NZ709355B2

NZ709355B2 - New bicyclic compounds and their use as antibacterial agents and ?-lactamase inhibitors

Info

Publication number: NZ709355B2
Application number: NZ709355A
Authority: NZ
Inventors: Jehangir Khan; Rong Ling; Samarendra N Maiti; Dai Nguyen
Original assignee: Fedora Pharmaceuticals Inc
Filing date: 2012-12-11
Publication date: 2018-01-04

Abstract

Microbial drug resistance is an unavoidable consequence resulting from abuse and overuse of antimicrobial agents. Given the degree of popularity of ?-lactam antibiotics, it is not surprising that the prevalence of ?-lactamase-producing strains is increasing worldwide. ?-lactamases are able to hydrolyze the ?-lactam antibiotics resulting in the loss of antibacterial activity. The present invention addresses this problem by providing compounds that inhibit some of the ?-lactamase enzymatic function either alone or in synergy with other ?-lactam antibiotics, increasing the potency of ?-lactam antibiotics. In particular, the present invention provides a compound of formula (I) wherein: M is hydrogen or a pharmaceutically acceptable salt-forming cation; Y is OR1 or NR2R3, and R1, R2, R3 and M are as defined herein. Also, methods of treating bacterial infection, pharmaceutical compositions, molecular complexes and processes for preparing compounds are disclosed. lyze the ?-lactam antibiotics resulting in the loss of antibacterial activity. The present invention addresses this problem by providing compounds that inhibit some of the ?-lactamase enzymatic function either alone or in synergy with other ?-lactam antibiotics, increasing the potency of ?-lactam antibiotics. In particular, the present invention provides a compound of formula (I) wherein: M is hydrogen or a pharmaceutically acceptable salt-forming cation; Y is OR1 or NR2R3, and R1, R2, R3 and M are as defined herein. Also, methods of treating bacterial infection, pharmaceutical compositions, molecular complexes and processes for preparing compounds are disclosed.

Description

New Bicyclic Compounds and Their Use as Antibacterial Agents and β−Lactamase Inhibitors Field of the invention The present invention relates to new bicyclic compounds, their preparation and their use as antibacterial agents either alone or in combination with an antibiotic (or plural antibiotics) for the treatment of ions caused by β−lactamase-producing pathogenic bacteria. The compounds of the present invention are β−lactamase ting or non-β−lactamase inhibiting (i.e., some of the compounds of the present invention by themselves would ly inhibit β−lactamase enzymatic function, and others of the compounds of the present invention by themselves would not inhibit some β−lactamase’s enzymatic function though they e synergy and increased potency of activity in combination with antibiotics, e.g., β−lactam antibiotics or non-β−lactam antibiotics). More ularly, the invention is concerned with methods for overcoming antibiotic resistance caused by B—lactamase producing bacteria, the method of preparation of the new compounds, pharmaceutical compositions containing the new compounds, methods of treatment, uses of the compounds, and other subject matter.

Background of the invention Microbial drug resistance is an unavoidable consequence resulting from abuse and overuse of antimicrobial agents. The rate at which resistance arises among microbial population is often dictated by the extent of use of ular agents in a given environment. Given the degree of popularity of B—lactam (also known as B-lactam) antibiotics, it is not surprising that the prevalence of B—lactamase (also known as B-Iactamase) producing strains is increasing worldwide. The most significant known mechanism d to the development of bacterial resistance to the B—lactam antibiotics is the. production of class-A, class-B, class-C and class-D B—lactamases that are able to hydrolyze the B—lactam antibiotics resulting in the loss of antibacterial ty. A enzymes preferentially hydrolyze penicillins, class-B - enzymes yze all B—lactams including carbapenems, class-C B—Iactamases have a substrate profile favoring cephalosporin hydrolysis, whereas ate ence for class D B—lactamases e oxacillin and cloxacillin.

The possibility of rescuing individual B—lactam antibiotics by combination with a B—lactamase inhibitor that inactivates the B—lactamase before it can hydrolyze the B—lactam antibiotic has been demonstrated with clinically useful combination between penicillins such as amoxicillin, ampicillin, piperacillin and ticarcillin and B—lactamase inhibitors such as anic acid, sulbactam and tazobactam. Further potential combinations have been described involving various B—lactam antibiotics and newly ed B—lactamase inhibitors including bicyclic ctams, exomethylene penems and 6—diazabicyclo[3.2.1]octane—2-carboxamide derivatives.

As a result of point mutations and d transfer, the diversity of B—lactamases is increasing constantly. The tly commercial p—lactamase inhibitors are insufficient to [Annotation] mbs counter these new B-lactamases — particularly ineffective against class C producing sms, newly emerged extended-spectrum B-lactamases (ESBLs) and carbapenemases like IMP, VIM, OXA, KPC, and NDM. Thus there is a need for broad-spectrum B—lactamase inhibitor to combat over 900 amases including the newly emerged B—lactamases.

Recently, n diazabicyclic compounds have been disclosed in which is hereby incorporated by reference in its entirety. In addition, a number of diazabicyclic heterocycles have been disclosed in the following patents as B—lactamase inhibitors: US 2003/0199541 A1, US 2004/0157826 A1, US 2004/0097490 A1, US 2005/0020572 A1, US 2006/7112592 B2, US 2006/0189652 A1, US 2008/7439253 32, US 2009/0018329 A1, EP 1307457 B1, EP 1537117 B1, A2, W0 2002/10172 A1, A2, A1, A1, WO 42285 A1, WO 90320 A1, US 2010/0092443 A1, A2, US 2012/0165533 A1.

The compounds of the present invention are new and the structural features are signiﬁcantly distinct from the compounds described in the patent references cited above.

Summary of the Invention In a ﬁrst aspect of the present invention, there is provided a nd of formula (I): ‘OSO3M n: M is hydrogen or a pharrnaceutically acceptable anning cation; Y is 0R1; R1 is a radical selected from the group consisting of: (1) C37 cycloalkyl which is fused with a C57 membered saturated heterocycle containing N as a heteroatom; (2) Bridged bicyclic ring system having optionally one N as a heteroatom; and (3) C57 membered saturated heterocycles fused to a C34; ed ring system through a common carbon atom to form a spiro system ning one heteroatom selected from O or N and the free N atom present in either ring may be optionally substituted with a group selected from: straight chain or branched C1-C6 alkyl; straight chain or branched C1-C6 alkyl substituted with at least one halogen or hydroxy group; amino; amino substituted with at least one C1-C6 alkyl group; halogen; hydroxy; carboxy; alkoxycarbonyl; romethoxy; alkylamine; alkylamine substituted with at least one C1-C6 alkyl group; carboxamide; thiocarboxamide; ic acid; sulfate; acylamino; sulfonylamino; sulfonamide; urea; thiourea; sulfonylurea; hydroxamic acid; acyl; oromethyl carbonyl; cyano; amidino; guanidine; aryloxy; heterocyclyl; heteroaryl; heterocyclyloxy; and ylammonium, or a ated compound of any such compound.

In a second aspect of the present invention, there is provided a use of a compound as recited in the first aspect of the present invention, or a pharmaceutically able salt of any such compound, or a ated compound of any such compound or salt, for the manufacture of a medicament effective in the treatment of a bacterial infection.

In a third aspect of the present invention, there is ed a pharmaceutical composition containing as an active ingredient, at least one compound as recited in the first aspect of the present invention.

In a fourth aspect of the present invention, there is provided a use of a compound as recited in the first aspect of the present ion, or a pharmaceutically acceptable salt of any such compound, or a deuterated compound of any such compound or salt, and at least one β−lactam antibiotic, at least one salt of a β−lactam antibiotic, at least one hydrate of a β−lactam antibiotic or at least one prodrug of a β−lactam antibiotic for the manufacture of a medicament effective in the treatment of a bacterial infection.

In a fifth aspect of the present invention, there is provided a use of a compound as recited in the first aspect of the present invention, or a pharmaceutically acceptable salt of any such compound, or a deuterated compound of any such compound or salt, and at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an otic or at least one prodrug of an antibiotic for the manufacture of a medicament effective in the treatment of a bacterial infection.

In a sixth aspect of the t invention, there is provided a molecular complex sing a compound as recited in the first aspect of the present invention and at least one solvent.

In a h aspect of the present invention, there is provided a process for preparing a compound recited in the first aspect of the present invention, wherein M = H, and wherein the process comprises: [A] Reacting substituted hydroxylamine (V) with an acid (VI) in presence of a coupling agent ed from the group consisting of EDCI, CC and PyBop to provide an intermediate of formula (VII); [Annotation] mbs [B] Removing the benzyl protecting group of the intermediate (VII) with a source of hydrogen in presence of Pd catalyst to provide debenzylated product ; R1 O é\NJI’I,qH 0’ ‘OH VIII [C] Contacting compound (VIII) with a ing agent in the presence of solvent to obtain compound of formula (la) dNJl (#—“CL ‘OSO3M wherein: M is hydrogen or a pharmaceutically acceptable orming cation; Y is NR2R3; R2 is hydrogen; R3 is a radical selected from any of following groups consisting of: CFacO-, CH3802-, and NH2802-; or a deuterated compound of any such compound.

In a ninth aspect of the present invention, there is provided a use of a compound as recited in the eighth aspect of the present invention, or a pharmaceutically acceptable salt of any such compound, or a deuterated compound of any such compound or salt, for the manufacture of a medicament effective in the treatment of a bacterial infection.

In a tenth aspect of the present invention, there is provided a pharmaceutical composition containing as an active ient, at least one compound as recited in the eighth aspect of the present invention.

In an eleventh aspect of the present invention, there is provided a use of a compound as d in the eighth aspect of the present invention, or a pharmaceutically acceptable salt of any such compound, or a deuterated nd of any such compound or salt, and at least one β−lactam antibiotic, at least one salt of a am otic, at least one hydrate of a β−lactam antibiotic or at least one prodrug of a β−lactam antibiotic for the manufacture of a medicament effective in the treatment of a bacterial infection.

In a twelfth aspect of the present invention, there is provided a use of a compound as recited in the eighth aspect of the present invention, or a pharmaceutically acceptable salt of any such compound, or a deuterated compound of any such compound or salt, and at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic for the manufacture of a medicament effective in the treatment of a ial infection.

In a thirteenth aspect of the present invention, there is provided a molecular complex comprising a compound as recited in the eighth aspect of the present invention and at least one In a fourteenth aspect of the present invention, there is provided a process for ing a compound recited in the eighth aspect of the t invention, wherein M = H, and n the process comprises: [A] Reacting substituted hydrazine (Va) with an acid (VI) in presence of a coupling agent selected from the group ting of EDCI or HOBT-DCC and PyBop to provide an intermediate of formula (VIIa), [Annotation] mbs R2 o F52 H0)“ 3 R3‘“~NJI'~.

R —N\NH2 + N —> H q 0: an 0) an Va VI Vlla [B] ng the benzyl protecting group of the intermediate (Vlla) with a source of en in presence of Pd catalyst to provide the debenzylated product (Vllla), R2 o R3-lll‘NJl,,u 0)— DH Vllla [C] Contacting compound (Vllla) with a sulfating agent in the presence of solvent to obtain compound of formula (lb) II?2 0 R’s—N‘NﬁqH 0303M Detailed description of the invention In one aspect, the present invention relates to new, low molecular weight diazabicyclic compounds (some of which have potent broad—spectrum amase inhibitory activity and others do not have such activity) that when used in combination with a B—Iactam antibiotic or with other non B-lactam antibiotics enhance the ty of the antibiotic against class A, Class B, class C, and class D enzyme producing organisms and thereby e the antibacterial properties. The compounds are therefore useful in the treatment of ial infections in humans or animals either alone or in combination with B—lactam antibiotics and/or with other non B—lactam antibiotics.

In accordance with the present invention, there are provided (A) new compounds of general formula (I), (B) pharmaceutically able salts of the compounds of formula (I), (C) pharmaceutically acceptable solvates of the compounds of formula (I) and of their salts, and (D) deuterated compounds of compounds of (A), (B) and (C), y, (i) compounds of a (I) modified in that they have been deuterated, (ii) ceutically acceptable salts of compounds of a (I) modified in that they have been deuterated, and (iii) phannaceutically solvates of compounds of formula (I) and of their salts modified in that they have been deuterated): Wherein; M is hydrogen or a phannaceutically able salt forming cation, a "pharmaceutically acceptable salt" refers to a salt of a compound, which salt possesses the desired pharmacological ty of the parent compound, reference to specified compounds “modified in that they have been deuterated" refers to compounds obtained by modifying the specified compounds so that one or more hydrogen atoms in the compound have been replaced with or converted to deuterium, Y = OR' or NR2R3, In the formula (I), when Y = OR', R1 is a radical selected from any of the following groups: (1) C14; straight or branched chain alkyl which is optionally substituted. Non-limiting examples of such compounds are: ‘l J1 ‘i HO/\/0\N)h" /O‘N /\/0\NJ'~.

H H I N N N 1010 0 JV ? 0 j WNM‘NJ'QH N *0 MUN N )—N )—N\ )—N‘ 0 bSO3H 0 0803H 0 0803H 0 Ci cw ° HZNJLNNO‘NJI" NNO‘NJI'? HOJK/OWJI'“? H H H H N N N )—N\ )—N\ )—N\ O 0803H O 0803H 0 OSO3H XO‘NJ’? HNQONO‘NJI‘f \ro‘NJ’? H H H N N N s N\ s N\ 5 N\ OSOgH O 0303H 0 0803H o o o 0 0303H OSO3H 0 b803H 0 o o |/\N/\/O\H/lL II," o=§\} H N HOJXCIN o )—N\ )—N 0303H 0 b803H HN\lO/VONJQQ l, HNQ o o )—N O/VO‘NJI'"'Q (lo/VO‘NJI’I.QH N N O ‘0803H ) N //J' N 1111 (2) CM cycloalkyl which is ally substituted. Non-limiting es of such compounds are: 0 b303H 0 b303H (3) Cu saturated heterocycles containing at least one heteroatom selected from O, N and S wherein the said heterocycle is optionally substituted. Furthermore the ring 8 is optionally oxidized to 8(0) or S(O)2 and the free ring N atom may optionally take a substituent. Non-limiting examples of such compounds are: O‘NJl, O‘NJl , 1,. 1,, 70"“)I], HN H H “N H N HN N N 1212 1313 o o o O‘NJL O‘NJL,“ 0‘N Ln.

HN/Y H H HN H ‘0 N HN/jH‘N N N )—N )—N\ )—N\ 0 OSO3H O OSO3H O 0803H o o otNJ'I otNJlun 0 j) O N o o)—N\ o o)—N\ N /N— OSO3H /o 0803H /N\ O bsoaH (4) Heterocyclyl (CM) alkyl wherein the said heterocycle has the same definition as defined in (3). Furthermore, the said heterocycle is optionally substituted. Non- ng examples of such compounds are: 0“; J? Cc i? @L ‘? O\N ’I,' O\N ’l,‘ O\NJ’1I’ H H H N N N N\ 5 N\ s N\ O OSO3H O 0803H O OSOSH O bSO3H OSOsH 0 b803H / >\\ i? J? J? O 0‘” ll CL0‘” [1,, CL0‘” ’I N N N b803H O bSO3H 0 bSO3H 1414 N N N H H H N‘ N N }—N )-——N //'—N O b803H O ‘osogH O b803H L o 0. J O N j N\ O OSO3H (5) 05-7 membered saturated heterocycles which is ally fused with a 03-7 membered cycloalkyl group to form a bicyclic ring system where the bicyclic ring system so formed is fused either through two nt carbon atoms or through a N atom shared by both the rings and the other end of the cycloalkyl chain is attached to the adjacent carbon atom of the molecule. Furthermore, each ring of the said bicyclic ring system is optionally substituted. Non-limiting examples of such compounds are: 1O bSO3H O bSO3H O ‘oso3H (6) 05-7 membered ted heterocycles which is optionally fused with another 05.7 saturated heterocycle to form a bicyclic ring system where the bicyclic ring system so formed is fused either through two adjacent carbon atoms or through a N atom shared by both the rings. Furthermore, each ring of the said bi-cyclic ring system is optionally substituted. Non-limiting examples of such compounds are: 1515 O b503H N O b503H (7) 03-7 cycloalkyl which is optionally fused with a 05-7 membered saturated heterocycle containing at least one heteroatom selected from O, N and 8. Furthermore, the said ic ring is optionally substituted. Non-limiting examples of such compounds are: 0 ‘osoaH O b803H O b803H (8) d bicyclic ring system having optionally one or two heteroatoms ed from O, N and 8. Furthermore, the bicyclic ring system is optionally substituted either at the carbon atom or at the free N atom present in the ring. Non-limiting examples of such compounds are: (9) C57 membered saturated heterocycles which is optionally fused with 05-7 membered heteroaryl ring where the bicyclic ring system so formed is fused either 1616 through two adjacent carbon atoms or through N atom shared by both the rings.

Non-limiting examples of such compounds are: [\ o\ J‘l O\ J,‘i o J HN ‘N N HN N N H H H N N / N / O 0303” OSOgH O b803H H3c’ j O‘Nif” HN O‘N HN H H N N HN/ / I /’ N\ :0 4 N\ \N O OSOgH O OSOgH (10) 05-7 membered saturated heterocycles which is optionally fused to a 03-5 membered ring system h a common carbon atom to form a spiro system optionally containing one heteroatom selected from O, N and S that is present in the spiro ring where the ring S is ally ed to 8(0) or S(O)2 and the free N atom present in either ring may optionally take a substituent. Non—limiting examples of such 1O compounds are: 0 bSO3H bSO3H (11) 05-7 membered heteroarylalkyl which is optionally substituted. Non—limiting examples of such compounds are: 1717 o o | l, \ O\N/L/,l I (/\N/\/()\N/L 1,, H H /N N N4 N N\ N\ O OSO3H O OSO3H o o 0 O\ /U’I,‘ O\N/U//I' O\N/UIII' 6 u 1 H O H L \ \N \N \N \ [‘1 \ I N //L_¥N U—— )‘N\ \ N\ O bSO3H 0 OSO3H N\ 0 OSO3H o o O O\N/U’I,l ’n ON)», H O H | / I H N HN \_N [O 27" 02—N , }——N OSO3H OSO3H N\ 0. bSO3H o o o O\N/U’I,’ O\N/Ull" O‘N/Hl’n H H H / "(:1 / / N— N "O }'N, (EN/ )——N\ NJ_ )“iN HNJK o b803H /N"/ 0 0803H O 0803 o o O\N/U’/,l O‘N/Hl’“ O\N/Ulll' )—' / / N / N s—<NH2 O / J—N J )—N OSO3H 0’1 \ 0- S OSO3H O OSO3H o H RN 0 <\N]/\/N O\ fl O\NJL,,I HNWO‘N L H N H N_,;jN/ N N )‘N )——N \ O OSO3H / 0303” O bSO3H //\NH o N/ O \ / Cl) NWKWQNJLQ, QVINJLH, QN/ ow» H H H N N N ' )—N )———N }—N\ O b803H O b803H 0 OSOaH 1818 In the above formula (I), when Y = 0R1, several non-limiting examples of the compounds of the present invention are mentioned below: HONQNJL,“ AN)l, /\/0\NJL,N H H N N N O O oso3H 0303H ‘oso3H o o o o HzN/VO\NJI, (:1l J\/O LI 0\ LI, HZN \NJ Q / m N N N N )—-N\ //"_N\ O 0 OSO3H OSO3H O OSO3H 0 ii 0 0 0 HzN/[LNNO‘N \‘ // j? H2N’S‘N/\/O‘N HOJk/O‘N j? H H H H H N N N )—N }——N\ )———N\ O 0803H O OSO3H 0 0803H . b303H bSO3H ‘oso3H o o o XO‘NJ’ o\ in O‘NJL,‘ H D/ H Q N gH N }—N %N\ //’—N\ O OSO3H O OSO3H O OSO3H o o o N»,l, N».I, 1919 N2 NO oHﬂ o l/OIL om |/Olv NH A H/ N NH \NH V Nlﬁ, N \ N N\ NI %WWN O \OSO H O wO O 3H \oSOH3 N2 O OI/II A \ HN O A Q OHm NH OHﬂNH ,, Iv HN NH N g w (\lw.

“N N \ Nx Nlh SO O 0m H O 3 \oS05H O |/CL O Q Q OHﬂ g / \ A NH M N N NH \N N , N gNH u O N Mk NthN . N\ 0 \OS O 3 H oSOum“ O \oSOw o Ol/In, A \ o\ 0 OHW H NH H g N NH , HN NH N T H NW N\ NJP(HIM N N 0 OSOunno \OSO O 3H \OSOw O\ |/O|n A Q OI/In, A O\ II gNH ,. NH ,.

O N S WW , OQ w // v 9 N\ O N O O8O 0 3H N\OSO3H O \OSw HN A \ OHW ,, O\ O Ol/l/ NH UN 70 NH \NH Nlﬁv N N /g WW N N\ O \OSO \OsO3H O O%H3 LNI. NH O DNA A.

QNOHﬂ ,, N N H N Nmk N Num; % O \O 0 \O N\ 3H 80o.H O %m.H HN HN 2020 2121 OSO3H O OSO3H O OSO3H o o o L o \\ o\N o\N)1/,,, VNQ/ O‘NJI’ (N H H “N \ H HN N o H2N N N Jr—N J—N o )*—N OSO3H O 0803H NH2 0 OSO3H O OSO3H O bSO3H 0 0503.4 H Q ‘? a . o Ow HN ON)“ 0\ J,“ H H O n ' N . / N }—'N\ \ J—N l O N OSO3H O OSO3H OSO3H o o o l, I, | HN O\N)/l' HN ‘ H H (\N/VO\NJH N N N’J N / / / / N //'—N\ ‘N 2—H }*N\ O HN‘N OSO3H O / OSO3H O OSO3H j? C? /, / O\ jI, ,, N ,, 2222 2424 °I (”L 0' H2N O\ )0“ o O\NJ~,, OJ—N J—N 0803H 0 0803H H .

HNQO/VO‘NJL'“Q- N HN\lO/VONJ o o . Ll N H ONO\NJLI“QH N N H J—N Hi OSOaH O 0803H 0 0803 In another embodiment, in the formula (I), Y is NR2R3.

Wherein, R2 is hydrogen, optionally substituted 01-6 lower alkyl, even more preferably R2 is In the a (I), when Y = NR2R3; R3 is a radical selected from any of the following groups: (1) 01-6 straight or branched chain alkyl which is optionally substituted. Non-limiting examples of such compounds are: (2) 03-7 cycloalkyl which is optionally substituted. Non-limiting es of such compounds are: 2525 //j'—N ' )—N\ O ‘osogH O bSO3H O OSOsH (3) 04-7 saturated heterocycles containing at least one atom selected from O, N and S wherein the said cycle is optionally substituted. Furthermore the ring S is optionally oxidized to 8(0) or S(O)2 and the free ring N atom may optionally take a substituent. Non—limiting examples of such compounds are: 0 o HN\NJII,‘| H \NJIU'l N N HN(3H; (3 H GH HOSO3H o s N N O bSO3H O OSO3H o o HNSHMi0 R )L,“ lit JIM, HNQ 32 012 osogH (4) 01-5 straight or branched chain alkyl carbonyl which is optionally substituted. Non- Iimiting examples of such compounds are: 0 o H o N\ J“, L, H l w u ' WN‘u AWN o N H o N o N 7J——N )—N }—‘N o OSO3H O b803H O 0803H o )th o )l, WNW)» In, \ll/ N\ N N ' H H IO H 0 N 2626 \N I,' H o N N O N //I—N ”liN N o ‘osoaH O OSO3H OSOaH o o O \/\H/ M Q ” \N/\\< H o N o N , \ o N //l—N\ //L—N\ 0 (DJ—N OSO3H O OSO3H OSO3H (5) 03.7 cycloalkyl carbonyl which is optionally substituted. Non-limiting examples of such compounds are: NJIMO O O H | H H t In, ’n.

H WN\N I ©\V<N\N H H 0 N o N b803H O bSO3H (6) C4_7 membered ted heterocyclyl carbonyl containing at least one heteroatom selected from O, N and 8 wherein the said heterocycle is optionally substituted.

Furthermore the ring S is optionally oxidized to 8(0) or S(O)2 and the free ring N atom may optionally take a substituent. Non-limiting examples of such compounds are: 0 o o NH H H NH H N\ )L, H” N\ L“ N\ L, O N O N o N g—N )—N\ J—N O OSOgH O OSOgH O OSOgH l O N O O 0% l 1M l W lH H N , N , H H H o N o N o N 2828 o / o o Cam”) QH I N H H N ”JI I I, \NSW” ”J \ I, ‘ ’1, o N o N o N A—N J—N )—-N\ 0 OSOaH 0 0803H 0 OSOaH H o O Q 0 N H 0 0803H 0 0803H HNNN\”JI,,,4 Q N 3 N\ O 0803H (7) C3_7 membered saturated heterocyclyl (C15) alkyl carbonyl wherein the said heterocycle has the same definition as defined in (6). The free ring N atom may optionally take a tuent. Non-limiting examples of such compounds are: “\N/H/ N\N/u’/,,H \ “\N/llln.

HN H H N H' N\ N\ N\ O 0803H O OSO3H O 0803H o o o H H H WN\ J No A, N\ A, N H N \ N H N H N H o N o N o N j N\ s N\ c N\ 0 0803H O 0803H O 0803H o o o wN‘MJMH I WM”)H I HNE)”| 0 N HN o N o N N /}—~N\ J—N HN )——N / O 0803H O OSO3H O 1O OSOgH 2929 O O N , H )l, H )1.9 /\\< N " N '4 N ' H /\\< ON “O O H OEgN O H g 0 o o b803H O b803H (8) C640 aryl carbonyl which is optionally substituted. Non-limiting examples of such compounds are: @N\NJI’0 o H I ”\n/N\NJ’/,,CO H I H H o N o N j N\ j N\ O 0803H O OSO3H N\NJ’I,4‘i K ‘i NsN I], H H o N o N )~———N\ 7L—N O OSO3H O OSO3H (9) Cmoaryl (Cm) alkyl carbonyl which is optionally substituted. Non-limiting examples of such compounds are: 0 bsoaH ’ O 1O OSO3H (10) C5-6 membered heteroaryl yl containing at least one heteroatom selected from O, S and N wherein the heteroaryl is optionally substituted. miting es of such compounds are: 303O (11) 05.5 aryl (01-5) alkyi carbonyl wherein the said heteroaryl has the same definition as defined in (10). Non-limiting examples of such compounds are: H I, V \MJII‘Q‘ \ u “IQ \ \u) (“Q|, \ i N N O O O N \ NH \ s \ o 3131 (12) In the formula (I), when Y = NR2R3; R3 may also be selected from the following groups like , CH3SOZ-, NHZCO-, NH2802—. Non-limiting examples of such compounds are: 0 O V H H N )l, N Jl, F3Cti 0 m\N a S: \N " HzN \N I' N in c O bSO3H O OSO3H bSO3H Q“ I, ,s’ ‘N HzN \b H j N\ O oso3H are: )_N 1 0 bSO3H bSO3H (14) 05-6 membered heteroaryl which is optionally substituted. Non-limiting examples of such compounds are: (15) In the formula (I), when Y = NR2R3; R2 and R3 together may form an optionally substituted ring system and the said ring may contain another heteroatom ed from O, N, and 8. Furthermore, the ring may be optionally substituted. miting examples of such compounds are: 3232 E: O O/Yo O N\ l,l, a HN/Tofg l, \ l ‘N ,.

O OSOsH O bSO3H O OSO3H H “YOO Q j ul,“ bj,“ N \ O _ l N 0 bSO3H 0803H o bSO3H In the above formula (I), when Y = NR2R3, several non-limiting examples of such nds of the present invention are mentioned below: H J' H Ci H / ‘N \/ 7” \< ‘N H H N N N 3434 HN HN \NH A. \NH N#. O \OSO3H AWHO HN OH/ NH n, OSO H O \kﬂHM O”.// NH IN 0”” HN \NH I: on (ﬁlm-N ‘ \NH N‘# O o H o HN OHw, . o HN \NH I,A WW OHw NlﬁMN o O \Ow3H O 3535 3636 bSO3H ‘oso3H \ HN HN NH I. HM on M 3 NH O Nlﬁ 0 OS0”mo \0S0H3 0 bSO3H KJY/ I OSO3H bSO3H 3737 HN OHM O HN/ H I. 2N «0 \NH H H2N “Sq\0 \NH OSO H O \OSO 3 3H obA‘N OHM HNbA‘N OH,/ \NH IvA NH Nlﬁ,N O \oSo3H o bSO3H No AUno 0 N on NV OHw \NH I; NH oSo H 0 \oSo3H 3838 NH2 .

H N2 H N O 2 O O “(:1 N\N)lhl’H N\ )l,’ N\NJ|/ H H H o N o N //L—N, )——-N }—N o 0803H o b803H 0 OSOaH H o 0 NH H H 2 0 N l HNNNtNJ/u,l ? H | '/\ll/N\N ,, H H H o N o N o N }—N )———N )~—N O bSO3H O bSO3H O ‘oso3H NHz l O l O /N\/\WN\NJIH O WNNJL,T L H H H FWNNJL o N o N H }'N )—N\ o N J N o b303H O OSO3H o o bSO3H ‘H N ‘ 2 O H RH\N WHANJI’M,O / / O II; )|// H O H RH\ - o IQ o IQ )—N\ )_‘N\ )—-_N\ O OSO3H O OSO3H O 0803H Examples of the groups for forming a pharmaceutically acceptable salt represented by M in the formula (I) include: inorganic base salts, ammonium salts, c base salts, basic amino acid salts, inorganic acid addition salts, and organic acid addition salts. Inorganic bases that can form the inorganic base salts include alkali metals (e.g., sodium, potassium, and lithium) and alkaline earth metals (e.g., calcium and magnesium). Organic bases that can form the organic base salts include n-propylamine, n-butylamine, cyclohexylamine, benzylamine, octylamine, ethanolamine, diethanolamine, diethylamine, triethylamine, ohexylamine, ne, choline, N-methylglucamine, morpholine, pyrrolidine, piperidine, N-ethylpiperidine and N-methylmorpholine. Basic amino acids that can form the basic amino acid salts include lysine, ne, ornithine and histidine. As will be appreciated by one 3939 skilled in the art, the compounds of formula (I) containing a basic nitrogen atom are capable of forming acid addition salts. Such salts with pharmaceutically acceptable acids are included in the invention. Examples of such acids are hydrochloric, hydrobromic, phosphoric, sulphuric, citric, oxalic, maleic, fumaric, glycolic, mandelic, tartaric, aspartic, succinic, malic, formic, acetic, trifluoroacetic, methanesulfonic, sulfonic, trifluoromethanesulfonic, benzenesulfonic, p—toluenesulfonic and the like.

Moreover, some compounds of formula (I) when they contain a basic group such as NH, NH2 or pyridine and the like may form an inner, zwitterionic salt with OSOaH; such inner salts are also included in this invention.

. Another aspect of the present invention is to e all possible isomers of formula (l). As used herein, the term ‘isomers’ refers to different compounds that have the same molecular a but differ in arrangement and configuration of the atoms, such as rical isomers and optical isomers. For a given compound ofthe present invention, it is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore the invention es enantiomers, reoisomers or racemates of the compound. By definition ‘enantiomers’ are a pair of stereoisomers that are non-superimposable mirror images of each other, and 1:1 mixture of a pair of enantiomers is a racemic mixture. By definition, ereoisomers’ are stereoisomers that have at least two asymmetric carbon atoms but which are not mirror-images of each other. When a compound of formula (I) is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or 8.

Compounds may also exist in several tautomeric forms including the enol form, the keto form, and mixtures of any of the foregoing. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.

A variety of protecting groups conventionally used in the am field to protect a reactive onal group present in the le of formula (I) can be used. ‘Protecting group’ refers to a group of atoms that when attached to a reactive functional group in a molecule masks, reduces or ts reactivity of the functional group. Examples of protecting groups can be 4040 found in Green et al., “Protective Groups in Organic Chemistry”, (Wiley, 2””, 1991) and Harrison et al., “Compendium of Synthetic Organic Methods,” Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not d to , , trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert—butoxycarbonyl (Boc), trimethylsiiyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and tuted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like. Examples of hydroxy protecting groups include, but are not limited to, those where the hydroxyl group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers. 1O The term ‘optionally substituted’ refers to unsubstituted or substituted with one ortwo of the following substituents each of which is independently selected from: -Lower alkyl including from one to six carbon atoms in any arrangement, e.g., methyl, ethyl, i-propyl or t-butyl -Amino -Substituted amino such as , )2 — Q , -NHCHZCH3, —NHPH, -NHBu‘, -Alkoxy such as —OCH3, -OCZH5_, -OPri (i.e., isopropyloxy), -VOBut (i.e., isobutyloxy) —Hydroxyalkyl such as —CH20H, -CHQCH20H -Halogen such as F, Cl, Br -Hydroxy -Carboxy —Alkoxycarbonyl such as -COOCH3, —COOCgH5, -COOPri, and t ' -Ha|oa|kyl such as —CHzCl, -CH2F -Trifluoromethyl -Trifluoromethyloxy -Alkylamine such as H2, -CHZCH2NH2 4141 -Substituted alkylamine such as —CH2NHCH3, -CH2N(CH3)2, 2NHCH3, -CHZCH2N(CH3)2, \‘NQ -Carboxamide -Thiocarboxamide -Sulfonic acid -Acylamino -Sulfony|amino -Sulfonamide -Substituted sulfonamide such as CH3, -SOZNHCHZCH3, Pr‘, -SOZNHBu‘, -soZNH@F -SOZNH’©CH3 -SOZNH@‘CF3 —Urea (-NHCONH2) which may be optionally substituted -Thiourea (-NHCSNH2) which may be optionally substituted -Sulfonylurea (-NHSOZNH2) which may be optionally substituted -Oxo (=0) when oxygen is bonded through double bond to a carbon atom -Oxyimino (=N-O—A) where the nitrogen is bonded through double bond to a carbon atom which is attached to the rest of the molecule and A can be hydrogen, or optionally substituted straight or branched lower alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl -Hydroxamic acid (-CONHOH) -Acy| (-COCH3) -Trifluoromethyl carbonyl (-COCF3) -Cyano (-CN) -Amidino -C(=NH)NH2 which may be optionally substituted 4242 -Guanidino -NHC(=NH)NH2 which may be optionally substituted —Aryloxy -Heterocyclyl -Heteroaryl -Heterocycly|oxy -Heteroaryloxy -Heterocyclylalkyloxy -Trialkylammonium The substituent ned above could be substituted at the carbon atom or at the free N— atom of the molecule as appropriate.

Among the compounds of formula (l), a particular subject of the invention are those in which M is hydrogen or a ceutically acceptable salt forming cation.

A group of preferred examples of compounds of the formula (I), when Y = OR‘, are from the ing Table 1. o ‘ososm Y = OR1 = point of attachment with 0 Table 1: List of compounds Compound No. M R 4343 nd No.

HZN/\/' 12 HN 13 Na HQ(>\/ 4444 nd No. R1 1- ﬁ—‘ 14 O J— _L_ 16 5 HN: 7 HN; ; 18 HZN,,,,O’* 19 HZNO/* HzN‘O'W 21 W 22 {D’* 23 Cr 1_ ‘L. 24 @l‘\\\* 4545 nd No. 36 Na *J\(O'Na+ 4646 Compound No. R ___1__ .__4_.__ 37 00N/\/.

‘|\* N .I _____l__ _1 N "* 42 (X:N 43 00N .———_——i—‘— * 44 do0 45 D HZN * 4747 nd No. R1 48 HSC\ H < 3 __l_ J__ H30\ H30~@ N t 51 Q# ________J_ _._ 53 < _—l_ '1— —l_ —1 r— 4848 .m No. M 57 H \ 58 H 59 H 60 H 61 H 62 H 63 H HN 64 H .. :1 65 H O 66 H 8 67 H Hapr N 4949 nd No. M R1 68 H / N '1— ‘L— 69 H l ___r 70 Na \Si\ 71 H \\N/ 72 H N/ NH \—_—/ .4— J—— 73 H HZNJK/* J_ _1 74 H —T ———I* 75 H YNO/ J— + 76 H HN o —l— T— o 77 H “5—H HZN/Icg \ / T o 78 H >—N‘ ,* 505O nd No. 79 HO/V‘ 82 Na 83 Na 84 Hac+3 CH3_ 5151 nd No. 1 M R 91 H HN * 92 H VNQ/ HN * 93 H VNg “*T "r HN . 94 H yNCF 95 Na 9 00“” 96 H 0/ HN * 97 H .__.__________J_ 98 H HN\N/ T—— _I_ 99 H Q /\/* 100 Na C,“ o o 101 H Ao/L JL 5252 nd No. 103 N\O 104 Na NlNH 109 HQ*\ H3C*O 5353 .______.__*_l_ Compound No. R 111 HNQﬂkCH3 T H 112 Q 113 HNQ'* __,L___ 114 3/} 117 CNN N/\/ -————————i— 119 (\N/V o://S\) N I _L —L— 5454 nd No. 131 Na 5555 nd No. 5656 d No. M 1R 141 H (M 142 .N.“ H#NJ f 4 143 H HN< I 144 H r/ 145 H / 146 H o\\N 147 H H N\ 4! * 148 H N(Cr # + 149 .N.u ON/ 4. 150 m HNQ0 LI 4 mN * 1 H v 1 1 152 .Na (k 1V* 5757 Compound No. M R1 . l . 153 H HM;0N1 ___l_ .1. 154 H ”Na O/\/* 155 H * ______—l _l_ A group of preferred examples of compounds of the formula (I), when Y = NR2R3, are from the following Table 2. 0 ‘030m Y = NR2R3 = point of attachment with N Table 2: List of compounds '1 *1— Compound No. M R2 R3 1 H H H30’* ___J j— + 2 H H \/* +— + 1— 3 H H \( _ 7‘ 4 H CH3 H30’* ‘1 _i H CH2CH3 \/* _1 J_.‘ a H CH(CH3)2 \( _L _.__ 5858 *7— T ﬁ— Compound No. R2 R3 _ +_ *1. 7 H % ___L L. 8 “ d 9 H _.1_ _L._ _._| 14 H “D” 1— +— «1 H / “—1 _L..___ 16 H chK 1 HM;— 17 H W ‘4‘— —1 ——[ 18 H H H —1—‘ ‘JF * 19 CH3 “39% 4_ ﬁ_L _.J_._,_ CH3 /\H/ 5959 ‘ nd No. R2 R3 21 CH3 H 1—— —+—— 22 CH2CH3 “30% 23 CHZCH3 W 24 H *6 H W 26 H H C\ * 27 H H“ CH3 0 23 H FBCAW _____________J_____ H C\3 OW* 29 H ,30 H HzNﬂo _l__ NH2 31 H __+_____ ____LL * 32 H M _ * 33 H W 606O nd No. R2 R3 ' J.

’ H30 H Hac/ﬁf’a: ' O 36 H ' Fﬁ‘“ 37 H F/ﬁ/ﬁ _1__ 40 H HZNZ EN) 4 4— H * 41 H N _J. _L 42 H O 1_ _._ H * 43 N H [ﬁo Jr J— 44 CH3 6161 UUIIU I‘U‘ I'l 45 H H ”WO _L _L F__ * 46 H H HN » 47 H H O9/4O _1._ ‘ * 48 H H (DA0 49 H H ”JO/<0 50 H H o 51 H H 4— _l_ 52 H H MNH 0 —r —+ 4— A: 53 H H . m HN O [— H + * 54 H H Wo .— 1—— __l_ 55 H H V/jf n- 1— 56 H H 6262 nd No. 66 CH3 67 CHZCH3 6363 nd No. 70 CH3 71 CHZCH3 6464 —T —_—I_ Compound No. R2 R3 _—T_ 78 F N._ o 79 CH: \ / 80 H m\NH 0 __J_ _4_ 81 H Ws 0 ~ ——————l —1— ——t— 82 H Wo o 83 H l \ N O 84 H l/ O 85 H l N\ o 86 H H2N\</ﬂ . s o 87 CH3 HzNﬁj/Y S O _;___ 88 CH3 I N/ O __J.* + .__l_ F3C * 89 H \H/ _T O 90 H H3c/E\S\’* 6565 Compound No. R2 R3 " T" ——" H2N 91 H 27'* 92 H ‘ HZN/§\’* 94 CH3 * _______L 95 H * \\ / ﬂ_—__L_____.J__ 1* N/ _._1 l_.._ 97 C** ___~___________L._~______~_._J 98 <»\* ____._.___.____,_______._____J_ 99 4* * ﬁ— ’1’ HN/\ 100 4* * _._l 101 Q * 102 4"\1 103 (i’\”’0 I— [— o/\*/o 104 ‘ <\ ’ 6666 W * .d No. .M R2 R3 L. 4 [T 1 05 6 H W/\ F nT r 1 06 H //\* \* 1 07 H //\ \mm N Um; 1 08 H ﬁ¢¢* 1 09 H H 1 1 0 H C”ma 1 1 1 H H * ? *1 W * 1 1 2 H H W...2 1 1 3 ‘ H H * + L .

W...2 1 1 4 H CH3 * i F ﬂ 1 1 5 H IN H * 6767 T— “c— r Compound No. M R2 R3 116 H H FAR? ————_-—_+_— ——1 + HZN 117 H H K1» i‘ # —+ H 118 H H KW 119 H H W, J..— lt is also an object of this invention to provide a ation of a compound of general formula (I) having antibacterial activity with another existing antibacterial agent, thus causing synergistic effect and the use of the same as drugs for the treatment of bacterial infections. it is another object of the invention to provide methods for preparing the compounds of the ion of formula (l). it is a further object of the invention to provide pharmaceutical compositions comprising a compound of formula (I) of this invention (some of which directly inhibit B—lactamase enzymatic function and others of which do not directly t B—lactamase’s enzymatic function (at pharmaceutically accessible concentrations) as an active ingredient in combination with an antibiotic (e.g., a B—lactam antibiotic or some other non B-lactam antibiotic) and a suitable amount of ceutically acceptable carrier or diluent, so as to provide a form for proper administration to a patient. These compositions can be stered by parenteral, in ular uscular route, oral, sublingual, rectal, aerosol or by local route in a topical application on the skin and the mucous membranes. Suitable 6868 pharmaceutical vehicles e excipients such as starch, glucose, lactose, sucrose, gelatin, gum arabic, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.

Other examples of suitable pharmaceutical vehicles have been described in the art gton’s Science and Practice of Pharmacy, 21St Edition, 2006). itions of the present disclosure, if d, can also contain minor amounts of wetting, dispersing or emulsifying agents, or pH buffering agents, and vatives. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be included. Pharmaceutical compositions can be formulated in a conventional manner. Proper formulation is dependent 1O upon the route of administration chosen. The present pharmaceutical compositions can take the form of injectable preparations, suspensions, emulsions, coated tablets, pellets, gelatin-capsules, capsules containing liquids, powders, granules, sustained-release formulations, suppositories, aerosols, sprays, ointments, creams or any other form suitable for use.

In another aspect, the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ient in an antibacterial ition in admixture with a carrier.

In another , the present invention also provides for the use, in the cture of a medicament, of a compound within formula (I) above as an active ingredient. in another , the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient, along with one or more antibiotics (e.g., a B—lactam antibiotic or some other non B-lactam antibiotic), in an cterial composition in admixture with a r.

In another aspect, the present invention also provides for the use, in the manufacture of a medicament, of a compound within formula (I) above as an active ingredient, along with one or more antibiotics (e.g., a B—lactam antibiotic or some other non B-lactam antibiotic). 6969 The parenteral administration which includes intramuscular, intraperitonial, aneous and intravenous use, sterile solutions of the active ingredient are usually prepared and the pH of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be lled to render the preparation isotonic. Suitable solvents include saline solution (e.g., 0.9% NaCl solution) and apyrogenic sterile water.

Pharmaceutical compositions for oral delivery can be, for example, in the form of tablets, lozenges, aqueous or oily suspensions, granules, s, ons, capsules, syrups, or elixirs. Orally administered compositions'can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame, or rin, flavoring agents such as peppermint, oil of wintergreen, cherry, coloring agents, and preserving agents to provide a pharmaceutically palatable preparation. Moreover, when in tablet form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Oral compositions can include rd vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. For oral liquid preparations, for e, suspensions, elixirs, and solutions, le carriers, excipients, or ts e water, saline, alkyleneglycols (e.g_. propylene glycol), polyalkylene glycols (e.g., polyethylene glycol), oils, alcohols, slightly acidic buffers g from about pH 4 to about pH 6 (e.g., acetate, citrate, ascorbate ranging from about 5 mM to about 50 mM), and the like. Additionally, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, and the like can be added.

For topical formulations of nds of the present invention, creams, gels, ointments or viscous lotions can be used as appropriate delivery forms. Topical ry systems also include transdermal patches containing at least one compound of formula (I) to be administered. Delivery h the skin can be achieved by diffusion or by more active energy sources such as iontophoresis or electrotransport. ations of a compound of the t invention, for topical use, such as in creams, ointments, and gels, can include an oleaginous or water soluble ointment base, for example, topical compositions can include 707O vegetable oils, animal fats, and in n embodiments, semisolid hydrocarbons obtained from petroleum. Topical compositions can further include white ointment, yellow ointment, cetyl esters wax, oleic acid, olive oil, paraffin, petrolatum, white petrolatum, spermaceti, starch glycerite, white wax, yellow wax, lanolin, and glyceryl monostearate. Various water- e ointment bases can also be used, including glycol ethers and tives, polyethylene glycols, polyoxyl 4O stearate, and polysorbates.

In a pharmaceutical composition containing a compound of this invention, the weight ratio of active ingredient to carrier will normally be in the range of 1:20 to 20:1. The administered daily dose varies according to the illness treated, and the administration route. However in 1O most ces, an effective dose (e.g., in some instances, a B—lactamase ting dose) of a compound of a (I) or a pharmaceutically acceptable salt thereof will be a daily dose in the range from about 1 to about 500 mg per kilogram of body weight orally, and from about 1 to about ‘500 mg per kilogram of body weight parenterally. The weight ratio of the compound of t invention and an antibiotic (if it is being administered with an antibiotic, 6.9., a am antibiotic or some other non B-lactam antibiotic) will normally be in the range from 1:20 to 20:1.

In some aspects cf the present invention, anadditional object is to provide an ed method for the treatment of bacterial infections caused by B—lactamase producing bacteria in a patient in need of Such treatment comprising administering to the patient a therapeutically effective amount of at least one nd chosen from formula (I) or a pharmaceutically acceptable salt thereof in combination with a known B—lactam antibiotic. in such an aspect of the present invention, the compounds increase the cterial effectiveness of B—lactamase susceptible am antibiotics, that is, they increase the effectiveness of the antibiotic against infections caused by B—lactamase producing microorganisms in mammalian subjects, particularly in human. In these aspects of the present invention, this makes the compounds of formula (I) and pharmaceutically acceptable salts f, valuable for co-administration with B—lactam antibiotics. In the treatment of a bacterial infection in such 7171 aspects of the present invention, said compounds of formula (I) or a pharmaceutically salt thereof can be mixed with the B—lactam antibiotic, and the two agents thereby administered simultaneously. When co-administered with a am antibiotic in such aspects of the t invention, the combination of the compound of the invention and the antibiotic can provide a synergistic effect. The term ‘synergystic effect’ refers to the effect produced when two or more agents are co-administered is greater than the effect produced when the agents are administered individually. atively, the compound of formula (I) or a salt thereof can be administered as a separate agent during a course of treatment with the antibiotic.

‘Therapeutically effective amount’ refers to the amount of a' compound that, when administered to a subject for treating a e, or at least one of the clinical symptoms of a disease, is sufficient to affect such ent of the disease, disorder, or symptom. The eutically effective amount can vary depending, for example, on the compound, the disease, disorder, and/or symptoms of the disease, severity of the disease, disorder, and/or symptoms of the disease, the age, weight, and/or health of the patient to be treated, and the judgement of the prescribing physician.

The term ‘B—lactam antibiotic’ refers to a compound with antibiotic property that contains a B—lactam functionality. es of B—lactam otics which can be used in combination with the compounds of the present invention represented by formula (I) are commonly marketed penicillins, cephalosporins, , carbapenems and monobactams.

Examples of am antibiotics which can be used in combination with the compounds of the present ion represented by formula (I) are commonly used penicillins, such as amoxicillin, ampicillin, azlocillin, mezlocillin, llin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, methicillin, illin, talampicillin, oxacillin, cloxacillin, dicloxacillin and commonly used cephalosporins such as cephalothin: cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, cephapirin, cefuroxime, cefoxitin, cephacetrile, cefotiam, cefotaxime, cefatriazine, cefsulodin, razone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, cefepime, 7272 ceftazidime, cefpiramide, ceftriaxone, cefbuperazone, cefprozil, cefixime, ceﬁobiprole, ceftaroline, cefalonium, cefminox, ceforanide, nam, cefoxitin, cefotetan, loracarbef, cefdinir, cefditoren, cefetamet, cefcapene, cefdaloxime, ceftibuten, cefroxadine, latamoxef (moxalactam), and CXA-101. From the carbapenem class of B~lactam antibiotics such as imipenem, meropenem, panipenem, em, doripenem, ertapenem and the like could be used. From ctam class of ﬁ—lactam antibiotics such as aztreonam, carumonam, tigemonam, and the like could be used as the combination partner of antibiotic.

Examples of antibiotics (which are not ﬁ—lactam antibiotics) which can be used in combination with the compounds of the present invention (i.e., nds of formula (I) above, salts thereof, solvates of such compounds and salts, and ated compounds of any such compounds) include aminoglycosides, quinolones, tetracyclines, glycylcyclines, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramin, oxazolidinones, polymyxins, and other compounds known to have cterial properties.

‘Pharmaceutically acceptable solvate’ refers to a molecular complex of a compound with one or more solvent molecules in a iometric or non-stoichiometric amount. Such solvent les are those commonly used in the pharmaceutical art, which are known to be innocuous to recipient, e.g., water, ethanol, and the like. A molecular complex of a compound or moiety of a compound and a t can be stabilized by non-covalent intra- molecular forces such as, for example, electrostatic forces, Van der Waals forces or hydrogen bonds. The term hydrate refers to a complex where the one or more solvent molecules are water.

Among the compounds of a (I), a particular subjeCt of the invention is the compounds with the following names. The following es illustrate the invention, and are not intended to be limiting of its scope. To the contrary, the claims are intended to cover alternatives, modifications, and equivalents.

The non-limiting examples of the nds of the t invention are: 7373 )—N-(2—hydroxyethoxy)oxo-6—(su|fooxy)-1,6—diazabicyclo[3.2.1]octane—Z- carboxamide (28,5R)-N-methoxyoxo(sulfooxy)—1,6—diazabicyclo[3.2.1]octane—Z-carboxamide ' (28,5R)—7-oxo-N—propoxy(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)—N—(2-aminoethoxy)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2— carboxamide (2S,5R)-N-(2-aminopropoxy)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—Z- carboxamide (2S,5R)-N-(2-amino—2—oxoethoxy)oxo-6—(suIfooxy)-1,6-diazabicyc|o[3.2.1]octane-Z- carboxamide (28,5R)-N-[2-(carbamoylamino)ethoxy]oxo—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane— 2-carboxamide (28,5R)—7-oxo—N-[2-(sulfamoylamino)ethoxy]—6-(suIfooxy)-1,6—diazabicyc|o[3.2.1]octane- 2—carboxamide [({[(28,5R)—7-oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]oct-2—y|]carbonyl}amino)oxy]acetic acid 2—methyl[({[(28,5R)oxo(su|fooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]propanoic acid (2S,5R)oxo-N-[2—(piperidinyloxy)ethoxy](suIfooxy)-1,6-diazabicyclo[3.2.1]octane- 2-carboxamide )—7-oxo—N-(propanyloxy)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide (28,5R)—N-tert—butoxyoxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)-N—(cyclobutyloxy)oxo-6—(suIfooxy)—1,6-diazabicyclo[3.2.1]octane-Z- carboxamide (2S,5R)-N-(cyclopentyloxy)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—Z- carboxamide (2S,5R)-N—(cyclohexy|oxy)oxo—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2— carboxamide (2 S,5R)—N-(cyc|oheptyloxy)oxo—6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane-Z- carboxamide 7474 )-N-[(3-aminocyclopentyl)oxy]-7—oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2- carboxamide (28,5R)-N—[(2-aminocyclopentyl)oxy]oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)-N-{[3—(methy|amino)cyclopentyl]oxy}oxo(sulfooxy)-1,6— diazabicyclo[3.2.1]octane-2—carboxamide (2S,5R)-N-{[4-(dimethylamino)cyclohexyl]oxy}oxo-6—(sulfooxy)-1,6- diazabicyclo[3.2.1]octane—2-carboxamide (2S,5R)-N-[(3-aminocyclohexyl)oxy]-7—oxo-6—(sulfooxy)—1,6—diazabicyclo[3.2.1]octane 1O carboxamide (28,5R)-N-{[3-(methylamino)cyclohexyl]oxy}oxo-6—(suIfooxy)—1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)oxo-N-(pyrro|idinyloxy)-6—(su|fooxy)—1,6—diazabicyclo[3.2.1]octane carboxamide (28,5R)oxo-N-[(5-oxopyrrolidinyl)oxy](sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane carboxamide (28,5R)—N—[(1-acety|pyrrolidiny|)oxy]oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane- 2-carboxamide (28,5R)-N-[(1-methy|pyrrolidiny|)oxy]oxo(sulfooxy)-1,6—diazabicyc|o[3.2.1]octane— 2—carboxamide )oxo-N-(piperidinyloxy)-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2- carboxamide (28,5R)oxo-N-(piperidinyloxy)(su|fooxy)-1,6—diazabicyc|o[3.2.1]octane carboxamide )-N-(azetidinyloxy)oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)oxo-6—(su|fooxy)-N-(tetrahydro-2H—pyranyloxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (28,5R)oxo-6—(sulfooxy)-N—(tetrahydro-2H—thiopyranyloxy)-1 ,6- 3O diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)-N-[(1,1-dioxidotetrahydro-2H—thiopyranyl)oxy]—7-oxo-6—(su|fooxy)-1,6- diazabicyclo[3.2.1]octane—2—carboxamide 7575 (28,5R)—N-(azepanyloxy)oxo-6—(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)-N-(1,4-oxazepan—6—yloxy)oxo-6—(suIfooxy)-1,6—diazabicyclo[3.2.1]octane—2- carboxamide )—N-[(1-methy|piperidinyI)oxy]oxo-6—(su|fooxy)-1,6-diazabicyclo[3.2.1]octane- 2-carboxamide (28,5R)-N-[(1-carbamimidoylpiperidin—4-yl)oxy]oxo-6—(su|fooxy)—1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (28,5R)oxo-N-(pyrrolidinylmethoxy)-6—(su|fooxy)-1,6—diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)oxo-N—(piperidinylmethoxy)(sulfooxy)-1,6—diazabicyclo[3.2.1]octane-Z- carboxamide (2S,5R)—7-oxo-N-(piperidin—3-ylmethoxy)-6—(su|fooxy)-1,6-diazabicyclo[3.2.1]octane—2- carboxamide )oxo-N—(piperidinylmethoxy)(sulfooxy)-1,6—diazabicyc|o[3.2.1]octane amide (28,5R)—N-(morpholin—3—ylmethoxy)-7—oxo—6—(su|fooxy)—1 ,6—diazabicyclo[3.2.1]octane-2— carboxamide (28,5R)—7-oxo—N-(piperazinylmethoxy)-6—(su|fooxy)-1,6—diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)oxo(sulfooxy)-N-(thiomorpholin-3—ylmethoxy)-1,6—diazabicyclo[3.2.1]octane— 2-carboxamide (2S,5R)-N-(decahydroquinolinyloxy)oxo—6-(sulfooxy)-1,6—diazabicyclo[3.2.1]octane- 2—carboxamide- (28,5R)-N—(hexahydro-1H-pyrrolizin-2—yloxy)-7—oxo(sulfooxy)-1 ,6- diazabicyc|o[3.2.1]octanecarboxamide (2S,5R)-N—(octahydroindoliziny|oxy)oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane- 2-carboxamide (2S,5R)-N-(octahydropyrro|o[1 ,2-a]pyrazin—8-y|oxy)oxo-6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (2S,5R)—N—(octahydropyrro|o[1,2—a]pyrazinyloxy)-7—oxo-6—(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide 7676 (2S,5R)-N-(octahydrofuro[2,3-c]pyridinyloxy)oxo(sulfooxy)-1,6— diazabicyclo[3.2.1]octane-2—carboxamide )-N-(3-azabicyc|o[3.1.0]hexyloxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane—2-carboxamide )-N—(decahydroquino|inyloxy)oxo—6-(su|fooxy)-1,6-diazabicyc|o[3.2.1]octane— 2-carboxamide (28,5R)—N—(hexahydro-4aH—cyclopenta[b][1,4]dioxinyloxy)—7-oxo(sulfooxy)-1,6- diazabicyc|o[3.2.1]octane—2—carboxamide (28,5R)-N-(octahydrocyclopenta[c]pyrrol—5-yloxy)oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)-N-(hexahydro-1H-cyclopenta[c]furanyloxy)-7—oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)-N—(hexahydro-1H-cyclopenta[c]thiopheny|oxy)oxo—6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)-N-(bicyclo[2.2.1]heptyloxy)oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane- 2-carboxamide (28,5R)—N—[(7,7—dimethylbicyclo[2.2.1]hepty|)oxy]oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide )—N-(1-azabicyclo[2.2.2]oct—3-yloxy)oxo—6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)—N-(8-azabicyclo[3.2.1]octyloxy)-7—oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)-N-[(8—methylazabicyclo[3.2.1]oct-3—yl)oxy]-7—oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)—7-oxo(sulfooxy)-N-(4,5,6,7-tetrahydrothieno[3,2—c]pyridin-7—yloxy)-1 ,6- diazabicyc|o[3.2.1]octane-2—carboxamide (28,5R)-N—(6,7-dihydro-5H—pyrrolo[1,2—a]imidazolyloxy)oxo(sulfooxy)-1,6— diazabicyclo[3.2.1]octanecarboxamide (2S,5R)—N-(7—azaspiro[4.5]dec-10—yloxy)oxo(suIfooxy)-1 ,6— diazabicyclo[3.2.1]octanecarboxamide (28,5R)-N-(7—oxaspiro[4.5]dec-10—yloxy)-7—oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide 7777 (28,5R)-N-(1H-imidazoIylmethoxy)oxo(suIfooxy)-1,6-diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)—7-oxo(sulfooxy)-N-(4,5,6,7-tetrahydro-1H-4,7-methanoindazoI—3-ylmethoxy)— 1 ,6-diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)oxo-N-(1H-pyrazoIylmethoxy)(sulfooxy)—1 ,6—diazabicyclo[3.2.1]octane amide (28,5R)—7-oxo-N—[2-(pyridinyl)ethoxy]—6-(suIfooxy)-1,6-diazabicyc|o[3.2.1]octane—2— carboxamide (28,5R)—7-oxo-N-[2—(piperidinyl)ethoxy](suIfooxy)-1 ,6-diazabicyclo[3.2.1]octane-2— 1O carboxamide (2 S,5R)oxo-N—[2-(piperazin-1 -yl)ethoxy](sulfooxy)-1 zabicyclo[3.2.1]octane-Z- carboxamide (28,5R)oxo-N—[(1-sulfamoy|pyrrolidinyl)oxy]—6-(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane—Z-carboxamide (28,5R)-N—{[1-(methy|sulfamoyl)pyrrolidinyl]oxy}oxo(suIfooxy)-1,6- diazabicyclo[3.2.1]octane—2—carboxamide (28,5R)-N-[(1-carbamoy|pyrrolidinyl)oxy]-7—oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane—2—carboxamide (28,5R)-N—[(5-carbamoy|pyrrolidin-3—y|)oxy]-7—oxo(sulfooxy)-1 ,6 diazabicyclo[3.2.1]octane—2—carboxamide (28,5R)-N-[(1-carbamimidoylpyrrolidinyl)oxy]-7—oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)—N-[(1-ethanimidoylpyrrolidinyl)oxy]-.7-oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)-N-{[1-(iminomethyl)pyrrolidinyl]oxy}oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (2 S,5R)oxo—6-(sulfooxy)-N-(tetrahydrofu ranyloxy)-1 ,6—diazabicyclo[3.2.1]octane—Z- amide (28,5R)—7-oxo(sulfooxy)-N—(tetrahydro-2H—thiopyran—3-yloxy)-1 ,6- diazabicyclo[3.2.1]octane—Z-carboxamide (28,5R)-N-[(4-methylpiperidinyl)methoxy]—7-oxo(suIfooxy)—1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide 7878 (28,5R)—N-(1,4—oxazepan-2—ylmethoxy)oxo(suIfooxy)-1,6+diazabicyclo[3.2.1]octane- 2-carboxamide )-7—oxo—6—(sulfooxy)-N-(tetrahydrofuran-2—y1methoxy)—1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (28,5R)oxo(su|fooxy)-N-(4,5,6,7-tetrahydrofuro[3,2-c]pyridinyloxy)-1,6— icyclo[3.2.1]octane—Z-carboxamide )-N-[(1-methy|—4,5,6,7-tetrahydro-1H-pyrazo|o[3,4-c]pyridinyl)oxy]oxo (sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)oxo-6—(sulfooxy)-N—(4,5,6,7-tetrahydro-1H—pyrazolo[3,4-c]pyridin—4—yloxy)-1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)—N—[2-(1H-imidazoIy|)ethoxy]-7—oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane— 2-carboxamide (28,5R)—N-[(4-f|uoropyrrolidin-3—yl)oxy]oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane— 2—carboxamide (28,5R)-N—(1,2—oxazolidinyloxy)—7-oxo(su|fooxy)-1,6-diazabicyclo[3.2.1]octane—2- carboxamide ' (28,5R)oxo-N—(pyrazolidinyloxy)(suIfooxy)-1,6-diazabicyclo[3.2.1]octane—2— carboxamide (2S,5R)-N-[(4-aminopyrro|idinyI)oxy]oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane- 2-carboxamide (28,5R)oxo-N-[(4-oxopyrrolidiny|)oxy](su|fooxy)-1,6-diazabicyclo[3.2.1]octane-2— carboxamide (28,5R)—N-[(4-hydroxypyrrolidinyl)oxy]oxo-6—(suIfooxy)-1 ,6— diazabicyclo[3.2.1]octanecarboxamide (28,5R)—N—{[(4E)(hydroxyimino)pyrrolidinyl]oxy}oxo—6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)-N-{[(4E)(methoxyimino)pyrrolidinyl]oxy}oxo-6—(suIfooxy)-1,6- diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)-N-{[(4E)—4-{[(1,5-dihydroxyoxo-1,4-dihydropyridin-2— yl)methoxy]imino}pyrrolidinyl]oxy}oxo(su|fooxy)-1,6—diazabicyclo[3.2.1]octane carboxamide 7979 (28,5R)-N-[(4,4-dimethylpyrrolidinyl)oxy]oxo—6-(sulfooxy)-1,6- diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)-N—[(4-fluoropiperidinyl)oxy]oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane— 2—carboxam ide (28,5R)-N-[(3—fluoropiperidinyl)oxy]-7_—oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane- 2—carboxamide (28, 5R)oxo-N-[(5-oxopiperidinyl)oxy](suIfooxy)-1 ,6-diazabicyclo[3.2. 1 ]octane—2— carboxamide (28,5R)-N-[(5,5-dimethylpiperidinyl)oxy]oxo(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (28, 5R)-N—(2-methoxyethoxy)oxo—6-(suIfooxy)-1 ,6-diazabicyclo[3.2. 1 ]octane-Z— carboxamide (28,5R)-N—[2-(morpholin-4—yl)ethoxy]-7—oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)oxo—N-[2-(pyrrolidiny|)ethoxy](sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2— carboxamide (28,5R)—7—oxo-N-[2-(piperidiny|)ethoxy]—6—(suIfooxy)-1,6—diazabicyclo[3.2.1]octane—Z- carboxamide (28,5R)-N-[2—(1,1-dioxidothiomorpholiny|)ethoxy]—7-oxo(sulfooxy)-1,6- icyclo[3.2.1]octane-2—carboxamide (28,5R)-N-[(1-methylazetidin—3-y|)oxy]oxo-6—(suIfooxy)-1,6-diazabicyclo[3.2.1]octane— 2—carboxamide (28,5R)—N-{[5-(dimethylcarbamoyl)pyrrolidinyl]oxy}—7-oxo(sulfooxy)—1 ,6- icyclo[3.2.1]octane-Z-carboxamide methyl 4-[({[(28,5R)oxo(sulfooxy)—1 ,6—diazabicyclo[3.2.1]oct y|]carbony|}amino)oxy]prolinate (28,5R)-N-{[6-(dimethylcarbamoyl)piperidiny|]oxy}—7-oxo(suIfooxy)-1,6- icyclo[3.2.1]octanecarboxamide (28,5R)-N—[(1-methylpyrrolidin-2—yl)methoxy]oxo-6—(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide ’ (28,5R)—N—[(1-acety|pyrrolidin-2—yl)methoxy]oxo(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane-Z-carboxamide 808O (28,5R)-N—[(1-carbamoy|pyrroIidin-Z-yl)methoxy]oxo-6—(suIfooxy)-1 ,6- icyclo[3.2.1]octane—2—carboxamide )oxo-N-[(1—suIfamoylpyrrolidinyl)methoxy]-6—(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (2 S,5R)-N—[(1 -carbamimidoylpyrrolidin—2-yl)methoxy]oxo-6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—Z-carboxamide (28,5R)-N—[(1—methyl-1H—pyrazo|y|)methoxy]oxo—6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (28,5R)-N-[(1-methyl-1H-imidazoI-2—yl)methoxy]oxo(suIfooxy)-1 ,6- 1O diazabicyclo[3.2.1]octanecarboxamide (2S,5R)-N—[(1-methyI-4,5,6,7-tetrahydro-1H—4,7-methanoindazoIyl)methoxy]oxo (sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarboxamide (2S,5R)-N-[(1,8-dimethyI-4,5,6,7-tetrahydro-1H—4,7-epiminoindazolyl)methoxy]-7—oxo- fooxy)-1,6-diazabicyclo[3.2.1]octane—2-carboxamide (2S,5R)—N—(1H-benzimidazoI-2—ylmethoxy)oxo—‘6-(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (2S,5R)-N-(2,3-dihydro-1H—indolylmethoxy)oxo-6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (2S,5R)-N-[(2—methyl-1H-imidazoIyl)methoxy]oxo(suIfooxy)-1 ,6— diazabicyclo[3.2.1]octanecarboxamide (2S,5R)—N-[(1-methy|—1H-imidazoIyl)methoxy]oxo(suIfooxy)-1 ,6— diazabicyclo[3.2.1]octane—Z-carboxamide (2S,5R)-N-[(1-methy|-1H-imidazolyl)methoxy]oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (28,5R)—N-[(2—amino-1,3-thiazolyl)methoxy]oxo-6—(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (28,5R)—N-(1,3-oxazolylmethoxy)bxo(su|fooxy)—1,6-diazabicyclo[3.2.1]octane-2— carboxamide (2 S,5R)oxo(su|fooxy)—N-(1 ,3-thiazoI—4—ylmethoxy)-1 ,6-diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)-N-[(1-methy|—1H—1,2,3-triazoIyl)methoxy]—7—oxo-6—(sulfooxy)-1,6- diazabicyclo[3.2.1]octane-2—carboxamide 8181 (28,5R)—N-(1H—imidazoIyImethoxy)—7-oxo—6-(su|fooxy)-1,6-diazabicyclo[3.2.1]octane—2- carboxamide )-N-[2-(1H-imidazo|yl)ethoxy]oxo(suIfooxy)—1 zabicyclo[3.2.1]octane- 2-carboxamide (28,5R)—N-[1-(1H—imidazo|yl)ethoxy]oxo(suIfooXy)-1,6—diazabic‘yclo[3.2.1]octane- 2—carboxamide (28,5R)—N-[(1-methyl-1H-pyrroI—2-yl)methoxy]oxo(su|fooxy)—1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)-N-(1,2—oxazolylmethoxy)oxo-6—(sulfooxy)-1 ,6.-diazabicyc|o[3.2.1]octane—2- 1O carboxamide (2S,5R)oxo(su|fooxy)-N-(1H—1,2,4-triazoIylmethoxy)-1 ,6— diazabicyclo[3.2.1]octane—2-carboxamide (2S,5R)-N-[(5-methylpyraziny|)metthy]oxo(su|fooxy)—1,6- diazabicyclo[3.2.1]octane—Z-carboxamide (2S,5R)—N—[(2-aminocyclopropyl)oxy]oxo(suIfooxy)-1,6-diazabicyclo[3.2.1]octane . carboxamide (28,5R)-N-(morpholinylmethoxy)oxo(su|fooxy)-1 ,6-diazabicyclo[3.2.1]octane—2- carboxamide (28,5R)-N—[2—(azetidinyloxy)ethoxy]-7—oxo-6—(sulfooxy)-1,6-diazabicyclo[3.2.1]octane- 2-carboxamide (28,5R)oxo—N-[2—(pyrroIidinyloxy)ethoxy](su|fooxy)-1 ,6-diazabicyc|o[3.2.1]octéne— 2-carboxamide )—7-oxo-N-[2—(piperidinyloxy)ethoxy](sulfooxy)-1,6-diazabicyclo[3.2.1]octane- 2-carboxamide (2S,5R)-N-methyloxo(sulfooxy)-1,6-diazabicyc|o[3.2.1]octane—2-carbohydrazide (2S,5R)-N-ethyloxo(suIfooxy)—1,6—diazabicyclo[3.2.1]octane—2-carbohydrazide (2S,5R)oxo—N-(propany|)(sulfooxy)-1,6-diazabicyc|o[3.2.1]octane-Z- carbohydrazide (28,5R)—N,N-dimethyI-7—oxo(sulfooxy)—1,6-diazabicyc|o[3.2.1]octane—2— 3O carbohydrazide (28,5R)—N,N-diethy1oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane-Z-carbohydrazidé 8282 (28,5R)oxo-N‘,N'-di(propan-2—y!)(sulfooxy)-1,6—diazabicyclo[3.2.1]octane-Z- carbohydrazide (28,5R)-N'-cyclopropyloxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2- carbohydrazide )-N'—cyclobutyloxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-Z-carbohydrazide (28,5R)-N‘-cyc|opentyIoxo(su1fooxy)-1,6-diazabicyc|o[3.2.1]octane—2— carbohydrazide (28,5R)oxo—N'-(piperidin-4—yl)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide ' (28,5R)oxo-6—(sulfooxy)-N‘—(tetrahydro-2H—pyrany|)-1,6—diazabicyc|o[3.2.1]octane—2- carbohydrazide (28,5R)-7—oxo—6-(sulfooxy)-N-(tetrahydro-2H—thiopyran-4—yl)-1 ,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide (28,5R)oxo-N‘-(piperidin-3—yI)(suIfooxy)-1,6-diazabicyc|o[3.2.1]octane carbohydrazide (28,5R)oxo-N—(pyrro|idinyI)-6—(su|fooxy)-1,6-diazabicyclo[3.2.1]octane-Z- carbohydrazide (28,5R)-N‘-(1,1-dioxidotetrahydro-2H—thiopyran-4—yl)oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide (28,5R)-N-acetyloxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—Z-carbohydrazide (28,5R)oxo-N-propanoyl(sulfooxy)-1,6—diazabicyclo[3.2.1]octane-Z-carbohydrazide )-N-(2-methylpropanoyI)—7-oxo(sulfooxy)-1,6-diazabicyc|o[3.2.1]octane—2- carbohydrazide (2S,5R)-N-acetyI—N-methyl-7—oxo(sulfooxy)—1,6—diazabicyclo[3.2.1]octane ydrazide (2S,5R)-N'—methyl-7—oxo-N'-propanoyI(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (28,5R)-N'-methyl—N-(Z-methyIpropanoyl)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide (2S,5R)-N‘-acetyI-N'-ethyI-7—oxo(sulfooxy)—1,6-diazabicyclo[3.2.1]octane carbohydrazide 8383 (28,5R)-N'-ethyloxo-N'-propanoyl-G-(sulfooxy)—1,6-diazabicyclo[3.2.1]octane—2— carbohydrazide (28,5R)-N'—(2,2—dimethylpropanoyl)oxo(sulfooxy)—1,6-diazabicyclo[3.2.1]octane-Z- ydrazide (28,5R)-N'-butanoyI—7-oxo(sulfooxy)—1,6-diazabicyclo[3.2.1]octane—Z-carbohydrazide (28,5R)—N'—(2-methylbutanoyl)—7-oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane carbohydrazide (28,5R)—N'-[(dimethy|amino)acety|]oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2- carbohydrazide 1O (28,5R)oxo—6-(su|fooxy)-N-(4,4,4-trifluoropropanoyl)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (28,5R)-N'-(methoxyacetyl)—7—oxo(sulfooxy)—1,6-diazabicyclo[3.2.1]octane-2— carbohydrazide (28,5R)—N'-[(2R)aminopropanoyl]oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—Z- carbohydrazide (non-preferred name) (28,5R)-N'-[amino(phenyl)acetyl]—7-oxo(sulfooxy)—1,6-diazabicyc|o[3.2.1]octane ydrazide (2S,5R)—N'-(cyclopropylcarbonyl)-7—oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2— carbohydrazide )-N'-(cyc|obutylcarbonyI)oxo—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (28,5R)—N'-[(2,2-dimethylcyclopropyl)carbonyl]-7—oxo(sulfooxy)-1 ,6— diazabicyclo[3.2.1]octane-Z—carbohydrazide (2 S,5R)—N'-[(2-methylcyclopropyl)carbonyl]oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—Z-carbohydrazide (28,5R)—N'-[(2,2-difluorocyclopropyl)carbonyl]oxo(sulfooxy)-1 ,6- diazabicyc|o[3.2.1]octane—2-carbohydrazide (28,5R)—N'-[(2-fluorocyclopropyl)carbonyI]oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide 3O (28,5R)-N'-(cyclopentylcarbony1)oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octéne carbohydrazide 8484 (2S,5R)—N‘-(cyclohexylcarbonyI)oxo(suIfooxy)—1,6-diazabicyclo[3.2.1]octane—2— carbohydrazide (28,5R)-N‘-{[(2R)aminocyclopentyl]carbonyI}oxo(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carbohydrazide (28, 5R)—7-oxo-N‘-(pyrrolidinylcarbonyI)(suIfooxy)-1 ,6-diazabicyclo[3.2. 1 ]octane—2— carbohydrazide (2S,5R)oxo-N‘-(pyrrolidinylcarbony|)—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2— carbohydrazide (28,5R)oxo-N‘-(piperidin—2—ylcarbonyI)(sulfooxy)—1,6-diazabicyclo[3.2.1]octane—2— 1O carbohydrazide (28,5R)-N'-methy|oxo-N'—(pyrro|idiny|carbonyI)(su|fooxy)-1 ,6- diazabicyclo[3.2.1]octane—Z-carbohydrazide (28,5R)oxo-N‘-(piperidinylcarbonyl)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2— carbohydrazide (2S,5R)-7—oxo-N‘-(piperidinylcarbonyl)(suIfooxy)-1,6—diazabicyc|o[3.2.1]octane—2- carbohydrazide (28,5R)—7-oxo(su|fooxy)-N'-(tetrahydro-2H—pyran-4—ylcarbony|)-1 ,6- diazabicyclo[3.2.1]octane—2—carbohydrazide (2 N‘-[(1-methy|pyrrolidin-2—yl)carbonyl]—7-oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carbohydrazide (28,5R)4N'-[(1—methylpiperidinyl)carbonyI]oxo(sulfooxy)-1,6- diazabicyc|o[3.2.1]octane-Z—carbohydrazide (28,5R)—7-oxo(sulfooxy)-N-(tetrahydro-2H-thiopyran—4-ylcarbonyI)-1 ,6- icyclo[3.2.1]octane-Z-carbohydrazide (28,5R)-N‘-[(1,1-dioxidotetrahydro-2H—thiopyranyl)carbonyI]oxo-6—(suIfooxy)-1,6- diazabicyclo[3.2.1]octane—Z-carbohydrazide (28,5R)oxo-N‘-(pyrrolidinylacetyl)(sulfooxy)-1 zabicyclo[3.2.1]octane-2— carbohydrazide (28,5R)-7—oxo-N‘—(pyrrolidinylacetyI)-6—(su|fooxy)-1,6—diazabicyc|o[3.2.1]octane—2- 3O carbohydrazide (28,5R)-N‘-[(1-methy|pyrro|idiny|)acety|]oxo-6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide 8585 (2S,5R)—N‘-(cyc|opropylacetyI)oxo(su|fooxy)-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide (2S,5R)oxo-N'-(piperidinylacetyI)(su|fooxy)-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide (28,5R)-N‘-[(1—methylpiperidinyl)acetyI]oxo(sulfooxy)-1 ,6— diazabicyc|o[3.2.1]octane—Z—carbohydrazide (28,5R)-7—oxo-N‘-(piperidin-3—ylacetyI)(su|fooxy)-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide (2S,5R)—7-oxo-N'-(piperidiny|acetyI)(su|fooxy)-1,6-diazabicyclo[3.2.1]octane—2— ydrazide (28,5R)-N‘-[(1-methy|piperidinyl)acetyl]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide (28,5R)oxo-l\l'-(pyrrolidiny|acety|)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (28,5R)—7-oxo-l\l'—(piperaziny|acetyI)(su|fooxy)-1,6-diazabicyc|o[3.2.1]octane—2- carbohydrazide (28,5R)-N'-(morpholinylacetyl)oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z- carbohydrazide (28,5R)oxo—l\l'—(phenylcarbonyl)(sulfooxy)-1,6—diazabicyclo[3.2.1]octane-2— carbohydrazide (28,5R)-N'-(naphthalenylcarbonyl)—7-oxo-6—(suIfooxy)-1,6-diazabicyclo[3.2.1]octane-Z- carbohydrazide )-l\l'-methy|ono-N'-(phenylcarbonyl)(sulfooxy)-1,6-diazabicyc|o[3.2.1]octane- 2-carbohydrazide (28,5R)-N'-ethyIoxo-N'-(phenylcarbonyl)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide (28,5R)oxo-N'-(phenylacetyl)(sulfooxy)—1,6-diazabicyclo[3.2.1]octane ydrazide (28,5R)-N‘-(naphthalenylacetyl)oxo(suIfooxy)-1,6-diazabicyclo[3.2.1]octane-Z- 3O carbohydrazide (28,5R)-N'-methyl-7—oxo-N'—(phenylacetyI)-6—(su|fooxy)-1aB-diazabicyclo[3.2.1]octane carbohydrazide 8686 (28,5R)-N'-ethyIoxo-N-(phenylacetyl)-6—(sulfooxy)—1,6—diazabicyc|o[3.2.1]octane—2— carbohydrazide (2S,5R)oxo-N'-(pyridin-2—ylcarbonyI)(sulfooxy)-1,6—diazabicyclo[3.2.1]octane-2— carbohydrazide (28,5R)-7—oxo—N'-(pyridinylcarbonyl)(su|fooxy)-1,6—diazabicyclo[3.2.1]octane—2- carbohydrazide (2S,5R)oxo-N'-(pyridinylcarbonyl)-6—(sulfooxy)—1,6-diazabicyclo[3.2.1]octane—2— carbohydrazide (28,5R)oxo-6—(su|fooxy)-N'—(thiophenylcarbonyl)-1,6—diazabicyclo[3.2.1]octane—Z- ydrazide (28,5R)-N-(furany|carbony|)oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]octane-2— carbohydrazide (28,5R)oxo(sulfooxy)—N—(thiophen—2-ylcarbony|)—1,6-diazabicyclo[3.2.1]octane—Z- carbohydrazide (2S,5R)-N-(furanylcarbonyl)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2— ydrazide (28,5R)—N-methy|—7-oxo-N'-(pyridiny|carbonyl)—6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide (28,5R)oxo-N'-(1H-pyrro|-2—ylacety|)(su|fooxy)-1,6-diazabicyclo[3.2.1]octane-2— carbohydrazide (2S,5R)oxo(su|fooxy)-N—(thiophenylacetyl)-1,6-diazabicyclo[3.2.1]octane—Z- carbohydrazide (28,5R)-N—[(2—amino-1,3-thiazolyl)carbonyl]—7-oxo—6—(sulfooxy)-1,6- diazabicyc|o[3.2.1]octane-Z-carbohydrazide )—N-(furan-2—ylacetyI)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide » (28,5R)—7-oxo-N-(pyridin-2—ylacetyl)(sulfooxy)—1,6-diazabicyclo[3.2.1]octane—2— carbohydrazide (2 S,5R)-7—oxo-N-(pyridinylacetyI)—6-(sulf_ooxy)-1 ,6—diazabicyclo[3.2.1]octane—2- 3O carbohydrazide (2S,5R)—7-oxo—N—(pyridinylacetyl)(sulfooxy)—1,6—diazabicyclo[3.2.1]octane-Z- carbohydrazide 8787 (28,5R)-N'—[(2—amino-1,3-thiazoIyl)acetyl]oxo-6—(sulfooxy)—1 ,6- diazabicyc|o[3.2.1]octane—Z-carbohydrazide (28,5R)-N'—[(2—amino-1,3-thiazoIyl)acetyI]-N-methyloxo-6—(suIfooxy)-1,6— diazabicyclo[3.2.1]octane—Z-carbohydrazide (28,5R)-N'—methy|-7—oxo-N'-(pyridinylacetyI)(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—Z-carbohydrazide (28,5R)oxo-6—(suIfooxy)-N-(trifluoroacety|)-1,6—diazabicyclo[3.2.1]octane carbohydrazide (28,5R)-N'-(methylsuIfony|)—7-oxo(sulfodxy)-1,6-diazabicyclo[3.2.1]octane-2— 1O carbohydrazide 2-{[(28,5R)oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2,1]oct bonyl}hydrazinecarboxamide 2-{[(28,5R)oxo-6—(su|fooxy)-1,6—diazabicyclo[3.2.1]oct-2— yl]carbonyl}hydrazinesulfonamide (28,5R)—7-oxo-N-phenyl(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—Z-carbohydrazide (28,5R)-N'-methyloxo-N-phenyl-6—(suIfooxy)—1,6—diazabicyclo[3.2.1]octane carbohydrazide (28, 5R)—7—oxo-N'—(pyridinyl)-6—(sulfooxy)-1 ,6—diazabicyclo[3.2. 1 ]octane—Z- ydrazide (28,5R)—I\I'-methyIoxo-N'-(pyridinyl)(suIfodxy)-1,6—diazabicyclo[3.2.1]octane-Z- carbohydrazide (28,5R)oxo-N-(piperidiny|)—6—(su|fooxy)-1,6—diazabicyclo[3.2.1]octane—2- carboxamide (28,5R)oxo-N—(pyrrolidinyl)(su|fooxy)—1,6—diazabicyclo[3.2.1]octane-Z- carboxamide (28,5R)-N—(morpholinyl)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2- carboxamide (28,5R)oxo-N-(piperazinyl)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane , carboxamide 3O (28,5R)ox_o-6—(sulfooxy)—N-(thiomorpholinyl)—1,6—diazabicyclo[3.2.1]octane—2- carboxamide 8888 (28,5R)—N—(1,1-dioxid0thiomorpholinyl)oxo-6—(sulfooxy)-1,6- diazabicyclo[3.2.1]octane—2-carboxamide (2S,5R)—7-oxo-N-(2-oxopiperidinyl)—6-(sulfony)-1 ,6—diazabicyclo[3.2.1]octane—2- carboxamide (28,5R)oxo-N-(3-oxomorpholin—4-yl)—6-(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2- carboxamide (28, 5R)oxo-N-(2—oxopiperazin-1 -yl)(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2- carboxamide ‘ (28, 5R)oxo(sulfooxy)-N-(tetrahydropyrimidin-1 (2H)-y|)—1 ,6- diazabicyclo[3.2.1]octane-Z-carboxamide (2S,5R)oxo-N-(2-oxotetrahydropyrimidin-1(2H)—yl)(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (28,5R)-N-(3-aminopiperidinyl)—7—oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2— carboxamide (28, 5R)-N'-[(2-aminocyclopropyl)carbony|]oxo(sulfooxy)-1 ,6— diazabicyclo[3.2.1]octane—2—carbohydrazide (28,5R)-N'-[(2-aminocyclopropyl)carbonyl]-N'-methyl—7-oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide (2S, 5R)—N'—(azetidinylcarbony|)—7-oxo(su|fooxy)—1 ,6-diazabicyclo[3.2.1]octane carbohydrazide (28, 5R)-N'-(azetidinylcarbonyl)oxo(su|fooxy)—1 ,6-diazabicyclo[3.2. 1 ]octane—2- carbohydrazide )—N'—[(28)—2-aminopropanoyI]oxo(suIfooxy)-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide (28, 5R)-N'—[(28)-2—aminopropanoyl]-N‘-methy|oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—Z-carbohydrazide )-l\l‘-[3-(dimethylamino)propanoyI]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane—Z-carbohydrazide (28,5R)-N'—[(3,3-difluorocyclobutyl)carbonyl]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide (28,5R)-N'-[(3—aminocyclobutyl)carbony|]oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide 8989 (2S,5R)-N‘-{[3-(methylamino)cyclobutyl]carbonyl}-7—oxo(sulfooxy)—1 ,6— diazabicyclo[3.2.1]octanecarbohydrazide (28,5R)—N‘-{[3-(dimethylamino)cyclobutyl]carbonyl}—7-oxo-6—(sulfooxy)—1 ,6— diazabicyclo[3.2.1]octane—2-carbohydrazide The compounds of the present invention of formula (l, when Y = 0R1) can be readily prepared by the following reaction Scheme 2 and examples using y available starting materials, reagents and conventional synthesis procedures known to those of ry skill in this art. The methods differ according to the kind of substituted hydroxylamines of general formula (V) used to prepare the bicyclic diazaoctane derivatives. The ic intermediate acid (Vl) may be prepared following the patent literature .

Compounds of general a (I, Y = 0R1, M = H) can be prepared by coupling an appropriately substituted hydroxylamine (V) with the bicyclic acid (VI) in presence of a suitable coupling reagent to give the desired intermediate (VII). The coupling reagents useful for carrying out this step include, but are not limited to, EDCI, HOBT-DCC, HATU, HOBT, PyBop and the like. The organic solvents useful in the reaction are notparticularly limited and include any of those which do not adversely affect the coupling reaction. Typical ts include DCM, chloroform, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, dimethylsulfoxide, itrile, and the like. The on is ly d Out at a temperature of from about 0 °C to about 30 °C and preferably at room temperature under nitrogen. After completion of the reaction the desired t can be easily separated by conventional methods such as column chromatography, crystallization or similar methods.

In the following step, the intermediate (VII) could be converted to compound (Vlll) under an atmosphere of hydrogen or hydrogen mixed with an inert diluent such as nitrogen or argon in the presence of a hydrogenation catalyst. The catalysts used in this hydrogenation reaction are the type of agents known in the art for this kind of deprotection and l examples are the noble metals, such as nickel, palladium, platinum and rhodium. Examples of the catalysts are platinum, platinum oxide, palladium, palladium oxide and the like. The catalyst is usually present in the amount from about 1 to about 50 weight percent and ably from about 5 3O to about 10 weight percent based on the compound of formula (l). It is often convenient to suspend the catalyst on an inert support. A particularly convenient catalyst is palladium suspended on an inert support such as carbon, e.g 10 % by weight palladium on carbon.

This reaction may be conveniently effected at ambient temperature at 40 psi until reaction is complete (2 to 12 hours). Suitable solvents for this reaction are those which substantially dissolve the starting al of the formula (Vll), are sufficiently volatile to be d by evaporation and do not themselves suffer hydrogenation. Examples of such ts include 9090 methanol, ethanol, dioxane, ethyl e, tetrahydrofuran or a mixture of these solvents.

Upon completion, the hydroxy intermediate (VIll) can be ed by silica gel column chromatography or in many cases can be directly carried out to the next step without further purification.

Sulfation of the intermediate (Vlll) can be achieved using a sulfating reagent (e.g., pyridine- 803 x, ClSOaH and DMF-SOS complex) in an appropriate solvent (e.g., pyridine or 2- ne), e.g., as described in the literature (US 4337197 A1, J. Am. Chem. 800., 1982, 104, 060). Thus, SOs-Py complex can be added to a solution of the ediate (Vlll) in a solvent in excess amount, if d, to force the reaction to completion. The organic 1O solvents useful for this transformation are not particularly limited and include those which do not adversely affect the on. Typical solvents include, but not limited to, pyridine, yl formamide, dimethylacetamide, itrile, DCM, and the like. The transformation can be carried out at from 10 °C to 40 °C, and more preferably at room temperature. The. product (IX) can be isolated by standard procedure that is by filtering the reaction mixture, concentrating the filtrate, suspending the concentrate in a saturated aqueous potassium dihydrogenphosphate on, g the aqueous layer with ethyl acetate, adding excess amount of tetrabutylammonium en sulfate to the aqueous layer, extracting the mixture with organic solvent, such as ethyl acetate, combining the organic layers, drying and concentrating to provide the tetrabutylammonium salt intermediate. ng the intermediate (IX) with an acid to obtain a compound of formula (la, M = H), wherein R1 has the same definition as in formula (I). Suitable organic acids include trifluoroacetic acid, methanesulfonic acid, oromethane sulfonic acid, and formic acid. The treatment is suitably conducted at a temperature in a range from about —10 °C to about 30 °C and is typically conducted at a temperature in a range of from about 0 °C to about 10 °C. _ The substituted hydroxylamines (V) used in the invention can be prepared by a two steps procedure using the methods well known in the art. Thus, the alcohol (II) is reacted with N- hydroxyphthalimide (III) in presence of PPh3 under Mitsunobu conditions to provide the intermediate (lV). Treating (IV) with hydrazine hydrate in presence of a solvent provides the desired substituted hydroxylamine (V) which can be used without further purification 3O (Scheme 1).

Similarly, compounds of general formula (I, Y = NR2R3, M = H) can be prepared by coupling an appropriately substituted hydrazine (Va) with the bicyclic acid (VI) in presence of a le coupling reagent to give the desired intermediate (Vlla). Utilizing the intermediate (Vlla) and carrying out similar sets of experiments as described for (la), the desired compounds (lb, M = H) of the present invention can be obtained as shown in Scheme 3. The 9191 substituted hydrazines (Va) used in the present invention can be ed from the commercial source or can be prepared by the known literature procedure.

Scheme1 O O R1-OH + N-OH —> N—Q1 ~’ O‘NH2 O 0 II III IV V Schemez B1 0 O an O \OBn V VI VII F51 0 i“ 0 I ‘I I, o I 0 9292 Scheme 3 0 OBn ' Va Vl Vila R2 o $2 0 3'? R3411 l, R3-N In“ R ‘N Examples In the examples, the following abbreviations have been used: Bn: benzyl Boc: N-tert—butoxycarbonyl br s: broad singlet CDCl3: deuterated chloroform CD3OD: deuterated methanol d: doublet D20: ium oxide DCC: N,N'-dicyclohexylcarbodiimide DCM: dichloromethane DlAD: diisopropyl azodicarboxylate DMAP: 4-dimethylaminopyridine 9393 EDCI: 1-(3—dimethylamino—propyl)ethylcarbodiimide hydrochloride El: electron impact ES: electron spray FAB: fast atom bombardment g: gram(s) h: hour(s) HOBT: N-hydroxybenzotriazole HATU: 2-(7-aza-1H—benzotriazol—l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HPLC: erformance liquid chromatography Hz: Hertz J: coupling constant m: multiplet mL: milliliter(s) mmol: millimole(s) MHz: rtz MS: mass spectrometry m/z: mass—to-charge ratio NMR: nuclear magnetic resonance Pd/C: palladium on carbon PyBop: (benzotriazol-1—yloxy)tripyrrolidinophosphonium hexafluorophosphate s: singlet t: triplet 9494 TFA: trifluoroacetic acid THF: tertrahydrofuran : chemical shift in parts per million (ppm) by frequency Example 1 (28,5R)Oxo-N-[(3R)-pyrroli_diny|oxy](sulfooxy)-1,6-diazabicyc|o[3.2.1]octane carboxamide (Compound 1, Table 1) (.0. 41,, )—-N 0 bSO3H Step 1. tert-Butyl (3R)[({[(ZS,5R)(benzyloxy)—7-oxo-1,6- diazabicyclo[3.2.1.]octyl]carbonyl}amino)oxy]pyrrolidinecarboxylate (3) X0Si 0 O ”\O . )1“ N ‘NH2 Ho Q 2“: \“O‘N/Hl’u B°°‘“C/ H N Cl 0%!“an )——N 0 can 1 3 To a solution of (28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.15 g, 0.54 mmol) in dry DCM (20 mL) were added tert—butyl (3R) (aminooxy)pyrrolidine-1—carboxylate 2 (0.17 g, 0.81 mmol, J. Med. Chem. 2008, 51, 4601- 4608), 1-hydroxybenzotriazole (0.11 g, 0.81 mmol) and 1-ethyl-(3— dimethylaminopropyl)carbodiimide hydrochloride (0.16 g, 0.81 mmol) at room temperature.

The reaction e was stirred at room temperature overnight, and then trated under . The residue was ed by column chromatography to give compound tert- butyl (3R)-3—[({[(2S,5R)-6—(benzyloxy)-7—oxo-1 ,6-diazabicyc|o[3.2.1]oct 2O yl]carbonyl}amino)oxy]pyrrolidine—1-carboxylate 3 (0.23 g, 93%) as a clear thick oil. 1H NMR (400 MHZ, CDCI3): 5 1.26 (9H, s), 1.62 (1H, m), 1.96 (3H, m), 2.17 (1H, m), 2.28 (1H, m), 2.75 (1H, d, J = 11.6 Hz), 3.01 (1H, d, J = 12.0 Hz), 3.31-3.66 (5H, m), 3.96 (1H, m), 4.64 (1H, m), 4.89 (1H, d, J = 11.2 Hz), 5.04 (1H, d, J =11.6 Hz), 7.41 (5H, m), 9.16 (1H, br S). 9595 Step 2. tert-Butyl (3R)—3-[({[(2$,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]pyrrolidine—1 -carboxylate (4) 0 ,U, WON/U“- Boo—NS“ H O Boc—N _—_> H O A )—N N\ O ‘OH O OBn 3 4 To a solution of tert—butyl -[({[(2S,5R)(benzyloxy)-7—oxo-1,6-diazabicyclo[3.2.1]oct-2— yl]carbonyl}amino)oxy]pyrrolidinecarboxylate 3 (0. 23 g, 050 mmol) in methanol (15 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The st was ed out through Celite, and the filtrate was evaporated to give tert-butyl (3R)[({[(2S,5R)hydroxyoxo-1,6—diazabicyclo[3.2.1]oct 1O yl]carbonyl}amino)oxy]pyrrolidinecarboxylate 4 (0.18 g, 93%) as a colorless foam. 1H NMR (400 MHZ, CD3OD): 5 1.43 (9H, s), 1.68-2.09 (4H, m), 2.20 (2H, m), 3.03 (1H, d, J = 12.0 HZ), 3.20 (3H, m), 3.60 (1H, d, J =12.0 Hz), 3.70 (1H,. s), 3.86 (1H, d, J = 7.2 Hz), 4.60 (1H, m), 2 protons were not observed in CD30D.

Step 3. tert-Butyl (3R)[({[(28,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct- 2-yl]carbonyl}amino)oxy]pyrrolidinecarboxylate pyridine salt (5) o o \\.o\ J,“ \“O‘N’U” Boo—NO Q Q Boc—N H O a—N. 0 OH OH b803H' Pyridine 4 5 To a solution of tert—butyl (3R)[({[(2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct—2— bonyl}amino)oxy]pyrrolidinecarboxylate 4 (0.18 g, 0.486 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.31 g, 1.94 mmol).

The mixture was stirred at room temperature for 20 h, filtered and evaporated to give tert- butyl (3R)[({[(28,5R)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octyl]carbonyl}amino)- rrolidinecarboxylate pyridine salt 5 (0.22 g crude) which was used in the next step without purification. 9696 Step 4. N,N,N-Tributylbutanaminium ({[(2$,5R)({[(3R)(tert- butoxycarbonyl)pyrrolidinyl]oxy}carbamoyl)oxo-1,6-diazabicyclo[3.2.1]oct-G- }sulfonyl)oxidanide (6) Q J,“ \,.o. /U//,, Boc~NQ\ H Q BOG—NO I2 —————————> N Q )—-N o) N O bso3H - Pyridine oso3- BU4N+ tert—Butyl (3R)—3—[({[(2S,5R)oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octyl]carbonyl}- amino)oxy]pyrrolidinecarboxylate pyridine salt 5 (0.22 g, 0.48 mmol) was introduced into a concentrated aqueous solution of monosodium dihydrogen phosphate solution (7 mL) so as to obtain a pH of 4. The e was washed with ethyl acetate, then added tetrabutyl 1O ammonium hydrogen sulfate (0.10 g, 0.30 mmol) and d at room temperature for 10 min.

The mixture was extracted with ethyl acetate (3 x 10 mL), and the extracts were combined, dried over sodium sulfate and evaporated to give N,N,N-tributylbutanaminium ({[(28,5R)— 2-({[(3R)-1—(tert-butoxycarbonyl)pyrrolidinyl]oxy}carbamoyl)oxo-1,6-diazabicyclo[3.2.1]- octyl]oxy}sulfonyl)oxidanide 6 (0.245 g, 80%) as a white solid. 1H NMR (400 MHz, CDClg): 5 1.00 (12H, t, J = 7.2 Hz), 1.43 (17H, m), 1.65 (8H, m), 1.90 (3H, m), 2.18 (2H, m), 2.34 (1H, m), 2.82 (1 H, d, J =12 Hz), 3.28 (8H, m), 3.30-3.66 (5H, m), 3.94 (1H, d, J = 7.6 Hz), 4.35 (1H, m), 4.66 (1 H, s), 9.17 (1H, br 5).

Step 5. (2S,5R)0xo-N-[(3R)-pyrrolidinyloxy](sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 1, Table 1) 0 j) WOW)l/ HNQ\“0‘ ll'» Boc—N H H ‘——_“’ N %N H‘ \ o 0 0803- BU4N+ 0803H nd 1, Table 1 2O 6 To a solution of N,N,N-tributylbutan—1-aminium ({[(2S,5R)({[(3R)(teIt- butoxycarbonyl)pyrrolidin-3—yl]oxy}carbamoyl)oxo-1 zabicyclo[3.2.1]oct-6— yl]oxy}sulfonyl)oxidanide 6 (0.245 g, 0.35 mmol) in DCM (14 mL) was added trifluoroacetic acid (0.70 mL, 9.08 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white itate was collected by centrifugation. The solid was triturated with acetonitrile (2 x) and the white solid was 9797 collected by centrifugation. The white solid was purified by HPLC on a prep-X Bridge-19 x 250 mm column and freeze-dried to give (28,5R)oxo-N—[(3R)-pyrrolidin—3-yloxy] oxy)-1,6-diazabicyclo[3.2.1]octanecarboxamide Compound 1 (Table 1) (0.03 g, %) as a white solid. 1H NMR (400 MHz, D20):51.73(1H, m), 1.87 (1H, m), 1.95-2.13 (3H, m), 2.16-2.40 (2H, m), 2.99 (1H, d, J = 12.4 Hz), 3.19 (1H, d, J = 11.6 Hz), 3.26—3.90 (3H, m), 3.46 (1H, d, J = 13.2 Hz). 3.96 (1H, d, J = 7.2 Hz), 4.08 (1H, s), 3 protons were not observed in D20.

HPLC: 97.24 % MS (ES'): m/z: [M]'= 348.89 1O Example 2 (ZS,5R)Oxo-N-[(3S)-pyrrolidinyloxy](sulfooxy)—1,6-diazabicyclo[3.2.1]octane carboxamide (Compound 2, Table 1) 0. fl),, N '.

HNCl’ H O //‘—N O ‘oso3H Step 1. ‘ tert-Butyl -[({[(28,5R)(benzyloxy)oxo-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]pyrrolidinecarboxylate (8) HO Q 7 Boo—NO) H QN O: N‘ O Nan 1 8 To a mixture of (2S,5R)—6-(benzyloxy)oxo—1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (4.0 mL) were added tert-butyl (3S) (aminooxy)pyrrolidinecarboxy|ate 7 (0.164 g, 0.814 mmol, A1), 1- ybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was d at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 8 (0.22 g, 88 %) as a white foam. 9898 'H NMR (400 MHz, 00013): 6 1.46 (9H, s), 1.61 (1H, m), 1.93 (3H, m), 2.17 (1H, m), 2.30 (1H, m), 2.72 (1H, d, J = 11.6 Hz), 2.99 (1H, m), 3.45 (5H, m), 3.99 (1H, m), 4.60 (1H, m), 4.92 (1H,d,J=11.6 Hz), 5.04 (1H, d, J: 11.6 Hz), 7.42 (5H, m), 9.00 (1H. brs).

MS (ES‘) m/z: [M—H]' calcd for C23H31N406: 459.22. Found: 459.08.

Step 2. tert-Butyl (3S)[({[(2$,5R)hydroxyoxo-1,6-diazabicyclo [3.2.1]oct yl]carbony|}amino)oxy]pyrrolidinecarboxylate (9) O ' JL, O‘N /u 0.

Boo—NO, ['3 Q 300 Nd_ ___. H a }—N. N‘ o OH O OBn 8 9 A mixture of tert-butyl (3S)[({[(28,5R)-6—(benzyloxy)oxo-1,6-diazabicyclo[3.2.1] oct yl]carbony|}amino)oxy]pyrrolidinecarboxylate 8 (0.22 g, 0.48 mmol) and Pd/C (0.070 g) in methanol (10 mL) was enated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 9 (0.19 g, quant. yield) as a light yellow foam. 1H NMR (400 MHz, CD30D): 5 1.46 (9H, m), 1.75-2.20 (6H, m), 3.03 (1H, d, J = 11.6 Hz), 3.17 (1H, m), 3.44 (3H, m), 3.63 (1H, d, J: 13.2 Hz), 3.69 (1H, m), 3.86 (1H, d, J = 7.2 Hz), 4.58 (1 H, t, J = 3.6 Hz). 2 protons were not observed in CDSOD.

MS (ES'): m/z [M-H]' calcd for C16H25N406: 369.18. Found: 369.06.

Step 3. utyl (3S)[({[(ZS,5R)oxo(sulfooxy)-1,6-diazabicyclo [3.2.1] octy|]carbonyl}amino)oxy]pyrro|idinecarboxylate (10) 6N4...‘1 o. JIM, Boc—Ncm 0 N BOO—N ———» H o )——N 0 ‘0H 0%“bSO3H 9 10 To a mixture of tert—butyl (3S)[({[(28,5R)—6-hydroxyoxo-1,6—diazabicyclo[3.2.1]oct—2- bony|}amino)oxy]pyrrolidinecarboxylate 9 (0.19 g, 0.51 mmol) in pyridine (7.0 mL) was added sulfur trioxide pyridine x (0.326 g, 2.05 mmol). The mixture was stirred at room temperature for 23 h and concentrated to provide a residue which was subjected to chromatography to give 10 (0.11 g, 48 %) as a white solid. 9999 1H NMR (400 MHz, CD3OD): 5 1.47 (9H, s), 1.80-2.20 (6H, m), 3.07 (1H, d, J = 12 Hz), 3.27 (1H, m), 3.44 (3H, m), 3.60 (1H, m), 3.92 (1H, d, J = 11.6 Hz), 4.14 (1H, m), 4.59 (1H, m). 2 protons were not observed in CD3OD.

MS (ES‘): m/z [M-H]‘ calcd for C16H25N4OQS: 449.13. Found: 448.99.

Step 4. (ZS,5R)Oxo-N-[(3S)-pyrrolidinyloxy](sulfooxy)-1,6- icyclo[3.2.1]octanecarboxamide (Compound 2, Table 1) O‘N/H’“ OW)”| F - HN H H O ____. N #N O3 N‘ Compound 2, Table 1 To a mixture of tert-butyl (3S)[({[(28,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2— bonyl}amino)oxy]pyrrolidinecarboxylate 10 (0.11 g, 0.24 mmol) in DCM (4.0 mL) was added trifluoroacetic acid (0.20 mL) at 0°C. The mixture was d at 0°C for 1 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 2 (Table 1)(30.4 mg, 36 %) as a white solid. lH NMR (400 MHz, D20): 51.74-183 (2H, m), 1.91-2.11 (3H, m), 2.18—2.22 (1H, m), 2.98 (1H, d, J = 12 Hz), 3.17 (1H, m), 3.27-3.34 (3H, m), 3.45 (1H, dd, J = 0.8 Hz, 13.6 Hz), 3.94 _ (1H, m), 4.06 (1H, m), 4.71 (1H, m). 3 protons were not observed in D20.

HPLC: 96.77 % MS (ES'): m/z [M-H]' calcd for C11H17N4O7S: 349.08. Found: 348.95.

Example 3 (ZS,5R)Oxo-N-[(3R)-piperidinyloxy](sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide (Compound 3, Table 1) 0\ flI], N " N .111 H 100100 Step 1. tert-Butyl (3R)[({[(2S,5R)(benzyloxy)oxo-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]piperidinecarboxylate (12) To a solution of (28.5R)-6—(benzy|oxy)oxo-1,6-diazabicyclo[3.2.1]octane-Z-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added tert—butyl (3R)—3- (aminooxy)piperidinecarboxylate 11 (0.19 g. 0.86 mmol, J. Med. Chem. 2008, 51, 4601- 4608), 1—hydroxybenzotriazole (0.14 g, 1.03 mmol) and l-(3- ylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.03 mmol) at room temperature.

The on mixture was stirred at room temperature overnight, and then concentrated 1O under vacuum. The residue was purified by column chromatography to give tert—butyl (3R)-3— [({[(2 S,5R)—6—(benzyloxy)oxo-1 ,6-diazabicyclo[3.2.1]oct bony|}amino)oxy]piperidinecarboxylate 12 (0.28 g, 82 %) as a white solid. 1H NMR (400 MHz, coma); 6 1.46 (9H, s), 1.61 (1H, m), 1.33 (2H, m), 2.01 (4H, m), 2.31 (1H, m), 2.79 (1H, d, J = 11.2 Hz), 2.99 (3H, m), 3.30 (1H, s), 3.60-4.11 (4H, m), 4.33 (1H, d, J = 11.6 Hz), 5.05 (1H, d, J = 11.6 Hz), 7.39 (5H, m), 9.96 (1H, br s).

Step 2. tert-Butyl (3R)[({[(2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidinecarboxylate (13) 0 J?ll, ‘ \N '- o\ ,, .H N ’1 III }____N\ /Bn N 800 o 0 12 13 To a solution of tert—butyl (3R)[({[(28,5R)(benzyloxy)oxo—1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidinecarboxylate 12 (0. 28 g, 0.59 mmol) in methanol (20 mL) was added 5% Pd/C (0.25 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the te was evaporated to give tert-butyl (3R)-3—[({[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidinecarboxylate 13 (0.21 g, 91%) as a white solid. 101101 1H NMR (400 MHz, CD30D): 8 1.45 (9H, s), 1.68-1.98 (6H, m), 2.05 (1H, m), 2.22 (1H, m), 3.03 (1H, d, J = 12.0 Hz), 3.13 (1H, d, J = 11.6 Hz), 3.28-3.59 (4H, m), 3.71 (1H, s), 3.87 (2H, m), 2 s were not observed in CD30D.

Step 3. tert-Butyl (3R)[({[(ZS,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct- arbonyl}amino)oxy]piperidinecarboxylate pyridine salt (14) o o “1‘ )—~\ “1‘ /,‘——N BOG O 8°C OH 0 \0803H.pyridlne To a on of terf-butyl (3R)[({[(28,5R)'hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidinecarboxylate 13 (0.21 g, 0.55 mmol) in dry pyridine (8 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.35 g, 2.20 mmol). 1O The mixture was stirred at room temperature for 20 h, filtered and evaporated to give tert- butyl (3R)[({[(28,5R)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidine-1—carboxylate pyridine salt 14 (0.30 g crude) which was used in the next step without purification.

Step 4. N,N,N-Tributylbutanaminium ({[(2$,5R)({[(3R)(tert- butoxycarbonyl)piperid_inyl]oxy}carbamoyl)—7-oxo-1,6-diazabicyclo[3.2.1]oct yl]oxy}sulfonyl)oxidanide (15) 0\ Jill, O I, >IIIH H N _____> N --"H N l l N 300 0 Boc \ ' 05031-1. pyridine o + oso3 Bu N4 14 15 ted-Butyl (3R)[({[(2S,5R)oxo(sulfooxy)—1 ,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidinecarboxylate pyridine salt 14 (0.30 g, 0.55 mmol) was introduced into a concentrated s solution of monosodium dihydrogen phosphate solution (8 mL) so as to obtain a pH of 4. The mixture was washed with ethyl acetate, then added tetrabutyl um hydrogen sulfate (0.117 g, 0.34 mmol) and stirred at room temperature for 10 min. The mixture was extracted with ethyl acetate (3 x 20 mL), and the extracts were combined, dried over sodium sulfate and evaporated to give. N,N,N- ylbutanaminium ({[(2S,5R)({[(3R)-1—(teI1-butoxycarbonyl)piperidin-3— 102102 yl]oxy}carbamoyl)oxo-1,6-diazabicyclo[3.2.1]oct—6-yl]oxy}sulfonyl)oxidanide 15 (0.3 g, 77%) as a white solid. 1H NMR (400 MHz, CDCI3): '6 0.98 (12H, t, J = 7.2 Hz), 1.42 (17H, m), 1.65 (8H, m), 1.77 (4H, m), 2.05 (3H, m), 2.33 (1H, m), 2.85 (1H, d, J = 11.6 Hz), 2.96 (2H, m), 3.24 (9H, m), 3.65 (1H, m), 3.95 (2H, m), 4.10 (1H, m), 4.13 (1H, s), 10.00,(1H, br s).

Step 5. (ZS,5R)Oxo-N-[(3R)-piperidinyloxy](sulfooxy)-1,6- diazabicyclo[3.2.1]octane-Z-carboxamide (Compound 3, Table 1) , O‘NJL,“ 0’011))“, O” H Q H O N )N—N . (N1 + //L—N Boc 0 bso3Bu4N o b803H ' compound 3, Table 1 To a solution of N, N, N-tributylbutan-1 -aminium ({[(28,5R)—2-({[(3R)—1-(ten‘- 1O carbonyl)piperidinyl]oxy}carbamoyl)oxo-1 ,6—diazabicyclo[3.2.1]oct yl]oxy}sulfonyl)oxidanide 15 (0.30 g, 0.42 mmol) in DCM (17 mL) was added trifluoroacetic acid (0.84 mL, 10.9 mmol) dropwise at 0 °C. The reaction e was d for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with itrile (2 x) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)oxo-N-[(3R)-piperidinyloxy](sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide Compound 3 (Table 1) (0.045 g, 29.41 %) as a white solid. 1H NMR (400 MHz, CD30D): 6 1.60-1.78 (3H, m), 1.80-2.08 (5H, m), 2.92-3.04 (2H, m), 3.14—3.26 (2H, m), 3.30 (1H, d, J = 13.2 Hz), 3.94—4.02 (2H, m), 4.08 (1H, d, s), 4.18 (1H, s), 3 protons were not observed in CD30D.

HPLC: 95.81 % MS (ES'): m/z: [M]‘= 363.02 103103 Example 4 (23,5R)Oxo-N—[(3S)—piperidin—3-yloxy](sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide (Compound 4, Table 1) N .....H Step 1. tert-Butyl (3S)[({[(ZS,5R)(benzyloxy)—7-oxo-1,6- diazabicyclo[3.2.1]oct—2-yl]carbonyl}amino)oxy]piperidinecarboxylate (17) To a solution of (2S,5R)(benzyloxy)-7—oxo-1,6—diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added ted-butyl — (aminooxy)piperidine-1—carboxylate 16 (0.19 g, 0.86 mmol,'J. Med. Chem. 2008, 51, 4601— 4608), 1-hydroxybenzotriazole (0.14 g, 1.03 mmol) and 1-ethyl-(3- dimethylaminopropyl)carbodiimide hloride (0.20 g, 1.03 mmol) at room temperature.

The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was ed by column chromatography to give ten-butyl (38) [({[(2 S,5R)(benzyloxy)oxo-1 ,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidinecarboxylate 17 (0.28 g, 82 %) as a white solid. 1H NMR (400 MHz, 00013): 8 1.46 (9H, s), 1.61 (1H, m), 1.83 (2H, m), 2.01 (4H, m), 2.31 (1H, m), 2.79 (1H, d, J = 11.2 Hz), 2.99 (3H, m), 3.30 (1H, s), 3.60-4.11 (4H, m), 4.88 (1H, d, J = 11.6 Hz), 5.05 (1H, d, J =11.6 Hz), 7.39 (5H, m), 9.96 (1H, br s). 104104 Step 2. tert-Butyl (3S)[({[(ZS,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct-Z- yl]carbonyl}amino)oxy]piperidinecarboxylate (18) O“\\O\m/UII"' O ‘\,\O\N/UI,," N ---HH _> O H N Bn N Q-HIH o \o/ l km 17 18 To a solution of teIf-butyl (3S)[({[(28,5R)-6—(benzyloxy)oxo-1,6—diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidine—1—carboxylate 17 (0. 28 g, 0.59 mml) in methanol (20 mL) was added 5 % Pd/C (0.25 g). The mixture was hydrogenated at 35 psi en atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give teIf-butyl (38)[({[(28,5R)-6—hydroxyoxo-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]piperidinecarboxylate 18 (0.22 g, 97 %) as a white solid. 1H NMR (400 MHz, CDCla): 5 1.45 (9H, s), .98 (6H, m), 2.05 (1H, m), 2.22 (1H, m), -3.03 (1H, d, J = 12.0 Hz), 3.13 (1 H, d, J = 11.6 Hz), 3.28-3.59 (4H, m), 3.71 (1H, s), 3.87 (2H, m), 2 protons were not observed in CD30D.

Step 3. tert-Butyl (3S)[({[(28,5R)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct- 2-yl]carbonyl}amino)oxy]piperidinecarboxy|ate pyridine salt (19) 0 OH 3°C 0 \OSO H . pyridine ‘8 3 To a solution of teIf-butyl (3S)[({[(28,5R)-6—hydroxyoxo-1,6—diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidinecarboxy|ate 18 (0.22 g, 0.57 mmol) in dry ne (8 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.40 g, 2.51 mmol).

The mixture was stirred at room temperature for 20 h, filtered and evaporated to give tert- butyl (3S)[({[(ZS,5R)oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidinecarboxylate pyridine salt 19 (0.23 g crude) which was used in the next step without purification. 105105 Step 4. N,N,N-Tributylbutanaminium ({[(ZS,5R)({[(3S)(tert- butoxycarbonyl)piperidinyl]oxy}carbamoyl)—7-oxo-1,6-diazabicyclo[3.2.1]oct yl]oxy}sulfonyl)oxidanide (20) ——‘-———> 11 IH . )4N O }——uulH//L—N\ 0303H" pyridine ‘ + 19 20 felt-Butyl (38)[({[(28,5R)oxo(sulfooxy)—1,6-diazabicyclo[3.2.1]oct-2— y|]carbonyl}amino)oxy]piperidinecarboxylate pyridine salt 19 (0.23 g, 0.42 mmol) was uced into a concentrated aqueous solution of monosodium dihydrogen phosphate solution(8 mL) so as to obtain a pH of 4. The mixture was washed With ethyl acetate, then added tetrabutyl ammonium hydrogen sulfate (0.088 g, 0.26 mmol) and stirred at room 1O temperature for 10 min. The mixture was extracted with ethyl acetate (3 x 20 mL), and the extracts were combined, dried over sodium sulfate and ated to give N,N,N- tributylbutanaminium ({[(28,5R)({[(3S)—1-(teIt-butoxycarbonyl)piperidin }carbamoyl)oxo—1,6—dlazabicyclo[3.2.1]octyl]oxy}sulfonyl)oxidanide 20 (0.23 g, 52.5 %) as a white solid. 1H NMR (400 MHz, 00013): 6 0.98 (12H, t, J = 7.2 Hz), 1.42 (17H, m), 1.65 (8H, m), 1.77 (4H, m), 2.05 (3H, m), 2.33 (1H, m), 2.85 (1H, d, J = 11.6 Hz), 2.96 (2H, m), 3.24 (9H, m), 3.65 (1H, m), 3.95 (2H, m), 4.10 (1H, m), 4.13 (1H, s), 1000 (1H, br s).

Step 5. (2S,5R)—7-Oxo-N-[(3S)-piperidinyloxy](sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 4, Table 1) 00“11:3 ___. 06Nil/O HOSO3BU4N+ H0503“ compound 4, Table 1 To a on of N, N,N—tributylbutan—1 -aminium ({[(28,5R)—2-({[(3S)(ten‘- butoxycarbonyl)piperidinyl]oxy}carbamoyl)—7—oxo-1,6-diazabicyclo[3.2.1]oct yl]oxy}sulfonyl)oxidanide 20 (0.23 g, 0.32 mmol) in DCM (15 mL) was added trifluoroacetic acid (0.64 mL, 8.32 mmol) dropwise at 0 °C. The reaction e was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2 x) and the white solid was 106106 collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (2S,5R)oxo—N-[(3S)-piperidinyloxy]—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2— carboxamide Compound 4 (Table 1) (0.008 g, 6.8 %) as a white solid. 1H NMR (400 MHz, CD30D): 8 1.60-1.78 (3H, m), 1.80-2.08 (5H, m), 2.92-3.04 (2H, m), 3.14-3.26 (2H, m), 3.30 (1H, d, J = 13.2 Hz), .02 (2H, m), 4.08 (1H, d, s), 4.18 (1H,_s), 3 protons were not observed in CD3OD.

HPLC: 97.05 % MS (ES‘): m/z [M]‘= 363.02 Example 5 1O Sodium ,5R)[(cyclohexyloxy)carbamoyl]-7goxo-1,6-diazabicyclo[3.2.1]oct yl}oxy)sulfonyl]oxidanide (Compound 5, Table 1) ,N’u""' N .....H )—N\ _ O 0803 N; Step 1. (2S,5R)(Benzyloxy)-N-(cyclohexyloxy)oxo-1,6- diazabicyclo[3.2.1]octanecarboxamide (22) ﬁn, <:>—O\ /N/UIII" HO NH2 0 H N IIII H N IIIIH 21 I _. g—N\ /B.

N\ /Bn 0 0 22 To a solution of )(benzyloxy)—7-oxo-1,6—diazabicyclo[3.2.1]octane—2—carboxylic acid 1 (0.2 g, 0.72 mmol) in dry DCM (20 mL) were added (aminooxy)cyclohexane 21 (0.1 g, 0.86 mmol, US 2008/146625 A1), 1-hydroxybenzotriazole (0.14 g. 1.1 mmol) and 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.2 g, 1.1 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was ed by column chromatography to give (28,5R)-6—(benzyloxy)- N-(cyclohexyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxamide 22 (0.24 g, 89.5 0/a) as a clear thick oil. 107107 1H NMR (400 MHz, CDCla): 6 1.23 (3H, m), 1.42 (2H, m), 1.54 (1H, m), 1.68 (1H, m), 1.76 (2H, m), 2.02 (4H, m), 2.36 (1H, m), 2.80 (1H, d, J = 11.6 Hz), 2.99 (1H, d, J = 12.0 Hz ), 3.30 (1H, s), 3.86 (1H, m), 3.96 (1H, d, J = 7.2 Hz), 4.89 (1H, d, J = 11.2 Hz), 5.04 (1H, d, J = 12.0Hz), 7.39 (5H, m), 8.92 (1H, br s).

Step 2. (28,5R)-N-(Cyclohexyloxy)hydroxyoxo-1,6- diazabicyclo[3.2.1]octanecarboxamide (23) 22 - 23 To a solution of )—6—(benzyloxy)-N—(cyclohexyloxy)oxo-1 ,6- diazabicyclo[3.2.1]octanecarboxamide 22 (0.24 g, 0.64 mml) in methanol (20 mL) was added 5 % Pd/C (0.30 g). The mixture was hydrogenated at 35 psi hydrogen atmosphere at room temperature for 1 h. The st was filtered out through Celite, and the filtrate was evaporated to give (2S,5R)-N-(cyclohexyloxy)hydroxy-7—oxo-1 ,6- diazabicyclo[3.2.1]octanecarboxamide 23 (0.155 g, 85 %) as a colorless foam. 1H NMR (400 MHz, CD30D): 6 1.32 (3H, m), 1.44 (2H, m), 1.55 (1H, m), 1.79 (3H, m), 1.87 (3H, m), 2.06 (1H, m), 2.16 (1H, m), 3.10 (2H, m), 3.70 (1H, s), 3.80 (2H, m), 2 protons were not observed in CD30D.

Step 3. (ZS,5R)-N-(Cyclohexyloxy)oxo(suIfooxy)-_1,6- diazabicyclo[3.2.1]octanecarboxamide pyridine salt (24) /N/Ll’ Q /N/UI Q 0 H O N H H __.___> N (I H 2 N\ 4 N\ 0 OH 0 OSOSH -pyridine 23 24 To a solution of (28,5R)-N—(cyclohexyloxy)—6-hydroxyoxo-1,6-diazabicyclo[3.2.1]octane amide 23 (0.155 g, 0.55 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.40 g, 2.51 mmol). The mixture was stirred at room temperature for 20 h, filtered and evaporated to give (28,5R)-N—(cyclohexyloxy)oxo 108108 (sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarboxamide pyridine salt 24 (0.21 g crude) which was used in the next step without purification.

Step 4. N,N,N-Tributylbutanaminium [({(2S,5R)-2—[(cyclohexyloxy)carbamoyl]- 7-oxo-1,6-diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide (25) J’Il, NJ/l’h NQ""H ——_—> NQ""H //‘—N )— \ \ - + O . . O OSOGH . pyridine 0803 Bu4N 24 25 (28,5R)-N—(Cyclohexyloxy)oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octanecarboxamide pyridine salt 24 (0.21 g, 0.47 mmol) was introduced into a concentrated aqueous solution of monosodium dihydrogen phosphate solution (8 mL) so as to obtain a pH of 4. The mixture was washed with ethyl acetate, then added tetrabutyl ammonium en sulfate (0.11 g, 0.32 mmol) and stirred at room temperature for 10 min. The mixture was extracted with ethyl acetate (3 x 20 mL), and the extracts were combined, dried over sodium sulfate and evaporated to give N,N,N-tributylbutanaminium [({(28,5R)[(cyclohexyloxy)carbamoyl] oxo-1,6-diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide 25 (0.16 g, 56 %) as a white solid. 1H NMR (400 MHZ, CDCI3): 5 1.00 (12H, t, J =‘7.2 Hz), 1.18 (3H, m), 1.46 (12H, m), 1.66 (12H, m), 1.94 (2H, m), 2.15 (1H, m), 2.38 (1H, m), 2.84 (1H, d, J = 11.2 Hz), 3.29 (8H, m), 3.87 (1H, m), 3.93 (1H, d, J = 8.0 Hz), 4.35 (1H, s), 8.98 (1H, br s).

Step 5. Sodium [({(28,5R)—2-[(cyclohexyloxy)carbamoyl]oxo-1,6- diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide und 5, Table 1) O O Oo.N J1,“H O H O —» Oo\N )1,“ 24:1 - + 0 OH bSO3Bu4N 0803H compound 5, Table 1 To a sion of N,N,N-tributylbutanaminium ,5R)[(cyclohexyloxy)carbamoyl]- 7-oxo-1,6-diazabicyclo[3.2.1]oct-6—yl}oxy)sulfonyl]oxidanide 25 (0.16 g, 0.26 mmol) in water (20 mL) was added DOWEX 50WX4 (2 g). The mixture was stirred at room temperature for 2 h, and then filtered. The filtrate was freeze-dried to give a yellow solid which was ed by HPLC and freeze-dried to give sodium [({(2S,5R)[(cyclohexyloxy)carbamoyl]oxo-1,6- 109109 diazabicyclo[3.2.1]octy|}oxy)sulfonyl]oxidanide Compound 5 (Table 1) (0.05 g, 50 %) as a white solid. 1H NMR (400 MHz, CD3OD): 6 1.22-1.35 (3H, m), 1.38-1.45 (2H, m), 1.55 (1H, m), 1.78—1.89 (4H, m), 1.91—1.97 (3H, m), 2.07 (1H, m), 2.10 (1H, m), 3.10 (1H, d, J = 11.6 Hz), 3.80 (1H, m), 3.90 (1H, d, J = 6.8 Hz), 4.15 (1H, m), 1 proton was not observed in CD30D.

HPLC: 96.82 % MS (ES‘): m/z [M-Na]’= 362.08 Example 6 (2S,5R)Oxo-N—(piperidinyloxy)(sulfooxy)—1,6-diazabicyclo[3.2.1]octane amide (Compound 6, Table 1) Step 1. tert-Butyl (2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidinecarboxylate (27) O/NHZ 0 Jim J /” ' ’I, O H HO '1 | 26 N .mH N .vIlH - N Bn 0 \ / N Bn \ / N O o l 1 C To a solution of (2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.3 g, 1.085 mmol) in dry DCM (20 mL) were added tert-butyl 4-(aminooxy)piperidine carboxylate 26 (0.29 g, 1.302 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1- hydroxybenzotriazole (0.22 g, 1.63 mmol) and 1-ethyl-(3—dimethylaminopropyl)carbodiimide hloride (0.31 g, 1.63 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert—butyl 4-[({[(28,5R)(benzyloxy)oxo-1,6- 110110 diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]piperidine-1ecarboxylate 27 (0.5 g, 98 0/o) as a clear thick oil. 1H NMR (400 MHz, CDClg): 6 1.45 (9H, s), 1.64 (4H, m), 1.93 (3H, m), 2.34 (1H, m), 2.75 (1H, d, J =11.6 Hz), 3.00 (1H, d, J =11.6 Hz), 3.13 (2H, m), 3.31 (1H, s), 3.77 (2H, m), 3.96 (1H, d, J = 7.2 Hz), 4.04 (1H, m), 4.92 (1H, d, J = 11.6 Hz), 5.05 (1H, d, J =11.6 Hz), 7.41 (5H, m), 8.99 (1H, brs).

Step 2. tert-Butyl 4-[({[(2S,5R)—6-hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbony|}amino)oxy]piperidinecarboxylate (28) O ’ O ,N/UQ ,N/u'"" . O H N ””H | H 4- 77 (5 G.” 0 \ 27 Boo 1O To a solution of tert—butyl 4—[({[(28,5R)(benzyloxy)—7-oxo-1,6—diazabicyclo[3.2.1]oct yl]carbony|}amino)oxy]piperidine-1—carboxy|ate 27 (0.5 g, 1.05 mm!) in methanol (30 mL) was added 5 % Pd/C (0.5 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through , and the filtrate was evaporated to give tert-butyl (28,5R)hydroxy-7—oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidinecarboxylate 28 (0.395 g, 98 °/o) as a colorless foam. 1H NMR (400 MHz, CD30D): 6 1.45 (9H, s), 1.60 (2H, m), 1.85 (4H, m), 2.06 (1H, m), 2.18 (1H, m), 3.25 (4H, m), 3.73 (3H, m), 3.84 (1H, d, J = 7.2 Hz), 4.00 (1H, m), 2 protons were not ed in CD30D.

Step 3. tert-Butyl 4-[({[(28,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbony|}amino)oxy]piperidinecarboxylate pyridine salt (29) O O N I!” H N .m H )— __—_> OJ—N\ OSOSH . pyridine 28 29 To a solution of tert-butyl 4—[({[(28,5R)hydroxy—7—oxo-1,6-diazabicyclo[3.2.1]oct-2— yl]carbonyl}amino)oxy]piperidinecarboxylate 28 (0.395 g, 1.03 mmol) in dry pyridine (15 111111 mL) under nitrogen atmosphere was added su|fur trioxide pyridine complex (0.8 g, 4.86 mmol). The mixture was stirred at room temperature for 20 h, filtered and evaporated to give tert—butyl 4-[({[(28,5R)oxo(sulfooxy)—1.6-diazabicyclo[3.2.1]oct y|]carbony|}amino)oxy]piperidinecarboxylate pyridine salt 29 (0.49 g crude) which was used in the next step without purification.

Step 4. N,N,N-Tributylbutanaminium ,5R)({[1-(tert- carbonyl)piperidinyl]oxy}carbamoyl)—7-oxo-1,6-diazabicyclo[3.2.1]oct yl]oxy}sulfonyl)oxidanide (30) O \0803H . pyridine ososBu4N N 1 I Boc Boc 30 ted'BUty' 4-[({[(2S.5R)ox0—6-(sulfooxy)-1,6-diazabicycio[3.2.1]oct y|]carbony|}amino)oxy]piperidinecarboxy|ate pyridine salt 29 (0.49 g, 1.02 mmol) was introduced into a concentrated aqueous so|ution of dium dihydrogen phosphate solution (11 mL) so as to obtain a pH of 4. The mixture was washed with ethyl acetate, then added tetrabutyl ammonium hydrogen sulfate (0.31 g, 0.91 mmol) and d at room temperature for 10 min. The mixture was extracted with ethyl acetate (3 x 40 mL), and the extracts were combined, dried over sodium sulfate and evaporated to give N,N,N- tributylbutanaminium ({[(28,5R)({[1-(tert-butoxyca_rbonyl)piperidinyl]oxy}carbamoyl)— 7-oxo-1,6-diazabicyclo[3.2.1]octyl]oxy}sulfonyl)oxidanide 30 (0.64 g, 87 %) as a white solid. 1H NMR (400 MHz, CDCI3): 51.00 (12H, t, J = 7.2 Hz), 1.43 (17H, m), 1.67 (11H, m), 1.88 (3H, m), 2.19 (1H, m), 2.36 (1H, m), 2.82 (1H, d, J = 11.6), 3.17 (2H, m), 3.29 (9H, m), 3.78 (2H, m), 3.94 (1H, d, J = 8.0 Hz), 4.06 (1H, m), 4.35 (1H, s), 9.06 (1H, br s). 112112 Step 5. (2S,5R)Oxo-N—(piperidinyloxy)(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 6, Table 1) O O O\NJ|’I,. o.N)L, H I /N N _. HN N N _ '+ }—N o ‘ 0 0803Bu4N ‘oso3H compound 6, Table 1 To a solution of N, N, N-tributylbutan-1 -aminium ,5R)({[1-(tert— carbonyl)piperidinyl]oxy}carbamoyl)oxo-1,6—diazabicyclo[3.2.1]oct-6— yl]oxy}su|fony|)oxidanide 30 (0.64 g, 0.89 mmol) in DCM (36 mL) was added trifluoroacetic acid (1.78 mL, 23.1 mmol) dropwise at 0 0C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by fugation. The solid was triturated with acetonitrile (2 x) and the white solid was 1O collected by centrifugation. The white solid was purified by HPLC and -dried to give (2S,5R)oxo-N-(piperidin-4—yloxy)(sulfooxy)—1,6-diazabicyclo[3.2.1]octane carboxamide Compound 6 (Table 1) (0.08 g, 25 %) as a white solid. 1H NMR (400 MHz, CD3OD): 51.68 (1H, m), 1.70-1.87 (3H, m), 1.90 - 2.01 (4H, m), 2.94- 3.04 (3H, m), 3.16 (1H, m), 3.25 (2H, m), 3.92 (1H, d, J = 6.4 Hz), 4.07 (2H, m), 3 protons were not observed in CD30D.

HPLC: 98.21 % MS (ES'): m/z [M]'= 362.92 Example 7 Sodium [({(2S,5R)oxo[(tetrahydro-2H-pyranyloxy)carbamoyl]-1,6- diazabicyclo[3.2.1]oct—6-yl}oxy)sulfonyl]oxidanide (Compound 7, Table 1) 113H3 Step 1. (28,5R)—6-(Benzyloxy)oxo-N—(tetrahydro-2H-pyranyloxy)—1 ,6- diazabicyclo[3.2.1]octanecarboxamide (32) O,NHZ O O /U/’/, JIM” N IIIIH N "ll H }——-N\ ——> /Bn )— 0 O O O To a solution of (2S,5R)(benzyloxy)oxo-1,6-diazabicyc|o[3.2.1]octanecarboxylic acid 1 (0.204 g, 0.74 mmol) in dry DCM (20 mL) were added nooxy)tetrahydro-2H—pyran 31 (0.131 g, 1.11 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.142 g, 1.11 mmol) and 1-ethy|—(3-dimethylaminopropyl)carbodiimide hydrochloride (0.201 g, 1.11 mmol) at room temperature. The reaction mixture was stirred at room temperature ght and concentrated under vacuum. The residue was purified by column chromatography to give (28,5R)(benzyloxy)oxo-N-(tetrahydro-2H—pyran-4—yioxy)—1 ,6- diazabicyclo[3.2.1]octanecarboxamide 32 (0.26 g, 93 %) as a clear thick oil. 1H NMR (400 MHz, 00013): 5 1.69 (4H, m), 1.97 (3H, m), 2.32 (1H, m), 2.75 (1H, d, J = 11.2 Hz), 3.00 (1H, d, J = 11.6 Hz), 3.31 (1H. s), 3.99 (3H, m), 4.06 (1H, m), 4.89 (1H, d, J = 11.2 Hz), 5.04 (1H, d, J = 11.6 Hz), 7.41 (5H, m), 8.94 (1H, br s).

Step 2. (28,5R)Hydroxyoxo-N-(tetrahydro-2H—pyranyloxy)-1,6- diazabicyc|o[3.2.1]octanecarboxamide (33) j o ,N J N .uIH 0/” "I'H 0W— ———> N Bn (5 HO OH 32 33 To a solution of )—6-(benzyloxy)—7—oxo-N-(tetrahydro-2H—pyran-4—yloxy)—1 ,6— diazabicycio[3.2.1]octanecarboxamide 32 (0. 26 g, 0.69 mml)'in methanol (20 mL) was added 5 % Pd/C (0.30 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (28,5R)—6—hydroxy—7-oxo-N-(tetrahydro-2H—pyranyloxy)—1 ,6— diazabicyclo[3.2.1]octanecarboxamide 33 (0.19 g, 99 %) as a colorless foam. 114114 1H NMR (400 MHz, CD3OD): 5 1.65 (2H, m), 1.81 (1H, m), 1.95 (3H, m), 2.08 (1H, m), 2.15 (1H, m), 3.05 (2H, m), 3.45 (2H, m), 3.70 (1H, s), 3.84 (1H, d, J = 7.2 Hz), 3.91 (2H, m), 4.04 (1H, m), 2 protons were not observed in CD3OD.

Step 3. (2S,5R)—7-Oxo(sulfooxy)-N-(tetrahydro-2H-pyranyloxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide pyridine salt (34) OmJWCl H /N ' N ”NH ———> o H )—~\ N ~an O OH yak O OSOSH. pyridine 33 34 To a solution of (2 S,5R)hydroxyoxo—N—(tetrahydro-2H—pyranyloxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide 33 (0.197 g, 0.69 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide pyridine x (0.44 g, 2.76 mmol). 1O The mixture was stirred at room temperature for 20 h, filtered and evaporated to give (28,5R)oxo(sulfooxy)-N-(tetrahydro-2H—pyranyloxy)-1,6-diazabicyclo[3.2.1]octane-2— carboxamide pyridine salt 34 (0.28 g crude) which was used in the next step t ﬁon.

Step 4. N,N,N-Tributy|butanaminium [({(ZS,5R)oxo[(tetrahydro-2H-pyran- 4-yloxy)carbamoyl]-1,6-diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide (35) j 0 ll,“ > /N /L|/,I" O H /N (j N .uIH O H }—‘N N ullH O yridine ' N\ 0803“. p )_ + o 0803 Bu4N (2 S,5R)—7-Oxo(s ulfooxy)-N-(tetrahyd ro-2H-pyran—4-yloxy)-1 ,6—diazabicyclo[3.2.1]octane carboxamide pyridine salt 34 (0.28 g, 0.63 mmol) was introduced into a concentrated aqueous solution of monosodium dihydrogen phosphate on (9 mL) so as to obtain a pH of 4. The mixture was washed with ethyl e, then added tetrabutyl ammonium hydrogen sulfate (0.13 g, 0.38 mmol) and stirred at room temperature for 10 min. The mixture was ted with ethyl acetate (3 x 20 mL), and the extracts were combined, dried over sodium sulfate and evaporated to give N,N,N-tributylbutanaminium [({(2S,5R)oxo [(tetrahydro-2H—pyran—4-yloxy)carbamoyl]—1 ,6—diazabicyclo[3.2.1]oct-6 115115 yl}oxy)sulfonyl]oxidanide 35 (0.21 g, 55 %) as a white solid. 1H NMR (400 MHz, CDCls): a 1.00 (12H, t, J = 7.2 Hz), 1.47 (8H, m), 1.69 (11H, m), 1.88 (3H, m), 2.17 (1H, m), 2.35 (1H, m), 2.86 (1H, d, J = 11.2 Hz), 3.31 (8H, m), 3.46 (1H, m), 3.99 (2H, m), 4.12 (1H, m), 4.32 (1H, s), 9.17 (1H, br s).

Step 5. Sodium [({(28,5R)oxo[(tetrahydro-2H-pyranyloxy)carbamoyl]-1,6- diazabicyclo[3.2.1]octyl}oxy)sulfonylloxidanide (Compound 7, Table 1) o O 0H m0111"“ . o-N)I,,,, —. o N /}-—N + )—N 0 b803Bu4N 0 OSO3H compound 7, Table 1 To a suspension of N,N,N-tributylbutanaminium ,5R)oxo—2-[(tetrahydro-2H-pyran- 4-yloxy)carbamoyl]—1,6-diazabicyclo[3.2.1]oct-6—y|}oxy)sulfonyl]oxidanide 35 (0.21 g, 0.34 1O mmol) in water (20 mL) was added DOWEX 50WX4 (2g). The mixture was stirred at room temperature for 2 h and ed. The filtrate was freeze-dried to give a yellow solid which was purified by HPLC and freeze-dried again to give sodium [({(2S,5R)oxo[(tetrahydro-2H- pyranyloxy)carbamoyl]-1,6-diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide Compound 7 (Table 1) (0.07 g, 46 %) as a white solid. 1H NMR (400 MHz, CD30D): 6 1.65 (2H, m), 1.81-1.98 (4H, m), 2.09 (1H, m), 2.19 (1 H, m), 3.10_(1H, d, J = 11.6 Hz), 3.24 (1H, d, J = 12.0 Hz), 3.47 (2H, m), 3.95 (3H, m), 4.15 (1H, m), 1 proton was not observed in CD30D.

HPLC: 98.88 % MS (ES‘): m/z [M]‘= 364.02 Example 8 (2S,5R)—N-(Azetidinonxy)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane amide (Compound 8, Table 1) N nil H g...

N O ‘ososH 116116 Step 1. tert-Butyl 3-[({[(2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct bonyl}amino)oxy]azetidinecarboxylate (37) O . o J 0 Ill‘ >\~~&o HO ><O \NH2 My 0 O\N Jill" N ..11H 36 H // Bn ‘1_ N ———~> [QWH O o }——N\ /Bn 0 O To a solution of compound (28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octane carboxylic acid 1 (0.193 g. 0.70 mmol) in dry DCM (20 mL) were added utyl 3- (aminooxy)azetidine-1—carboxylate 36 (0.198 g. 1.05 mmol, J. Med. Chem. 2008, 51, 4601- 4608). 1-hydroxybenzotriazole (0.142 g, 1.05 mmol) and 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.201 g, 1.05 mmol) at room temperature.

The reaction mixture was stirred at room temperature overnight, and then concentrated 1O under vacuum. The e was purified by column chromatography to give tert—butyl 3- [({[(28, 5R)—6-(benzyloxy)oxo-1 .6-diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]azetidine- 1-carboxylate 37 (0.15 g, 48 %) as a clear thick oil. 1H NMR (400 MHz. CDCla): 5 1.42 (9H, s). 1.65 (1H. m). 1.99 (2H, m). 2.32 (1H, m), 2.37 (1H, d. J = 11.6 Hz), 2.99 (1H. d. J = 12.0Hz), 3.32 (1H. s), 3.99 (3H. m), 4.09 (2H, m), 4.72 (1H. m), 4.88 (1H, d. J = 11.6 Hz). 5.05 (1H. d. J = 11.6 Hz). 7.37 (5H. m), 9.03 (1H, br 3).

Step 2. tert-Butyl 3-[({[(2$,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]azetidinecarboxylate (38) >¥N:}o o O >—N:>'O\ o O \NJJ/hl' )1], _t_ ,CL. H .—.__> O N }—N + ,0... H \ /Bn l N\ O O O OH 37 38 To a on of utyl 3-[({[(28.5R)-6—(benzyloxy)oxo—1,6—diazabicyclo[3.2.1]oct—2- yl]carbonyl}amino)oxy]azetidinecarboxylate 37 (0. 15 g. 0.34 mml) in methanol (15 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite. and the filtrate was evaporated to give tert-butyl 3-[({[(28,5R)-6—hydroxy-7—oxo-1,6- diazabicyclo[3.2.1]oct—2-yl]carbonyl}amino)oxy]azetidinecarboxylate 38 (0.11 g, 91 %) as a colorless foam. 117117 1H NMR (400 MHz, CD30D): 6 1.44 (9H, s), 1.78 (1H, m), 1.91 (1H, m), 2.08 (1H, m), 2.21 (1H, m), 2.98 (1H, d, J =12 Hz), 3.11 (1H, d, J =12 Hz), 3.70 (1H, 8), 3.85 (1H, d, J = 7.6 Hz), 3.95 (2H, m), 4.10 (2H, m), 4.74 (1H, m), 2 protons were not observed in CD30D.

Step 3. tert-Butyl 3-[({[(2S,5R)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct—2- yl]carbonyl}amino)oxy]azetidinecarboxylate pyridine salt (39) o o 9% j ¥~&wo O o N '1 N ““H l N uIIlH )—N\ ;_N\ O OH O OSOSH. pyridine 38 ’ 39 To a solution of tert-butyl 3-[({[(28,5R)—6-hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]azetidine—1—carboxylate 38 (0.11 g, 0.31 mmol) in dry pyridine (6 mL) . under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.197 g, 1.24 mmol). 1O The mixture was stirred at room temperature for 20 h, filtered and evaporated to give tert- butyl ‘3-[({[(28,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]azetidinecarboxylate pyridine salt 39 (0.10 g crude) which was used in the next step without purification.

Step 4. N,N,N-Tributylbutanaminium ({[(2S,5R)({[1-(tert- butoxycarbonyl)azetidinyl]oxy}carbamoyl)oxo-1,6-diazabicyclo[3.2.1]oct }sulfonyl)bxidanide (40) o 0 §¥N:>'O\NJJI,MO_ >¥Nyo O \NJ/h" + H . + N IIIIH \ O O OSOaBu4N OSOaH. pyridine tert—Butyl 3-[({[(28,5R)oxo-6—(sulfooxy)-1 .6—diazabicyclo[3.2.1]oct yl]carbony|}amino)oxy]azetidine—1-carboxylate ne salt 39 (0.13 g, 0.31 mmol) was introduced into a concentrated aqueous solution of monosodium dihydrogen phosphate solution (8 mL) so as to obtain a pH of 4. The mixture was washed with ethyl acetate, then added tetrabutyl ammonium en sulfate (0.1 g, 0.29 mmol) and stirred at room temperature for 10 min. The mixture was extracted with ethyl acetate (3 x 10 mL), and the ts were combined, dried over sodium sulfate and evaporated to give N,N,N- 118118 tributylbutan-1—aminium ({[(28,5R)—2-({[1-(tert-butoxycarbonyl)azetidinyl]oxy}carbamoyl) oxo-_1,6-diazabicyclo[3.2.1]octyl]oxy}sulfonyl)oxidanide 40 (0.1 g, 51 %) as a white solid. 1H NMR (400 MHz, CDCI3): 5 0.98 (12H, t, J = 7.2 Hz), 1.39 (17H, m), 1.70 (8H, m), 1.90 (1H, m), 2.05 (1H, m), 2.20 (1H, m), 2.35 (1H, m), 2.78 (1H, d, J =12 Hz), 3.00 (8H, m), 3.33 (1H, m), 4.00 (5H, m), 4.36 (1H, m), 5.01 (1H, m), 9.20 (1H, br s).

Step 5. (2S,5R)-N-(Azetidinyloxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 8, Table 1) 1.701) Q1,, 0‘ )1,“ _.__. HU N //|—~N\ \ O O 0803_ Bu4N+ 0803H Compound 8, Table 1 To a solution of N,N,N-tributylbutanaminium ({[(28,5R)({[1-(tert— carbonyl)azetidinyl]oxy}carbamoyl)—7-oxo-1,6-diazabicyclo[3.2.1]oct y|]oxy}sulfonyl)oxidanide 40 (0.1 g, 0.15 mmol) in DCM (8.8 mL) was added trifluoroacetic acid (0.44 mL, 5.7 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the e and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2 x) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (28,5R)—N—(azetidin-3—yloxy)oxo—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarboxamide Compound 8 (Table 1) (0.01 g, 20 %) as a white solid. 1H NMR (400 MHz, D20): 6 .08 (4H, m), 2.98 (1H,d, J = 12.4 Hz), 3.18 (1H, d, J = 11.6 Hz), 3.96 (1H, d, J = 6.8 Hz), 4.09 (3H, m), 4.28 (2H, m), 4.80 (1H, m), 3 protons were not observed in D20.

HPLC: 92.34 % MS (ES'): m/z [M]‘= 334.92 119119 Example 9 (28,5R)-N-(2-Aminoethoxy)—7-oxo(sulfooxy)-1,6-diazabicyclo [3.2.1]octane carboxamide (Compound 9, Table 1) HZN/\/ \NJO ’r, N unH o 0803H Step 1. tert-Butyl {2-[({[(2S,5R)(benzyloxy)—7-oxo-1,6-diazabicyclo[3.2.1] oat yl]carbony|}amino)oxy]ethy|}carbamate (42) HO/lill"I Boc O O \n/V \NHZ Boc 41 \N/\/O \N 1,.

N uiIH _—___> H H g g.— N ....H To a mixture of (28, 5R)(benzyloxy)oxo-1 ,6-diazabicyclo[3.2.1]Octanecarboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (4.0 mL) was added utyl [2— (aminooxy)ethyl]carbamate 41 (0.143 g, 0.814 mmol, US 2005/54701 A1), 1- ybenzotriazole (0.110 g, 0.814 mmol), 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) and DMAP (0.100 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 42 (0.21 g, 89 %) as a white foam. 1H NMR (400 MHZ, :51.44(9H,s), 1.65 (1H, m), 1.93 (2H, m), 2.31 (1H, m), 2.76 (1H. d, J: 12 Hz), 3.04 (1H, d, J = 11.2 Hz), 3.26 (2H, m), 3.38 (1H, m), 3.91 (2H, m), 3.98 (1H, d, J =12 Hz), 4.89 (1H, d, J =11.2 Hz), 5.07 (1H, d, J =11.2 Hz), 5.41 (1H, br s), 7.41 (5H, m), 9.30 (1H, br 3).

MS (ES+): m/z [M+H]+ calcd for C21H31N406: 435.22. Found: 435.02. 120120 Step 2. tert-Butyl {2-[({[(2S,5R)—6-hydroxyoxo-1,6-diazabicyclo[3.2.1]oct bonyl}amino)oxy]ethyl}carbamate (43) O O BOC\N/\/O\N/UIII" BOC\N/\/O\N/Llu'I .

A—N .Bn }—N~ O ‘0 O OH A mixture of tert—butyl {2—[({[(28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyl}carbamate 42 (0.21 g, 0.48 mmol) and Pd/C (0.063 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through celite pad and concentrated to provide '43 (0.17 g, quant. yield) as a light yellow foam. 1H NMR (400 MHz, CD30D): 6 1.44 (9H, s), 1.75 (1H, m), 1.92 (1H, m), 2.05 (1H, m), 2.23 1O (1H, m), 3.04 (1H, d, J = 12 Hz), 3.12 (2H, m), 3.69 (1H, s), 3.89 (3H, m), 6.74 (1H, br s). 3 s were not observed in CD3OD.

MS‘(ES'): m/z [M—H]' caICd for C14H23N405: 343.16. Found: 343.00.

Step 3. tert-Butyl {2-[({[(2S,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyl}carbamate (44) B°°\ /\/O\ /u” Boc N N \N/\/O\N/U,1,.

H H ____, N I'HH H H o}—N‘0H N IIIIH ”IF—N 0 \OSOSH 43 - 44 To a mixture of utyl {2-[({[(28,5R)hydroxyoxo-1,6—diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyl}carbamate 43 (0.17 g, 0.49 mmol) in pyridine (7.0 mL) was added sulfur trioxide pyridine complex (0.314 g, 1.98 mmol). The e was stirred at room temperature for 23 h and concentrated to provide a residue which was subjected to tography to give 44 (0.19 g, 92 %) as a white solid. 1H NMR (400 MHz, CD30D): 5 1.44 (9H, s), 1.80 (1H, m), 1.92 (1H, m), 2.07 (1H, m), 2.20 (1H, m), 3.06 (1H, d, J= 12 Hz), 3.28 (2H, m), 3.88 (4H, m), 4.15 (1H, m). 3 protons were not observed in CD3OD.

MS (ES‘): m/z [M-H]' calcd for C14H23N4OQS: 423.12. Found: 422.93. 121121 Step 4. (28,5R)—N—(2-aminoethoxy)oxo(sulfooxy)-1,6-diazabicyclo ]octanecarboxamide (Compound 9, Table 1) O (1 HN/\/O\N/H’IQ| H Boc N —’ HzN/\/O\”/l’/:.QN //L'N 2"“ 0 b803H 0 bso3H 44 compound 9, Table 1 To a mixture of ted-butyl {2-[({[(2S,5R)-7—oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbony|}amino)oxy]ethyl}carbamate 44 (0.19 g, 0.45 mmol) in DCM (6.0 mL) was added trifluoroacetlc acid (0.30 mL) at 0°C. The mixture was stirred at 0°C for 1 h, concentrated and washed with ether. The white solid was ted by centrifugation. The crude product was purified by preparative HPLC to provide Compound 9 (Table 1) (44 mg) as a white solid.

‘H NMR (400 MHz, D20): 81.75 (1H, m), 1.86 (1H, m), 1.95 (1H, m), 2.04 (1H, m), 3.03 (1H, 1O d, J = 12 Hz), 3.19 (3H, m), 3.98 (1H, d,,J = 6.8 Hz), 4.08 (3H, m). 4 protons were not observed in D20.

HPLC: 90.18 %.

MS (ES‘): m/z [M-H]' calcd for C9H15N4O7S: 323.07. Found: 322.95. e 10 (ZS,5R)-N-(8-Azabicyclo[3.2.1]octyloxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 27, Table 1) 122122 Step 1. tert-Butyl 3-[({[(ZS,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]azabicyclo[3.2.1]octanecarboxylate (46) W) 7/ 0 HO O/NHZ N IIIHH 45 | __.__> ’I To a solution of (28,5R)(benzyloxy)—7-oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.15 g, 0.54 mmol) in dry DCM (20 mL) were added tert—butyl 3—(aminooxy) yclo[3.2.1]octanecarboxylate 45 (0.15 g, 0.62 mmol, J. Med. Chem. 2008, 51, 4601— 4608), 1-hydroxybenzotriazole (0.11 g, 0.81 mmol) and 1-ethyl—(3- 'dimethylaminopropyl)carbodiimide hydrochloride (0.16 g, 0.81 mmol) at room temperature.

The on mixture was stirred at room temperature overnight and concentrated under . The residue was purified by column chromatography to give tert-butyl 3—[({[(28,5R)- 6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct-2—yl]carbonyl}amino)oxy] azabicyclo[3.2.1]octanecarboxylate 46 (0.26 g, 96 %) as a white solid. 1H NMR (400 MHz, 00013): 6 1.46 (9H, s), 1.50-1.80 (7H, m), 1.83-2.04 (5H, m), 2.32 (1H, m), 2.72 (1H, d, J =11.6 Hz), 2.99 (1H, d, J =11.2 Hz), 3.29 (1H, m), 3.95 (1H, d, J = 7.2 Hz), 4.20-4.38 (2H, m), 4.89 (1H, d, J = 11.2 Hz), 5.05 (1H, d, J = 11.6 Hz), 7.39 (5H, m), 8.90 (1H, brs). 123123 Step 2. tert-Butyl 3-[({[(2$,5R)—6—hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]—8-azabicyclo[3.2.1]octanecarboxylate (47) J N N\ /B” \ 47 0 46 OH To a solution of tert—butyl '3-[({[(2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]-8—azabicyclo[3.2.1]octane-8—carboxylate 46 (0. 26 g, 0.52 mml) in methanol (20 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen here at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give ted-butyl 3-[({[(2S,5R)hydroxyoxo—1,6— diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]azabicyclo[3.2.1]octane—8—carboxylate 1O 47 (0.14 g, 66 %) as a white solid. 1H NMR (400 MHz, CD30D): 5 1.48 (9H, s), 1.62-1.76 (4H, m), 1.79-1.85 (1H, m), 1.89-2.00 (3H, m), 2.02-2.11 (3H, m), 2.15-2.20 (1H, m), 3.04-3.17 (2H, m), 3.69 (1H, s), 3.83 (1H, d, J = 7.2 Hz), 4.24 (2H, m), 4.35 (1H, m), 2 protons were not observed in CD30D.

Step 3. tert-Butyl 3-[({[(2$,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct y|]carbonyl}amino)oxy]azabicyclo[3.2.1]octanecarboxylate (48) 75¢? ﬁﬁo Q 0 )1 ————+ L — Q o—N . . Q N rIH N ”H //J~—N\ //I'—N\ 47 0 OH 48 0 OSOSH To a solution of ted—butyl 3-[({[(2S,5R)-6—hydroxy—7-oxo-1,6—diazabicyclo[3.2.1]oct—2- yl]carbonyl}amino)oxy]-8—azabicyclo[3.2.1]octanecarboxylate 47 (0.14 g, 0.34 mmol) in dry ne (6 mL) under en atmosphere was added sulfur de pyridine complex (0.22 124124 g, 1.36 mmol). The mixturewas stirred at room temperature for 20 h, filtered and evaporated.

The crude nd was suspended in aqueous acid (a e of NaHzPO4 and H3PO4 to pH 3) and extracted with ethyl acetate (30 mL x 2). The organic ts were combined, washed with brine, dried over sodium sulfate and evaporated to give tert-butyl 3-[({[(28,5R)— 6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy] azabicyclo[3.2.1]octane—8—carboxylate 48 (0.077 g) which was used in the next step without purification.

Step 4. (28,5R)-N-(8-Azabicyclo[3.2.1]octyloxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 27, Table 1) l30c N 0 12 mmHN o 0 \0803H O \osoaH ' 48 compound 27, Table 1 To a solution of teIt-butyl 3-[({[(28,5R)oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]azabicyclo[3.2.1]octanecarboxylate 48 (0.077 g, 0.17 mmol) in DCM (7 mL) was added trifluoroacetic acid (0.34 mL, 4.42 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2 x) and the white solid was collected by centrifugation. The White solid was purified by HPLC and freeze-dried to give (28,5R)-N-(8-azabicyclo[3.2.1]oct—3—yloxy)oxo- 6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2-carboxamide Compound 27 (Table 1) (0.003 g, 7 %) as a white solid. 1H NMR (400 MHz, c0300): 5 1.70-2.14 (9H, m), 2.16 - 2.58 (3H, m), 3.07” (1H, d, J = 11.2 Hz), 3.25 (1H, d, J = 11.6 Hz), 3.91 (1H, d, J = 7.2 Hz), 4.00 (2H, m), 4.16 (1H, m), 4.26 (1H, m), 3 protons were not observed in CD30D.

HPLC: 81.82 °/o MS (ES'): m/z [M-H]'= 388.96 125125 Example 11 (28,5R)—N-[(1-Methylpiperidinyl)oxy]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 67 Table 1) —N©—o\N/UI,,..

N I: n H }—~. 0 OSO3H Step 1. 4-(Aminooxy)methylpiperidine (50) ng ———» ago—NH. 49 50 To a on of 2-[(1—methylpiperidin—4-yl)oxy]-1H-isoindole-1,3(2H)-dione 49 (1.18 g, 4.53 mmol) in a mixture of ethanol (3 mL) and DCM (18 mL) was added hydrazine hydrate (0.268 g, 4.53 mmol). The reaction mixture was stirred at room temperature for 4.5 h. Precipitate was filtered off. The filtrate was ated and sonicated in ethyl acetate (20 mL). Solid was filtered off and filtrate was evaporated to give the residue which was subjected to chromatography to give 50 (0.15 g, 25 %) as a colorless oil. 1H NMR (400 MHz, CD3OD): 5 1.60 - 1.70 (2H, m), 1.88 - 1.97 (2H, m), 2.23 - 2.33 (5H, m), 2.64 - 2.74 (2H, m), 3.51-3.59 (1H, m), 2 protons were not observed in CD30D.

Step 2. (ZS,5R)(Benzyloxy)-N-[(1-methylpiperidinyl)oxy]oxo-1,6- diazabicyclo[3.2.1]octanecarboxamide (51) 1 510 0 To a mixture of (28, (benzyloxy)-7—oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (10 mL) were added 4-(aminooxy)—1- methylpiperidine 50 (0.129 g, 0.99 mmol), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylaminopropyl) iimide hydrochloride (0.156 g, 0.814 mmol) 126126 tially at room temperature. The mixture was stirred at room temperature for 16 h, diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography to give 51 (0.065 g, 31 %) as a yellow oil. 1H NMR (400 MHz, CD30D): 6 1.64—2.02 (7H, m), 2.11-2.19 (1H, m), .38 (5H, m), 2.62-2.80 (2H, m), 3.00 (2H, s), 3.58 (1H, s), 3.80-3.90 (2H, m), 4.91 (2H, q, J = 11.2 Hz), 7.30-7.50 (5H, m), one proton was not observed in CD3OD.

MS (ES+): m/z [M+H]+ ca|cd for C20H28N4O4: 389.47. Found: 389.02.

Step 3. (28,5R)Hydroxy-N-[(1-methylpiperidiny|)oxy]oxo-1,6- diazabicyclo[3.2.1]octaneca‘rboxamide (52) O O _N<:>‘O\N)J~,n<:lH —————> H N ' ' I' H - I I l H —NC>.O‘NJ“<QN //J N. /Bn O O O//J N‘OH 51 52 A mixture of (2S,5R)(benzyloxy)-N-[(1-methylpiperidin-4—yl)oxy]oxo-1,6- diazabicyclo[3.2.1]octanecarboxamide 51 (0.065 g, 0.167 mmol) and Pd/C (0.060 g) in methanol (30 mL) was hydrogenated at 35 psi at room temperature for 2 h. The mixture was filtered h a Celite pad and concentrated to provide 52 (0.050 g, quantitative) as a light yellow solid.

IH NMR (400 MHZ, : 6 1.76—2.21 (8H, m), 2.37 (3H, s), 2.39—2.48 (2H, m), 2.80-2.90 (2H, m), 3.00-3.17 (2H, m), 3.68—3.72 (1H, m), 3.85 (1H, d, J = 7.6 Hz‘), 3.91-3.98 (1H, m), 2 protons were not observed in CD3OD.

MS (ES'): m/z [M+H]" calcd for C13H22N4O4: 299.34. Found 299.0.

Step 4. (28,5R)-N-[(1-Methy|piperidiny|)oxy]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide ( Compound 67, Table 1) o o o.N )l,“ ON)1,“ )—~ }’N 0 .

O OH OSO3H 52 nd 67, Table 1 To a mixture of (28,5R)hydroxy-N-[(1-methylpiperidinyl)oxy]oxo-1,6- diazabicyclo[3.2.1]octanecarboxamide 52 (0.047 g, 0.517 mmol) in pyridine (1.5 mL) was 127127 added sulfur trioxide pyridine complex (0.070 g, 1.438 mmol). The mixture was stirred at room temperature for 16 h , evaporated to dryness. The residue Was sonicated in ethyl acetate (5 mL), solid was obtained and subjected to chromatography to give Compound 67 (Table 1) (0.024 g, 40 %) as a white solid. 1H NMR (400 MHz, CD30D): 5 1.78-2.37 (8H, m), 2.90 (3H, s), .16 (2H, m), 3.20-3.41 (3H, m), .65 (1H, m), 3.92-3.98 (1H, m), 4.12—4.22 (2H, m), 2 protons were not observed in CD30D.

HPLC: 96.05 % MS (ES+): m/z [M+H]+ calcd for C13H22N4O7S: 379.41. Found: 378.93. 1O Example 12 (28,5R)—N—(2-Aminooxoethoxy)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide (Compound 73, Table 1) O O JK/O )1 \N ”1 HZN " H ‘\\H N u 0 OSOSH Step 1. (28,5R)-N-(2-Aminooxoethoxy)(benzyloxy)—7-oxo-1,6- diazabicyclo[3.2.1]octanecarboxamide (54) ’1," 2 2 /U\/O\ J1“ H0 53 HZN " N nu H ” —___> N . I I I H To a mixture of (28,5R)(benzyloxy)—7—oxo-1,6—diazabicyclo[3.2.1]octane-2—carboxylic acid 1 (0.200 g, 0.723 mmol, US 0572 A1) in DCM (6.0 mL) were added 2-(aminooxy) acetamide 53 (0.098 g, 1.086 mmol), 1-hydroxybenzotriazole (0.147 g, 1.086 mmol) and 1- ethyl-(3—dimethylaminopropyl) carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The e was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was ted to chromatography to give 54 (0.203 g, 81 %) as a white solid. 128128 1H NMR (400 MHz, CD30D):51.70(1H, m), 1.90 (1H, m), 2.00 (1H, m), 2.15 (1H, m), 2.96 (2H, m), 3.56 (1H, m), 3.89 (1H, d), 4.33 (2H, s), 4.98 (2H, ABq), 7.36 (3H, m), 7.46 (2H, m). 3 protons were not ed in CDaoD.

MS (ES+): m/z [M+H]" calcd for C15H21N405: 349.15. Found: 349.39.

Step 2. (ZS,5R)-N-(2-Aminooxoethoxy)hydroxyoxo-1,6- diazabicyclo[3.2.1]octanecarboxamide (55) O O /U\/O\N/u’h,' O HzN /U\/O\ I”; _____, HZN N N ””H N u A IIH N\ /Bn }——N O O , 0 OH A mixture of (2 S,5R)—N-(2-aminooxoethoxy)(benzyloxy)oxo-1 ,6— diazabicyclo[3.2.1]octanecarboxamide 54 (0.11 g, 0.40 mmol) and Pd/C (0.040 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 55 (0.10 g, 98 %) as a white solid. 1H NMR (400 MHZ, CD30D): 5 1.76 (1H, m), 1.92 (1H, m), 2.07 (1H,‘m), 2.19 (1H, m), 2.98 (1H, d, J = 11.6 Hz), 3.11 (1H, m), 3.69 (1H, m), 3.88 (1H, d, J = 7.6 Hz), 4.35 (2H, s). 4 protons were not observed in CDaoD.

MS (ES‘): m/z [M—H]~ calcd for 4O5: 257.09. Found: 257.44.

Step 3. (ZS,5R)—N—(2-Amin0oxoethoxy)oxo(sulfooxy)—1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 73, Table 1) o .. l, L0\ i M‘WQ i Q _____, N )N——N )‘N 0 ‘0H 0 OSOgH Compound 73, Table 1 To a e of (28,5R)-N—(2-aminooxoethoxy)—6-hydroxy-7—oxo—1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide 55 (0.11 g, 0.43 mmol) in pyridine (4.0 mL) was added sulfur trioxide ne complex (0.27 g, 1.70 mmol). The mixture was stirred at room temperature overnight and concentrated to provide a residue which was dissolved in KH2P04 (7 mL), extracted with ethyl acetate and freeze-dried to give a white solid which was purified by HPLC to provide Compound 73 (Table 1) (3.6 mg) as a white solid. 129129 1H NMR (400 MHz, 020): 81.73 (1H, m), 1.82 (1H, m), 1.95 (1H, m), 2.03 (1H, m), 3.02 (1H, d, J = 12.0 Hz), 3.18 (1H, m), 3.95 (1H, d, J = 6.4 Hz), 4.08 (1H, m), 4.38 (2H, s). 4 protons were not observed in D20.

HPLC: 88.53 % MS (ES‘): m/z [M-H]' calcd for C9H13N4OBS: 337.05. Found: 336.90. e 13 (23,5R)-N—{[(ZS)Aminopropyl]oxy}oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane- 2-carboxamide (Compound 74, Table 1) NH2 0 Nomi/LIME]H ~‘ l N .IIIH .TFA 0%— OSO3H Step 1. tert-Butyl [(1S)hydroxymethylethyl]carbamate (57) KHZ BHH—Boc 56 57 To a e of (S)—(+)—2 aminopropanol 56 (3.76 g, 50 mmol) and triethylamine (6.97 mL, 50 mmol) in THF (70 mL) at 0 °C under nitrogen was added dropwise di-tert—butyl dicarbonate (10.91 g, 50 mmol) in THF (30 mL). The mixture was stirred at room temperature for 2 h. Solvent was evaporated off. Residue was ved in ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and evaporated to provide 57 , 8.29 g, 95 %) as a white solid which was used in the next step without purification.

IH NMR (400 MHZ, CDC13)5 5 1.15 (3H, d, J = 6.8 Hz), 1.46 (9H, S), 3.42—3.61 (3H, m), 3.75 (1H, br s), 4.94 (1H, br s).

MS (ES+): m/z [M+H]+ calcd for C3H17N03: 176.23. Found: 175.96. 130130 Step 2. tert-Butyl {(1S)[(1,3-dioxo-1,3-dihydro-2H—isoindolyl)oxy] methylethyl}carbamate (58) 57 58 To a mixture of tyl [(1S)—2-hydroxy—1-methylethyl]carbamate 57 (4.03 g, 23.0 mmol), N-hydroxyphthalimide (5.63 g, 34.5 mmol) and triphenylphosphine (9.05 g, 34.5 mmol) in anhydrous THF (172 mL) at 0 °C under nitrogen was added DlAD (6.69 mL, 34.5 mmol) in ous THF (40 mL) over 15 minutes. The mixture was stirred at 0 °C for 30 min and at room temperature for 2.5 h. t was evaporated off and the residue was subjected to chromatography to give a white solid 58 (7.38 g). 1O 1H NMR (400 MHz, CDCls): 5 1.26 (3H, d, J = 6.8 Hz), 1.43 (9H, s), 3.90—4.03 (1H, m), 4.12- 4.30 (2H, m), 5.20 (1H, br s), 7.71—7.88 (4H, m).

MS (ES+): m/z [M+H]+ calcd for C16H20N205: . Found: 320.89.

Step 3. tert-Butyl [(1S)(aminooxy)methylethyl]carbamate (59) H N—Boc )\‘u“ H O H N—Boc o\N ______+ % To a solution of ted-butyl {(1S)[(1,3-dioxo-1,3-dihydro—2H-isoindolyl)oxy] methylethyl}carbamate 58 (1.2 g, 3.74 mmol) in a mixture of ethanol (3 mL) and DCM (20 mL) was added hydrazine hydrate (0.215 mL, 3.74 mmol). The reaction mixture was stirred at room temperature for 6 h. Precipitate was filtered off, the filtrate was evaporated and the residue was subjected to tography to give 59 (0.55 g, 77 %) as a white solid. 1H NMR (400 MHZ, CD3OD): 51.03 (3H, d, J = 6.8 Hz), 1.36 (9H, s), 3.38—3.42 (1H, m), 3.53- 3.56 (1H, m), 3.89 (1H, br s), 4.79 (1H, br s), 5.54 (2H, br s). 131131 Step 4. tert—Butyl {(2S)[({[(ZS,5R)(benzyloxy)oxo—1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]propanyl}carbamate (60) H N—Boc )3 Boc To a mixture of (28,5R)—6-(benzyloxy)—7-oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.150 g, 0.543 mmol) in DCM (15 mL) were added tert—butyl [(1S)(aminooxy) methylethyi]carbamate 59 (0.176 g, 0.923 mmol), 1—hydroxybenzotriazole (0.110 g, 0.814 mmol)'and 1~ethyl-(3-dimethylaminopropyl) carbodiimide hloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 18 h, d with DCM, washed with water and brine, dried over sodium sulfate and 1O concentrated to provide a e which was subjected to chromatography to give 60 (0.237 g, 97 %) as a white solid.

‘H NMR (400 MHZ, CD013): 51.67(3H, d. J = 6.8 Hz), 1.42 (9H, s), 1.63-1.69 (1H, m), 1.91- 2.05 (2H, m), .33 (1H, m), 2.81 (1H, d, J = 12.0 Hz), 3.04-3.07 (1H, m), 3.29 (1H, 8), 3.66-3.70 (1H, m), 3.87-3.96 (3H, m), 4.83-5.07 (3H, m), 7.32-7.42 (5H, m), 9.72 (1H, br 8).

MS (ES’): m/z [M-H]‘ calcd for C22H32N406: 447.52. Found: 447.47.

Step 5. tert-Butyl {(2S)—1-[({[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct- 2-yl]carbonyl}amino)oxy]propanyl}carbamate (61) A mixture of tert-butyl {(28)[({[(2S,5R)(benzy|oxy)oxo—1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]propanyl}carbamate 60 (0.237 g, 0.528 mmol) and Pd/C (0.200 g) in methanol (20 mL) was hydrogenated at 35 psi at room temperature for 2 h. The mixture was ed through a Celite pad and concentrated to provide 61 (crude, 0.189 g, quant.) as a colorless foam which was used in the next step without purification. 132132 Step 6. tert-Butyl {(ZS)[({[(ZS,5R)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]propanyl}carbamate (62) To a mixture of tert—butyl {(2S)[({[(2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct—2- yl]carbonyl}amino)oxy]propanyl}carbamate 61 (0.189 g, 0.527 mmol) in pyridine (5.0 mL) was added sulfur trioxide pyridine complex (0.233 g, 1.466 mmol). The mixture was stirred at room temperature for 20 h. Solid was filtered off. The te was evaporated to e a residue which was subjected to chromatography to give 62 (0.214 g, 93 °/o) as a light yellow foam. 1H NMR (400 MHZ, CDC'a): 5 1.20 (3H, d, J = 6.0 HZ), 1.42 (9H, m), 1.80-2.27 (4H, m), 3.03 (1H, d, J = 12.0 HZ), 3.27-3.35 (1H, m), .97 (3H, m), 4.26 (1H, s), 5.13 (1H, br s), 3 protons were not observed in moisture-containing CDCI3.

MS (ES'): m/z [M-H]‘ calcd for C15H26N4OQS: 437.46. Found: 437.38.

Step 7. (28,5R)-N-{[(ZS)Aminopropyl]oxy}oxo(sulfooxy)—1,6- icyclo[3.2.1]octanecarboxamide (Compound 74, Table 1) H w H or NOW/[Ling ' . H ’ N NOE/l/mgN )—N TFA O 0%N bSO3H 0303“ 62 Compound 74, Table 1 To a mixture of tert-butyl 1-[({[(28,5R)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]propanyl}carbamate 62 (0.214 g, 0.488 mmol) in DCM (9.0 mL) was added trifluoroacetic acid (0.44 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, concentrated and washed with ether-The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 74 (Table 1) (27 mg) as a light yellow solid. 1H NMR (400 MHz, CD30D): 51.27(3H, d, J = 6.8 Hz), 1.78—2.25 (4H, m), 3.03 (1H, d, J = 12.0 Hz), 3.22-3.30 (1H, m), 3.51-3.60 (1H, m), .90 (1H, m), 3.96-4.07 (2H, m), 4.12- 4.18 (1H, m), 4 protons were not observed in CD30D. 133133 HPLC: 83.80 % MS (ES‘) m/z: [M-H]' calcd for C10H13N4O7S: 337.34. Found: 33696.

Example 14 (28,5R)—N-[(1-Carbamimidoylpiperidinyl)oxy]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 75, Table 1) NH 0 H2NLNGQ JM 0 “H N “ . ;_N\ 0 OSOSH Step 1. t-butyl [{4-[(1,3-dioxo-1,3-dihydro-2H-isoindolyl)oxy]piperidin yl}methylylidene]biscarbamate (64) N—OH HonNHBoc O NHBoc ———+ NBoc (iii—004NBoc ' 53 64 1O To a mixture of N-hydroxyphthalimide (1.89 g, 11.62 mmol), di-tert—butyl [(4-hydroxypiperidln- 1-yl)methylylidene]biscarbamate 63 (2.00 g, 5.81 mmol, US 2004/209921 A1) and triphenylphosphine (3.05 g, 11.62 mmol) in THF (100 mL) was added diisopropyl arboxylate (2.47 mL, 12.78 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to e a residue which was . subjected to chromatography to give 64 (0.9 g) as a white solid. 1H NMR (400 MHz, CDCI3): 5 1.49 (18H, s), 2.04 (4H, m), 3.57 (2H, br s), 3.89 (2H, br s), 4.50 (1H, m), 7.76 (2H, m), 7.85 (2H, m), 10.20 (1H, br 5).

MS (ES+): m/z [M+H]+ calcd for C24H33N407: 489.23. Found: 489.07. 134134 Step 2. Di-tert-butyl {[4-(aminooxy)piperidinyl]methylylidene} biscarbamate (65) 1504351NHBoc Boc NBoc BocHN1.ng To a mixture di-tert-butyl [{4-[(1,3-dioxo-1,3—dihydro-2H-isoindolyl)oxy]piperidin yl}methylylidene]biscarbamate 64 (2.30 g, 4.71 mmol) in a solution of DCM (40 mL) and ethanol (6 mL) was added hydrazine hydrate (0.270 mL, 4.71 mmol) at room temperature.

The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 65 (0.72 g, 43 %) as a white foam.

‘H NMR (400 MHz, 00013): a 1.47 (9H, s), 1.50 (9H, s), 1.72 (2H, m), 1.95 (2H, m), 3.38 (2H, m), 3.77 (3H, m), 5.30 (2H, s), 10.15 (1H, s).

MS (ES+): m/z [M+H]+ calcd for C15H31N405: 359.23. Found: 359.07.

Step 3. Di-tert-butyl [{4-[({[(2$,5R)(benzyloxy)—7-oxo-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]piperidinyl}methylylidene] bamate (66) 0' ' a,"'0'” H BocHN —NH2 Boc HO k :6 . 65 NC>—‘O\ I”, BocHN ' II H To a mixture of (28,5R)(benzy|oxy)oxo-1,6-diazabicyc|o[3.2.1]octanecarboxylic acid 1 (0.200 g, 0.723 mmol, US 0572 A1) in DCM (6.0 mL) was added di-tert—butyl {[4- (aminooxy)piperidinyl]methylylidene}biscarbamate 65 (0.389 g, 1.086 mmol), 1- hydroxybenzotriazole (0.147 g, 1.086 mmol) and |—(3-dimethylaminopropyl) carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was ted to chromatography to give 66 (0.33 g, 74 %) as a white solid. 1H NMR (400 MHZ, CDCI3): 6 1.48 (18H, m), 1.62 (2H, m), 1.82 (2H, m), 2.01 (4H, m), 2.32 (1H, m), 2.77 (1H, d, J = 11.6 Hz), 3.03 (1H, d, J = 11.2 Hz), 3.32 (1H, s), 3.43 (2H, br s), 135135 3.78 (2H, br s), 3.95 (1H, d, J = 7.6 Hz), 4.09 (1H, m), 4.92 (2H, ABq), 7.41 (5H, m), 8.95 (1 H, S (ES+)Z m/z [M+H]+ calcd for CaoH45N503: 617.33. Found: 617.18.

Step 4. Di-tert-butyl [{4-[({[(ZS,5R)hydroxyoxo-1,6-diazabicyclo [3.2.1]oct yl]carbony|}amino)oxy]piperidinyl}methylylidene]biscarbamate (67) Boc O JL/l’ B0031 BocHN NOVO\ 1' —————» BocHN NW N .... H N. /Bn 66 0 O 67 NO A mixture of di-tert-butyl [{4-[({[(28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]piperidin-1—yl}methy|ylidene] biscarbamate 66 (0.26 g, 0.42 mmol) and Pd/C (0.080 g) in methanol (10 mL) was hydrogenated at 1 atm at room ature for 3 h. 1O The mixture was filtered through Celite pad and concentrated to provide 67 (0.21 g, 98 %) as a white solid.

IH NMR (400 MHz, CD30D): 6 1.51 (18H, 3), 1.60 (1H, m), 1.96 (3H, m), 2.06 (3H, m), 2.17 (1H, m), 3.04 (1H, d, J = 11.6 Hz), 3.12 (1H, m), 3.64 (2H, m), 3.71 (1H, m), 3.84 (3H, m), 4.18 (1H, m). 3 protons were not observed in CD30D.

MS (ES+): m/z [M+H]+ calcd for CzaHggNSOB: 527.28. Found: 527.09.

Step 5. Di-tert-butyl [{4-[({[(ZS,5R)-7—oxo(sulfooxy)—1,6-diazabicyclo[3.2.1] oct- 2-yl]carbonyl}amino)oxy]piperidinyl}methylylidene]biscarbamate (68) BocHNLWBoc Q ~__. N:NNMC}JGm e7 J_N 68 030H To a e of di-tert—butyl [{4-[({[(28,5R)—6-hydroxyoxo-1,6—diazabicyclo[3.2.1] oct 2O yl]carbonyl}amino)oxy]piperidinyl}methylylidene]biscarbamate 67 (0.26 g, 0.50 mmol) in ne (8.0 mL) was added sulfur de pyridine complex (0.23 g, 1.49 mmol). The mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 68 (0.20 g, 67 %) as a white solid. 1H NMR (400 MHz, : 61.47 (18H, 3), 1.80 (3H, m), 1.94 (3H, m), 2.10 (1H, m), 2.20 (1H, m), 3.10 (1H, d, J =11.6 Hz), 3.25 (1H, m), 3.43 (2H, m), 3.75 (2H, m), 3.92 (1H, d, J = 6.0 Hz), 4.14 (2H, m), 3 protons were not observed in CD30D.

MS (ES’) m/z: [M—H]“ calcd for 023H37N5011S: 605.22. Found: 605.03. 136136 Step 6. (28,5R)—N-[(1-Carbamimidoylpiperidinyl)oxy]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide und 75, Table 1) o O\N/l//,.Ci BOCNYUO‘”JL"© H _—* ”My/O "Q O)"N 0}— CSO3HN NH2 NHBoc CSO3H 68 nd 75, Table 1 To a mixture of di—tert—butyl [{4-[({[(2S,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1] oct yl]carbonyl}amino)oxy]piperidinyl}methylylidenelbiscarbamate 68 (0.15 g, 0.25 mmol) in DCM (5.0 mL) was added trifluoroacetic acid (1.0 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and at room temperature for 2 h, concentrated and washed with ether. The white solid was collected by centrifugatlon. The crude product was purified by preparative HPLC to provide Compound 75 (Table 1) (40 mg) as a white solid. 1O 1H NMR (400 MHz, 020): 6160—210 (8H, m), 3.01 (1H, d, J = 12 Hz), 3.22 (3H, m), 3.56 (2H, m), 3.96 (1H, d, J = 6.8 Hz), 4.09 (2H, m). 5 s were not observed in D20.

HPLC: 95.56 % MS (ES'): m/z [M-H]‘ calcd for C13H21N507S: 405.12. Found: 404.93.

Example 15 (28,5R)—7-Oxo-N-[2-(piperidinyloxy)ethoxy](sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 76, Table 1) O\ ’1, I'll H 137B7 Step 1. tert-Butyl 4-{2-[(1,3-dioxo-1,3-dihydro-ZH-isoindol-Z- yl)oxy]ethoxy}piperidinecarboxylate (70) N—OH 800*NQONOH O / \ N—O o N—Boc ‘59 ' To a solution of tert—butyl 4-(2-hydroxyethoxy)piperidine-1—carboxylate 69 (0.9 g, 3.67 mmol, A1) in THF (28 mL) were added N-hydroxyphthalimide (0.9 g, 5.51 mmol), triphenylphosphine (1.44 g, 5.51 mmol) and DIAD (1.07 mL, 5.51 mmol) sequentially at 0 °C under en. The mixture was stirred at 0 °C for 30 min and at room temperature for 16 h.

Solvent was evaporated off and the e was subjected to chromatography to give 70 (0.69 g, 48 %) as a white solid.

IH NMR (400 MHZ, CDCI3): 8 1.27-1.40 (11H, m), 1.67—1.75 (2H, m), 2.95-3.00 (2H, m), 3.42—3.46 (1H,-m), 3.56-3.59 (2H, m), 3.76-3.80 (2H, m), 4.29-4.31 (2H, m), 7.67-7.78 (4H, MS (ES+): m/z [M+H]+ calcd for C20H25N206: 391.44. Found: 391.02.

Step 2. tert-Butyl aminooxy)ethoxy]piperidinecarboxylate (71) ”-0 O N_B°C ———-—* HzN—O O‘CN—Boc O 70 71 To a on of tert-butyl 4—{2-[(1,3-dioxo—1,3-dihydro-2H—isoindo|yl)oxy]ethoxy}piperidine- 1-carboxylate 70 (0.57 g, 1.46 mmol) in a mixture of ethanol (1 mL) and DCM (6 mL) was added hydrazine hydrate (0.086 g, 1.46 mmol). The reaction mixture was stirred at room temperature for 16 h. Precipitate was filtered off. The te was evaporated and the residue was ted to chromatography to give 71 (0.327 g, 86 %) as a colorless oil. 1H NMR (400 MHZ, CD30D): 8 1.45—1.57 (11H, m), 1.80—1.90 (2H, m), 3.00-3.19 (2H, m), 3.45-3.51 (2H, m), 3.62-3.68 (1H, m), 3.75-3.85 (4H, m), 5.50 (2H, br S).

MS (ES+): m/z [M+H]+ calcd for C12H24N204: 261.34. Found: 261.04. 138138 Step 3. tert-Butyl 4-{2-[({[(2$,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct- arbonyl}amino)oxy]ethoxy}piperidinecarboxylate (72) /~,, HO Mm N—Boc J“; N -"'H . BocN o/\/0\HHO'Q”(H O 0 To a mixture of )(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octane-2—carboxylic acid 1 ( 0.150 g, 0.543 mmol, US 0572 A1) in DCM (4.0 mL) were added ten-butyl 4—[2- oxy)ethoxy]piperidinecarboxylate 71 (0.240 g, 0.543 mmol), 1- hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethy|-(3-dimethylamino- propyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was d at room temperature for 16 h, diluted with DCM, washed with water, brine, 1O dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography to give 72 (0.276 g, 98 %) as a colorless foam. 1H NMR (400 MHz, CDCI3): 5 1.46-1.67 (12H, m), 1.84-2.04 (4H, m), 2.30—2.35 (1H, m), 2.77 (1H, d, J = 11.6 Hz), 2.98-3.09 (3H, m), 3.31 (1H, s), 3.45-3.53 (1H, m), 3.64-3.85 (4H, m), 3.94 (1H, d, J = 7.6 Hz), 4.05-4.11 (2H, m), 4.90 (1H, d, J = 11.2 Hz), 5.05 (1H, d, J = 12.0 Hz), 7.35-7.46 (5H, m), 1 proton was not observed in moisture-containing CDCI3..

MS (ES'): m/z [M-H]' calCd for C25H33N4O7: 517.62. Found: 517.13.

Step 4. tert-Butyl 4-{2-[({[(2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbony|}amino)oxy]ethoxy}piperidinecarboxylate (73) 0\ jn, 0\ N .uiIH \ /Bn 60.

O O O OH 72 73 A mixture of ten-butyl 4-{2-[({[(28,5R)-6—(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct-2— yl]carbony|}amino)oxy]ethoxy}piperidinecarboxylate 72 (0.270 g, 0.521 mmol) and Pd/C (0.270 g) in methanol (25 mL) was hydrogenated at 35 psi at room temperature for 2 h. The mixture was filtered through a Celite pad and concentrated to provide 73 (0.221 g, 99 %) as a light grey solid. 1H NMR (400 MHZ, CDCI3): 5 .58 (11H, m), 1.70-2.05 (4H, m), 2.11-2.20 (1H, m), 2.33-2.42 (1H, m), 2.90-3.20 (4H, m), 3.46-3.60 (2H, m), 3.68—3.85 (6H, m), 3.90-3.96 (1H, m), 4.05-4.18 (1H, m), 9.61 (1H, br s). 139139 MS (ES'): m/z [M—H]‘ calcd for C19H32N407: 427.49. Found: 426.98.

Step 5. tert-Butyl 4-{2-[({[(ZS,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethoxy}piperidinecarboxylate (74) j 0 BOG—NGONO\ 1,, O\ 1,, IZ Q BOG—N O/\/ ”/U 0 ....H IIIIH a—N. ;._N\ O OH 73 0 74 0803H To a mixture of tert—butyl 4-{2-[({[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethoxy}piperidine-1—carboxy|ate 73 (0.221 g, 0.516 mmol) in pyridine (5.0 mL) was added sulfur trioxide pyridine complex (0.228 g, 1.434 mmol). The mixture was stirred at room temperature for 20 h. Solid was ed off. The filtrate was evaporated to provide a residue which was subjected to chromatography to give 74 (0.197 g, 75 %) as a 1O light yellow solid. 1H NMR (400 MHz, CD30D): 5 1.40-1.53 (11H, m), 1.79-1.97 (4H, m), 2.05-2.09 (1H, m), 2.19-2.24 (1H, m), 3.05-3.18 (3H, m), 3.21—3.28 (1H, m), 3.53-3.61 (1H, m), .78 (4H, m), 3.92 ,(1H, d, J = 6.8 Hz), 4.00-4.06 (2H, m), 4.12-4.18 (1H, m).

MS (ES‘): m/z [M-H]' calcd for C19H32N4O1OS: 507.55. Found: 506.92.

Step 6. (28,5R)Oxo-N-[2-(piperidinyloxy)ethoxy](sulfooxy)-1,6- icyclo[3.2.1]octanecarboxamide (Compound 76, Table 1) O ' . O Boc—NC>—O/\/O‘N/ll, l, HN (DA/ow) H “—5 H N N )*N /l/———N O bSO3H O bSO3H 74 . Compound 76, Table 1 To a e of tert—butyl 4-{2-[({[(28,5R)oxo-6—(sulfooxy)-1,6—iazabicyclo[3.2.1]oct—2— yl]carbonyl}amino)oxy]ethoxy}piperidinecarboxy|ate 74 (0.195 g, 0.386 mmol) in DCM (9.0 2O mL) was added trifluoroacetic acid (0.44 mL) at 0 °C. The mixture was d at 0 °C for 1 h, concentrated and washed with ether. The white solid 'was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 76 (Table 1) (25 mg) as a white solid. 1H NMR (400 MHz, CD30D): 5180-201 (6H, m), 2.06-2.15 (1H, m), 2.18-2.22 (1H, m), 3.04- 3.12 (4H, m), .27 (1H, m), 3.72—3.78 (4H, m), 3.90 (1H, d, J = 6.0 Hz), 4.02-4.06 (2H, m), 4.15 (1H, d, J = 3.2 Hz), 3 protons were not observed in CD3OD. 140140 HPLC: 92.51 % MS (ES'): m/z [M-H]‘ calcd for C14H24N4OBS: 407.45. Found: 406.93.

Example 16 (ZS,5R)—7-Oxo-N—[2-(sulfamoylamino)ethoxy](su|fooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide und 77, Table 1) n 0 H2N_ﬁ_m_¥o—N l’ 0 H 0 OSOSH Step 1. tert-Butyl ({2-[(1,3-dioxo-1,3-dihydro-2H-isoindolyl)oxy]ethyl} sulfamoyl)carbamate (77) CI—S—N*0 o . a 76 0 N—O/\/NH HCI H II 2 “—’ , N—O/\/N—ﬁ—NHBoc 1O To a mixture of 2-(2-aminoethoxy)-1H-isoindole-1,3(2H)-dione hydrochloride 75 (0.53 g, 2.19 mmol, EP 16744522 A1, 2006), tert—b‘utyl (chlorosulfonyl)carbamate 76 (0.71 g, 3.28 mmol, A1) in DCM (10 mL) was added triethylamine (0.92 mL', 6.57 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 7 h and concentrated to e a residue which was subjected to chromatography to give 77 (0.63 g, 74 %) as a white foam. 1H NMR (400 MHZ, CDCI3): 5 1.50 (9H, s), 3.49 (2H, m), 4.36 (2H, t, J = 4.8 Hz), 6.28 (1H, t, J= 4.8 Hz), 7.11 (1H, s), 7.79 (2H, m), 7.86 (2H, m).

MS (ES‘): m/z [M-H]‘ calcd for C15H18N307S: . Found: 383.94. 141141 Step 2. tert-Butyl {[2-(aminooxy)ethy|]sulfamoyl}carbamate (78) H ‘11 P.

N—O/\/N—ﬁ—NHBoc —————~—» HZN—ONN—ﬁ—NHBOC O O 0 78 To a mixture of tert—butyl ({2-[(1,3-dioxo-1,3-dihydro-2H—isoindoly|)oxy]ethyl} sulfamoyl)carbamate 77 (0.62 g, 1.61 mmol) in a solution of DCM (10 mL) and ethanol (2 mL) was added ine hydrate (0.092 mL, 1.61 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 78 (0.18 g, 44 %) as a white solid. 1H NMR (400 MHz, CDCI3): a 1.49 (9H. s), 3.33 (2H, m), 3.81 (2H, m), 5.28 (2H, br s), 5.93 (1H, brs), 7.24 (1H, br s).

MS (ES+): m/z [M+H]+ ca|cd for C7H18N3058: 256.10. Found: 255.91.

Step 3. tert-Butyl ({2-[({[(2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbony|}amino)oxy]ethyl}sulfamoyl)carbamate (79) ll, 0 0 HO/ H N—o/VH—g—NHBoc 2 g—N (i N .,.. H ll I| H—\—O—N’l"l., %_ O O H N\O/Bn N ”NH . )’—N\ /Bn 1 79 o 0 To a e of (28,5R)—6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.200 g, 0.723 mmol) in DCM (6.0 mL). was added tert—butyl {[2— (aminooxy)ethy|]sulfamoyl}carbamate 78 (0.276 g, 1.085 mmol), 1—hydroxybenzotriazole (0.147 g, 1.086 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, d with DCM and concentrated to provide a residue which was subjected to chromatography to give 79 (0.35 g, 93 %) as a white solid. 1H NMR (400 MHz, CDCI3): a 1.48 (9H, m), 1.64 (1H, m), 1.95 (2H, m), 2.33 (1H, m), 2.76 (1H, d. J = 11.2 Hz), 3.01 (1H, d, J = 12.0 Hz), 3.32 (1H, s), 3.38 (2H, br s), 3.95 (1H, d, J = 7.2 Hz), 4.03 (2H, m), 4.92 (2H, ABq), 6.38 (1H, br s), 7.26 (1H, m), 7.41 (5H, m), 9.20 (1H, MS (ES+): m/z [M+H]+ ca|cd for C21H32N50882 . Found: 514.00. 142142 Step 4. tert-Butyl ({2-[({[(2$,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyl}sulfamoyl)carbamate (80) H O O J'— O BocHN—s—N l n H—_\——O——N/L’~. BocHN ﬁ ﬁxO—N’H’M.

O H ______> O H N ""H N inlH //‘~— N~ /Bn 80 A—N. 79 o o 0 OH A mixture of tert—butyl ({2-[({[(2S,5R)(benzy|oxy)oxo—1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyi}sulfamoyl)carbamate 79 (0.35 g, 0.67 mmol) and Pd/C (10 %, 0.12 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was ed through Celite pad and concentrated to provide 80 (0.25 g, 88 %) as a white foam..

'H NMR (400 MHz, CD30D): 6 1.48 (9H, s), 1.80 (1H, m), 1.96 (1H, m), 2.06 (1H, m), 2.20 1O (1H, m), 3.03 (1H, d, J = 11.6 Hz), 3.12 (1H, m), 3.28 (2H, m), 3.70 (1H, m), 3.84 (1H, d, J = 8.0 Hz), 3.98 (2H, t, J = 5.6 Hz). 4 protons were not observed in CD30D.

MS (ES+): m/z [M+H]+ calcd for C14H26N5OBS: 424.15. Found: 423.97.

Step 5. tert-Butyl ({2-[({[(28,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yi]carbonyl}amino)oxy]ethyl}sulfamoyl)carbamate (81) 9’ or 'C') B HN—S—N BocHN—s—N oc R (I)! H_—\—O——N’H”u, ('3' “KO—7,21 , I _ , N ""H N ""H OSOaH To a mixture of ted-butyl {[(28,5R)hydroxyoxo-1,6-diazabicycio[3.2.1]oct yl]carbonyl}amino)oxy]ethy|}sulfamoyl)carbamate 80 (0.25 g, 0.59 mmol) in ne (10.0 mL) was added sulfur trioxide pyridine complex (0.28 g, 1.77 mmol). The mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 81 (0.20 g, 67 %) as a white solid. 1H NMR (400 MHz, : 61.48 (9H, s), 1.83 (1H, m), 1.91 (1H, m), 2.06 (1H, m), 2.21 (1H, m), 3.08 (1H, d, J =11.6 Hz), 3.24 (1H, m), 3.28 (2H, m), 3.91 (1H, d, J = 7.2 Hz), 3.98 (2H, t, J = 5.6 Hz), 4.15 (1H, m). 4 protons were not observed in CD30D.

MS (ES‘): m/z [M-H]' calcd for C14H24N5O11S2: . Found: 501.97. 143143 Step 6. (28,5R)0xo-N-[2-(sulfamoylamino)ethoxy](su|fooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 77, Table 1) O O (l? /H/, (‘3' /u’o BocHN—S—N/\/O /\/O\ \N Q N N Q n H H ————> n H H O N O N )_N\ j N\ O osogH O OSOsH 81 Compound 77, Table 1 To a mixture of ten-butyl ({2-[({[(28,5R)-7—oxo-6—(sulfooxy)-1,6—diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyl}sulfamoyl)carbamate 81 (0.20 g, 0.40 mmol) in DCM (5.0 mL) was added trifluoroacetic acid (1.0 mL) at 0°C. The mixture was stirred at 0°C for 0.5 h and at room temperature for 2 h, trated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to e Compound 77 (Table 1) (37 mg, 23 %) as a white solid. 1O 1H NMR (400 MHz, D20): 5168-206 (4H, m), 3.00 (1H, d, J = 12.0 Hz), 3.17-3.22 (3H, m), 3.94 (3H, m), 4.07 (1H, d, J = 2.8 Hz). 5 protons were not observed in D20.

HPLC: 95.56 % MS (ES‘) m/z: [M-H]' calcd for C9H16N509821 402.04. Found: 401.99.

Example 17 (ZS,5R)-N-[2-(Carbamoylamino)ethoxy]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 78, Table 1) 144144 Step 1. utyl ({2-[(1,3-dioxo-1,3-dihydro-2H—isoindolyl)oxy]ethyl} carbamoyl)carbamate (83) 0 i1 Cl—H—N 0 O H O N—O/\/N—-l-LNHBocH N—O/\/NH2HC| ___, O O 75 83 To a mixture of 2-(2-aminoethoxy)-1H—isoindole—1,3(2H)—dione hydrochloride 75 (0.40 g, 1.65 mmol, EP 1674452 A1, 2006), tert—butyl (chlorocarbonyl)carbamate 82 (1.70 g crude, US 2005/187277 A1) in DCM (10 mL) was added triethylamine (0.69 mL, 4.95 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 83 (0.56 g, 96 %) as a white solid. 1O 1H NMR (400 MHz, : 5 1.50 (9H, s), 3.64 (2H, m), 4.30 (2H, t, J = 5.2 Hz), 6.91 (1H, br s), 7.75 (2H, m), 7.87 (2H, m), 8.45 (1H, m).

Step 2. utyl {[2-(aminooxy)ethyl]carbamoyl}carbamate (84) To ' a mixture of tert—butyl ({2-[(1,3-dioxo-1,3-dihydro-2H—isoindolyl)oxy]ethyl} carbamoyl)carbamate 83 (0.56 g, 1.59 mmol) in a solution of DCM (10 mL) and ethanol (2 mL) was added hydrazine hydrate (0.091 mL, 1.59 mmol) at room temperature. The mixture was d at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 84 (0.25 g, 72 %) as a white solid. 1H NMR (400 MHz, CDCI3): 5 1.49 (9H, s), 3.53 (2H, q, J = 5.2 Hz), 3.76 (2H, t, J = 5.2 Hz), 5.51 (2H, br s), 6.83 (1H, br s), 7.80 (1H, br s). 145145 Step 3. tert-Butyl {[(28,5R)—6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyl}carbamoyl)carbamate (85) . O (1 HZN—O/\/N——[(H , NHBoc / '0" H o ' 0 HO 84 | ’_—" >—N BocHN ”KO—u Q 471 N\ /Bn N ""H O 0 2.. 1 85 o ‘0 To a mixture of (2S,5R)(benzyloxy)oxo-1,6—diazabicyclo[3.2.1]octane-2—carboxylic acid 1 (0.210 g, 0.760 mmol, US 2005/20572 A1) in DCM (6.0 mL) were added tert—butyl {[2- (aminooxy)ethyl]carbamoyl}carbamate 84 (0.250 g, 1.140 mmol), 1-hydroxybenzotriazole (0.154 g, 1.140 mmol) and 1—ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.218 g, 1.140 mmol) sequentially at room temperature. The mixture was d at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 85 (0.31 g, 85 %) as a white solid. 1H NMR (400 MHz, CDClg): 8 1.48 (9H, m), 1.64 (2H, m), 1.98 (2H, m), 2.34 (1H, m), 2.77 (1H, d, J = 11.2 Hz), 3.02 (1H, m), 3.28 (1H, m), 3.47 (1H, m), 3.63 (1H, m), 3.97 (2H, m), 4.90 (2H, ABq), 6.79 (1H, br s), 7.39 (5H, m), 8.11 (1H, m), 9.77 (1H, s).

MS (ES+) m/z: [M+H]+ calcd for C22H32N5O7: 478.23. Found: 478.10.

Step 4. tert-Butyl ({2-[({[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyl}carbamoy|)carbamate (86) O>—_N OI O H_\—0~N 7 N—\_ _ R BOCHN O H BOCHN m " N ""H 85 0 ‘0 86 0 ‘OH A miXture of tert—butyl ({2-[({[(2S,5R)(benzyloxy)—7-oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyl}carbamoyl)carbamate 85 (0.31 g, 0.64 mmol) and Pd/C (10 %, '20 0.11 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The e was filtered through Celite pad and concentrated to provide 86 (0.25 g, tative) as a white foam. 1H NMR (400 MHz, : 6 1.48 (9H, s), 1.80 (1H, m), 1.92 (1H, m), 2.05 (1H, m), 2.20 (1H, m), 3.02 (1H, d, J = 11.6 Hz), 3.15 (1H, m), 3.51 (2H, t, J: 5.6 Hz), 3.70 (1H, m), 3.85 (1H, d, J = 7.2 Hz), 3.94 (2H, t, J = 5.6 Hz). 4 protons were not observed in CD30D.

MS (ES‘) m/z: [M—H]' calcd for C15H24N5O7: 386.17. Found: 386.07. 146146 Step 5. tert-Butyl ({2-[({[(2$,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyl}carbamoyl)carbamate (87) WNIii—0““!jIll" Ox} 0 BOCHN ”KO—NJ,“ H " BOCHN H N -||IH —> N -IIlH o N‘OH 2 N\ 85 0803H To a mixture of teIt-butyl ({2-[({[(2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethy|}carbamoyl)carbamate 86 (0.25 g, 0.65 mmol) in pyridine (10.0 mL) was added sulfur trioxide pyridine complex (0.30 g, 1.94 mmol). The mixture was stirred at room temperature overnight and trated to provide a residue which was subjected to tography to give 87 (0.25 g, 83 %) as a white solid.

'H NMR (400 MHz, CD30D): 61.49 (9H, s), 1.83 (1H, m), 1.93 (1H, m), 2.07 (1H, m), 2.21 1O (1H, m), 3.07 (1H, d, J = 21.0 Hz), 3.27 (1H, m), 3.51 (2H, t, J = 5.2 Hz), 3.92 (1H, m), 3.95 (2H, t, J = 5.2 Hz), 4.15 (1H, m). 4 protons were not observed in CD30D.

MS (ES') m/z: [M-H]' calcd for C15H24N501OS: 466.12. Found: 466.01.

Step 6. )-N-[2-(Carbamoylamino)ethoxy]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 78,.Table 1) o o BocHN—U—N/\/0\NJI"’o l HzN—U—N/\/O‘NJO l H H .—~—> H H N N )—N\ }_—N\ O OSO3H O OSO3H 87 Compound 78, Table 1 15 To a mixture of tert—butyl ({2-[({[(2S,5R)oxo(sulfooxy)—1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]ethyl}carbamoyl)carbamate 87 (0.25 g, 0.54 mmol) in DCM (5.0 mL) was added trifluoroacetic acid (1.0 mL) at 0°C. The e was stirred at 0 °C for 0.5 h and at room temperature for 2 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 78 (Table 1) (11 mg, 5.6 %) as a white solid.

‘H NMR (400 MHz, D20): 188 (2H, m), 1.90-2.09 (2H, m), 2.98 (1H, d, J = 12.0 Hz), 3.17-3.21 (1H, m), 3.24 (2H, t, J = 5.2 Hz), 3.84 (2H, t, J = 5.2 Hz), 3.93 (1H, d, J = 7.6 Hz), 4.07 (1H, s). 5 protons were not observed in D20.

HPLC: 85.17 % MS (ES') m/_z: [M-H]"calcd for N5088: 366.07. Found: 365.96. 147147 Example 18 Disodium [({[(2S,5R)oxo(sulfonatooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]acetate (Compound 82, Table 1) /O‘NJII"QCiH «H //L—N o ‘ososNa Step 1. tert-Butyl [({[(2S,5R)(benzyloxy)oxo-1,6-diazabicyc|o[3.2.1]oct yl]carbonyl}amino)oxy]acetate (89) /H"~ ’ )l/ l' HO AOJK/O\NH2 k0 O \N )—.N\ /Bn ————_> PN\ /Bn 0 0 o o 1 89 To a on of (28,5R)(benzyloxy)oxo-1,6—diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added utyl (aminooxy)acetate 88 (0.13 1O g, 0.86 mmol, Organic Letters, 2002, 4(6) 869-872), 1—hydroxybenzotriazole (0.15 g, 1.11 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.10 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and trated under vacuum. The residue was purified by column chromatography to give ted-butyl [({[(28,5R)(benzyloxy)-7—oxo-1 ,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]acetate 89 (0.23 g, 79 %) as a white solid. 1H NMR (400 MHz, CDCl3): 6 1.49 (9H, s), 1.65 (1H, m), 1.98 (2H, m), 2.33 (1H, m), 2.72 (1H, d, J = 11.6 Hz), 2.99 (1H, d, J = 11.2 Hz), 3.30 (1H, s), 3.95 (1H, d, J = 7.2 Hz), 4.34 (2H, m), 4.89 (1H, d, J =11.2 Hz), 5.04 (1H, d, J = 12.0 Hz), 7.39 (5H, m), 9.68 (1H, br s).

Step 2. tert-Butyl [({[(2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]acetate (90) O ii 0 i) o/,U\/ l 0 /'~. /U\/o / \N ‘ o \N H —__——> H N -III H N .111 H //l—N\O/Bn )——N\ o 0 OH 148148 To a solution of tert—butyl [({[(2S,5R)—6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]acetate 89 (0. 23 g, 0.57 mml) in methanol (20 mL) was added 5 % Pd/C (0.30 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room ature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give terf-butyl [({[(28,5R)-6—hydroxyoxo-1,6—diazabicyclo[3,2.1]oct yl]carbonyl}amino)oxy]acetate 90 (0.16 g, 89 %) as a clear thick oil. 1H NMR (400 MHz, CD30D): 6 1.48 (9H, s), 1.77 (1H, m), 1.90 (1H, m), 2.06 (1H, m), 2.20 (1H, m), 3.10 (2H, m), 3.70 (1H, m), 3.84 (1H, d, J = 7.2 Hz), 4.35 (2H, m), 2 protons were not observed in CD30D. 1O Step 3. tert-Butyl [({[(ZS,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]acetate pyridine salt (91) o O o t l l JK/O\ /Il’r. o\ / o N O N H ——————> N --||H N .ulH }———‘N )tN\ O O OH \QsoaH . pyridine 90 91 To a solution of terf—butyl [({[(2S,5R)hydroxy—7—oxo-1,6—diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]acetate 90 (0.16 g, 0.51 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.325 g, 2.04 mmol). The mixture was stirred at room temperature for 20 h, filtered and ated to give terf-butyl 8,5R)oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]'oct-2—yl]carbonyl}amino)oxy]acetate pyridine salt 91 (0.20 g crude) which was used in the next step without purification.

Step 4. Tributylbutanaminium [({(28,5R)[(2-tert-butoxy oxy)carbamoyl]oxo-1,6-diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide (92) O 0 0 01 O/U\/O\ﬁ/l"u':]H --~H ——“* O/U\/O\ﬁ Q T N ‘l‘ N -"'H Ar—N - ;—~ \osoaH ' . . \ .

O - pyridine O 0303 Bu4N 91 92 terf-Butyl [({[(2 S,5R)oxo(sulfooxy)—1 ,6—diazabicyclo[3.2,1]octyl]carbonyl}amino)oxy] acetate pyridine salt 91 (0.20 g, 0.51 mmol) was introduced into a concentrated aqueous solution of monosodium dihydrogen phosphate solution (8 mL) so as to obtain a pH of4. The mixture was washed with ethyl acetate, then added utyl ammonium hydrogen sulfate 149149 (0.10 g, 0.29 mmol) and stirred at room temperature for 10 min. The e was extracted with ethyl acetate (3 x 10 mL), and the extracts were combined, dried over sodium sulfate and evaporated to give N,N,N—tributylbutanaminium [({(2S,5R)—2-[(2-tert—butoxy oxoethoxy)carbamoyl]oxo-1,6-diazabicyclo[3.2.1]oct—6-yl}oxy)sulfony|]oxidanide 92 (0.15 g, 46 % in 2 steps) as a white solid. 1H NMR (400 MHz, CDCI3):51.01 (12H, t, J = 7.2 Hz), 1.42 (17H, m), 1.65 (9H, m), 1.90 (1H, m), 2.18 (1H, m), 2.34 (1H, m), 2.76 (1H, d, J = 11.6), 3.29 (9H, m), 3.91 (1H, d, J = 7.2 Hz), 4.34 (3H, m), 9.78 (1H, br 5).

Step 5. Disodium [({[(ZS,5R)oxo(sulfonatooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]acetate und 82, Table 1) (1 ' o o o +OkOﬁJI/ng "“6N NaO/lk/OHJLMQ~ o)—N )ﬁN b303- Bu4N+ O ‘osoaNa 92 nd 82, Table 1 To a solution ' of N,N,N—tributy|butanaminium [({(28,5R)—2-[(2-tert—butoxy oxoethoxy)carbamoyl]—7-oxo-1,6-diazabicyc|o[3.2.1]octyl}oxy)sulfonyl]oxidanide 92 (0.15 g, 0.24 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.50 mL, 6.49 mmol) dropwise at 0 °C. The reaction mixture was stirred for 1 h, then ated. The residue after washing with ether (3 x) was suspended in water (5 mL) and DOWEX 50WX4 (1 g) was added. The mixture was stirred at room temperature for 1 h, and then ed. The filtrate was freeze— dried, purified by HPLC and freeze-dried again to give disodium [({[(28,5R)Oxo (sulfonatooxy)-1,6-diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]acetate Compound '82 2O (Table 1) (0.012 g, 15%) as a white solid. 1H NMR (400 MHz, CD3OD):61.82(1H, m), 1.91 (1H, m), 2.06 (1H, m), 2.22 (1H, m), 3.09 (1H, d, J = 12.0 Hz), 3.24 (1H, d, J = 10.8 Hz), 3.92 (1H, d, J = 7.6 Hz), 4.14 (1H, m), 4.25 (2H, m), 1 proton was not observed in CD3OD. ’ HPLC 95.36% MS (ES‘): m/z [M-2Na+H]'= 337.86. 150150 Example 19 (2S,5R)Oxo-N-[(ZS)-pyrrolidinylmethoxy](sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 16, Table 1) Q.NH NJ,(? 0 OSOSH Step 1. tert-Butyl (2S)—2-{[({[(2S,5R)(Benzyloxy)oxo-1,6-diazabicyclo [3.2.1]octyl]carbony|}amino)oxy]methyl}pyrrolidinecarboxylate (94) J, 0 ' < :N HO "'—'—O—NH2 N ""H I I'»._O__N)JH"' )—~~ H N ”UH /Bn ’ o o N. /Bn To a mixture of (2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.200 g, 0.720 mmol, US 2005/20572 A1) in DCM (6.0 mL) were added tert—butyl (2S) [(aminooxy)methyl]pyrrolidinecarboxylate 93 (0.234 g, 1.085 mmol, US 2007/118830 A1), 1-hydroxybenzotriazole (0.147 g, 1.085 mmol) and 1-ethyl—(3-dimethylamino propyl) carbodiimide hloride (0.208 g, 1.085 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a e which was subjected to chromatography to give 94 (0.30 g, 88 %) as a white foam. 1H NMR (400 MHZ, : 8 1.47 (9H, s), 1.70 (1H, m), 1.94 (5H, m), 2.29 (1H, m), 2.89 (1H, d, J =12 Hz), 3.03 (1H, m), 3.27 (1H, m), 3.36 (2H, m), 3.73 (1H, m), 3.83 (1H, m), 3.93 (1H, m), 4.12 (1H, m), 4.89 (1 H, d, J = 11.2 Hz), 5.07 (1 H, d, J = 11.2 Hz), 7.41 (5H, m), 10.12 (1H, br 5). One proton was not observed in moisture-containing CDClg.

M8 (E87): m/z [M+H]+ calcd for Cz4H35N406: 475.26. Found: 475.38. 151151 Step 2. tert-Butyl (ZS)-2~{[({[(28,5R)—6-hydroxyoxo-1,6-diazabicyclo[3.2.1] oct- 2-yl]carbonyl}amino)oxy]methyl}pyrrolidinecarboxylate (95) Q“/Boc O 800 )1 Q“ j N H N uan O \O/Bn }—N\ 94 95 O OH A mixture of tert—butyl (28){[({[(28,5R)(benzyloxy)—7-oxo-1,6-diazabicyclo [3.2.1]oct yl]carbonyl}amino)oxy]methyl}pyrrolidinecarboxylate 94 (0.30 g, 0.63 mmol) and Pd/C (0.10 g) in methanol (10 mL) was enated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to e 95 (0.26 g, quant. yield) as a white foam. 1H NMR (400 MHz, CD30D): 6 1.46 (9H, s), 1.72-2.22 (7H, m), 3.06 (1H, m), 3.12 (1H, m), 3.30 (3H, m), 3.69 (1H, m), 3.37-4.05 (4H, m). 2 protons were not ed in CD30D.

MS (ES+) m/z: [M+H]+ calcd for C17H29N406: 385.21. Found: 385.33.

Step 3. tert-Butyl (ZS){[({[(2S,5R)Oxo(sulfooxy)-1,6-diazabicyclo [3.2.1]octy|]carbonyl}amino)oxy]methyl}pyrro|idinecarboxy|ate (96) /B00 :N/Boc O < :N j I’. Jul” I’u.

'--O—N '0 ”'-——O_N ————> I H H > -'”H )— NQHIHN o ‘oso H 95 3 - O OH 96 To a mixture of tert-butyl (28)—2-{[({[(28,5R)—6-hydroxyoxo-1,6—diazabicyclo[3.2.1] oct bonyl}amino)oxy]methyl}pyrrolidinecarboxylate 95 (0.26 g, 0.67 mmol) in pyridine (10.0 mL) was added sulfur trioxide pyridine complex (0.32 g, 2.03 mmo|). The mixture was stirred at room temperature for 23 h and concentrated to provide a residue which was subjected to chromatography to give 96 (0.20 g, 64 %) as a white solid. 1H NMR (400 MHz, CD3OD): 6 1.46 (9H, s), 1.83-2.18 (7H, m), 3.10 (2H, m), 3.27 (2H,‘m), 3.72-4.10 (5H, m), 4.15 (1H, m). 2 protons were not observed in CD30D.

MS (ES'): m/z [M-H]' calcd for C17H27N4OQS: 463.15. Found: 463.22. 152152 Step 4. (ZS,5R)Oxo-N-[(2S)-pyrrolidinylmethoxy](sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 16, Table 1) ‘ “\o—N/l“3 N H t , )1,“ O N M N “'H ———> H N -IIH )—Nt N O. 0303” o ‘osoaH compound 16, Table 1 To a mixture of tenf—butyl (28){[({[(28,5R)oxo(sulfooxy)-1,6-diazabicyclo [3.2.1]oct yl]carbony|}amino)oxy]methyl}pyrrolidinecarboxylate 96 (0.20 g, 0.43 mmol) in DCM (4.0 mL) was added trifluoroacetic acid (0.20 mL) at 0°C. The mixture was stirred at 0°C for 1 h and at room temperature for 2h, concentrated and washed with ether. The white solid was collected by centrifugation. Half of the crude product was ed by preparative HPLC (3 % MeOH in water) to provide Compound 16 (Table 1) (12 mg) as a white solid. 1O ‘H NMR (400 MHz, D20): 61.60-2.05 (8H, m), 3.03-3.15 (2H, m), 3.20 (2H, m), 3.78—3.90 (3H, m), 4.00-4.05 (2H, m). 3 s were not observed in 020.

HPLC: 96.10 % MS (ES‘): m/z [M-H]' calcd for C12H19N4O7S: 363.10. Found: 363.16.

Example 20 '15 (ZS,5R)-N-Methoxyoxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarboxamide und 28, Table 1) O\NJII’I,Q3H N --~H )—~. 0 0803H Step 1. (2S,5R)(Benzyloxy)-N-methoxyoxo-1,6-diazabicyclo[3.2.1]octane carboxamide (98): o HaC\ c|:H3 o I o—NHZ .HCl HO (IN/U]. 97 H N ,Bn N~ ,Bn 0 O O O 98 153153 To a mixture of (2S,5R)—6-(benzyloxy)—7-oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.334 g, 1.21 mmol) in DCM (25.0 mL) were added O-methylhydroxylamine 97 (0.193 g, 2.31 mmol), 1-hydroxybenzotriazole (0.25 g, 1.85 mmol), 1-ethy|—(3—dimethylaminopropyl) carbodiimide hydrochloride (0.35 g, 1.82 mmol) and 4-di(methylamino)pyridine (0.34 g, 2.78 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide airesidue, which was subjected to chromatography to give (2S,5R)(benzyloxy)-N—methoxyoxo-1 ,6— diazabicyclo[3.2.1]octanecarboxamide 98 (0.17 g, 46 %) as a white foam. 1H NMR (400 Cl3):61.67(1H, m), 1.99 (2H, m), 2.30 (1H, m), 2.80 (1H, d, J = 11.6 Hz), 3.01 (1H, m), 3.33 (1H, m), 3.77 (3H, s), 3.92 (1H, d, J: 7.6 Hz), 4.87 (1H, d, J =.11.6 Hz), 4.98 (1H, d, J: 11.6 Hz), 7.36 (5H, m), 9.34 (1H, br 5).

Step 2. (28,5R)hydroxy-N-methoxy-7—oxo-1,6-diazabicyclo[3.2.1]octane carboxamide (99): CH3 0 , c 0‘ /UII’I. 6 I é—N. ‘ ,Bn //L——N o 0 ~ A mixture of (2S,5R)(benzyloxy)-N-methoxyoxo-1,6-diazabicyclo[3.2.1]octane carboxamide 98 (0.17 g, 0.56 mmol) and 5 % Pd/C (0.2 g) in methanol (15 mL) was hydrogenated at 10 psi for 1 h. The mixture was filtered through Celite pad and concentrated to provide (2S,5R)—6—hydroxy-N-methoxyoxo-1,6-diazabicyclo[3.2.1]octane-2—carboxamide 99 (0.12 g, quant. yield) as a white foam. 1H NMR (400 MHz, : 5 1.78-2.23 (4H, m), 3.03 (1H, d, J = ), 3.11 (1H, m), 3.50 (4H, m), 3.81 (1H, d, J = 7.6 Hz). 2 protons were not observed in CD30D.

Step 3. (2S,5R)-N—methoxyoxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane amide (Compound 28, Table 1) O 0| H3C\O~N/HIII' H H3C\O'u/l/’l' N "H ——> N ~»H 2—N )—N. 0 ‘OH o OSOaH compound 28, Table 1 154154 To a mixture of (2S,5R)hydroxy-N-methoxyoxo-1,6—diazabicyclo[3.2.1]octane carboxamide 99 (0.12 g, 0.55 mmol) in pyridine (7.0 mL) was added sulfur trioxide pyridine complex (0.35 g, 2.20 mmol). The mixture was stirred at room temperature for 23 h and concentrated to provide a residue, which was purified by chromatography and again purified by HPLC and -dried to give (28,5R)-N—methoxyoxo-6—(sulfooxy)-1,6- icyclo[3.2.1]octane-2—carboxamide compound 28 (Table 1) (0.02 g, 12 %) as a white solid. 1H NMR (400 MHz, CD30D): 6181-196 (2H, m), 2.09 (1H, m), 2.21 (1H, m), 3.09 (1H, d, J = 11.6 Hz), 3.24 (1H, m), 3.71 (3H, s), 3.90 (1H, d, J: 6.8 Hz), 4.14 (1H, m). 2 protons were not observed in CD30D.

HPLC 96.87 % MS (ES‘): m/z [M-H]‘= 293.89 Example 21 ' (28,5R)-N-[(1-methyl-1H-imidazoIyl)methoxy]oxo—6-(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 137, Table 1) . N n’ O N\Z*_\b-N/Lh| N . IlH J—M 9 O O—ﬁ—OH.

Step 1. )(benzyloxy)—N-[(1-methyl-1H-imidazolyl)methoxy]oxo-1,6- diazabicyclo[3.2.1]octanecarboxamide (101) 1 , 101 To a mixture of (2S,5R)-6—(benzyloxy)—7—oxo-1,6—diazabicyclo[3.2.1]octane—2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) was added 5-[(aminooxy)methyl]methyl-1H- imidazole 100 (0.172 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1- 155155 ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was ted to chromatography to give 101 (0.40 g, quantitative yield) as a white foam.

MMhMt,CDCM:6156UH,m)191QH,mL221UH,mL265(Hld,J=120 Hz), 2.95 (1H, d, J = 11.6 Hz), 3.30 (1H, s), 3.82 (3H, s), 3.91 (1H, d, J = 11.2 Hz), 4.84 (3H, n0,504(1H,d,J=1113H3,705(1H,$,733(5H,n0,762(1H,s) MS (ES+) m/z: [M+H]+ calcd for C19H24N504: 386.2. Found: 386.1.

Step 2. )hydroxy-N-[(1-methyl-1H-imidazolyl)methoxy]oxo—1,6- diazabicyclo[3.2.1]octanecarboxamide (102) N/ .

/ . N O h/ 0 ~91)va may“...

H G N -IlH N . IIH 02—N‘0Aph O)—N\OH 101 . 102 A mixture of (2S,5R)(benzyloxy)—N—[(1-methyl-1H-imidazol-5—yl)methoxy]-7—oxo-1,6— diazabicyclo[3.2.1]octanecarboxamide 101 (0.40 g, 0.90 mmol) and Pd/C (0.13 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give a residue which was subjected to chromatography to give 102 (0.21 g, 75 %) as a white foam. 1H NMR (400 MHz, CD30D): 5E1.74 (1H, m), 1.89 (1H, m), 2.04 (1H, m), 2.15 (1H, m), 2.91 (1H, d, J = 12.0 Hz), 3.09 (1H, m), 3.67 (1H, s), 3.79 (1H, d, J = 6.8 Hz), 3.85 (3H, s), 4.92 (2H, m), 7.07 (1H, s), 7.73 (1H, s). 2 protons were not ed in CD30D.

MS (ES+) m/z: [NH'H]+ CalCd for C12H18N504: 29613 Found: 29610 Step 3. (2S,5R)-N-[(1-methyl-1H-imidazolyl)methoxy]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 137, Table 1).

/ / N - ﬁ/ O N NJ—ﬂo_N/Hl“- N'r\/)—~\O_N/UI’H0 )—-——N\ 0 )———~N 0H 0 \OSOﬁi 102 Compound 137, Table 1 156156 To a mixture of )-6—hydroxy-N-[(1-methyl-1H-imidazolyl)methoxy]oxo-1,6- diazabicyclo[3.2.1]octane—2-carboxamide 102 (0.21 g, 0.71 mmol) in pyridine (6 mL) was added sulfur trioxide pyridine complex (0.33 g, 2.13 mmol). The mixture was stirred at room temperature for 23 h and concentrated to provide a residue which was subjected to flash chromatography to give Compound 137 (Table 1) (64 mg) as a white solid. 1H NMR (400 MHz, 020): 8:1.62 (1H, m), 1.75 (1H, m), 1.91 (2H, m), 2.82 (1H, d, J: 11.6 Hz), 3.13 (1H, d, J = 11.2 Hz), 3.86 (3H, s). 3.89 (1H, s), 4.05 (1H, s), 4.93 (2H, s), 7.49 (1H, s), 8.61 (1H, 5). Two s were not observed in D20.

HPLC: 98.14 % MS (ES‘) m/z: [M-H]' calcd for C12H16N5O7S: 374.1. Found: 373.9.

Example 22 1-(Acetyloxy)ethyl (3S)[({[(ZS,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct bonyl}amino)oxy]pyrrolidinecarboxylate (Compound 101, Table 1) o 0‘” N N ”H O O }——N >—o o ‘osogH Step 1. 1-(Acetyloxy)ethy| (3S)[({[(2S,5R)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]pyrrolidinecarboxy|ate (Compound 101, Table 1) do\u/L’r,,(/\]‘i O 0 N02 HN N vIIH + /U\oAOJLO J: i 2““! o ‘osogH compound 2, Table 1 103 o\ )l,,_ O O )—N >Lo o, ‘oso3H compound 101, Table 1 To a mixture of (28,5R)—7—oxo-N-[(3S)-pyrrolidinyloxy]-6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide Compound 2 (Table 1) (0.030 g, 0.086 mmol, 157157 Example 2) in DMF (dimethyl formamide) (1.5 mL) was added 1-{[(4- nitrophenoxy)carbonyl]oxy}ethyl acetate 103 (0.027 g, 0.102 mmol, J. Med. Chem, 1988, vol 31, 2, p318-322) and triethylamine (0.023 mL, 0.171 mmol) sequentially at room temperature.

The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography and preparative HPLC to give Compound 101 (Table 1) (0.011g) as a white solid. 1H NMR (400 MHz, CD30D): 61.47 (3H, m), 1.82-2.00 (2H, m), 2.04-2.06 (3H, m), 2.10 (1H, m), 2.27 (2H, m), 3.08 (1H, dd, J = 4.2, 12.0 Hz), 3.24—3.30 (2H, m), 3.41-3.53 (3H, m), 3.65 (1H, m), 3.94 (1H, d, J = 7.6 Hz), 4.15 (1H, s), 4.62 (1H, s), 6.76 (1H, m). 2 protons were not ed in CD30D.

HPLC: 86.89 % MS (ES‘): m/z [M-H]‘ calcd for C16H23N4O11S: 479.11. Found: 479.04.

Example 23 (2S,5R)oxo-N—(piperidinylmethoxy)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide oroacetate (Compound 50, Table 1) GAO‘N/U/higH H N -IIH )—N 0 ‘ 0 ‘o—:s:-0H ' 0 Step 1. utyl 2-[(aminooxy)methyl]piperidinecarboxylate (105) Boc 0 1 §0C 104 105 To a mixture of tert—butyl 2-{[(1,3-dioxo-1,3-dihydro—2H—isoindol-2—yl)oxy]methyl}piperidine carboxylate 104 (1.50 g, 4.16 mmol) in a solution of methanol (20 mL) was added methylhydrazine hydrate (4.16 mmol) at room temperature. The mixture was stirred at room temperature ght, filtered and concentrated to e a residue which was ted to chromatography to give 105 (0.50 g, 53 %) as a white solid. 1H NMR (400 MHz, CDCI3): 5 1.36-1.60 (15H, m), 2.75 (1H, m), 3.53 (1H, m), 3.91 (2H, m), 4.57 (1H, br s), 5.70 (2H, br s). 158158 Step 2. . tert-butyl 2-{[({[(ZS,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1] oct yl]carbony|}amino)oxy]methyl}piperidinecarboxylate (106) O'NHZ J///,(? 800 0 1 05 /u//,’ 1 106 To a mixture of (2S,5R)(benzyloxy)—7—oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tyl 2- [(aminooxy)methyl]piperidinecarboxylate 105 (0.312 g, 1.358 mmol), 1- ybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to 1O provide a residue which was subjected to chromatography to give 106 (0.40 g, 91 %) as a white foam. 1H NMR (400 MHz, : 6 1.41 (9H, m), 1.61 (6H, m), 1.97 (2H, m), 2.29 (1H, m), 2.78 (3H, m), 2.97 (1H, m), 3.26 (1H, m), 3.70 (1H, m), 3.99 (2H, m), 4.15 (1H, m), 4.51 (1H, m), 4.88 (1H, d, J = 11.6 Hz), 5.06 (1H, m), 7.42 (5H, m). One proton was not observed in moisture containing CDCl3.

MS (ES‘) m/z: [M—H]' calcd for C25H35N405: 487.2. Found: 487.1.

Step 3. tert-butyl 2-{[({[(ZS,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbony|}amino)oxy]methyl}piperidinecarboxylate (107) ° NjN Bee //, )1”, " IIH 1070 A mixture of tert—butyl 2~{[({[(2$,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbony|}amino)oxy]methyl}piperidinecarboxylate 106 (0.40 g, 0.82 mmol) and Pd/C (0.13 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give 107 (0.33 g, quantitative yield) as a white foamf 159159 1H NMR (400 MHz, CD30D): 51.45 (9H, s), 1.60 (5H, m), 1.80 (2H, m), 1.93 (1H, m), 2.04 (1H, m), 2.21 (1H, m), 2.84 (1H, m), 2.99 (1H, m), 3.31 (1H, m), 3.68 (1H, s), 3.89 (1H, s), 4.02 (3H, m), 4.47 (1H, m). Two protons were not observed in CD30D.

MS (ES+) m/z: [M+H]+ calcd. For C15H31N406: 399.2. Found: 399.1.

Step 4. tert-butyl 2-{[({[(28,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]methyl}piperidinecarboxylate (108) mf::l [:ET/\O_N,ﬂ:r::lHHo Ho—s—OH 1070108 5 To a mixture of utyl 2-{[({[(2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct—2- y|]carbonyl}amino)oxy]methy|}piperidinecarboxylate 107 (0.33 g, 0.83 mmol) in pyridine (4.0 mL) was added sulfur trioxide pyridine complex (0.38 g, 2.48 mmol). The e was stirred at room temperature for 23 h and concentrated to provide a residue which was subjected to chromatography to give 108 (0.27 g, 69 %) as a white foam. lH NMR (400 MHz, CD30D): 51.45 (10H, m), 1.63 (4H, m), 1.84 (2H, m), 1.92 (1H, m), 2.06 (1H, m), 2.21 (1H, m), 2 87 (1H, m), 3.09 (1H, m), 3.24 (2H, m), 3.91 (2H, m), 4.03 (1H, m), 4.11 (1H, m), 4.46 (1H, m). Two protons were not observed in CD30D.

Step 5. (28,5R)—7-oxo-N-(piperidinylmethoxy)(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide trifluoroacetate (Compound 50, Table 1) 8% O [::]//\Oﬁu/JH”0 H --—-——————-> O—N’JL“ TFA N "'H N ”H }——N\ O O § \ 0 o—s—OH O o 108 Compound 50 1 , Table To a mixture of tert-butyl 2-{[({[(2S,5R)-7—oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct bonyl}amino)oxy]methyl}piperidinecarboxy|ate 108 (0.27 g, 0.58 mmol) in DCM (8.0 mL) was added trifluoroacetic acid (0.40 mL) at 0°C. The mixture was stirred at 0°C for 3 h, concentrated and washed with ether, EtOAc and DCM to give TFA salt of nd 50 (Table 1) (61 mg) as a white solid as a pair of diastereomers. 160160 1H NMR (400 MHz, D20): 81.38 (2H, m), 1.54 (1H, m), 1.75 (5H, m), 2.01 (2H, m), 2.85 (1H, m), 3.00 (1H, m), 3.21 (1H, m), 3.36 (2H., m), 3.91 (3H, m), 4.08 (1H, s). Three protons were not observed in D20.

HPLC: 95.23 % MS (ES‘) m/z: [M-H]' calcd for N4O7S: 377.1. Found: 377.0.

Example 24 Sodium ({[(2S,5R)({[(3S)methylpyrrolidinyl]oxy}carbamoyl)oxo-1,6- icyclo[3.2.1]octyl]oxy}sulfonyl)oxidanide (Compound 149, Table 1) OMCiH N N “‘H / o)—~N‘osoaNa 1O Step 1. (28,5R)—6-(benzyloxy)-N-{[(3S)methylpyrrolidinyl]oxy}oxo-1,6- diazabicyclo[3.2.1]octane—2-carboxamide (110) HoJl/n. / 0le 109 @9111) N N "‘H //"—N\O/\ 02—N‘04 Ph Ph To a mixture of (28,5R)(benzy|oxy)oxo—1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.25 g, 0.90 mmol, U82005/20572 A1, 2005) in DCM (20 mL) was added (3S)—3- (aminooxy)methylpyrrolidine 109 (0.32 g, 1.39 mmol, J. Med. Chem., 2008, 51, 4601- 4608), 1-hydroxybenzotriazole (0.18 g, 1.33 mmol), and 1-ethyI-(3-dimethylamino propyl) carbodiimide hydrochloride (0.26 g, 1.36 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, then concentrated in vacuo to provide a residue, which was subjected to chromatography to give 110 (0.26 g, 77 %) as a yellow foam. 1H NMR (400 MHz, : 6 1.60 (1H, m), 2.00 (4H, m), 2.26 (4H, m), 2.71 (1H, d, J = 11.7 Hz), 2.84 (1H, m), 2.93 (4H, m), 3.12 (1H, m), 3.30 (1H, m), 3.97 (1H, d, J = 6.3 Hz), 4.74 (1H, br s), 4.90 (1H, d, J =11.3 Hz), 5.04 (1H, d, J = 11.3 Hz), 7.39 (5H, m).

MS (ES+) m/z: [M+H]+ calcd for C19H27N4O4: 375.20. Found: 375.21 161161 Step 2. (23,5R)hydroxy-N-{[(3S)methylpyrrolidinyl]oxy}oxo-1,6- diazabicyclo[3.2.1]octanecarboxamide (111) 001113‘i (j‘W'Q| N N "'H N N "'H / %N o ‘0“):h 0 OH 110 111 A mixture of (2S,5R)—6-(benzyloxy)—N—{[(3S)methylpyrrolidin-3—yl]oxy}oxo-1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide 110 (0.26 g, 0.69 mmol) and Pd/C (0.50 g) in methanol (25 mL) was hydrogenated at 20 psi at room temperature for 2 hours. The mixture was filtered through a Celite pad and concentrated to provide 111 (0.20 g) as a white foam. 1H NMR (400 MHz, CD30D): 6 1.99 (3H, m), 2.29 (3H, m), 2.99 (3H, s), 3.03 (1H, d, J = 11.7 Hz), 3.15 (1H, m), 3.41 (2H, m), 3.66 (2H, d, J = 13.3 Hz), 3.71 (1H, br s), 3.89 (1H, d, J = 7.8 Hz), 4.74 (1H, m). 2 protons were not observed in CD30D.

MS (ES+) m/z: [M+H]+ calcd for C12H21N4O4: 285.16. Found: 285.19.

Step 3. Sodium ({[(ZS,5R)({[(3S)methy|pyrrolidinyl]oxy}carbamoyl) oxo-1,6-diazabicyclo[3.2.1]octyl]oxy}sulfonyl)oxidanide (Compound 149, Table O 1 M @0110 / )— N N‘ O O OH' ‘osoaNa 111 Compound 149, Table 1 To a mixture of (2S,5R)-6—hydroxy—N—{[(3S)—1-methylpyrrolidinyl]oxy}oxo-1,6- diazabicyclo[3.2.1]octanecarboxamide 111 (0.21 g, 0.74 mmol) in pyridine (5 mL) was added sulfur trioxide pyridine complex (0.24 g, 1.51 mmol). The mixture was stirred at room temperature overnight. The e was concentrated in vacuo, then d with toluene and concentrated in vacuo (repeated twice). The residue was washed with DCM, then the organics were decanted off to giVe a sticky residue (repeat twice). The e Was dried to give an off white solid. The crude product was passed through a resin column (DOWEX 50W X4) eluting with water, then lyophilized to afford Compound 149 (Table 1) (0.017 g, 8 %, over 2 steps) as sodium salt as a white solid. 162162 1H NMR (400 MHz, D20):51.76(2H, m), 1.97 (2H, m), 2.15 (1H, m), 2.28 (1H, m), 2.84 (3H, s), 2.99 (1H, d, J: 12.1 Hz), 3.16 (1H. d. J: 12.5 Hz), 3.30 (2H, br m), 3.54 (2H, br s), 3.92 (1H, d, J = 5.5 Hz), 4.05 (1H, d, J = 3.1 Hz), 4.65 (1H, m), 2 protons were not observed in DZO.

HPLC: 93.67 %.

MS (ES') m/z: [M-H]' calcd for C12H19N40782 363.10. Found: 363.05.

Example 25 (ZS,5R)-N-{[trans(methylamino)cyclopentyl]oxy}oxo(suIfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Com pound 45, Table 1) .'0| .

HN .gH.\ \ O O— -OH Step 1. cis(methylamino)cyclopentanol (113) E300 OH H~~<j —+ . WCW 112 113 To an ice-cold mixture of tert-butyl [cis (1R,3R)hydroxycyclopentyl]carbamate 112 (0.32 g, 1.59 mmol, U82005/54658 A1 ,, 2005) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (1 M solution in tetrahydrofuran, 3.2 mL, 3.2 mmol). The mixture was refluxed for 4 hours, cooled to room temperature then ed with a m amount of saturated sodium sulfate on. Solid sodium sulfate was added to the mixture to give a suspension. The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to afford 113 as colorless oil. The oil was used in the next step without further purification. 1H NMR (400 MHz,CDCl3):51.54(1H, m), 1.66 (1H, m), 1.83 (4H, m), 2.38 (3H, s), 3.21 (1H, m), 4.24 (1H, m).

MS (ES+) m/z: [M+H]+ calcd for CsH14NO: 116.11. Found: 116.05. 163163 Step 2. tert-butyl (cishydroxycyclopentyl)methylcarbamate (114) HN~O/ §°° OH / ——> N / \O/ To a mixture of cis—3-(methylamino)cyclopentanol 113 (1.59 mmol) in DCM (20 mL) was added di—terf-butyldicarbonate (0.35 g, 1.59 mmol) followed by triethylamine (0.45 mL, 3.23 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo to give a yellow oil which was purified by chromatography to give 114 (0.18 g, 52 %, over 2 steps) as a white foam. 1H NMR (400 MHz, : 5 1.46 (9H, s), 1.64 (2H, m), 1.79 (2H, m), 1.94 (1H, m), 2.18 (1H, ddd, J = 15.1, 9.2, 5.9 Hz), 2.83 (3H, s), 4.23 (2H, m). 1 proton was not observed in 00013.

MS (ES+) m/z: [M+H]+ calcd for C11H21N03: 216.16. Found: 216.15.

Step 3. tert-butyl [(1,3-dioxo-1,3-dihydro-2H—isoindol yl)oxy]cyclopentyl}methylcarbamate (115) $06 OH $00 O\N N N / U —» 7 <3 114 115 An ice-cold mixture of terf—butyl (cishydroxycyclopentyl)methylcarbamate 114 (0.19 g, 0.88 mmol), N-hydroxyphthalimide (0.29 g, 1.78 mmol), and triphenylphosphine (0.46 g, 1.75 mmoL) in tetrahydrofuran (10 mL) was treated with diisopropylazodicarboxylate (0.40 g, 1.98 mmol). The e was stirred at room temperature ght, then concentrated in vacuo to a yellow foam which was purified by chromatography to give 115 (0.19 g, containing DlAD uct) as a yellow oil. The mixture was used in the next step without further purification. 1H NMR (400 MHz, CDCI3):51.69(2H, m), 2.04 (2H, m), 2.20 (2H, m), 2.77 (3H, s), 4.95 (2H, m), 7.76 (2H, m), 7.85 (2H, m).

.MS (ES+) m/z: [M+H]+ calcd for C19H25N205: 361.18. Found: 361.15.

Step 4. tert-butyl [trans(aminooxy)cyclopentyl]methylcarbamate (116) B00 0 B00 0 /HI @ —~ /HI - O 115 116 164164 A mixture of tert-butyl {trans-3—[(1,3-dioxo-1,3-dihydro-2H-isoindol yl)oxy]cyclopentyl}methylcarbamate 115 (0.19 g, 0.53 mmol) was treated with hydrazine hydrate (0.03 g, 0.60 mmol). The mixture was stirred at room temperature for 2 hours. The solid was filtered off and the filtrate was concentrated in vacuo. The e was diluted with DCM, and the insoluble solid was filtered off. The filtrate was concentrated in vacuo to give an oil which was purified by tography to give 116 (0.09 g, 44 % over 2 steps) as a light yellow oil. 1H NMR (400 MHz, CDCla): 5 1.46 (9H, s), 1.53 (1H, m), 1.68 (2H, m), 1.95 (3H, m), 2.72 (3H, s), 4.20 (1H, m), 4.60 (1H, br s), 5.28 (2H, br s).

MS (ES+) m/z: [M+H]+ calcd for C11H22N203: 231.17. Found: 231.15.

Step 5. tert-butyl {trans[({[(ZS,5R)(benzyloxy)oxo-1,6- diazabicyclo[3.2.1]octyI]carbonyl}amino)oxy]cyclopentyl}methylcarbamate (117) 1 117 To a mixture of (28,5R)—6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.25 g, 0.90 mmol, U82005/20572 A1, 2005) in DCM (20 mL) was added utyl [trans- 3-(aminooxy)cyclopentyl]methylcarbamate 116 (0.32 g, 1.39 mmol), 1-hydroxybenzotriazole (0.18 g, 1.33 mmol), and 1-ethyl-(3-dimethylamino propyl) carbodiimide hloride (0.26 g, 1.36 mmol) sequentially at room temperature. The mixture was d at room temperature for 6 hours, then concentrated in vacuo to provide a residue which was subjected to chromatography to give 117 (0.45 g, contains some byproduct) as a white foam. 1H NMR (400 MHZ, CDCIa): 5 1.45 (9H, s), 1.77 (10H, m), 2.31 (1H, m), 2.72 (3H, s), 2.78 (1H, dd, J = 11.3, 3.1 Hz), 3.15 (1 H, br d, J= 14.1 Hz), 3.30 (1 H, br s), 3.96 (1H, br d, J = 7.4 Hz), 4.60 (2H, m), 4.90 (1 H, d, J = 11.3 Hz), 5.05 (1H, d, J =11.3 Hz), 7.40 (5H, m).

MS (ES+) m/z: [M+H]+ calcd for C25H37N406: 489.27. Found: 489.20. 165165 Step 6. tert-butyl {trans[({[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct- 2-yl]carbonyl}amino)oxy]cyclopentyl}methylcarbamate (118) O O O‘NJL’h O\NJ//,’l gH QI‘IH H N AHH /N\ )~N /N, ‘oAph . o O Boc NbH A mixture of tert—butyl {trans[({[(28,5R)-6—(benzyloxy)—7—oxo-1,6—diazabicyclo[3.2.1]oct-2— yl]carbonyl}amino)oxy]cyclopentyl}methylcarbamate 117 (0.90 mmol) and Pd/C (0.50 g) in ol (20 mL) was hydrogenated at 30 psi at room temperature for 1 hour. The mixture was filtered through a Celite pad and concentrated to provide 118 (0.40 g) as a white foam. 1H NMR (400 MHz, 00300): 5 1.46 (9H, s), 1.80 (9H, m), 2.20 (1H, m), 2.74 (3H, s), 3.11 (2H, m), 3.70 (1H, br s), 3.83 (1H, d, J = 7.4 Hz), 4.50 (1H, br s), 4.67 (1H, m). 2 protons were not observed in CD30D.

MS (ES+) m/z: [M+H]+ calcd for C18H30N405: 399.22. Found: 399.15.

Step7. tert-butyl {trans[({[(28,5R)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]cyclopentyl}carbamate (119) O\NJ]'" 0‘” " gH QMH ———~——> g N "'H » /N, J—N. F? 118 119 To a mixture of tyl {trans[({[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct y|]carbony|}amino)oxy]cyclopentyl}methy|carbamate 118 (0.40 g, 1.00 mmol) in pyridine (10 mL) was added sulfur de pyridine complex (0.24 g, 1.50 mmol). The mixture was stirred at room temperature for 3 days. The reaction showed little conversion to the product by 1H NMR. Additonal sulfur trioxide pyridine complex (0.46 g, 2.90 mmol ) and pyridine (5 mL) were added to the mixture, and stirring was continued for 1 day. Conversion was 50 % by 1H NMR, so more sulfur trioxide pyridine complex (0.62 g, 3.90 mmol) and ne (10 mL) were added, and stirring was continued for 1 day. The solid was filtered off and the te was concentrated in vacuo. The residue was diluted with DCM and the solid was filtered off again. The filtrate was concentrated in vacuo, then subjected to chromatography to give 119 (0.20 g, 47 %, over 3 steps) as a pale yellow solid. 166166 1H NMR (400 MHz, CD30D): 5 1.46 (9H, s), 1.87 (9H, m), 2.19 (1H, m), 2.74 (3H, s), 3.10 (1H, d, J = 11.7 Hz), 3.27 (1H, m), 3.91 (1H, d, J = 7.0 Hz), 4.15 (1H, br s), 4.51 (1H, br s), 4.79 (1H, m). 2 s were not observed in CD30D.

MS (ES') m/z: [M-H]' calcd for C18H29N4OQS: 477.17. Found: .

Step 8. (28,5R)-N—{[trans(methylamino)cyclopentyl]oxy}oxo(sulfooxy)- 1,6-diazabicyclo[3.2.1]octanecarboxamide (Compound 45, Table 1) . o O\N 1;.

H O‘N/Uhu N --:H /N N\ gH i o Owl—1 // O)— O 3°C 0 0— -OH HN\ .

Compound 45, Table 1 To a mixture of tert-butyl methyl{trans-3—[({[(2 S,5R)oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]cyclopentyl}carbamate 119 (0.20 g, 0.42 1O mmol) in DCM (4.0 mL) was added trifluoroacetic acid (0.20 mL) at 0 °C. The mixture was stirred at 0 °C for 30 minutes, then at room temperature for.2 hours. The mixture was concentrated in vacuo to give a yellow oil, then diluted with diethyl ether and sonicated. The suspension was filtered to give an off-white solid. The solid was purified by trituating with methanol and diethyl ether to give a white suspension. The white solid was collected by vacuum tion (hygroscopic) to give a residue on the filter paper. Theresidue was washed with methanol and diethyl ether, and the washings were discarded. The e was dissolved in water and the aqueous solution was lyophilized to a white solid to afford Compound 45 (Table 1) (45 mg, 22 °/o, as a mixture of diastereoisomers, trifluoroacetate salt) as a white solid. 1H NMR (400 MHz, D20): 5 1.72 (6H, m), 1.98 (3H, m), 2.17 (1H, m), 2.28 (1H, m), 2.57 (3H, s), 2.98 (1H, dd, d, J= 12.1, 4.7 Hz), 3.19 (1H, d, J =11.7 Hz), 3.63 (1H, m), 3.94 (1H, d, J = 7.4 Hz), 4.07 (1H, d, J = 3.1), 4.50 (1H, d, J = 2.0 Hz). 2 protons were not observed in D20. 19F NMR (376 MHz, 020): 5 -76.05.

HPLC: 90.9 % MS (ES‘) m/z: [M-H]' calcd for N4O7S: 377.11. Found: 37705. 167167 Example 26 Sodium [({(2S,5R)[(1H-imidazoIylmethoxy)carbamoyl]oxo—1,6- diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide (Compound 142, Table 1) HNNN WO_Nj H N rllH )—N. 9 O O—§—ONa Step 1. tert-butyl4-{[(1,3-dioxo-1,3-dihydro-2H-isoindolyl)oxy]methyl}-1H- olecarboxylate (121) N—OH N O NN O Boo/NWOH'4 Boc\NVK—O—N ———-————-—~——> 12o . 121 0 To a mixture of 2-hydroxy-1H—isoindole—1,3(2H)-dione (2.70 g, 16.6 mmol); tert—butyl 4- xymethyl)—1H-imidazole-1—carboxy|ate 120 (Bu/I.Chem.Soc., Japan, 2002, Vol 75, No 1O 11, 526, 1.64 g, 8.27 mmol) and triphenylphosphine (4.34 g, 16.6 mmol) in THF (100 mL) was added DIAD (3.52 mL, 18.2 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a e which was subjected to chromatography to give 121 (1.7 g, 61 %) as a white foam.

‘H NMR (400 MHz, CDCl3):51.61 (9H, s), 5.17 (2H, m), 7.56 (1H, s), 7.64 (2H, m), 7.82 (2H, m), 8.01 (1H, s).

MS (ES+) m/z: [M+H]+ calcd for C17H13N305: 344.13. Found: 344.08.

Step 2. tert—butyl 4-[(aminooxy)methyl]—1H-imidazolecarboxylate (122) NN O NN BOC\N\/K_O_N>;,:© BOC\N«(j—NW O 122 To a mixture of tert—butyl 4-{[(1,3-dioxo-1,3-dihydro-2H-isoindolyl)oxy]methyl}-1H- imi‘dazole—1-carboxylate 121 (1.72 g, 5.00 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine hydrate (0.287 mL, 5.00 mmol) at room temperature. The mixture 168168 was stirred at room temperature overnight, filtered and concentrated to e a residue which was washed with ether and methanol to give 122 (0.54 g, 51 °/o) as a white solid. 1H NMR (400 MHz, : 5 1.62 (9H, m), 4.64 (2H, s), 5.51 (2H, br s), 7.38 (1H, s), 8.06 (1H, 3).

MS (ES+) m/z: [M+H]+ calcd for CgH15N3O3: 214.12. Found: 214.09.

Step 3. tert-butyl 4-{[({[(2$,5R)(benzyloxy)oxo-1,6-diazabicyclo [3.2.1]oct yI]carbonyl}amino)oxy]methyI}-1H-imidazolecarboxylate (123) O BOC\N\/k/ O—NH2 7\N O 3°C ”wk )1, \ )1.

HO ’1 ’ - 122 O—N .

N "'H H N IIIH 1 123 To a mixture of (28,5R)—6—(benzyloxy)—7—oxo—1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) was added tert—butyl 4-[(aminooxy)methyl]-1H— imidazolecarboxylate 122 (0.289 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and trated to provide a residue which was subjected to chromatography to give 123 (0.40 g, 94 °/o) as a colorless oii. lH NMR (400 MHz, CD013): 5 1.62 (9H, s), 1.95 (3H, m), 2.34 (1H, dd, J: 6.0, 14.4 Hz), 2.76 (1H, d, J = 11.6 Hz), 3.00 (1H, m), 3.29 (1H, s), 3.93 (1H, d, J = 6.8 Hz), 4.86 (3H, m), 5.06 (1H, d, J = 11.6 Hz), 7.40 (6H, m), 8.10 (1H, 5). One proton was not observed in moisture— cOntaining CDClg.

MS (ES+) m/z: [M+H]+ calcd for CZ3H30N506: 472.22. Found: 472.11.

Step 4. tert-butyl [(2$,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbony|}amino)oxy]methyl}-1H-imidazoIecarboxy|ate (124).

\N\ C? kN K /l/,, BOC‘Na /l”v,(1 ' o——N ________. O——N H N «H H N «H N )——N o ‘oAph 0 OH 169169 A mixture of terf-butyl 4-{[({[(2S,5R)(benzyloxy)oxo—1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]methy|}-1H-imidazolecarboxylate 123 (0.40 g, 0.85 mmol) and Pd/C (0.10 g) in methanol (15 mL) was hydrogenated at 1 atm at room temperature for 13 h. The mixture was filtered through Celite pad and concentrated to provide 124 (0.33 g, quantitative) as a white foam. 1H NMR (400 MHz, CD30D): 6 1.63 (9H, s), 1.80-2.20 (4H, m), 3.08 (2H, m), 3.69 (1H, s), 3.82 (1H, d, J = 7.6 Hz), 4.80 (2H, s), 7.64 (1H, s), 8.19 (1H, s). 2 protons were not observed in CD30D.

MS (ES+) m/z: [M+H]+ calcd for C15H24N505: 382.17. Found: 382.10. 1O Step 5. sodium ,5R)[(1H-imidazoIylmethoxy)carbamoyl]oxo-1,6- diazabiCyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide (Compound 142, Table 1) />N 0 RN 0 Boc\N\/ko—N/ll HN\/ko——N/l / l, H ——> H N ...H N «H )—N //L—N 0 _‘0H o 0803 Na 124 compound 142, Table 1 To a mixture of terf-butyl 4-{[({[(2S,5R)—6—hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]methyl}—1H-imidazolecarboxylate 124 (0.33 g, 0.86 mmol) in pyridine (10.0 mL) was added sulfur trioxide pyridine x (0.40 g, 2.60 mmol). The mixture was stirred at room temperature for 3 days and concentrated to provide a residue, which' was subjected to chromatography to give a yellow solid which was purified by ion- exchange resin (Dowex50 Na+ form, water) to give Compound 142 (Table 1) (10.7 mg) as a white solid. 1H NMR (400 MHz, D20): 61.57-176 (2H, m), .99 (2H, m), 2.79 (1H, d, J = 12.4 Hz), 2.06 (1H, d, J = 12.4 Hz), 3.83 (1H, d, J = 7.2 Hz), 3.99 (1H, m), 4.72 (2H, s), 7.14 (1H, s), 7.69 (1 H, s). 3 protons were not observed in D20.

HPLC: 87 %.

MS (ES‘) m/z: [M-Na]' calcd for C11H14N5078Na: . Found: 359.97. 170170 Example 27 (2S,5R)oxo-N-[2-(pyridinyI)ethoxy](sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide und 69, Table 1) O\NJ’/,l0| o ‘oso3H Step 1. (2S,5R)(benzyloxy)oxo-N-[2-(pyridinyl)ethoxy]-1,6- diazabicyclo[3.2.1]octanecarboxamide (126) 1 126 To a solution of (2S,5R)—6-(benzy|oxy)—7-oxo-1,6-diazabicycio[3.2.1]octane-2—carboxy|ic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added 2-[2-(aminooxy)ethyl]pyridine 125 (0.12 g, 0.86 mmol, J. Med. Chem. 1997, 40(15), 2363-2373), 1-hydroxybenzotriazole (0.14 g, 1.10 mmol) and 1-ethy|-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.10 mmol) at room temperature. The on mixture was stirred at room temperature ght, and then concentrated under vacuum. The residue was purified by column chromatography to give (28,5R)(benzyioxy)—7-oxo-N-[2-(pyridinyl)ethoxy]—1,6—diazabicyclo[3.2.1]octane- 2-carboxamide 126 (0.26 g, 91%) as a clear thick oil. 1H NMR (400 MHz, CDCI3): 51.62 (1H, m), 1.95 (2H, m), 2.30 (1H, m), 2.75 (1H, d, J: 11.6 Hz), 2.92 (1H, d, J: 11.2 Hz), 3.24 (3H, m), 3.95 (1H, d, J: 7.6 Hz ), 4.27 (2H, m), 4.87 (1H, d, J: 11.2 Hz), 5.02 (1H, d, J: 11.2Hz), 7.34 (6H, m), 7.70 (1H, d, J: 8.0 Hz ), 7.79 (2H, m), 8.53 (1H, br s). 171171 Step 2. )hydroxyoxo-N-[2-(pyridinyl)ethoxy]-1,6- diazabicyclo[3.2.1]octanecarboxamide (127) To a solution of (28,5R)—6-(benzyloxy)oxo-N—[2-(pyridinyl)ethoxy]-1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide 126 (0.26 g, 0.65 mml) in ol (20 mL) was added 5% Pd/C (0.25 g). The mixture was hydrogenated at 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the te was evaporated to give (2S,5R)hydroxyoxo-N-[2-(pyridinyl)ethoxy]-1 ,6- diazabicyclo[3.2.1]octanecarboxamide 127 (0.10 g, 50%) as a white foam. 1O 1H NMR (400 MHz, CDCl3): 8 1.78 (1H, m), 1.97 (1H, m), 2.11 (1H, m), 2.28 (1H, m), 2.91 (1H, d, J = 12.0 Hz), 3.20 (2H, m), 3.70 (1H, s), 3.97 (1H, d, J = 7.6 Hz), 4.26 (2H, m), 7.30 (2H, m), 7.72 (2H, m), 8.47 (1H, s), 1 proton was not observed.

Step 3. (28,5R)oxo-N—[2-(pyridinyl)ethoxy](su|fooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 69, Table 1) o o OWL, otNJL.

N ———-> / )———N\OH / o Dyi—N‘osoaH 127 Compound 69, Table 1 To a solution of (2 S,5R)—6-hydroxyoxo-N-[2-(pyridinyl)ethoxy]-1 ,6- diazabicyclo[3.2.1]octanecarboxamide 127 (0.10 g, 0.33 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.30 g, 1.88 mmol).

The mixture was stirred at room temperature for 20 h, filtered and evaporated. The residue 2O was purified by HPLC and freeze dried to give (28,5R)oxo-N-[2—(pyridinyl)ethoxy] oxy)-1,6-diazabicyclo[3.2.1]octane-2—carboxamide Compound 69 (Table 1) (0.00259, 2%) as a white solid. 1H NMR (400 MHz, CD3OD): 8 1.83 (1H, m), 1.91 (1H, m), 2.08 (1H, m), 2.21 (1H, m), 3.06 (1H, d, J =12.0 Hz), 3.13 (2H, t, J = 6.4 Hz), 3.25 (1H, m), 3.86 (1H, d, J = 7.2 Hz), 4.14 (1H, s), 4.23 (2H, t, J = 6.4 Hz), 7.27 (1H, m), 7.46 (1H, d, J = 8.0 Hz), 7.76 (1H, m), 8.45 (1H, d, J = 2.4 Hz), 2 protons were ot observed in CD30D. 172172 HPLC: 76.3% MS (ES'): m/z: [M]'= 385.06 Example 28 sodium ,5R)oxo—2-{[(5-oxopyrrolidinyl)oxy]carbamoyl}-1,6- diazabicyclo[3.2.1]octyl]oxy}sulfo'nyl)oxidanide (Compound 150, Table 1) A‘O‘ﬁ I".

N «H O J~N o ‘oso3Na Step 1. (28,5R)(benzyloxy)oxo-N-{[(3R)—5-oxopyrrolidinyl]oxy}-1,6- diazabicyclo[3.2.1]octanecarboxamide (129) 1 129 To solution of (2S,5R)(benzyloxy)-7—oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (25 mL) were added (4R)(aminooxy)pyrroiidinone 128 (0.12 g, 0.86 mmol, J. Med. Chem. 1997, , 2363-2373), 1-hydroxybenzotriazole (0.14 g, 1.10 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.10 mmol) and 4-dimethylaminopyridine (0.13 g, 1.08 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum.

The residue was purified by column chromatography to give (28,5R)(benzyloxy)oxo-N- {[(3R)oxopyrrolidinyl]oxy}-1,6-diazabicyc|o[3.2.1]octanecarboxamide 129 (0.22 g, 82%) as a white solid. 1H NMR (400 MHz, CDCI3): 51.66 (1H, m), 1.96 (2H, m), 2.29 (1H, m), 3.56 (2H, m), 2.78 (1H, d, J = ), 3.00 (1H, d, J = 12.0 Hz), 3.33 (1H, s), 3.58 (2H, m), 3.93 (1H, d, J = 7.6 - Hz ), 3.93 (1H, m), 4.84 (1H, m), 4.88 (1H, d, J =12.0 Hz), 5.03 (1H, d, J = 11.2Hz), 6.15 (1H, br s), 7.41 (5H, m), 9.63 ('1H, br s). 173173 Step 2. (ZS,5R)hydroxyoxo-N-{[(3R)oxopyrrolidinyl]oxy}-1,6- diazabicclo[3.2.1]octanecarboxamide (130) \\O\N/U’/,’ “\O\N/u//I' HM? H OH —’ HN/P H “0“” 4 N‘ B“ O O O] o o N‘OH 129 130 To a solution of (2S,5R)(benzyloxy)—7-oxo-N-{[(3R)—5-oxopyrrolidinyl]oxy}—1 ,6- diazabicyclo[3.2.1]octanecarboxamide 129 (0.22 g, 0.59 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated at 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out h , and the filtrate was evaporated to give (28,5R)hydroxyoxo-N-{[(3R)oxopyrrolidin—3-yl]oxy}-1 ,6- diazabicyclo[3.2.1]octanecarboxamide 130 (0.156 g, 93 %) as a white foam. 1H NMR (400 MHz, CD30D): 6 1.79 (1H, m), 1.97 (1H, m), 2.09 (1H, m), 2.22 (1H, m), 2.46 (1 H, d, J = 16.4 Hz), 2.64 (1H, dd, 6.8 Hz, 18.0 Hz), 3.01 (1H, d, J = 11.6 Hz), 3.12 (1H, m), 3.59 (3H, m), 3.85 (1H, d, J = 7.2 Hz), 4.74 (1H, m), 3 protons were not observed in CD30D.

Step 3. sodium ({[(ZS,5R)oxo{[(5-oxopyrrolidinyl)oxy]carbamoyI}-1,6- diazabicyclo[3.2.1]octyl]oxy}sulfonyl)oxidanide (Compound 150, Table 1) O O tow/”l,“ ~“O‘N/Ul'“ ...; . Q... _. .9 . Q )-——-N N O O OH o o OSO3Na 130 Compound 150, Table 1 To a solution of (2S,5R)hydroxy-7—oxo—N-{[(3R)oxopyrrolidinyl]oxy}-1,6- diazabicyclo[3.2.1]octane—2-carboxamide 130 (0.156 g, 0.55 mmol) in dry pyridine (9 mL) under nitrogen here was added sulfur de pyridine complex (0.40 g, 2.51 mmol).

The mixture was stirred at room temperature for 20 h, then filtered and evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation.

The' white solid was purified by resin DOWEX 50WX4 column using water as eluent and freeze dried to give sodium ({[(28,5R)oxo{[(5-oxopyrrolidin—3-yl)oxy]carbamoyl}-1,6- diazabicyclo[3.2.1]oct-6—yl]oxy}sulfonyl)oxidanide nd 150 (Table 1) (0.025 g, 12%) as a white solid. 1H NMR (400 MHZ, CD3OD): 61.84 (1H, m), 1.93 (1H, m), 2.07 (1H, m), 2.20 (1H, m), 2.47 (1H, d, J = 18.0 Hz ), 2.65 (1H, dd, J = 6.4 Hz and 18.0 Hz), 3.05 (1H, d, J = 11.6 Hz), 3.24 174174 (1H, m), 3.59 (2H, m), 3.92 (1H, d, J = 6.8 Hz), 4.14 (1H, m), 4.75 (1H, m), 2 protons were not observed in CD3OD.

HPLC'. 97.3% MS (ES‘): m/z: [M]'= 362.97 Example 29 Sodium [({(ZS,5R)[(1,4-oxazepanylmethoxy)carbamoyl]oxo-1,6- diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide (Compound 13, Table 1) (L fl , 0 o.N N «H o ‘osoaNa Step 1. tert-butyl 2-{[({[(ZS,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct 1O yl]carbony|}amino)oxy]methy|}-1,4-oxazepanecarboxylate (132) [x] 80c 4,. N HO Q CLo C 1V0 o o ‘NHZ N "'H Jl, 131 o a Q N «H O_'0 )‘NxBn O O’ 1 132 To a solution of (28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.22 g, 0.80 mmol) in dry DCM (20 mL) were added tert—butyl 2—[(aminooxy)methyI]-1,4- oxazepane-4—carboxylate 131 (0.23 g, 0.93 mmol, US 2010/0168080 and J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.15 g, 1.12 mmol) and 1-ethyI-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.12 mmol) at room temperature.

The reaction mixture was stirred at room temperature overnight and c0ncentrated under . The residue was ed by column chromatography to give utyl 2- {[({[(2S,5R)(benzyloxy)—7—oxo-1,6-diazabicyclo[3.2.1]octy|]carbonyl}amino)oxy]methyl}- 1,4-oxazepanecarboxylate 132 (0.32 g, 80%) as a clear thick oil. 1H NMR (400 MHz, CDCI3): 5 1.46 (9H, s), 1.62 (2H, m), 2.01 (4H, m), 2.34 (1H, m), 2.77 (1H, m), 3.03 (2H, m), 3.30 (2H, m), 3.49 (1H, m), 3.57-4.00 (5H,m), 4.11 (1H, m), 4.89 (1H, d, J = 11.6 Hz ), 5.04 (1H, d, J = 11.6 Hz), 7.39 (5H, m), 9.39 (1H, m). 175175 Step 2. tert-butyl [(ZS,5R)hydroxyoxo-1,6-diazabicyclo[3.-2.1]oct yl]carbonyl}amino)oxy]methyI}-1,4-oxazepanecarboxylate (133) $00 I30¢ O\ I!" OLO‘N/ul’h ____, O H N «H N ...H )‘N Bn 0%N\OH O O’ 132 133 To a solution of tert-butyl 2—{[({[(28,5R)-6—(benzyloxy)oxo—1,6-diazabicyclo[3.2.1]oct-2— yl]carbonyl}amino)oxy]methyl}-1,4-oxazepanecarboxylate 132 (0. 32 g, 0.63 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated at 15 psi hydrogen atmosphere at room temperature for 1 h. The st was filtered out through.

Celite, and the filtrate was evaporated to give tert—butyl 2-{[({[(28,5R)—6—hydroxyoxo-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]methyl}-1,4-oxazepanecarboxylate 133 (0.205 g, 78%) as a colorless foam. 1H NMR (400 MHz, : 8 1.47 (9H, s), 1.70-1.98 (4H, m), 2.05 (1H, m), 2.18 (1H, m), 3.08 (2H, m), 3.41-4.00 (10H, m), 4.06 (1H, m), 2 protons were not observed in CD300.

Step 3. tert-butyl 2—{[({[(2$,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]methyl}-1,4-oxazepanecarboxylate pyridine salt (134) Boo ‘ l I300 N N j\/O\ O O /U”I 0‘ /u”l.

O n O ————> H N ...H N -"H }+N\ }—N o OH o ‘oso3H - Pyridine 133 To a solution of tert—butyl 2-{[({[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yi]carbonyl}amino)oxy]methyl}—1,4-oxazepanecarboxylate 133 (0.20 g, 0.48 mmol) in dry pyridine (6 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.34 g, 2.14 mmol). The e was stirred at room temperature for 20 h, then filtered and evaporated. The residue was washed 4 times with ether to give tert—butyl 2-{[({[(28,5R) oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2—yl]carbonyl}amino)oxy]methyl}-1,4—oxazepane— 4-carboxylate pyridine salt 134 (0.16 g) which was used in the next step without purification. 176176 Step 4. . sodium [({(ZS,5R)[(1,4-oxazepan-2—ylmethoxy)carbamoyl]oxo-1,6- diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide und 13, Table 1) E'ioc H COLON». O\ ’I, o u H a N ”H . [H )‘N )——N o ‘ososrxia o ‘ososH - Pyridine 134 Compound 13, Table To a solution of ten-butyl 2-{[({[(2S,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyi}amino)oxy]methyl}-1,4-oxazepanecarboxylate pyridine salt 134 (0.16 g, 0.28 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.30 mL, 3.89 mmol) dropwise at 0 °C.

The reaction mixture was stirred for 1 h then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The white solid was purified by resin DOWEX 50WX4 column using water as eluent and freeze dried to give sodium [({(2S,5R)[(1,4—oxazepanylmethoxy)carbamoyl]—7-oxo-1 ,6— icyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide Compound 13 (Table 1) (0.04 g, 34%) as a white solid. 1H NMR (400 MHZ, D20): 6168 (1H, m), 1.79 (1H, m), 1.93 (4H, m), 2.97 (1H, d, J = 11.2 HZ), 3.13 (2H, m), 3.24 (2H, m), 3.32 (1H, m), 3.61 (1H, m), 3.78-3.99 (4H, m), 4.04 (2H, m), 2 protons were not ed in D20.

HPLC: 97.4% MS (ES‘) m/z: [M]'= 393.04 Example 30 Sodium [({(2$,5R)[(1,4-oxazepanyloxy)carbamoyl]oxo-1,6- diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide und 35, Table 1) 0. Jim, 0 //'~—N o ‘ososNa Using the similar procedures as described earlier but using ten—butyl 6-(aminooxy)-1,4- oxazepanecarboxylate, Compound 35 (Table 1) was prepared as a diastereoisomeric mixture as a white solid in 20 % yield. 177177 1H NMR (400 MHz, CD30D): 51.82 (1H, m), 1.94 (1H, m), 2.07 (1H, m), 2.23 (1H, m), 3.00 (1H, d, J = 12.0 Hz), 3.09 (1H, d, J = 12.0 Hz), 3.21 (1H, m), 3.44 (2H, m), 3.63 (1H, m), 3.85—4.04 (5H, m), 4.15 (1H, s), 4.36 (1H, m), 2 protons were not observed in CD3OD.

HPLC: 95.5% MS (ES‘): m/z: [M]'= 379.01 Example 31 Sodium ({[(2$,5R){[2-(1H-imidazolyl)ethoxy]carbamoyl}oxo-1,6- diazabicyc|o[3.2.1]octyl]oxy}sulfonyl)oxidanide (Compound 100, Table 1) g/NxO—N/l/H'QI .

J—N”N IH o ‘osoaNa 'Using the similar procedures as describe earlier but using O-(2-(1H—imidazol-1— yl)ethyl)hydroxylamine, nd 100 (Table 1) was prepared as a white solid.

‘H NMR (400 MHz, 020): 61.64-1.90 (4H, m), 2.90 (1H, d, J = 12.0 Hz), 3.06'(1H, d, J = 12.0 Hz), 3.78 (1H, d, J = 6.8 Hz), 4.00 (1H, m), 4.06 (2H, m), 4.15 (2H, m), 6.89 (1H, s), 7.09 (1H, s), 7.67 (1H, s). 2 protons were not observed in D20.

HPLC: 87.4 %, MS (ES‘) m/Z‘. [M-Na]' calcd for C12H16N5078: 374.08. Found: 374.01.

Example 32 Sodium ({[(2$,5R)—7-oxo{[(3R)-tetrahydrofuranyloxy] carbamoyl}-1,6- diazabicyclo[3.2.1]octyl]oxy}sulfonyl)oxidanide (Compound 95, Table 1) Duo—N)”(lH N «H o ‘osoaNa Using the similar procedures as describe earlier but using O-[(3R)-tetrahydrofuran yl]hydroxylamine, Compound 95 (Table 1) was prepared as a white solid. 1H NMR (400 MHz, 020): 1.83 (2H, m), .03 (4H, m), 2.94 (1H, d, J = 12.8 Hz), 3.14 (1H, d, J: 12.8 Hz), .73 (2H, m), 3.75-3.93 (3H, m), 4.04 (1H, m), 4.60 (1H, m). 2 protons were not observed in D20. 178178 HPLC: 95.2 %, MS (ES‘) m/z: [M-Na]; calcd for N3088: 350.07. Found: 349.99.

Example 33 Sodium ({[(ZS,5R){[(1-methy|-4,5,6,7-tetrahydro-1H-pyrazo|o[3,4-c]pyridin yl)oxy]carbamoyl}oxo-1,6-diazabicyc|o[3.2.1]octyl]oxy}sulfonyl) oxidanide und 70, Table 1) HN o~N/l"”(i — QMH /N\N/ }—N . o ‘osoaua Step 1. tert-butyl 3-dioxo-1,3-dihydro-2H-isoindolyl)oxy]methyl-1,4,5,7- tetrahydro-6H-pyrazolo[3,4-c]pyridinecarboxylate (136) To amixture of 2-hydroxy—1H—isoindole-1,3(2H)-dione (2.95 g, 18.1 mmol), teIT-butyl 4- hydroxy—1-methyl—1,4,5,7—tetrahydro—6H—pyrazolo[3,4—c]pyridine—6—carboxylate 135 (U82005/245505 A1, 2.29 g, 9.04 mmol) and triphenylphosphine (4.74 g, 18.1 mmol) in THF (100 mL) was added DlAD (3.85 mL, 19.9 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 136 (2.5 g, 35 °/o) as a yellow solid. 1H NMR (400 MHz, CDClg): 5 1.52 (9H, s), 3.29 (2H, m), 3.76 (3H, s), 4.25-5.16 (2H, m), .44 (1H, m), 7.80 (5H, m).

MS (ES+) m/z: [M+H]+ calcd for Con23N405: 399.17. Found: 399.11. 179179 Step 2. utyl nooxy)methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridinecarboxylate (137) 136 - 137 To a mixture of tenf-butyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2—yl)oxy]methyl-1,4,5,7- tetrahydro-6H—pyrazolo[3,4-c]pyridinecarboxylate 136 (2.50 g, 6.27 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine hydrate (0.360 mL, 6.27 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was washed with ether and methanol to give 137 (1.06 g, 62 %) as a white foam. 1O 1H NMR (400 MHz, CDCI3): 8 1.50 (9H, s), 2.88 (1H, m), 3.76 (3H, s), 4.05 (1H, m), 4.57 (1H, m), 4.78-5.10 (2H, m), 5.47 (2H, m), 7.51 (1H, s).

MS (ES+) m/z: [M+H]+ calcd for C12H21N403: 269.16. Found: 269.10.

Step 3. tert-butyl 4-[({[(2$,5R)(benzyloxy)—7-oxo-1,6-diazabicyclo[3.2.1] act yl]carbonyl}amino)oxy]methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine carboxylate (138) 1 138 To a mixture of (28, 5R)—6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) were added tenf—butyl 4-(aminooxy)methyl- 1,4,5,7-tetrahydro-6H4pyrazolo[3,4-c]pyridine—6-carboxylate 137 (0.360 g, 1.358 mmol), 1- ybenzotriazole (0.183 g, 1.358 mmol) and l—(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to 180180 provide a residue which was subjected to chromatography to give 138 (0.42 g, 89 %) as a white foam. 1H NMR (400 MHz, : 8 1.50 (9H, s), 1.62 (1H, m), 2.00 (2H, m), 2.32 (1H, m), 2.70- 3.10 (3H, m), 3.29 (1H, s), 3.76 (3H, s), 4.06 (2H, m), 4.58 (1H, m), 4.88 (1H, d, J = 11.6 Hz), 4.99 (2H, m), 5.04 (1H, d, J = 11.6 Hz), 7.42 (5H, m), 7.60 (1H, s). One proton was not observed.

M8 (E87) m/z: [M+H]+ calcd for 026H35N606: 527.26. Found: .

Step 4. tert-butyl 4-[({[(2S,5R)hydroxyoxo-1,6—diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine 1O carboxylate (139). 138 139 A‘ mixture of tert—butyl 4-[({[(2S,5R)(benzyloxy)oxo-1,6—diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]-1—methyl-1,4,5,7—tetrahydro-6H-pyrazolo[3,4-c]pyridinecarboxylate 138 (0.42 g, 0.80 mmol) and Pd/C (0.13 g) in methanol (20 mL) was hydrogenated at one atm. at room temperature for 13 h. The mixture was filtered through Celite pad and concentrated to give a residue which was subjected to chromatography to provide 139 (0.33 g, 94 %) as a white solid. 1H NMR (400 MHz, CD30D): 8 1.51 (9H, s), 1.80—2.30 (4H, m), 3.07 (3H, m), 3.70 (1H, m), 3.77 (3H, s), 3.90 (1H, m), 4.23 (1H, br s), 4.45 (1H, br s), 4.98 (2H, d, J = 8.4 Hz), 7.58 (1H, br s). 2 protons were not observed in CD30D.

MS (ES‘) m/z: [M-H]' calcd for C19H27N606: 435.20. Found: 435.11. 181181 Step 5. utyl 1-methy|—4-[({[(28,5R)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]-1,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridinecarboxylate (140) o—N)“‘i N «H 5" 139 140 To a mixture of tert—butyl 4-[({[(2S,5R)hydroxyoxo—1,6-diazabicyclo[3.2.1]oct, yl]carbonyl}amino)oxy]methy|-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine—6-carboxylate 139 (0.33 g, 0.76 mmol) in pyridine (10.0 mL) was added sulfur trioxide pyridine x (0.35 g, 2.27 mmol). The mixture was stirred at room temperature for 23 h and concentrated to provide a residue which was subjected to chromatography to give 140 (0.35 g, 90 %) as a 1O light yellow foam.

IH NMR (400 MHz, CD30D): 6 1.50 (9H, s), 1.80—2.00 (4H, m), 3.12 (1H, d, J = 11.2 Hz), 3.27 (2H, m), 3.77 (3H, s), 3.96 (1H, m), 4.16 (1H, m), 4.30 (1H, m), 4.50 (1H, m), 5.00 (2H, m), 7.58 (1H, br s). 2 protons were not observed in CD30D.

MS (ES‘) m/z: [M—H]‘ calcd for C19H27NGOQS: 515.16. Found: 515.04.

Step 6. sodium ({[(28,5R){[(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridinyl)oxy]carbamoyl}oxo-1,6-diazabicyclo[3.2.1]octyl]oxy}sulfonyl) oxidanide (Compound 70, Table 1) 0l .

HJWQH —" N «H o ‘osoaH ‘oso3Na 140 Compound 70, Table 1 To a mixture of tert-butyl 1-methyl[({[(2S,5R)'oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]—1,4,5,7-tetrahydro-6H-pyrazolo[3,4— dinecarboxylate 140 (0.35 g, 0.68 mmol) in DCM (8.0 mL) was added trifluoroacetic acid (0.40 mL) at 0°C. The mixture was d at 0°C for 1 h, concentrated and washed with ether. The white solid was collected by centrifugatlon. The crude product was purified by ion- exchange resin 50 Na+ form, water) to give Compound 70 (Table 1) (30 mg) as a . white solid as a pair of diastereoisomers. 182182 1H NMR (400 MHz, D20): 51.67-182 (2H, m), 1.90-2.02 (2H, m), 2.72 (1H, m), 2.86—2.95 (1H, m), 3.13 (1H, m), 3.28 (1H, d, J: 14.4 Hz), 3.56 (3H, s), 3.72 (1H, d, J = 16.0 Hz), 3.87— 4.10 (3H, m), 4.82 (1H, S), 7.46 (1H, s). 3 protons were not observed in D20.

HPLC: 94.1 % MS (ES') m/z: [M-Na]' calcd for C14H19N607S: 415.11. Found: 415.03.

Example 34 Sodium [({(2$,5R)oxo[(pyrazolidinyloxy)carbamoyl]-1,6-diazabicyclo[3.2.1]oct- 6—y|}oxy)sulfonyl]oxidanide (Compound 104, Table 1) HN j, )——N o ‘osoBNa Step 1. di-tert-butyl 4-[(1,3-dioxo-1,3-dihydro-2H-isoindoly|)oxy]pyrazolidine- 1,2-dicarboxylate (142) , (jig—0H o Boc\130+: Boc\ Boc’N 3M 141 142 To a mixture of 2-hydroxy-1H—isoindole-1,3(2H)-dione (1.72 9, 10.541 mmol), di—tert—butyl 4- hydroxypyrazolidine—1,2-dicarboxylate 141 (Journal of otics, 1993, Vol 46, (12), 1866- 1882, 1.52 g, 5.27 mmol) and triphenylphosphine (2.76 g, 10.54 mmol) in THF (50 mL) was added DIAD (2.24 mL, mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue, which was ted to chromatography to give 142 (1.8 g, 79 %) as a white foam. 1H NMR (400 MHZ, CDCI3): 5 1.48 (9H, s), 1.52 (9H, s), 3.30 (1H, dd, J = 4.0, 13.6 Hz), 3.71 (1H, d, J = 14.0 HZ), 4.11 (1H, m), 4.50 (1H, d, J = 13.2 Hz), 5.13 (1H, br s), 7.77 (2H, m), 7.87 (2H, m).

MS (ES+) m/z: [M+H]+ calcd for C21H28N3O7: 434.19. Found: 434.10. 183183 Step 2. di-tert-butyl 4-(aminooxy)pyrazo|idine-1,2-dicarboxylate (143) Boc \0}” N Boc \ 806/ Boc’N"”30"“: 142 143 To a mixture of di-te/t-butyl 4-[(1,3-dioxo-1,3-dihydro-2H—isoindolyl)oxy]pyrazolidine-1,2- dicarboxylate 142 (1.81 g, 4.18 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine e (0.240 mL, 4.18 mmol) at room temperature. The e was stirred at room temperature overnight, filtered and concentrated to provide a residue which was ted to chromatography to give 143 (1.04 g, 83 %) as a white foam. 1H NMR (400 MHz, CDCI3): 6 1.48 (18H, m), 2.99 (1H, m), 3.62 (1H, m), 3.78 (1H, dd, J = 5.6 Hz and 12.0 Hz), 4.43 (2H, m), 5.38 (2H, br s). 1O MS (ES+) m/z: [M+H]+ calcd for C13H25N305: 304.19. Found: 304.15.

Step 3. di-tert-butyl 4-[({[(2$,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1] oct- 2-yl]carbonyl}amino)oxy]pyrazolidine-1,2-dicarboxylate (144) BOC\N O l :>'O“NH2 /H Boc’N O HO " 143 Boc\N )L,' N «H I :>—O—N Boc’N H N "'H ‘144 To a mixture of (28,5R)—6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in . DCM (10.0 mL) were added di—terf—butyl 4— (aminooxy)pyrazolidine-1,2-dicarboxylate 143 (0.411 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was ted to tography to give 144 (0.43 g, 85 %) as a white foam. 1H NMR (400 MHz, CDCI3): 6 1.46 (18H, s), 1.62 (1H, m), 2.00 (2H, m), 2.30 (1H, m), 2.68 (1H, m), 3.00 (2H, m), 3.29 (1H, s), 3.51 (1H, m), 3.86 (1H, m), 3.98 (1H, m), 4.42 (1H, m), 4.86 (1H, m), 4.88 (1H, d, J: 11.2 Hz), 5.04 (1H, d, J = 11.2 Hz), 7.42 (5H, m), 9.14 (1H, m).

MS (ES+) m/z: [M+H]+ calcd for C27H40N508: 562.29. Found: 562.22. 184184 Step 4. di-tert-butyl 4-[({[(ZS,5R)hydroxy—7-oxo-1,6-diazabicyclo[3.2.1] act yl]carbonyl}amino)oxy]pyrazolidine-1,2-dicarboxylate (145) Boc’NBOC\N}O NJ, H [\Q-"H Boc\ ? /myO‘NJM' N Boc N lH ‘ APh O O //l._N 0 OH 144 145 A mixture of di-teIt—butyl 4-[({[(28,5R)(benzyloxy)-7—oxo-1,6—diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]pyrazolidine-1,2-dicarboxylate 144 (0.43 g, 0.80 mmol) and Pd/C '(0.14 g) in methanol (15 mL) was hydrogenated at 1 atm at room temperature for 3 h. The e was filtered through Celite pad and concentrated to give 145 (0.39 g, quant.) as a light brown foam.

'H NMR (400 MHz, CD30D): 8 1.48 (18H, s), 1.80-2.20 (4H, m), 3.02-3.13 (3H, m), 3.55 (1H, m), 3.70 (1H, m), 3.86 (1H, m), 3.93 (1H, m), 4.24 (1H, m), 4.79 (1H, m). 2 protons were not observed in CD30D.

MS (ES‘) m/z: [M-H]‘ calcd for N508: 470.22. Found: 470.14.

Step 5. di-tert-butyl 4-[({[(28,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1] act yl]carbonyl}amino)oxy]pyrazolidine-1,2-dicarboxylate (146) Boc\ Cl) - Boc/E3o~ﬁg N "'H ——> Boo/Nmy-..»H a O)‘N\OH . IH . )—N o ‘oso3H 145 - 146 To a mixture of di-teIt-butyl 4-[({[(2S,5R)hydroxy—7-oxo—1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]pyrazolidine-1,2—dicarboxylate 145 (0.39 g, 0.82 mmol) in ne (10.0 mL) was added sulfur trioxide pyridine complex (0.39 g, 2.48 mmol). The mixture was d at room temperature for 23 h and concentrated to provide a residue which was ted to chromatography to give 146 (0.31 g, 68 %) as a white foam. 1H NMR (400 MHz, CD3OD): 5 1.48 (18H, s), 1.80-2.20 (4H, m), 3.07 (1H, d, J = 12.4 Hz), 3.23 (2H, m), 3.55 (1H, m), 3.93 (2H, m), 4.14 (1H, m), 4.25 (1H, d, J = 12.4 Hz), 4.81 (1H, t, J = 5.6 Hz). 2 protons were not observed in CD3OD.

MS (ES') m/z: [M-H]‘ calcd for C20H32N5011S: 550.18. Found: 550.05. 185185 Step 6. sodium [({(28,5R)oxo[(pyrazolidinyloxy)carbamoyl]-1,6- diazabicyclo[3.2.1]octyl}oxy)sulfonyl]oxidanide (Compound 104, Table 1) oc ”(3‘04“)th H0304“)_ B 9 \ n Boc’N H —-—> ”N H N ...H N «H )*N )‘N O \0303H O ‘0803Na Compound 104, Table 1 To a mixture of t—butyl 4-[({[(28,5R)oxo(sulfooxy)—1 ,6-diazabicyc|o[3.2.1] oct bonyl}amino)oxy]pyrazolidine-1,2-dicarboxylate 146 (0.33 g, 0.60 mmol) in DCM (5.0 mL) was added trifluoroacetic acid (0.60 mL) at 0°C. The mixture was stirred at 0°C for 0.5 h and at room temperature for 5.5 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by ion—exchange resin (Dowex50 Na+ form, water) to give Compound 104 (Table 1) (22.5 mg) as a white solid. 1H NMR (400 MHZ, D20): 1.82 (2H, m), 1.87-2.02 (2H, m), 2.92 (1H, d, J = 11.6 Hz), 3.08-3.15 (3H, m), 3.25 (2H, d, J= 13.6 Hz), 3.90 (1H, d, J= 6.4 HZ), 4.01 (1H, m), 4.79 (1H, m). 4 protons were not observed in D20.

HPLC: 93.18 %, MS (ES‘) m/z: [M-Na]‘ calcd for C10H15N507SNa: 350.08. Found: 34999.

Example 35 Sodium ({[(28,5R){[(1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol yl)methoxy]carbamoyl}oxo-1,6-diazabicyc|o[3.2.1]octyl]oxy}sulfonyl)oxidanide . (Compound 131, Tabel, 1) \ IN )‘m.

O—NH Q o ‘osoaNa 186186 Step 1. 2-[(1-methyI-4,5,6,7-tetrahydro-1H-4,7-methanoindazolyl)methoxy]-1H- isoindole-1,3(2H)-dione (148) N~OH N- $ W .

N O O mN OH O~N 147 0 To a mixture of 2-hydroxy-1H—isoindole-1,3(2H)-dione (4.10 g, 25.2 mmol), (1-methyl- 7-tetrahydro-1H—4,7—methanoindazol-3—yl)methanol 147 (2.24 g, 12.6 mmol) and triphenylphosphine (6.59 g, 25.2 mmol) in THF (100 mL) was added DIAD (5.35 mL, 27.6 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a e, which was subjected to chromatography to give 148 (1.80 g, 62 %) as a yellow solid.

‘HNMR(MmhMt,CDCM:611OUH,mL124UH,mL161(ﬁtd,J=10Ha,187@H, nﬁ,333(1H,Q,342(1H,Q,371(3H,$,512(2H,nn,717(2H,n0,781(2H,m) MS (ES+) m/z: [M+H]+ calcd for C13H13N303: 324.13. Found: 324.08.

Step 2. 3-[(aminooxy)methyl]methyl-4,5,6,7-tetrahydro-1H-4,7- methanoindazole (149) ll ' - 0 . ‘N N 0"“ -——————-—-——————> O’NHZ 148 ‘ 149 To a mixture of I, 2-[(1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazoIyl)methoxy]-1H- isoindoIe-1,3(2H)-dione 148 (1.80 g, 5.57 mmol) in a solution of DCM (20 mL) and ethanol (4 mL) was added hydrazine hydrate (0.32 mL, 5.57 mmol) at room temperature. The mixture was d at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 149 (0.68 g, 64 %) as a colorless oil. 1H NMR (400 MHz, CDCI3):51.09(1H, m), 1.26 (1H, d, J = 6.0 Hz), 1.64 (1H, d, J = 8.8 Hz), 1.88 (2H, m), 1.99 (1H, m), 3.35 (2H, d, J = 8.4 Hz), 3.79 (3H, s), 4.65 (2H, ABq), 5.24 (2H, br 5).

MS (ES+) m/z: [M+H]+ calcd for C10H16N30:'194.13. Found: 194.08. 187187 Step 3. (28,5R)—6-(benzyloxy)-N-[(1-methyl-4,5,6,7-tetrahydro-1H-4,7— methanoindazolyl)methoxy]oxo-1,6-diazabicyclo[3.2.1]octanecarboxamide (150) O \ / l\/l /u O——NH2 -N 0 I,“ 149 HO \ / O N/U’I,‘ N "'H H }—N O-IIH \ /\ l O 0 N . O \OAPh To a mixture of (28,5R)—6-(benzyloxy)—7—oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) were added 3—[(aminooxy)methyl]methyl¥ 4,5,6,7-tetrahydro-1H-4,7-methanoindazole 149 (0.172 g, 1.358 mmol), 1- hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1—ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, d with DCM and concentrated to _ provide a residue which was subjectedto chromatography to give 150 (0.34 g, 83 %) as a white foam. 1H NMR (400 MHZ, CDCl3): 8 1.08 (2H, m), 1.25 (1H, d, J = 6.4 Hz), 1.63 (2H, m), 1.95 (5H, m), 2.38 (1H, m), 2.80 (1H, m), 2.92 (1H, m), 3.30 (1H, s), 3.36 (2H, s), 3.78 (3H, s), 3.94 .15 (1H, d, J= 7.6 Hz), 4.85 (3H, m), 5.03 (1H, d, J= 11.2 Hz), 7.41 (5H, m), 9.10 (1H, 8).

MS (ES+) M+H]+ calcd for C24H29N504: 452.23. Found: 452.15.

Step 4. . (28,5R)—6-hydroxy-N-[(1-methyl-4,5,6,7-tetrahydro-1H—4,7- methanoindazolyl)methoxy]oxo-1,6-diazabicyclo[3.2.1]octanecarboxamide (151) / / wow/lN\N O wN\N O - \ / l, \ O’N/l- l, H H N «H N «H )—'N\0/\ //L—N\ 0 Ph 0 OH - 150 151 A mixture of (2S,5R)—6-(benzyloxy)-N—[(1methyl-4,5,6,7-tetrahydro-1H—4,7-methanoindazol- 3-yl)methoxy]-7—_oxo-1,6-diazabicyclo[3.2.1]octanecarboxamide 150 (0.34 g, 0.75 mmol) and Pd/C (0.12 g) in ol (15 mL) was hydrogenated at 1 atm at room temperature for 3 188188 h. The mixture was filtered through Celite pad and concentrated to give 151 (0.27 g, quantitative yield) as a white foam. 1H NMR (400 MHz, CD3OD): 5 1.14 (2H, m), 1.23 (1H, d, J: 6.4 Hz), 1.66 (1H, d, J = 8.0 Hz), 1.85 (4H, m), 2.03 (1H, m), 2.21 (1H, m), 3.02 (2H, m), 3.42 (1H, s), 3.45 (1H, s), 3.68 (1H, s), 3.76 (3H, s), 3.80 (1H, d, J = 7.2 Hz), 4.71 (2H, m). 2 protons were not observed in CD3OD.

MS (ES+) m/z: [M+H]+ calcd for C17H24N504: 262.18. Found: 262.12.

Step 5. sodium ({[(2$,5R){[(1-methyl-4,5,6,7-tetrahydro-1H-4,7- methanoindazolyl)methoxy]carbamoyl}oxo-1,6-diazabicyclo[3.2.1]oct 1O yl]oxy}sulfonyl)oxidanide (Compound 131, Table 1) SK:,( / ‘ O N\ 0 m. \ ,N J. 0*” Q _. O~NH Q N -"H N I: :H }—N\ }——N\ O OH O OSOaNa 151 nd 131, Table 1 ' To a e of (28,5R)hydroxy-N-[(1-methyl-4,5,6,7—tetrahydro-1H-4,7-methanoindazol-3— yl)methoxy]oxo-1,6-diazabicyclo[3.2.1]octane—2—carboxamide 151 (0.27 g, 0.75 mmol) in pyridine (10.0 mL) was added sulfur trioxide pyridine complex (0.35 g, 2.24 mmol). The mixture was d at room temperature for 23 h and concentrated to provide a residue which was ted to ion—exchange resin column (Dowex50 Na+ form, water) togive Compound 131 (Table 1) (177 mg, 51 °/o) as a white solid.

IH NMR (400 MHz, CD3OD): 51.12(2H, m), 1.67 (1H, d, J = 8.8 Hz), 1.80 (1H, m), 1.91 (4H, m), 2.08 (1H, m), 2.20 (1H, m), 3.05 (1H, t, J = 12.4 Hz), 3.17 (1H, m), 3.24 (1H, s), 3.45 (1H, s), 3.77 (3H, s), 3.87 (1H, d, J = 5.6 Hz), 4.13 (1H, s), 4.78 (2H, m). One proton was not observed in D20.

HPLC: 91.05 %, MS (ES') m/z: [M-Na]‘ calcd for C17H22N504SNa: 440.12. Found: 440.00. 189189 Example 36 (28,5R)oxo-N-(piperidinylmethoxy)(sulfooxy)-1 zabicyclo[3.2.1]octane carboxamide (Compound 51, Table 1) o}— ‘0-§_OH Step 1 . Step1: tert-butyl 3-{[({[(23,5R)(benzyloxy)oxo-1 ,6-diazabicyclo[3.2.1] oct—2-yl]carbonyl}amino)oxy]methyl}piperidine-1 -carboxylate (153) ‘N O—NH 0 0A 2 HOJL’I: 152 Boc\N O—N 1,, - I [H -1|H O ‘OAPh O5 ‘OAph 1 153 To a mixture of (28,5R)—6—(benzyloxy)—7—oxo—1,6-diazabicyclo[3.2.1]octane-2—carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert—butyl inooxy)methyl]piperidine- 1-carboxylate 152 (0.312 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1- ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 153 (0.37 g, 84 %) as a white foam. 1H NMR (400 MHZ, CDCI3): 8 1.45 (9H, m), 1.53 (5H, m), 190 (3H, m), 2.31 (1H, m), 2.77 (3H, m), 2.97 (1H, m), 3.30 (1 H, m), 3.70 (5H, m), 4.88 (1H, d, J = 11.6 Hz), 5.06 (1H, d, J = 11.6 Hz), 7.42 (5H, m). One proton was not observed in moisture ning CDCI3.

MS (ES+) m/z [M+H]+ calcd for C25H37N408: 489.2. Found: 489.2. 190190 Step 2. Step2: tert-butyl [(2S,5R)hydroxyoxo-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]methy|}piperidinecarboxylate (154) Boc\ /u/,/ 12 N 0" , 300‘ ’ O’N/l/ll'I N N -I|H H N -uH A mixture of tert-butyl 3-{[({[(2$,5R)-6—(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct—2- y|]carbonyl}amino)oxy]methy|}piperidinecarboxylate 153 (0.40 g, 0.82 mmol) and Pd/C (0.13 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give 154 (0.33 g, tative yield) as a white foam. 1H NMR (400 MHZ, CD30D): 51.28 (1H, m), 1.45 (10H, m), 1.68 (1H, m), 1.80 (4H, m), 2.04 (1H, m), 2.20 (1H, m), 2.75 (1H, m), 2.84 (1H, m), 3.10 (2H, m), 3.74 (5H, s), 4.02 (1H, m).

Two protons were not observed in CD30D.

MS (ES+) m/z: [M+H]" calcd for C13H31N4061 399.2. Found: 399.1.

Step 3. Step 3. tert-butyl [(2S,5R)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]methyl}piperidinecarboxylate (155) J ' Boc\N //,, O-N Boc\N O—NJ/l”‘i H H N -uH ———_—* N -uH //J——N\ }—N 0 0 0H 0 ‘0—5—0H 154 155 5 To .a mixture of tenf—butyl 3-{[({[(2$,5R)—6-hydroxyoxo—1,6-diazabicyclo[3.2.1]oct-2— yl]carbonyl}amino)oxy]methyl}piperidinecarboxylate 154 (0.33 g, 0.83 mmol) in pyridine (4.0 mL) was added sulfur trioxide pyridine complex (0.38 g, 2.48 mmol). The mixture was stirred at room ature for 23 h and concentrated to provide a residue which was subjected to chromatography to give 155 (0.33 g, 83 %) as a white foam.

‘H NMR (400 MHz, CD30D): 51.30 (1H, m), 1.42 (10H, m), 1.67 (1H, m), 1.90 (4H, m), 2.08 (1H, m), 2.20 (1H, m), 2.70 (1H, m), 2 85 (1H, m), 3.10 (1H, d, J = 12.0 Hz), 3.26 (1H, m), 3.74 (2H, m), 3.88 (2H, m), 4.15 (2H, m). Two protons were not observed in CD30D. 191191 MS (ES') m/z [M-H]' calcd for C13H29N409$Z 477.2. Found: 477.1.

Step 4. Step 4 (28,5R)oxo-N-(piperidinylmethoxy)(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 51, Table 1).

\Uo—HJIIQ”Ho . o)— ‘o-ﬁ_on "DAD-”JagI I” oTFAod— ‘O_ﬁ_OH 155 nd 51, Table 1 To a mixture of tert—butyl 3-{[({[(2$,5R)-7—oxo—6-(sulfooxy)—1,6—diazabicyclo[3.2.1]oct-2— yl]carbony|}amino)oxy]methyl}piperidine—1-carboxylate 155 (0.33 g, 0.69 mmol) in DCM (8.0 mL) was added triﬂuoroacetic acid (0.40 mL) at 0°C. The mixture was stirred at 0°C for 3 h, concentrated and washed with ether, EtOAc and DCM to give TFA salt of nd 51 (Table 1) (62 mg) as a white solid as a pair of diastereomers. 1H NMR (400 MHz, D20): 51.21 (1H, m), 1.58-2.06 (8H, m), 2.72 (1H, t, J: 12.0 Hz), 2.80 (1 H, t, J = 12.0 Hz), 2.98 (1 H, d, J = 11.2 Hz), 3.21 (2H, m), 3.40 (1H, d, J = 11.6 Hz), 3.72 (1 H, m), 3.79 (1 H, m), 3.93 (1H, d, J = 7.2 Hz), 4.08 (1 H, 5). Three protons were not observed in D20.

HPLC: 92.31 % MS (ES‘) m/z [M-H]‘ calcd for C13H21N4O7S: 377.1 . Found: 377.0.

Example 37 Sodium (28,5R)—N—(morpholinylmethoxy)oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 152, Table 1) 192192 Step 1. tert-butyl 2-{[({[(2$,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1] oct yl]carbonyl}amino)oxy]methyl}morpholinecarboxylate (157) BORUO’NHZ I o o )l,’ o 156 J _ ,, To a mixture of (28,5R)-6—(benzyloxy)oxo-1,6v-diazabicyclo[3.2.1]octane-2—carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tenf—butyl 2- [(aminooxy)methyl]morpholinecarboxylate 156 (0.317 g, 1.358. mmol), 1- hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl—(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was d at room temperature overnight, diluted with DCM and concentrated to provide a residue which was ted to chromatography to give 157 (0.35 g, 79 %) as a colorless oil.

‘H NMR (400 MHz, CDCl3): 5 1.45 (9H, m), 1.60 (1H, m), 1.90 (2H, m), 2.30 (1H, m), 2.78 (2H, m), 3.00 (2H, m), 3.30 (1H, m), 3.56 (1H, m), 3.70 (1H, m), 3.87 (6H, m), 4.92 (1H, d, J = 11.6 Hz), 5.06 (1H, d, J: 11.6 Hz), 7.42 (5H, m), 9.36 (1H, s).

MS (ES') m/z: calcd for C24H33N4O7: 489.2. Found: 489.2.

Step 2. tert-butyl 2-{[({[(2$,5R)-6—hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]methyl}morpholinecarboxylate (158) BOC\N/\K\O”qu/I"QK/o N -..H —————»BOC\N/\ﬂoﬂuJ‘/MQK/O N ...H //‘—N %~N. o \OBn 0 OH 157 158 A mixture of tert—butyl 2-{[({[(2S,5R)(benzyloxy)oxo—1,6—diazabicyclo[3.2.1]oct—2— yl]carbonyl}amino)oxy]methyl}morpholinecarboxylate 157 (0.35 g, 0.71 mmol) and Pd/C (0.12 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was ed through Celite pad and concentrated to give 158 (0.29 g, quantitative yield) as a white foam. 193193 1H NMR (400 MHz, CD30D): 61.46 (9H, m), 1.79 (1H, m), 1.92 (1H, m), 2.04 (1H, m), 2.19 (1H, m), 2.80 (1H, m), 2.90 (1H, m), 3.08 (2H, m), 3.49 (1H, m), 3.68 (2H, m), 3.90 (6H, m). 2 protons were not observed in CD30D.

MS (ES+) m/Z'. [M+H]+ calcd for C17H29N4O7: 401.2. Found: 401.2.

Step 3. tert-butyl [(ZS,5R)oxo(sulfooxy)-1,6-diazabicyc|o[3.2.1]oct yl]carbonyl}amino)oxy]methyl}morpholinecarboxylate (159) O .

Boc\ Boc HJCI),N JIM. o ‘QH O . 0803H 158 159 To a e of tert-butyl 2-{[({[(28,5R)-6—hydroxyoxo-1,6-‘diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]methyl}morpholine—4—carboxylate 158 (0.29 g, 0.72 mmol) in pyridine (5.0 mL) was added sulfur trioxide pyridine complex (0.34 g, 2.17 mmol). The mixture was stirred at room temperature for 23 h and concentrated to provide a residue which was subjected to chromatography to give 159 (0.29 g, 83 °/o) as a white foam. 1H NMR (400 MHz, CD30D): 51.46 (9H, s), 1.82 (1H, m), 1.90 (1H, m), 2.09 (1H, m), 2.22 (1H, m), 2.78 (1H, m), 2.90 (1H, m), 3.10 (1H, d, J = 11.6 Hz), 3.22 (1H, m), 3.50 (1H, m), 3.68 (1H, m), 3.90 (6H, m), 4.14 (1H, m). Two protons were not observed in CD30D.

MS (ES') m/z: [M-H]‘ calcd for C17H27N4O1OS: 479.2. Found: 479.1.

Step 4. Sodium (28,5R)-N-(morpholinylmethoxy)—7-oxo(sulfooxy)-1,6- icyclo[3.2.1]octane—2-carboxamide (Compound 152, Table 1) . .

Boc\ JII, NCono—N " NJI . Q... _._. .

”I‘M o ‘osogH o N‘osogNa 15g Compound 152, Table 1 To a mixture tart-butyl 2-{[({[(28,5R)oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]oct—2— y|]carbonyl}amino)oxy]methyl}morpholinecarboxylate 159 (0.29 g, 0.60 mmol) in DCM (8.0 mL) Was added trifluoroacetic acid (0.40 mL) at 0°C. The mixture was stirred at 0°C for 3 h, concentrated and washed with ether to give Compound 152 (Table 1) as a TFA salt, which was converted to sodium salt by treating with Dowex 50 to give the corresponding sodium salt (74 mg) as a white solid as a pair of diastereomers. 194194 1H NMR (400 MHz, D20): 8160-210 (4H, m), 2.98-3.18 (3H, m), .35 (3H, m), 3.80 (1H, t, J = 12.1Hz), 3.90-4.18 (6H, m). Three protons were not observed in D20.

HPLC: 98.23 % MS (ES‘) m/z: ‘ calcd for C12H19N4038Na: 379.1. Found: 379.0.

Example 38 (28,5R)oxo-N-(piperidin-2S-ylmethoxy)(sulfooxy)—1,6-dia2abicyclo[3.2.1]octane amide N “\\\O-u/l/lh‘i I N -IIH )——N‘ 9 O O-ﬁ-OH Step 1. tert-butyl {[(2S,5R)—6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1] oct- 1O 2-yl]carbonyl}amino)oxy]methyl}piperidinecarboxylate (161) N \\\ " ' O~NH2 Boc O )l. O ' HO ,, 160 N )l “‘\\O—N 11,.

N -"H O H N “H 1 , To a mixture of (2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert—butyl 28- [(aminooxy)methyl]piperidine-1—carboxylate 160 (0.312 g, 1.358 mmol), 1- hydroxybenzotriazole (0.183 g,. 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 161 (0.35 g, 80 %) as a white foam. 1H NMR (400 MHz, CDCI3): 5 1.41 (9H, m), 1.61 (6H, m), 1.97 (2H, m), 2.29 (1H, m), 2.78 (3H, m), 2.97 (1H, m), 3.26 (1H, .m), 3.70 (1H, m), 3.99 (2H, m), 4.15 (1H, m), 4.51 (1H, m), 4.88 (1H, d, J = 11.6 Hz), 5.06 (1H, m), 7.42 (5H, m). One proton was not observed in moisture containing CDCl3.

MS (ES') m/z: [M-H]' calcd for C25H35N403: 487.2. Found: 487.1. 195195 Step 2. utyl ZS-{[({[(ZS,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]methyl}piperidinecarboxylate (162).

Boo O 800 O ' ' N “\\\O‘NJ I“l N “\\\O-NJ| I,‘ H "“9 H N «H N «H J—N. .

O OBn O OH 161 162 A mixture of ten‘-butyl 28-{[({[(2S,5R)(benzy|oxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)oxy]methyl}piperidinecarboxy|ate 161 (0.40 g, 0.82 mmol) and Pd/C (0.13 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give 162 (0.27 g, quantitative yield) as a white foam. 1H NMR (400 MHz, CD30D): 61.45 (9H, s), 1.60 (5H, m), 1.80 (2H, m), 1.93 (1H, m), 2.04 (1H, m), 2.21 (1H, m), 2.84 (1H, m), 2.99 (1H, m), 3.31 (1H, m), 3.68 (1H, s), 3.89 (1H, s), 4.02 (3H, m), 4.47 (1H, m). Two protons were not observed in CD30D.

MS (ES+) m/z: [M+H]+ calcd for C18H31N406: 399.2. Found: 399.1.

Step 3. tert-butyl ZS-{[({[(28,5R)H7-oxo(sulfooxy)-1,6-diazabicyc|o[3.2.1]oct yl]carbonyl}amino)oxy]methyl}piperidinecarboxylate (163) §OC j B00 0 N ’1’, N J, .(\‘\O__N ,x“\o__u ”I.

H ’—’ N «H » N «H )——N )—N 0 OH 0 ‘ososH' 162 163 To a e of ted-butyl {[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct-2— y|]carbonyl}amino)oxy]methyl}piperidine—1-carboxy|ate 162 (0.33 g, 0.83 mmol) in ne (4.0 mL) was added sulfur trioxide pyridine complex (0.38 g, 2.48 mmol). The mixture was stirred at room temperature for 23 h and concentrated to provide a residue which was subjected to chromatography to give 163 (0.24 g, 69 %) as a white foam. 1H NMR (400 MHz, CD30D): 61.45 (10H, m), 1.63 (4H, m), 1.84 (2H, m), 1.92 (1H, m), 2.06 (1H, m), 2.21 (1H, m), 2 87 (1H, m), 3.09 (1H, m), 3.24 (2H, m), 3.91 (2H, m), 4.03 (1H, m), 4.11 (1H, m), 4.46 (1H, m). Two protons were not observed in CD30D. 196196 Step 4. (28,5R)oxo-N—(piperidin-ZS-ylmethoxy)(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (164) B00 0 . O ’ H N "\\\O—N/Ll"I N _\\\\O_N/LI,,l H _’ H N ...H N (IIH éL——N 4L——N o YDSO3H o YDSO3H 163 164 To a mixture of tert—butyl 2-{[({[(28,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct bonyl}amino)oxy]methyl}piperidinecarboxy|ate 163 (0.27 g, 0.58 mmol) in DCM (8.0 mL) was added trifluoroacetic acid (0.40 mL) at 0°C. The mixture was d at 0°C for 3 h, concentrated and washed with ether, EtOAc and DCM to give 164 (53 mg) as a white foam. 1H NMR (400 MHz, D20): 81.20 (2H, m), 1.36 (1H, m), 1.60 (5H, m), 1.77 (2H, m), 1.90 (1H, m), 2.65 (1H, m), 2.82 (1H, m), 3.00 (1H., m), 3.15 (2H, m), 3.70(1H, m), 3.80 (2H, m), 3.90 (1H, 5). Three protons Were not observed in D20.

HPLC: 95.22 % MS (ES') m/z: [M-H]' calcd for C13H21N4O7S: 377.1. Found: 377.0.

Example 39 (ZS,5R)oxo-N-(piperidin-2R-ylmethoxy)—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide N O—n/JM'l N «H 4L——N o Yaso3H Step 1. tert-butyl ZS-{[({[(ZS,5R)(benzyloxy)—7-oxo-1,6-diazabicyclo[3.2.1] oct- 2-yl]carbonyl}amino)oxy]methyl}piperidinecarboxy|ate (166) ifN O’NH j’ 2 E900 a. 165 ' O—NJM'C; HO N N ‘”H H N ”H To a mixture of (2S,5R)—6-(benzyloxy)oxo-1,6-diazabicycio[3.2.1]octane—2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl 28- [(aminooxy)methyl]piperidine—1-carboxylate 165 (0.312 g, 1.358 mmol), 1- 197197 hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3—dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to e a residue which was subjected to chromatography to give 169 (0.35 g, 80 %) as a white foam. 1H NMR (400 MHz, CDCI3): 5 1.41 (9H, m), 1.61 (6H, m), 1.97 (2H, m), 2.29 (1H, m), 2.78 (3H, m), 2.97 (1H, m), 3.26 (1H, m), 3.70 (1H, m), 3.99 (2H, m), 4.15 (1H, m), 4.51 (1H, m), 4.88 (1H, d, J = 11.6 Hz), 5.06 (1H, m), 7.42 (5H, m). One proton was not observed in moisture containing CDCI3. 1O MS (ES') m/z: [M-H]‘ calcd for C25H35N408: 487.2. Found: 487.1.

Step 2. tert—butyl 2S§{[({[(ZS,5R)hydroxy-7—oxo-1,6-diazabicyc|o[3.2.1]oct yl]carbonyl}amino)oxy]methyl}piperidinecarboxylate (170) Boc 0 30¢ O :11 JL #1 JL.

I O‘ﬁ . N 'IIH N "‘H 169 170 A e of tert-butyl 2S-{[({[(28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct—2- yl]carbonyl}amino)oxy]methyl}piperidinecarboxylate 169 (0.40 g. 0.82 mmol) and Pd/C (0.13 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The e was filtered through Celite pad and trated to give 170 (0.27 g, quantitative yield) as a white anm. 1H NMR (400 MHz, CD30D): 51.45 (9H, s), 1.60 (5H, m), 1.80 (2H, m), 1.93 (1H, m), 2.04 (1H, m), 2.21 (1H, m), 2.84 (1H, m), 2.99 (1H, m), 3.31 (1H, m), 3.68 (1H, s), 3.89 (1H, s), 4.02 (3H, m), 4.47 (1H, m). Two protons were not observed in CD30D. ' MS (ES+) m/z: [M+H]+ calcd for C13H31N405: 399.2. Found: 399.1.

Step 3. tert-butyl 2S-{[({[(28,5R)oxo(sulfooxy)-1,6-dia2abicyclo[3.2.1]oct. yl]carbonyl}amino)oxy]methyl}piperidinecarboxylate (171) Boc 0 Bee 0 N o—NJ’“ N O-NJl, H ”—’ H N ...H N «H 0 ‘OH 0 ‘oso3H 170 171 198198 To a mixture of tert—butyl 28-{[({[(28,5R)hydroxy-7—oxo-1,6-diazabicyclo[3.2.1]oct—2- yl]carbony|}amino)oxy]methyl}piperidinecarboxyiate 170 (0.33 g, 0.83 mmol) in pyridine (4.0 mL) was added sulfur trioxide ne complex (0.38 g, 2.48 mmol). The mixture was stirred at room temperature for 23 h and concentrated to provide a residue which was subjected to chromatography to give 171 (0.24 g, 69 %) as a white foam. 1H NMR (400 MHz, CD30D): 81.45 (10H, m), 1.63 (4H, m), 1.84 (2H, m), 1.92 (1H, m), 2.06 (1H, m), 2.21 (1H, m), 2 87 (1H, m), 3.09 (1H, m), 3.24 (2H, m), 3.91 (2H, m), 4.03 (1H, m), 4.11 (1H, m), 4.46 (1H, m). Two protons were not observed in CD30D.

Step 4. (2S,5R)oxo-N-(piperidin-2R-ylmethoxy)(sulfooxy)-1,6- 1O diazabicyc|o[3.2.1]octanecarboxamide (172) o ‘osoaH 0 ‘OSOaH 171 172 To a mixture of utyl 2-{[({[(28,5R)oxo(sUlfooxy)-1,6—diazabicyc|o[3.2.1]oct-2— yl]carbony|}amino)oxy]methyl}piperidinecarboxylate 171 (0.27 g, 0.58 mmol) in DCM (8.0 mL) was added trifluoroacetic acid (0.40 mL) at 0°C. The mixture was stirred at 0°C for 3 h, concentrated and washed with ether, EtOAc and DCM to give 172 (53 mg) as a white solid. 1H NMR (400 MHz, D20): 5 1.38 (2H, m), 1.54 (1H, m), 1.75 (5H, m), 2.01 (2H, m), 2.85 (1H, m), 3.00 (1H, m), 3.21 (1H, m), 3.36 (2H., m), 3.91 (3H, m), 4.08 (1H, s). Three protons were not ed in D20.

HPLC: 95.22 % MS (ES‘) m/z: [M-H]' calcd for C13H21N4O7S: 377.1. Found: 377.0.

Examp|e 40 (2S,5R)-N'-acetyl-‘7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarbohydrazide (Compound 16, Table 2) OH1)”I . N 199199 Step 1. (28,5R)—N‘-Acetyl(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octane carbohydrazide (174) O AN’NHZ H H “Cl \[f N H0 173 ‘N —-——> H 0 N To a mixture of (2S,5R)—6-(benzyloxy)oxo—1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.200 g, 0.720 mmol, U82005/20572 A1) in DCM (6.0 mL) were added acetohydrazide 173 (0.090 g, 1.085 mmol), 1-hydroxybenzotriazole (0.147 g, 1.085 mmol), 1-ethyl-(3- dimethylamino propyl) carbodiimide hydrochloride (0.208 g. 1.085 mmol) and MN- dimethylaminopyridine sequentially at room temperature. The e was stirred at room temperature ght, diluted with DCM and concentrated to provide a residue, which was 1O subjected to tography to give 174 (0.14 g, 60 %) as a white foam.

‘H NMR (400 MHz. CDCI3):51.60(1H,m), 1.96 (2H, m), 2.06 (3H, s), 2.34 (1H, m), 3.09 (1H, m), 3.15 (1H, d, J =12 Hz), 3.32 (1H, m), 4.01 (1H, d, J = 8.4 Hz), 4.90 (1H, d, J = 11.2 Hz), .07 (1H, d, J =11.2 Hz), 7.26—7.44 (5H, m), 7.74 (1H, br s), 8.54 (1H, brs).

MS (ES*): m/z [M+H]+ calcd for C16H21N4O4: 333.16. Found: 333.21.

Step 2. )-N‘-AcetyIhydroxyoxo-1,6-diazabicyclo[3.2.1]octane carbohydrazide (175) Hj » 7:10 ~30”N. .N,,,Cl 174 175 A mixture of (2S,5R)-N—acetyl(benzyloxy)—7-oxo-1,6—diazabicyclo[3.2.1]octane-2— carbohydrazide 174 (0.14 g, 0.43 mmol) and Pd/C (0.070 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 175 (0.10 g, 95 %) as a white foam.

'H NMR (400 MHz, CD30D): 5 1.71-1.78 (1H, m), 1.88—1.93 (1H, m), 2.04 (3H, s), 2.06-2.09 (1H, m), .29 (1H, m), 3.13 (1H, m), 3.22 (1H, d, J: 12 Hz), 3.69 (1H, m), 3.93 (1H, d, J = 8.4 Hz). 3 protons were not observed in CD30D.

MS (ES+): m/z [M+H]+ calcd for C9H15N4O4: 243.11. Found: 243.18. 200200 Step 3. (ZS,5R)—N'-Acetyloxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane carbohydrazide (Compound 16, Table 2) \n/N\”/H’I,AH ( \n/ \u/ll’l.

O N O N H H o bH O bSO3H 175 Compound 16, Table 2 To a mixture of (2S,5R)-N-acetylhydroxyoxo-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide 175 (0.10 g, 0.41 mmol) in pyridine (5.0 mL) was added sulfur trioxide pyridine complex (0.19 g, 1.24 mmol). The mixture was stirred at room temperature for 23 h and concentrated to provide a residue which was subjected to chromatography to give Compound 16 (Table 2) (0.040 g, 30 %) as a light yellow solid. 1H NMR (400 MHz, D20): 51.64-169 (1H, m), 1.76-1.81 (1H, m), 1.88-1.98 (4H, m), 2.03- 2.09 (1H, m), 3.03 (1H, d, J = 12.0 Hz), 3.20 (1H, m), 4.00 (1H, m), 4.05 (1H, m). 3 protons were not observed in D20.

HPLC: 89.2 % MS (ES'): m/z [M-H]' calcd for C9H13N4O7S: 321.05. Found: .

The corresponding sodium salt of compound 16 (Table 2) was prepared in the following manner: To a mixture of (28,5R)-N-acetylhydroxyoxo-1,6-diazabicyclo[3.2.1]octane carbohydrazide 175 (0.20 g, 0.78 mmol) in pyridine (10.0 mL) was added sulfur trioxide pyridine complex (0.37 g, 2.35 mmol). The mixture was d at room temperature for 24 h and concentrated to provide a e which was subjected to purification by change resin (Dowex50 Na+ form, water) and reverse phase column to give sodium salt of nd 16 (Table 2) (42 mg) as a white solid.

]H NMR (400 MHz, D20): 51.64-1.69(1H, m), 1.76-1.81 (1H, m), 1.88-1.98 (4H, m), 2.03- 2.09 (1H, m), 3.03 (1H, d, J= 12.0 Hz), 3.20 (1H, m), 4.00 (1H, m), 4.05 (1H, m). 3 protons were not observed in D20.

HPLC: 96.5 % MS (ES') m/z: [M-Na]‘ calcd for C9H13N4O7SNa: 321.05. Found: 321.05. 201201 Example 41 (ZS,5R)-N'-methyloxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarbohydrazide (Compound 1, Table 2) /N\N/H/,,.H //‘———N O bso3H Step 1. tert-butyl 2-{[(2$,5R)(benzyloxy)oxo—1,6-diazabicyclo[3.2.1]oct yl]carbonyl}methylhydrazinecarboxylate (177) j,, ><O/U\T,NH2 0 H0 " 176 +0 (11 J,“ N T l G o N To a on of (28,5R)—6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.2 g, 0.72 mmol) in dry DCM (10 mL) were added tert—butyl 1- 1O methylhydrazinecarboxylate 176 (0.16 g, 1.08 mmol), 1-hydroxybenzotriazole (0.15 g, 1.08 mmol), 1-ethyl—(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.08 mmol) and 4-dimethylaminopyridine (0.13 g, 1.08 mmol) at room temperature. The reaction e was stirred at room ature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 2—{[(2S,5R)—6-(benzyloxy)oxo- 1,6-diazabicyclo[3.2.1]octyl]carbonyl}methylhydrazinecarboxylate 177 (0.25 g, 86%) as a clear thick oil. 1H NMR (400 MHz, 00013): 8 1.46 (9H, s), 1.58 (1H, m), 1.97 (2H, m), 2.37 (1H, m), 3.04— 3.16 (5H, m), 3.29 (1H, m), 3.96 (1H, d, J = 6.8 Hz), 4.90 (1H, d, J = 11.2 Hz), 5.05 (1H, d, J =11.6Hz), 7.38 (5H, m), 8.32 (1H, br s). 202202 Step 4. tert-butyl 2-{[(2$,5R)—6—hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}methylhydrazinecarboxylate (178) .gO N +0El.uj,,© )—N }‘N.

O ‘osn O OH 177 178 To a solution of tert-butyl 2—{[(2S,5R)—6-(benzyloxy)oxo-1,6—diazabicyclo[3.2.1]oct—2— yl]carbonyl}methylhydrazinecarboxylate 177 (0.29 g, 0.72 mml) in methanol (15 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert—butyl 2—{[(2S,5R)—6-hydroxy-7—oxo—1,6-diazabicyclo[3.2.1]oct—2— yl]carbonyl}methylhydrazinecarboxylate 178 (0.22 g, 98%) as a colorless foam. 1O 1H NMR (400 MHz, : 8 1.46 (9H, s), 1.74 (1H, m), 1.92 (1H, m), 2.07 (1H, m), 2.26 (1H, m), 3.01-3.22 (5H, m), 3.71 (1H,m), 3.88 (1H, m), 2 protons were not observed in CD30D.

Step 5. tert-butyl yl{[(28,5R)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octyl]carbonyl}hydrazinecarboxylate pyridine salt (179) NI j +0 l j? ____.. tr H ‘m o N 0 N )—~N vi—N - O bH O pyridine. OSO3H 179 To a solution of tert—butyl 2-{[(2S,5R)—6—hydroxy-7—oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}methylhydrazinecarboxylate 178 (0.22 g, 0.7 mmol) in dry pyridine' (10 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.56 g, 3.5 mmol).

The mixture was stirred at room temperature for 20 h, filtered and evaporated to give tert- butyl 1-methyl{[(2S,5R)oxo—6~(sulfooxy)—1,6-diazabicyclo[3.2.1]oct-2— yl]carbonyl}hydrazinecarboxylate pyridine salt 179 (0.33 g crude) which was used in the next step without purification. 203203 Step 6. ,N,N,N-tributylbutanaminium ({[(28,5R){[2-(tert-butoxycarbonyl) methylhydrazinyl]carbonyl}oxo-1,6-diazabicyclo[3.2.1]oct yl]oxy}sulfonyl)oxidanide (180) +0 1‘1 )1, +0 ”will. \ll/ E Q \g/ H O O N 1 OWL—N. 0 . . NbSO3' Bu4N+ OSO3H pyridine 180 ted-butyl 1-methyl{[(2S,5R)-7—oxo-6—(sulfooxy)-1 zabicyclo[3.2.1]oct—2— yl]carbonyl}hydrazinecarboxylate pyridine salt 179 (0.33 g, 0.7 mmol) was introduced into a concentrated aqueous solution of monosodium dihydrogen phosphate solution (12 mL) so as to obtain a pH of 4. The mixture was washed with ethyl acetate, then added tetrabutyl ammonium hydrogen sulfate (0.136 g, 0.4 mmol) and stirred at room temperature for 10 min. 1O The mixture was extracted with ethyl e (3 x 20 mL), and the extracts were combined, dried over sodium sulfate and ated to give N,N,N—tributylbutanaminium ({[(28,5R)- (ter1—butoxycarbonyl)-2—methylhydrazinyl]carbonyl}oxo-1,6—diazabicyclo[3.2.1]oct yl]oxy}sulfonyl)oxidanide.180 (0.31 g, 70%) as a white solid. 1H NMR (400 MHz, CDCI3): 8 1.00 (12H, t, J = 7.2 Hz), 1.18 (3H, m), 1.46 (12H, m), 1.66 (12H, m), 1.94 (2H, m), 2.15 (1H, m), 2.38 (1H, m), 2.84 (1H, d, J = 11.2 Hz), 3.29 (8H, m), 3.87 (1H, m), 3.93 (1H, d, J = 8.0 Hz), 4.35 (1H, s),_8.98 (1H, br 5).

Step 7. (2S,5R)-N'-methyloxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 1, Table 2) 4ON.,,'ﬁ Hi?N.

T” Q ———~ o N NQ 2—11 )iN._ O 0803- Bu4N+ O OSOgH 180 Compound 1, Table 2 To a solution of N,N,N-tributylbutan—1-aminium ({[(28,5R){[2-(ted—butoxycarbonyl) methylhydrazinyl]carbonyl}-7—oxo—1,6-diazabicyclo[3.2.1]oct—6—yl]oxy}sulfonyl)oxldanide 180 (0.31 g, 0.49 mmol) in DCM (20 mL) was added trifluoroacetic acid (1.2 mL, 15.55 mmol) dropwise at 0 °C. The reaction’ mixture was stirred for 2 h, then evaporated. Ether was added to the residue and the ing white itate was collected by centrifugation. The solid was triturated with acetonitrile (2 x) and the white solid was collected by centrifugation. The white solid was purified by HPLC and freeze-dried to give (28,5R)—N—methyl—7-oxo—6- 204204 (sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2—carbohydrazide Compound 1 (Table 2) (0.01 g, 6.9 %) as a white solid. 1H NMR (400 MHz, CD3OD): 5 1.77 (2H, m), 1.95 (1H, m), 2.05 (1H, m), 2.97 (5H, m), 3.16 (1H, d, J = 12.0Hz), 3.26 (4H, m), 3.89 (1H, d, J = 7.6 Hz), 4.06 (1H, m), 3 protons were not observed in CD3OD.

MS (ES'): m/z [M-H]‘= 293.04 Example 42 )—7-oxo-N'-(phenylcarbonyl)—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 64, Table 2) ’ N\ OSOSH Step 1. (2R,5R)(benzyloxy)oxo-N'-(phenylcarbonyl)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (182) o H O )1, ‘NHZ R J,“ HO 0 {j 181 0 N A‘N —————~ )_N\ \OBn O ‘ OBn 1 182 To solution of (28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 ' (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added benzohydrazide 181 (0.118 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4— (dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was d at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2R,5R)(benzyloxy)—7-oxo-N‘— (phenylcarbonyl)-1,6-diazabicyclo[3.2.1]octane-2—carbohydrazide 182 (0.35 g, 98%) as a white solid. 1H NMR (400 MHz, CDCI3): 5 1.58-1.74 (1H, m), 2.02 (2H, m), 2.36 (1H, m), 3.11 (1H, d, J = 12.0 Hz), 3.22 (1H, d, J =12.0 Hz), 3.32 (1H, s), 4.05 (1H, d, J = 7.2 Hz ), 4.90 (1H, d, J = 205205 11.2 Hz), 5.04 (1H, d, J = 11.6 Hz), 7.41 (7H, m), 7.51 (1H, m), 7.79 (2H, d, J = 8.4 Hz ), 8.74 (1H, brs), 8.79 (1H, br s).

Step 2. (2R,5R)hydroxyoxo-N‘-(phenylcarbonyl)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (183) ©1”‘N”QO O H H H —-> @N‘NJQH O N To a solution of . , (2R,5R)(benzyloxy)—7-oxo-N'-(phenylcarbonyl)—1 ,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide 182 (0.33 g, 0.88 mml) in methanol (20 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was 1O evaporated to give (2R,5R)hydroxyoxo-N'-(phenylcarbonyl)-1,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide 183 (0.19 g, 89%) as a ess foam. 1H NMR (400 MHz, CD3OD): 6 1.80 (1H, .m), 1.98 (1H, m), 2.07 (1H, m), 2.33 (1H, m), 3.20 (1H, d, J = 11.6 Hz), 3.35 (1H, m), 3.74 (1H, s), 4.02 (1H, d, J = 7.6 Hz), 7.47 (2H, m), 7.57 (1H, m), 7.86 (2H, m), 3 protons were not ed in CD3OD.

Step 3. (2R,5S)oxo-N‘-(phenylcarbonyl)(sulfooxy)-1,6- diaza‘bicyclo[3.2.1]octanecarbohydrazide (Compound 64, Table 2) [ j 0 O H H' N\ /H//,' ©\n/N\ /u/I,’ ' O N O N I; N\ I: N\ 0 OH 0 OSO3H nd 64, Table 2 To a solution of )hydroxy-7—oxo-N‘—(phenylcarbonyl)-1,6-diazabicyclo[3.2.1]octane- 2—carbohydrazide 183 (0.197 g, 0.69 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.44 g, 2.76 mmol). The mixture was stirred at room temperature for 20 h, filtered and evaporated. The e was purified by‘column chromatography followed by HPLC on a prep-X Bridge-30x100 mm column and freeze—dried to give (2R,5S)—7—oxo-N'-(phenylcarbonyl)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide Compound 64 (Table 2) (0.05 g, 16.7%) as a white solid. 206206 1H NMR (400 MHz,CD30D):51.83(1H, m), 1.99 (1H, m), 2.10 (1H, m), 2.33 (1H, m), 3.29- 3.39 (2H, m), 4.09 (1H, d, J = 7.2 Hz), 4.19 (1H, s), 7.49 (2H, m), 7.56 (1H, m), 7.89 (2H, m), 3 protons were not observed in CD3OD.

HPLC: 98.2% MS (ES‘) m/z: [M]‘= 383 Example 43 (2R,5S)oxo(sulfooxy)-N'-(trifluoroacety|)-1,6-diazabicyclo[3.2.1]octane ydrazide (Compound 89, Table 2) F3C\n/N\NJL,,IH o ‘oso3H 1O Step 1. (2R,5R)(benzyloxy)oxo-N'-(trifluoroacetyl)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (185) 0' FC N.

Ho’lL Hr NHz F38 H J, o T \ u O N N 184 1 185 To solution of (2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octane-2—carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added 2,2,2—trifluoroacetohydrazide 184 (0.17 g, 1.35 mmol, Aldrich), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl—(3— dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4- (dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room ature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5R)(benzyloxy)-7—oxo-N-(trifluoroacetyl)— 1,6-diazabicyclo[3.2.1]octane-2—carbohydrazide 185 (0.224 g, 65%) as a white solid. 1H NMR (400 MHz, : 8 1.62(1H, m), 2.01 (2H, m), 2.33 (1H, m), 2.99 (1H, d, J = 12.0 Hz), 3.07 (1H, d, J = 12.0 Hz), 3.34 (1H, s), 4.03 (1H, d, J = 7.2 Hz ), 4.90 (1H, d, J = 11.2 Hz), 5.04 (1H, d, J = 11.6 Hz), 7.39 (5H, m), 8.59 (1H, br s), 8.68 (1H, br s). 207207 Step 2. (2R,5R)hydroxyoxo-N'-(trif|uoroacetyl)-1,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide (186) To a solution of (2R,5R)-6—(benzyloxy)—7-oxo-N-(trifluoroacetyl)-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide 185 (0.224 g, 0.58 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The e was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The st was filtered out through Celite and the filtrate was evaporated to give (2R,5R)—6-hydroxyoxo-N-(trifluoroacetyl)-1,6- diazabicyclo[3.2.1]octanecarbohydra2ide 186 (0.15 g, 88%) as a colorless foam. 1H NMR (400 MHz, CD30D): 5 1.77 (1H, m), 1.95 (1H, m), 2.06 (1H, m), 2.30 (1H, m), 3.17 (1H, m), 3.33 (1H, m), 3.73 (1H, s), 3.97 (1H, d, J = 7.2 Hz), 3 protons were not observed in CD30D. ‘ Step 3. (2R,5S)oxo(sulfooxy)-N'-(trifluoroacetyl)—1,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 89, Table 2) - o O H H 1 FC N )1, F3C N\ )1,“ 3 M q ___2 gm. Q\N I, o N l N\ 1711 0 OH o ‘ososH 186 nd 89, Table 2 To a solution of (2R,5R)—6-hydroxyoxo-N-(trifluoroacetyl)-1,6—diazabicyclo[3.2.1]octane carbohydrazide 186 (0.15 g, 0.51 mmol) in dry pyridine (9 mL) under en atmosphere was added sulfur trioxide pyridine complex (0.38 g, 2.37 mmol). The mixture was stirred at room temperature for 20 h, filtered and evaporated. The residue was purified by column tography followed by HPLC on a prep-X Bridge-30x100 mm column and freeze—dried to give (2R,5S)oxo(sulfooxy)-N‘-(trifluoroacetyl)—1,6-diazabicyclo[3.2.1]octane carbohydrazide Compound 89 (Table 2) (0.02 g, 10.5%) as a white solid. 1H NMR (400 MHz, CD30D)251.81 (1H, m), 1.96 (1H, m), 2.06 (1H, m), 2.32 (1H, m), 3.05 (1H, d, J =11.6 Hz), 3.31 (1H, m), 4.01 (1H, d, J = 8.0Hz), 4.16 (1H, s), 3 protons were not observed in CD30D. 208208 HPLC: 92.6% MS (ES') m/z: [M]‘= 375 Example 44 (2R,5S)-N'-(methylsulfonyl)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 90 , Table 2) H3C-MrsN)’ o N ‘ wt 0 . OSO3H Step 1. (2R,5R)(benzyloxy)—N‘-(methylsulfonyl)oxo-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (188) j ll/N\ H3c—s NH2 Oo/H‘ J,“ HO 0 H3013, E, N 187 0 N J‘N ________—_____> /}'_‘N\ o ‘OBn 0 CB” 1 188 To solution of (2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octane—2-carboxylic acid 1 (0.67 g, 2.42 mmol) indry DCM (60 mL) were added methanesulfonohydrazide 187 (0.40 g, 3.63 mmol), 1-hydroxybenzotriazole (0.44 g, 3.63 mmol), 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.72 g, 3.63 mmol) and 4- (dimethylamino)pyridine (0.44 g, 3.63 mmol) at room temperature. The on mixture was stirred at room temperature overnight and concentrated under vacuum. The e was purified by column chromatography to give (2R,5R)(benzyloxy)-N'-(methylsu|fonyl)—7-oxo- 1,6-diazabicyclo[3.2.1]octanecarbohydrazide 188 (0.37 g, 42%) as awhite solid. 1H NMR (400 MHZ, CDCI3): 5 1.67(1H, m), 2.02 (2H, m), 2.26 (1H, m), 2.79 (1H, d, J = 11.6 Hz), 3.02 (3H, s), 3.09 (1H, d, J = 12.8 Hz), 3.32 (1H, s), 4.12 (1H, d, J = 6.8 Hz ), 4.89 (1H, ,20 d, J =11.2 Hz), 5.03 (1H, d, J = 11.2 Hz), 7.16 (1H, br s), 7.39 (5H, m), 9.08 (1H, br s). 209209 Step 2. (2R,5R)hydroxy-N’-(methylsulfonyl)oxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (189) O\\ /N\ )I’h, O\ \N/l , I.

N H C:S/ H C/S 3 H H 3 n H o N O N ———-————-——> l 188 189 To a solution of (2R,5R)—6-(benzyloxy)-N'-(methy1sulfony|)oxo-1,6- icyclo[3.2.1]octanecarbohydrazide 188 (0.37 g, 1.044 mml) in methanol (35 mL) was added 5 % Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmOSphere at room temperature for 1 h. The catalyst was filtered through Celite and the filtrate was evaporated to give (2R,5R)—6-hydroxy-N‘-(methylsulfonyl)—7-oxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide 189 (0.276 g, 99 %) as a colorless foam. 1H NMR (400 MHz, CD30D): 8 1.78 (1H, m), 1.95 (1H, m), 2.06 (1H, m), 2.24 (1H, m), 3.01 (3H, s), 3.03 (1H, d, J = 12.0 Hz), 3.14 (1H, d, J = 11.6 Hz), 3.69 (1H, s), 3.91 (1H, d, J = 7.6 Hz), 3 s were not observed in CD30D.

Step 3. (2R,5S)-N'-(methy|sulfonyl)oxo(su|fooxy)-1,6- diazabicyc|o[3.2.1]octanecarbohydrazide (Compound 90, Table 2) O j O\\ H\ /H// N 4' \\ /N\ ’1’, N . H 0/85 H (348 3 ll H 3 H H O N O N //j ”x A‘N o ‘ososH Compound 90, Table 2 189 To a solution of (2R,5R)—6-hydroxy-N'-(methylsulfonyl)oxo—1,6-diazabicyclo[3.2.1]octane- 2-carbohydrazide 189 (0.276 g, 0.99 mmol) in dry pyridine (18 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.70 g, 4.37 mmol). The mixture was stirred at room temperature for 20 h, ed and evaporated. The e was ed by column chromatography followed by trituration with a mixture of MeOH: DCM: Ether (1 :1 :1) (4 X) to give (2R,5S)—N'-(methylsuIfonyl)oxo(sulfooxy)¥1,6- diazabicyclo[3.2.1]octanecarbohydrazide Compound 90 (Table 2) (0.12 g, 34 %) as a white solid. 210210 1H NMR (400 MHz, CD3OD):51.81 (1H, m), 1.96 (1H, m), 2.06 (1H, m), 2.32 (1H, m), 3.05 (1H, d, J = 11.6 Hz), 3.31 (1H, m), 4.01 (1H, d, J = 8.0Hz), 4.16 (1H, s), 3 protons were not observed in CD3OD. ' HPLC: 91.8% MS (ES’) m/z: [M]'= 357 e 45 (28,5R)-N'-(cyclopentylcarbonyl)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 38, Table 2) 0 NW)“l O ‘oso3H 1O Step 1. (28,5R)(benzyloxy)-N‘-(cyclopentylcarbonyl)oxo-1,6— diazabicyclo[3.2.1]octanecarbohydrazide (191) o H o ‘NHZ HO/Ul'“ ’ o H j ‘N - , 190 o)/—N ——————-———————> OBn }—N\ O OBn To a solution of (2S,5R)(benzyioxy)—7-oxo-1,6—diazabicyclo[3.2.1]octanecarboxyiic acid 1 (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added cyciopentanecarboxyhydrazide 190 (0.173 g, 1.35 mmol,), 1-hydroxybenzotriazoie (0.19 g, 1.35 mmol), i—(3- dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4- (dimethyiamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified to give (2S,5R)-6—(benzy|oxy)—N'-(cyc|opentyicarbonyl)—7-oxo-1 ,6- diazabicycio[3.2.1]octanecarbohydrazide 191 (0.33 g, 94%) as a white solid. 1H NMR (400 MHz, CDCI3): 5 1.50-2.00 (11H, m), .38 (1H, m), 2.60-2.70 (1H, m), 3.05 (1H, d, J = 12.0 Hz), 3.20 (1H, d, J = 12.0 HZ), 3.30 (1H, s), 3.98 (1 H, m ), 4.90 (1H, d, J = 11.2 Hz), 5.04 (1H, d, J =11.6 Hz), 7.30-7.48 (5H, m), 7.85 (1H, br s), 8.60 (1H, br 5).

MS (ES+) m/z: [M]+ = 387 211211 Step 2. (28,5R)-N'-(cyclopentylcarbonyl)hyd -oxo-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (192) H o o N\N/H/,NQ o H /ll, H N O an O NbH 191 192 To a solution of (ZS,5R)—6-(benzyloxy)-N'-(cyclopentylcarbonyl)oxo—1 ,6— _diazabicyclo[3.2.1]octane—2-carbohydrazide 191 (O. 33 g, 0.84mi) in methanol (20 mL) was added 10% Pd/C (0.30 g). The mixture was hydrogenated under 15 psi hydrogen here at room temperature for 1 h. The catalyst was filtered h , and the filtrate was evaporated to give (28,5R)-N-(cyclopentylcarbonyl)hydroxyoxo—1,6- diazabicyclo[3.2.1]octane—2-carbohydrazide 192 (0.24 g, 98%) as a colorless foam. 1H NMR (400 MHz, CD30D): 5 1.50-2.12 (10H, m), 2.21-2.33 (1H, m), 2.63-2.80 (1H, m), 3.10-3.38 (3H, m), 3.70 (1H, s), 3.98 (1H, d, J = 7.6 Hz), 3 protons were not observed in CD30D.

Step 3. (2S,5R)-N'-(cyc|opentylcarbonyl)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 38, Table 2) o 0 o i, 0 MN)» N N . _________, )——N 5 Q)—'N\ o bH O 0803H Compound 38, Table 2 To a solution of (28,5R)—N—(cyclopentylcarbonyl)hydroxyoxo—1 ,6— diazabicyclo[3.2.1]octanecarbohydrazide 192 (0.24 g, 0.81 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide'pyridine x (0.36 g, 2.25 mmol).

The mixture was stirred at room temperature for 72 h, filtered and'evaporated. The residue was ed by column chromatography followed by HPLC on a prep-X Bridge-30x100 mm column and freeze-dried to give (28,5R)—N'-(cyclopentylcarbonyl)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide Compound 38 (Table 2) (0.12 g, 40%) as a light brown solid. 1H NMR (400 MHz, CD3OD): 5 1.60—1.99 (10H, m), 2.06-2.10 (1H, m), 2.25-2.31 (1H, m), 2.68-2.74 (1H, m), 3.26—3.33 (2H, m), 4.02 (1H, d, J = 7.6 Hz), 4.15 (1H, br s). 3 protons were not observed in CD30D. 212212 HPLC: 92.01% MS (ES‘) m/z: [M]'= 375 Example 46 (2R,58)-N‘-(2-methylpropanoyl)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 18, Table 2) QMJ"Q ﬂOSO3H Step 1. (2R,58)(benzyloxy)-N‘-(2-methylpropanoyl)oxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (194) )1, NW].H . O 1 194 1O To a solution of (2S,5R)(benzy|oxy)-7—oxo-1,6-diazabicyclo[3.2.1]octane—2—carboxy|ic acid 1 (0.25 g, 0.90 mmol) in dry DCM (20 mL) were added 2-methylpropanehydrazide 193 (0.14 g. 1.35 , 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3— dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4- (dimethylamino)pyridine (0.16 g, 11.35 mmol) at room temperature. The reaction mixture was stirred at room ature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2R,58)—6-(benzyloxy)-N-(2-methylpropanoyl)oxo-1,6- diazabiCyclo[3.2.1]octane-2—carbohydrazide 194 (0.30 g, 92.6%) as a white solid. 1H NMR (400 MHz, CDCls): 6 1.12 (6H, m), 1.60 (1H, m), 1.94 (2H, m), 2.29 (1H, m), 2.47 (1H, q, J = 6.8 Hz), 3.06 (1H, d, J = 12.0 Hz), 3.18 (1H, d, J = 11.6 Hz), 3.30 (1H, s), 3.99 (1H, d, J = 7.2 Hz ), 4.90 (1H, d, J = 10.8 Hz), 5.04 (1H, d, J = 11.2 Hz), 7.40 (5H. m), 8.07 (1H, br s), 8.61 (1H, brs). 213213 Step 2. (2R,5$)hydroxy-N'-(2-methylpropanoyl)oxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (195) H ‘i )Yil- Jr, AWNW)“ u H ————————» o N O NCI I %— N\ N OH \ O 194 195 To a solution of )—6-(benzyloxy)—N—(2-methylpropanoy|)oxo-1,6-diazabicyclo[3.2.1]octane-2~ carbohydrazide 194 (0. 30 g, 0.83 mml) in methanol (20 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was ﬁltered out through Celite, and the ﬁltrate was evaporated to give (2R,SS)hydroxy- N-(2—methylpropanoyl)—7-oxo-1,6-diazabicyclo[3.2.1]octanecarbohydrazide 195 (0.21 g, 95%) as a colorless foam. 1H NMR (400 MHz, CD30D):51.16(6H,m), 1.74 (1H, m), 1.94 (1H, m), 2.02 (1H, m), 2.29 (1H, m), 2.53 (1H, m), 3.14 (1H, d, J = 12.0 Hz), 3.26 (1H, m), 3.70 (1H, s), 3.94 (1H, d, J = 7.2 Hz), 3 protons were not observed in CD30D.

Step 3. (2R,5$)-N'-(2-methylpropanoyl)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide und 18, Table 2) AWNWJL.OH H G )YHWJL.o o H __+ o "Q OH //]~—‘N 0 O ‘oso3H Compound 18, Table 2 To a solution of (2R,58)hydroxy-N-(2-methylpropanoyl)oxo-1,6-diazabicyclo[3.2.1]octane carbohydrazide 195 (0.21 g, 0.78 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide ne complex (0.70 g, 4.40 mmol). The mixture was stirred at room temperature for 20 h, filtered and evaporated. The e was puriﬁed first by column tography followed by HPLC on a prep-X Bridge-30x100 mm column and freeze-dried to give (2R,5S)—N—(2-methylpropanoyI)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide Compound 18 (Table 2) (0.03 g, 11%) as a grey solid. 1H NMR (400 MHz, CD30D):61.64(6H, m), 1.80 (1H, m), 1.94 (1H, m), 2.07 (1H, m), 2.29 (1H, m), 2.53 (1H, m), 3.30 (2H, m), 4.01 (1H, d, J = 7.6 Hz), 4.15 (1H, s), 3 protons were not observed in CD30D.

HPLC: 97.5 % 214214 MS (ES‘) m/z: [M]' = 349 Example 47 (2R,5S)-N'-(cyclopropylcarbonyl)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 32, Table 2) /LMQH I O N //L‘N\ Step 1. (2R,5S)(benzyloxy)—N'-(cyclopropylcarbonyl)oxo-1,6- diazabicyc|o[3.2.1]octanecarbohydrazide (197) AYN‘NWH J‘i :1 i ,, O ‘u 196 O N 1 197 To a solution of (28,5R)—6-(benzyloxy)oxo—1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 1O (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added ropanecarbohydrazide 196 (0.135 g, 1.35 mmol), 1-hydroxybenzotria20le (0.19 g, 1.35 mmol). 1-ethyl—(3- dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35' mmol) and 4— (dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and concentrated under vacuum. The residue was purified by column tography to give (2R,5S)(benzyony)—N-(cyclopropylcarbonyl)oxo-1,6- diazabicyclo[3.2.1]octane'carbohydrazide 197 (0.27 g, 84%) as a white solid. 1H NMR (400 MHZ, CDClg): 5 0.83 (2H, m),1.04 (2H, m), 1.62 (2H, m), 2.02 (2H, m), 2.34 (1H, m), 3.04 (1H, d, J = 12.0. Hz), 3.15 (1H, d, J = 12.0 Hz), 3.29 (1H, s), 4.00 (1H, d, J = 7.6 Hz )', 4.89 (1H, d, J = 11.2 Hz), 5.03 (1H, d, J =11.2 Hz), 7.38 (5H, m), 8.29 (1H, brs), 8.57 (1H, br s). 215215 Step 2. (2R,5S)-N'-(cyc|opropylcarbonyl)hydroxyoxo-1,6- diazabicyc|o[3.2.1]octane-Z-carbohydrazide (198) AWHWJOL, O H C1 ——————»AWHWJL,H O ,0 }—‘N\ 1"“. o OBn O OH 197 198 To a solution of (2R,5S)—6-(benzyloxy)—N-(cyclopropylcarbonyl)—7-oxo—1,6-diazabicyclo[3.2.1]octane- 2-carbohydrazide 197 (0. 27 g, 0.75 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was ed out through Celite, and the filtrate was evaporated to give (2R,58)-N- (cyclopropylcarbonyl)—6-hydroxy—7-oxo-1,6-diazabicyclo[3.2.1]octanecarbohydrazide 198 (0.20 g, 98%) as a colorless foam. 1H NMR (400 MHz, CD30D): 5 0.86 (2H, m), 0.91 (2H, m), 1.65 (1H,m), 1.76 (1H, m), 1.94 (1H, m), 2.04 (1H, m), 2.26 (1H, m), 3.13 (1H, d, J = 13.2 Hz), 3.23 (1H, d, J = 12.0 Hz ), 3.70 (1H, s), 3.94 (1H, d, J = 7.2 Hz), 3 protons were not observed in CD30D.

Step 3. (2R,5$)-N'-(cyclopropylcarbonyl)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide und 32, Table 2) O O AH/N\N/UIIHQH H An/N\N/UII“QH H O N ———> O N k”. fN 198 Compound 32, Table 2 To a solution of )—N‘—(cyclopropylcarbonyl)hydroxy—7-oxo—1,6—diazabicyclo[3.2.1]octane carbohydrazide 198 (0.20 g, 0.75 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide pyridine x (0.70 g, 4.40 mmol). The mixture was stirred at room temperature for 20 h, filtered and evaporated. The residue was puriﬁed first by column chromatography followed by HPLC on a prep—X Bridge-30x100 mm column and freeze-dried to give (2R,5S)-N-(cyclopropylcarbonyI)—7-oxo(su|fooxy)-1,6odiazabicyclo[3.2.1]octane carbohydrazide Compound 32 (Table 2) (0.035 g) as a grey solid. 1H NMR-(400 MHz, CD30D): 8 0.83 (2H, m), 0.90 (2H, m), 1.66 (1H, m), 1.78 (1H, m), 1.94 (1H, m), 2.06 (1H, m), 2.28 (1H, m), 3.30 (2H, m), 4.01 (1H, d, J = 7.6 Hz), 4.14 (1H, s), 3 protons were not observed in CD30D.

HPLC: 98.4% 216216 MS(ES)an[MI=347 Example 48 (23,5R)-N'-(cyclobutylcarbonyl)oxo(sulfooxy)—1,6-diazabicyc|o[3.2.1]octane carbohydrazide (Compound 33, Table 2) 0 H—N/L"Ol, N «H 4L——N o YasosH Step 1. (ZS,5R)—6-(benzyloxy)-N‘-(cyclobutylcarbonyl)—7-oxo-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (200) [fk o o NHNH2 l 0 H )l.

HO ’“ N‘” N -HH N -~H 199 1 200 To a e of (28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added cyclobutanecarbohydrazide 199 (0.155 g, 1.358 mmol), oxybenzotriazole (0.186 g, 1.358 mmol) and 1—ethyl—(3- dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, d with DCM and concentrated to provide a residue, which was subjected to chromatography to give 200 (0.34 g, quant. yield) as a white foam. 1H NMR (400 MHZ, CDCI3): 51.60 (1H, m), 1.90 (4H, m), 2.21 (2H, m), 2.30 (3H, m), 3.10 (3H, m), 3.30 (1H, m), 3.40 (2H, br s), 4.00 (1H, d, J = 7.4 HZ), 4.90 (1H, d, J = 11.2 HZ), .07 (1H, d, J =11.2 Hz), 7.26-7.44 (5H, m).

MS (ES+) m/z: [M+H]+ calcd for C19H25N4O4: 373.2. Found: 373.2. 217217 Step2. (28,5R)—N‘-(cyclobutylcarbonyl)hydroxy—7-oxo-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (201) o 141*.L, O o h».

N "'H ——> EX H OH N o ‘OBn 200 201 A mixture of (2S,5R)(benzyloxy)-N'-(cyclobutylcarbonyl)oxo—1 ,6- diazabicyclo[3.2‘.1]octanecarbohydrazide 200 (0.34 g, 0.91 mmol) and Pd/C (0.12 g) in ol (20 mL) was hydrogenated at 1 atm at room ature for 3 h. The mixture was filtered through Celite and concentrated to provide 201 (0.30 g, quant. yield) as a white foam. 1H NMR (400 MHz, CD3OD): 8 1.86 (1H, m), 1.90 (3H, m), 2.00 (2H, m), 2.09 (2H, m), 2.10 (3H, m), 3.20 (2H, m), 3.71 (1H, s), 3.94 (1H, d, J = 7.4 Hz). 3 protons were not observed in CD3OD.

MS (ES') m/z: [M-H]' calcd for C12H17N4O4: 281.1. Found: 281.0.

Step 3. (28,5R)-N'-(cyc|obutylcarbonyl)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 33, Table 2) o o H jI], H j’I, N-N ' N-N ' H H N «H . N «H x/‘wN. )—~ 0 OH 0 ‘oso3H 201 compound 33, Table 2 To a mixture of )-N—(cyclobutylcarbonyl)hydroxy—7-oxo-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide 201 (0.91 mmol) in pyridine (5.0 mL) was added sulfur trioxide pyridine x (0.52 g, 3.33 mmol). The mixture was stirred at room temperature for 3 days and concentrated to provide a residue which was subjected to chromatography and HPLC purification to give Compound 33 (Table 2) (29 mg, 9 % yield) as a white solid. 1H NMR (400 MHz, D20): 81.60-2.10 (8H, m), 3.05-3.13 (2H, m), 3.16—3.25 (1H, m). 4.00 (1H, d, J = 7.4 Hz), 4.08 (1H, s). 3 protons were not observed in D20.

HPLC: 98.31 % MS (ES') m/z: [M-H]' calcd for C12H17N4OgS: 361.1. Found: 361.0. 218218 Example 49 (2S,5R)—7-oxo-N'-propanoyl(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 17, Table 2) H Nfl )NNQ; 0 OSO3H Step 1. (28,5R)—6-(benzyloxy)oxo-N‘-propanoyI-1,6-diazabicyclo[3.2.1]octane- 2-carbohydrazide (203) 1 203 To a mixture of (28, 5R)—6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added propanehydrazide 202 (0.120 g, 1O 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino ) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature, The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 203 (0.31 g, 99 %) as a white foam. 1H NMR (400 MHz, : 5 1.20 (3H, t, J = 7.4 Hz), 1.62 (1H, m), 1.98 (2H, m), 2.12 (1H, m), 2.38 (2H, m), 3.10 (1H, d, J =12.1 Hz), 3.19 (1H, d, J: 12.1 Hz), 3.30 (1H, s), 3.90 (2H, br s), 4.02 (1H, d, J: 7.4 Hz), 4.90 (1H, d, J: 11.3 Hz). 5.05 (1H, d, J: 11.3 Hz), 7.42 (5H, MS (ES+) m/z: [M+H]+ calcd for C11H23N4O4: 347.2. Found: 347.2. 219219 Step 2. (ZS,5R)hydroxyoxo-N‘-propanoyl-1,6-diazabicyclo[3.2.1]octane carbohydrazide (204) O O H_ )L O H )' J—Ns )—~. 0 OBn O OH A mixture of (28,5R)—6-(benzyloxy)-7—oxo-N‘-propanoyl-1,6-diazabicyclo[3.2.1]octane carbohydrazide 203- (0.31 g, 0.89 mmol) and Pd/C (0.12 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 16 h. The mixture was filtered through Celite and concentrated to provide 204 (0.24 g, quant. yield) as a white foam.

‘H NMR (400 MHz, CD30D): 8 1.18 (3H, t, J = 7.4 Hz), 1.75 (1H, m), 1.85 (1H, m), 1.96 (1H, m), 2.08 (1H, m), 2.30 (2H, m), 3.18 (1H, m), 3.30 (1H, m), 3.70 (1H, br s), 3.95 (1H, d, J = 1O 7.4 Hz). 3 protons were not observed in CD3OD.

MS (ES') m/z: [M-H]‘ calcd for N4O4: 255.1. Found: 255.0.

Step 3. (28,5R)oxo-N'-propanoyl(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 17, Table 2) o l o l, H- 1’" N "'H -—————> )—N N \ ‘oso3H 0 OH 204 Compound 17, Table 2 To a mixture of (2S,5R)—6-hydroxyoxo-N-propanoyl-1,6—diazabicyclo[3.2.1]octane carbohydrazide 204 (0.24 g, 0.93 mmol) in pyridine (5.0 mL) was added sulfur trioxide ne complex (0.44 g, 2.81 mmol). The mixture was stirred at room ature for 23 h and concentrated to provide a residue which was subjected to chromatography and HPLC purification to give nd 17 (Table 2) (0.053 g, 17 %) as a white solid.

‘H NMR (400 MHz, D20): 5 0.98 (3H, t, J: 7.8 Hz), 1.65 (1H, m), 1.80 (1H, m), 1.95 (1H, m), 2.05 (1H, m), 2.18 (2H, q, J = 7.8 Hz), 3.05 (1H, d, J = 12.1 Hz), 3.18 (1H, d, J = 12.9 Hz), 4.00 (1H, d, J = 7.8 Hz), 4.05 (1H, m). 3 protons were not observed in D20.

HPLC: 97.12 % MS (ES‘) m/z: [M-H]‘ calcd for C10H15N40782 335.1. Found: 335.0. 220220 Example 50 (ZS,5R)oxo-N-(piperaziny|)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide (Compound 100, Table 2) m )1,“ HN N—N \_J H N NIH //L—~N o ‘osoaH Step 1. tert-butyl 4-({[(2S,5R)(benzyloxy)—7-oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)piperazinecarboxylate (206) /_ \ Boc—N o N—NH2 J, 2 O HO 205 m )1, Boo—N N—N N ...H _ \ / H N . x ;H 1 206 4 To a solution of (28,5R)(benzyioxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.17 g, 0.615 mmol) in dry DCM (10 mL) were added tert—butyl 4—aminopiperazine—1— 1O carboxylate 205 (0.19 g, 0.923 mmol), 1-hydroxybenzotriazoie (0.125 g, 0.923 mmol), 1— ethyl-(3—dimethyiaminopropyi)carbodiimide hydrochioride (0.177 g, 0.923 mmol) and 4- ylaminopyridine (0.113 g, 0.923 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under . The residue was purified by column chromatography to give tert—butyl 4-({[(28,5R)(benzyloxy)oxo- 1,6—diazabicyclo[3.2.1]oct—2-yl]carbonyi}amino)piperazinecarboxy|ate 206 (0.25 g, 88%) as a clear thick oil. 1H NMR (400 MHz, 00013): 8 1.46 (9H, s), 1.62 (1H, m), 1.95 (2H, m), 2.38 (1H, m), 2.70 (1H, d, J = ), 2.76 (4H, m), 2.99(1H, d, J = 12.0 Hz), 3.30 (1H, m), 3.57 (4H, m), 3.89 (1H, d, J = 8.0 Hz), 4.90 (1H, d, J = 11.6 Hz), 5.04 (1H, d, J =12.0 Hz), 7.21 (5H, m), 8.90 (1H, br s). 221221 Step 2. tert-Butyl 4-({[(2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)piperazinecarboxy|ate (207) Boc~N/—\N—N/lL BOC_N/—\N_N). . \_J H N "'H \_J H N --IH }_N\ ’ )—N\ O OBn o OH 206 207 To a on of tert—butyl 4-({[(2S,5R)(benzyloxy)oxo—1,6-diazabicyclo[3.2.1]oct-2— yl]carbonyl}amino)piperazinecarboxylate 206 (0.25 g, 0.54 mml) in methanol (15 mL) was added 10% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert—butyl 4-({[(2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)piperazinecarboxylate 207 (0.20 g, 99%) as a colorless foam. 1O 1H NMR (400 MHz, CD30D‘): 6 1.48 (9l-l, s), 1.78 (1H, m), 1.88 (1H, m), 2.07 (1H, m), 2.20 (1H, m), 2.75 (4H, m), 2.99 (1H, d, J = 12.0 Hz), 3.11 (1H, d, J = 11.6 Hz), 3.53 (4H, m), 3.70 (1H,m), 3.80 (1H, d, J = 7.2 Hz), 2 protons were not observed in CD30D.

Step 3. tert-Butyl 28,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)piperazinecarboxylate (208) o O /—\ )lm. /—\ )l, Boc—N N—N ~ _N\_JN_ \_J H 0an Boc lNl ' Q-HH )—N\ }—N O OH ‘ 207 O OSO3H 208 To a solution of tert-butyl 4-({[(28,5R)—6-hydroxy-7—oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}amino)piperazinecarboxylate 207 (0.20 g, 0.54 mm'ol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.34 g, 2.16 mmol). _The mixture was stirred at room ature for 20 h, filtered and ated. The residue was purified by column chromatography to give tert—butyl 4-({[(28,5R)oxo-6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]oct-2—yl]carbonyl}amino)piperazine-1—carboxylate 208 (0.129, 49.6%) as a white solid. 1H NMR (400 MHZ, CD30D): 6 1.45 (9H, s), 1.86 (2H, m), 2.07 (1H, m), 2.23 (1H, m), 2.75 (4H, m), 3.03 (1H, d, J = 11.2 HZ), 3.21 (1H, m), 3.52 (4H, m), 3.85 (1H, d, J =11.2 HZ), 4.14 (1 H, m), 2 protons were not observed in CD30D. 222222 Step 4. (28,5R)oxo-N—(piperazinyl)(sulfooxy)-1,6- icyclo[3.2.1]octanecarboxamide (Compound 100, Table 2) Cl) 0 Boo—N N—N) HN/ ~,.

\——/ H N «H \——/ H N "'H )—N '//1——N o ~‘oso3H o ‘oso3H 208 nd 100, Table 2 To a solution of terT-butyl 4—({[(28,5R)oxo—6—(sulfooxy)-1,6—diazabicyclo[3.2.1]oct yl]carbonyl)amino)piperazine-1—carboxylate 208 (0.12 g, 0.27 mmol) in DCM (12.5 mL) was added trifluoroacetic acid (1.0 mL, 12.96 mmol) dropwise at 0 °C. The reaction e was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitriie (2 x) and the white solid was collected by centrifugation. This white solid was purified by HPLC on a 1O prep-X Bridge-19x250 mm column and freeze-dried to give (28,5R)—7-oxo-N-(piperazinyl)- 6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarboxamide Compound 100 (Table 2) (0.11 g, 88%) as a white solid. 1H NMR (400 MHz, CD30D): 6 1.77 (2H, m), 1.95 (1H, m). 2.05 (1H, m), 2.97 (5H, m), 3.16 (1H, d, J = 12.0Hz), 3.26 (4H, m), 3.89 (1H, d, J = 7.6 Hz), 4.06 (1H, m), 3 protons were not observed in CD30D.

HPLC: 81.5 % MS (ES‘) m/z: [M]‘= 348.01 Example 51 (2S,5R)—N—(morpholinyl)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide (Compound 99, Table 2) ’ m Ci 0 N—N)“ LJ H N -uIH 223223 Step 1. )—6—(benzyloxy)—N—(morpholin—4-yl)oxo-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (210) O N—NH j 2 \—/ 0 HO 209 F—\ )1,I O N_N N "’H > ———————————————————> \_/ H N "'H 1 , 210 To a on of (28,5R)-6—(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.23 g, 0.83 mmol) in dry DCM (15 mL) were added morpholinamine 209 (0.13 g, 1.25 mmol), 1-hydroxybenzotriazole (0.19 g, 1.41 mmol), l-(3— dimethylaminopropyl)carbodiimide hydrochloride (0.24 g, 1.25 mmol) and 4- dimethylaminopyridine (0.15 g, 1.23 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (28,5R)—6-(benzyloxy)-N—(morpholinyl)oxo-1,6- icyc|o[3.2.1]octanecarboxamide 210 (0.255 g, 85%) as a clear thick oil. 1H NMR (400 MHZ, CDCla): 51.62 (1H, m), 1.97 (2H, m), 2.38 (1H, m), 2.71 (1H, d, J :11.6 Hz), 2.82 (4H, m), 3.00 (1H, d, J = 11.2 Hz), 3.30 (1H, s), 3.8 (4H, m), 3.90 (1H, d, J = 8.0 Hz), 4.90 (1H, d, J = 11.2 HZ), 5.04 (1H, d, J = 12.0 Hz), 7.37 (5H, m), 8.90 (1H, br s).

Step 2. ‘ (28,5R)hydroxy-N—(morpholin-4_-yl)—7-oxo-1,6- diazabicyclo[3.2.1]octanecarboxamide (211) O O O/“\N_N)l’m OmN_N)‘/l“l \_/ H QMH ’ \—/ I Z -'|H o ‘OBn 0 OH 210 211 To a solution of (2S,5R)-6—(benzyloxy)-N—(morpholinyl)oxo—1 ,6- diazabicyclo[3.2.1]octanecarboxamide 210 (0.255 g, 0.71 mml) in methanol (15 mL) was added 10% Pd/C (0.5 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2 S,5R)hydroxy—N-(morpholinyl)oxo-1 ,6— diazabicyclo[3.2.1]octane—2-carboxamide 211 (0.19 g, quantitative yield) as a colorless foam. ’ 224224 1H NMR (400 MHz, CD3OD): 5 1.77 (1H, m), 1.95 (1H, m), 2.06 (1H, m), 2.20 (1H, m), 2.81 (4H, m), 3.00 (1H, d, J =11.2 Hz), 3.11 (1H, d, J = 11.6 Hz), 3.69 (1H, m), 3.76 (4H, m), 3.80 (1H, d, J = 7.2 Hz), 2 protons was not observed in CD30D.

Step 3. (28,5R)-N—(morpholinyI)oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 99, Table 2) mN—N/l/l"Ci 0 N—N/UII" o \_/ H [0,44 U H ————————-——+ N -~H Z—N ¢L_N 211 Compound 99, Table 2 To a solution of (2S,5R)h'ydroxy-N—(morpholin-4—yl)—7—oxo-1,6-diazabicyclo[3.2.1]octane—2- carboxamide 211 (0.19 g, 0.71 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.29 g, 1.82 mmol). The mixture was stirred at room 1O ature for 20 h, filtered and evaporated. The residue was purified by HPLC on 0x100mm_5um column and freeze-dried to give (2S,5R)-N-(morpholinyl)oxo-6— (sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarboxamide Compound 99 (Table 2) (0.005g, 2%) as a white solid. 1H NMR (400 MHz, CD3OD): 5 1.82 (2H, m), 2.07 (1H, m), 2.21 (1H, m), 2.80 (4H, m), 3.05 (1H, d, J = 11.2 Hz), 3.20 (1H, m), 3.80 (4H, m), 3.89 (1H, d, J = 11.2 Hz), 4.16 (1H, s), 2 protons were not observed in CD30D.

MS (ES‘) m/z: [M]_‘= 348.89 Example 52 )-N'-acetyl-N'-methyloxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 19, Table 2) lit, 225225 Step 1. (2R,58)-N‘-acetyl(benzyloxy)-N'-methyloxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (213) | 1 j) \n/N‘NHZ l J HO 0 \f ﬂ 212 0 N )‘N N o. \OBn o OBn 1 213 To a solution of (28,5R)—6—(benzyloxy)—7-oxo—1,6-diazabicyclo[3.2.1]octane-2—carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added ylacetohydrazide 212 (0.14 g, 1.59 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1~ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The on mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was d by column chromatography to give (2R,SS)-N—acetyl 1O (benzyloxy)—N-methyloxo-1,6-diazabicyclo[3.2.1]octane-2~carbohydrazide 213 (0.20 g, 64%) as a white solid. 1H NMR (400 MHz, CDClg): 6 1.65 (1H, m), 1.83-2.12 (5H, m), 2.32 (1H, m), 2.70 (1H, d, J = 12.0 Hz), 3.05-3.37 (5H, m), 4.01 (1H, m ), 4.88-5.07 (2H, m), 7.41 (5H, m), 8.55 (0.5H, br s), 8.76 (0.5H, br s).

Step 2. (2R,SS)-N'-acetylhydroxy-N'-methyloxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (214) l j l' rN-N rN\N . yo . .9 o ‘OBn 0 OH 213 214 To a solution of‘ )-N-acetyl-6—(benzyloxy)-N-methyloxo-1,6-diazablcyclo[3.2.1]octane carbohydrazide 213 (0. 20 g, 0.57 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the ﬁltrate was evaporated to give (2R,SS)-N-acetyl hydroxy-N—methyloxo-1,6—diazabicyclo[3.2.1]octane—2—carbohydrazide 214 (0.15 g, 99%) as a colorless foam. 1H NMR (400 MHz, CD30D): 6 1.82 (1H, m), 1.89-2.10 (5H, m), 2.25 (1H, m), 2.93 (1H, d, J = 12.0 Hz), 3.11-3.26 (4H, m), 3.72 (1H, s), 3.95 (1H, d, J = 7.2 Hz), 2 s were not observed in CDgOD. 226226 Step 3. )-N'-acetyl-N'-methyloxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 19, Table 2) l o I N. Jim INW). t .. l O H Q )—N )‘N.

O OH o 0803H 214 Compound 19, Table 2 To a solution of )—N-acetylhydroxy-N—methyloxo-1,6—diazabicyclo[3.2.1]octane carbohydrazide 214 (0.15 g, 0.58 mmol) in dry pyridine (8 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.70 g, 4.40mmol). The mixture was stirred at room temperature for 40 h, filtered and evaporated. The residue was purified by column chromatography followed by HPLC on a prep-X Bridge-30x100 mm column and freeze-dried to give (2R,5S)-N~acetyl-N-methyloxo(sulfooxy)—1,6-diazabicyclo[3.2.1]octane-2—carbohydrazide 1O Compound 19 (Table 2) (0.030 g, 15%) as a grey solid. 1H NMR (400 MHZ, CD3OD): 6 1.82 (1H, m), 1.96 (1H, m), 2.02 (3H, s), 2.11 (1H, m), 2.26 (1H, m), 2.99 (1H, d, J = 12.4 Hz), 3.11 (3H, s), 3.34 (1H, m), 4.02 (1H, d, J = 8.0 Hz), 4.16 (1H, s), 2 protons were not ed in CD3OD.

HPLC: 95.4 % .15 MS (ES') m/z: [M]' = 335 Example 53 (ZS,5R)oxo-N'-(pyridin-Z-ylcarbonyl)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 72, Table 2) QrN‘NJ/UQ/ O l H l O N 227227 Step 1. (28,5R)(benzyloxy)oxo-N'-picolinoyl-1,6-diazabicyclo[3.2.1]octane- 2-carbohydrazide (21 6) l H \N N. / o NH2 l H J).(l J) \ N- , o N N HO H N 215 0 N J— ——--—-> N 2H\ 0 QB” o ‘OBn 1 216 To a solution of (28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.276 g, 1.0 mmol) in dry DCM (30 mL) were added 215 (0.206 g, 1.5 mmol), 1— hydroxybenzotriazole (0.211 g, 1.5 mmol), l-(3—dimethylaminopropyl)carbodiimide hydrochloride (0.292 g, 1.5 mmol) and 4—(dimethylamino)pyridine (0.178 g, 1.5 mmol) at room temperature. The on mixture was stirred at room temperature overnight, and concentrated under vacuum. The residue was purified by column chromatography to give 216 (0.36 g, 90%) as a white solid. 1H NMR (400 MHz, CDCl3):61.65(1H, m), 2.01 (2H, m), 2.42 (1H, m), 3.13 (1H, d, J = 12.0 Hz), 3.19 (1H, d,‘J =12 Hz), 3.33 (1H, s), 4.11 (1H,d, J = 7.2 Hz), 4.92 (1H, d, J = 11.6 Hz), .063 (1H, d, J = 11.2 Hz), 7.42 (6H, m), 7.85 (1H, t, J = 8.6 Hz), 8.12 (1H, d, J = 9.6 Hz), 8.58 (1H, d, J = 7.2 Hz), 8.67 (1H, br s), 9.75 (1H, br 5).

Step 2. (28,5R)hydroxy—7—oxo-N'—picolinoy|-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide (217) / O H‘ g N\ )‘N A mixture of (28,5R)—6—(benzyloxy)oxo-N'-picolinoyl—1,6-diazabicyclo[3.2.1]octane-2— carbohydrazide 216 (0.30 g, 0.76 mmol) and Pd/C (0.40 g) in methanol (100 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered h Celite pad and concentrated to provide 217 (0.23 g, quant. yield) as a white foam. 1H NMR (400 MHz, CD30D): 6 1.50-2.40 (4H, m), 1.75 (1H, m), 3.20 (1H, m), 3.35 (1H, m), 3.71 (1H, m), 4.05 (1H, m), 7.60 (1H, m), 8.00 (1H, m), 8.18 (1H, m), 8.70 (1H, m). 3 protons were not observed in CD30D.

MS (ES‘) m/z: [M+H]‘ calcd for C13H16N504: 306.2. Found: 306.1. 228228 Step 3. (ZS,5R)oxo-N'-(pyridinylcarbonyl)-6—(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 72, Table 2) / O / O N ‘5’ r. N \u r.

' J—N. ' )—N. o OH 0 0803H Compound 72, Table 2 To a mixture of (28,5R)—6-hydroxyoxo-N'—picolinoyl—1,6—diazabicyclo[3.2.1]octane carbohydrazide 217 (0.23 g, 0.75 mmol) in pyridine (10 mL) was added sulfur trioxide pyridine complex (0.35 g, 2.26 mmol). The mixture was stirred at room temperature for 24 h.

NMR showed no reaction, additional sulfur trioxide pyridine complex (0.70 g, 4.52 mmol) was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated and subjected to chromatography to give 140 mg‘off—whlte solid; 80 mg of this 1O product was further purified by HPLC to give Compound 72 (Table 2) (0.030 g, 20 %) as a white solid.

‘H NMR (400 MHz, D20): 61.68 (1H, m), 1.82 (1H, m), 1.93 (1H, m), 2.08 ), 3.13 (1H, dd = 12.1 Hz), 3.22 (1H, d, J = 12.1 Hz), 4.07 (2H, m), 7.46 (1H, m), 7.86 (2H, m), 8.46 (1H, d, J = 4.69 Hz). 3 protons were not observed in D20.

HPLC: 91.81 %.

MS (ES') m/z: [M-H]' calcd for C13H14N5078: 384.3. Found: 3840. e 54 )-N'-(methoxyacetyl)oxo(sulfooxy)-1,6-diazabicyclo [3.2.1]octane carbohydrazide (Example 29 , Table 2) Meow—N4'Q,,H 229229 Step 1. (2S,5R)—(benzyloxy)-N'-(methoxyacetyl)oxo-1,6-diazabicyclo [3.2.1]octanecarbohydrazide (219) o fNHNHZ )1 M90 o 1' ‘ 21s )«MNH ‘ "* MeO H ' N N ...H «H o ‘osn To a mixture of (28,5R)(benzyloxy)oxo-1,6—diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 2-methoxyacetohydrazide 218 (0.141 g, 1.358 mmol), oxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature.

The mixture was d at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give 219 (0.27 g, 82 %) as a 1O white foam. 1H NMR (400 MHz, CDCla):51.60(1H, m), 1.99 (2H, m), 2.40 (1H, m), 3.10 (2H, s), 3.32 (1H, s), 3.46 (3H, s), 3.04 (2H, s), 4.06 (1H, m), 4.90 (1H, d, J = 11.2 Hz), 5.05 (1H, d, J =11.2 Hz), 7.42 (5H, m).

MS (ES‘) m/z: [M—H]‘ calcd for C10H15N405: 347.2. Found: 361.1.

Step 2. (28,5R)—6-hydroxy-N'-(methoxyacetyl)oxo-1,6-diazabicyclo [3.2.1]octanecarbohydrazide (220) }H_N/lo l, 0 1,. ’.

MeO H N ...H ———> MeO}H_N/lH N «H 219 220 A mixture of (28,5R)(benzyloxy)-N-(methoxyacetyl)oxo-1,6-diazabicy'clo [3.2.1]octane- 2-carbohydrazide 219 (0.27 g, 0.74 mmol) and Pd/C (0.10 g) in ol (20 mL) was hydrogenated at 1 atm at room ature for 3 h. The mixture was filtered through Celite and concentrated to provide 220 (0.19 g, 90 %) as a white foam. 1H NMR (400 MHz, CD30D): 5 1.75 (1H, m), 1.90 (1H, m), 1.96 (1H, m), 2.08 (1H, m), 2.28 (1H, m), 3.17 (1H, m), 3.30 (1H, m), 3.44 (3H, s), 3.70 (1H, br s), 3.95 (1H, d, J = 7.6 Hz), 4.03 (2H, s). 3 protons were not observed in CD30D.

MS (ES‘) m/z: [M—H]‘ calcd for C10H15N405: 271.1. Found: 271.1. 230230 Step 3. )-N'-(methoxyacetyl)oxo(sulfooxy)-1,6-diazabicyclo [3.2.1]octanecarbohydrazide (Compound 29, Table 2) H Nj Me0~)\.N—l’:ll OHM _ ————» MeOleNl 0,.“ ‘osogH 220 Compound 29, Table 2 To a mixture of (2S,5R)hydroxy-N'—(methoxyacetyl)oxo-1,6-diazabicyclo ]octane- 2—carbohydrazide 220 (0.19 g, 0.70 mmol) in pyridine (5.0 mL) was added sulfur trioxide ne complex (0.32 g, 2.10 mmol). The mixture was stirred at room temperature for 2 days and concentrated to provide a residue, which was subjected to chromatography followed by HPLC separation to give Compound 29 (Table 2) (9 mg) as a white solid.

IH NMR (400 MHz, D20): 61.67 (1H, m), 1.82 (1H, m), 1.92 (1H, m), 3.05 (1H, d, J = 12.4 Hz), 3.20 (1H, m), 3.30 (3H, s), 4.00 (2H, s), 4.04 (2H, m). 3 protons were not observed in D20.

HPLC: 91.84 % MS (ES‘) m/z: [M—H]‘ calcd for C10H15N4OaS: 351.1. Found: 351.0.

Example 55 (ZS,5R)oxo-N'-(pyrrolidinylcarbonyl)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide trifluoroacetate (Example 42 , Table 2) Q/‘OL j ’ N~N F/Kz/OH HN H H OHM o )—~N\ O 0803H 231231 Step 1. tert-butyl 3-[(2-{[(28,5R)—6-(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinyl)carbonyl]pyrrolidinecarboxy|ate (222) ,NH2 0 N O O 1 222 To a mixture of (28,5R)-6—(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.304 g, 1.10 mmol) in DCM (20.0 mL) were added tert—butyl 3- (hydrazinecarbonyl)pyrrolidine-1—carboxylate 221 (0.380 g, 1.65 mmol), 1- hydroxybenzotriazole (0.223 g, 1.65 mmol) and 1-ethyl-(3—dimethylaminopropyl) carbodiimide hydrochloride (0.315 g, 1.65 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, concentrated to provide a residue which was ted to chromatography to give 222 (0.48 g, slightly ) as a white foam.

Step 2. tert—butyl 3-[(2-{[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct bonyl}hydrazinyl)carbonyl]pyrrolidinecarboxylate (223) 0 j O O 3):” I,“ N-—N Boo—N 0'“ m’ N—N Boc—NQ/KHH 0"“ N\ )—N\ O OBn O OH A e of tert—butyl 2-(2—((28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]-octane carbonyl)hydrazinecarbonyl)pyrrolidinecarboxylate 222 (0.48 g, 0.984 mmol) and Pd/C (0.60 g) in methanol (100 mL) was hydrogenated at 1 atm at room temperature for 1.5 h. The mixture was filtered through Celite pad and concentrated to give 223 (0.39 g, slightly impure) as an off-white foam. 232232 Step 3. tert-butyl 3-[(2-{[(2S,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinyl)carbonyl]pyrrolidinecarboxylate (224) O 0 JL. M)“: Boo—N Ni} [O ————> BOG—N H H H OHM To a mixture of tert—butyl 2-(2-((28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]-octane-2— carbonyl)hydrazinecarbonyl)pyrrolidine-1—carboxylate 223 (0.390 g, 0.984 mmol) in pyridine (15 mL) was added sulfur trioxide pyridine complex (0.461 g, 2.952 mmol). The mixture was d at room temperature for 23 h. Additional sulfur trioxide pyridine complex (0.461 g, 2.952 mmol) was added. The mixture was stirred at room temperature over the weekend and concentrated to provide a residue which was ted to chromatography to give 224 (0.245 g, 52 %) as an off-white solid. 1H NMR (400 MHz, D20): 61.25 (9H, s), 1.66 (1H, m), 1.84 (1H, m), 1.95 (2H, m), 2.10 (2H, m), 3.04 (2H, m), 3.10—3.60 (5H, m), 4.05 (2H, m). Three protons were not ed in CD30D. ' MS (ES‘) m/z: [M-H]‘ calcd for C17H26N5098: 476.5. Found: 476.1.

Step 4. (28,5R)Voxo-N‘-(pyrrolidinylcarbonyl)—6-(sulfooxy)-1,6- icyclo[3.2.1]octanecarbohydrazide trifluoroacetate (Compound 42, Table NJ,“l o o N J, O \0303H )—N . \OSO3H 224 Compound 42, Table 2 To a mixture of tert—butyl 2-(2-((28,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane carbonyl)hydrazinecarbonyl)pyrrolidinecarboxylate 224 (0.20 g, 0.42 mmol) in DCM (8.0 mL) was added trifluoroacetic acid (0.40 mL) at 0°C. The mixture was stirred at 0°C for 1 h, concentrated and washed with ether and MeOH to give Compound 42 (Table 2) (90 mg) as a white solid as a pair of diastereomers. 233233 1H NMR (400 MHz, D20): 51.63(1H, m), 1.76 (1H, m), 1.88 (1H, m), 2.01 (2H, m), 2.23 (1H, m), 3.00 (1H, m), 3.19 (4H, m), 3.35 (2H., m), 4.00 (2H, m). Four protons were not observed in D20. 19F NMR (376.5 MHz, 020): 5 — 75.79 HPLC: 62.09% and 34.89 %. (Two isomers).

MS (ES') m/z: [M+H]+ calcd for C12H20N507S: 378.4. Found: 3781.

Example 56 (2R,5S)-N'-methyloxo-N'-propanoyl-6—(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 20, Table 2) WW)1 o osogH Step 1. (2R,5$)(benzyloxy)-N'-methyloxo-N'-propanoyl-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (226) o NH2 J' o t. it /\ll/ 5, ' N 225 0 N * 1 226 To a solution of (2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added N-methylpropanehydrazide 225 (0.14 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4- (dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room ature overnight and concentrated under vacuum. The residue was purified by column 'chromatography to give (2R,5S)(benzyloxy)-N'-methyloxo-N‘- propanoyl-1,6-diazabicyclo[3.2.1]octane-2—carbohydrazide 226 (0.19 g, 59%) as a white solid. 1H NMR (400 MHz, CDCla): 8 1.04—1.18 (3H, m), 1.65 (1H, m), 1.98 (2H, m), .20 (3H, m), 2.68-3.32 (6H, m), 3.72-4.02 (1H, m), 4.80-5.05 (2H, m), 7.41 (5H, m), 8.54 (0.5H, br s), 8.63 (0.5H, br s). 234234 Step 2. (2R,5S)—6-hydroxy-N‘-methy|—7-oxo-N'-propanoyl-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (227) l O l N\ /U’/,' N\ JL/u “of i Q Al? i Q PM //‘~N.

O OBn O OH 226 227 To a solution of (2R,5S)—6-(benzyloxy)-N-methyloxo-N-propanoyl-1,6— diazabicyclo[3.2.1]octane—2-carbohydrazide 226 (0. 19 g, 0.52 mml) in ol (20 mL) was added 5% Pd/C (0.20 g). The mixture was hydrogenated under 10 psi hydrogen here at room temperature for 1 h. The catalyst was filtered through Celite, and the filtrate was evaporated to give (2R,58)-6—hydroxy—N-methyloxo-N—propanoyl-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide 227 (0.11 g, 79%) as a brown foam. 1O 1H NMR (400 MHz, CD30D): 5 1.04-1.14 (3H, m), 1.69-1.80 (2H, m), 1.85-2.14 (2H, m), 2.22 - 2.40 (2H, m), 2.90-3.34 (5H, m), 3.73 (1H, s), 3.95 (1H, d, J = 7.2 Hz), 2 protons were not observed in CD30D.‘ Step 3. (2R,5$)-N'-methyloxo-N'-propanoyl(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 20, Table 2) ' /\[Of H jg Wm. __>‘ H jg N\ N\ O 0H 0 OSO3H 227 Compound 20, Table 2 To a solution of (2R,5S)—6-hydroxy-N-methyloxo-N-propanoyl—1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide 227 (0.11 g, 0.41 mmol) in dry pyridine (6 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.60 g, 3.80 mmol).

The mixture was stirred at room temperature for 40 h, filtered and evaporated. The e was purified first by column chromatography ed by washing several times with a mixture of methanol and diethyl ether (1:9) to give (2R,58)-N-methyl-7—oxo—N-propanoyl-6— oxy)-1,6—diazabicyclo[3.2.1]octane—2-carbohydrazide Compound 20 (Table 2) (0.015 g, 10.5 %) as a white solid. 1H NMR (400 MHZ, CD30D): 6 1.05 (3H, t, J = 7.4 Hz), 1.81 (1H, m), 1.94 (1H, m), 2.08 (1H, m), 2.26 (3H, m), 2.99 (1H, d, J = 12.0 Hz), 3.11 (3H, s), 3.31 (1H, m), 4.02 (1H, d, J = 7.6 235235 Hz), 4.17 (1H, s), 2 s were not observed in CD30D.

HPLC: 91.8% MS (ES') m/z: [M]‘= 349 Example 57 (2R,58)—7-oxo(sulfooxy)-N‘-(3,3,3-trifluoropropanoyl)-1,6-diazabicyclo[3.2.1]octane- 2-carbohydrazide (Compound 28, Table 2) . 0 ti. )1.

F3C/\H/ n O N o OSO3H Step 1. (2R,5S)(benzyloxy)—7-oxo-N’-(3,3,3-trifluoropropanoyl)-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (229) N\ O J01 ROW NHz H. J HO O FSC/\n/ N N 228 O N 7/(~N .__.—_._——————_—. )‘N ‘OBn o OBn o .

To a solution of (28,5R)—6-(benzyioxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (40 mL) were added 3,3,3-trifluoropropanehydrazide 228 (0.19 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), I—(3- dimethylaminopropy|)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4- (dimethyiamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by co|umn chromatography to give (2R,5S)(benzyloxy)¥7-oxo-N'-(3,3,3- oropropanoyI)-1,6-diazabicyclo[3.2.1]octane-2—carbohydrazide 229 (0.26 g, 72%) as a white solid. 1H NMR (400 MHz, coc13): 8 1.60 (1H, m), 1.99 (2H, m), 2.26 (1H, m), 3.08 (2H, m), 3.23 (2H, m), 3.33 (1H, s), 3.97 (1H, d, J = 7.2 Hz ), 4.89 (1H, d, J = 11.2 Hz), 5.02 (1H, d, J = 11.2 Hz), 7.39 (5H, m), 8.82 (2H, brs). 236236 Step 2. (2R,5S)hydroxyoxo-N’-(3,3,3-trifluoropropanoyl)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (230) j N f n/H\[|:i1 q, F30/\n/ ‘N 0 N )‘N. ' J—N O ‘OH 0 OBn To a solution of (2R,5S)(benzyloxy)oxo-N'—(3,3,3-trifluoropropanoyl)—1,6- diazabicyclo[3.2.1]octanecarbohydrazide 229 (0. 26 g, 0.65 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was enated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the te was ated to give (2R,SS)-6—hydroxyoxo-N-(3,3,3-trifluoropropanoyl)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide 230 (0.19 g, 93.6%) as a colorless foam. 1O 1H NMR (400 MHz, CDSOD):.51.76(1H, m), 1.93 (1H, m), 2.04 (1H, m), 2.28 (1H, m), 3.15- 3.34 (4H, m), 3.71 (1H, s), 3.94 (1H, d, J = 7.2 Hz), 3 protons were not observed in CDSOD.

Step 3. (2R,5S)oxo(sulfooxy)-N’-(3,3,3-trifluoropropanoyl)-1,6- diazabicyc|o[3.2.1]octanecarbohydrazide (Compound 28, Table 2) : fl H N\ N\ f PM o PM oII,’ ————> O N )‘N kw. 0 -OH 0 osoya 230 Compound 28, Table 2 To a solution of )—6-hydroxy-7—oxo-N—(3,3,3-trifluoropropanoyl)—1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide 230 (0.19 9,061 mmol) in dry pyridine (7 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.70 g, 4.40 mmol).

The mixture was stirred at room temperature for 20 h, filtered and evaporated. The residue was purified by column chromatography followed by washing several times with a mixture of methanol and diethyl ether (1:9) to give (2R,5S)—7-oxo(sulfooxy)—N—(3,3,3- trifluoropropanoyl)-1,6-diazabicyclo[3.2.1]octane-2—carbohydrazide Compound 28 (Table 2) (0.040 g, 16.8%) as a pink solid. 1H NMR (400 MHz, CD30D):.51.80(1H,m), 1.93 (1H, m), 2.06 (1H, m), 2.27 (1H, m), 3.23- 3.34 (4H, m), 4.01 (1H, d, J = 7.6 Hz), 4.15 (1H, s), 3 protons were not observed in CD30D.

HPLC: 94.2% 237237 MS (ES') m/z: [M]'= 389 Example 58 (2R,58)-N',N'-dimethyl-7—oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 4, Table 2) > o . ‘osoaH Step 1. (ZS,5R)(benzyloxy)-N',N'-dimethyloxo-1,6-diazabicyclo[3.2.1]octane- 2-carbohydrazide (232) HOJI’I,l N\ / I, NHZ /N\u/l I" N 231 N To a solution of (28,5R)(benzyloxy)oxo-1,6—diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.276 g, 1.0 mmol) in dry DCM (20 mL) were added 231 (0.09-g, 1.5 mmol), 1- hydroxybenzotriazole (0.203 g, 1.5 mmol), and 1—ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.288 g, 1.5 mmol) at room temperature. The reaction mixture was stirred at room temperature ght and concentrated under vacuum. The residue was purified by column chromatography to give 232 (0.25 g, slightly impure) as a colorless oil.

Step 2. )hydroxy-N',N'-dimethy|oxo-1,6-diazabicyclo[3.2.1]octane carbohydrazide (233) 232 233 A mixture of )—6-(benzyloxy)-N',N'—dimethyloxo-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide 232 (0.25 g, 0.78 mmol) and Pd/C (0.30 g) in methanol (80 mL) was ' hydrogenated at 1 atm at room temperature for 1 h. The mixture was filtered through Celite 238238 pad and concentrated to provide 233 (0.17 g) as a white foam which was used in the next step without purification.

Step 3. )-N',N'-dimethyloxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane- 2-carbohydrazide (Compound 4, Table 2) N P N\ O \O,S\:OH 233 Compound 4, Table 2 To a mixture of (28,5R)—6-hydroxy-N',N'-dimethyl-7—oxo-1,6—diazabicyclo[3.2.1]octane carbohydrazide 233 (0.17 g, 0.78 mmol) in pyridine (10 mL) was added sulfur trioxide pyridine x (0.36 g, 2.34 mmol). ). The mixture was stirred at room temperature for 24 h and concentrated to provide a residue which was subjected to chromatography ed by HPLC separation to give Compound 4 (Table 2) (0.0036 g, 1.5 % for three steps) as a white solid. . 1H NMR (400 MHz, 020): 61.68 (2H, m), 1.94 (2H, m), 2.38 (6H, s), 2.90 (1H, d, J = 12.0 Hz), 3.13 (1H, d, J = 12.4 Hz), 3.81 (1H, d, J = 7.2 Hz), 4.02 (1H, s). 2 protons were not observed in DZO.

HPLC: 93.82% MS (ES') m/z: [M-H]' calcd for CgH15N4OSS: 307.3. Found: 307.0.

Example 59 (2R,5S)-N'-butanoyloxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarbohydrazide (Compound 25, Table 2) 239239 Step 1. (2R,5$)(benzyloxy)-N'-butanoyloxo—1,6-diazabicyclo[3.2.1]octane carbohydrazide (235) K} 0 j V\ro]/ \ NHZ “\ )L N 234 O )‘N _____, 1“”.

\OBn o OBn 1 235 To a solution of (28,5R)-6—(benzyloxy‘)oxo-1,6—diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (40 mL) were added butanehydrazide 234 (0.14 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4- hylamino)pyridine (0.16 g, 1.35 mmol) at room ature. The on mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give )(benzyloxy)—N-butanoyloxo-1,6— diazabicyclo[3.2.1]octanecarbohydrazide 235 (0.31 g, 95%) as a white solid. 1H NMR (400 MHz, 00013): 6 0.96 (3H, t, J = 7.4 Hz), 1.60—1.72 (3H, m), 1.97 (2H, m), 2.05-2.33 (3H, m), 3.06 (1H, d, J =12.0 Hz), 3.16(1H, d, J =12.0 Hz), 3.31 (1H, s), 4.00 (1H, d, J = 7.2 Hz), 4.90 (1H, d, J = 11.2 Hz), 5.04 (1H, d, J =11.6 Hz), 7.38 (5H, m), 7.86 (1H, br s), 8.58 (1H, br 5).

Step 2. )-N‘-butanoylhydroxyoxo-1,6-diazabicyclo[3.2.1]octane carbohydrazide (236) O O H )1, H N. N )1, WN ‘ '* l—N, . gait 0 CB” 0 OH To a solution of (2R,5S)(benzyloxy)—N-butanoyloxo-1,6-diazabicyclo[3.2.1]octane carbohydrazide 235 (0. 31 g, 0.86 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-N~butanoyl~6- hydroxyoxo~1,6-diazabicyclo[3.2.1]octane—2—carbohydrazide 236 (0.21 g, 90%) as a brown foam. 1H NMR (400 MHZ, CD3OD): 6 0.97(3H, t, J = 7.4 HZ), 1.63—1.79 (3H, m), 1.92 (1H, m), 1.98 (1H, m), 2.08—2.30 (3H, m), 3.14 (1H, d, J = 11.6 Hz), 3.25 (1H, d, J = 12.0 Hz), 3.70 (1H, s), 3.94 240240 (1H, d, J = 7.6 Hz), 2 protons were not ed in CD30D.

Step 3. (2R,5$)-N'-butanoyloxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 25, Table 2) H O . N JL, W\N ,1 N\ 11I,” A—M -—-—-> 0 OH %N 0 ‘osogH 235 Compound 25, Table 2 To a solution of 236 (0.21 g, 0.77 mmol) in dry ne (10 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (1.20 g, 7.60 mmol). The mixture was stirred at room temperature for 20 h, filtered and evaporated. The e was purified first by column chromatography followed by HPLC on a prep-X Bridge-30x1OO mm column and freeze-dried to give (2R,5S)-N-butanoyloxo—6—(sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarbohydrazide 1O Compound 25 (Table 2) (0,020 g, 7.5%) as a pink solid. 1H NMR (400 MHz, 00300): 5 97 (3H, t, J = 7.4 Hz), 1.57 (2H, m), 1.77 (1H, m), 1.93 (1H, m), 2.07 (1H, m), 2.22-2.30 (3H, m), 3.30 (2H, m), 4.01 (1H, d, J = 7.6 Hz), 4.15 (1H, s), 3 protons were not observed in CD30D.

HPLC: 95.2% MS (ES’) m/z: [M]‘ = 349 Example 60 (2S,5R)oxo-N‘-(pyridinyl)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 95, Table 2) GWQ‘iHN— N «H /}—N\ O OBn 241241 Step 1. (2S,5R)—6-(benzyloxy)oxo-N‘-(pyridiny|)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (238) o / \ NHNH2 ’ HO/l/II‘Q QM” Om/ll N 1H , To a mixture of (2S,5R)(benzyloxy)—7-oxo-1,6-diazabicyclo[3.2.1]octane—2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 3-hydrazinopyridine dihydrochloride 237 (0.120 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3- dimethylamino ) carbodiimide hloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 238 1O (0.20 g, 60 °/o) as a white foam.

‘H NMR (400 MHz, CDCl3):51.62(1H, m), 1.97 (2H, m), 2.25 (1H, m), 2.84 (1H, d, J: 11.6 Hz), 3.14 (1H, d, J = 11.2 Hz), 3.34 (1H, m), 4.06 (1H, m), 4.91 (1H, d, J = 11.2 Hz), 5.05 (1H, d, J = 11.2 Hz), 7.18 (1H, m), 7.42 (5H, m), 8.14 (1H, m), 8.22 (1H, m), 8.67 (1H, s). 2 protons were not observed in moisture-containing CDCls.

MS (ES+) m/z: [M+H]+ calcd for C11H23N4O4: 347.2. Found: 347.2.

Step 2. (28,5R)hydroxyoxo-N’-(pyridinyl)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (239) A mixture of (2S,5R)—6—(benzyloxy)oxo-N-(pyridinyl)-1,6-diazabicyclo[3.2.1]octane carbohydrazide 238 (0.20 g, 0.54 mmol) and Pd/C (0.08 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was ed h Celite pad and concentrated to provide 239 (0.13 g, 87 %) as a white foam. 1H NMR (400 MHz, CD30D): 81.80(1H, m), 2.00 (1H, m), 2.09 (1H, m), 2.22 (1H, m), 3.07 (1H, d, J = 11.6 Hz), 3.21 (1H, m), 3.72 (1H, br s), 4.03 (1H, d, J = 0.8 Hz), 7.25 (2H, m), 7.96 (1H, m), 8.10 (1H, s). 3 protons were not observed in CD30D. 242242 MS (ES+) m/z: [M+H]+ calcd for C12H16N503: 278.1. Found: 278.1.

Step 3. (ZS,5R)oxo—N'-(pyridinyl)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane- 2-carbohydrazide (Compound 95, Table 2) @H—NJ'“ 0| 0““ / \ NW)?" H H N‘ ——>N— N «H }—N\ }——N 0 OH o ‘osoaH 239 Compound 95, Table 2 To a mixture of )hydroxy-7—oxo—N‘—(pyridinyl)-1,6-diazabicyclo[3.2.1]octane-2— carbohydrazide 239 (0.13 g, 0.47 mmol) in pyridine (6.0 mL) was added sulfur trioxide pyridine complex (0.44 g, 2.80 mmol). The mixture-was stirred at room temperature for 2 days and concentrated to provide a residue which was subjected to chromatography ed by HPLC separation to give Compound 95 (Table 2) (6.9 mg) as a white solid. 1O 1H NMR (400 MHz, CD3OD): 61.81 (1H. m), 2.00 (1H, m), 2.12 (1H, m), 2.26 (1H, m). 3.09 (1H, d, J: 11.6 Hz), 3.36 (1H, m), 4.12 (1H, d, J: 2.8 Hz), 4.18 (1H, m), 7.74 (2H, m), 8.19 .(2H, m). 3 protons were not observed in CD3OD.

HPLC: 94.63 %.

MS (ES') m/z: [M-H]‘ calcd for N5058: 356.1. Found: 356.0 Example 61 (2R,5S)-N'-[(dimethylamino)acetyl]oxo(sulfooxy)-1,6-diazabicyc|o[3.2.1]octane carbohydrazide (Compound 27, Table 2) \ HJL, NWN' 243243 Step 1. (2R,58)(benzyloxy)-N‘-[(dimethylamino)acetyl]oxo-1,6- icyclo[3.2.1]octanecarbohydrazide (241) To a solution of (2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (40 mL) were added 2-(dimethylamino)acetohydrazide 240 (0.32 g, 1.68 mmol), 1—hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl—(3- dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4- (dimethylamino)pyridine (0.40 g, 3.36 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)(benzyloxy)—l\l‘-[(dimethylamino)acetyl]- 7-oxo-1,6-diazabicyclo[3.2.1]octanecarbohydrazide 241 (0.15 g, 44.5%) as a white solid. 1H NMR (400 MHz, CDClg): 5 1.61 (1H, m), 1.98 (2H, m). 2.33 (7H, m), 3.12 (4H, m), 3.31 (1H, s), 4.03 (1H, d, J = 7.2 Hz), 4.90 (1H, d, J = 11.2 Hz), 5.05 (1H, cl, J = 11.6 Hz), 7.38 (5H, m), 8.40 (2H, br s).

Step 2. (2R,58)—N‘-[(dimethylamino)acetyl]—6-hydroxyoxo-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (242) \anj/ \ n ‘1’ N " , H G ‘N o H Q 241 242.

To a on of (2R,58)-6—(benzy|oxy)-l\l‘-[(dimethylamino)acetyl]—7—oxo-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide 241 (0. 15 g, 0.40 mml) in methanol (20 mL) was added 5% Pd/C (0.20 g). The mixture was hydrogenated under 10 psi en atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite and the filtrate was evaporated to give (2R,58)-N‘-[(dimethylamino)acetyl]—6—hydroxy-7—oxo—1 .6- diazabicyclo[3.2.1]octanecarbohydrazide 242 (0.10 g, 88%) as a white foam. 244244 1H NMR (400 MHz, CD30D): 81.75(1H, m), 1.94 (1H, m), 2.05 (1H, m), 2.28 (1H, m), 2.42 (6H, s), 3.27 (4H, m), 3.70 (1H, s), 3.95 (1H, d, J = 7.2 Hz), 3 protons were not observed in CD30D.

Step 3. (2R,58)-N'-[(dimethylamino)acetyl]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 27, Table 2) O H H .l \ JL, \ N \ ,, N N ' /\ii/ N. N L..-N )‘N 0 ‘OH ‘oso3H 242 Compound 27, Table 2 To a solution of (2R,5S)-N-[(dimethylamino)acetyl]—6-hydroxyoxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide 242 (0.10 g, 0.35 mmol) in dry ne (6 mL) under nitrogen here was added sulfur trioxide pyridine complex (0.60 g, 3.80 mmol).

The mixture was stirred at room temperature for 20 h, filtered and evaporated. The residue was ed by column chromatography to give (2R,5S)-N-[(dimethylamino)acetyl]-7—oxo (sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarbohydrazide, Compound 27 (Table 2) (0.020 g, 12.7%) as a brown solid. 1H NMR (400 MHz, CD30D):51.72(1H, m), 1.93 (1H, m), 2.09 (1H, m), 2.30 (1H, m), 2.98 (6H, s), 3.27 (4H, m), 4.06 (1H, d, J = 7.6 Hz), 4.17 (1H, s), 3 protons were not observed in CD30D.

HPLC: 92.3 % MS (ES‘) m/z: [M]'= 364 EXample 62 (2R,58)-N'-[(2,2-dimethylcyclopropyl)carbonyl]oxo(sulfooxy)-1,6- diazabicyc|o[3.2.1]octanecarbohydrazide (Compound 34, Table 2) 245245 Step 1. (ZS,5R)(benzyloxy)-N'—((R)-2,2-dimethylcyclopropanecarbonyl)—7-oxo- 1,6-diazabicyclo[3.2.1]octanecarbohydrazide (244) HN—NH2 O O Jlll H N\ JLI HO I. O u I.

.N O N %~. *—* )—~. 0 OBn O OBn To a solution of (2S,5R)—6—(benzyloxy)—7-oxo-1,6—diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.276 g, 1.0 mmol) in dry DCM (20 mL) were added 243 (0.173 g, 1.35 mmol), 1- ybenzotriazole (0.203 g, 1.5 mmol), and 1-ethy|—(3-dimethylaminopropyl)carbodiimide hydrochloride (0.288 g, 1.5 mmol) at room temperature. The reaction e was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give 244 (0.350 g, 91%) as a white foam.

Step 2. (ZS,5R)-N'-((S)-2,2-dimethylcyclopropanecarbonyl)hydroxyoxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (245) . 245 A mixture of (2S,5R)-6—(benzyloxy)—N'-((R)-2,2-dimethylcyclopro'panecarbonyl)oxo-1,6- icyclo[3.2.1]octane—2-carbohydrazide 244 (0.35 g, 0.90 mmol) and Pd/C (0.50 g) in methanol (80 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 245 (0.27 g, quant.) as an off-white solid. 246246 Step 3. (2R,5S)—N'-[(2,2-dimethylcyclopropyl)carbonyl]oxo(sulfooxy)-1,6- icyclo[3.2.1]octane-2~carbohydrazide (Compound 34, Table 2) o ‘oso3H 245 Compound 34, Table 2 To a e of (2S,5R)—N'—((S)-2,2-dimethylcyclopropanecarbonyl)hydroxyoxo—1,6- diazabicyclo[3.2.1]octanecarbohydrazide 245.(0-27 g, 0.90 mmol) in pyridine (6 mL) was added sulfur trioxide pyridine complex (0.42 g, 2.70 mmol). ). The mixture was stirred at room temperature for 24 h and concentrated to provide a residue which was subjected to chromatography to give Compound 34 (Table 2) (0.166 g) as an ite solid. lH NMR (400 MHz, D20): 50.80 (1H, m), 0.91 (1H, m), 0.98 (3H, s), 1.04 (3H, s), 1.47 (1H, m), 1.69 (1H, m), 1.84 (1H, m), 1.95 (1H, m), 2.09 (1H, m), 3.10 (1H, t, J = 11.0 Hz), 3.22 (1H, d, J = 12.0 Hz), 4.03 (1H, d, J = 7.2 Hz), 4.09 (1H, s). 3 protons were not observed in D20.

HPLC: 97.82 % MS (ES') m/z: [M-H]‘ calcd for C13H19N4078: 375.4. Found: 375.0.

Example 63 (2R,5S)-N'-(2-methylbutanoyl)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 26, Table 2) an/N‘N/Ll’n'i]H l O N 247247 Step 1. (23,5R)—6-(benzyloxy)—N'-(2-methylbutanoyl)oxo—1,6-diazabicyclo [3.2.1]-octanecarbohydrazide (247) 0 w‘NH2 H j’ O/H,’ O N\N ”a H "O 246 O N ””—" )— l—l 1 247 To a on of (28,5R)(benzyloxy)-7—oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.276 g, 1.0 mmol) in dry DCM (20 mL) were added 246 (0.174 g, 1.5 mmol), 1— hydroxybenzotriazole (0.203 g, 1.5 mmol), and 1-ethyl—(3—dimethylaminopropyl)carbodiimide hydrochloride (0.288 g, 1.5 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column tography to give 247 (0.260 g, 70%) as a colorless sticky mass.

Step 2. (23,5R)—6-hydroxy-N'-(2-methylbutanoyl)oxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (248) O O WN‘NJ"MQH H H H ° N WN‘NJL’I,Q H H O OBn O OH 247 248 A mixture of (28,5R)(benzyloxy)-N'-(2-methylbutanoyl)—7—oxo-1,6-diazabicyclo [3.2.1]- octanecarbohydrazide 247 (0.26 g, 0.69 mmol) and Pd/C (0.30 g) in methanol (80 mL) was hydrogenated at 1 atm at room temperature for 2.5 h. The mixture was filtered through Celite pad and trated to provide 248 (0.18 g) as an off-white solid which was used in the next step t purification.

Step 3. (2R,5$)-N'-(2-methylbutanoyl)oxo(suIfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 26, Table 2) WHWJ’II. WNWJLMQH H Cl H 0 N )‘N\ 0%N\O,SH:Oo Compound 26, Table 2 248248 To a e of )hydroxy-N'-(2-methylbutanoyl)oxo—1,6- diazabicyclo[3.2.1]octanecarbohydrazide 248 (0.18 g, 0.63 mmol) in pyridine (6 mL) was added sulfur trioxide pyridine complex (0.30 g, 1.89 mmol). The mixture was stirred at room temperature for 24 h and concentrated to provide a residue which was subjected to chromatography followed by H‘PLC separation to give Compound 26 (Table 2) (0.0095 g) as a white solid. 1H NMR (400 MHz, D20): 5 0.76 (3H, m), 1.00 (3H, d, J = 6.8 Hz), 1.40 (2H, m). 1.70 (1H, m), 1.81 (1H, m), 1.96 (1H, m), 2.09 (1H, m), 2.25 (1H, m), 3.10 (1H, d, J: 12.0 Hz), 3.21 (1H, d, J = 12.0 Hz), 4.03 (1H, d, J = 7.6 Hz), 4.08 (1H, s). 3 protons were not observed in D20.

HPLC: 98.38 % MS (ES‘) m/z: [M-H]' calcd for C12H19N4078: 363.4. Found: 363.0.

Example 64 (2S,5R)-N'-[amino(phenyl)acetyl]-7—oxo(su|fooxy)-1,6-diazabicyc|o[3.2.1]octane carbohydrazide trifluoroacetate (Compound 31, Table 2) H j . ,, N .IIH o ‘osoaH Step 1. tert-butyl [2-(2-{[(2S,5R)(benzyloxy)oxo-1,G-diazabicyclo [3.2.1]oct- 2-y|]carbonyl}hydrazinyl)oxophenylethyl]carbamate (250) NHNH2 0 - HO/L’"‘l W O ' H—NJL NHBoc N ”'H Pin-2‘ H N «H . )—N\ ———‘> NHBoc O OBn okN‘oen 1 250 To a mixture of (28,5R)-6—(benzyloxy)-7—oxo—1,6-diazabicyclo[3.2.1]octanecarboxy|ic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl razinyloxo phenylethyl)carbamate 249 (0.360 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g 1.358 mmol) sequentially at room temperature. The e was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 250 (0.40 g, 84 %) as a white foam. 249249 1H NMR (400 MHz, CDClg): 6 1.42 (9H, s), 1.62 (1H, m), 1.97 (2H, m), 2.25 (1H, m), 3.10 (2H, m), 3.27 (1H, m), 3.94 (1H, m), 4.91 (1H, d, J= 11.6 Hz), 5.05 (1H, d, J: 11.6 Hz), 5.34 (1H, m), 5.60 (1H, m), 7.42 (10H, m), 8.30—8.50 (2H, m).

MS (ES‘) m/z: [M-H]‘ calcd for C27H32N506: 522.2. Found: 522.1.

Step 2. tert-butyl [2-(2-{[(2_S,5R)-6—hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinyl)—2—oxophenylethyl]carbamate (251) . O 0 WV 5N)”.

NHBoc //]——7N NHBoc )—N O \OBn O \OH 250 251 A mixture of terf-butyl [2-(2-{[(2S,5R)—6-(benzyloxy)oxo—1,6-diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinyl)oxopheny|ethyl]carbamate 250 (0.40 g, 0.76 mmol) and Pd/C (0.20 g) in methanol (15 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered h Celite pad and concentrated to provide 251 (0.34 g, quant. yield) as a white foam. 1H NMR (400 MHz, CD30D): 6 1.44 (9H, s), 1.45 (1H, m), 1.88 (1H, m), 2.05 (1H, m), 2.25 (1H, m), 3.11-3.28 (2H, m), 3.71 (1H, br s), 3.94 (1H, d, J: 7.6 Hz), 5.30 (1H, m), 7.25 (2H, m), 7.30 (3H, m). 4 protons were not observed in CD30D.

MS (ES‘) m/z: [M-H]‘ calcd for C20H26N506: 432.2. Found: 432.1.

Step 3. tert-butyl [2-oxo(2-{[(2$,5R)oxo(sulfooxy)-1,6-diazabicyclo ]octyl]carbonyl}hydrazinyl)—1-phenylethyl]carbamate (252) O H jl,, O 1 N—N NW) ~ N «H H , N --:H NHBoc 7L_N\ NHBoc )~—N 0 OH 0 ‘oso3H 251 252 To a mixture of terf-butyl [2-(2-{[(2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}hydraziny|)oxo—1~phenylethyl]carbamate 251 (0.33 g, 0.76 mmol) in pyridine (6.0 mL) was added sulfur trioxide pyridine x (0.71 g, 4.46 mmol). The mixture was stirred at room temperature for 2 days and concentrated to provide a residue which was ted to chromatography to give 252 (0.25g, 64 %) as a white solid. ‘ 250250 1H NMR (400 MHz, CDsoD): 51.44 (9H, s), 1.78 (1H. m), 1.90 (1H, m), 2.12 (1H, m), 2.26 (1H, m), 3.30 (2H, m), 4.12 (2H, m), 5.30 (1H, m), 7.38 (3H, m), 7.45 (2H, m). 4 protons were not observedin CD30D.

M8 (E87 m/Z: [M'Hl‘ caICd for ConngsOgS: 512.1. Found: 512.1.

Step 4. (28,5R)-N'-[amino(phenyl)acetyl]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide trifluoroacetate (Compound 31, Table o o H H NHBOC N NH2 N o ‘oso3H o ‘oso3H 252 Compound 31, Table 2 To a mixture of tert-butyl [2—oxo—2-(2-{[(28,5R)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct— 1O 2-yl]carbonyl}hydrazinyl)-1—phenylethyl]carbamate 252 (0.25 g, 0.48 mmol) in DCM (8.0 mL) was added trifluoroacetic acid (0.40 mL) at 0°C. The e was stirred at 0°C for 3 h, concentrated and washed with ether to give Compound 31 (Table 2) (0.14 g) as a white solid as a pair of diastereomers in a ratio of 1:2. 1H NMR (400 MHz, 020): 51.55 (1H, m), 1.80 (1H, m), 1.95 (1H, m), 2.08 (1H, m), 3.04 (1H, m), 3.22 (1H, d, J = 11.2 Hz), 4.02 (1H, d, J = 6.0 Hz), 4.08 (1H, m), 5.15 (1H, s), 7.42 (5H, m). Five protons were not ed in D20.

HPLC: 92.19 % MS (ES') m/z: [M—H]‘ calcd for C15H18N5078: 412.1. Found: 412.0.

Example 65 (28,5R)—N'-(2,2-dimethylpropanoyl)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 24 , Table 2) H )0! , N—N ' N «H 251251 Step 1. (28,5R)(benzyloxy)-N'-(2,2-dimethylpropanoyl)oxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (254) HO/lL'“ A2~N2HSNH2 H—Nij 2"“ g‘osn To a mixture of (2S,5R)—6—(benzyloxy)—7—oxo-1,6-diazabicyclo[3.2.1]octane-2—carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 2,2-dimethylpropanehydrazide 253 (0.137 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1—ethyl-(3- dimethylamino propyl) carbodiimide hloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a e which was subjected to chromatography to give 254 1O (0.32 g, 94 %) as a white foam.

‘HNMR (400 MHz, CDCI3): 5 1.24 (9H, m), 1.62 (1H, m), 1.99 (2H, m), 2.31 (1H, m), 3.10 (2H, m), 3.28 (1H, m), 4.01 (1H, d, J = 3.2 Hz), 4.91 (1H, d, J = 11.2 Hz), 5.05 (1H, d, J = 11.2 Hz), 7.42 (5H, m), 7.64 (1H, s), 8.48 (1H, 3).

MS (ES‘) m/z: [M—H]' calcd for N4O4: 373.2. Found: 373.1.

Step 2. (28,5R)-N'-(2,2-dimethylpropanoyl)—6-hydroxyoxo-1,6— diazabicyclo[3.2.1]octanecarbohydrazide (255) 0 H—N/l‘1 ' O H ii’I, ‘ H H N "‘H ————> N . i lH )——N //L—-N\ Q ban 0 OH 254 255 A e of (2S,5R)—6-(benzyloxy)-I\I'-(2,2—dimethylpropanoyl)oxo—1 ,6— diazabicyclo[3.2.1]octane—2—carbohydrazide 254 (0.32 g, 0.86 mmol). and Pd/C (0.15 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature overnight. The mixture was filtered through Celite pad and concentrated to provide 255 (0.25 g, quant. yield) as a white foam. 252252 ‘H NMR (400 MHz, : 6 1.25 (9H, s), 1.75 (1H, m), 1.92 (1H, m), 2.05 (1H, m), 2.28 (1H, m), 3.14 (1H, m), 3.30 (1H, m), 3.70 (1H, br s), 3.94 (1H, d, J = 7.2 Hz). 3 s were not observed in CD30D.

MS (ES+) m/z: [M+H]+ calcd for N4O4: 285.1. Found: 285.1.

Step 3. (2S,5R)-N'-(2,2-dimethylpropanoyl)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 24, Table 2) 0 HN—N)I,“ O H j’n, H N‘ﬁ N ———> N _..H -HH ”1"” okN‘osogH Compound 24, Table 2 To a mixture of (2S,5R)-N'—(2,2—dimethylpropanoyl)-6—hydroxy-7~oxo-1 ,6— diazabicyclo[3.2.1]octanecarbohydrazide 255 (0.25 g, 0.85 mmol) in pyridine (10.0 mL) 1O was added sulfur trioxide pyridine complex (0.42 g, 2.58 mmol). The mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography followed by HPLC separation to give Compound 24 (Table 2) (20mg) as a white solid. 1H NMR (400 MHz, D20): 5 1.08 (9H, s), 1.65 (1H, m), 1.80 (1H, m), 1.95 (1H, m), 2.10 (1H, m), 3.10 (1H, d, J = 12.4 Hz), 3.22 (1H, d, J = 12.0 Hz), 4.02 (1H, d, J = 7.6 Hz), 4.08 (1H, m).

Three protons were not observed in D20.

HPLC: 93.08 %.

MS (ES‘) m/z: [M-H]' calcd for CZOH19N4O7S: 363.1. Found: 363.0.

Example '66 (2S,5R)oxo-N-(2-oxopiperidiny|)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide (Compound 103, Table 2) CNN)”‘1H N «H 253253 Step 1. (2S,5R)(benzyloxy)oxo-N—(2-oxopiperidinyl)-1,6— diazabicyclo[3.2.1]octanecarboxamide (257) J“-OI < N—NH2 O o HO 256 J.

N_N '1, oilv—N‘osn )‘N To a mixture of (28, 5R)—6—(benzyloxy)—7—oxo-1 ,6—diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 1-aminopiperidinone 256 (31 mg, 0.27 mmol), ), HOBt (38 mg, 0.27 mmol), DMAP (32 mg, 0.27 mmol) and EDCl (53 mg, 0.27 mmol). The mixture was stirred at room ature for 48 h and purified by column to afford 257 as foam (55 mg, 82%). 1HNMR (CDCI3): 8.45 (1H, s), 7.40 (5H, m), 4.99 (2H, dd), 4.02 (1H, d), 3.70 (1H, m), 3.43 (1H, m), 3.32 (2H, m), 3.07 (1H, m), 2.40 (3H, m), 1.90 (6H, m), 1.60 (1H, m).

Step 2. (2S,5R)—6-hydroxyoxo-N—(2-oxopiperidinyl)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (258) 0 o o o < N—NJ1”" N ___, dbl—NJ,"H (1 To a solution of compound 257 (55 mg, 0.148 mmol) in 10 mL of MeOH was added 100 mg of Pd/C (10%, wet). The mixture was enated at room temperature for 2 h. The catalyst was removed by tion through Celite pad. The filtrate was concentrated to afford compound 258 as a colorless gum (37 mg, 88%). 1HNMR(CD3OD): 3.98 (1H, d), 3.72 (1H, m), 3.55 (2H, m), 3.30 (1H, m), 3.18 (1H, m), 2.49 (2H, m), 2.30 (1H, m), 1.90 (7H, m). 254254 Step 3. (ZS,5R)oxo-N-(2-oxopiperidinyl)(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide und 103, Table 2) o 0 o 0 I, l, ———> N—N/l H H N N }—N ¢L—~N 0 ‘OH 0 ‘osogH Compound 103, Table 2 To a solution of compound 258 (35 mg, 0.124 mmol) in 5 mL of pyridine was added sulphur trioxide pyridine complex (190 mg, 1.24 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 72 h. After silica gel column followed by HPLC. purification, pure compound 103 (Table 2) was obtained as a white solid (20 mg, 45%) 1HNMR(CD30D): 4.18 (1H, s), 4.03 (1H, d), 3.58 (2H, m), 3.30 (2H, m), 2.50 (2H, m), 2.30 (1H, m), 1.90 (7H, m) HPLC: 93 %.

MS (ES‘) m/z: [M-H]‘ Found: 361.0.

Example 67 (2R,58)-N'-(azetidinylcarbonyl)oxo-6’-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (Compound 112, Table 2) \j\n/N\N/LH'QHO N I; N\ Step 1. tert-butyl {[(2R,5$)(benzyloxy)oxo-1,64diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinyl)carbonyl]azetidinecarboxylate (260) /kO/[LNO i H o ii ST HO o N. 1 ﬁg 259 ”LR,"12 O Q 1 260 255255 To a solution of (2S,5R)-6—(benzyloxy)oxo-1,6—diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added utyl 3- (hydrazinylcarbonyl)azetidinecarboxylate 259 (0.29 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature ght and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 3-[(2-{[(2R,58)—6— (benzyloxy)oxo-1,6—diazabicyclo[3.2.1]octyl]carbonyl}hydrazinyl)carbonyl]azetidine carboxylate 260 (0.35 g, 81%) as a white solid. 1H NMR (400 MHz, 00013)») 1.38 (9H, s), 1.63 (1H, m), 1.99 (2H, m), 2.31 (1H, m), 3.15 (2H, m), 3.28 (2H, s), 4.00 (1H, d, J= 7.6 Hz), 4.10 (4H, m), 4.90 (1H, d, J = 11.2 Hz), 5.04 (1H, d, .1 = 11.6 Hz), 7.39 (5H, m), 7.86 (1H, br s), 8.54 (1H, br s).

Step 2. tert-butyl 3-[(2-{[(2R,58)—6-hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinyl)carbonyl]azetidinecarboxylate (261) XOJL'DYHEEQo . o 0 N ﬁXOJLNQYH-” 1g 0 QB“ H 0 OH 260 251 To 'a solution of tert-butyl 3-[(2-{[(2R.58)-6—(benzyloxy)—7-oxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinyl)carbonyl]azetidinecarboxylate 260 (0. 35 g, 0.74 mml) in methanol (25 mL) was added 5% Pd/C (0.40 g). The e was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the 2O filtrate was evaporated to give tert-butyl 3-[(2-{[(2R,58)—6-hydroxyoxo-1,6- diazabicyclo[3.2.1]octyl]carbonyl}hydrazinyl)carbonyl]azetidine—1-carboxylate 261 (0.25 g, 88%) as a white foam. 1H NMR (400 MHZ, CD30D): 5 1.44 (9H, s), 1.76 (1H, m), 1.91 (1H, m), 2.05 (1H, m), 2.26 .(1H, m), 3.15 (1H, m), 3.25 (1H, m), 3.40 (1H, m), 3.71 (1H, s), 3.95 (1H, d, J = 7.2 Hz), 4.08 (4H, m), 3 protons were not observed in CD30D. 256256 Step 3. tert-butyl 3-[(2-{[(2R,53)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinyl)carbonyl]azetidinecarboxylate (262) /%)LN;\\[O(H ijo NSEI/Hﬂj/IOo Z / V )—N\ O OH )——‘N 0 ‘ososH 261 262 To a solution of ted-butyl 3-[(2-{[(2R,58)-6~hydroxyoxo—1,6-diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinyl)carbonyl]azetidinecarboxylate 261 (0.25 g, 0.65 mmol) in dry pyridine (10 mL) under nitrogen atmosphere was added sulfur trioxide pyridine x (0.60 g, 3.80 mmol). The mixture was d at room temperature for 20 h, filtered and ated. The residue was purified first by column chromatography to give ted-butyl 3-[(2— {[(2R,58)—7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]oct 1O yl]carbonyl}hydrazinyl)carbonyl]azetidine—1-carboxylate 262 (0.18 g, 60%) as a white solid. 1H NMR (400 MHz, CD30D): 8 1.30 (9H, s), 1.81 (1H, m), 1.94 (1H, m), 2.05 (1H, m), 2.26 (1H, m), 3.30 (2H, m), 3.41 (1H, m), 4.04 (5H, m), 4.16 (1H, s), 3 protons were not observed in CD30D.

Step 4. ‘ (2R,5S)-N'-(azetidinylcarbonyl)oxo(sulfooxy)-1,6- ' diazabicyclo[3.2.1]octanecarbohydrazide (Compound 112, Table 2) kJL'O o 0 “all”, o C1 ”SYN, JL, N ,.

N _, H 0 o NCl o )‘N OSOgH o ‘ososH 262 Compound 112, Table 2 To a solution Iterf-butyl 3—[(2-{[(2R,5S)oxo-6—(sulfooxy)-1,6-diazabicyclo[3.2.1]oct—2- yl]carbonyl}hydrazinyl)carbonyl]azetidinecarboxylate 262 (0.18 g, 0.39 mmol)'in DCM (18 mL) was added trifluoroacetic acid (1.45 mL, 1879 mmol) se at 0 °C. The reaction mixture was stirred for 1 h then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with a mixture of MeOH:ether (1:5, 6X) and the white solid was collected by centrifugation to give (2R,5S)—N- (azetidinylcarbonyl)—7-oxo(sulfooxy)-1,6-dlazabicyclo[3.2.1]octane-2—carbohydrazide Compound 112 (Table 2) (0.04 g, 28%) as a white solid. 257257 1H NMR (400 MHz, 1.66(1H, m), 1.77 (1H, m), 1.90 (1H, m), 2.04 (1H, m), 3.03 (1H, d, J: 12.4 Hz), 3.17 (1H, m), 3.65 (1H, m), 4.02 (2H, m), 4.12 (4H, m), 4 protons were not observed in D20.

HPLC 92.40% MS (ES') m/z: [M]‘= 362 Example 68 (28,5R)oxo-N'-(pyrrolidinylcarbonyi)(suIfooxy)-1,6-diazabicyc|o[3.2.1]octane carbohydrazide trifluoroacetate und 41, Table 2) O o W1H l F30 OH HH ‘5 N (”H V )——N o ‘oso3H Step 1. tert-butyl 2-(2-((2$,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]- octanecarbonyl)hydrazinecarbonyl)pyrrolidinecarboxylate (264) Boo 0 <"'j/1LNHNl-i2 j 800 O O HO l, N NIH <Nj/kN—_NJH H N "‘H To a mixture of (28, 5R)—6—(benzy|oxy)oxo-1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.304 g, 1.10 mmol) in DCM (20.0 mL) were added tert—butyl 3- (hydrazinecarbonyl)pyrrolidinecarboxylate 263 (0.380 g, 1.65 mmol), 1- hydroxybenzotriazole (0.223 g, 1.65 mmol) and 1-ethyl-(3—dimethylaminopropyl) carbodiimide hydrochloride (0.315 g, 1.65 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, concentrated to e a residue, which was subjected to chromatography to give 264 (0.34 g) as a white solid. 258258 Step 2. tert-butyl 2-(2-((2S,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]-octane carbonyl)hydrazinecarbonyl)pyrrolidinecarboxylate (265) B00 0 Boo O N /l‘/,‘I/ N All, N N I: N .HH N "III 4L——N\ éL__N\ o OBn O OH 264 265 A mixture of tert—butyl 2-(2-((28,5R)—6-(benzyloxy)oxo-1,6—diazabicyclo[3.2.1]-octane carbonyl)hydrazinecarbonyl)pyrrolidinecarboxylate 264 (0.34 g, 0.70 mmol) and Pd/C (0.30 g) in methanol (80 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Ceiite pad and concentrated to give 265 (0.28 g, quant.) as an off-white solid.

Step 3. tert-butyl2-(2-((2S,5R)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane- 2-carbonyl)hydrazinecarbonyl)pyrrolidinecarboxylate (266). 800 O O Boo O O \ NﬂNJm,, I N N H H N_”J,,L,H N ‘IIH ————-> N -||H )—N 2—N 0 ‘OH 0 ‘osoyi 255 266 To a mixture of tert-butyl (28,5R)hydroxy—7-oxo-1,6-diazabicyclo[3.2.1]-octane—2— yl)hydrazinecarbonyl)pyrrolidinecarboxylate 265 (0.28 g, 0.70 mmol) in pyridine (6 mL) was added sulfur tridxidepyridine complex (0.33 g, 2.10 mmol). The mixture was stirred at room temperature for 24 h and concentrated to provide a residue, which was subjected to chromatography to give 266 (0.290 g, 87 %) as an off—white solid.

‘H NMR (400 MHz, 5'1.24 and 1.27 (9H, 2s), 1.60 — 2.20 (8H, m), 3.02 (1H, m), 3.16 (1H, m), 3.28 (2H, m), 4.01 (2H, m), 4.181(1H, m). Three s were not observed in CD30D. 259259 Step 4. (28,5R)—7-oxo-N‘-(pyrrolidin—2-ylcarbonyl)(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide trifluoroacetate (Compound 41, Table B00 0 0 \ ..

N N—‘NJ/h'‘i j”.

H H H N "‘H —.———» <Nj/U\N___u N "'H )———N //L_N o ‘osoaH O ‘0303H Compound 41, Table 2 To a mixture of tert-butyl 2—(2—((2$,5R)—7—oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]-octane-2— carbonyl)hydrazinecarbonyi)pyrrolidine‘carboxy|ate 266 (0.29 g, 0.61 mmol) in DCM (12. mL) was added trifluoroacetic acid (0.60 mL) at 0°C. The mixture was d at 0°C for 2 h, concentrated and washed with ether and MeOH to give Compound 41 (Table 2) (69.8 mg) as a white solid as a pair of diastereomers. 1O 1H NMR (400 MHz, D20): 51.65(1H, m), 1.81 (1H, m), 1.90-2.10 (5H, m), 2.34 (1H, m), 3.03 (1H, m), 3.16-3.31 (3H, m), 4.03 (2H, m), 4.33 (1H, m). Four protons were not observed in D20. “ l9F NMR (376.5 MHz, D20): 6 - 75.75 HPLC: 94.84 %, MS (ES‘) m/z: [M+H]+ calcd for C12H20N5078: 378.4. Found: 378.0.

Example 69 (28,5R)-N‘-[(2,2-difluorocyclopropyl)carbonyl]oxo(su|fooxy)-1,6- icyclo[3.2.1]octanecarbohydrazide (Compound 36, Table‘2) O HMQ(i // .

FA< H N «H , )_N o ‘oso3H 260260 Step 1. (ZS,5R)(benzyloxy)-N'-[(2,2-difluorocyclopropy|)carbonyl]oxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (268) NHNH2 L I F O H :3,h N -I|H _—.———-———> N ‘IIH To a mixture of (2S,5R)(benzyloxy)-7—oxo-1,6—diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 2,2— difluorocyciopropanecarbohydrazide 267 (0.184 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) tially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was ted to chromatography to give 268 (0.36 g, quant. yield) as a white foam. 1H NMR (400 MHz, CDCI3): 5 1.62 (1H, m), 1.80 (1H, m), 2.00 (2H, m), 2.18 (1H, m), 2.36 (1H, m), 2.44 (1H, m), 3.10 (1H, m), 3.30 (1H, m), 4.00 (2H, m), 4.91 (1H, d, J = 11.2 HZ), .05 (1H, d, J: 11.2 Hz), 7.42 (5H, m), 8.40 (1H, br 5), 8.60 (1H, br S).

MS (ES+) m/z: [M+H]+ calcd for CiaH21F2N4O4: 395.1. Found: 395.1.

Step 2. (28,5R)—N'-[(2,2-difluorocyclopropyl)carbonyl]hydroxyoxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (269) o . o O N/”“ O H H—N/u“ H J::::ln.H F j —————- Fl F K 1: g::::l~IH F 5L———N 4L‘—*N\ o ‘OBn 0 OH 268 269 A mixture of )-6¥(benzyloxy)-I\I'-[(2,2-difluorocyclopropyl)carbonyI]oxo-1,6— diazabicyclo[3.2.1]octanecarbohydrazide 268 (0.36 g, 0.90 mmol) and Pd/C (0.15 g) in methanol (20 mL) was hydrogenated at 1 atm at room ature overnight. The mixture was filtered through Celite pad and concentrated to provide 269 (0.37 g, quant. yield) as a white foam. 1H NMR (400 MHz, CD30D): 5 1.75-2.10 (4H, m), 2.25 (1H, m), 2.60 (1H, m), 2.70 (1H, m), 3.20 (2H, m), 3.70 (1H, br s), 3.95 (1H, d, J = 7.6 Hz). 3 protons were not observed in CD30D. 261261 MS (ES‘) m/z: [M-H]‘ calcd for C11H13F2N4O4: 303.1. Found: 303.0.

Step 3. (28,5R)-N'-(2,2-dimethylpropanoyl)oxo-6—(sulfooxy)—1,6- diazabicyclo[3.2.1]octane¢arbohydrazide (Compound 36, Table 2) O ‘i H )1,“ HM) a N ”H _—> F }—N . o . ‘osoaH 269 Compound 36, Table 2 To a mixture of (28,5R)—N'—[(2,2—difluorocyclopropyl)carbonyl]-6—hydroxyoxo-1,6- diazabicyclo[3.2.1]octane—2-carbohydrazide 269 (0.37 g, 1.21 mmol) in pyridine (10.0 mL) was added sulfur trioxide pyridine complex (0.57 g, 3.65 mmol). The mixture was d at room ature overnight and concentrated to provide a residue, which was subjected to tography and followed by HPLC separation to give Compound 36, (Table 2) (60 mg) as a white solid as a pair of diastereoisomers. 1H NMR (400 MHz, 020): 5 1.65 (1H, m), 1.72—2.00 (4H, m), 2.05 (1H, m), 2.52 (1H, m), 3.05 ~ (1H, d, J = 12.0 Hz), 3.18 (1H, d, J = 12.0 Hz), 4.01-4.05 (2H; m). Three protons were not observed in D20.

HPLC: 92.75 %.

MS (ES') m/z: [M—H]‘ calcd for C11H13F2N4O7S: 383.1. Found: 382.9.

Example 70 (28,5R)—7-oxo-N‘-[(2$)-piperidin—2-ylcarbonyl](sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 43, Table 2) C’Wrnjqu’nNH O a H Q 262262 Step 1. tert—butyl (2S)[(2-{[(ZS,5R)(benzy|oxy)oxo-1,6- diazabicyclo[3.2.1]octyl]carbony|}hydrazinyl)carbonyl]piperidinecarboxylate (271) Boc\ }§—NHNH2 /Boc a o H0)“ {’3 0 . 270 1 N\N('3 H N «H N "'H l.__ )——N O N‘OBn O \OBn To a solution of (28,5R)(benzyloxy)oxo—1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added tert—butyl (28) (hydrazinylcarbonyl)piperidine—1—carboxylate 270 (0.33 g, 1.35 mmol), 1- hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g. 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and trated under vacuum. The residue was purified by column chromatography to give tert-butyl (28)[(2-{[(28,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]oct yl]carbony|}hydrazinyl)carbonyl]piperidinecarboxylate 271 (0.37 g, 82%) as a white solid. 1H NMR (400 MHz, CDCI3): 5 1.37-1.72 (15H, m), 1.95 (2H, m), 2.31 (2H, m), 3.05 (2H, m), 3.22 (2H, m), 4.06 (2H,‘m), 4.86 (1H, m), 4.90 (1H, d, J = 11.2 Hz), 5.05 (1H. d, J = 11.6 Hz), 7.38 (5H, m), 8.11 (1H, br 5). 8.34 (1H, br s).

Step 2. tert-butyl -[(2-{[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct- 2-yl]carbonyl}hydrazinyl)carbonyl]piperidine-1—carboxylate (272) 271 272 To a solution of tert—butyl (28)[(2-{[(2S,5R)(benzyloxy)oxo-1.6-diazabicyclo[3.2.1]oct— 2-yl]carbonyl}hydra'zinyl)carbonyl]piperidinecarboxylate 271 (0. 37 g, 0.74 mml) in methanol (25 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room ature for 1 h. The catalyst was filtered out h Celite, and the filtrate was evaporated to give tert-butyl (2S)[(2-{[(2S,5R)-6—hydroxyoxo- 263263 1 ,6-diazabicyclo[3.2.1)octyl]carbonyl}hydrazinyl)carbonyl]piperidinecarboxylate 272 (0.29 g, 96%) as a white foam. ' 1H NMR (400 MHz, CD30D): 5 1.47 (12H, m), 1.65 (2H, m), 1.76 (1H, m), 1.94 (1H, m), 2.04 (1H, m), 2.26 (2H, m), 3.15 (2H, m), 3.26 (1H, m), 3.70 (1H, s), 3.94 (2H, m), 4.79 (1H, m), 3 protons were not observed in CD30D.

Step 3. tert-butyl (28)[(2-{[(2$,5R)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octyl]carbonyl}hydrazinyl)carbonyl]piperidinecarboxylate (273) N/BO:I O] O/ H j N\ ’ . N J 'n,’f \N O-IIH ’I(if N H H N 'H O 4 N‘OH .

O O N\OSO3H 272 273 1O To a solution of tert-butyl —[(2—{[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinyl)carbonyl]piperidinecarboxylate 272 (0.29 g, 0.70 mmol) in dry pyridine (10 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.65 g, 4.12 mmol). The e was stirred at room temperature for 20 h, filtered and evaporated. The residue was purified first by column chromatography using DCM: EtAcO: MeOH (20:30:50) as eluent to give tert—butyl (28)[(2-{[(28,5R)-7—oxo-6—(sulfooxy)-1,6- diazabicyclo[3.2.1]octyl]carbonyl}hydrazinyl)carbonyl]piperidine—1—carboxylate 273 (0.30 g, 87%) as a white solid. 1H NMR (400 MHz, : 5 1.47 (12H, m), 1.64 (2H, m), 1.80 (1H, m), 1.93 (1H, m), 2.01 (1H, m), 2.25 (2H, m), 3.17 (3H, m), 3.99 (2H, m), 4.15 (1H, s), 4.79 (1H, m), 3 protons were not observed in CD30D.

Step 4. (28,5R)oxo-N'-[(2$)-piperidih-Z-ylcarbonyl](sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 43, Table 2) /Boc O NH O N. H )1. , O H- )1. 7,]if N\N . ’I N ~——> H OHM-l (if H N ...H O )‘N ’é N\ O ‘OSOSH O OSCgH 273 compound 43, Table 2 264264 To a solution utyl (2S)[(2-{[(2S,5R)—7-oxo(sulfooxy)—1,6-diazabicyclo[3.2.1]oct-2— yl]carbonyl}hydrazinyl)carbonyl]piperidinecarboxylate 273 (0.30 g, 0.61 mmol) in DCM (30 mL) was added trifluoroacetic acid (2.42 mL, 31.38 mmol) dropwise at 0 °C. The reaction mixture was d for 1 h then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with a mixture of MeOHzether (1:5, 6X) and the white solid was ted by centrifugation to give (2S,5R)—7- oxo-N‘-[(2S)-piperidinylcarbonyl]-6—(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2— carbohydrazide Compound 43 (Table 2) (0.09 g, 38%) as a white solid.

‘H NMR (400 MHz, D20):61.51 (2H, m), 1.63 (1H, m), 1.75 (2H, m), 1.93 (1H, m), 2.05 (2H, m), 2.91 (1H, m),3.03 (1H, d, J: 12.4 Hz), 3.18 (2H, m), 3.33 (1H, m), 3.89 (1H, d, J = 11.6 Hz), 4.03 (2H, m), 4.54 (1H, m), 4 protons were not observed in D20.

HPLC: 93.40% MS (ES‘) m/z: [M-H]' = 390 Example 71 . (Compound 30, Table 2) NH2 TFA o j—HN—MJL'QO N //L—‘N » o ‘oso3H Step 1. tert-butyl 1-(2-{[(ZS,5R)(benzyloxy)oxo-1,6- diazabicyc|o[3.2.1]octyl]carbonyl}hydrazinyl)oxopropan-Z-yl]carbamate (275) B0c \ 1 275 To a solution of 1 (250 mg, 0.9 mmol) in 20 mL of DCM were added tert-butyl [(2R)—1- hydrazinyloxopropanyl]carbamate 274 (275 mg, 1.35 mmol), HOBt (183 mg 1.35 mmol), DMAP (162 mg, 1.35 mmol) and EDCl (260 mg, 1.35 mmol). The mixture was stirred at room temperature for 48 h and purified by column to afford compound 275 as foam (400 mg, 95%). 265265 ‘HNMR ): 8.48 (1H, s); 8.35 (1H, s); 7.40 (5H, m); 4.95 (3H, m); 4.25 (1H, m); 4.00 (1H, m); 3.30 (1H, m); 3.08 (2H, m); 2.30 (m, 1H); 2.00 (m, 2H); 1.58 ( 1H, m); 1.40 (m, 12H).

Step 2. tert-butyl [(2R)(2-{[(28,5R)hydroxyoxo-1,6-diazabicyclo[3.2.1]oct- 2-yl]carbonyl}hydrazinyI)oxopropanyl]carbamate (276) NHBOC NHBOC O O #HN‘N/l’l"l J' ’I.

H ' #HN—M o O N N }~N )—N. o ‘OBn 0 OH 275 276 To a solution of compound 275 (400 mg, 0.86 mmol) in 30 mL of MeOH was added 0.8 g of Pd/C (10%, wet). The mixture was hydrogenated at room temperature for 2 h. The catalyst was removed by filtration through a celite pad. The filtrate was trated to afford compound 276 as a colorless gum (320 mg, 99%). 1HNMR (CD3OD): 4.15 (1H, m); 3.98 (1H, d); 3.70 (1H, m); 3.20 (2H, m); 2.30 (1H, m); 2.10 (1H, m); 1.90 (1H, m); 1.75 (1H, m); 1.45 (9H, s); 1.35 (3H, d).

Step 3. tert-butyl [(2R)oxo(2-{[(2S,5R)oxo(sulfooxy)-1,6- icyclo[3.2.1]octyl]carbonyl}hydrazinyl)propanyl]carbamate (277) NHBOC O NHBOC ‘S/‘HN‘ﬁ/l O l, ’“ . 0 0H //‘——N 0 ‘oso3H To a solution of compound 276 (320 mg, 0.858 mmol) in 15 mL of pyridine was added sulphur trioxide pyridine complex (1.5 g, 9.6 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 15 h. After column purification, compound 277 was obtained as foam (300 mg, 77%). 1HNMR (CD30D): 4.20 (2H, m); 4.00 (1H, d); 3.20 (2H, m); 2.30 (1H, m); 2.10 (1H, m); 1.90 (1H, m); 1.80 (1H, m); 1.45 (9H, s); 1.35 (3H, d). 266266 Step 4. (28,5R)-N'-[(2R)aminopropanoyl]oxo(sulfooxy)-1,6- icyclo[3.2.1]octanecarbohydrazide trifluoroacetate (Compound 30, Table NHBOC (DI NH2 0 TFA /L’ #HN-N/ul’“ O N "——'> H O N }——N\ 0 )~——N OSOsH o ‘osoaH Compound 30, Table 2 To a solution of compound 277 (150 mg. 0.33' mmol) in DCM at 0 °C was added TFA (0.5 mL) slowly. After addition, the mixture was stirred at 0 °C for 2 h then diluted with 50 mL of EtZO. The solid was collected by filtration and washed with additional amount of EtZO and dried to afford the crude product Compound 30 (Table 2) as a white solid (100 mg. HPLC 76%). Re-precipitation of 50 mg of this crude product with CM afforded 20 mg of Compound 30 (Table 2) as a white solid. 1HNMR(D20): 4.00 (3H. m); 3.20 (1H, m); 3.10 (1H, m); 2.10 (1H. m); 1.90 (1H. m); 1.80 (1H. m); 1.65 (1H, m).

HPLC: 84%.

MS (ES‘) m/z: [M-1]'= 350 Example 72 (28,5R)—N-{[(3S)—1-carbamimidoy|pyrro|idiny|]oxy}oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (Compound 92, Table 1) H2N ‘? N& ) O-N ’ o ‘ososH Using the similar procedure as described in Example 14, the intermediate 278 was prepared- and used for making compound 92 (Table 1). 267267 Step 1. di-tert-butyl {(3S)[({[(ZS,5R)(benzyloxy)-7—oxo-1,6-diazabicyclo [3.2.1]octyl]carbonyl}amino)oxy]pyrrolidinyl}methylylidene]biscarbamate (279) O 0‘0-NH2 NBoc BOCHN/[LD—O-NJL"O //"—N\ O OBn )—N O \OBn ' 279 To a mixture of (2S,5R)(benzyloxy)-7—Oxo—1,6-diazabicyclo[3.2.1]octanecarboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (20.0 mL) were added t-butyl {(E)—[(3S)-3— oxy)pyrrolidin-1—yl]methylylidene} biscarbamate 278 (0.478 g, 1.358 mmol), 1- hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The 1O mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 279 (0.34 g, 62 %) as white foam.

’H NMR (400 MHz, CDCl3): 5.1.45 (18H, s), 1.62 (1H, m), 2.00 (4H, m), 2.30 (2H, m), 2.77 (1H, d, J = 12.0 Hz), 2.95 (1H, d, J =10.8 Hz), 3.29 (1H, s), 3.80 (2H, m), 3.92 (2H, m), 4.72 (1H, m), 4.90 (2H, ABq), 7.41 (5H, m). Two protons were not observed in moisture— containing CDCl3. ' MS (ES+) m/z: [M+H]+ calcd for ngH43N503: 603.3. Found: 603.2.

Step 2. di-tert-butyl [{(3S)[({[(ZS,5R)—6-hydroxyoxo-1,6-diazabicyclo ]octyl]carbonyl}amino)oxy]pyrrolidinyl}methylylidene]biscarbamate (280) NBoc NBoc JL O BOCHN 1 N[3‘ )1,“ N )L, O‘N " H [OHM _—’. 0.0 N Owl—i ’; N\ )F~—_N O OBn o ‘QH 279 280 A mixture of t—butyl [{(3S)—3-[({[(28,5R)(benzyloxy)oxo-1,6-diazabicyclo [3.2.1]oct- 2-yl]carbonyl}amino)oxy]pyrrolidin-1—yl}methy|ylidene]biscarbamate 279 (0.34 g, 0.56 mmol) and Pd/C (0.15 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 268268 h. The mixture was filtered through Celite pad and concentrated to provide 280 (0.28 g, 97 %) as white solid. 1H NMR (400 MHz, CD30D): 5 1.48 (19H, m), 1.92 (3H, m), 2.10 (2H, m), 2.25 (1H, m), 3.00 (1H, d, J = 11.6 Hz), 3.11 (1H, m), 3.64 (5H, m), 4.62 (1H, m). 3 protons were not observed, in CD30D.

MS (ES+) m/z: [M+H]+ calcd for CZZH37N608: 513.2. Found: 513.2.

Step 3. di-tert-butyl [({[(2$,5R)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octyl]carbony|}amino)oxy]pyrrolidinyl}methylylidene] biscarbamate (281) NBOC NBOC BCCHN D. _N/[ /, .‘ II‘D‘Q—N/l n,I, H N "'H H N ..H 0 0H - . o ‘oso3H 1O 281 To a e of di-tert-butyl [{(3S)[({[(2S,5R)hydroxy—7-oxo-1,6—diazabicyclo[3.2.1]oct—2- yl]carbonyl}amino)oxy]pyrrolidinyl}methylylidene] biscarbamate 280‘ (0.28 g, 0.54 mmol) in pyridine (6.0 mL) was added sulfur trioxide ne x (0.26 g, 1.63 mmol). The mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 281 (0.30 g, 94 %) as white solid. 1H NMR (400 MHz, CDSOD): 51.47 (18H, s), 1.80 (1H, m), 1.94 (1H, m), 2.10 (1H, m), 2.20 (3H, m), 2.40 (1H, m), 3.05 (1H, d, J = 11.6 Hz), 3.33 (1H, m), 3.90 (4H, m), 4.16 (1H, s), 4.70 (1H, s). 3 protons were not observed in CD30D.

MS (ES+) m/z: [M+H]+ calcd for 022H37N6011S: 593.2. Found: 593.2.

Step 4. (28,5R)-N—{[(3S)carbamimidoylpyrrolidinyl]oxy}ox056-(sulfooxy)- 1,6-diazabicyclo[3.2.1]octanecarboxamide (Compound 92, Table 1) NBoc NH JL (1 ' JL 0 BocHN Ne /lnh ()~N g..._ H2N N /JL“ H _. O—ou Q )"N }—N O VDSOaH o YasoaH 281 Compound 92, Table 1 To a mixture of di-tert-butyl [{(3S)[({[(28,5R)-7—oxo—6-(sulfooxy)-1,6-diazabicyclo [3.2.1]oct-2—yl]carbonyl}amino)oxy]pyrrolidinyl}methylylidene]biscarbamate 281 (0.30 g, 0.51 mmol) in DCM (6.0 mL) was added trifluoroacetic acid (0.3 mL) at 0°C. The mixture was 269269 stirred at 0°C for 0.5 h followed by at room temperature for 2 h and concentrated to provide a residue which was purified by HPLC to give Compound 92 (Table 1) (8.8 mg) as white solid.

‘H NMR (400 MHz, D20): 51.67-182 (2H, m), 1.90-2.11 (3H, m), .22 (1H, m), 2.99 (1H, d, J = 11.6 Hz), 3.15 (1H, d, J = 11.2 Hz), 3.42-3.58 (4H, m), 3.90 (1H, d, J = 6.0 Hz), 4.05 (1H, s). 4.60 (1H, m). 5 protons were not observed in D20.

HPLC: 96.6 % MS (ES') m/z: [M—H]' calcd for C12H19N507S: 391.1. Found: 390.9.

Example 73 (28,5R)—N‘-[(3,3-difluorocyclobutyl)carbonyl]oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (Compound 116, Table 2) o ‘oso3H Step 1. ' (28,5R)(benzyloxy)-N'-[(3,3-difluorocyclobutyl)carbonyl]oxo-1,6: diazabicyclo[3.2.1]octanecarbohydrazide (283) . F PAC H j N F _ \NHZ F H HO - o l . NW)“.

N H A—Nx W» o N o OBn To a solution of (2S,5R)(benzyloxy)oxo-1,6-diazabicyclo[3.2.1]octane—2-carboxylic acid 1 (0.25 g, 0.901 mmol) in dry dichloromethane (30 mL) were added 3,3- difluorocyclobutanecarbohydrazide 282‘ (0.20 g, 1.35 mmol), oxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was d at room temperature overnight and concentrated under . The residue was purified by column chromatography to give' 283 (0.32 g, 87%) as a white solid. 1H NMR (400 MHZ, CDCI3): 81.61 (1H, m), 1.98 (2H, m), 2.28 (1H, m), 2.74 (2H, m), 2.88 (3H, m), 3.10 (2H, m), 3.33 (1H, s), 3.97(1H, d, J = 7.2 Hz), 4.90 (1H, d, J = 11.2 Hz), 5.03 (1H, d, J =11.6 Hz), 7.39 (5H, m), 8.31(1H, br s), 8.66 (1H, br s). 270270 Step 2. (28,5R)-N'-[(3,3-difluorocyclobutyl)carbonyl]hydroxyoxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide (284): To a solution of (28,5R)—6-(benzyloxy)-N'-[(3,3-difluorocyclobutyl)carbonyl]-7—oxo-1 ,6- diazabicyclo[3.2.1]octane-2—carbohydrazide 283 (0. 32 g, 0.78 mml) in ol (25 mL) was added 10% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere. at room temperature for 1 h. The st was filtered out through Celite, and the filtrate was evaporated to give 284 (0.24 g, 96%) as a white foam. 1H NMR (400 MHz, CD30D): 5 1.76 (1H, m), 1.94 (1H, m), 2.05 (1H, m), 2.26 (1H, m), 2.78 (4H, m), 2.98 (1H, m), 3.15 (1H, m), 3.24 (1H, d, J: 12.00 Hz), 3.71 (1H, s), 3.94 (1H, d, J: 8.0 Hz), 3 protons were not observed in CD30D.

Step 3. (28,5R)-N'-[(3,3-difluorocyclobutyl)carbonyl]oxo(sulfooxy)-1,6; icyclo[3.2.1]octanecarbohydrazide und 116, Table 2) F F AQ\V(N\N/L’I,I(\1O WN\NJII“QO H H 0 ‘OH 0 ‘oso3H , Compound 116, Table 2 To a solution of (28,5R)-N'-[(3,3-difluorocyclobutyl)carbonyl]hydroxyoxo-1,6- diazabicyclo[3.2.1]octanecarbohydrazide 284 (0.24 g, 0.75 mmol) in dry pyridine (10 mL) under nitrogen atmosphere was added sulfur trioxide pyridine complex (0.60 g, 3.80 mmol).

The mixture was stirred at room temperature for 20 h, filtered and evaporated. The residue was purified by column chromatography to give (2S,5R)—N—[(3,3-difluorocyclobutyl)carbonyl]- 7-oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octanecarbohydrazide Compound 116 (Table 2) (0.12 g, 40%) as a white solid. 1H NMR (400 MHz, CD30D): 5 1.80 (1H, m), 1.92 (1H, m), 2.06 (1H, m), 2.27 (1H, m), 2.67-2.93 (4H, m), 2.97 (1‘H, m), 3.30 (2H, m), 4.03 (1H, d, J= 7.2 Hz), 4.15 (1H, s), 3 s were not observed in CD30D. 271271 HPLC: 91.0% MS (ES‘) m/z: [M]‘ = 397 Example 74 (28,5R)-N'-{[(1R,2R)aminocyclopentyl]carbony|}oxo(sulfooxy)—1,6- diazabicyclo[3.2.1]octanecarbohydrazide trifluoroacetate (Compound 40, Table 2) O’ 0 N. A. if M Q 0 N TFA VL—N o ‘oso3H Step 1. tert-butyl R)[(2-{[(ZS,5R)(benzyloxy)oxo-1,6- diazabicyclo[3.2.1]octyl]carbonyl}hydrazinyl)carbonyl]cyclopentyl}carbamate (286) NHBoc O.’ N "If ‘NH2 HO/“m, 0 285 O, H l,“ N [If {i o N 1 286 To a solution of felt-butyl [(1R,2R)(hydrazinylcarbonyl)cyclopentyl]carbamate 285 (0.15 g, 0.54 mmol) in 20 mL of DCM were added compound 1 (0.2 g, 0.82 mmol), HOBt (0.11 g, 0.82 mmol), DMAP (0.2 g, 1.64 mmol) and EDCI (0.16 g, 0.82 mmol). The mixture was stirred at room temperature for 18 h and purified by column chromatography to afford compound 286 as a solid (0.22 g, 82%). 1HNMR (CDClg): 1.44 (9H, s), 1.70 (4H, m), 2.00 (4H, m), 2.20 (1H, m), 2.40 (1H, m), 2.80 (1 H, s), 3.08 (1H, m), 3.30 (2H, m), 4.10 (2H, m), 4.90 (1H, s), 5.00 (2H, dd), 7.40 (5H, m), 8.33 (1H, s), 9.92 (1H, 5).

MS (ES+): 502. ’ 272272 Step 2. tert-butyl {(1R,2R)[(2-{[(28,5R)hydroxyoxo-1,6- diazabicyclo[3.2.1]octyl]carbonyl}hydrazinyl)carbonyl]cyclopentyl}carbamate (287) NHBoc NHBoc 0’ram)1“,o O’er‘N)1,“o (I) H O ’ H O )—M (DJ—”tOH 286 287 To a solution of compound 286 (0.22 g, 0.44 mmol) in 10 mL of CH30H was added 0.1 g of Pd-C (10%, wet). The mixture was enated at room temperature for 16 h. The catalyst was removed by filtration through a pad of . The filtrate, was concentrated to afford compound 287 as a solid(0.15 g, 83%).

CD30D): 1.44 (9H, s), 1.80 (3H, m), 2.10 (6H, m), 2.30 (1H, m), 2.60 (1H, m), 3.20 1O (2H, m), 3.70 (1H, m), 3.98 (1H, d), 4.10 (1H, m).

MS (ES+): 412.

Step 3. tert-butyl {(1R,2R)[(2-{[(28,5R)—7-oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octyl]carbonyl}hydrazinyl)carbonyl]cyclopentyl}carbamate (288) o \OH 0 ‘osoaH 288 To a on of compound 287 (15 g, 0.36 mmol) _in 5 mL of pyridine was added sulphur trioxide pyridine complex (0.58 g, 3.6 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 16 h. After silica gel column purification, compound 288 was obtained as a solid (0.14 g, 78%). 1HNMR(CD3,OD): 1.44 (9H, s), 1.70 (4H, m), 2.10 (6H, m), 2.30 (1H, m), 2.60 (1H, m), 4.20 (4H, m).

MS (ES-): 490 273273 Step 4. (28,5R)—N‘-{[(1R,2R)—2-aminocyclopentyl]carbonyl}oxo(sulfooxy)— 1,6-diazabicyclo[3.2.1]octanecarbohydrazide trifluoroacetate (Compound 40, Table 2) NHBoc NH2 <1, ii, 0.7,, ii if u ' —+ l u o N o N 288 Compound 40, Table 2 To a solution of compound 288 (0.1 g, 0.2 mmol) in DCM (10 mL) at _0 °C was added TFA (0.5 mL) dropwise. After addition, the mixture was stirred at 0 °C for 3 h then diluted with 50 mL of ether. The solid was ted by filtration and washed with additional ether and dried to afford the title compound Compound 40 (Table 2) as a white solid (0.07 9,72%) 1HNMR (CD3OD): 1.82 (6H, m), 2.23 (4H, m), 2.83 (2H, m), 3.87 (2H, m), 4.04 (1H, d), 4.15 (1H, 5).

MS (ES—): 390 274274 Antibacterial activity and synergistic activity: Compounds of the present invention alone, ceftazidime alone, meropenem alone, aztreonam alone and as a combination with these antibiotics were tested for minimum inhibitory concentration (MIC, ug/mL) against ia listed in Tables 3 — 9. In the Tables 10 - 12, compounds of the present invention were tested in combination with various otics against metallo B-Iactamase producing bacteria. 275275 2.20834. :E\mE$~.xm $3 New H E am tou :EM «:5 HHHHHHHallIHIHagHHH IIHHIHE II mozoszcm HHHIIH %H%H%HHH% HHHIIH 522358 a a a a V E HH I. I. HH%HEHH HHHHHHH HIE HHHHHIII II H SEE: 32/5 3mmw .xm 2:35 watts Ii! 3.35 .345 BEBE III gag .758 EH :25 350 2: Ea .80: .2202 lg 8&3?me? ﬁgﬁgHﬁﬁﬁgﬁlg gagagﬂagHHHHHHHEIIHIIHHHHE 5-0% .12; 33:85:50 33%;;ng SEBESEEEXS 335w E £2390 $3523 EN 52228:. as 821% 88 5% 5% 8mm 2 8:. 358. New 52228. @228. .26 2 .5; E E 2% “m _._§§ a: 2 8.83 33a 8.83 was, 858a 833 8595 8.85 =8 .< __8.w . . . . . . . . HHHHHHHgéQ_EH!é gm Eeézsm 8::_>_2_8m 276276 u v -u‘ “VIA-nu, A VA,Au-uA-,uu.—u.u Emcowb~< SEE—t Nmow «A 2A Nmow Noow Noow Noow meow Noow mg m .0 Sow Sow Noow Nwow «A 2A mNH 3 .0 .0 Nmow Nwow Nmow Nmow wEiﬁmtwu SEE 37.n— all wE§~mtwu 28 + SEE 8:03....“ I. 1.08, ::z2!. E33055. 17$ £22 0% (ZI vim 22.2358 033 Z: E .xm 95?.

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Chemother., 28, pp 775—776 (1991)] . The tration of inhibitor (le0) which inhibits by 50% the reaction of hydrolysis of nitroceﬁn by the enzyme is determined. Table 13 shows the results.

Table 13 Test for B-lactamase Inhibitory Activity Example No. leo ( pM) leo (pM) TEM-1 CMY-Z EX. 40 0052 :l: 0.004 0.008 t 0.001 0.091 t 0.009 0.327 i 0.020 In light of the data described herein, persons of skill in the art would expect that all of the nds within the scope of formula (I), salts of such nds, solvates of such compounds and salts thereof, and deuterated compounds of all such compounds, salts and solvates (i.e., compounds of formula (I) ed in that they have been deuterated, salts of compounds of formula (l) modified in that they have been deuterated, and solvates of such nds and salts, modified in that they have been deuterated) would be effective on their own as cterial compounds, and in combination with [3-lactam antibiotics.

Efficacy of the amase tors can be evaluated in combination with ceftazidime (CAZ) aztreonam (AZT), meropenem (MER) and other class of cephalosporins and carbapenems in murine infection models such as septicemia, pneumoniae and thigh infection models (Ref: Andrea Endimiani et. al. Antimicrob. Agents and Chemother Jan 2011, pp-82—85). For murine acute lethal septicemia model, mice were infected by the intraperitoneal injection of the clinical strains resulting in death of the untreated controls within 24-48 hrs. In particular, a fresh predetermined bacterial inoculum of approximately 3.3 x 105 to 3.6 x 105 CFU (colony forming units) in 5% hog gastric mucin grown overnight. Thirty minutes post infection, a single subcutaneous dose of CAZ with and without B-lactamase inhibitor was initiated and the survival ratio monitored for 5 days twice daily. For each strain tested, the dosing regimen used are CAZ alone ( doses of 512, 1024 & 2048 mglkg of body weight) and CAZ plus B-lactamase inhibitor at ratio of 2:1, 4:1, 8:1 & 16:1 (CAZ doses were 4, 8, 16, 32 & 64 mglkg for each . The median effective dose for 50% (EDSO) of animals was determined by a erized program of Probit analysis. Survival ratesstratified for different dosing regimen were also obtained. For 286286 experimental pneumoniae model, immunocompromised mice were used and intratracheally ed with ella pneumoniae strains. Mice in this model develop bacteraemia pneumoniae and fatal disease within 2 to 4 days with lung ial burden at 16—18 hrs post infection of 10“ to 1013 cfu/gm lung, Treatment with CAZ and inhibitor at a ratio of 2/1 & 4/1 demonstrate efficacy with significant ‘3 to 6 log reduction in lung counts compared to CAZ alone and is relevant to the clinical situation. Human testing of the B—lactamase inhibitor can be conducted in combination with partner otic at a set ratio ing standard clinical development practice.

Below are a series of numbered passages, each of which defines subject matter within 1O the scope of the present inventive subject matter: Passage 1. A compound of formula (I): Y—N/[I"'‘i’ N _ o ‘ososm wherein: M is hydrogen or a pharmaceutically acceptable salt-forming cation; Y is 0R1; R1 is a radical ed from the group consisting of: (1) (31-5 straight or branched chain alkyl which is optionally substituted; (2) 03-7 cycloalkyl which is optionally substituted; (3) 04.7 saturated heterocycles containing at least one heteroatom selected from O, N and S wherein the said heterocycle is optionally tuted, the ring S is optionally oxidized to 8(0) or S(O)2 and the free ring N atom may optionally take a substituent; (4) Heterocyclyl (01.6) alkyl wherein the said heterocycle has the same definition as d in (3), and the said heterocycle is optionally substituted; 287287 05-7 membered saturated cycles optionally fused with a 03-7 membered cycloalkyl group to form a bicyclic ring system where the bicyclic ring system so formed is fused either-through two adjacent carbon atoms or through a N atom shared by both the rings and the other end of the cycloalkyl chain is ed to the adjacent carbon atom of the le, each ring of the said bicyclic ring system independently optionally substituted; (6) 05-7 membered saturated heterocycles optionally fused with another 05.7 saturated heterocycle to form a bicyclic ring system where the bicyclic ring system so formed is fused either through two adjacent carbon atoms or h a N atom shared by both the rings, each ring of the said bi-cyclic ring system independently optionally substituted; (7) C3_7cycloalkyl which is optionally fused with a 057 membered saturated heterocycle containing at least one heteroatom selected from O, N and S the said bicyclic ring optionally substituted; (8) Bridged bicyclic ring system having optionally one or two atoms selected from O. N and S, the bicyclic ring system optionally substituted either at the carbon atom or at the free N atom present in the ring; (9) CW membered saturated heterocycles optionally fused with 05.7 membered heteroaryl ring where the bicyclic ring system so formed is fused either through two adjacent carbon atoms or through N atom shared by both the rings; (10) 05-7 membered saturated heterocycles optiOnally fused to a C36 membered ring system h a common carbon atom to form a spiro system ally containing one heteroatom selected from O, N and S that is present in the spiro ring where the ring 8 is optionally oxidized to 8(0) or S(O)2 and the free N atom t in either ring may optionally take a substituent; and 288288 (11) 05.7membered heteroaryl (01.5) alkyl which is optionally substituted, or a deuterated compound of any such compound.

Passage 2. A compound of formula (l): Y—N/ll o 0803M wherein: M is hydrogen or a ceutically acceptable orming cation; Y is NR2R3; R2 is en or optionally substituted 01-5 lower alkyl; R3 is a radical ed from any of following groups consisting of: (1) 01-5 straight or branched chain alkyl which is optionally substituted; (2) 03.7 cycloalkyl which is optionally substituted; (3) ‘ 04-7 saturated heterocycles containing at least one heteroatom selected from O, N and 8 wherein the said heterocycle is optionally substituted, the ring 8 is optionally oxidized to 8(0) or S(O)2 and the free ring N atom may optionally take a substituent; (4) 01-5 straight or ed chain alkyl carbonyl which is optionally substituted; (5) 03.7 cycloalkyl yl which is optionally substituted; (6) 04-7 membered saturated heterocyclyl carbonyl containing at least one heteroatom selected from O, N and 8 wherein the said heterocycle is optionally substituted, the 289289 ring 8 is ally oxidized to 8(0) or S(O)2 and the free ring N atom may optionally take a substituent; (7) 03-7 membered saturated heterocyclyl (01.5) alkyl carbonyl wherein the said heterocycle has the same definition as defined in (6), and the free ring N atom may optionally take a substituent; (8) 06.10 aryl carbonyl which is optionally substituted; (9) Ce-1oaryl (01.6) alkyl carbonyl which is optionally tuted; (10) 05-6 membered heteroaryl yl containing at least one heteroatom selected from O, S and N n the heteroaryl is optionally substituted; (11) 05.6 heteroaryl (01-5) alkyl carbonyl wherein the said heteroaryl has the same definition as defined in (10); (12) CF300-{CH38021 NHZCO-, and NH2802- ; (13) 06.10 aryl which is optionally substituted; (14) 05-6 membered heteroaryl which is optionally substituted; (15) or R2 and R3 together may form an optionally substituted ring system and the said ring may contain r heteroatom selected from O, N, and S, or a ated compound of any such compound.

Passage 3. A compound as recited in passage 1 or passage 2, wherein M is hydrogen.

Passage 4. A compound as recited in passage 1 or e 2, wherein M is a pharmaceutically acceptable salt-forming cation. 290290 Passage 5. A compound as recited in passage 2, wherein R2 is hydrogen or 01.5 lower alkyl.

Passage 6. A compound as recited in any one of passages 1-5, wherein R1 R2 and R3 are optionally substituted with one or two substituents independently selected from the ing: Lower alkyl, amino, substituted amino, alkoxy, hydroxyalkyl, halogen, y, carboxy, alkoxycarbonyl, haloalkyl, trifluoromethyl, trifluoromethyloxy, alkylamine, substituted alkylamine, ' amide, thiocarboxamide, sulfonic acid, sulphate, acylamino, sulfonylamino, substituted or unsubstituted sulfonamide, substituted or unsubstituted urea, substituted or unsubstituted thiourea, oxo, oxyimino, hydroxamic acid, acyl, trifluoromethyl carbonyl, cyano, o, guanidino, aryloxy, heterocyclylalkyloxy, and heteroaryloxy. e 7. A compound as recited in passage 1, which is selected from the following group of compounds: 0 O o HONO‘NJL’ /O‘u)’~gl A/O‘NJLM N N N }_N\ )—_N\ )_N O O OSO3H OSOsH O 0803H 0 k 0! ° i N N N }—N N\ N 0 0 0 OSO3H 0803H OSO3H it , ‘l o a H2N N/VO‘N’ H2N’S‘N/\/O‘N)”’ Ho/U\/O‘N/L H H H H H N N N )“N }—-N\ )‘N O OSOaH O osogH O OSOaH ~ 292292 %N o8OH3 0 \oSoH3 HN O OH/ W OH/ W o \NH NH 0,.

NW HN ifN\ 0 Os03H \0s0°H W0 O O\NH |/ Clan NW A o OH/x N \NH O mO3H Os0;H W0NH O O OHW, Wf\NH W Q I/ (H NM 7NH W O NbSa;H \OmaH 293293 O3H o)— b803HN o)— b303HN O 0803H 0 b803H O 0803H O\N j?/ O\N j?ll" j/ HN H N H o N £O\N N J—N / N . )—N ”M H )—N\ 0803H O 0803H O 0803H o\ ‘? , j? ‘? Q” \ H . l N a” N /N \N N \ \N N'H )‘N ' \ N'H }—N\ O }—N OSO3H O OSO3H O . OSO3H O OSO3H O b803H O bSO3H o o o o o\ JIM, o o\ )L, 0‘ L “s—N N >—N N ' N \ /\\ H H HN HN N H o HZN N N )—N )—N o O )—N OSO3H O 0803H NH2 0 0803H 295295 296296 o OSO3H 0 bSOsH O HNQ N HN 0 0 -~ H Q J—N N NQ o )—N Jr~~ OSOgH o b803H o b803H and ceutically acceptable salts of such compounds, and deuterated compounds of such compounds and salts.

Passage 8. A compound as recited in passage 2, which is selected from the following group of compounds: 297297 O bSO3H O 0803H O b803H O O H H JL H I Jh, ”‘ J’ LN )*N\ O o bso3H O N‘oso H OSOSH 3 o o H o N\N I . H , l “NJ,“I «3 H dH N N dH N HH »—~\ 0 S O OSO3H O J~N OSOSH O OSOSH o o o N\N/[/H | “\N/Ln,l “\NJ’Ml ”“3 H N HN/J/ H H N (j N H‘ )——N\ .

O 0803H O H 0303H 0 O OSO3H 298298 ”N OH” MN we \NH I.A \NH Nllh 0 o \omH3 OIIL/ A0 . m. HN NH . \NH m.

O \OS00H kN\ 299299 300300 O O RN 0 l,“ HM L,,, NW)». o” HH H H O N HN3” H 0“ HQ N o N / O OSO3H O OSO3H O 0803H ‘ O O Hwy,“ O N/\\( Hwy,“ RNA,“ O H N/\\( H H o N N/\\( - fHNJ o N f /}—N\ oJ o N - O /}—N\ 0803H O OSO3H 0- OSO3H QHNJ'”o o o L CO “NJ,“L ' H H ©\KN\NJM o N H o N o N )‘N\ 0 )‘N\ )‘N\ 0803H O OSO3H 0 0803H ,‘CI) NxN/L’z,H CI) 0 o H H H\ Jill, o N o N {j Q }—N )— o O b803H 0 b803H )“N 0 OSO3H AL o o 0 JL, HM L,, / '3 H JI, WN ' N H H \ L W H H N\ 9' N\ L O N\ OSO3H O OSO3H 0 , 0803H /Nl o H o o N\ JIM N/l H \ \ N\ J N , J1, N ' s /anN ' H H o N H o N N )*N o //'—N\ 0 }—N\ OSO3H O 0803H O OSO3H 301301 IN OH,/ IN 0)I» \ NH m. NH S 0 \ / N we 0 H /N N”m. O HN oHﬂ H N I. o\\S/\HN/ OHW 2 «0 NH A“ H2N \O \NH N%,N \OSO3H o \OSO O ‘osoaH 303303 NH2 I o I 0 H o - H An/N\”J (1 l, N N\ / \/\n/ J'~,, ” Q F)D\n/N\N In, 0 N 0 N H o N (gt—Nb (DJ—N )—N SO3H 0303“ O OSO3H H N2 RH H N ii / KWH ii / n ‘i O No O 0N O No }—N\ )‘N )—N O 0803H O 0803H O 0803H and pharmaceutically acceptable salts of such compounds, and deuterated compounds of such nds and salts.

Passage 9. A compound of formula (I) as deﬁned in e 1, wherein the compound is ed from the group consisting of: (2S,5R)-N—(2~hydroxyethoxy)—7—oxo—6-(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane—2- carboxamide (ZS,5R)-N—methoxy—7-oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane-2—carboxamide (2 S,5R)—7-oxo-N-propoxy-6—(sulfooxy)—1 ,6-diazabicyclo[3.2.1]octane-2—carboxamide (2S,5R)-N—(2-aminoethoxy)oxo(suifooxy)-1,6-diazabicyclo[3.2.1]octane carboxamide (2S,5R)-N—(2-aminopropoxy)—7—oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane-2— carboxamide (2S,5R)-N—(2-amino-2—oxoethoxy)—7-oxo-6—(sulfooxy)—1 ,6-diazabicyclo[3.2.1]octane carboxamide (2 S,5R)—N-[2-(carbamoylamino)ethoxy]—7—oxo(sulfooxy)-1 ,6—diazabicycio[3.2.1]octane- 2-carboxamide 304304 (2 S,5R)—7-oxo~N-[2-(sulfamoylamino)ethoxy]-6—(sulfooxy)—1 ,6—diazabicyclo[3.2.1]octane- 2—carboxamide [({[(2 S,5R)-7—oxo(su|fooxy)-1 ,6-diazabicyclo[3.2.1]octyl]carbonyl}amino)oxy]acetic acid 2—methyl—2—[({[(2S,5R)—7-oxo-6—(sulfooxy)-1 ,6—diazabicyclo[3.2.1]oct—2— yl]carbonyl}amino)oxy]propanoic acid (2 S,5R)-7«oxo-N-[2-(piperidin-4—yloxy)ethoxy]—6—(sulfooxy)—1 ,6-diazabicyc|o[3.2.1]octane- 2-carboxamide (2S,5R)oxo—N-(propan—Z-yloxy)-6—(suIfooxy)-1 ,6-diazabicyc|o[3.2.1]octane—Z- carboxamide (2 S,5R)-N—tert-butoxyoxo-6—(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane~2-carboxamide (2 S,5R)-N—(cyclobutyloxy)oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane carboxamide (2S,5R)-N—(cyclopentyloxy)—7-oxo(sulfooxy)-1 ,6~diazabicyclo[3.2.1]octane-Z- amide )-N-(cyclohexyloxy)oxo-6—(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane-2— amide (2S,5R)-N-(cyclohéptyloxy)oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane carboxamide (2S,5R)-N-[(3-aminocyclopentyl)oxy]oxo(sulfooxy)—1 ,6—diazabicyclo[3.2.1]octane—Z- carboxamide )—N-[(2-aminocyclopentyl)oxy]—7-oxo-6—(sulfooxy)-1 ,6—diazabicyc|o[3.2.1]octane carboxamide (2S,5R)—N—{[3-(methylamino)cyclopentyl]oxy}oxo—6-(sulfooxy)-1 ,6- diazabicyc|o[3.2.1]octane—2-carboxamide (2S,5R)-N-{[4-(dimethylamino)cyclohexy|]oxy}oxo(sulfooxy)-1 ,6— diazabicyclo[3.2.1]octane—2-carboxamide (2S,5R)-N-[(3-aminocyclohexyl)oxy]—7-oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z- carboxamide 305305 (2 S,5R)-N-{[3—(methylamino)cyclohexy|]oxy}oxo-6—(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (2 S,5R)—7—oxo-N-(pyrrolidin-3—yloxy)(su|fooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z- amide (2 S,5R)oxo-N—[(5-oxopyrrolidinyl)oxy](sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane—2— amide (28,5R)-N-[(1-acetylpyrrolidin—3-yl)oxy]oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane— oxamide (2 S,5R)-N-[(1-methy|pyrro|idinyl)oxy]—7—oxo—6-(sulfooxy)-1 ,6- 1O diazabicyc|o[3.2.1]octane—2—carboxamide (2 S,5R)—7-oxo-N-(piperidinyloxy)(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z- carboxamide , (2S,5R)oxo-N—(piperidinyloxy)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2— carboxamide (2 S,5R)—N—(azetidinyloxy)oxo-6—(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane—2- carboxamide (2 S,5R)—7—oxo(sulfooxy)-N-(tetrahydro~2H—pyrany|oxy)-1 ,6- diazabicyc|o[3.2.1]octane-2—carboxamide (2S,5R)-7—oxo(su|fooxy)-N—(tetrahydro-2H-thiopyran—4—yloxy)—1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (2 S,5R)-N-[(1 ,1-dioxidotetrahydro-2H—thiopyranyl)oxy]oxo(sulfooxy)-1,6— diazabicyclo[3.2.1]octane—2—carboxamide (2 S,5R)—N—(azepany|oxy)oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z- carboxamide (28.5R)-N—(1,4—oxazepan-6—yloxy)—7-oxo—6-(suIfooxy)—1 ,6—diazabicyc|o[3.2.1]octane-Z- carboxamide (2 S,5R)—/_V—[(1—methylpiperidin-4—yl)oxy]—7-oxo-6—(sulfooxy)—1 ,6-diazabicyclo[3.2‘1]octane- 2—carboxamide (2 S,5R)—N—[(1 —carbamimidoylpiperidin-4—yl)oxy]—7-oxo—6-(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octanecarboxamide 306306 )—7-oxo-N—(pyrrolidinylmethoxy)—6-(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane—Z- carboxamide (2S,5R)—7-oxo-N~(piperidin—Z-ylmethoxy)(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2— carboxamide (2 S,5R)-7—oxo-N—(piperidiny|methoxy)(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane carboxamide (2S,5R)—7-oxo—N—(piperidiny|methoxy)(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2- carboxamide (2 S,5R)—N—(morpholin-3—ylmethoxy)oxo(sulfooxy)-1 ,6—diazabicyc|o[3.2.1]octanev2- carboxamide (2S,5R)—7-oxo-N-(piperazinylmethoxy)—6—(sulfooxy)—1 ,6-diazabicyclo[3.2.1]octane—Z- carboxamide (2 S,5R)—7—oxo(sulfooxy)—N-(thiomorpholin—3-ylmethoxy)-1 ,6—diazabicyclo[3.2.1]octane- 2-carboxamide (2 S,5R)—N-(decahyd roquinolin—4-yloxy)oxo-6—(sulfooxy)-1 ,6-diazabicyclo[3.2. 1 e- 2—carboxamide (2 S,5R)-N-(hexahydro~1 H—pyrrolizin—2-yloxy)oxo-6—(sulfooxy)-1 ,6- Vdiazabicyclo[3.2.1]octane—2-carboxamide (2 S,5R)—N—(octahydroindolizinyloxy)—7-oxo-6—(sulfooxy)-1 zabicyclo[3.2.1]octane- 2-carboxamide (28,5R)-N-(octahyd ropyrro|o[1 ,2-a]pyraziny|oxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane—2-carboxamide )-N-(octahydropyrrolo[1 ,2-a]pyraziny|oxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (2 S,5R)-N—(octahyd rofuro[2,3-c]pyridinyloxy)oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (2 S,5R)—N—(3-azabicyc!o[3.1 .0]hexyloxy)oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (2 S,5R)-N—(decahydroquinolinyloxy)'oxo—6-(sulfooxy)—1,6—diazabicyclo[3.2.1]octane— 2-carboxamide 307307 (2 S,5R)—N-(hexahydro-4aH—cyclopenta[b][1 ,4]dioxin-6—yloxy)oxo—6—(sulfooxy)-1 ,6— diazabicyclo[3.2.1]octane—2-carboxamide (2 S,5R)—N—(octahyd rocyclopenta[c]pyrrol—5—yloxy)-7—oxo(sulfooxy)-1 ,6— diazabicyclo[3.2.1]octane—2—carboxamide (2 S,5R)—N—(hexahydro-1 H-cyclopenta[c]furan—5-yloxy)oxo_—6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (2S,5R)—N—(hexahydro~1H—cyclopenta[c]thiophen—5-yloxy)oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (2 N—(bicyclo[2 .2. 1 ]hept—2-yloxy)oxo(su|fooxy)—1 ,6—diazabicyclo[3.2.1]octane— 2—carboxamide (2 N—[(7,7—dimethylbicyclo[2.2. 1 2-yl)oxy]—7-oxo(su|fooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (2 S,5R)-N—(1 -azabicyclo[2.2.2]oct-3—y|oxy)-7—oxo—6-(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (2 S,5R)-N-(8-azabicyclo[3.2. 1 ]oct-3eyloxy)oxo—6-(sulfooxy)-1 ,6- icyclo[3.2.1]octane-2—carboxamide (2 S,5R)-N-[(8—methy|—8-azabicyclo[3.2.1 ]oct-3—yI)oxy]—7-oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (2 S,5R)—7—oxo(su|fooxy)-N-(4,5,6,7-tetrahydrothieno[3,2—c]pyridiny|oxy)-1 ,6— diazabicyclo[3.2.1]octane—2—carboxamide (2S,5R)~N-(6,7-dihydro—5H-pyrro|o[1 ,2-a]imidazolyloxy)oxo—6-(sulfooxy)—1 ,6« diazabicyclo[3.2.1]octanecarboxamide (2 S,5R)—N-(7—azaspiro[4.5]dec-1 0-yloxy)oxo(su|fooxy)-1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (2 S,5R)—N-(7-oxaspiro[4.5]dec—1 0-yloxy)-7—oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octanecarboxamide (2 S,5R)—N-(1 H—imidazoIy1methoxy)oxo(su|fooxy)-1 ,6-diazabicyclo[3.2.1]octane—2— carboxamide (2 S,5R)-7—oxo—6—(sulfooxy)-N-(4,5,6,7-tetrahyd ro-1 H—4,7—methanoindazolylmethoxy)- 1 ,6—diazabicyc|o[3.2.1]octane-2—carboxamide 308308 )oxo-N-(1H-pyrazolyImethoxy)(su|fooxy)-1 ,6—diazabicyclo[3.2.1]octane-2— carboxamide (2 S,5R)-7—oxo—N—[2-(pyridinyl)ethoxy]-6—(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane~2— carboxamide (28,5R)—7-oxo~N-[2—(piperidinyl)ethoxy](sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane—2— carboxamide (2 S,5R)—7—oxo-N-[2-(piperazin-1 —yl)ethoxy]—6-(suIfooxy)—1 zabicyclo[3.2.1]octane carboxamide (2 S,5R)oxo~N-[( 1 -sulfamoy|pyrrolidinyl)oxy]—6-(sulfooxy)—1 .6- diazabicyc|o[3.2.1]octanecarboxamide (2 S,5R)-N-{[1 -(methylsuIfamoyl)pyrrolidinyl]oxy}0xo(sulfooxy)‘-1 ,6— diazabicyclo[3.2.1]octanecarboxamide (2 S,5R)—N-[(1 -carbamoylpyrrolidin-S-yl)oxy]—7-oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (2 S,5R)-N-[(5-carbamoylpyrrolidin-3—yl)oxy]oxo(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (2S,5R)-N-[(1—carbamimidoylpyrrolidinyl)oxy]-7—oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane~2-carboxamide (2 N-[(1 —ethanimidoylpyrrolidin—3—yl)oxy]—7-oxo(sulfooxy)-1 ,6- icyc|o[3.2.1]octane—2-carboxamide (28,5R)—N-{[1-(iminomethyl)pyrrolidin—3-yl]oxy}—7-oXo(sulfooxy)—1 ,6— diazabicyclo[3.2.1]octane—2—carboxamide (2 S,5R)—7-oxo-6~(sulfooxy)-N-(tetrahydrofu ranyloxy)-1 ,6—diazabicyc|o[3.2.1]octane—2- carboxamide (2 S,5R)oxo(sulfooxy)-N—(tetrahydro-2H—thiopyran-3—yloxy)—1 ,6- diazabicyclo[3.2.1]octanecarboxamide (2 S,5R)—N—[(4-methy|piperidinyl)methoxy]oxo(sulfooxy)-1 ,6— diazabicyclo[3.2.1]octane—2-carboxamide (2 S,5R)—N-(1 ,4-oxazepanylmethoxy)—7-oxo(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane- 2-carboxamide 309309 (2S,5R)—7-o_xo(su|fooxy)—N—(tetrahydrofuranylmethoxy)—1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)—7-oxo(sulfooxy)-N-(4,5,6,7-tetrahydrofuro[3,2—c]pyridinyloxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide )-N-[(1-methy|—4,5,6,7-tetrahydro-1H-pyrazolo[3,4—c]pyridinyl)oxy]—7-oxo—6- (sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2-carboxamide )—7-oxo-6—(su|fooxy)—N-(4,5,6,7-tetrahydro-1H-pyrazolo[3,4—c]pyridiny|oxy)-1 ,6— diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)—N-[2-(1H—imidazol—1—y|)ethoxy]—7-oxo-6—(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane— 2—carboxamide )-N-[(4-fluoropyrrolidinyl)oxy]—7-oxo—6-(sulfooxy)—1,6-diazabicyclo[3.2.1]octane- 2-carboxamide (2 S,5R)—N-(1 ,2—oxazolidin-4—yloxy)oxo—6-(sulfooxy)—1 ,6-diazabicyclo[3.2.1]octane carboxamide 1(28,5R)—7-oxo-N-(pyrazolidin-4—yloxy)(suIfooxy)-1,6-diazabicyc|o[3.2.1]octane—2- carboxamide (28,5R)—N-[(4—aminopyrrolidinyl)oxy]-7—oxo—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane- 2—carboxamide (28,5R)—7-oxo-N-[(4—oxopyrrolidin—3—yl)oxy](sulfooxy)-1,6-diazabicyc|o[3.2.1]octane-2— carboxamide (2S,5R)—N—[(4-hydroxypyrrolidin-3—y|)oxy]oxo—6-(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide » (28,5R)-N-{[(4E)—4-(hydroxyimino)pyrrolidinyl]oxy}—7-oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)-N-{[(4E)—4-(methoxyimino)pyrrolidinyl]oxy}-7~oxo(sulfooxy)-1 ,6- diazabicyc|o[3.2.1]octane—Z—carboxamide (28,5R)-N—{[(4E)—4—{[(1,5—dihydroxyoxo-1 ,4—dihydropyridin-2~ yl)methoxy]imino}pyrrolidinyl]oxy}oxo—6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z- carboxamide 310310 (2 S,5R)-N-[(4,4-dimethylpyrrolidinyl)oxy]-7—oxo—6—(su|fooxy)-1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (28,5R)-N—[(4-fluoropiperidin-3—yl)oxy]—7-oxo(sulfooxy)—1 ,6-diazabicyclo[3.2.1]octane— 2—carboxamide (2 N—[(3-f|uoropiperidinyl)oxy]oxo—6-(sulfooxy)-1 ,6-diazabicyc|o[3.2.1]octane— 2-carboxamide (2S,5R)—7-oxo-N-[(5-oxopiperidinyl)oxy](sulfooxy)—1,6-diazabicyclo[3.2.1]octane carboxamide (28,5R)—N—[(5,5—dimethylpiperidinyl)oxy]—7—oxo~6-(sulfooxy)-1 ,6— 1O diazabicyclo[3.2.1]octane-2—carboxamide (2 S,5R)-N-(2—methoxyethoxy)—7-oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)-N-[2-(morphoIinyl)ethoxy]oxo(sulfooxy)-1 ,6-diazabicyc|o[3.2.1]octane carboxamide (2 S,5R)—7—oxo—N—[2-(pyrrolidin—1 -yl)ethoxy]—6-(sulfooxy)-1 za bicyc|o[3.2.1]octane carboxamide (2S,5R)—7-oxo-N-[2-(piperidinyl)ethoxy](sulfooxy)—1 ,6-diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)—N-[2—(1,1—dioxidothiomorphoIinyl)ethoxy]oxo-6—(su|fooxy)-1 ,6— diazabicyclo[3.2.1]octane—2-carboxamide (28,5R)-N-[(1-methylazetidin-3—yl)oxy]-7—oxo(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane— 2—carboxamide )-N-{[5-(dimethylcarbamoyl)pyrrolidin-3—yl]oxy}oxo—6-(su|fooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide methyl (2S,5R)oxo-6—(sulfooxy)-1 ,6—diazabicyclo[3.2.1]oct—2— yl]carbonyl}amino)oxy]prolinate (2S,5R)-N-{[6-(dimethylcarbamoyl)piperidin-3—yl]oxy}oxo-6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)—N-[(1-methylpyrrolidinyl)methoxy]oxo—6-(sulfooxy)—1 ,6- diazabicyclo[3.2;1]octane—2-carboxamide 311311 (2 S,5R)—N-[(1 —acetylpyrrolidinyl)methoxy]oxo—6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2~carboxamide (2 S,5R)—N-[(1 —carbamoylpyrrolidinyl)methoxy]-7—oxo—6—(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (2 S,5R)oxo-N—[(1—suIfamoylpyrrolidin—2—yl)methoxy]—6-(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (2 S,5R)—N-[(1-carbamimidoylpyrrolidinyl)methoxy]—7—oxo-6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (28,5R)-N-[(1-methy|—1 zoI-3—yl)methoxy]-7—oxo-6—(sulfooxy)-1 ,6- 1O diazabicyclo[3.2.1]octane-Z-carboxamide (28,5R)-N—[(1-methyI-1H—imidazoI—Z-yl)methoxy]—7-oxo(sulfooxy)-1 ,6- diazabicyc|o[3.2.1]octane-2—carboxamide (28,5R)-N-[(1-methyI-4,5,6,7-tetrahydro-1H-4,7-methanoindazolyl)methoxy]oxo (sulfooxy)—1 ,6—diazabicyclo[3.2.1]octane-Z-carboxamide (28,5R)—N—[(1 ,8—dimethyl-4,5,6,7-tetrahydro-1H-4,7-epiminoindazoI—3-yl)methoxy]¢7—oxo— 6—(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—Z-carboxamide (28,5R)—N-(1H-benzimidazol—Z-ylmethoxy)—7—oxo—6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (28,5R)—N—(2,3-dihydro—1H-indoIylmethoxy)—7-oxo—6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide ' (2 S,5R)—N—[(2-methyl-1 H-imidazoI-4—yl)methoxy]-7—oxo—6—(sulfooxy)-1 ,6- diazabicyc|o[3.2.1]octane-2—carboxamide (28,5R)—N—[(1—methyl-1H-imidazoI—4-yl)methoxy]—7-oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-2—carboxamide (28,5R)—N—[(1-methyl-1H-imidazolyl)methoxy]—7-oxo(sulfooxy)-1 ,6- diazabicyc|o[3.2.1]octanecarboxamide )—N—[(2-amino-1 ,3-thiazoI-4—yl)methoxy]-7—oxo(su|fooxy)-1 ,6- diazabicyclo[3 .2 . 1 ]octa’ne-Z-carboxamide (28,5R)-N—(1 zoI—4-ylmethoxy)—7-oxo(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane carboxamide 312312 (2 S,5R)—7-oxo—6-(su|fooxy)-N-(1 ,3-thiazoI-4—ylmethoxy)-1 ,6-diazabicyclo[3.2.1]octane-Z- amide (28,5R)-N-[(1-methyl-1H—1 ,2,3—triazolyl)methoxy]—7—oxo—6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (2 S,5R)-N-(1 H-imidazoly|methoxy)—7-oxo(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane—Z— carboxamide )—N-[2-(1H—imidazolyl)ethoxy]—7-oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane- 2-carboxamide (28,5R)-N-[1—(1H-imidazo|—5—y|)ethoxy]oxo(suIfooxy)-1,6-diazabicyclo[3.2.1]octane- 1O oxamide (28,5R)—N—[(1methyl-1H—pyrrol—Z-yl)methoxy]—7-oxo-6~(sulfooxy)-1 ,6— diazabicyc|o[3.2.1]octanecarboxamide (2 S,5R)-N-(1 ,2-oxazol—3-ylmethoxy)oxo(su|fooxy)-1 zabicyclo[3.2.1]octane—Z— carboxamide (2 S,5R)oxo(sulfooxy)-N-(1 H-1 ,2,4-triazol-3—ylmethoxy)—1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (2 S,5R)-N—[(5—methylpyrazinyl)methoxy]-7—oxo(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octanecarboxamide (28,5R)-N-[(2-aminocyclopropyl)oxy]—7-oxo—6—(sulfooxy)-1,6-.diazabicyclo[3.2.1]octane—2- carboxamide (2S,5R)—N—(morpholin—2—yImethoxy)—7—oxo—6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane-Z- carboxamide (2S,5R)—N-[2—(azetidinyloxy)ethoxy]—7—oxo($ulfooxy)-1 ,6~diazabicyclo[3.2.1]octane- 2—carboxamide (2S,5R)—7—oxo—N-[2-(pyrrolidinyloxy)ethoxy](sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—Z-carboxamide (2S,5R)-7—oxo—N—[2-(piperidin-3—yloxy)ethoxy]-6—(su|fooxy)-1 ,6-diazabicyc|o[3.2.1]octane- 2—carboxamide or a deuterated compound of any such compound. 313313 Passage 10. A compound of formula (I) as defined in passage 2, wherein the nd is selected from the group consisting of: )-N-methy|—7-oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2-carbohydrazide (2 S,5R)—N-ethyI-7—oxo—6-(suIfooxy)—1 zabicyclo[3.2.1]octane—Z-carbohydrazide (2 S,5R)—7—oxo—N-(propanyl)-6—(sulfooxy)—1 ,6—diazabicyclo[3.2.1]octane-Z- carbohydrazide (2S,5R)-N,N-dimethyi-7—oxo(sulfooxy)—1,6-diazabicyclo[3.2.1]octane-Z- carbohydrazide (2S,5R)—N,N-diethyl—7-oxo(sulfooxy)—1 ,6-diazabicyc|o[3.2.1]octane-Z—carbohydrazide (2S,5R)oxo-N,N-di(propanyI)—6-(su|fooxy)-1,6—diazabicyclo[3.2.1]octane-Z- carbohydrazide (2 S,5R)-N—cyclopropyl-7—oxo—6-(sulfooxy)—1 ,6—diazabicyclo[3.2.1]octane-Z- carbohydrazide (2 S,5R)-N-cyclobutyl—7-oxo-6~(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane-2—Carbohydrazide (2 S,5R)—N-cyclopentyloxo-6—(sulfooxy)-1 zabicyclo[3.2.1]octane—2- carbohydrazide ‘ (28, 5R)—7—oxo—N-(piperidin-4—yl)-6—(suifooxy)-1 ,6-diazabicyclo[3.2. 1 ]octane-Z- carbohydrazide (2 S,5R)—7-0xo(sulfooxy)—N-(tetrahydro-2H—pyran-4—yl)-1 ,6-diazabicycio[3.2.1]octane— 2-carbohydrazide (2 S,5R)—7-oxo—6—(suifooxy)-N-(tetrahydro-2H—thiopyran-4—yl)-1 ,6- diazabicyclo[3.2.1]octane—2-carbohydrazide (28,5R)oxo-N—(piperidinyl)(suIfooxy)-1,6—diazabicyclo[3.2.1]octane—Z— carbohydrazide (2 S,5R)oxo-N-(pyrrolidinyl)—6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z- carbohydrazide 314314 (2 S,5R)—N—(1 ,1—dioxidotetrahydro-2 H-thiopyran-4—yl)oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane—2—carbohydrazide (2 S,5R)—N-acetyIoxo-6—(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2—carbohydrazide (2 S,5R)—7-oxo—N-propanoyl(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octanecarbohydrazide (2 S,5R)-N-(2-methy|propanoy|)-7—oxo(sulfooxy)-1 zabicyc|o[3.2.1]octane—2- carbohydrazide (2 S,5R)—N-acetyl-N'-methy|—7-oxo(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane—2— carbohyd razide (2 S,5R)—N-methy|—7-oxo-N-propanoyI(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2- carbohydrazide (2 S,5R)-N-methy|—N—(2-methylpropanoyl)—7-oxo(su|fooxy)-1 ,6- diazabicyclo[3.2.1]octane—2~carbohydrazide (2S,5R)-N-acetyl-N'—ethy|—7-oxo(su|fooxy)—1 zabicyclo[3.2.1]octane—2— carbohydrazide (2 S,5R)-N'-ethyloxo—N-propanoyl(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane-2— ydrazide (2S,5R)-N-(2,2-dimethylpropanoyl)oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—2— carbohydrazide (2S,5R)—N-butanoyloxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2-carbohydrazide (2S,5R)—N-(2-methy|butanoyI)-7—oxo(suIfooxy)-1 ,6—diazabicyclo[3.2.1]octane—2- carbohydrazide (2 S,5R)-N-[(dimethylamino)acetyl]oxo-6—(sulfooxy)-1 ,6-diazabicyc|o[3.2.1]octane-2— carbohydrazide (2 S,5R)oxo-6—(sulfooxy)—N-(4,4,v4-trifluoropropanoyl)-1 ,6—diazabicyclo[3.2.1]octane carbohydrazide (2S,5R)—N-(methoxyacetyl)oxo-6—(suIfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2— ydrazide (2 S,5R)—N—[(2R)-2—aminopropanoyl]—7—oxo—6-(sulfooxy)-1 ,6—diazabicyclo[3.2. 1 ]octane—2— carbohydrazide 315315 (2 S,5R)—N—[amino(phenyl)acetyl]oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2— carbohydrazide (2 S,5R)-N—(cyc|opropy|carbonyl)—7-oxo(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane carbohydrazide (2 S,5R)-N-(cyclobutylcarbonyI)oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1 ]octane carbohydrazide (2 S,5R)—N-[(2,2-dimethylcyclopropyl)carbonyl]oxo(sulfooxy)-1 ,6— diazabicyclo[3.2.1]octane—2~carbohydrazide (2 N-[(2-methylcyclopropyl)carbonyI]oxo-6—(sulfooxy)-1 .6- 1O diazabicyclo[3.2.1]octane—2-carbohydrazide (2 N-[(2,2-diﬂuorocyclopr0pyl)carbonyl]—7-oxo-6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2-carbohydrazide (2 S,5R)—N-[(2-fluorocyclopropyl)carbonyl]—7-oxo(sulfooxy)-1 ,6-‘ diazabicyclo[3.2.1]octane-2—carbohydrazide (2 S,5R)-N—(cyclopentylcarbonyl)oxo(sulfooxy)—1 ,6-diazabicyc|o[3.2.1]octane—Z— carbohydrazide (28,5R)-N-(cyclohexylcarbonyl)—7-oxo(sulfooxy)-1,6—diazabicyclo[3.2.1]octane carbohyd razide (28,5R)-N-{[(2R)aminocyclopentyl]carbonyl}oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octane—2-carbohydrazide (2 S,5R)oxo—N—(pyrrolidin—2-ylcarbonyl)—6-(sulfooxy)-1 zabicyclo[3.2.1]octane—2- carbohydrazide (2 S,5R)—7-oxo-N-(pyrrolidin—3-ylcarbonyl)—6—(sulfooxy)-1 ,6—diazabicyclo[3.2,1]octane carbohydrazide (28,5R)-7—oxo-N—(piperidinylcarbonyl)(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-Z— carbohydrazide (28,5R)—N-methyl—7—oxo-N—(pyrrolidin-2—ylcarbonyl)—6-(sulfooxy)—1 ,6- diazabicyc|o[3.2.1]octane-Z-carbohydrazide (2S,5R)—7—oxo—N-(piperidin—3-ylcarbonyl)(sulfooxy)-1 ,6-diazabicyc|o[3.2.1]octane-2— carbohydrazide 316316 (2 S,5R)-7—oxo-N-(piperidin-4—ylcarbonyl)—6-(sulfooxy)—1 ,6-diazabicyclo[3.2.1]octane carbohydrazide (28,5R)—7-oxo-6—(su|fooxy)-N-(tetrahydro-2H—pyra carbonyl)-1 ,6- diazabicyclo[3.2.1]octane—2-carbohydrazide (28,5R)—N—[(1—methylpyrrolidin-2—yl)carbonyl]—7-oxo—6-(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane~2—carbohydrazide (2 S,5R)—N—[(1 -methylpiperidinyl)carbonyI]oxo-6—(su|fooxy)-1 ,6- diazabicyclo[3.2.1]octane—2-carbohydrazide (2 S,5R)oxo-6—(su|fooxy)—N-(tetrahydro-2 H—thiopyran-4—ylcarbonyl)-1 ,6— diazabicyclo[3.2.1]octane—2—carbohydrazide (28,5R)—N-[(1 ,1—dioxidotetrahydro-2H—thiopyrany|)carbonyI]oxo-6—(suIfooxy)—1 ,6- diazabicyclo[3.2.1]octane—Z-carbohydrazide (2S,5R)—7-oxo-N—(pyrrolidinylacetyl)—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane—2- carbohydrazide (28,5R)—7—oxo-N-(pyrrolidin-3—ylacetyl)(suIfooxy)—1,6-diazabicyclo[3.2.1]octane-2— yd razide (28,5R)—N-[(1-methy|pyrro|idinyl)acety|]oxo(sulfooxy)-1 ,6- icyclo[3.2.1]octane—ZLCarbohydrazide (2 S,5R)—N-(cyclopropylacetyl)oxo—6-(sulfooxy)-_ 1 ,6-diazabicyclo[3.2.1]octane carbohydrazide (28,5R)-7—oxo-N-(piperidinylacetyI)-6—(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane-Z- carbohydrazide (28,5R)—N-[(1-methylpiperidinyl)acetyl]-7—oxo—6—(suIfooxy)-1 ,6- diazabicyclo[3.2.1]octane-Z—carbohydrazide (28,5R)-7—oxo—N—(piperidin-3—ylacetyl)~6-(sulfooxy)-1 zabicyc|o[3.2.1]octane-Z- carbohyd razide ' (28,5R)—7—oxo-N—(piperidin—4—ylacetyl)—6—(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z— carbohydrazide (2 S,5R)—N-[(1 —methy|piperidin—4—yl)acetyl]—7-oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane—Z-carbohydrazide' 317317 (2S,5R)—7-oxo-N-(pyrrolidinylacetyl)(sulfooxy)-1,6—diazabicyclo[3.2.1]octane—Z- ydrazide (2S,5R)-7—oxo-N-(piperazinylacetyl)(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z- carbohydrazide (ZS,5R)-N-(morpholinylacety|)oxo-6—(sulfooxy)-1 ,6-diazabicyc|o[3.2.1]octane-Z- carbohydrazide (2 S,5R)—7—oxo—N—(phenylcarbonyl)—6—(su|fooxy)-1 ,6—diazabicyclo[3.2.1]octane—Z- carbohydrazide (2 S,5R)—N-(naphthalen-Z-ylcarbonyl)oxo(sulfooxy)-1 zabicyclo[3.2.1]octane-Z— ' carbohydrazide (2 N-methyloxo—N—(phenylcarbonyl)-6—(sulfooxy)—1 ,6—diazabicyclo[3.2.1]octane— 2—carbohyd razide (2 S,5R)—N-ethyloxo-N—(phenylcarbonyl)-6—(sulfooxy)—1 ,6-diazabicyc|o[3.2.1]octane—2— carbohydrazide (2S,5R)—7-oxo-N—(phenylacetyI)(su|fooxy)-1 zabicyclo[3.2.1]octane—Z- carbohydrazide (2 S,5R)-N—(naphthaleny1acetyI)—7—oxo—6—(sulfooxy)-1 ,6-diazabicyclo[3.2. 1 ]octane-Z- carbohydrazide (2 S,5R)-N-methyIoxo-N-(phenylacetyl)—6-(sulfooxy)—1 ,6—diazabicyclo[3.2.1]octane-Z- carbdhydrazide (2S,5R)-N-ethyloxo—N-(phenylacetyl)-6—(sulfooxy)—1 ,6-diazabicyclo[3.2.1]octane-Z- . carbohydrazide (2S,5R)—7-oxo-N-(pyridin—2—ylcarbony|)—6-(su|fooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z- carbohydrazide (28,5R)—7-oxo-N-(pyridinylcarbonyI)(sulfooxy)—1 ,6-diazabicyclo[3.2.1]octane—Z- carbohydrazide (2S,5R)-7—oxo-N-(pyridinylcarbonyl)—6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane carbohydrazide (28,5R)-7—oxo-6—(sulfooxy)-N.-(thiophen~3~ylcarbonyl)-1 ,6—diazabicyclo[3.2.1]octane—Z- ‘30 carbohydrazide 318318 (2S,5R)—N-(furan—3-ylcarbonyl)oxo—6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2- carbohydrazide (2S,5R)-7—oxo-6—(sulfooxy)-N—(thiophenylcarbony|)—1,6-diazabicyclo[3.2.1]octane—2— carbohydrazide (2 S,5R)—N—(furan-2—ylcarbonyl)—7-oxo—6-(suIfooxy)—1 ,6-diazabicyclo[3.2.1]octane—2- carbohydrazide (2S,5R)-N-methy|—7-oxo—N-(pyridin-3—ylcarbonyl)(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide (2 S,5R)-7—oxo-N—(1 H-pyrrol—2-ylacetyl)~6-(sulfooxy)—1 zabicyclo[3.2.1]octane~2— carbohydrazide (2 S,5R)—7—oxo(sulfooxy)-N-(thiophenylacetyl)-1 ,6-diazabicyclo[3.2.1]octane—Z- carbohydrazide (28,5R)-N-[(2-amino-1 ,3—thiazolyl)carbony|]oxo—6—(su|fooxy)—1 ,6— diazabicyclo[3.2.1]octane—2—carbohydrazide_ (2 S,5R)-N-(furanylacetyl)—7-oxo(sulfooxy)-1 ,6—diazabicyclo[3.2.1]octane—2- carbohydrazide )-7—oxo—N-(pyridinylacetyl)(sulfooxy)—1 ,6-diazabicyclo[3.2.1]octane—2— carbohyd razide (2 S,5R)oxo—N—(pyridinylacetyl)(sulfooxy)—1 ,6—diazabicyclo[3.2.1]octane-Z- carbohydrazide (28,5R)oxo-N-(pyridinylacetyI)(suIfooxy)-1 ,6—diazabicyclo[3.2.1]octane—2- ydrazide (2 S,5R)-N—[(2—amino—1 ,3—thiazoI—4-yl)acetyl]oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (28,5R)—N—[(2-amino~1 ,3-thiazol-4—yl)acetyI]-N—methyl—7-oxo—6-(sulfooxy)-1 .6- diazabicyc|o[3.2.1]octane—Z-carbohydrazide ' (2 S,5R)—N-methyl-7—oxo-N-(pyridinylacetyl)(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-Z—carbohydrazide (2 S,5R)oxo(sulfooxy)-N—(trifluoroacetyl)—1 ,6-diazabicyclo[3.2.1]octane—2- carbohyd razide 319319 (2 S,5R)—N'-(methy|suIfonyI)oxo(su|fooxy)-1 ,6—diazabicyclo[3.2.1]octane-2— carbohydrazide 2—{[(ZS,5R)—7-oxo(su|fooxy)—1 zabicyclo[3.2.1]oct yl]carbonyl}hydrazinecarboxamide 2—{[(28,5R)—7-oxo-6—(sulfooxy)-1 ,6—diazabicyclo[3.2.1]oct yl]carbonyl}hydrazinesulfonamide (ZS,5R)-7—oxo-N'-phenyI(sulfooxy)—1,6—diazabicyclo[3.2.1]octane—Z—carbohydrazide (28,5R)—N-methyl-7—oxo-N—phenyl—6-(su|fooxy)—1 ,6—diazabicyclo[3.2.1]octane carbohydrazide 1O (28,5R)—7-oxo-N—(pyridi’n—3-yI)—6—(sulfooxy)-1 zabicyc|o[3.2.1]octane carbohyd razide (ZS,5R)-N-methyloxo-N-(pyridinyl)—6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—Z- carbohydrazide (28,5R)—7—oxo-N-(piperidin—1-yl)(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane-Z- _15 carboxamide (28,5R)—7~oxo-N-(pyrrolidinyl)(sulfooxy)-1 zabicyclo[3.2.1]octane-2— carboxamide (ZS,5R)-N-(morpholin—4-yl)—7-oxo-6—(sulfooxy)-1 ,6—diazabicyc|o[3.2.1]octane-Z- carboxamide ' (2S,5R)-7—oxo-N—(piperazin-1—yl)(sulfooxy)-1 ,6-diazabicyc|o[3.2.1]octane-Z— carboxamide (2S,5R)oxo-6—(sulfooxy)—N-(thiomorpholinyl)-1,6—diazabicyclo[3.2.1]octane—2— carboxamide (28,5R)—N-(1 xidothiomorpholinyI)—7-oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane—Z-carboxamide (2S,5R)-7—oxo-N—(2-oxopiperidin-1—y|)—6-(su|fooxy)-1 ,6—diazabicyclo[3.2.1]octane-2— carboxamide (ZS,5R)—7-oxo-N-(3-oxomofpholinyI)(su|fooxy)-1 ,6-diazabicyc|o[3.2.1]octane—Z- carboxamide 320320 (28, 5R)—7-oxo-N-(2-oxopiperazin-1 —y|)-6—(sulfooxy)-1 zabicyclo[3.2.1]octane carboxamide (28, 5R)—7—oxo(sulfooxy)—N-(tetrahyd ropyrimidin-1 (2 —1 ,6- diazabicyclo[3.2.1]octane—2—carboxamide (28, 5R)—7~oxo—N-(2-oxotetrahydropyrimidin-1 (2 (sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane—2-carboxamide (28, 5R)-N—(3-aminopiperidin-1 -yl)-7~oxo—6-(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2- carboxamide (28,5R)-N-[(2-aminocyclopropyl)carbonyl]—7—oxo—6—(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octane-2—carbohydrazide (28,5R)-N-[(2-aminocyclopropy|)carbony|]-N'-methy|—7-oxo-6—(suIfooxy)-1 ,6- diaZabicyclo[3.2.1]octane-Z—carbohydrazide (28, 5R)-N-(azetidinylcarbonyI)oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane carbohydrazide (28,5R)-N-(azetidinylcarbonyl)oxo—6—(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane carbohydrazide (28, 5R)-N-[(28)—2-aminopropanoyl]—7-oxo(sulfooxy)-1 ,6-diazabicyclo[3.2.1]octane—2- carbohydrazide ‘ (28, 5R)—N—[(2 S)—2-aminopropanoyI]-N—methyIoxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (2 N—[3-(dimethylamino)propanoyl]~7—oxo(sulfooxy)—1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (2 8,5R)-N—[(3,3-difluorocyclobutyl)carbonyl]oxo—6-(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane—2-carbohydra‘zide (2 8.5R)-N-[(3-aminocyclobutyl)carbonyl]oxo-6—(su|fooxy)-1 ,6- diazabicyclo[3.2.1]octanecarbohydrazide (28,5R)-N-{[3-(methylamino)cyclobljtyl]carbonyl}—7-oxo—6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane~2-carbohydrazide (2 8,5R)-N-{[3-(dimethylamino)cyc|obutyl]carbonyI}—7-oxo-6—(sulfooxy)-1 ,6- diazabicyclo[3.2.1]octane-Z-carbohydrazide, 321321 'or a deuterated compound of any such compound.

Passage 11. A method of treating a bacterial infection comprising administering to a mammal in need thereof an antibacterially-effective amount of a compound as d in any one of es 1-10.

Passage 12. A pharmaceutical composition containing as an active ingredient, at least one compound as recited in any one of passages 1-10. e 13. A pharmaceutical composition containing, as an active ingredient, (i) at least one nd as recited in any one of passages 1-10 and (ii) at least one B—lactam antibiotic, at least one salt of a B—lactam antibiotic, at least one hydrate of a B—lactam antibiotic or at least one prodrug of a B—lactam antibiotic.

Passage 14. A pharmaceutical composition containing, as an active ingredient, (i) at least one nd as recited in any one of passages 1-10 and (ii) at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic.

Passage 15. A pharmaceutical composition suitable for the treatment of ial ions in mammals, comprising a pharmaceutical composition as recited in passage 13 or passage 14 and a pharmaceutically acceptable carrier.

Passage 16. A method of treating bacterial infection, comprising stering to a mammal in need thereof a ation of (i) an effective amount of a compound as recited in any one of passages 1—10 and (ii) an effective amount of at least one B—lactam antibiotic, at least one salt of a B—lactam antibiotic, at 'least one hydrate of a B—lactam antibiotic or at least one prodrug of a B—lactam antibiotic. 322322 Passage 17. A method of treating bacterial infection, comprising administering to a mammal in need f a combination of (i) an effective amount of a compound as recited in any one of passages 1-10 and (ii) an ive amount of at least one antibiotic, at least one salt' of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic.

Passage 18. A method for the treatment of bacterial infection, by inhibiting bacterial B—lactamases, comprising administering to a mammal in need thereof a pharmaceutical composition as d in any one of passages 12-15.

Passage 19. A method as recited in passage 18, wherein the pharmaceutical composition is administered separately, aneously or spread over time, 1O Passage 20. A method or a pharmaceutical ition as recited in passage 13 or passage 16, wherein a ratio of the weight of (i) the compound of formula (I) to the weight of (ii) at least one B—lactam antibiotic, at least one salt of a B—lactam antibiotic, at least one hydrate of a B—lactam otic or at least one prodrug of a B—lactam antibiotic, is in the range of 1:20 to 20:1. e 21. A method or a pharmaceutical composition as recited in passage 14 or passage 17, wherein a ratio of the weight of (i) the compound of formula (l) to the weight of (ii) at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic, is in the range of 1:20 to 20:1.

Passage 22. A molecular complex comprising a compound as recited in any one of es 1- and at least one solvent.

Passage 23. A lar complex as recited in passage 22, wherein the solvent comprises water.

Passage 24. A process for preparing a compound recited in passage 1, wherein M = H, and wherein the s comprises: 323323 [A] Reacting substituted hydroxylamine (V) with an acid (VI) in presence ofa coupling agent selected from the group consisting of EDCl, HOBT-DCC and PyBop to provide an intermediate of a (Vll); [B] Removing the benzyl protecting group of the intermediate (Vll) with a source of hydrogen in presence of‘Pd catalyst to e debenzylated product (Vlll); otNJ‘zh,I x/L—N 0 OH [C] Contacting compound (Vlll) with a sulfating agent in the ce of solvent to obtain compound of formula (la) F5 1 ON)i, Passage 25. A process for preparing a compound recited in passage 2, wherein M = H, and wherein the process comprises: 324324 [A] Reacting substituted hydrazine (Va) with an acid (VI) in presence of a coupling agent selected from the group consisting of EDCl or HOBT-DCC and PyBop to provide an intermediate of formula (Vlla), Va Vl Vl la [B] Removing the benzyl protecting group of the intermediate (Vlla) with a source of hydrogen in presence of Pd catalyst to provide the debenzylated product (Vllla), F320 R3_ N\N/lI, j N\ 0 OH Vllla [C] Contacting compound (Vllla) with a sulfating agent in the presence of solvent to obtain compound of formula (lb) Passage 26. A method or a ceutical composition as recited in any one of passages 13, 16 and 20, wherein the at least one B—lactam antibiotic, ceutically acceptable salt of a B—lactam antibiotic, hydrate of a am antibiotic or g of a B—lactam antibiotic is 325325 selected from the group consisting of amoxicillin, ampicillin, azlocillin, mezlocillin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, inam, methicillin, ciclacillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, cephalothin, cephaloridine, or, cefadroxil, cefamandole, cefazolin, cephalexin, dine, ceftizoxime, cefoxitin, ‘cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone, cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefozopran, cefepime, cefuzonam, cefpimizole, cefclidin‘, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet l, cefcapene pivoxil, cefditoren pivoxil, cefuroxime, xime axetil, loracarbacef, latamoxef, CXA—101, imipenem, meropenem, em, panipenem, ertapenem, doripenem, aztreonam, carumonam, pharmaceutically acceptable salts of said B~lactam otics, hydrates of said am antibiotics, and prodrugs of said B—lactam antibiotics.

Passage 27. A method or a pharmaceutical composition as recited in any one of passages 14, 17 and 21, n the at least one antibiotic, pharmaceutically acceptable salt of an antibiotic, hydrate of an antibiotic or g of an antibiotic is selected from the group consisting of aminoglycosides, quinolones, tetracyclines, glycylcyclines, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramin, oxazolidinones, polymyxins. 326326 INVE

Claims

CLAIM :

1. A compound of formula (I): wherein: M is hydrogen or a ceutically acceptable salt-forming cation; Y is 0R1; R1 is a l selected from the group consisting of: (1) CM cycloalkyl which is fused with a 05.7 membered saturated heterocycle containing N as a heteroatom; (2) Bridged bicyclic ring system having ally one N as a heteroatom; and (3) CW membered saturated heterocycles fused to a CM membered ring system through a common carbon atom to form a spiro system containing one heteroatom selected from O or N and the free N atom present in either ring may be optionally substituted with a group selected from: straight chain or branched C1-C6 alkyl; straight chain or branched 01—05 alkyl substituted with at least one halogen or y group; amino; amino substituted with at least one C1-Ce alkyl group; halogen; hydroxy; carboxy; alkoxycarbonyl; triﬂuoromethoxy; alkylamine; alkylamine tuted with at least one C1-Cs alkyl group; carboxamide; thiocarboxamide; sulfonic acid; e; acylamino; sulfonylamino; sulfonamide; urea; ea; sulfonylurea; hydroxamic acid; acyl; triﬂuoromethyl carbonyl; cyano; amidino; guanidine; aryloxy; heterocyclyl; heteroaryl; heterocyclyloxy; and trialkylammonium, or a deuterated compound of any such compound. ation] mbs 327327

2. A compound as recited in claim 1, wherein the radical R1 is substituted, wherein the substituent is independently selected from the following: amino, substituted amino, cyano, amidino, guanidino, and, heterocyclylalkyloxy.

3. A compound as recited in claim 1 or claim 2, which is selected from the following group of nds: 0 o o L WI, WI, HN7%) N N N O/l/P' O)” HN b803H ”N b803H O). b303H Effl, N bSO3H 0 o HN o bSO3H and pharmaceutically acceptable salts of such compounds, and deuterated compounds of such compounds and salts.

4. A compound of a (I) as deﬁned in claim 1, wherein the compound is selected from the group consisting of: (2S.5R)—N—(3-azabicyclo[3.1 .0]hexyloxy)oxo—6—(su|fooxy)-1 ,6- diazabicyclo[3.2. 1 ]octanecarboxamide (2S,5R)-N-(decahydroquinolinyloxy)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane- 2-carboxamide (2S,5R)-N-(octahydrocyclopenta[c]pyrrolyloxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (2S,5R)-N-(bicyclo[2.2.1]heptyloxy)oxo(sulfooxy)-1,6-diazabicyclo[3.2.1]octane- oxamide (2S,5R)-N-[(7,7-dimethylbicyclo[2.2.1]heptyl)oxy]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (2S,5R)-N-(1-azabicyclo[2.2.2]octyloxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (2S,5R)-N-(8-azabicyclo[3.2.1]octyloxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (2S,5R)-N-[(8-methylazabicyclo[3.2.1]octyl)oxy]oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (2S,5R)-N-(7-azaspiro[4.5]decyloxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide (2S,5R)-N-(7-oxaspiro[4.5]decyloxy)oxo(sulfooxy)-1,6- diazabicyclo[3.2.1]octanecarboxamide or a deuterated compound of any such compound.

5. Use of a compound as recited in any one of claims 1 to 4, or a pharmaceutically acceptable salt of any such compound, or a deuterated nd of any such compound or salt, for the manufacture of a medicament ive in the treatment of a ial infection.

6. A pharmaceutical composition containing as an active ingredient, at least one nd as recited in any one of claims 1 to 4.

7. Use of a compound as recited in any one of claims 1 to 4, or a pharmaceutically acceptable salt of any such compound, or a deuterated compound of any such compound or salt, and at least one β−lactam antibiotic, at least one salt of a β−lactam 329329 antibiotic, at least one hydrate of a tam antibiotic or at least one prodrug of a B—lactam antibiotic for the manufacture of a medicament effective in the treatment of a ial infection.

8. Use of a nd as recited in any one of claims 1 to 4, or a pharmaceutically acceptable salt of any such compound, or a deuterated compound of any such compound or salt, and at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic for the manufacture of a medicament effective in the treatment of a bacterial infection.

9. A molecular x comprising a nd as recited in any one of claims 1 to 4 and at least one solvent.

10. A process for preparing a compound recited in any one of claims 1 to 4, wherein M = H, and wherein the process ses: [A] Reacting substituted hydroxylamine (V) with an acid (VI) in presence of a coupling agent selected from the group consisting of EDCI, HOBT—DCC and PyBop to provide an intermediate of formula (VII); R1 O E1 .4on (1N JIM. N —» H q [B] Removing the benzyl protecting group of the intermediate (VII) with a source of hydrogen in presence of Pd catalyst to provide debenzylated product (VIII); [Annotation] mbs 330330 VIII [C] Contacting compound (VIII) with a sulfating agent in the presence of solvent to obtain compound of formula (la)

11. A compound of formula (I): wherein: M is hydrogen or a pharmaceutically acceptable salt-forming ; Y is NR2R3; R2 is hydrogen; R3 is a radical selected from any of following groups consisting of: CF3CO-, CH3SOT. and NH2802—; or a deuterated nd of any such compound.

12.A compound as recited in claim 11, which is selected from the ing group of compounds: 331331 and pharmaceutically acceptable salts of such compounds, and deuterated compounds of such compounds and salts.

13. A compound of formula (I) as deﬁned in claim 11, wherein the compound is selected from the group consisting of: (2S,5R)—7-oxo—6—(sulfooxy)-N-(trifluoroacetyl)-1 zabicyclo[3.2.1]octane carbohydrazide 2-{[(2$,5R)—7—oxo—6—(sulfooxy)—1 ,6-diazabicyclo[3.2.1]oct-2— yl]carbonyl}hydrazinesulfonamide or a deuterated compound of any such compound.

14. Use of a nd as recited in any one of claims 11 to 13, or a pharmaceutically acceptable salt of any such compound, or a deuterated nd of any such compound or salt for the manufacture of a medicament effective in the treatment of a bacterial infection.

15. A pharmaceutical ition containing as an active ingredient, at least one compound as recited in any one of claims 11 to 13.

16. Use of a compound as recited in any one of claims 11 to 13, or a pharmaceutically acceptable salt of any such compound, or a deuterated nd of any such compound or salt and at least one B—lactam antibiotic, at least one salt of a p—lactam antibiotic, at least one hydrate of a am antibiotic or at least one prodrug of a B—lactam antibiotic for the manufacture of a medicament effective in the treatment of a bacterial infection. 332332

17. Use of a compound as recited in any one of claims 11 to 13, or a ceutically acceptable salt of any such compound, or a deuterated compound of any such nd or salt and at least one antibiotic, at least one salt of an antibiotic, at least one hydrate of an antibiotic or at least one prodrug of an antibiotic for the manufacture of a medicament effective in the treatment of a bacterial infection, .

18. A molecular complex comprising a compound as recited in any one of claims 11 to 13 and at least one solvent.

19. A process for preparing a compound recited in any one of claims 11 to 13, wherein M = H, and wherein the process comprises: [A] Reacting substituted hydrazine (Va) with an acid (VI) in presence of a coupling agent selected from the group consisting of EDCI or HOBT—DCC and PyBop to provide an ediate of formula (Vlla), I32 . R3-N\NJL,' R3_N‘NHZ + N _. H q 0 an O} an Va VI Vlla [B] Removing the benzyl protecting group of the intermediate (Vlla) with a source of hydrogen in presence of Pd catalyst to e the debenzylated t (Vllla), $2 0 R3-N\qu’I,, 0’ bH Vllla [Annotation] mbs 333333 [C] Contacting compound (Vllla) with a sulfating agent in the presence of solvent to obtain compound of formula (lb) R2 0 R -ﬁ~NJL/lq3 0‘ bSO3M Fedora Pharmaceuticals Inc. By the Attomeys for the ant SPRUSON & FERGUSON #2?» Per: