentrated and purified by silica gel column chromatography (60-120 mesh) using petroleum ether: EtOAc (7: 3) to produce another 19.1 g of the title compound as a yellow solid. The total yield was 76%.

[0624] UPLC :C 9 H 10 N 2 O 5 S is 257 (M-1)

[0625] 1 HNMR(400MHz,DMSO-d 6 ): δ4.36-4.38 (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).

[0626] Intermediate 39: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(tert-butyldimethyl tert-Butyl (((((((((((((((- ...

[0627]

[0628] To a solution of tert-butyl (2S,5S)-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) 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) at room temperature. After 2 hours, the reaction mixture was concentrated onto silica gel and purified. Silica gel chromatography (0%-50% ethyl acetate / hexanes) afforded the desired product (25.2 g, 78%) as a yellow oil.

[0629] MS :598ES+(C 27 H 43 N 3 O 8 SSi)

[0630] 1 HNMR(300MHz,DMSO-d 6 )δ: 0.00 (s, 6H); 0.83 (s, 9H); 1.31 (m, 9H); 1.34 (m, 3H); 3.10-3.25 (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).

[0631] Intermediate 40: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-4-methyl tert-Butyl-5,6-dihydropyridine-1(2H)-carboxylate

[0632]

[0633] To a solution of tert-butyl (2S,5R)-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 (1 M in THF) (2.175 mL, 2.17 mmol). After 90 minutes, the reaction mixture was concentrated onto silica gel. Silica gel chromatography (0%-70% ethyl acetate / hexanes) afforded the desired product (0.732 g, 90%) as a tan foam.

[0634] MS :484ES+(C 21 H 29 N 3 O 8 S)

[0635] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0636] Intermediate 41: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonylamino)-1-(tert-butyloxycarbonyl) 4-Methyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid

[0637]

[0638] Chromium oxide (VI) (10 mg, 0.10 mmol) was added to a solution of periodic acid (6 g, 31.26 mmol) in wet acetonitrile (60 mL) (0.75% by volume water) at room temperature. The mixture was stirred until complete dissolution was achieved. The periodic acid / chromium oxide solution (60 mL, 3 equivalents) formed before was added dropwise to a solution of (2S, 5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (intermediate 40, 5 g, 10.34 mmol) in wet acetonitrile (60 mL) (0.75% by volume) at room temperature. After 30 minutes, the reaction mixture was diluted with ether and washed with 10% citric acid, saturated sodium bicarbonate and brine. The organic matter was dried over magnesium sulfate, filtered and concentrated to give an orange foam (4.16 g, 81%).

[0639] MS :498ES+(C 21 H 27 N 3 O 9 S)

[0640] 1 HNMR(300MHz,DMSO-d 6 )δ: 1.26 (m, 9H); 1.31 (m, 3H); 3.02-3.25 (m, 1H); 3.90 (m, 1H); 4.17 (m, 3H); 4.6 5-4.77 (m, 1H); 5.12-5.21 (m, 2H); 5.68 (m, 1H); 5.88 (m, 1H); 7.92-8.17 (m, 4H).

[0641] Intermediate 42: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-4-carboxylic acid tert-Butyl-5,6-dihydropyridine-1(2H)-carboxylate

[0642]

[0643] To a solution of (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-methyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 41, 4.16 g, 8.36 mmol) in DMF (35 mL) was added ammonium chloride (0.895 g, 16.72 mmol), HATU (4.77 g, 12.54 mmol) and DIEA (5.84 mL, 33.45 mmol) at room temperature. After 15 minutes, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and washed twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-80% ethyl acetate / hexanes) was run twice to obtain the desired product (2.16 g, 52%) as a yellow foam.

[0644] MS :497ES+(C 21 H 28 N 4 O 8 S)

[0645] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0646] Intermediate 43: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-methyl-1,2,5,6- Tetrahydropyridine-2-carboxamide

[0647]

[0648] To a solution of tert-butyl (2S,5R)-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) was added zinc bromide (0.700 mL, 13.05 mmol) at room temperature. 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 give the desired product (1.450 g, 84%) as a yellow foam.

[0649] MS :397ES+(C 16 H 20 N 4 O 6 S)

[0650] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0651] Intermediate 44: (2S,5R)-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

[0652]

[0653] 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) was added PS-thiophenol (3-(3-mercaptophenyl)propionamidomethylpolystyrene) (1.55 mmol / g) (9.12 g, 14.13 mmol) at room temperature. After stirring overnight at room temperature, the reaction mixture was filtered through a sintered funnel and the resin was washed twice with DCM. The filtrate was concentrated to give a yellow oil. Silica gel chromatography (0%-5% methanol / dichloromethane) gave a 3 to 1 mixture of trans and cis isomers (0.473 g, 63.4%) as a light yellow oil. The mixture was carried forward without separation.

[0654] MS :212ES+(C 10 H 17 N 3 O 2 )

[0655] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0656] Intermediate 45: (2S,5R)-6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane- 3-ene-2-carboxamide

[0657]

[0658] To a solution of ((2S,5R)-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) was added 0.1 mL of 4-nitropropanediol (2% ethyl acetate) at 0 °C. L / min rate as a solution in acetonitrile (1.5mL) triphosgene (0.241g, 0.81mmol). Once the addition is complete, the reaction is warmed to room temperature and stirred for two days. The reaction mixture is 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 / hexane) gave the product (0.312g, 64.8%) as a light yellow oil.

[0659] MS :238ES+(C 11 H 15 N 3 O 3 )

[0660] 1 HNMR(300MHz,DMSO-d 6 )δ: 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).

[0661] Example 31: (2R)-2-(((2S,5R)-2-Carbamoyl-4-methyl-7-oxo-1,6-diazabicyclo [3.2.1] Ethyl 2-fluoroacetate (oct-3-en-6-yl)oxy)

[0662]

[0663] Example 32: (2S)-2-(((2S,5R)-2-Carbamoyl-4-methyl-7-oxo-1,6-diazabicyclo [3.2.1] Ethyl 2-fluoroacetate (oct-3-en-6-yl)oxy)

[0664]

[0665] Examples 31-32

[0666] 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, 0.2972 g, 1.25 mmol) in methanol (6 mL) was added 1,3-dimethylbarbituric acid (0.391 g, 2.51 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.145 g, 0.13 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours and then concentrated to give 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 at room temperature overnight, then diluted with ethyl acetate and filtered through a 0.45 μm filter to remove solid potassium carbonate. The filtrate was washed twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-65% ethyl acetate / hexanes) gave a 1:1 mixture of diastereomers, 372 mg, 99%. Separation of diastereomers was performed on reverse phase HPLC (Atlantis T3, 19 mm x 150 mm, 5 μm, 20%-40% acetonitrile in water, 20 mL / min, 15 min). Both diastereomers were obtained after lyophilization as white solids.

[0667] The following product was obtained:

[0668] Example 31: (first eluting diastereomer): 108.8 mg, 29%

[0669] MS :302ES+(C 12 H 16 FN 3 O 5 )

[0670] 1 HNMR(300MHz,DMSO-d 6 )δ: 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 (brs, 1H).

[0671] Example 32: (Second eluting diastereomer): 103.3 mg, 27%

[0672] MS :302ES+(C 12 H 16 FN 3 O 5 )

[0673] 1 HNMR(300MHz,DMSO-d 6 )δ: 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 (brs, 1H).

[0674] The stereochemistry of the two diastereomers was assigned based on the order of elution and based on the inhibitory activity of the corresponding carboxylic acids (Examples 33 and 34): the more active acid from the first eluting diastereomer was assigned as the R-isomer.

[0675] Example 33: (2R)-2-(((2S,5R)-2-Carbamoyl-4-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl)oxy)-2-fluoroacetic acid lithium salt

[0676]

[0677] To a solution of (2R)-2-(((2S,5R)-2-carbamoyl-4-methyl-7-oxo-1,6-diazabicyclo-[3.2.1]oct-3-en-6-yl)oxy)-2-fluoroacetic acid ethyl ester (Example 31, 96.6 mg, 0.32 mmol) in THF (3 mL) and water (1 mL) at 0°C was added lithium hydroxide (0.337 mL, 0.34 mmol). The reaction mixture was kept in an ice bath and stirred for 15 minutes. An additional 0.2 equivalents of lithium hydroxide was added. After 15 minutes, the reaction mixture was adjusted to pH = 7 with 0.5N HCl. THF was evaporated and the remaining aqueous solution was frozen and lyophilized to give a light yellow solid. Reverse phase HPLC (YMC Carotenoid C30, 19 mm x 150 mm, 5 μm coupled with Synergi Polar RP 21.2 mm x 100 mm, 4 μm, 0%-40% acetonitrile in water, 20 mL / min, 15 min) afforded the title compound as a white solid after lyophilization, 34.8 mg, 40%.

[0678] MS :274ES+(C 10 H 12 FN 3 O 5 )

[0679] 1 HNMR(300MHz,DMSO-d 6 )δ: 1.83 (m, 3H); 3.21 (m, 2H); 3.91 (m, 1H); 4.16 (m, 1H); 5.33 (m, 1H); 5.44 (m, 1H); 7.27 (br s, 1H); 7.53 (br s, 1H).

[0680] Example 34: (2S)-2-(((2S,5R)-2-Carbamoyl-4-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl)oxy)-2-fluoroacetic acid lithium salt

[0681]

[0682] The title compound was prepared from (2S)-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 32, 91.8 mg, 0.30 mmol) according to the procedure of Example 33. Purification conditions were the same to give an off-white solid after lyophilization, 11.7 mg, 14%.

[0683] MS :274ES+(C 10 H 12 FN 3 O 5 )

[0684] 1 HNMR(300MHz,DMSO-d 6 )δ: 1.81 (m, 3H); 3.21 (m, 2H); 3.87 (m, 1H); 4.16 (m, 1H); 5.25 (m, 1H); 5.45 (m, 1H); 7.28 (br s, 1H); 7.54 (br s, 1H).

[0685] Example 35: (2R)-2-(((2S,5R)-2-Carbamoyl-4-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl)oxy)-2-fluoroacetic acid isopropyl ester

[0686]

[0687] Example 36: (2S)-2-(((2S,5R)-2-Carbamoyl-4-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl)oxy)-2-fluoroacetic acid isopropyl ester

[0688]

[0689] 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) was added 1,3-dimethylbarbituric acid (0.197 g, 1.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.073 g, 0.06 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours and then concentrated to give an orange film. The orange film was dissolved in DMF (4 mL). Potassium carbonate (0.175 g, 1.26 mmol) and isopropyl 2-bromo-2-fluoroacetate (Intermediate 18, 0.377 g, 1.90 mmol) were added. The reaction mixture was stirred at room temperature for 4.5 hours, then diluted with ethyl acetate and filtered through a 0.45 μm filter to remove solid potassium carbonate. The filtrate was washed twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-65% ethyl acetate / hexanes) gave a 1:1 mixture of diastereomers, 196 mg, 98%. Separation of the diastereomers was performed on reverse phase HPLC (Atlantis T3, 19 mm x 150 mm, 5 μm, 20%-40% acetonitrile in water, 20 mL / min, 15 min). The two diastereomers were obtained after lyophilization as white solids.

[0690] Example 35: (first eluting diastereomer): 58.6 mg, 31%.

[0691] MS :316ES+(C 13 H 18 FN 3 O 5 )

[0692] 1 HNMR(300MHz,DMSO-d 6 )δ: 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 (brs, 1H).

[0693] Example 36: (Second eluting diastereomer): 53.8 mg, 29%.

[0694] MS :316ES+(C 13 H 18 FN 3 O 5 )

[0695] 1 HNMR(300MHz,DMSO-d 6 )δ: 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 (brs, 1H).

[0696] Intermediates 46-50 are intentionally omitted.

[0697] Intermediate 51: (R)-tert-butyl 4-(cyclopropyl(hydroxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate

[0698]

[0699] To a solution of (R)-4-formyl-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (Aldrich, 12.44 g, 54.26 mmol) in THF (150 mL) was added cyclopropylmagnesium bromide (217 mL, 108.52 mmol) at -78 °C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water and diluted with ethyl acetate and brine. The resulting emulsion was filtered through diatomaceous earth and the layers were separated. The organic matter was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate / hexane) obtained the title compound as a light yellow oil (12.47 g, 85%).

[0700] 1 H NMR(300MHz,DMSO-d 6 )δ: 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).

[0701] Intermediate 52: (R)-4-(Cyclopropanecarbonyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester

[0702]

[0703] To a solution of (R)-4-(cyclopropyl(hydroxy)methyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (intermediate 51, 12.47 g, 45.95 mmol) in DCM (300 mL) was added Dess-Martin periodinane (29.2 g, 68.93 mmol) at room temperature. The reaction mixture was stirred overnight, then diluted with ethyl acetate and washed with saturated sodium bicarbonate. An emulsion was formed and filtered through diatomaceous earth. The layers were separated and the organics were washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate / hexane) obtained the title compound as a colorless oil (11.15 g, 90%).

[0704] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0705] Intermediate 53: (S)-tert-butyl 4-(1-cyclopropylvinyl)-2,2-dimethyloxazolidine-3-carboxylate

[0706]

[0707] To a suspension of potassium tert-butoxide (9.29 g, 82.80 mmol) in diethyl ether (250 mL) was added methyl triphenylphosphonium bromide (29.6 g, 82.80 mmol) at room temperature. 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)-4-(cyclopropanecarbonyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (intermediate 52, 11.15 g, 41.40 mmol) in diethyl 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 solution was extracted once with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-15% ethyl acetate / hexane) obtained the title compound as a colorless oil (9.84 g, 89%).

[0708] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0709] Intermediate 54: (S)-1-(tert-Butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-ylcarbamic acid Tert-butyl ester

[0710]

[0711] To a solution of (S)-4-(1-cyclopropylvinyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (intermediate 53, 8.25 g, 30.86 mmol) in methanol (100 mL) was added p-toluenesulfonic acid monohydrate (1.174 g, 6.17 mmol) at room temperature. The reaction mixture was heated to 80 ° C overnight. 0.2 equivalents of p-toluenesulfonic acid monohydrate were 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, 15.43 mmol) were added. The reaction mixture was stirred for two days and then concentrated. The residue was dissolved in ethyl acetate and washed once with saturated sodium bicarbonate. 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, 30.86 mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove solids and washed twice with brine. 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%).

[0712] MS :342ES+(C 18 H 35 NO 3 Si)

[0713] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0714] Intermediate 55: (S)-1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-amine

[0715]

[0716] To a solution of (S)-1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-ene-2-ylcarbamic acid tert-butyl ester (intermediate 54, 6.77 g, 19.82 mmol) in DCM (100 mL) was added zinc bromide (17.86 g, 79.28 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. An additional 1 equivalent of zinc bromide 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 obtain the title compound as a yellow oil (4.61 g, 96%).

[0717] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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, 1H).

[0718] Intermediate 56: (S)-1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-yl (2-(methoxy tert-Butyl (methyl)amino)-2-oxoethyl)carbamate

[0719]

[0720] 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-methylacetamide (Intermediate 4, 3.16 g, 17.36 mmol) according to the procedure described for Intermediate 5. The desired product was obtained as a light yellow oil (4.94 g, 64%).

[0721] MS :443ES+(C 22 H 42 N 2 O 5 Si)

[0722] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0723] Intermediate 57: (S)-1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-yl (2-oxo tert-Butyl pentyl)carbamate

[0724]

[0725] The suspension of cerium chloride (III) (27.8g, 112.95mmol) in THF (100mL) was vigorously stirred at room temperature for 2 hours. The suspension was cooled to -78 ° C and (E)-prop-1-enyl magnesium bromide (0.5M THF solution) (226mL, 112.95mmol) was added dropwise. The mixture was stirred at -78 ° C for 1.5 hours. Then (S)-1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-ene-2-yl (2-(methoxy(methyl)amino)-2-oxoethyl)carbamic acid tert-butyl ester (intermediate 56, 5g, 11.30mmol) in THF (20mL) was added dropwise at -78 ° C. The reaction was stirred at -78 ° C for 30 minutes, then warmed to 0 ° C and kept for 15 minutes. The reaction was quenched with 10% citric acid, further diluted with water and extracted twice with ether. The organics were washed once with brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0% to 20% ethyl acetate / hexanes) provided the title compound as a light yellow oil (4.0 g, 84%).

[0726] MS :424ES+(C 23 H 41 NO 4 Si)

[0727] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0728] Intermediate 58: (S)-2-((tert-butyldimethylsilyloxy)methyl)-3-cyclopropyl-5-oxo-5,6-dihydro- Hydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0729]

[0730] The title compound was prepared from (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-yl(2-oxopent-3-enyl)carbamate (Intermediate 57, 4 g, 9.44 mmol) according to the procedure described for Intermediate 7, except that the reaction mixture was heated at 110° C. overnight. The desired product was obtained as a light brown oil (2.97 g, 82%).

[0731] MS:382ES+(C 20 H 35 NO 4 Si)

[0732] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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, 1H).

[0733] Intermediate 59: (2S,5S)-2-((tert-butyldimethylsilyloxy)methyl)-3-cyclopropyl-5-hydroxy-5, 6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0734]

[0735] The title compound was prepared from (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-cyclopropyl-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 58, 2.97 g, 7.78 mmol) following the procedure described for Intermediate 10. The desired product was obtained as a tan oil (2.74 g, 92%).

[0736] MS :384ES+(C 20 H 37 NO 4 Si)

[0737] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0738] Intermediate 60: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(tert-butyldimethyl tert-Butyl (((((((((((((((((- ...

[0739]

[0740] The title compound was prepared from tert-butyl (2S,5S)-2-((tert-butyldimethylsilyloxy)-methyl)-3-cyclopropyl-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) according to the procedure described for Intermediate 11. The desired product was obtained as a light yellow oil (3.19 g, 71%).

[0741] MS :624ES+(C 29 H 45 N 3 O 8 SSi)

[0742] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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, 4H).

[0743] Intermediate 61: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-cyclopropyl-2-(hydroxymethyl) tert-Butyl)-5,6-dihydropyridine-1(2H)-carboxylate

[0744]

[0745] The title compound was prepared from tert-butyl (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-3-cyclopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 60, 3.19 g, 5.11 mmol) following the procedure described for Intermediate 12. The desired product was obtained as a tan foam (2.35 g, 90%).

[0746] MS :510ES+(C 23 H 31 N 3 O 8 S)

[0747] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0748] Intermediate 62: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butyloxycarbonyl) 1,2,5,6-tetrahydropyridine-2-carboxylic acid

[0749]

[0750] The title compound was prepared from tert-butyl (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-cyclopropyl-2-(hydroxymethyl)-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%).

[0751] MS :524ES+(C 23 H 29 N 3 O 9 S)

[0752] Intermediate 63: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3-cyclohexane Propyl-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0753]

[0754] 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 (Intermediate 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%).

[0755] MS :523ES+(C 23 H 30 N 4 O 8 S)

[0756] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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, 4H).

[0757] Intermediate 64: (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-cyclopropyl-1,2,5, 6-Tetrahydropyridine-2-carboxamide

[0758]

[0759] The title compound was prepared from tert-butyl (2S,5R)-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 25. The desired product was obtained as an orange foam (0.518 g, 68%).

[0760] MS :423ES+(C 18 H 22 N 4 O 6 S)

[0761] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0762] Intermediate 65: (R)-5-(allyloxyamino)-3-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide

[0763]

[0764] The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 64, 0.518 g, 1.23 mmol) according to the procedure described for Intermediate 26. The desired product was obtained as a light yellow oil (0.171 g, 59%). The product was a mixture of diastereomers.

[0765] MS :238ES+(C 12 H 19 N 3 O 2 )

[0766] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0767] Intermediate 66: (2S,5R)-6-(allyloxy)-3-cyclopropyl-7-oxo-1,6-diazabicyclo[3.2.1] Oct-3-ene-2-carboxamide

[0768]

[0769] The title compound was prepared from (R)-5-(allyloxyamino)-3-cyclopropyl-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%).

[0770] MS :264ES+(C 13 H 17 N 3 O 3 )

[0771] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0772] Example 37: (2R)-2-(((2S,5R)-2-Carbamoyl-3-cyclopropyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl)oxy)-2-fluoroacetic acid isopropyl ester

[0773]

[0774] Example 38: (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 isopropyl ester

[0775]

[0776] To a solution of (2S,5R)-6-(allyloxy)-3-cyclopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (intermediate 66, 0.15 g, 0.57 mmol) in methanol (3 mL) was added 1,3-dimethylbarbituric acid (0.178 g, 1.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.066 g, 0.06 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours and then concentrated to give an orange film. The orange film was dissolved in DMF (4 mL). Potassium carbonate (0.157 g, 1.14 mmol) and 2-bromo-2-fluoroacetic acid isopropyl ester (intermediate 18, 0.340 g, 1.71 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate and filtered through a 0.45 μm filter to remove solid potassium carbonate. The filtrate was washed twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-65% ethyl acetate / hexane) gave a 1:1 mixture of diastereomers, 166.3 mg, 86%. The separation of diastereomers was performed on a reverse phase HPLC (Atlantis T3, 19 mm x 150 mm, 5 μm, 20%-40% acetonitrile in water, 20 mL / min, 15 min). The two diastereomers were obtained after freeze drying as white solids.

[0777] Example 37: (first eluting diastereomer): 47.3 mg, 24%

[0778] MS :342ES+(C 15 H 20 FN 3 O 5 )

[0779] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0780] Example 38: (Second eluting diastereomer): 49.8 mg, 26%.

[0781] MS :342ES+(C 15 H 20 FN 3 O5 )

[0782] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0783] Example 39: (2R)-2-(((2S,5R)-2-Carbamoyl-3-cyclopropyl-7-oxo-1,6-diazabicyclo [3.2.1] 6-oct-3-en-yl)oxy)-2-fluoroacetate

[0784]

[0785] Example 40: (2S)-2-(((2S,5R)-2-Carbamoyl-3-cyclopropyl-7-oxo-1,6-diazabicyclo [3.2.1] Ethyl 2-fluoroacetate (oct-3-en-6-yl)oxy)

[0786]

[0787] To a solution of (2S,5R)-6-(allyloxy)-3-cyclopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (intermediate 66, 0.2972 g, 1.13 mmol) in methanol (6 mL) was added 1,3-dimethylbarbituric acid (0.352 g, 2.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.11 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours and then concentrated to give an orange film. The orange film was dissolved in DMF (6 mL). Potassium carbonate (0.468 g, 3.39 mmol) and ethyl bromofluoroacetate (0.534 mL, 4.52 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate and filtered through a 0.45 μm filter to remove solid potassium carbonate. The filtrate was washed twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-65% ethyl acetate / hexane) gave a 1:1 mixture of diastereomers, 303.7 mg, 82%. The separation of diastereomers was performed on a reverse phase HPLC (Atlantis T3, 19 mm x150 mm, 5 μm, 20%-40% acetonitrile in water, 20 mL / min, 15 min). The two diastereomers were obtained after freeze drying as white solids.

[0788] Example 39: (first eluting diastereomer): 107 mg, 29%

[0789] MS :328ES+(C14 H 18 FN 3 O 5 )

[0790] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0791] Example 40: (Second eluting diastereomer): 110.9 mg, 30%.

[0792] MS :328ES+(C 14 H 18 FN 3 O 5 )

[0793] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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 (brs, 1H).

[0794] Example 41: (2R)-2-(((2S,5R)-2-Carbamoyl-3-cyclopropyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl)oxy)-2-fluoroacetic acid lithium salt

[0795]

[0796] To a solution of (2R)-2-(((2S,5R)-2-carbamoyl-3-cyclopropyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)-2-fluoroacetic acid ethyl ester (Example 39, 96.6 mg, 0.30 mmol) in THF (3 mL) and water (1 mL) at 0°C was added lithium hydroxide (1 M) (0.310 mL, 0.31 mmol). The reaction mixture was kept in an ice bath and stirred for 15 minutes. An additional 0.2 equivalents 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 give a light yellow solid, 90.4 mg. Reverse phase HPLC (YMC Carotenoid 30, 19 mm x 150 mm, 5 μm coupled to Synergi Polar RP, 21.2 mm x 100 mm, 4 μm, 0%-25% acetonitrile in water, 20 mL / min, 5 min) afforded the title compound as a white solid, 45.9 mg, 52%.

[0797] MS :300ES+(C 12 H 14 FN 3 O 5 )

[0798] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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 (brs, 1H).

[0799] Example 42: (2R)-2-(((2S,5R)-2-Carbamoyl-3-cyclopropyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl)oxy)-2-fluoroacetic acid lithium salt

[0800]

[0801] To a solution of (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 40, 96.6 mg, 0.30 mmol) in THF (3 mL) and water (1) at 0°C was added lithium hydroxide (1 M) (0.310 mL, 0.31 mmol). The reaction mixture was kept in an ice bath and stirred for 15 minutes. An additional 0.2 equivalents 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 give a light yellow solid, 90.4 mg. Reverse phase HPLC (YMC Carotenoid 30, 19 mm x 150 mm, 5 μm coupled to Synergi Polar RP, 21.2 mm x 100 mm, 4 μm, 0%-25% acetonitrile in water, 20 mL / min, 5 min) afforded the title compound as a white solid, 41.2 mg, 45%.

[0802] MS :300ES+(C 12 H 14 FN 3 O 5 )

[0803] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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 (brs, 1H).

[0804] Example 43: 2-(((2S,5R)-2-carbamoyl-3-cyclopropyl-7-oxo-1,6-diazabicyclo[3.2.1] Oct-3-en-6-yl)oxy)-2-fluoroacetic acid lithium salt

[0805]

[0806] (2R)-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 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 added. The mixture was frozen and lyophilized to give a white solid, 16 mg.

[0807] MS :300ES+(C 12 H 14 FN 3 O 5 )

[0808] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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 (brs, 1H).

[0809] Intermediate 67: 2-Bromo-2,2-difluoro-acetic acid (1-isopropyl-2-methyl-propyl) ester

[0810]

[0811] 2-Bromo-2,2-difluoroacetyl chloride (0.49 mL, 5.17 mmol) was added dropwise 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. The reaction mixture was stirred overnight at 35 ° C. The reaction was quenched with 10 mL of 1N hydrochloric acid. The layers were separated. The organic matter was washed twice with water, once with brine, then dried over magnesium sulfate, filtered and concentrated to obtain the title compound as a dark orange oil, 1.95 g, quantitative. The crude product was used in the next step.

[0812] <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (300 MHz, CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> -d) δ: 0.95 (m, 12H); 2.06 (m, 2H); 4.74 (m, 1H).

[0813] Example 44: 2-[[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1] Oct-3-en-6-yl]oxy]-2,2-difluoroacetic acid (1-isopropyl-2-methyl-propyl) ester

[0814]

[0815] 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) was added potassium carbonate (210.27 mg, 1.52 mmol) and 2-bromo-2,2-difluoroacetic acid (1-isopropyl-2-methyl-propyl) ester (intermediate 67, 623.28 mg, 2.28 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. Two equivalents of 2-bromo-2,2-difluoro-acetic acid (1-isopropyl-2-methyl-propyl) ester were added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and filtered to remove potassium carbonate. The filtrate was washed three times with 1:1 brine: water. The organic matter was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-15% acetone / dichloromethane) afforded the title compound as a light orange viscous film after lyophilization, 44.6 mg, 13%.

[0816] MS :390ES+(C 17 H 25 FN 3 O 5 )

[0817] 1 H NMR (300 MHz,DMSO-d 6 )δ: 0.86 (m, 12H); 1.64 (s, 3H); 1.99 (m, 2H); 3.15 (m, 1H); 3.85 (m, 1H); 4.0 7 (m, 1H); 4.28 (s, 1H); 4.69 (m, 1H); 6.03 (m, 1H); 7.42 (s, 1H); 7.85 (s, 1H).

[0818] Intermediate 68: (2R)-2-bromo-2-fluoro-octyl acetate

[0819]

[0820] To a suspension of (2R)-2-bromo-2-fluoro-acetic acid; (1S)-1-phenylethylamine (Intermediate 168, 642.8 mg, 2.31 mmol) and 1-octanol (554 mg, 5.78 mmol) in DCM (9 mL) was added trimethylchlorosilane (1.19 mL, 9.39 mmol) dropwise at room temperature. The suspension became a solution and stirred at room temperature overnight. The reaction mixture was washed three times with water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-10% ethyl acetate / hexanes) obtained the title compound as a colorless liquid, 554.9 mg, 89%.

[0821] <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (300 MHz, CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> -d)δ: 0.84 (m, 3H); 1.24 (m, 10H); 1.61 (m, 2H); 4.22 (m, 2H); 7.25 (d, 1H).

[0822] Example 45: (2R)-2-[[(2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1]Oct-3-en-6-yl]oxy]-2-fluoro-octyl acetate

[0823]

[0824] 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 (2R)-2-bromo-2-fluoro-octyl acetate (Intermediate 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 mixture was stirred for 10 minutes, then diluted with ethyl acetate and washed three times with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated to give an orange oil. Silica gel chromatography (0%-60% ethyl acetate / hexanes) obtained the title compound as a white solid, 247.9 mg, 84%.

[0825] MS :386ES+(C 18 H 28 FN 3 O 5 )

[0826] 1 H NMR (300 MHz,DMSO-d 6 )δ: 0.86 (m, 3H); 1.25 (m, 10H); 1.59 (m, 5H); 3.04 (m, 1H); 3.78 (m, 1H); 4.0 4 (m, 1H); 4.16 (m, 3H); 6.00 (m, 1H); 6.24 (d, 1H); 7.37 (s, 1H); 7.81 (s, 1H).

[0827] Intermediate 69: (2R)-2-Bromo-2-fluoro-octyl acetate

[0828]

[0829] The title compound was prepared according to the procedure of Intermediate 68 from (2R)-2-bromo-2-fluoro-acetic acid; (1S)-1-phenylethylamine (Intermediate 168, 526.2 mg, 1.89 mmol) and methanol (260 mg, 5.68 mmol) to afford a white oil / solid, 260 mg, 80%.

[0830] <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (300 MHz, CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> -d)δ: 3.84 (s, 3H); 6.52 (d, 1H).

[0831] Example 46: (2R)-2-[[(2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl]oxy]-2-fluoroacetic acid methyl ester

[0832]

[0833] The title compound was prepared according to the procedure of Example 45 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 (2R)-methyl 2-bromo-2-fluoroacetate (Intermediate 69, 0.09 mL, 1.52 mmol) to give a white foam, 81.2 mg, 46%.

[0834] MS :288ES+(C 11 H 14 FN 3 O 5 )

[0835] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0836] Intermediate 70: (2R)-2-bromo-2-fluoro-acetic acid allyl ester

[0837]

[0838] The title compound was prepared according to the procedure of Intermediate 68 from (2R)-2-bromo-2-fluoro-acetic acid; (1S)-1-phenylethylamine (Intermediate 168, 510 mg, 1.83 mmol) and allyl alcohol (0.37 mL, 5.5 mmol) to give a colorless liquid, 100 mg, 28%.

[0839] <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (300 MHz, CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> -d) δ: 4.71 (m, 2H); 5.31 (m, 2H); 5.86 (m, 1H); 6.55 (d, 1H).

[0840] Example 47: (2R)-2-[[(2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1]Oct-3-en-6-yl]oxy]-2-fluoro-allyl acetate

[0841]

[0842] The title compound was prepared according to the procedure of Example 45 from (2S,5R)-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 (2R)-2-bromo-2-fluoro-acetic acid allyl ester (Intermediate 70, 100 mg, 0.51 mmol) to give a white foam, 61.3 mg, 77%.

[0843] MS :314ES+(C 13 H 16 FN 3 O 5 )

[0844] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0845] Intermediate 71: (2R)-2-bromo-2-fluoro-propyl acetate

[0846]

[0847] The title compound was prepared according to the procedure of Intermediate 68 from (2R)-2-bromo-2-fluoro-acetic acid; (1S)-1-phenylethylamine (Intermediate 168, 444.9 mg, 1.6 mmol) and 1-propanol (0.3 mL, 4 mmol) to give a colorless liquid, 318 mg, 100%.

[0848] <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (300 MHz, CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> -d) δ: 0.92 (t, 3H); 1.67 (m, 2H); 4.19 (m, 2H); 6.51 (d, 1H).

[0849] Example 48: (2R)-2-[[(2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1]Oct-3-en-6-yl]oxy]-2-fluoropropyl acetate

[0850]

[0851] The title compound was prepared according to the procedure of Example 45 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 (2R)-2-bromo-2-fluoro-acetic acid propyl ester (Intermediate 71, 302.78 mg, 1.52 mmol) to give a white viscous foam, 156 mg, 65%.

[0852] MS :316ES+(C 13 H 18 FN 3 O 5 )

[0853] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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, 1H).

[0854] Intermediate 72: (2R)-2-bromo-2-fluoro-acetic acid isobutyl ester

[0855]

[0856] The title compound was prepared according to the procedure of Intermediate 68 from (2R)-2-bromo-2-fluoro-acetic acid; (1S)-1-phenylethylamine (Intermediate 168, 487.5 mg, 1.75 mmol) and 2-methyl-1-propanol (0.4 mL, 4.38 mmol) to give a colorless liquid, 373 mg, 100%.

[0857] <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (300 MHz, CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> -d) δ: 0.91 (d, 6H); 1.97 (m, 1H); 4.00 (m, 2H); 6.51 (d, 1H).

[0858] Example 49: (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 isobutyl ester

[0859]

[0860] The title compound was prepared according to the procedure of Example 45 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 (2R)-2-bromo-2-fluoro-acetic acid isobutyl ester (Intermediate 72, 372.73 mg, 1.75 mmol) to give a sticky white foam, 161 mg, 64%.

[0861] MS :330ES+(C 14 H 20 FN 3 O 5 )

[0862] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0863] Intermediate 73: (2R)-2-Bromo-2-fluoro-butyl acetate

[0864]

[0865] According to the procedure of Intermediate 68. The title compound was prepared from (2R)-2-bromo-2-fluoro-acetic acid; (1S)-1-phenylethylamine (Intermediate 168, 400 mg, 1.44 mmol) and 1-butanol (0.33 mL, 3.6 mmol) to obtain a colorless liquid, 322 mg, quantitative.

[0866] 1 H NMR(300MHz,CDCl 3 -d) δ: 0.88 (t, 3H); 1.33 (m, 2H); 1.65 (m, 2H); 4.23 (m, 2H); 6.50 (d, 1H).

[0867] Example 50: (2R)-2-[[(2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] Oct-3-en-6-yl]oxy]-2-fluoro-acid butyl ester

[0868]

[0869] The title compound was prepared according to the procedure of Example 45 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 (2R)-2-bromo-2-fluoro-acetic acid butyl ester (Intermediate 73, 322.49 mg, 1.51 mmol) to give a sticky white foam, 198 mg, 79%.

[0870] MS :330ES+(C 14 H 20 FN 3 O 5 )

[0871] 1 H NMR(300MHz,DMSO-d 6 )δ: 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).

[0872] Intermediate 74: (2R)-2-Bromo-2-fluoro-acetic acid pentyl ester

[0873]

[0874] The title compound was prepared according to the procedure of Intermediate 68 from (2R)-2-bromo-2-fluoro-acetic acid; (1S)-1-phenylethylamine (Intermediate 168, 474.2 mg, 1.71 mmol) and 1-pentanol (0.46 mL, 4.26 mmol) to give a colorless liquid, 363 mg, 93%.

[0875] 1 H NMR(300MHz,CDCl 3 -d) δ: 0.88 (m, 3H); 1.28 (m, 4H); 1.60 (m, 2H); 4.17 (m, 2H); 6.45 (d, 1H).

[0876] Example 51: (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 pentyl ester

[0877]

[0878] The title compound was prepared according to the procedure of Example 45 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 (2R)-2-bromo-2-fluoro-acetic acid pentyl ester (Intermediate 74, 362.73 mg, 1.6 mmol) to give a sticky white foam, 225 mg, 86%.

[0879] MS :344ES+(C 15 H 22 FN 3 O 5 )

[0880] 1 H NMR(300MHz,DMSO-d 6 )δ: 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).

[0881] Intermediate 75: (2R)-2-Bromo-2-fluoro-acetic acid hexyl ester

[0882]

[0883] The title compound was prepared according to the procedure of Intermediate 68 from (2R)-2-bromo-2-fluoro-acetic acid; (1S)-1-phenylethylamine (Intermediate 168, 400 mg, 1.44 mmol) and hexanol (0.45 mL, 3.6 mmol) to give a colorless liquid, 313 mg, 90%.

[0884] <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (300 MHz, CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> -d) δ: 0.86 (m, 3H); 1.22 (m, 6H); 1.59 (m, 2H); 4.17 (m, 2H); 6.45 (d, 1H).

[0885] Example 52: (2R)-2-[[(2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1]oct-3-en-6-yl]oxy]-2-fluoroacetic acid hexyl ester

[0886]

[0887] The title compound was prepared according to the procedure of Example 45 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 (2R)-2-bromo-2-fluoro-acetic acid hexyl ester (Intermediate 75, 313.62 mg, 1.3 mmol) to give a sticky white foam, 224 mg, 82%.

[0888] MS :358ES+(C 16 H 24 FN 3 O 5 )

[0889] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0890] Intermediate 76: 1-Chloroethyl isopropyl carbonate

[0891]

[0892] To a solution of 2-propanol (0.64mL, 8.39mmol) and pyridine (0.79mL, 9.79mmol) was added 1-chloroethyl chloroformate (0.76mL, 6.99mmol) at -78°C. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture became a solid white mass and was ultrasonically treated in dichloromethane. The resulting suspension was concentrated and the white solid was dissolved in ethyl acetate and washed with water and brine. The organic matter was dried over magnesium sulfate, filtered and concentrated to obtain the title compound as a colorless liquid, 1.29g, 99%.

[0893] <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR (300 MHz, CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> -d) δ: 1.35 (m, 6H); 1.84 (d, 3H); 4.96 (m, 1H); 4.44 (m, 1H).

[0894] Example 53: (2R)-2-[[(2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] 1-isopropoxycarbonyloxyethyl [oct-3-en-6-yl]oxy]-2-fluoroacetate

[0895]

[0896] 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-fluoroacetic acid (Example 4, 194.46 mg, 0.71 mmol), N,N-diisopropylethylamine (0.12 mL, 0.71 mmol) and 1-chloroethyl isopropyl ester (Intermediate 76, 237.15 mg, 1.42 mmol) in DMF (5 mL) was added tetrabutylammonium chloride (162.22 mg, 0.71 mmol) at room temperature. The reaction mixture was heated at 40 °C for ~4 hours, then diluted with ethyl acetate and washed twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated to give an orange oil. Silica gel chromatography (0% to 50% ethyl acetate / hexanes) provided the title compound as a 1:1 mixture of diastereomers as a white foam, 33.2 mg, 11%.

[0897] MS :404ES+(C 16 H 22 FN 3 O 8 )

[0898] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0899] Example 54: (2R)-2-(((2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] Benzyl 2-fluoroacetate

[0900]

[0901] A solution of DBU (8.83 mL, 58.57 mmol) in DMF (30 mL) was added dropwise to (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) -2-bromo-2-fluoroacetic acid benzyl ester (intermediate 171, 14.47 g, 58.57 mmol) in DMF (100 mL) at -40 ° C under nitrogen for 30 minutes. The resulting solution was stirred at -40 ° C for 30 minutes and then quenched with water (15 mL). The reaction mixture was extracted with ethyl acetate (3x20 mL). The combined organics were washed with brine (3x20 mL), dried over sodium sulfate, filtered and concentrated. Silica gel chromatography (0% to 40% ethyl acetate / petroleum ether) afforded the title compound as a white solid, 8.8 g, 45%.

[0902] MS :364ES+(C 17 H 18 FN 3 O 5 )

[0903] 1 H NMR (400 MHz,DMSO-d 6 )δ: 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).

[0904] Intermediate 77: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-1,6-diazo Heterobicyclo[3.2.1]oct-3-ene-2-carboxylic acid

[0905]

[0906] 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 methyl ester (Intermediate 185, 538.5 mg, 1.65 mmol) in DCE (3 mL) in a 20 mL microwave vial was added trimethyltin hydroxide (477.17 mg, 2.64 mmol). The reaction was run in the microwave at 80 °C for 2 hours. The solvent was removed and the resulting residue was dissolved in ethyl acetate and washed three times with 0.01 N potassium bisulfate and once with brine. The organics were dried over sodium sulfate, filtered and concentrated to give an orange foam, 649 mg, 100%.

[0907] MS :313ES+(C 14 H 24 N 2 O 4 Si)

[0908] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0909] Intermediate 78: 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]hydrazine]-2-oxo-acetamide

[0910]

[0911] 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, 397.5 mg, 1.02 mmol) in DMF (6 mL) at 0°C was added oxalohydrazide (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 solution contained some product and was extracted once with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered and concentrated to give a yellow oil. Silica gel chromatography (0%-5% methanol) afforded the title compound as a light yellow solid, 142 mg, 35%.

[0912] MS:398ES+(C 16 H 27 N 5 O 5 Si)

[0913] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0914] Intermediate 79: 5-[(2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-1,6-dimethoxy Azabicyclo[3.2.1]oct-3-en-2-yl]-1,3,4-oxadiazole-2-carboxamide

[0915]

[0916] To a solution 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]hydrazine]-2-oxo-acetamide (Intermediate 78, 142 mg, 0.36 mmol) in DCM (6 mL) was added 4-nitrobenzenesulfonyl chloride (79.17 mg, 0.36 mmol) and N,N-diisopropylethylamine (0.19 mL, 1.07 mmol) at room temperature. The reaction mixture turned yellow and stirred for 30 minutes, then diluted with dichloromethane and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated to give an orange oil. Silica gel chromatography (0%-5% methanol / dichloromethane) obtained the title compound as an orange foam, 93.8 mg, 69%.

[0917] MS :380ES+(C 16 H 25 N 5 O 4 Si)

[0918] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0919] Intermediate 80: 5-[(2S,5R)-6-hydroxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-3- [2-enyl]-1,3,4-oxadiazole-2-carboxamide

[0920]

[0921] 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 an additional 2 equivalents of HF-pyridine were added and the reaction was stirred for an additional hour. The reaction mixture was concentrated to afford the title compound as a tan solid, 245 mg, 99%.

[0922] MS :266ES+(C 10 H 11 N 5 O 4 )

[0923] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0924] Intermediate 81: Ethyl (2S)-2-[[(2S,5R)-2-(5-carbamoyl-1,3,4-oxadiazol-2-yl)-3-carboxylate 7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]-2-fluoroacetate

[0925]

[0926] 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-fluoroacetate (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 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated to give 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 was a 7:3 mixture of diastereomers.

[0927] MS :370ES+(C 14 H 16 FN 5 O 6 )

[0928] 1 H NMR (300 MHz,DMSO-d 6 )δ: 1.25 (m, 3H); 1.72 (s, 3H); 3.20 (m, 2H); 4.19 (m, 1H); 5.30 (m, 1H); 6.25 (m, 1H); 6.26 (m, 1H); 8.26 (s, 1H); 8.65 (s, 1H).

[0929] Example 55: 2-[[(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-acetic acid lithium salt

[0930]

[0931] To a solution of (2S)-2-[[(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]-ethyl 2-fluoroacetate (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. An additional 0.5 equivalents of lithium hydroxide was added. After 10 minutes, the reaction mixture was treated with an additional 0.5 equivalents of oxyhydroxide. The reaction mixture was stirred for 20 minutes, neutralized with 0.5N HCl, frozen and lyophilized to obtain a yellow solid. Reverse phase ISCO (50 g RediSep Gold C18, 100% water, 4 min; then 0%-50% acetonitrile / water) afforded the title compound as an off-white solid, 26 mg, 36%. The compound was a 7:3 mixture of diastereomers.

[0932] MS :342ES+(C 12 H 12 FN 5 O 6 )

[0933] 1 H NMR (300 MHz,DMSO-d 6 )δ: 1.70 (s, 3H); 3.20 (m, 2H); 4.15 (m, 1H); 5.20 (s, 1H); 5.28 (m, 1H); 6.27 (m, 1H); 8.25 (s, 1H); 8.65 (s, 1H).

[0934] Intermediate 82: 2-(1,3-dioxoisoindolin-2-yl)oxyethanesulfonamide

[0935]

[0936] 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) was added diisopropyl azodicarboxylate (1.7 mL, 8.63 mmol) at 0°C. The reaction mixture turned dark orange and then light yellow. After stirring for ~3 hours, the reaction mixture was concentrated to give a viscous light yellow oil which was triturated with ethyl acetate / hexanes. The white solid was collected by filtration, which was the title compound, 1.8 g, 70%.

[0937] MS :271ES+(C 10 H 10 N 2 O 5 S)

[0938] 1 H NMR (300 MHz,DMSO-d 6 )δ: 3.52 (m, 2H); 4.50 (m, 2H); 6.96 (s, 2H); 7.87 (s, 4H).

[0939] Intermediate 83: 2-aminooxyethanesulfonamide

[0940]

[0941] To a solution of 2-(1,3-dioxoisoindolin-2-yl)oxyethanesulfonamide (Intermediate 82, 740 mg, 2.05 mmol) in DCM (20 mL) was added methylhydrazine (0.11 mL, 2.05 mmol) at room temperature. A precipitate formed immediately. The suspension was stirred at room temperature for ~2 hours and then concentrated. The solid was triturated with DCM and collected by filtration. The solid was triturated with methanol and the resulting white solid was filtered out. NMR of the solid indicated a by-product. The filtrate was concentrated to obtain the title compound as an off-white solid, 228.2 mg, 58%. NMR indicated 73% of the desired product.

[0942] 1 H NMR(300MHz,DMSO-d 6 )δ: 3.27 (m, 2H); 3.85 (m, 2H); 6.11 (bs, 2H); 6.79 (s, 2H).

[0943] Intermediate 84: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-N-(2-aminosulfonyl)- (acetylethoxy)-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide

[0944]

[0945] 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, 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 stirred at 0°C for 1 hour, then diluted with ethyl acetate and washed twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated to give a yellow oil. Silica gel chromatography (0%-80% ethyl acetate / hexanes) afforded the title compound as a colorless oil, 343 mg, 66%.

[0946] MS :435ES+(C 16 H 30 N 4 O 6 SiS)

[0947] 1 H NMR(300MHz,DMSO-d 6 )δ: 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, 1H).

[0948] Intermediate 85: (2S,5R)-6-hydroxy-3-methyl-7-oxo-N-(2-sulfamoylethoxy)-1,6-diazabi Cyclo[3.2.1]oct-3-ene-2-carboxamide

[0949]

[0950] 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. Two more equivalents of HF-pyridine were added and the reactants were stirred for another hour. After 6 hours, a total of 7 equivalents of HF-pyridine, the reaction was complete. The reaction mixture was filtered and an off-white solid was collected. The solid became gummy and stuck to the filter. The filter was rinsed with ethyl acetate and a small amount of methanol and the solid was transferred to a flask. The solvent was removed in vacuo to obtain the title compound as an off-white solid, 337 mg, 100%.

[0951] MS :321ES+(C 10 H 16 N 4 O 6 S)

[0952] Intermediate 86: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-(2-sulfamoylethoxycarbamoyl ethyl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[0953]

[0954] The title compound was prepared according to the procedure of Example 45 from (2S,5R)-6-hydroxy-3-methyl-7-oxo-N-(2-sulfamoylethoxy)-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-fluoroacetate (Intermediate 174, 0.08 mL, 0.65 mmol) to give a light yellow oil, 26.7 mg, 10%.

[0955] MS :425ES+(C 14 H 21 FN 4 O 8 S)

[0956] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0957] Example 56: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-(2-sulfamoylethoxycarbamoyl 1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid lithium salt

[0958]

[0959] To a solution of (2S)-2-fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-(2-sulfamoylethoxy-carbamoyl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]ethyl ester (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 0.5 equivalents of lithium hydroxide were added. After 15 minutes, another 0.5 equivalents of lithium hydroxide were added. After 30 minutes, the temperature was slightly raised and the reaction was complete. The reaction mixture was neutralized with 0.5N HCl, frozen and lyophilized to obtain 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 off-white solid, 11.3 mg, 29%.

[0960] MS :397ES+(C 12 H 17 FN 4 O 8 S)

[0961] 1 H NMR (300 MHz,DMSO-d 6 )δ: 1.56 (s, 3H); 3.02 (m, 1H); 3.26 (m, 1H); 3.98 (m, 5H); 5.20 (d, 1H); 6.03 (m, 1H); 7.06 (s, 2H).

[0962] Intermediate 87: (2S,5R)-6-allyloxy-3-methyl-7-oxo-N-(2-sulfamoylethyl)-1,6-diazepine Bicyclo[3.2.1]oct-3-ene-2-carboxamide

[0963]

[0964] The title compound was prepared according to the procedure of Intermediate 84 from (2S,5R)-6-allyloxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxylic acid (Intermediate 29, 208.5 mg, 0.88 mmol) and 2-aminoethanesulfonamide hydrochloride (281.1 mg, 1.75 mmol) to give a light oil, 86.6, 29%.

[0965] MS :345ES+(C 13 H 20 N 4 O 5 S)

[0966] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0967] Intermediate 88: (2S,5R)-6-hydroxy-3-methyl-7-oxo-N-(2-sulfamoylethyl)-1,6-diazabicyclo [3.2.1] Oct-3-ene-2-carboxamide

[0968]

[0969] 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 methanol (3 mL) was added 1,3-dimethylbarbituric acid (78.53 mg, 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (58.12 mg, 0.05 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then concentrated to give a dark orange oil, 76.5 mg, 100%.

[0970] MS :305ES+(C 10 H 16 N 4 O 5 S)

[0971] Intermediate 89: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-(2-sulfamoylethylcarbamoyl ethyl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[0972]

[0973] 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-fluoroacetate (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 dropwise. Additional ethyl (2S)-2-bromo-2-fluoroacetate (0.09 mL, 0.75 mmol) was added. Then, additional DBU (0.04 mL, 0.25 mmol) was added. After a further 15 minutes at 0 °C with occasional warming, an additional 0.5 equivalent of DBU was added. The reaction mixture was stirred at room temperature for a further 15 minutes. The reaction mixture was diluted with ethyl acetate and washed three times with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated to give an orange oil. Silica gel chromatography (0%-25% acetone / dichloromethane) gave the title compound accompanied by some triphenylphosphine oxide as an orange film, 77.3 mg, 75%.

[0974] MS :409ES+(C 14 H 21 FN 4 O 7 S)

[0975] Example 57: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-(2-sulfamoylethylcarbamoyl 1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid lithium salt

[0976]

[0977] To a solution of (2S)-2-fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-(2-sulfamoylethyl-carbamoyl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]ethyl acetate (Intermediate 89, 72.3 mg, 0.18 mmol) in THF (2 mL) and water (1 mL) was added 1 M lithium hydroxide (0.18 mL, 0.18 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. It was then neutralized with 0.5N hydrochloric acid, frozen and lyophilized to obtain a yellow solid. Reverse phase ISCO (100% water) obtained the title compound as a light yellow solid, 14.3 mg, 21%.

[0978] MS :381ES+(C 12 H 17 FN 4 O 7 S)

[0979] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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).

[0980] Example 58: 2-[[(2R)-2-[[(2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl]oxy]-2-fluoro-acetyl]oxymethoxycarbonylamino]-3-methylbutyric acid ethyl ester

[0981]

[0982] 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-fluoroacetic acid (Example 4, 100 mg, 0.37 mmol), Hunig's base (0.06 mL, 0.37 mmol) and ethyl 2-(chloromethoxycarbonylamino)-3-methylbutanoate (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 organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain an orange oil. Silica gel chromatography (0%-80% ethyl acetate / hexane) obtained the title compound (7 mg, 3.63%) as a white solid.

[0983] MS :475ES+(C 19 H 27 FN 4 O 9 )

[0984] 1 H NMR (300MHz, DMSO-d 6 )d: 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).

[0985] Intermediate 90: (2S)-2-[(1,3-dioxoisoindolin-2-yl)oxymethyl]pyrrolidine-1-carboxylic acid tert-butyl ester

[0986]

[0987] To a solution of diethyl azodicarboxylate (14.21 mL, 12.48 mmol) in THF (10 mL) at 0°C was added a solution of triphenylphosphine (3273.22 mg, 12.48 mmol) in THF (20 mL). The suspension was stirred at -10°C. After 20 minutes, the suspension became solid and 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 reaction mixture was allowed to warm to room temperature and stirred overnight. It was concentrated and the resulting oil was triturated with ethyl acetate / hexane. The precipitate was removed by filtration and the filtrate was concentrated onto silica gel. Silica gel chromatography (0%-40% EtOAc / hexanes) afforded the title compound (2.37 g, quantitative) as a light yellow solid.

[0988] MS :347ES+(C 18 H 22 N 2 O 5 )

[0989] Intermediate 91: tert-butyl (2S)-2-(aminooxymethyl)pyrrolidine-1-carboxylate

[0990]

[0991] To a solution of (2S)-tert-butyl 2-[(1,3-dioxoisoindolin-2-yl)oxymethyl]pyrrolidine-1-carboxylate (Intermediate 90, 2.06 g, 5.95 mmol) in DCM (20 mL) was added hydrazine monohydrate (2.14 mL, 17.84 mmol) at room temperature. A white precipitate was formed immediately. The suspension was stirred at room temperature for 1 hour and then filtered through celite. The filtrate was washed twice with brine / water (1:1), dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the title compound (1.35 g, quantitative) as a viscous oil.

[0992] 1 H NMR (300 MHz,CDCl 3 )δ: 1.50 (s, 9H); 1.85 (m, 4H); 3.32 (m, 2H); 3.63 (m, 1H); 4.25 (m, 2H).

[0993] Intermediate 92: (2S)-2-[[[(2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxy tert-Butyl 1,6-diazabicyclo[3.2.1]oct-3-ene-2-carbonyl]amino]oxymethyl]pyrrolidine-1-carboxylate

[0994]

[0995] The title compound was prepared according to the procedure of Intermediate 84 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 (2S)-tert-butyl 2-(aminooxymethyl)pyrrolidine-1-carboxylate (Intermediate 91, 1.28 g, 5.92 mmol) to give (585 mg, 19%) a white viscous foam.

[0996] MS: 511ES+(C 24 H 42 N 4 O 6 Si)

[0997] Intermediate 93: (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-carboxylic acid tert-butyl ester

[0998]

[0999] To a solution of (2S)-tert-butyl 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) was added HF at 0°C under nitrogen atmosphere. . Pyridine (24 μL, 0.94 mmol). The reaction mixture was stirred at room temperature for 3 hours and 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.

[1000] MS: 396ES+(C 18 H 28 N 4 O 6 )

[1001] Example 59: (2S)-2-((((2S,5R)-6-((S)-2-ethoxy-1-fluoro-2-oxoethoxy)-3-methyl- Tert-butyl 7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamido)oxy)methyl)pyrrolidine-1-carboxylate

[1002]

[1003] To a suspension of (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-carboxylic acid tert-butyl ester (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 (2S)-ethyl 2-bromo-2-fluoroacetate (Intermediate 174, 0.14 mL, 1.17 mmol). The reaction mixture 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 / hexane) to obtain the title compound (164 mg, 40%) as a sticky solid.

[1004] MS: 501ES+(C 22 H 33 FN 4 O 8 )

[1005] 1 H NMR (300 MHz,CDCl 3 )δ: 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, 1H); 4.01 (m, 1H); 4.28 (m, 2H); 4.35 (m, 2H); 5.75 (d, 1H); 6.10 (s, 1H).

[1006] Example 60: (2S)-2-Fluoro-2-(((2S,5R)-3-methyl-7-oxo-2-((((S)-pyrrolidin-2-yl)methyl (oxy)carbamoyl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)ethyl acetate TFA salt

[1007]

[1008] To a solution of (2S)-tert-butyl 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)pyrrolidine-1-carboxylate (Example 59, 76 mg, 0.15 mmol) in DCM (10 mL) was added TFA (0.58 mL, 7.59 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours and then concentrated. The residue was triturated with diethyl ether to obtain the title compound (53 mg, 83%) as a TFA salt.

[1009] MS: 401ES+(C 17 H 25 FN 4 O6 )

[1010] 1 H NMR (300 MHz,CDCl 3 )δ: 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).

[1011] Intermediate 94: (S)-2-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)-4,4-difluoropyrrolidine-1- Tert-butyl carboxylate

[1012]

[1013] The title compound was prepared according to the procedure of Intermediate 90 from (S)-4,4-difluoro-2-(hydroxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.8 g, 11.8 mmol) and was obtained as a light yellow sticky solid (4.3 g, 95%).

[1014] MS: 383ES+(C 18 H 20 F 2 N 2 O 5 )

[1015] Intermediate 95: (S)-tert-butyl 2-((aminooxy)methyl)-4,4-difluoropyrrolidine-1-carboxylate

[1016]

[1017] The title compound was prepared according to the procedure of Intermediate 91 from (S)-tert-butyl 2-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)-4,4-difluoropyrrolidine-1-carboxylate (Intermediate 94, 1.9 g, 4.97 mmol) to afford (1.25 g, 99%) an orange viscous oil.

[1018] 1 H NMR (300 MHz,CDCl 3 )δ: 1.51 (s, 9H); 2.42 (m, 2H); 3.63 (m, 2H); 3.85 (m, 2H); 4.97 (m, 1H).

[1019] Intermediate 96: (2S)-2-((((2S,5R)-6-((tert-butyldimethylsilyl)oxy)-3-methyl-7-oxy tert-Butyl-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamido)oxy)methyl)-4,4-difluoropyrrolidine-1-carboxylate ester

[1020]

[1021] The title compound was prepared according to the procedure of Intermediate 84 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, 1.3 g, 4.16 mmol) and (S)-tert-butyl 2-((aminooxy)methyl)-4,4-difluoropyrrolidine-1-carboxylate (Intermediate 95, 1.26 g, 4.99 mmol) to give (489 mg, 18%) a viscous white foam.

[1022] MS: 547ES+(C 24 H 40 F 2 N 4 O 6 Si)

[1023] Intermediate 97: (2S)-4,4-difluoro-2-((((2S,5R)-6-hydroxy-3-methyl-7-oxo-1,6-diazabi tert-Butyl cyclo[3.2.1]oct-3-ene-2-carboxamido)oxy)methyl)pyrrolidine-1-carboxylate

[1024]

[1025] The title compound was prepared according to the procedure of Intermediate 93 from tert-butyl (2S)-2-((((2S,5R)-6-((tert-butyldimethylsilyl)oxy)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamido)oxy)methyl)-4,4-difluoropyrrolidine-1-carboxylate (Intermediate 96, 489 mg, 0.89 mmol) and obtained as a white sticky solid (330 mg, 72%).

[1026] MS: 433ES+(C 18 H 26 F 2 N 4 O 6 )

[1027] Intermediate 98: (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-carboxylic acid Tert-butyl ester

[1028]

[1029] To a suspension of (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-carboxylic acid tert-butyl ester (intermediate 97, 300 mg, 0.69 mmol) and cesium carbonate (339 mg, 1.04 mmol) in ethyl acetate (15 mL) at 0 ° C. (2S)-ethyl 2-bromo-2-fluoroacetate (intermediate 174, 0.1 mL, 0.83 mmol) was added. 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 flash chromatography on silica gel (0-100%, EtOAc / hexanes) to obtain the title compound (70 mg, 18%) as a viscous white foam.

[1030] MS: 537ES+(C 22 H 31 F 3 N 4 O 8 )

[1031] Example 61: (2S)-2-(((2S,5R)-2-((((S)-4,4-difluoropyrrolidin-2-yl)methoxy)carbamyl ethyl)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)-2-fluoroacetate TFA salt

[1032]

[1033] The title compound was prepared according to the procedure of Example 60 from (2S)-tert-butyl 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) and was obtained as a TFA salt (20 mg, 85%).

[1034] MS :437ES+(C 17 H 23 F 3 N 4 O 6 )

[1035] 1 H NMR (300 MHz,CDCl 3 )δ: 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).

[1036] Intermediate 99: (2S)-2-[[(2S,5R)-2-[[(2S)-1-tert-butyloxycarbonylpyrrolidin-2-yl]methoxyamine [formyl]-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]-2-fluoroacetic acid

[1037]

[1038] To a solution of (2S)-tert-butyl 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)pyrrolidine-1-carboxylate (Example 59, 81 mg, 0.16 mmol) in THF (1 mL) and water (0.50 mL) was added lithium hydroxide (1 N, 0.01 mL, 0.40 mmol) at 0°C. The reaction mixture was stirred for 30 minutes. Dilute HCl solution (0.5 N) 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 give the title compound (50 mg, 65%) as a gum.

[1039] MS: 471ES-(C 20 H 29 FN 4 O 8 )

[1040] Example 62: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[[(2S)-pyrrolidin-2-yl]methyl [oxycarbamoyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid TFA salt

[1041]

[1042] The title compound was prepared according to the procedure of Example 60 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-yl]oxy]-2-fluoroacetic acid (Intermediate 99, 65 mg, 0.14 mmol) and obtained as a TFA salt (40 mg, 70%).

[1043] MS:473ES+(C 20 H 29 FN 4 O 8 )

[1044] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1045] Intermediate 100: (2S)-2-(((2S,5R)-2-((((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine- 2-yl)methoxy)carbamoyl)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)-2- Fluoroacetic acid

[1046]

[1047] The title compound was prepared according to the procedure of Intermediate 99 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, 37 mg, 0.07 mmol) and was obtained as a gum (35 mg, 90%).

[1048] MS: 507ES-(C 20 H 27 F 3 N 4 O 8 )

[1049] Example 63: (2S)-2-(((2S,5R)-2-((((S)-4,4-difluoropyrrolidin-2-yl)methoxy)carbamyl 1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)-2-fluoroacetic acid TFA salt

[1050]

[1051] The title compound was prepared according to the procedure of Example 60 from (2S)-2-(((2S,5R)-2-((((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methoxy)carbamoyl)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)-2-fluoroacetic acid (Intermediate 100, 35 mg, 0.07 mmol) to obtain (22 mg, 70%) of the TFA salt.

[1052] MS: 409ES+(C 15 H 19 F 3 N 4 O 6 )

[1053] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1054] Example 64: [(2R)-2-[[(2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1] oct-3-en-6-yl]oxy]-2-fluoro-acetyl]oxymethyl 2,2-dimethylpropanoate

[1055]

[1056] The title compound was prepared according to the procedure of Example 53 from (2R)-2-[[(2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]-2-fluoroacetic acid (Example 4, 47 mg, 0.17 mmol) and chloromethyl pivalate (0.05 mL, 0.34 mmol) to give (33.2 mg, 49.8%) of a white solid.

[1057] MS :388ES+(C 16 H 22 FN 3 O 7 )

[1058] 1 H NMR (300 MHz,DMSO-d 6 )δ: 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, 1H); 7.86 (bs, 1H).

[1059] Example 65: (2R)-2-[[(2S,5R)-2-Carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1]Oct-3-en-6-yl]oxy]-2-fluoroacetic acid indan-5-yl ester

[1060]

[1061] To a solution of (2R)-2-[[(2S, 5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-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. N, N'-dicyclohexylcarbodiimide (113.3 mg, 0.55 mmol) and DMAP (5.0 mg) were added. The reaction mixture was stirred at room temperature for 1 hour. The reactant was concentrated and then dissolved in EtOAC. The white solid formed was filtered out. The filtrate was concentrated. Silica gel chromatography (0-80% ethyl acetate / hexane) obtained the title compound (72 mg, 48%) as a white solid.

[1062] MS :390ES+(C 19 H 20 FN 3 O 5)

[1063] 1 H NMR (300 MHz,DMSO-d 6 )δ: 1.64 (s, 3H); 2.05 (m, 2H); 2.85 (m, 4H); 3.10 (m, 1H); 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).

[1064] Intermediate 101: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-N-(oxetane- 3-yl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1065]

[1066] 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 at room temperature for 30 minutes, then diluted with ethyl acetate, washed once with saturated sodium bicarbonate and three times with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0-2.5% methanol / dichloromethane) afforded the title compound (80 mg, 68%) as a yellow oil.

[1067] MS :368ES+(C 17 H 29 N 3 O 4 Si)

[1068] Intermediate 102: (2S,5R)-6-hydroxy-3-methyl-N-(oxetane-3-yl)-7-oxo-1,6-diazepine Bicyclo[3.2.1]oct-3-ene-2-carboxamide

[1069]

[1070] 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 mixture was stirred at room temperature for 1 hour. The solvent was removed.

[1071] MS: 254ES+(C 11 H 15 N 3 O 4 )

[1072] Intermediate 103: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-2-(oxetane-3-ylcarbamoyl)-7- Ethyl 1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[1073]

[1074] To a solution of (2S,5R)-6-hydroxy-3-methyl-N-(oxetane-3-yl)-7-oxo-1,6-diazabicyclo[3.2.1]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 (2S)-ethyl 2-bromo-2-fluoroacetate (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 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0-80% EtOAc / hexanes) obtained the title compound (58 mg, 82.2%) as a colorless oil. The compound is a 2:8 mixture of diastereomers

[1075] MS: 358ES+(C 15 H 20 FN 3 O 6 )

[1076] Example 66: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-2-(oxetane-3-ylcarbamoyl)-7- Oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid lithium salt

[1077]

[1078] To a solution of (2S)-2-fluoro-2-[[(2S,5R)-3-methyl-2-(oxetan-3-ylcarbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]ethyl ester (Intermediate 103, 56.3 mg, 0.16 mmol) in THF (1.0 mL) and water (0.5 mL) at 0°C was added lithium hydroxide (1 M) (0.50 mL, 0.50 mmol). The reaction mixture was stirred for 1 hour. The pH was adjusted to ~5-6 by adding HCl (1 N) solution. The solvent was removed. The sepabead column (first saturated with water, then saturated with ACN, then washed with water) was eluted with water (0%-5% ACN / water) to obtain the title compound (10 mg, 17.3%) as a white solid after lyophilization.

[1079] MS :330ES+(C 13 H 16 FN 3 O 6 )

[1080] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1081] Intermediate 104: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-N-[2-(methylsulfonyl)ethyl 1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1082]

[1083] The title compound was prepared according to the procedure of Intermediate 101 from 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, 300 mg, 0.96 mmol) in DMF (1.5 mL) and N-(2-amino-ethyl)-methanesulfonamide hydrochloride (251.5 mg, 1.44 mmol) and was obtained as a white solid (220 mg, 53%).

[1084] MS :433ES+(C 17 H 32 N 4 O 5 SiS)

[1085] Intermediate 105: (2S,5R)-6-hydroxy-N-[2-(methylsulfonylamino)ethyl]-3-methyl-7-oxo-1,6-diol Azabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1086]

[1087] The title compound was prepared from (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-N-[2-(methylsulfonamido)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 of Intermediate 102 to give a tan residue.

[1088] MS: 319ES+(C 11 H 18 N 4 O 5 S)

[1089] Intermediate 106: (2S)-2-Fluoro-2-[[(2S,5R)-2-[2-(methylsulfonylamino)ethyl-carbamoyl]-3-methyl ethyl 7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[1090]

[1091] The title compound was prepared from (2S,5R)-6-hydroxy-N-[2-(methylsulfonamido)-ethyl]-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 105, 80 mg, 0.25 mmol) and ethyl (2S)-2-bromo-2-fluoroacetate (Intermediate 174, 0.089 mL, 0.75 mmol) according to the procedure of Intermediate 103 and obtained as a white solid (25 mg, 18.8%). The compound was a 1:4 mixture of diastereomers.

[1092] MS: 423ES+(C 15 H 23 FN 4 O 7 S)

[1093] Example 67: (2S)-2-Fluoro-2-[[(2S,5R)-2-[2-(methylsulfonylamino)ethylcarbamoyl]-3-methyl- 7-Oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid lithium salt

[1094]

[1095] The title compound was prepared according to the procedure of Example 66 from ethyl (2S)-2-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) and obtained as a white solid after lyophilization (4.0 mg, 15.4%).

[1096] MS :395ES+(C 13 H 19 FN 4 O 7 S)

[1097] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1098] Intermediate 107: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-N-(oxazol-2-yl)methyl 1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1099]

[1100] The title compound was prepared according to the procedure of Intermediate 101 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-ylmethanamine hydrochloride (258.4 mg, 1.92 mmol) to give (120 mg, 23.9%) as a white solid.

[1101] MS :393ES+(C 18 H 28 N 4 O 4 Si)

[1102] Intermediate 108: (2S,5R)-6-hydroxy-3-methyl-N-(oxazol-2-ylmethyl)-7-oxo-1,6-diazabi Cyclo[3.2.1]oct-3-ene-2-carboxamide

[1103]

[1104] The title compound was prepared according to the procedure of Intermediate 102 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) to give a residue.

[1105] MS: 279ES+(C 12 H 14 N 4 O 4 )

[1106] Intermediate 109: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-2-(oxazol-2-ylmethylcarbamoyl)-7-oxo ethyl 1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[1107]

[1108] The title compound was prepared according to the procedure of Intermediate 103 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-fluoroacetate (Intermediate 174, 0.10 mL, 0.86 mmol) and obtained as a colorless oil (15 mg, 13.6%). This compound was a 15:85 mixture of diastereomers.

[1109] MS: 383ES+(C 16 H 19 FN 4 O 6 )

[1110] Example 68: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-2-(oxazol-2-ylmethylcarbamoyl)-7-oxo 1,6-Diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid lithium salt

[1111]

[1112] The title compound was prepared according to the procedure of Example 66 from ethyl (2S)-2-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 (Intermediate 109, 15 mg, 0.039 mmol) and obtained as a white solid after lyophilization (4.0 mg, 25.9%).

[1113] MS :355ES+(C 14 H 15 FN 4 O 6 )

[1114] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1115] Intermediate 110: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-N-(pyrazine- 2-aminomethyl)-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1116]

[1117] The title compound was prepared according to the procedure of Intermediate 101 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) to give (120 mg, 46.4%) as a white solid.

[1118] MS :404ES+(C 19 H 29 N 5 O 3 Si)

[1119] Intermediate 111: (2S,5R)-6-hydroxy-3-methyl-7-oxo-N-(pyrazin-2-ylmethyl)-1,6-diazabi Cyclo[3.2.1]oct-3-ene-2-carboxamide

[1120]

[1121] The title compound was prepared according to the procedure of Intermediate 102 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) to give a residue.

[1122] MS: 290ES+(C 13 H 15 N 5 O 3 )

[1123] Intermediate 112: (2S)-2-fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-(pyrazin-2-ylmethylcarbamoyl ethyl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[1124]

[1125] The title compound was prepared from (2S,5R)-6-hydroxy-3-methyl-7-oxo-N-(pyrazin-2-ylmethyl)-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 111, 70 mg, 0.24 mmol) and ethyl (2S)-2-bromo-2-fluoroacetate (Intermediate 174, 0.086 mL, 0.73 mmol) according to the procedure of Intermediate 103 to afford (50 mg, 52.5%) a colorless oil. The compound was a 15:85 mixture of diastereomers.

[1126] MS: 394ES+(C 17 H 20 FN 5O 5 )

[1127] Example 69: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-(pyrazin-2-ylmethyl-carbamyl 1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid lithium salt

[1128]

[1129] The title compound was prepared according to the procedure of Example 66 from ethyl (2S)-2-fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-(pyrazin-2-ylmethylcarbamoyl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate (Intermediate 112, 50 mg, 0.13 mmol) and obtained as a white solid after lyophilization (4.0 mg, 8.2%).

[1130] MS :366ES+(C 15 H 16 FN 5 O 5 )

[1131] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1132] Intermediate 113: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-N-(cyclopropylmethoxy)-3-methyl 7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1133]

[1134] The title compound was prepared according to the procedure of Intermediate 101 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 O-(cyclopropylmethyl)hydroxylamine (83.6 mg, 0.96 mmol) to give (100 mg, 40.9%) a colorless oil.

[1135] MS :382ES+(C 18 H 31 N 3 O 4 Si)

[1136] Intermediate 114: (2S,5R)-N-(cyclopropylmethoxy)-6-hydroxy-3-methyl-7-oxo-1,6-diazabi Cyclo[3.2.1]oct-3-ene-2-carboxamide

[1137]

[1138] The title compound was prepared according to the procedure of Intermediate 102 from (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-N-(cyclopropylmethoxy)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 113, 0.1 g, 0.26 mmol) to give a residue.

[1139] MS: 268ES+(C 12 H 17 N 3 O 4 )

[1140] Intermediate 115: (2S)-2-[[(2S,5R)-2-(cyclopropylmethoxycarbamoyl)-3-methyl-7-oxo-1, Ethyl 6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy-2-fluoroacetate

[1141]

[1142] The title compound was prepared from (2S,5R)-N-(cyclopropylmethoxy)-6-hydroxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 114, 60 mg, 0.22 mmol) and (2S)-ethyl 2-bromo-2-fluoroacetate (Intermediate 174, 0.08 mL, 0.67 mmol) according to the procedure of Intermediate 103 to afford (15 mg, 18%) a colorless oil. The compound was a 1:9 mixture of diastereomers.

[1143] MS: 372ES+(C 16 H 22 FN 3 O 6 )

[1144] Example 70: (2S)-2-[[(2S,5R)-2-(cyclopropylmethoxycarbamoyl)-3-methyl-7-oxo-1,6- Diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]-2-fluoro-acetic acid lithium salt

[1145]

[1146] The title compound was prepared according to the procedure of Example 66 from ethyl (2S)-2-[[(2S,5R)-2-(cyclopropylmethoxy-carbamoyl)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]-2-fluoroacetate (Intermediate 115, 15 mg, 0.04 mmol) and obtained as a white solid after lyophilization (4.5 mg, 32.5%).

[1147] MS :344ES+(C 14 H 18 FN 3 O6 )

[1148] 1 H NMR (300 MHz,D 2 O) δ: 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, 1H).

[1149] Intermediate 116: (2S,5R)-N-(3-amino-3-oxo-propyl)-6-[tert-butyl(dimethyl)silyl] Oxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1150]

[1151] The title compound was prepared according to the procedure of Intermediate 101 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 alaninamide hydrochloride (119.6 mg, 0.96 mmol) to give (140 mg, 57.2%) as a white solid.

[1152] MS :383ES+(C 17 H 30 N 4 O 4 Si)

[1153] Intermediate 117: (2S,5R)-N-(3-amino-3-oxo-propyl)-6-hydroxy-3-methyl-7-oxo-1,6-diol Azabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1154]

[1155] The title compound was prepared according to the procedure of Intermediate 102 from (2S,5R)-N-(3-amino-3-oxo-propyl)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 116, 140 mg, 0.37 mmol) to obtain a residue.

[1156] MS: 269ES+(C 11 H 16 N 4 O 4 )

[1157] Intermediate 118: (2S)-2-[[(2S,5R)-2-[(3-amino-3-oxo-propyl)carbamoyl]-3-methyl-7- Ethyl oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]-2-fluoroacetate

[1158]

[1159] According to the procedure of Intermediate 103, (2S,5R)-N-(3-amino-3-oxo-propyl)-6-hydroxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 117, 90 mg, 0.34 mmol), K 2 CO 3 (139.1 mg, 1.01 mmol) and ethyl (2S)-2-bromo-2-fluoroacetate (Intermediate 174, 0.12 mL, 1.01 mmol) were used to prepare the title compound, which was obtained as a white solid (26.0 mg, 20.8%). This compound was a 1:9 mixture of diastereomers.

[1160] MS: 373ES+(C 15 H 21 FN 4 O 6 )

[1161] Example 71: (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-acetic acid lithium salt

[1162]

[1163] The title compound was prepared according to the procedure of Example 66 from (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-acetic acid ethyl ester (Intermediate 118, 25 mg, 0.07 mmol) and obtained as a white solid after lyophilization (8 mg, 34.6%).

[1164] MS :345ES+(C 13 H 17 FN 4 O 6 ).

[1165] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1166] Intermediate 119: 2-[[(2S)-5-oxopyrrolidin-2-yl]methoxy]isoindoline-1,3-dione

[1167]

[1168] To a solution of diethyl azodicarboxylate (16.6 mL, 14.6 mmol, 40% wt) in THF (10 mL) was added a solution of triphenylphosphine (3.83 g, 14.6 mmol) in THF (20 mL) at -10 ° C. The suspension was stirred at -10 ° C. After 1 hour, a solution of (S)-(+)-5-(hydroxymethyl)-2-pyrrolidone) (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 stirred for 2 days. The reaction mixture was concentrated. Silica gel chromatography (0-100% EtOAc / hexane, then 10% MeOH / DCM) obtained the title compound (1.5 g, 83%) as a light yellow solid.

[1169] MS: 261ES+(C 13 H 12 N 2 O 4 )

[1170] Intermediate 120: (5S)-5-(aminooxymethyl)pyrrolidin-2-one

[1171]

[1172] 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) was added hydrazine monohydrate (0.84 mL, 17.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then washed with (3x20 mL) water. The aqueous layer was concentrated. The title compound (0.60 g, 79.9%) was obtained on a sepabead column as a white solid.

[1173] MS: 163ES+(C 8 H 6 N 2 O 2 )

[1174] Intermediate 121: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-N-[(5-oxy [(2-( ...

[1175]

[1176] The title compound was prepared according to the procedure of Intermediate 101 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, 250 mg, 0.80 mmol) and 5-(aminooxymethyl)pyrrolidin-2-one (Intermediate 120, 156.2 mg, 1.2 mmol) and obtained (55 mg, 16.2%) as a white solid.

[1177] MS: 425ES+(C 19 H 32 N 4 O 5 Si)

[1178] Intermediate 122: (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

[1179]

[1180] The title compound was prepared according to the procedure of Intermediate 102 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) to give a light yellow gum.

[1181] MS: 311ES+(C 13 H 18 N 4 O 5 )

[1182] Intermediate 123: (2S)-2-fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[(5-oxopyrrolidin-2-yl) Ethyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[1183]

[1184] 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 (2S)-ethyl 2-bromo-2-fluoroacetate (Intermediate 174, 0.04 mL, 0.34 mmol) according to the procedure of Intermediate 103 to afford (15 mg, 32.1%) a sticky solid. The compound was a 1:4 mixture of diastereomers.

[1185] MS: 415ES+(C17 H 23 FN 4 O 7 )

[1186] Example 72: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[(5-oxopyrrolidin-2-yl)methyl [oxycarbamoyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid lithium salt

[1187]

[1188] The title compound was prepared according to the procedure of Example 66 from ethyl (2S)-2-fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[(5-oxopyrrolidin-2-yl)methoxycarbamoyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate (Intermediate 123, 15 mg, 0.036 mmol) and was obtained as a white solid after lyophilization (7.0 mg, 40%).

[1189] MS :387ES+(C 15 H 19 FN 4 O 7 ).

[1190] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1191] Intermediate 124: [(2S)-5-oxopyrrolidin-2-yl]4-methylbenzenesulfonic acid methyl ester

[1192]

[1193] (S)-(+)-5-(Hydroxymethyl)-2-pyrrolidinone (2.0 g, 17.4 mmol) and p-toluenesulfonyl chloride (4.17 g, 21.9 mmol) were reacted in CH 2 Cl 2 To a stirred solution of 4% paraformaldehyde (50 mL) was added dimethylaminopyridine (111.4 mg, 0.91 mmol) and triethylamine (3.05 mL, 21.9 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 12 h. The reaction was then quenched with water and washed with CH 2 Cl 2 The aqueous layer was extracted. The combined organic extracts were washed with 1N HCl solution and purified by anhydrous Na 2 SO 4Drying. Removal of the 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.

[1194] MS :270ES+(C 12 H 15 NO 4 S).

[1195] Intermediate 125: 2-[(2S)-5-oxopyrrolidin-2-yl]acetonitrile

[1196]

[1197] To a solution of [(2S)-5-oxopyrrolidin-2-yl]4-methylbenzenesulfonic acid methyl ester (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 acetonitrile (200 mL), filtered through celite, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (9: 1 DCM / MeOH) to obtain the title compound (1.8 g, 86.8%) as a white solid.

[1198] MS :125ES+(C 6 H 8 N 2 O).

[1199] Intermediate 126: tert-Butyl N-[2-[(2S)-5-oxopyrrolidin-2-yl]ethyl]carbamate

[1200]

[1201] To a stirred solution of 2-[(2S)-5-oxopyrrolidin-2-yl]acetonitrile (Intermediate 125, 300 mg, 2.42 mmol) in methanol (15 mL) at 0°C was added di-tert-butyl dicarbonate (1.05 g, 4.83 mmol) and NiCl 2 .6H 2 O (57.4 mg, 0.24 mmol). Then, NaBH was added over 30 minutes. 4 (0.64 g, 16.9 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. Hunig's base (0.42 mL, 2.42 mmol) was added and then stirred for 30 minutes. The solvent was removed. The residue was dissolved in EtOAc and washed with saturated NaHCO 3 solution, washed with brine, and then with MgSO 4 Dry, filter and concentrate to obtain the title compound (0.50 g, 90.6%) as a white solid.

[1202] MS :229ES+(C 11 H 20 N 2 O 3 )

[1203] Intermediate 127: (5S)-5-(2-aminoethyl)pyrrolidin-2-one

[1204]

[1205] 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 stirred at room temperature for 2 hours. The solvent was removed to give the title compound as a TFA salt.

[1206] MS :129ES+(C 6 H 12 N 2 O)

[1207] Intermediate 128: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-N-[2-(5- [2-( ...

[1208]

[1209] The title compound was prepared according to the procedure of Intermediate 101 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 5-(2-aminoethyl)pyrrolidin-2-one TFA salt (Intermediate 127, 0.35 g, 1.44 mmol) and was obtained as a white solid (120 mg, 29.6%).

[1210] MS: 423ES+(C 20 H 34 N 4 O 4 Si)

[1211] Intermediate 129: (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

[1212]

[1213] The title compound was prepared according to the procedure of Intermediate 102 from (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-N-[2-(5-oxopyrrolidin-2-yl)ethyl]-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 128, 120 mg, 0.28 mmol) to give a white gum.

[1214] MS: 309ES+(C 14 H 20 N 4 O 4 )

[1215] Intermediate 130: (2S)-2-fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[(5-oxopyrrolidin-2-yl) Ethyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[1216]

[1217] According to the procedure of Intermediate 103, (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), K 2 CO 3 (179.3 mg, 1.3 mmol) and ethyl (2S)-2-bromo-2-fluoroacetate (Intermediate 174, 0.12 mL, 0.78 mmol) were used to prepare the title compound which was obtained as a white solid (30 mg, 28%). This compound was a 1:4 mixture of diastereomers.

[1218] MS: 413ES+(C 18 H 25 FN 4 O 6 )

[1219] Example 73: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[2-(5-oxopyrrolidin-2-yl) Ethylcarbamoyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid lithium salt

[1220]

[1221] The title compound was prepared according to the procedure of Example 66 from ethyl (2S)-2-fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[2-(5-oxopyrrolidin-2-yl)ethylcarbamoyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate (Intermediate 130, 30 mg, 0.07 mmol) and obtained as a white solid after lyophilization (8.0 mg, 25.8%).

[1222] MS :385ES+(C 16 H 21 FN 4 O 6 )

[1223] 1 H NMR(300MHz,D 2 O) δ: 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).

[1224] Intermediate 131: ((2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-N-(3-amino Sulfonylpropyl)-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1225]

[1226] The title compound was prepared according to the procedure of Intermediate 101 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 174, 300 mg, 0.96 mmol) and 3-aminopropane-1-sulfonamide hydrochloride (251 mg, 1.44 mmol) to give (198 mg, 47.7%) as a white solid.

[1227] MS :433ES+(C 17 H 32 N 4 O 5 SiS)

[1228] Intermediate 132: (2S,5R)-6-hydroxy-3-methyl-7-oxo-N-(3-sulfamoylpropyl)-1,6-diazabi Cyclo[3.2.1]oct-3-ene-2-carboxamide

[1229]

[1230] The title compound was prepared according to the procedure of Intermediate 102 from (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-N-(3-sulfamoylpropyl)-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 131, 200 mg, 0.46 mmol) to give a white gum.

[1231] MS: 319ES+(C 11 H 18 N 4 O 5 S)

[1232] Intermediate 133: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-(3-sulfamoylpropylcarbamoyl ethyl)-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[1233]

[1234] The title compound was prepared from (2S,5R)-6-hydroxy-3-methyl-7-oxo-N-(3-sulfamoylpropyl)-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 132, 100 mg, 0.31 mmol) and (2S)-ethyl 2-bromo-2-fluoro-acetate (Intermediate 174, 0.11 mL, 0.94 mmol) according to the procedure of Intermediate 103 and obtained as a white solid (22 mg, 16.7%). The compound was a 1:4 mixture of diastereomers.

[1235] MS: 423ES+(C 15 H 23 FN 4 O 7 S)

[1236] Example 74: (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]acetic acid lithium salt

[1237]

[1238] The title compound was prepared according to the procedure of Example 66 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) and obtained as a white solid after lyophilization (8.0 mg, 37%).

[1239] MS :395ES+(C 13 H 19 FN 4 O 7 S)

[1240] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1241] Intermediate 134: tert-Butyl N-[2-(sulfamoylamino)ethyl]carbamate

[1242]

[1243] A solution of tert-butyl N-(2-aminoethyl)carbamate (2.0 g, 12.5 mmol) and sulfonamide (2.0 g, 24.9 mmol) in dioxane (10 mL) was stirred at 90 ° C for 5 hours. The mixture was then filtered to remove insoluble matter and the filtrate was concentrated under reduced pressure. The residue was then dissolved in EtOAc, washed three times with dilute HCl solution, then washed with brine, and filtered through MgSO 4 Dry, filter and concentrate to obtain the title compound (1.2 g, 40.2%) as a yellow oil.

[1244] 1 H NMR(300MHz,DMSO-d 6 )δ: 1.39 (s, 9H); 2.92 (m, 2H); 3.04 (m, 6H); 6.50 (m, 3H); 6.75 (m, 1H).

[1245] Intermediate 135: 1-Amino-2-(sulfamoylamino)ethane TFA salt

[1246]

[1247] To a solution of tert-butyl N-[2-(sulfamoylamino)ethyl]carbamate (Intermediate 134, 1.2 g, 5.01 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 obtain the title compound as a yellow TFA salt.

[1248] MS :140ES+(C 2 H 9 N 3 O 2 S)

[1249] Intermediate 136: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-N-[2-(amino) [sulfonylamino)ethyl]-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1250]

[1251] The title compound was prepared according to the procedure of Intermediate 101 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-(aminosulfonylamino)ethane TFA salt (Intermediate 135, 365 mg, 1.44 mmol) to give (117 mg, 28.1%) as a white solid.

[1252] MS :434ES+(C 16 H 31 N 5 O 5SiS)

[1253] Intermediate 137: (2S,5R)-6-hydroxy-3-methyl-7-oxo-N-[2-(sulfamoylamino)ethyl]-1,6-dihydro- Azabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1254]

[1255] The title compound was prepared according to the procedure of Intermediate 102 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) to give the title compound as a white gum.

[1256] MS: 320ES+(C 10 H 17 N 5 O 5 S)

[1257] Intermediate 138: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[2-(sulfamoylamino)ethylamino Ethyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[1258]

[1259] 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-fluoroacetate (Intermediate 174, 0.089 mL, 0.75 mmol) according to the procedure of Intermediate 103 to afford (22.0 mg, 16.5%) as a white solid. The compound was a 3:7 mixture of diastereomers.

[1260] MS: 424ES+(C 14 H 22 FN 5 O 7 )

[1261] Example 75: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[2-(sulfamoylamino)ethyl-amino [formyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid lithium salt

[1262]

[1263] The title compound was prepared according to the procedure of Example 66 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) to give (13.0 mg, 44.1%) of a white solid.

[1264] MS :396ES+(C 12 H 18 FN 5 O 7 S)

[1265] 1 H NMR(300MHz,D 2 O) δ: 1.71 (s, 3H); 3.21-3.47 (m, 6H); 4.11 (m, 1H); 4.35 (m, 1H); 5.64-5.84 (d, 1H); 6.22 (m, 1H).

[1266] Intermediate 139: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-1,6-diazo Heterobicyclo[3.2.1]oct-3-ene-2-carbonitrile

[1267]

[1268] 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 (Intermediate 192, 3.0 g, 9.63 mmol) in DCM (50 mL) was added Burgess reagent (3.44 g, 14.4 mmol) in portions at room temperature over 2 hours. The reaction mixture was stirred for an additional 16 hours and then washed twice with 1:1 brine:water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0-25% ethyl acetate / hexanes) afforded the title compound (2.3 g, 81.3%) as a white solid.

[1269] MS :294ES+(C 14 H 23 N 3 O 2 Si)

[1270] Intermediate 140: N-[[(2S)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-1,6-dimethoxy Azabicyclo[3.2.1]oct-3-en-2-yl]methyl]carbamic acid tert-butyl ester

[1271]

[1272] 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 NiCl 2 .6H 2 O (97.2 mg, 0.41 mmol). Then NaBH was added over 30 min. 4 (1.08 g, 28.6 mmol). The reaction mixture was then warmed to room temperature and stirred for 1 hour. Hunig's base (0.71 mL, 4.09 mmol) was added and then stirred for 30 minutes. The solvent was removed. The residue was dissolved in EtOAc and washed with saturated NaHCO 3 solution, washed with brine, and then with MgSO 4 Dry, filter and concentrate.The residue was purified by silica gel chromatography (40 g, 0%-35% EtOAc / hexanes) to afford the title compound (0.58 g, 35.7%) as a white solid.

[1273] MS :398ES+(C 19 H 35 N 3 O 4 Si)

[1274] Intermediate 141: N-[[(2S,5R)-6-hydroxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-3- tert-Butyl]en-2-yl]methyl]carbamate

[1275]

[1276] The title compound was prepared according to the procedure of Intermediate 102 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) to give a white gum.

[1277] MS: 284ES+(C 13 H 21 N 3 O 4 )

[1278] Intermediate 142: (2S)-2-(((2S,5R)-2-(((tert-butoxycarbonyl)amino)methyl)-3-methyl-7-oxy ethyl 1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)-2-fluoroacetate

[1279]

[1280] 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-fluoroacetate (Intermediate 174, 0.063 mL, 0.53 mmol) according to the procedure of Intermediate 103 to afford (50 mg, 73.1%) as a white solid. The compound was a 1:9 mixture of diastereomers.

[1281] MS: 388ES+(C 17 H 26 FN 3 O 6 )

[1282] Example 76: (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 lithium salt

[1283]

[1284] The title compound was prepared according to the procedure of Example 66 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) and obtained as a white solid after lyophilization (35 mg, 67.9%).

[1285] MS :360ES+(C 15 H 22 FN 3 O 6 )

[1286] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1287] Example 77: (2S)-2-[[(2S,5R)-2-(Aminomethyl)-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1]Oct-3-en-6-yl]oxy]-2-fluoroacetic acid

[1288]

[1289] 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 and then concentrated. The residue was dissolved in pH 7 buffer and then loaded onto a sepabead column (first saturated with water, then saturated with ACN, then washed with water) and eluted with (0%-2.5% ACN / water) to obtain the title compound (8 mg, 37.7%) as a white solid after lyophilization.

[1290] MS :260ES+(C 10 H 14 FN 3 O 4 )

[1291] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1292] Intermediate 143: (2S,5R)-2-(aminomethyl)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-1,6- Diazabicyclo[3.2.1]oct-3-en-7-one

[1293]

[1294] 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 ZnBr 2 (170 mg, 0.75 mmol). The reaction mixture was stirred at room temperature for 16 hours, then concentrated and used in the next step without purification.

[1295] MS :298ES+(C 14 H 27 N 3 O 2 Si)

[1296] Intermediate 144: N-[[(2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-3-methyl-7-oxo-1,6- [3.2.1]oct-3-en-2-yl]methyl]acetamide

[1297]

[1298] To a solution of (2S,5R)-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) was added AcO 2 O (168 mg, 0.75 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then washed with water, saturated NaHCO 3 , washed with brine, and MgSO 4 Dry, filter and concentrate.The residue was purified by silica gel chromatography (0%-100% EtOAc / hexanes) to afford the title compound (70 mg, 78.7%) as a white solid.

[1299] MS :340ES+(C 16 H 29 N 3 O 3 4).

[1300] Intermediate 145: N-[[(2S,5R)-6-hydroxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-3- [2-enyl]methyl]acetamide

[1301]

[1302] The title compound was prepared according to the procedure of Intermediate 102 from 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]acetamide (Intermediate 144, 70 mg, 0.21 mmol) to give a white gum.

[1303] MS: 226ES+(C 10 H 15 N 3 O 3 )

[1304] Intermediate 146: (2S)-2-[[(2S,5R)-2-(acetamidomethyl)-3-methyl-7-oxo-1,6-diazepine Ethyl bicyclo[3.2.1]oct-3-en-6-yl]oxy]-2-fluoroacetate

[1305]

[1306] The title compound was prepared from N-[[(2S,5R)-6-hydroxy-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-2-yl]methyl]acetamide (Intermediate 145, 40 mg, 0.18 mmol) and ethyl (2S)-2-bromo-2-fluoroacetate (Intermediate 174, 0.063 mL, 0.53 mmol) according to the procedure of Intermediate 103 and obtained as a white solid after lyophilization (15 mg, 25.6%). The compound was a 15:85 mixture of diastereomers.

[1307] MS: 330ES+(C 14 H 20 FN 3 O 5 )

[1308] Example 78: (2S)-2-[[(2S,5R)-2-(acetamidomethyl)-3-methyl-7-oxo-1,6-diazabi Cyclo[3.2.1]oct-3-en-6-yl]oxy]-2-fluoro-acetic acid lithium salt

[1309]

[1310] The title compound was prepared according to the procedure of Example 66 from (2S)-2-[[(2S,5R)-2-(acetamidomethyl)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]-2-fluoro-acetic acid ethyl ester (Intermediate 146, 15 mg, 0.05 mmol) and obtained as a white solid after lyophilization (10 mg, 65.6%).

[1311] MS :302ES+(C 12 H 16 FN 3 O 5 )

[1312] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1313] Intermediate 147: (2S)-2-[[(2S,5R)-2-(aminomethyl)-3-methyl-7-oxo-1,6-diazabicyclo [3.2.1]oct-3-en-6-yl]oxy]-2-fluoroacetic acid ethyl ester TFA salt

[1314]

[1315] 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 ethyl ester (Intermediate 142, 97.4 mg, 0.25 mmol) in DCM (2 mL) was added trifluoroacetic acid (2.87 g, 25.2 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and then concentrated to give the title compound as a TFA salt.

[1316] MS: 288ES+(C 12 H 18 FN 3 O 4 )

[1317] Intermediate 148: tert-Butyl N-chlorosulfonylcarbamate

[1318]

[1319] At 0 °C, tert-butyl alcohol (1.9 mL, 20 mmol) was added to CH 2 Cl 2 To the stirred solution in 4% paraformaldehyde (12 mL) was added chlorosulfonyl isocyanate (1.4 mL, 15 mmol) over the course of 10 minutes. After stirring at 0°C for 5 minutes, the reaction mixture was warmed to room temperature and stirred for 20 minutes. The reaction mixture was concentrated in vacuo to one-third volume. The flask was placed back in a 0°C bath and the product crystallized from the solution. After 50 minutes, the product was collected by filtration and washed with hexane to obtain the title compound (2.8 g, 80.7%) as a white solid.

[1320] Intermediate 149: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[[(2,2,2-trifluoroacetyl) Ethyl]amino]methyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate

[1321]

[1322] To a solution of (2S)-2-[[(2S,5R)-2-(aminomethyl)-3-methyl-7-oxo-1,6-diazabicyclo-[3.2.1]oct-3-en-6-yl]oxy]-2-fluoro-acetic acid ethyl ester 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 room temperature for 30 min, then diluted with DCM, washed with water, brine, and filtered through MgSO 4Dry, filter and concentrate.The residue was purified by flash chromatography (0%-100% EtOAc / hexanes) to afford the title compound (38 mg, 39.6%) as a white solid.

[1323] MS: 384ES+(C 14 H 17 F 4 N 3 O 5 )

[1324] Example 79: (2S)-2-Fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[[(2,2,2-trifluoroacetyl)- Amino]methyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetic acid lithium salt

[1325]

[1326] The title compound was prepared according to the procedure of Example 66 from ethyl (2S)-2-fluoro-2-[[(2S,5R)-3-methyl-7-oxo-2-[[(2,2,2-trifluoroacetyl)amino]methyl]-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl]oxy]acetate (Intermediate 149, 38 mg, 0.10 mmol) and was obtained as a white solid after lyophilization (25 mg, 60.3%).

[1327] MS :356ES+(C 12 H 13 FN 3 O 5 )

[1328] 1 H NMR (300 MHz,D 2 O) δ: 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).

[1329] Intermediate 150: (2S,5R)-6-[tert-butyl(dimethyl)silyl]oxy-N-(cyanomethyl)-3-methyl-7-oxy 1,6-Diazabicyclo[3.2.1]oct-3-ene-2-carboxamide

[1330]

[1331] The title compound was prepared according to the procedure of Intermediate 101 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, 700 mg, 2.24 mmol) and aminoacetonitrile hydrochloride (207 mg, 2.24 mmol) to give (3...

Claims

1. A method for forming a compound of formula VI or a salt thereof: in, R 1 Yes-C(O)NR 7 R 8 、-C(O)OR 7 , -CN, optionally with a -C(O)NR 7 R 8 5-6 membered heteroaryl substituted with a group, or -NR 7 R 8 or -NR 7 COR 9 Substituted C1-C6 alkyl groups; R 2 and R 3 are each independently hydrogen or C1-C3 alkyl, provided that R 2 and R 3 At least one of them is not hydrogen; R 7 It is hydrogen; R 8 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, phenyl, C3-C6 cycloalkyl, 4-7 membered non-aromatic heterocyclic group or 5-6 membered heteroaryl, wherein R 8 The alkyl, alkoxy, phenyl, cycloalkyl, non-aromatic heterocyclic or heteroaryl groups represented by the present invention are optionally and independently substituted by 1 to 6 groups selected from the following: optionally substituted by one or two -F atoms, carboxyl groups or -CO(OC 1-6 alkyl), -NR'R", -NHS(O)2NR'R", -NHS(O)2(C1-C3 alkyl), -NR'R" and -C(O)NR'R"; R 9 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" together with the nitrogen to which they are attached form a 5-6 membered non-aromatic heterocyclic group; and PG and PG' are each independently an amine protecting group; The method comprises: Make the following compound: or a salt thereof reacting with PG'NHOH in the presence of an oxidant, a metal catalyst and an amine additive to form the compound of formula VI; in: The metal catalyst is a copper salt; and The oxidant is O2, air, FeCl3, MnO2, m-chloroperbenzoic acid (mCPBA), NaIO4, 2-iodobenzoic acid (IBX), (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO), benzoyl peroxide (BPO), HIO3, urea-H2O2, I2, N-chlorosuccinimide (NCS), Dess-Martin periodinane (DMP), H2O2 or N-methylmorpholine N-oxide (NMMO).

2. A method for forming a compound of formula VI or a salt thereof: in, R 1 Yes-C(O)NR 7 R 8 、-C(O)OR 7 , -CN, optionally with a -C(O)NR 7 R 8 5-6 membered heteroaryl substituted with a group, or -NR 7 R 8 or -NR 7 COR 9 Substituted C1-C6 alkyl groups; R 2 and R 3 are each independently hydrogen or C1-C3 alkyl, provided that R 2 and R 3 At least one of them is not hydrogen; R 7 It is hydrogen; R 8 is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, phenyl, C3-C6 cycloalkyl, 4-7 membered non-aromatic heterocyclic group or 5-6 membered heteroaryl, wherein R 8 The alkyl, alkoxy, phenyl, cycloalkyl, non-aromatic heterocyclic or heteroaryl groups represented by the present invention are optionally and independently substituted by 1 to 6 groups selected from the following: optionally substituted by one or two -F atoms, carboxyl groups or -CO(OC 1-6 alkyl), -NR'R", -NHS(O)2NR'R", -NHS(O)2(C1-C3 alkyl), -NR'R" and -C(O)NR'R"; R 9 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" together with the nitrogen to which they are attached form a 5-6 membered non-aromatic heterocyclic group; and PG and PG' are each independently an amine protecting group; The method comprises: Make the following compound: or a salt thereof is reacted with PG'N=O to form the compound of formula VI.

3. The method according to claim 1 or 2, wherein: The compound of formula VI is a compound of formula VII: or a salt thereof.

4. The method according to claim 1 or 2, wherein: R 2 It is a C1-C3 alkyl group.

5. The method according to claim 1 or 2, wherein: The compound of formula VI is the compound of formula VIII: or a salt thereof.

6. The method according to claim 1 or 2, wherein: R 3 It is a C1-C3 alkyl group.

7. The method according to claim 1 or 2, wherein: R 1 yes Where R 11 It is hydrogen or -C(O)NH2.

8. The method according to claim 1 or 2, wherein: R 1 Yes-C(O)NR 7 R 8 、-C(O)OR 7 or -CN.

9. The method according to claim 1 or 2, wherein: R 1 It is -C(O)NH2, -CH2NH2, -C(O)OH or -CN.

10. The method according to claim 1 or 2, wherein: R 1 It is -CN or -C(O)NH2.

11. The method according to claim 1 or 2, wherein: R 8 is: 1) phenyl optionally substituted by C1-C3 alkyl or C1-C3 alkyl-NH2, 2) C1-C3 alkyl or 3) C1-C3 alkoxy, wherein R 8 Each alkyl or alkoxy represented is optionally and independently substituted with -CN, -OH, -NH2, -SO2NH2, -NHSO2NH2, -C(O)NH2, -NHC(O)(C1-C3 alkyl), pyrazinyl, oxetanyl, oxazolyl, or pyrrolidinyl optionally substituted with one or more carboxyl, fluorine or -C(O)O(C1-C6 alkyl).

12. The method according to claim 1, wherein: The compound of formula VI is a compound of formula IX: or a salt thereof.

13. The method according to claim 1, wherein: The compound of formula VI is a compound of formula X: or a salt thereof.

14. The method according to claim 1 or 2, wherein: PG and PG' together with the nitrogen atom of the amine they protect each independently form a carbamate, amide or N-benzyl group.

15. The method according to claim 1 or 2, wherein: PG and PG' are each independently selected from tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), 2,2,2-trifluoroethoxycarbonyl (Troc), CF3CO, acetyl (Ac), p-toluenesulfonamide (Ts) and methanesulfonyl (Ms).

16. The method according to claim 1 or 2, wherein: PG and PG' are each tert-butyloxycarbonyl.

17. The method according to claim 1, wherein: The metal catalyst is selected from CuCl, CuBr, CuI, CuCN, CuSCN, CuBr-Me2S, Cu(OAc)2 and CuOTf.

18. The method according to claim 1, wherein: The amine additive is pyridine, N,N'-dimethylethane-1,2-diamine, 2,6-di-tert-butyl-4-methylpyridine, 1,10-phenanthroline, trans-cyclohexane-1,2-diamine, N1-(2-(diethylamino)ethyl)-N2,N2-diethylethane-1,2-diamine, cis-cyclohexane-1,2-diamine or N1,N1,N2,N2-tetramethylethane-1,2-diamine.

19. The method according to claim 1, wherein: The amine additive was (1R,2R)-cyclohexane-1,2-diamine.

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