CARBAPENEM COMPOUNDS

Field

Described herein are carbapenem compounds, their stereoisomers, pharmaceutically acceptable salts or N-oxides thereof, which may be useful for the treatment of bacterial infections, particularly drug-resistant bacterial infections. Also described herein are the processes for the preparation of compounds, the pharmaceutical compositions of these compounds and their use.in the treatment of bacterial infection.

Background

Antimicrobial resistance is the most important crisis in the antibacterial therapy. One of the mechanisms of resistance development is due to enzymes, which deactivate certain class of antibiotics by hydrolysis, e.g. β-lactam ring of β-lactam antibiotics. In the mid 1980's, it was found that the enzymes which are responsible for the deactivation of the β-lactams are β- lactamases, particularly Extended Spectrum β-Lactamase (ESBL). ESBL is produced mainly by Enterobacteriaceae group (Chaudhary et al., Indian Journal of Medical Microbiology, 2004, 22(2), 75-80, Extended Spectrum β-Lactamases (ESBL) - An Emerging Threat to Clinical Therapeutics).

The risk factors involved in the expression of ESBL are increased length of

hospitalization or ICU stay, increased severity of illness, use of a central venous or arterial catheter or urinary catheter, ventilatory support, hemodialysis, emergency abdorninal surgery, gastrostomy orjejunostomy, gut colonization, prior acLtninistration of antibiotics, particularly of oxyimino^-lactams (Falagas et al., Journal of Antimicrobial Chemotherapy, 2007 , 60, 1124- 1130, Risk factors of carbapenem-resistant Klebsiella pneumoniae infections: a matched case— control study).

The antibiotics whic are used as a last resort because of their broad spectrum of antimicrobial activity are carbapenems. Carbapenems such as Imipenem (US Pat. No. 41 4047 A), Meropenem (European Pat No. EP0126587 B 1), Ertapenem (European Pat No. EP0579826 Bl) and Doripenem (European Pat. No. EP0528678 Bl) are ultrabroad spectrum injectable antibiotics. These antibiotics give rise to cell death by bmding to penicillin-binding proteins (PBPs) and inhibiting cell wall biosynthesis. The emergence of carbapenemases belonging to class A and class D β-lactamases threatens their clinical utility.

It has been reported that the presence of a hydroxyethyl side chain in carbapenems provides stability to these compounds. (Surnita, Y et al., Journal of Antibiotics, 1995, 48(2), 188- 190).

Sunagawa et al., Journal of Antibiotics, 1997, 50(7), 621-627, discloses carbapenem compounds having antimicrobial activity.

Carbapenem compounds with potency against carbapenem-resistant gram negative bacteria have not been reported. Therefore, the development of a novel carbapenem compound with broad antibacterial spectrum, preferably a compound possessing potent activity against resistant bacteria which produce β-lactamase is desirable.

Still there remains a huge unmet medical need for new antimicrobial agents due to the emerging bacterial resistance over the current therapies.

Objective

The objective of the present invention is to provide carbapenem compounds, their stereoisomers, pharm ceutically acceptable salts or N-oxides thereof.

Yet another objective of the present invention is to provide processes for the preparation of Carbapenem compounds and pharmaceutical compositions containing these compounds.

A further objective of the present invention is to provide a method for preventing or treating bacterial infection and to provide carbapenem compounds as broad spectrum antibacterial agents.

Summary

The present invention relates to novel carbapenems. In particular, the present invention relates to a compound of formula ((I), (la) or (lb), or a stereoisomer, internal salt, N-oxide, or ^• pharmaceutically acceptable salt thereof. The compounds of formula (I), (la) or (lb), or a stereoisomer, internal salt, N-oxide, or pharmaceutically acceptable salt thereof can be useful in the treatment of bacterial infections. The present invention relates to compounds of formula (I)

or a stereoisomer, internal salt, N-oxide, prodrug, or pharmaceutically acceptable salt thereof: wherein:

A represents -N °R or -O ^z ;

Z represents -H or -C¾;

X represents -S- or -C¾-;

R* represents isoxazolyl;

R° is hydrogen or Ci-salkyl which is optionally substituted with one or two substituents selected from halogen, hydroxyl, cyano, carbamoyl, -SO ₂ NH2 and Ci^alkoxy;

R is:

. 1) -(CH ₂ )„C(=0)R ² , '

2) -(CH ₂ ) _n C(=S)R ² ,

3) -(CHzJnSOiR ² ,

4) -C _h alky! optionally substituted with -Cs^cycloalk l, or 5) -CH(=NH), or

R and R° together with the N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected fromN; O and S;

n is an integer selected from 0, 1, 2, 3, 4, 5 and 6;

R ¹ is:

1 ) . -CCHa)o*nAi C,

^■ 2) ^(CH ₂ ) ₀ .^-HetC, ^■ ,

3) ^CH ₂ ),- ₆ H(C=NH) H ₂ , or

.4) C ₂ - ₆ aminoalkyl optionally substituted with · ^{' *} a) -C(=0)Ci- ₆ alkoxy^

b) -C(=0)-pyn lidinyl substituted with -NR R ^y ,

cj -CR ^* =NR ^X , or

d) -COO-phenyl;

R ² is:

1) H,

2) Ci_ ₆ lk l optionally substituted with 1, 2 or 3 substitutents independently selected from halogen, -OH, -CN,

C _3-8 cycl6alkyl, -NR"R ^b , d-ealkoxy,

-COOCi-ealkyl, -S0 ₂ C _1-6 alkyl, -S(=0)C,^haloalkyl, -SCHF ₂ , Het A, -

AryA, -S-AryA, azetidine and azetidinone optionally substituted with Ci shydroxyalkyl,

3) C ₃ .gcycloalkyl substituted with Ci-ehaloalkyl or -NR ^x R ^y

4) optionally substituted with -COOR",

5) -C(=0)NR ^* R ^y ,

6) -C(=0)C _w alkoxy,

7) -NR ^* R ^y ,

8) -OH,

9) -COOH,

10) Ci^alkoxy,

11) Ci^haloalkyl,

12) Ci-shaloalkoxy,

13) AryA, or

14) HetA;

R is -COQ- or -COOR ⁵ ;

R ⁵ is hydrogen, a carboxylic acid protecting group or an ester prodrug moiety; AryA is 1) a substituted or unsubstituted 5- or 6-membered aromatic ring with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, or

2) a substituted or unsubstituted 9r or 10-membered bicyclic aromatic ring with 1, 2, 3, 4, 5 or 6 heteroatom ring atoms independently selected from N; 0 and S;

^■ HetA is a substituted or unsubstituted 5- to 10-membered saturated ring with 1 , 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, wherein any S atom in the ring is optionally oxidized;

AryC is . 1) a substituted or unsubstituted 5- or 6-membered aromatic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from N, O and S _s wherein the N atom is optionally quaiernized withf-CH _3l or

2) a substituted or unsubstituted 7- to 10-membered bicyclic aromatic ^' ring with 0, 1, 2 or 3 heteroatom ring atoms selected from N, S, and O;

HetC is a substituted or unsubstituted 4- to 8-merabered saturated ring with 1 or 2 heteroatom ring atoms selected from N _a O or S; .

R ^a is hydrogen, Q . ₆ alkyl, C ₃ . ₈ cycloalky 1, -CR"(=NR ^X ), -C(=NR ^X )N(R ^X ) _2>

- ;H ₂ C(=0)N(R ^x ) _2j -iCH ₂ ),-s OR* or -SOiCwalk l; ^'

R ^b is hydrogen or Ci galle I;

. R ^c is

1) H,

2) ^i^alkyl opu ^" onaUy subsn^ted with -NR ^b R ^j ₅ -C or -0¾

3) .

4) -(CH ₂ ),. ₃ C(=0) HCH ₂ CH ₂ OH,

5) ^CH ₂ ) _1-3 C(=0)NHOCH ₃ ,

6) -{CH ₂ ) ₁ .3C(=0)NHOBn ₎

7) -Ci-salkoxy,

8) pyridinyl,

9) ' -(CH io-pyrrolidinyl optionally substituted with -C(=0)NR ^x R ^y ,

10) tetrahydro-2H-pyran-4-yl, with NR ^x R ^y ,

13) -C(=Nti)-pynoUdin- 1 -yl optionally substituted with NR ^x R ^y ,

14) -{CH )].3-pyranyl optionally substituted with 1 or 2 substituents selected from oxo and methoxy,

15) -{CH ₂ )i-3-pyridinyl optionally substituted with one or more groups ^■ selected from -CH ₃ , -OH, and oxo,

16) -pheny]^(^)-pynolidinyl- R ^x R ^y .

17) - -phenyl-Ci Dy-piperazinyl, or

18) -phenyl-{CH ₂ )i.3- NR ^I R ⁵ '; R ^d is hydrogen, or C1. ₃ cyanoa.kyl, or

R ^c and R ^d are taken together, with the N to which they are attached, to form a substituted or unsubstituted 4- to 12-roembered heterocyclic ring or ring system with 0, 1, or 2 additional heteroatom ring atoms independently selected from N, O, and S, wherein the rings in the heterocyclic ring system can be bridged, ^' fused, spiro- linked or any combination of two thereof; wherein any nitrogen ring atom of the heterocyclic ring or ring system is Optionally quadricovalent; and wherein the heterocyclic ring or ring system is optionally substituted with 1, 2, 3 or 4 substituents independently selected from

1) -<CH2)o-3halogen,

2) 0X0,

3) =NH, .

4) -{CH^OH,

5) -Ci-salkyl optionally substituted with halogen, -CN and -OH,

6) -OCi-ealkyl,

7) -CH ₂ CH(OH)CH ₂ NH ₂ ,

8) -CH ₂ CH(F)CH ₂ NH ₂ ,

9). -C(=0)OH,

10) -{CH ₂ )o-3N ^b R ^j optionally substituted with 1 or 2 of-CH ₃ . -NH ₂ or halogen,

Π) -NHCH ₂ CN,

12) - HCH=NH,

13) - HCCO)^,

14) -NHC(=0)CH ₂ NHC(= H)NH ₂ ,

15), -C(= H)NH _2l

16) optionally substituted. with -OH,

17) . . - _T (CH ₂ )o-2C(=0)(CH ₂ )o _-2 NR ^h R ^j . optionally substituted with -NH ₂ or -OH,

18) -(CH ₂ )o _-2 C(=0)CH( H ₂ )(CH ₂ ) _0-2 OH ₁

19) -C(=0)NH(CH ₂ )i _-3 NH ₂ optionally substituted with -OH,

_. 2Ό) -C(=0)(CH ₂ )i _-3 H ₂ optionally substituted with-NH ₂ ,

21) -C(«)(CH ₂ )«NHC(= H)NH ₂ , '

22) -(CH ₂ )< _M NHCH ₂ CH ₂ NR ^h R ^j ,

23) -(CH ₂ ) _M NHC(= H)NH ₂ ,

24) -iC¾) _0- iNH(CH ₂ ) _! nC(=O)(CH ₂ ) _M NR ^h R ⁱ ,

25) ΟΗ ₂ ) ₀ .ιΝΗ80 ₂ (ΟΗ ₂ )ο- ₂ >β ,

26) -(CHi .NHSO CHj,

27) -ONH2,

28) -QNHC(=0)CH ₂ NHCH ₃ ,

30) -i- =0)-diazepinyl optionally substituted with -C(=N) H _2l

31) -C(=0)-^)iperazinyl,

_, 32) substituted with -NH ₂ ,

33) -NHCH2-pyridinyl optionally substituted with one or more groups selected from -CH ₃ , -OH, and oxo,

34) -NH-pyrimidinyl,

35) -(CH o-i-phenyl,

36) -{CH^o-2-piperazinyl,

37) -{CHJo^azeu^inyl optionally substituted with - H ₂ , -CH ₂ NH ₂ , or -OH,

38) -(CHi)o _-2 pyrrolidinyl optionally substituted with -NH ₂ , '

39) -(CH ₂ )o-2triazolyl optionally substituted with -CH ₂ H ₂ , and

40) -iCH ₂ )o- ₂ tetrazolyl;

R ^f is H, -C(=0)N(Ci _-6 alkyl) ₂ , -S0 ₂ C,_6aJltyl, -S0 ₂ N(R ^K ) ₂ , -Ci^ yclopent l-NCR^,

-C(=0)- yridinyl optionally substituted with one or.more groups selected from oxo, -0- ₃ lkyl and -OH, -C(=0)-pyrrolidinyl substituted with -NR ^a R ^b or halogen, -C(=0>-thiazolidinyl, - SOr-piperazine, or -SOr-pyrrolidinyl-NfR ¹¹ ^;

R ^B is hydrogen or Ci^alkyl, or

R ^f and R ⁸ .are taken together, with the N to which they are attached, to form morpholinyl; piperazinyl; pyrrolidinyl optionally substituted with -C¾; piperidinyl or thiomorpholinyl optionally substituted with -Ci _-6 alkyl or -N(R ) ₂ ; or triazolyl substituted with -CH ₂ NH ₂ ;

R ^h and R ^J is independently H, C^aHcyl, or C ₃ .gcycloalkyl;

R ¹ is -Ci-5 amino alkyl, -OC _!-6 alkyl, -C1. ₃ cyanoa.kyl, or -Ci-ehaloal yl optionally substituted with -NR R ^y ;

. R ^k is Ci-ealky 1, or thiazole substituted with - H ₂ ;

each R ^x and R ^y is independently hydrogen or C^aHcyl; and

wherein when HetA, AryA, Ar C, HetC, or the rings formed by combining R and R° are substituted, the substituents are 1 to 4 members selected from

1) halogen,

2) -OH,

-3) oxo,

4) -COOH,

5) -COOCi-ealkyl,

6) Ci-ealkyl,

Ci- ₆ alkoxy,

8) -CCH wO-Cjalkyl,

9) Ci-ehaloalkyl, 10) Ci^hydroxyalkyl,

11) C ₃ -C ₈ cycloaIkyl,

12) -C(=0)C _w alkyl,

13) -C(=0)C]^aminoalkyl,

14) -C^OJ R^, .

15) -(CH ₂ )<n R ^x R ^y ,

- 16) -iCH ₂ ) _0-3 ^f R ^g _J ^■

ΐη -(CH ₂ ) _] . ₃ -C(=0) R ^x R ^J ', ·

18) ^' -NHCH ₂ CN,

. 19) -NHC(=0)R\

20) -(CH ₂ )( NHS0 ₂ R ^x R ^y ,

21) -SC^ R , .

22) -CH=NH, ^{' ' ' ■} 23) -iCH ₂ y ₃ C(=NH)NH _2j

24) -iCH ₂ ) _M NHC(=NH)NH ₂ , ^■

25) -(CH ₂ ) _t2 -thienyl _>

26) -iCH ₂ Vrtetrazolyl,

27) - CH ₂ V ₂ -thiazolyl,

28) -(CH2)o. ₂ -pyridinyl optionally substituted with -CH ₃ or quatemized with -CH _{3 OT} .CH ₂ CONH _2J

29) ^CH ₂ )o- ₂ -triazolyl,

30) -iCH ₂ )o- ₂ -piperidinyl optionally substituted with -CH ₃ or quatemized with

31) substituted ith one or more of-(CH ₂ )o,

3NH ₂ and further optionally quatemized with ^■

32) -(CH ₂ )] _-3 -C(=0) ^yrolidinyl optionally substituted with -N "R , .

33) . -{C^jM -pyrolidinyl optionally substituted with -NR ^x R ^y ,

34) -C(=NH) -pyrolidinyl optionally substituted with -NR ^x R ^y _J ^' and

35) ^' . 4,5-dihydrothiazol-2-yl.

_, The present invention also relates to compounds of formula (lb)

or a stereoisomer, internal salt, N-oxide, prodrug, or pharmaceutically acceptable salt thereof: wherein: ' A represents -N °R or -OR ² ;

R ^z represents isoxazolyl;

R° is hydrogen or Ci-salkyl which is optionally substituted with one or two substituents selected from halogen, hydroxyl, cyano, carbamoyl, -SO2NH2 and Ci-salkpxy;

R is: · ■

-(CH ₂ ) _n C(=0)R ² ; ^'

or

R and R° together with the N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, 0 and S;

n is an integer selected from 0, 1, 2, 3, 4, 5 and 6;

R ¹ is: · ^"

3) C2-6aminoalkyl optionally substituted with

. b) -C( _>)-pyn-olidinyl substituted with -NR ^il R ^y , c) -CR^NR", or

d) -COO-phenyl;

R ² is:

H;

Ci-6alkyl optionally substituted with 1; 2 or 3 substitutents. independently selected from halogen, -OH, -CN,

C3.scycloaU yl ₃ -NR¾ ^b ,

-COOCi-eaU yl,

-S-AryA and azetidinone optionally substituted with Ci-ehydroxyalkyl;

C ₃ -gcycloalkyl substituted with Ci-ehal oalkyl or -NR ^* R ^y ;

-C ^NOC alk l optionally substituted with -CO OR*;

-C(=0 NR ^x R ^y ;

-NR ^x R ^y ; · · . ^' . ·

-OH; -COOH;

Ci-6alkoxy;

Ci-ihaloalkyl;

Ci-ehaloalkoxy;

AryA; or

HetA;

R ⁴ is -COCTor -COOR ^s ;

R ⁵ is hydrogen, a carboxylic acid protecting group or an ester prodrug moiety;

. AryA is 1) a substituted or unsubstituted 5- or 6-membered aromatic ring with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, or

2) a substituted or unsubstituted 9- or 10-membered bicyclic aromatic ring with 1, 2, 3, 4, 5 or 6 heteroatom ring atoms independently selected from N, 0 and S;

HetA is a substituted or unsubstituted 5- to 10-memhered saturated ring with 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, wherein any S atom in the ring is optionally oxidized;

AryC is 1) a substituted or unsubstituted 5- or 6-membered aromatic ring with 1, 2 or 3 heteroatom ring atoms independently selected from Ν, Ό and S, or

2) a substituted or unsubstituted 7- to 10-membered bicyclic aromatic ring 1 or 2

;

-{CH ₂ )i: ₃ C(=0)NHOBn; -Ci^alkoxy; pyridinyl; pyrrolidinyl optionally substituted with - C(=0)NR ^x R ^y ; teti^ydro-2H-pyran-4-yl;-(CH2)i _-3 C(=0)--diazepanyl;

-(CH ₂ )i _-3 C(=0)-pyrrolidm-l-yl substituted with R"R ^y ; -(CH ₂ )i.3-pyranyl optionally substituted with 1 or 2 substituents selected from oxo and methoxy;

-(CH ₂ )i.r-pyridinyl optionally substituted with one or more groups selected from-CH ₃ , -OH, and oxo; or

-phenyl-C(=0)-pyn'olio nyl-NR ^x R ^y _;

R ^d is hydrogen, Ci^alkyl, Ci- ₃ hydroxyalkyl or Ci. ₃ cyanoalkyl; or

R ^c and R ^d are taken together, with the N to which they are attached, to form a substituted or unsubstituted 4- to 12-membered heterocyclic ring or ring system with 0, 1, or 2 additional heteroatom ring atoms independently selected from N, O, and S, wherein the rings in the heterocyclic ring system can be bridged, fused, spiro-linked or any combination of two thereof; wherein any nitrogen ring atom of the heterocy clic ring or ring system is optionally

quadricovalent; and wherein the heterocyclic ring or ring system is optionally substituted with 1, 2, ^' 3 or 4 substituents independently selected from.

halogen;

oxo;

-OH;

-Ci-salkyl optionally substituted with -OH, halogen, or cyano;

-CH ₂ CH(OHjcH ₂ H ₂ ;

-C(=0)OH;

-(CH ₂ )o. ₃ NR ^h R ^j Optionally substituted with -NH ₂ or halogen;

-NHCH ₂ CN;

■ -NHCH=Mi;

-NHC(=Q)R'; ^'

-NHC(^)CH ₂ r¾C(=NH NH ₂ ;

-C(=NH)NH ₂ ; ^'

-C(=0)Ci _-i aminoalkyl optionally substituted with -OH; .

-(CH ₂ )o. ₂ C(=0)(CH ₂ V ₂ NR ^h R ^j ; ^'

-(CH ₂ ) _c . ₂ C(=O)CH( H ₂ )(CH ₂ ) ₀ - ₂ OH;

-C(=OX<¾V ₃ NHC(=NH)NH ₂ ;

-(CH ₂ ) _w NHCH ₂ CH ₂ NR ^h R ^j ;

-(CH ₂ )o. ₃ NHC(= ?H)NH ₂ ;

. -(CH ₂ )nNH(CH ₂ )o.i C(=0)(CH ₂ )o.iNR ^h R: ;

- ^■ -(CH _a )MNHSO _I CH3;

- -ONH ₂ ;

. -ONHC(=0)CH ₂ HCH ₃ ;

-C(=0) H-pyridinyl;

-C(=0)-piperazinyl;

-C(=0)-pyrrondinyl optionally substituted with -NH ₂ ;

-NECHr-pyridinyl optionally substituted with one or more groups selected from

-CH3. -OH, and oxo;

-NH-pyrimidixiyl;

-<CH ₂ )c-i-iJhenyl;

-(CH^^i enLzi yl;

-(CH ₂ )o. ₂ azetidinyl optionally substituted with - H ₂ , -CH ₂ M¼, or

-OH; ^' ·

-(CH ₂ )(). ₂ pyrrolidinyl optionally substituted with - H ₂ ;

■ -(CH ₂ )tt. ₂ triazolyl optionally substituted with -CH ₂ NH ₂ ; and -iCH ₂ ) _M tetrazolyl;

-C(=0)-pyridinyl optionally substituted with one or more groups selected from oxo, -Ci-jalkyl and -OH; -C(=0)-pyrrolidinyl substituted with -NR ^a R ^b or halogen; -C(=0)-tbiazoUdiny 1; - S02-piperazine; or-S02-pyn:olidinyl-N(R ^x )2;

R ^B is hydrogen 0r.C1.3aU.yl; or .

R ^f and R ^B are taken together, with the N to which they are attached, to form morpholinyl; piperazinyl; pyrrolidinyl optionally substituted with-CH ₃ ; piperidinyl or thiomorpholinyl optionally substituted with -Cj-ealkyl or -N(R*)2; or. triazolyl substituted with -CH2NH2;

R ^b and R ^J is independently H, Q-salkyl, or Cj.scycloalkyl;

R' is -Ci-s amino alkyl; -Ci.3cyanoalkyl; or-Ci-ehaloalkyl optionally substituted with -NR*R ^y ;

^' R ^k is Ci^alkyl; or thiazole substituted with -N¾;

each R* and R ^y is independently hydrogen or Ci^alkyl;

wherein wheii HetA, AryA, AryC, HetC or the rings formed by combining R and R° are substituted, the substituents are 1 to 4 members selected from

halogen;

-OH;

oxo;

-COOH;

-COOCi _-6 alkyl;

Ci^allcyl; ^'

-{CHij _M O-C.jalkyl;

C hydroxyaUcyl;

C ₃ -Cgcyclo alkyl;

-C(=0)Ci^alkyl;

-C(=0)NR¾ ^d ;

-iCHiJo-j R'R ⁸ ; ·

-NHCH2CN;

-ΝΗ0(=Ο)^;

-(CH2)o-i HS0 ₂ R ^it R ^y ;

-S0 ₂ NR¾ ^d ; -CH=NH;

-(CH ₂ )c- thieny 1 ;

-iCH ₂ )c-2-tetrazolyl;

-{CH2)o- ₂ -thiazolyl; -(CH ₂ )o. ₂ -pyri<iinyl optionally substituted with -C¾ or qmternized with -C¾; -(CH ₂ )o-2-triazolyl; and ^■

4,5-dihydrothiazol-2-yl.

The present invention also relates to a compound of formula (la), or a stereoisomer, interna] salt N-oxide, or ·

(la)

wherein: ■

A is NR°R or -triazoly 1 substituted with -CH ₂ OH;

R is: .

-C(=0>-C _M alkyl-NR ³ R ^b ;

-C(=0)CHF ₂ ; · .

-C(=0)CH2SCHF _2j

-C(=0)CH ₂ NH(CH ₂ ) ₂ 0Me,

-C(=0)CH ₂ pyrrolidine,

-C(=0)CH ₂ azetidme,

-C(=0)C¾ pyrrolidine optionally substituted with 1 or 2 substituents selected from fluorine and -CH ₂ NHMe,

-C(=0)CH ₂ -tetrazo]e optionally substituted with -C(C¾) ₃ , -CF ₃ , -CHF2, -C¾, -NHa-COOCi-ialk l, thienyl, -CH2NHCH ₃ , -ΝΗ _2> or

-COOCH2CH3; or.-S0 ₂ CH ₃ ; ^■

R° is H;

R ¹ is pyrrolidinyl substituted with 1 or 2 of -CO R ^c R ^d ; -CH ₂ NHS<¾NH ₂ or - CH ₂ -pyrrolidinyl optionally substituted with -NH ₂ ;

R ^a and R ^b are independently H, -Q-ealky 1, -C gcycloalkyl, -S.C^CHB ,

-CH(=NH), -C(=NH) H ₂ or -CH ₂ C(=0)1SIH ₂ ;

R ^c and R ^d are independently H, C1. ₃ a.kyl, -C(=NH)-pyrrolidinyl optionally substituted with -NH or

R ^c and R ^d are taken together, ith the N to which they are attached, to form a 4- to 12- member ^' ed heterocyclic ring or ring system with 0, 1, 2 or 3 additional heteroatom ring atoms selected from N and O;

.wherein any nitrogen ring atom of the heterocyclic ring or ring system is optionally quadricovaleht; the ring system is a bridged, fused or spiro ring ^" system; and the 4- to 12 membered heterocyclic ring or ring system is optionally substituted with 1, 2 br 3 substituents selected from

(=NH)

-C(=0)(CH ₂ )i.2NH ₂ ,

. -C(=0)CH ₂ NHCH ₃₎ ^■

-C¾CH(NH ₂ )CH ₂ NH2,

-C(=0) CHCNH ₂ )CH ₂ H _2i

-C(=0)CH(F)CH ₂ NH ₂ , ·

-C(=0)CH(NH ₂ )CH ₂ OH,

-CH ₂ GH(OH)CH ₂ NH ₂ ,

-C(=0)NH CH ₂ CH(OH)CH ₂ NH ₂ ,

-C(=NH)NH ₂ , .

-COOH,

-CH _3j ^"

-CH ₂ C(=0)NH ₂ ,

-CH ₂ NH C¾C(=0)NH ₂ , _.

-CH ₂ NR ^h R ^j ,

. -CH ₂ CH ₂ N¾,

-CT ₂ CH ₂ NH-C(=NH)--NH _2j

-CH ₂ NHS(¾NH ₂ ,

-CH ₂ OH,

-C(CH ₃ ) ₂ NH ₂ ,

-CH2F,

-OH,

-OMe,

- _ _Fj

-NR ^h R ^j ,

-NHCH=NH,

-NH-C(=NH>N¾

-NHCOCHr-NH-C(=NH)-NH ₂ ,

NHCOC¾NH ₂ ;

-<CH ₂ )o- ₃ NR ^b R ^J optionally substitute d with _-NH ₂ or halogens;

azetidinyl optionally substituted with -OH,

piperazinyl,ahd

triazolyl substituted with CH ₂ NH ₂ ; and

R ^b and R ^J are independently H, Ci^alkyl, or Cs-scycloalkyl. ^' Any of the combinations of A, X, Z, ¹ , and R* are encompassed by this disclosure and specifically provided by the invention.

In another aspect, described herein is also a pharmaceutical composition comprising a compound of formula (I), (la) or (lb), or a stereoisomer, pharmaceutically acceptable salt or N- . oxide thereof. ^'

In another aspect, the compounds described herein can also be combined with appropriate β-lactamase inhibitors to increase the antibiotic spectrum. In another aspect, the compounds described herein can also be combined with appropriate dehydropeptidase inhibitors. .

In another aspect, described herein is a process for preparation of a compound of formula (I), (la) or (lb), or a stereoisomer, pharmaceutically acceptable salt or N-oxide thereof.

In another aspect, described herein is also a method for preventing or treating a bacterial infection comprising administering a therapeutically effective amount of a compound of formula (I), (la) or (lb), or a stereoisomer, pharmaceutically acceptable salt, pharmaceutical composition or N-oxide thereof.

In another aspect, described herein is also a method for preventing or treating a gram negative and/or gram positive bacterial infection comprising administering a therapeutically effective amount of a compound of formula (I), (la) or (lb), or a stereoisomer, pharmaceutically ■ acceptable salt, pharmaceutical composition or N-oxide thereof.

In another aspect, described herein is also a method for preventing or treating a bacterial infection comprising administering a therapeutically effective amount of a compound of formula (Γ), (la) or (lb), in combination or alternation with one or more other anl-jriicrobia] agents.

Embodiments, sub-embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.

Detailed Description

The present invention is based, in part, oh the discover of carbapenem derivatives that - ^■ are bacteriocidal against a broad spectrum of bacteria.

In a first embodiment, the present invention relates to compound of formula (I), (la) or (lb), as described above, or a stereoisomer, internal salt, N-oxide, or pharmaceutically acceptable salt thereof.

In a second embodiment, the present invention relates to a compound of formula (Γ), (la) or (Tb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein A represents. -NR^R, and the other groups are as provided in the general formula for formula (Γ), (la) or (lb).

In another embodiment, A represents -NR° . In another embodiment X is -S-. In another embodiment Z is -CH ₃ .

In a third embodiment, the present invention relates to a compound of formula (1), (la) or (lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R° is hydrogen or methyl;

R is ·

R and R° together with the N to which they are attached form

1) [l,2,3-]triazolyl substituted with Q.salkyl, wherein the C alkyl is

substituted with halo, -NR ^a R ^b , -OH, or Ci. ₃ alkoxy; or

2) tetrazolyl optionally substituted with -NR ^a R ^b ;

and the other groups are as provided in the general formula for formula (I), (la) or (Ih), above or in the embodiments.

In another embodiment, R° is hydrogen or methyl;

R is

-iCH ₂ )„C(=0)R ² ; or

-(CH ₂ ) _n S0 ₂ R ² ; or

R and R° together with the N to which they are attached form-

1) [l ,2,3-]triazolyl substituted with C _h alky), wherein the C^alkyl is

substituted with halo, -NR°R ^b , -OH, or

2) tetrazolyl optionally substituted with -N ^.

In a fourth embodiment, the present invention relates to a compound of formula (I), (la) or (lb), or a stereoisomer, internal salt N-oxide, or phannaceutically acceptable salt thereof, . wherein n is 0 or 1, and the other groups are as provided in the general formula for formula (1), (la) or (lb), above or in the embodiments. In one aspect of this embodiment, n is 0.

In another embodiment, n is 0 or.1. In one aspect of this emhodiment, n is 0. '

In a fifth embodiment, the present invention relates to a compound of formula (I), (la) or

(lb), or a stereoisomer, internal salt N-oxide, or phannaceutically acceptable salt thereof, wherein R ¹ is: or -(CH ₂ )o.i-HetC, and the other groups are as provided in the general formula for formula (I), (la) or (lb), above or any of the ^' embodiments.

In another embodiment, R ¹ is -(Ciy^r-AryC or -{QHfc cn-HetC.

In another embodiment, R is -COOH.

In a sixth embodiment, the present invention relates to a compound of formula (I), (la) or (lb), or a stereoisomer, internal salt, N-oxide, or pharmaceutically acceptable salt thereof, wherein ^*

AryA is 1 ) a.5- to 6-membered aromatic ring with 0, 1 , _. 2, 3. or 4 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, -{CH ₂ )o-iNR' ^t R ^y , C ₃ -C ₈ cycloalkyl, -COOH, -COOCi-e lkyl, Ci^alkoxy, thienyl, and tetrazolyl, or 2) a 9- to ^' 10-membered bicyclic aromatic ring with 1 to 6 heteroatom ring atoms independently, selected from N, O and S, optionally substituted with 1 or 2 substituents selected from halogen,

HetA is a 5- to 10-membered saturated ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, -NR R ^y , -CH ₂ NR ^x R ^y , -OH, and oxo;

AryC is 1) a 5- or 6-membered aromatic ring with 0, 1 or 2 heteroatom ring atoms independently selected from N and S, optionally quatemized with C¾ and optionally substituted 1 to 3 substituents independently selected from -CH ₂ NR"R -CHr-pyrrolidiny], -OH, oxo, . pyridinyl which is optionally quatemized with methyl or -CH2CONH2, o -

2) a 7- to 10-membered bicyclic aromatic ring ^' with 3 heteroatom ring atoms selected from N; and

HetC is a 4- to 8-membered saturated ring with 1 or 2 N or O ring atoms, optionally substituted with 1 or 2 substituents independently selected from halogen, -OH, - (C¾)o _-3 R ^f R ^B , -CH=NH, ^C(=0)Ci^allcyl, -C(=NH) -NH _2l -CHHC=0) -pyrrolidiny 1■ optionally substituted with -NR ^x R ^y , -NH-C(= H) -N¾, -CHr-NH-C(=NH) - H ₂ , -C(=0)Ci- . saminoalkyl, -C(=0)NR ^c R ^d , -NR ^x R ^y , -NHS0 ₂ NR ^x R ^y , -S0 ₂ NR ^c R ^d , thiazolyl, and 4,5- dihydrothi)azol-2-yl; and the other groups are as provided in the general formula for formula (I), (la) or (Tb), above or any of the embodiments.

In another embodiment^ AryA is 1) a 5- to 6-membered aromatic ring with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 substituents independently selected from halo, Ci-ealkyl, Ci.6haioalkyl, -{CH ₂ )o- [NRxRy, Ci-C ₆ cycloalkyl, -COOH, -COOCi^alkyl, Ci-eaikoxy, tbienyl, and tetrazolyl; or

2) a 9- to 10-membered bicyclic aromatic ring with 1 to 6 heteroatom ring atoms independently ' selected from N, O and S, optionally substituted with 1 or 2 substituents selected from halb, Ci- ealkyl, and Ci-ehaloallcyl;

HetA is a 5- or 6-membered saturated ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 substituents independently selected from halo, -NR ^x R ^y , -OH, and oxo;

AryC is 1) a 5- or 6-membered aromatic ring with 1 or 2 heteroatom ring atoms independently selected from N and S, optionally substituted 1 to 3 substituents independently , selected from -CH2NR ^x R ^y ,-OH, oxo, pyridinyl which is optionally quaterpized with methyl; or

2) a 8-membered bicyclic aromatic ring with 3 heteroatom ring atoms . selected from N; and

HetC is a 4- to 6-membered saturated ring with 1 or 2 N ring atoms, optionally substituted with 1 or 2 substituents independently selected from halo; -Ci-salkyl optionally substituted with -NR ^f R ^g ; -CH=NH; -C(=0)Ci-sall yl; thiazolyl and 4,5- f formula (I), (la) salt thereof,

- 2) -CH ₂ CN,

3) -Ci.salk l optionally substituted with -NR ^h R ^J , pyrrolidinyl or -OH,

8) -C^alkoxy,

9) pyridinyl,

10) pyrrolidinyl optionally substituted with -C(=0)NR ^x R ^y ,

I I) -C(=NH)-pyn-olidin-l-yl optionally substituted withNR ^x R ^y , .

12) tetrahydro-2H-pyran-4-yl,

13) -CH ₂ CH ₂ C(= »)-diazepanyl _J

14) -CH ₂ CH ₂ C(=0)-pyrrolidin-l-yl substituted with NR R ^y ,

15) -CH ₂ -pyranyl optionally substituted with 1 or 2 substituents selected from oxo and methoxy,

16) -CH2-pyridinyl optionally substituted with -CH3, -OH, and oxo,

17) -phenyl-C(=<3)-piperazinyi,

18) -pheny-l-CH2-NR ^, R ^y , or

19) . -phenyl-C(=0)-pynOUdinyl-NR ^,! R ^y _;

. R ^d is hydrogen, or C _h alk 1; or

R ^e and R ^d are taken together, with the N to which they are attached, to form

a) a 4- to 8-membered heterocyclic ring with 0, 1, or 2 additional heteroatom ring atoms independently selected from N, O, and S, or

b) a 6- to 12-membered heterocyclic bi- or tricyclic ring with 0, 1, or 2 additional heteroatom ring atoms independently selected from N, O, and S, wherein the bicyclic ring is optionally bridged, fused, spirocyclic or any combination of two thereof,

and wherein any nitrogen ring atom of the heterocyclic ring or heterocyclic bicyclic ring is optionally quadricovalent; and wherein the heterocyclic ring or heterocyclic bicyclic ring is optionally substituted with 1, 2 or 3 substituents independently ^" selected from

1) halogen, 2) ^■ ^Ci^alkyl optionally substituted with 1· or 2 substituents selected from

or -OH,

15) -NR ^h R\

16) -NHCH ₂ CN,

17) -NHCH=NH, .

18) ^" -NHC(=0)R ^f ;

19) -NHS02N(C¾) ₂ , ,

20) ->3HC(=0)(CH ₂ )nNH(=NH)NH _2j

21 -OH,

25) o o,

26) . =MI,

27) -<CH ₂ )o.i-phenyl,

28) -^CH^o-r-piperazinyi,

29) ^C(=0)NH-pyridinyl,

30) -C(=0)-piperazinyl,

31 ) ^(=0)-pyrrolidinyl optionally substituted with - H ₂ ,

32) azetidinyi optionally substituted With -CH ₂ NH ₂ , - H ₂ , or -OH,

33) pyrrolidinyl optionally- substituted with -NH ₂ ,

34) -l^CHr- yridinyl substituted with oxo, -CH ₃ , and -OH,

35) -NH-pyrimidinyJ,

36) triazolyl optionally substituted with -CH ₂ NH ₂ , and

37) tetrazolyl;

IS and the other groups are as provided in the general formula for formula (I), (la) or (lb), above or any of the embodiments.

In another embodiment, R ^c is H; -CH ₂ CN; -Ci-salkyl optionally substituted with -NR ^h R'

-CH ₂ CH ₂ C(=0)NHOCH ₃ ; -CH ₂ CH ₂ C(=0)NHOBn; -Q-salkoxy; pyridinyl; pyrrohdinyl optionally substituted with -C(=0)NR ^x R ^y ;

terrahydro-2H-pyran-4-yl;--CH ₂ CH ₂ C(=0)-diazepanyl;

- ¾CH ₂ C(=0)^yrrohdin- l-yl substituted with NR*R ^y ; -CH ₂ -pyranyl optionally substituted with 1 or 2 substituents selected from oxo and methoxy;

-CHr- pyridinyl optionally substituted with -CH3, -OH, and oxo; or

-phenyl-C(=0 i3yrro]idinyl- R' ¹ R ^y _;

R ^d is hydrogen or Ci _-3 alkyl; or "

R ^e and R ^d are taken together, with the N to which they are attached, to form

a) a 4- to 8-membered heterocyclic ring with 0, 1, or 2 additional heteroatom ring atoms independently selected from N, 0, and S; or

b) a 6- to 12-membered heterocyclic bicyclic ring with 0, 1, or 2 additional heteroatom ring atoms independently selected from N, O, and S, wherein the bicyclic ring is optionally bridged, fused, spirocyclic or any combination of two thereof;

and wherein any nitrogen ring atom of the heterocyclic ring or heterocyclic bicyclic, ring is optionally quadricovalent; and wherein the heterocyclic ring or heterocyclic bicyclic ring is optionally substituted with 1 or 2 substituents independently selected from

halo;

-Ci-sa kyl optionally substituted with 1 or 2 substituents selected from halo, -CN, -NR ^b R ^j , and -OH; with -N¾ or halogens;

^(=0)C _t - ₆ aminoalk l optionally substituted with -OH;

-C(=0)OH;

-C(=0)(C¾)c ₃ NHC(=NH)NH ₂ ;

-<CH ₂ ) _M NHCH ₂ CH ₂ NR ^h R ^j ;

-<CH ₂ )o. ₃ NHC(=NH)NH ₂ ;

CH ₂ ) ₀ . ₁ NH(CH ₂ )o-iC(=0)(CH ₂ ) _(M NR ^h R ^j ;

-<CH ₂ )o.iNHS0 ₂ NH ₂ ;

-<CH ₂ )o.iNHS02(CH ₂ ) ₀ . ₂ H ₂ ;

-NHCH ₂ CN; . -NHCH=NH;

^• -NHS0 ₂ (CH ₃ ) ₂ ; ^'

-OH; ^' .

-O NH ₂ ; ' .

-ONHC(=0) CH ₂ NHCH ₃ ;

oxo ;

-{CH ₂ )o.i-phenyl;

' -C(=0)-piperazinyl;

-C(=0)-pyrrolidinyl optionally substituted with - H ₂ ;

azetidinyl optionally substituted with -CH ₂ NH2, -NH2, or -OH; pyrrolidinyl optionally substituted with -NH2;

- HCHy-pyridinyl substituted with oxo, -CH ₃ and -OH;

- H-pyrimidinyl;

triazolyl optionally substituted with -CH2NH2; and

tetrazolyl.

In an eighth embodiment, the present invention relates to a compound of formula (I), (la) or (lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein: ^■ .

R° is hydrogen and R is:

5) -C(=0)CF ₂ -Ci- ₆ alkyl,

6) -C(=0)CHFCH ₃ ,

8) -C(=0)CF ₂ CH ₂ OH,

10) -C(=0)CH ₂ OCOCH ₃ ,

Π) -C(=0)CH ₂ CN;

16) -C(=0)CH ₂ S-tetrazoIe optionally substituted with ^CH ₃ ,

20) -C{=0)CHr-tetrazole optionally substituted with -C(CH ₃ ) _3> -CF ₃ , -CHF ₂ , -CH ₃₎ Hr-COOCi^aJkyl, thienyl, -C-¾NHCH ₃ , -NH ₂ , or -COOEt,

21) -C(=0)CHr nazo\e optionally substituted with -CB ₂ NR ^a R ^b , or-CH ₃ and -CF _3> or-CF ₃ and -NH ₂ ,

22) -C(=0)CH ₂ -oxadiazole-CH ₂ NR ^a R ^b _>

23) . -CtO^tCHsir-tetrazale,

24) -C(0)CH2-azetidine,

25) . . -C(=0)CH(CH ₃ )-azetidine optionally substituted with oxo, hydroxyeth l, or both,

26) -C{=0)CH ₂ -pyrrolidinyl optionally substituted with one or more -F or— ' CH ₂ NHC¾,

27) -C(=0)CF ₂ -thienyl, ^%

28) ^■ -C(=0)-Ci ^alk l- R ^a R ^b ,

29) -C(=0)-pyn-olidinyl optionally substituted with F or ^" NH ₂₎

30) ^(=0>-4etrahydrofuran,

32) -CiOHjyrazine

33) -C(^)4biazoIiclhie optionally substituted with one or more oxo,

34) -C(=0)-pyrazole optionally substituted with CH ₃ and CF ₃ ,

35) optionally substituted with -OH or phenyl,

36) -Q^CHFC^alkyl, ,

44) -C(=0)C(=0)ONR ^a R ^b ,

47) -<CB ₂ ) _M C(=0)OCi- ₆ al]cy,

50) -C(=0)OCH ₂ CHF ₂ ; 51) -C(=0)OCH ₂ CF _3j

52) -CC^O^-ec cloalk l substituted with CFs or NH _2>

• 53) -d-ealkyl-^Nft^,

- 54) _. -C^alkyl- C _3-6 cycloalkyl,

56) -CH(=NH),or

R and R° together with the N to which they are attached form a [l,2,3-]triazole optionally substituted with -O¾0H, -CH ₂ OC¾, -CHjF, .-CH ₂ NH ₂ , -C¾NHCH ₃ , -C(=0)OCH ₃ , or a tetrazole optionally substituted with -NH ₂ ;_and the other groups are as provided in the general formula for formula (I), (la) or (lb).

^' In aother embodiment, R° is hydrogen and R is:

-C(=0)CHF ₂ ; _ .

-C(=0)CF ₃ ; . . ·

-C(=0)CH ₂ CF ₃ ;

-C(=0)CF ₂ CF ₃ ;

-C(=0)CF ₂ CH ₂ OH;

-C(=0)CH ₂ 0¾

-C(=0)CH ₂ OCOCH ₃ ; . · . . . .

-C(=0)CH ₂ CN; ·

-C(=0)CH ₂ S-tetrazole optionally substituted with -CH ₃ ; . 3) ₃ , -CF ₃ , -CHF _2l

-CH ₃₎ NHr-COOCi-eaUcyl, thienyl, -CH ₂ NHCH ₃ , -NH ₂ , or -COOEt; . optionally substituted with -CH ₂ NR'R ^b , or-CH ₃ and

^■ -CF ₃ , or -CF ₃ and -NH ₂ ;

-C(=0)CH ₂ -oxadiazole-CH ₂ NR ^a R ;

-CC^CfCKbJr-tetrazole; - ^(=0)CH(CH ₃ )-azetidine optionally substituted with oxo, hydroxyethyl, ^' or both; -C(=0)CF2-thienyl; -C(=0)-Ci^alkyl- R ^a R ^b ;

-C(=0)-pyrrolidiny! optionally substituted with F or NH ₂ ;

-C(=0)-tetrahydrofuran;

■ -C(=0)-piperazine;

-C(=0)-pyrazine;

-C(=0)-thiazolidine optionally substituted with one or more oxo;

^~ -C(=0)-pyrazole optionally substituted with CH ₃ and CF ₃ ;

optionally substituted with -OH or phenyl;

-C(=0)CHFCi _-6 alkyl;

-C(=0)CH(OH)C _1-6 alkyl;

-C(=0)CR^=NOC(CH ₃ ) ₂ COOH;

-C(=0)CR^NOCH ₃ ;

-C(=S)OC alkyl; .

-C(=0)C(=0)OH; -

- :( >)C<<>)NR¾ ^b ;

-C(=0)C(=0)ONR ^a R ^b ;

-C(=0)C(=0)OC _1-6 alkyl;

-(CH ₂ ) _M C(=P)(CH ₂ ) _1-6 OH;

-iCH ₂ )o. ₆ C(=0)(CH ₂ )i- ₆ 0Q.6-dkyl;

-C(=0)OCH ₂ CHF ₂ ;

-C(=0)OCH ₂ CF ₃ ;

substituted with CF ₃ or H ₂ ;

-C _h alky 1- C^ecycloalkyl;

. -(CH^wSO^CH^R';

. -CH(=NH); or

Rand R° together with the to which they are attached form a [l,2,3-]triazole optionally substituted with -CH ₂ OH, -CH ₂ OC¾, -CH ₂ F, -CH ₂ H ₂ , -CH ₂ NHCH ₃ , or -C(=0)OCH ₃ ; or a tetrazole optionally substituted with -NH ₂ .

In another embodiment, R ^& is hydrogen or Q-fialkyl which is optionally substituted with one or two substituents selected from halogen, hydroxy!, cyano, carbamoyl, -S0 ₂ NH ₂ and C _\ . ealkoxy;

R is:

1) -(CH ₂ ) _n C(=0)R ² , or 2) -(Cl -SC^R ² , or

. R and R° together with the N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0; 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S.

. In another embodiment, R° is hydrogen or which is optionally substituted with one or two substituents selected from halogen, hydroxy!, cyano, carbamoyl, -SO ₂ NH ₂ and Q. ealkoxy; ^■

R is:

1) -(CH ₂ ) _n C(=S)R ² , ^'

■ . · 2) -Cuealkyl optionally substituted with -Cs-icycloalk l, or.

3) -CH(=NH), ^' or

R and R° together with the N to which they are' attached form a substituted or unsubstituted 5-6 membered cyclic ring .with 0, 1, 2, 3 or 4 additional heterbatom ring atoms independently selected from , O and S.

In a ninth embodiment, the present invention relates to a compound of formula (I), (la) or

(In), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt, thereof, wherein R° is hydrogen and R is:

1) -C(=0)CHF _2>

2) -C(=0)CH ₂ NH ₂ , ^" .

3) -C(==0)CH ₂ NHCH ₃ ,

4) -C(=0)CH ₂ HC(=NH)NH ₂ ,

5) -C(=0)CHr-tetrazolyl, or

6) -S0 ₂ CH ₃ , or

R and R° combine together to form -triazolyl optionally substituted with -CH ₂ -OH; and the other groups are as provided in the general formula for formula (I), (la) or (lb), above.

In another embodiment, R° is hydrogen and R is:

. -C(==6)CHF ₂ ; . ^' .

-C(=0)CH ₂ N¾; . ^{" ■} .

-C(=0)CH ₂ NHCH ₃ ; '

-C(=0)CH ₂ NHC(=NH)NH ₂ ;

-C(=0)CHr-tetra2olyl; or

- R and R° combine together to form -triazolyl optionally substituted with -ΓΟ¾ Η.

In other embodiment, the present invention relates to a compound of formula (I), (la) or (lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹ is:

. 1) pyrrolidinyl substituted with 1 or 2 of

a) -CON ^, - - b) ^ON(CH ₃ )CH ₂ CH ₂ C( ))-pyrrohdin-l-yl substituted with N¾ diazepanyl,

c) -C¾NR ^f R ^g ,

d) -CH= H,

e) F, .

f) _. - (CH ₂ )o.iNHC(= H)NH ₂₃

g) -CH ₂ NHS02-pyrrolidinyl-NH2,

h) - H ₂ NH(C=0)-pyrrolidinyl substituted NH ₂ or F,

i) -<:H ₂ NH(C=0)^pyridinyl substituted with oxo,.CH ₃ and OH, j) -CH ₂ NH(C=0)-cyclopentyl- H _2j

k) -CH ₂ NHS02-piperazine,

1) -CH ₃ , or ^'

3) -C¾-pyridinyl,

4) thiazole substituted with pyridinyl wherein the pyridinyl is optionally substituted. with -CH ₃ or -CH ₂ C(=0)NH ₂ ,

thiazolyl or 4,5-dihydrothiazol-2-

6) - H ₂ CH ₂ -pyridinyl substituted with oxo, CH ₂ NH ₂ and OH,

7) -CHr-pyrrolidinyl substituted with acetyl and -NH ₂ , or -NHSO2NH2,

8) -CH ₂ -piperazine,

11) pyrazole optionally quaternized with -C¾ and optionally substituted with -CH ₂ pyrrolidine, or CH ₂ piperidine optionally quaternized with -CH ₃ and optionally substituted with -CH ₂ CH ₂ NH ₂ ,

12) -CH2-phenyl substituted with pyrazole optionally quaternized with -CH ₃ and substituted with -(CH ₂ ) ₃ NH ₂ , or

13) -CH ₂ CHiNHC0 ₂ -/er/-buty 1;

and the other groups are as provided in the general formula for formula (I), (la) or (lb), above or the seventh or eighth embodiments.

In another embodiment, R ¹ is: 1) pyn-oKdinyl substituted with 1 or 2 of .

-CONR ^c R ^d ;

substituted with N¾ or diazepanyl;

* -CH= H; '

F; · · .

-CH ₂ NHS02-pyrrolidinyl-NH2; .

substituted H ₂ or F;

-CH ₂ NH(C=0)-pyridinyl substituted with oxo, CH ₃ and OH;

. -CH ₂ NH(00)-cyclopentyl-NH2;

-CH ₂ HS0 ₂ -piperazine; or

3) -CH2-pyridinyl;

^' 4) thiazole substituted with pyridinyl wherein the pyridinyl is optionally substituted with CH ₃ ;

5) azeudinyl ^' substituted with thiazblyl or 4,5-dihydrotbiazol-2-yl;

6) -CH ₂ CHr^)yridinyl substituted with oxo, CH ₂ H ₂ and OH;

7) -CH2-pyrrolidinyl substituted with acetyl and -NH _2i or -NHS0 ₂ NH ₂ ; or

8) -CH ₂ -piperazine. .

In a tenth embodiment, the present invention relates, to a compound of formula (I), (la) or (lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R ¹ is pyrrolidinyl substituted with

- 1) -C(=0)NR ^c R ^d ;

2) -CH2NHSO2NH2, or 2;

wherein

R ^c is -CH ₃ ,

R ^d is -CH ₃ ;

R ^e and R ^d are taken together, with the N to which they are attached, to form

1) azetidinyl optionally substituted with-NHC(=NH)NHi,

2) pyrrolidinyl substituted with

a. one or two -NH2, b. -NHCHj,

d. one or two -OH,

e. -CH2NH2,

f. -NHC(=0)CH ₂ NH2, ^'

g. -NHC(=0)CH ₂ CHzNHz,

h. -NHC(=0)CH ₂ NH(= H)NH _2j

i. -NHCH=NH,

j. ^■ -F and -NHi,

k. -N¾ and -OH,

1. -NH ₂ and -CH3,

m. -NH ₂ and -CH ₂ OH,

n. -NH ₂ and -CH ₂ NH ₂ , ^'

0. -NH ₂ and -OMe, _> p. -OH and -CH ₂ NH ₂ ,

q. -CH2OH and -CH ₂ NH ₂₎

r. -NH _z and -COOH,

s. -NHC(=NH)N¾,

L -NHC(=NH)NH ₂ and -OH,

u. -NHC(=NH)NH ₂ and -CH ₂ OH,

v. -NHC(=NH NH ₂ and -NH _2j ^■

• w. . -NH2 and -CH ₂ NHS0 ₂ MH ₂ ,

y. -OH, -NH ₂ and -CH ₂ NH _2>

z. -OH, - H ₂ and -CH ₂ 0H, or

aa. triazolyl substituted with -(¾>£¾,· ^'

) piperidinyl substituted itrHCH _{2 2} NH ₂ , -CH ₂ NHCH _Z C(=0)NH ₂ , - CH ₂ CH ₂ NH ₂ , -CH ₃ and -NH ₂ , -CH2OH and -CH ₂ NH ₂ , -F and -N¾, -OH and -NH _2> -CONHCH2CH(OH)CH ₂ NH ₂ , or azetidinyl substituted with -OH or-piperazinyl,

) piperazinyl optionally substituted with one or two -CH ₃ , -CH ₂ H ₂ , - CHzOfcNHi, -C(=NH)NH ₂ , -CH ₂ CH ₂ NHC(==NH)NH ₂ , -C(=0)(CH ₂ )i. ₂ NH ₂ , -C(=0)CH NH ₂ )NH _2j -CH ₂ CH NH ₂ )CH ₂ NH ₂ , -^¾CHCF)CH^SI¾, -

) πιοφ^ΐίηγΐ optionally substituted with -CH ₂ NH ₂ ;

) 1,4-diazepane optionally substituted with -C(= H)NH ₂ ;

) octahydro-lH-pyrrolo[3,2-c]pyridiue optionally substituted with - CH ₂ CH ₂ NH ₂ , -CH ₂ CH(OH NH ₂ , or-C(=NH)NH ₂ , ) octahydrocyclopenta[c]pyrrole optionally substituted with

a. one or two -NH ₂ , '

. b. -NH ₂ and -CH ₂ OH,

c. -NH ₂ and -CH ₂ NH ₂ ,

• d. -NH _2j

e. - HC(=NH)NH ₂ ,

f. -NHC(=NH NH ₂ and -CH ₂ OH, or

g. s-OH, -r¾ and -CH ₂ OH, .

) octahydro-lH-pyrrolo[2,3-c]pyridine,

0) octahydro- lH-pyrrolo[3,2rc]pyridine optionally substituted with

-CH ₂ CH(OH)CH ₂ NH ₂₎ .

1 ) octahydro- 1 H-pyrrolo[3 ,4-b]pyridine optionally substituted with

-CH ₂ OH,

2) octahydropyrrolo[3,4-b]pymole optionally substituted with -CH ₂ 0H, -CH ₁ CH ₂ H ₂ , or-C(=NH) H. ^' ;

3) octahydro-lH-pyrrolo[3,4-c]pyriduie optionally substituted with-CH ₂ OH, or- COOH; ^'

4) 5,5-dimethyloctahydiO-lH-pyrrolo[3,2-c]pyridin- l— 5-ium,

5) octahydropyrrolo[3,4 _r c]pyrrole optionally substituted with -CH ₂ OH,

6) octahydropyrrolo[3,4-d]imidazole optionally substituted with =NH,

7) octahydro- lH*pyrrolo[3,2-b]pyridine,

8) octahydropyrrolo[3 -b][l,4]oxazine,

9) 3,6-dia2ahicyclo[3.2.0]heptane,

0) l,9-diazaspiro[5.5]undecane,

1) decahydro-1,6- naphthyridine,

2) 5,6,7,8rtetrahydroiinida2o[l,S-a]pyrazine optinally substituted with - Ή ₂ ,

3) 2,7-diazaspiro[4.4]nonane,

4) 2,8-diazaspLro[4.5]decane, ^■

5) 2,6-dia2aspiro[3.4]octane _J - ^■ 6) l,7-diazaspiro[3.5]nonane,

7) 2,7-diazaspiro[3.5]nonane,

8) l,8-diazaspiro[4.5]decane,

9) l,7-diazaspiro[4.5]decane,

0) 5-nxa-2-azaspiro[3.4] octane optionally substituted with

- ¾, ^' ·

1) 3,8-diaza-tricyclo[5.2.1.01,5]decane, or

2) 8-azaspiro[bicyclo[3.2.1]octane-3,3 'rpyrrolidine; and the other groups are as provided in the general formula for formula (Γ), (la) or (lb), above, or the embodiments.

In another embodiment, R ¹ is pyrrolidinyl substituted with

-CH2-pyrrolidinyl-NH ₂ ;

wherein

R ^e is -CH ₃ ,

R ^d is -o¾; ^■ . - R ^c and R ^d are taken together, with the N to which they are attached, to form

pyrrolidinyl substituted with

one or two -NH ₂ ,

-NHCH ₃ ,

two -OH,

. -NHCH=NH,

-NH ₂ and -OH,

-NHC(=NH)NH ₂ and -OH, or

triazolyl substituted wim ^' -CH ₂ NH ₂ ;

piperidinyl substituted with

-(CH ₂ )c- ₂ NH ₂ ,

F and -NH ₂ , or

^• azetidinyl substituted with -OH or piperazinyl;

piperazinyl optionally substituted with

one or two -C¾, . .

-CH ₂ CH ₂ NH ₂ ,

-C(= H)NH ₂ ,

-CH ₂ CH ₂ NHC(=NH) H ₂₅

-C(=0)(CH2) _1-2 NH ₂ ,

-C(=0)CH ₂ HCH ₃ ,

-C(=0)CH(NH ₂ )CH ₂ OH, or ■

-CH ₃ and -CH ₂ C(=0)NH ₂ ;

octahydro- lH-pyrrol0[3,2-cJpyridine; 1 , 7-diazaspiro[3.5]nonane;

2,7-diazaspiro [3.5]nonane;

' l,8-diazaspiro[4.5]decane; or

8-a2^piro|¾icyclo[3.2^]octane-3 _J 3 ^, -pyrrolidine].

In an eleventh embodiment, the present invention relates to a compound of formula (la), or a stereoisomer, internal saltN-oxide, or pharmaceutically acceptable salt thereof,

wherein:

A is NR¾ or -triazolyl substituted with -C¾OH;

R is:

-C(0)¾alk l-NR ^a R ^b ;

2) -C(=0)CHF _2>

3) -C(=0)CH ₂ SCHF ₂ ,

4) -C^OJC^NHCC^OMe,

5) -C(=0) CH ₂ py rrolidin,

6) -C(=0)CH ₂ azetidine,

7) -C(=0)C¾piperazine,

8) . -C(=0)C¾ pyrrolidine optionally substituted with 1 or 2 substituents selected from fluorine and -CH ₂ NH e,

10) -S0 ₂ CH ₃ ; ^■ .

R is H;

R ^1' is

1 ) pyrrolidiny 1 substituted with 1 or 2 of -CONR°R ^d ,

2) -CH ₂ NHS0 ₂ NH ₂ , or j ^'

3) ^' -CH ₂ -pyrrolidiny 1 optionally substituted with - H ₂ ;

R ^a and R are independently H, -Ci-ealkyl, -C ₃ . ₈ cycIoalkyl, -SChCHa,

-CH(=NH), -C(=NH)NH ₂ , or -CH ₂ C(=0)NH ₂ ; R° and R are independently H, Cijalkyl, -C(=NH)-pyrrolidinyl optionally substituted with -NH ₂ , or

R ^c and R ^d are taken together, with the N to which they are attached, to form a 4- to 12- ^■ membered heterocyclic ring or ring system with 0, 1, 2 or 3 additional heteroatom ring atoms selected from N and 0;

wherein any nitrogen ring atom of the heterocyclic ring or ring system is optionally . quadricovalent; the ring system is a bridged, fused or spiro ring system; and the 4- to 12- membered heterocyclic ring or ring system is optionally substituted with 1, 2 or 3 substituents selected from .

i) · =NH,

. 4) -CH ₂ CH( H ₂ )CH ₂ NH ₂ , ^■

5) -C(=0)CH( H ₂ )CH ₂ NH ₂ ,

6) -C(=0)CH(F)CH ₂ NH ₂ ,

-C(=0)CH(NH ₂ )CH ₂ OH,

8) - H ₂ CH(OH)CH ₂ NH ₂ ,

9) -C(=0) H CH ₂ CH(OH)CH ₂ TSfH ₂ ,

10) -C(=NH)NH ₂ ,

11) -COOH,

12) -CH _3l

13) -CH ₂ C(=0)NH _2>

14) -CH ₂ NH CH ₂ C(=0)NH ₂ ,

15) - H ₂ NR ^h R ^j ,

16) - H ₂ CH ₂ NH ₂ ,-

17) ^■ -CH ₂ CH ₂ NH-C(=NH)-NH ₂ ,

, 18) -CH ₂ NHS0 ₂ NH ₂ ,

19) -CH ₂ OH,

20) -C(CH ₃ ) ₂ NH ₂ , -

21) -CH ₂ F,

22) -OH,

23) -OMe,

24) ■ -F, ^■

^■ 25) -NR ^h R ^j ,

26) -NHCH=NH, ^'

27) -NH-C(=NH>NH ₂ ,

28) -NHCOCHr-NH-C(=NH NH ₂ ,

29) -NHCOCH ₂ NH ₂ ; , 30) -(CH ₂ )t3NR ^h R ^j optionally substituted with -NH ₂ or halogens,

31) azetidinyl optionally substituted with -OH,

32) ' piperazinyl, and

33) triazolyl substituted with'CH ₂ H ₂ ; and

R ^h and R ^j are independently H, Ci^alkyl, or Q-gcycloalkyl;

and the other groups are as provided in the general formula for formula (Γ), (la) or (lb), above, the embodiments.

In another embodiment, ing to formula la:

(la)

wherein:

A is t°R or -triazolyl substituted with -CH ₂ OH; .

R is: . ^'

-C^OJ-C _! ^alkyl-NR ;

-C(=0)CHF ₂ ;

-C(=0)CH ₂ -tetrazole optionally substituted with -C(CH ₃ ) ₃ , -CF ₃ , -CHF ₂ , -CH ₃ , -NHr-COOCi-ialkyl, thienyl, -CH ₂ NHCH _3s -NH ₂ , or

-COOCH ₂ CH ₃ ; or

-S0 ₂ CH ₃ ;

. R° is H;

R ¹ is pyrro idinyl substituted with 1 or 2 of-CONRH* ¹ ; -CH ₂ NHS 0 ₂ NH ₂ or -CH ₂ - pyrrohdinyl optionally- substituted with -NH ₂ ;

R ^a and R ^b are independently H, -C _h alk 1, -C ₃ , ₈ cycloalkyl, -SO ₂ OH ₁ ,

-CH(= H), -C(=NH)NH ₂ or -CH ₂ C(=0)NH ₂ ;

R ^11, and R ^d are independently C _h alky I, or

^■ R ^e and R ^d are taken together, with the N to which they are attached, to form a 4- to 10- membered heterocycUc ring or ring system with 0, 1, or 2 additional heteroatom ring atoms selected from N and O;

wherein any nitrogen ring atom of the heterocycUc ring or ring system is optionally quadricovalent; the ring system is a bridged, fused or spiro ring system; and the 4- to 12- membered heterocycUc ring or ring system is optionally substituted with 1 or 2 substituents selected from .

-C(=0)CH(NH ₂ )eH ₂ OH,

-C(=NH)NH _2l

'- ¾,

-CH ₂ C(=0) H _2>

-CH ₂ NH CH ₂ C(=0)NH ₂ ,

-C¾CH ₂ NH ₂ , - -CH ₂ C¾NH-C(=NH)- H _2l

-CH ₂ OH, ·

-OH,- -F,

. - R ^h Ri, .

-NHCH=NH, ·

-NH-C(=NH)-NH ₂ , · ^'

-NHCOCH ₂ NH ₂ ; ^'

-(CH ₂ )o-3NR ^b R- ⁱ optionally substituted with _-NH ₂ or halogens;

azetidinyl optionally substituted with -OH,

' piperazinyl.and

triazolyl substituted with CH ₂ NH ₂ ; and

R ^b and R! are independently H, C^aUcyl, or C3-scycloaUcyl.

In another embodiment the present invention relates to a compound of formula (I), (la) or (lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof wherein

R is hydrogen or Ci-6alkyl which is optionally substituted with one or two substituents selected from halogen, hydroxy], cyano, carbamoyl, -S0 H and Ci^alkoxy;

R is: .

1) . · _· -<CH ₂ ) _n C(=0)R ² ,

2) -(CH ₂ ) _n C(=S)R ² , _r . ^{" ' ■} 3) -{CH^SO^ ² , · ,

4) -C] _-6 a-kyl optionally substituted with -C3-6cycloalkyl, or ' 5) -CH(=NH), or

R and R° together with the N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S, provided that when R and R° together with the N to which they are attached form triazole, then Z is not H.

In another embodiment the present invention relates to a compound of formula (I), (la) or (lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein

R° is hydrogen ΌΓ Ci-ealkyl which is optionally substituted with one of two siibstituents selected from halogen, hydroxyl, cyano, carbamoyl, -S0 ₂ NH ₂ and Ci-ealkoxy;

R is:

1) <a¾)»C(=0) ² ,

2) -(CH ₂ ) _n C(=S)R ² , ^' ·

3) -{CH ₂ ) _n S0 ₂ R ² , .

• 4) -Ci-ealkyl. optionally substituted with -C3-6cycloalkyl, or

5) -CH(=NH), or

. ^" R and R° to gether with the N to- which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S, provided that when.R and R° together with the N to which they are attached form triazole or tetrazole, then Z is not H.

In another embodiment the present invention relates to a compound of formula (Γ), (la) or (lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptahle salt thereof, wherein

R is -(CH ₂ ) _n C(=0)R ² , -(CH ₂ ) _n C(=S)R ² , -(CH ₂ ) _n S0 ₂ R ² , or -CH(=NH); or

R and R° together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0,- 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;

with the provisos that

when R is -(CH ₂ ) _D C(=0)R ² , n is 0 and R° is H, then R ² is not unsubstituted C _h alky!; when R is -fCH ₂ )nC( ))R ² and n is not 0, R ² is not OH or NH ₂ ;

when R is -(CH ₂ ) ₀ S0 ₂ R ² and n is not-0, R ² is not OH orNH ₂ ; and ^'

when R and R° combine together to form triazole then Z is not H.

In another embodiment the present invention relates to a compound of formula (Γ), (la) or (lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein

R is -(CH ₂ ) _n C(=0)R ² , -iCH ₂ \C(rS) ² , -iCH ₂ ) _n S0 ₂ R ² , or -CH(=NH); or

R and R° together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently

In another embodiment the present invention relates to a compound of formula

a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein

R is -(CI¾).C(=0)R ² , -(CH ₂ ) _n C(=S)R ² , -iCH ₂ ) _n S0 ₂ R ² , or -CH(=NH); or R and R° together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, 0 and S; ^'

- provided that ' .

when R is -(CH^C^OJR ² , n is 0 and R° is H, then R ² is not unsubstituted Ci. ₆ alk !; and/or when R is -(CH ₂ ) _n C(=0)R ² and n is not 0, R ² is not OH or NH ₂ ; and/or

when R is -(C¾) _n S0 ₂ R ² and n is not 0, R ² is not OH or NH ₂ ; and/or

" when R and R° combine together to ^' form triazole or tetrazole then Z is not H.

In another embodiment the present invention relates to a compound of formula (I), (la) or (lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R is -(C¾ j„C(=0)R ² , CH ₂ ) _tt C(=S)R ² , -(C¾%S 0 ₂ R ² , or -CH(=NH>; or

R and R° together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3. or 4 additional heteroatom ring atoms independently selected from N, O and S; '

with the provisos that

when R is h is 0 and R° is H, then R ² is not unsubstituted Ci-ealkyl; when R is and n is not 0, R ² is not OH or NH ₂ ;

when R is -{CH ₂ ) ₀ S02R ² and n is not 0, R ² is not OH; and .

when R and R° combine together to form triazole or tetrazole, then Z is not H.

In another embodiment the present invention relates to a compound of formula (I), (la) or

(lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R is -(CH ₂ ) _n C(=0)R ² , -(C¾) _n C(=S)R ² , -(C¾) _n S0 ₂ R ² , or -CH(=NH); or

R and R° together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1 , 2, 3 or 4 additional heteroatom ring atoms independently ^' selected from N, O and S;

with the provisos that ^"

when R is -(CH ₂ ) _D C(=0)R ² , n is 0 and R° is H, then R ² is not unsubstituted C^aUcyl; when R is -(CH ₂ ) _n C(=0)R ² and n is not 0, R ² is not OH or NH ₂ ;

when R is -(CH ₂ ) _n S0 ₂ R ² and n is 0, R° is not H;

when R is and n is not 0, R ² is not OH; and

when R and R° combine together to form triazole then Z is not H.

In another embodiment the present invention relates to a compound of formula (I), (la) or (lb), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R is -(CH ₂ )„C(=0)R ² _J -(CH ₂ ) _n C(=S)R ² , -(CH ₂ ) _a S0 ₂ R ² , or -CH(=NH); or

R and R° together with N to which they are attached form a substituted or. unsubstituted

5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;

with the provisos that when R is -<CH ₂ ) _n C(=0)R ² , n is 0 and R° is H, then R ² is not unsubstituted Ci^alk l; . when R is -{CH ₂ ) _a C(=0)R ² and n is not 0, R ² is not OH or N¾

when R is - CH ₂ ) _n Sb2R ² and n is 0, R° is not H;

when R is -{CH^SOJl ² and n is not 0, R ² is not OH; and

. when R and R° combine together to form triazole or tetrazole then Z is not H. ^'

In another embodiment the present invention relates to a compound of formula (I), (la) or (lb), or a stereoisomer, internal saltN-oxide, or pharmaceutically acceptable salt thereof, wherein ^'

R tituted

5-6 membered cyclic ring with 0, 1, 2, 3. or 4 additional heteroatom ring atoms independently selected from N, O and S;

with the provisos that

when R is -{CH^CfOJR ² , n is 0 and R° is H, then R ² is not unsubstituted Ci-ealkyl; when R is -{C¾) _n C(=0)R ² and n is not 0, R ² is not OH or NH ₂ ;

when R is -<CH ₂ ) _n S0 ₂ R ² and n is 0, R° is not H; and

when R is - H ₂ ) _D S0 ₂ R ² and n is not 0, R ² is not OH.

In another embodiment of the present invention,

R is - C¾) _n C(=0)R ² , - CH ₂ ,C(=S)R ² , -{CH^S^R ² , or -CH(=NH); or .

R and R° together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S; . , ^*

with the provisos that

when.R is -{CH^CfOJR ² and n is 0, R° is not H;

when R is■^CH ₂ ) _II C(=0)R ² and n is not 0, R ² is not OH or NH ₂ ;

when R is -(CH^SO^ ² and n is 0, R° is not H; and

when R is -CCH ₂ ) _n S0 ₂ R ² and n is not 0, R ² is not OH.

In another embodiment of the present invention, R ¹ is C ₂ ^aminoalkyl optionally substituted with -CR*=NR .

. In another embodiment, A represents -NR°R. In another embodiment, A represents

-OR ¹

In another embodiment, Z represents -H. In another embodiment, Z represents -CH ₃ . In another embodiment, X represents -S-. In another embodiment, X _r represents -CH ₂ -. In another embodiment, R° is hydrogen.

In another embodiment, R is -{CH ₂ ) _n C(=0)R ² .

In another embodiment, R ¹ is In another embodiment, R ^! is HetC or -(CH^J^H^ HONH^

In another embodiment, R ^! is - CH ₂ )o.6-HetC. In another embodiment, R ¹ is - HetC. In another embodiment, R ^! is -{CH2)i-6NH(C=NH)NH2- In another embodiment, R ^! is -

In another embodiment, R ² is AryA. In another embodiment, R ² is tetrazole.

In another emrjodiment, R ⁴ is -CO2H.

In one embodiment, HetC is a substituted or unsubstituted pyrrolidine.

In one embodiment, R ^c is -C(=NH)-pyrrolidin-l-yl substituted with ISIH2.

In another embodiment, R ^d is hydrogen.

In another embodiment, R ^c and R ^d are taken together, with the N to which they are attached, to form a a heterocyclic ring or ring system selected from: azetidine, pyrrolidine, piperazine, o ^' ctahydropyrrolo[3,4-b]pyrrole, octahydro-lH-pyrrolb[3,2-c]pyridine, 2,7- diazaspiro[.4,4]-nonane, octahydropyrrolo[3,4-d] imidazole, and 3,8-diaza- tricyclo[5.2.1.01,5]decane, wherein the heterocyclic ring or ring system is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: =NH, -{CH2) _M OH, -

In another embodiment, R ^c and R ^d are taken together, with the N to which they are attached, to form a a heterocyclic ring or ring system selected from: zetidine, pyrrolidine, piperazine, octahydropyrrolo[3,4-b]pyrrole, octahydro-lH-pyrTolo[3,2-c]pyridine, 2,7- diazaspiro[4,4]-nonane, octahydropyrrolo[3,4-d] imidazole, and 3,8-diaza- wherein the heterocyclic ring or ring system is optionally substituted with.l, 2, 3 or 4 substituents independently selected from: -NH, -CH ₂ OH, OH, - CH ₂ CH(OH)CH ₂ NH2, ^' -{C^aMrt optionally substituted with -NH ₂ , -CH ₂ CH(NH ₂ )CH2NH2, - gen.

In another embodiment, HetC is substituted with one substituent selected from -

C(=0)NR ^e R ^d .

In another embodiment of the present invention, the pharmaceutically acceptable salt is selected from sodium, potassium, ^' calcium, magnesium and ammonium salts.

In a twelfth embodiment of the invention, the compound of the invention is selected from the exemplary species depicted in EXAMPLES 1 to 601 shown below, and pharmaceutically acceptable salts thereof.

In a thirteenth embodiment of the invention, the compound of the invention is selected from the exemplary species depicted in EXAMPLES 32, 44, 95, 103, 106, 112, 120, 121, 124, 129, 132, 135, 146, 149, 157, 158, 159, 161, 168, 169, 176, 178, 184, 186, 218, 219, 221, 242,264, 278, 283, 298, 314, 324, 352, 360, 361, 362, 363, 364^ 365, 366, 367, 368, 391, 395, 396, 397, 398, 400, 404, 411, 412, 413, 414, 419, 420, 425, 426, 427, 429, 431,

432, 433, 435, 437, 438, 439. 457, 481, 493, 505, 521, 523, 544, 545, 560, 566, 567, 571, 575, 576, 580, 584, 585, 593 shown below, and pharmaceutically acceptable salts thereof Reference to different embodiments with respect to Formula I or (I) compounds, specifically includes different embodiments of Formula I, such as Formulas la and lb, sub- embodiments of Formulas la and lb, other embodiments provided herein, and individual compounds described herein.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising a compound of Formula I or la or lb, .as defined herein, of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of (a), further comprising a beta- lactamase inhibitor.

(c) The pharmaceutical composition of (b), wherein the beta lactamase inhibitor is clinically approved Clavulariic acid and its salts, Sulbactam and its salts, Tazobactam and its salts, Avibactam and its salts, and Cilastatin and its salts. Other beta lactamase inhibitors include Relebactam, RPX 7009 and BAL 30072. .

(d) A pharmaceutical composition which comprises (i) a compound of formula (I), (la) or (lb), or a pharmaceutically acceptable salt thereof, and (ii) a beta lactamase inhibitor, wherein the compound of formula I or la or lb, and the beta lactamase inhibitor are each employed in an amount that renders the combination effective for overcoming drug resistance in a bacterial infection.

(e) The combination of (d), wherein the beta lactamase inhibitor is clinically approved Clavulanic acid and its salts ^' , Sulbactam and its salts.Tazohactam and its salts, Avibactam and its salts, and Cilastatin and its salts. Other beta lactamase inhibitors include Relehactam, RPX 7009 and BAL 30072

(f) A method for inhibiting bacterial peptidoglycan synthesis which comprises adrninistering to a subject in need of treatment an effective amount of a compound of Formula I or la or lb, or a pharmaceutically acceptable salt thereof.

, (g) A method for preventing and/or treating a bacterial infecti on which comprises adn-inistering to a subject in need of such treatment an effective amount of a compound of Formula I or la or Ih, or a- pharmaceutically .acceptable salt thereof.

(h) A method for treating a hacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of the composition of (a), (b), (c), (d), or (e). ^"

(i) The method of treating a bacterial infection as set forth in (f), (g), or (h), wherein the hacterial infection is due to Escherichia spp., or Pseudomonas spp., Staphylococcus spp., or Streptococcus spp.

The present invention also includes a compound of Formula I or la or lb, or a pharmaceutically acceptable salt thereof,

(1) for use in, (2) for use as a medicament for, or

(3) for use in the preparation (or manufacture) of a medicament for, medicine or inhibiting bacterial peptidoglycan synthesis or treating bacterial infection. In these uses, the compounds of

■ the present invention can optionally be employed in combination with one or more beta- lactamase inhibitors.

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

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

Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein the compound of the present invention or its salt employed therein is substantially pure.. With respect to a pharmaceutical composition comprising a compound of Formula I or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that ■ the term "substantially pure" is in reference to a compound of Formula I or its salt per se; i.e., the purity of the active ingredient in the composition.

Definitions: .

"Alkyl" means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Other groups having the prefix "alk", such as alkoxy and alkanoyl, also may be linear or branched, or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, penry!, hexyl, hepryl, octyl, and the like.

"Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may he linear or branched, or combinations thereof, unless otherwise defined.

Examples of alkenyl include vinyl, allyl, isnpropenyl, pentenyl, hexenyl, heptenyl, 1-prnpenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

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

"About", when modifying the quantity (e.g., kg, L, or equivalents) of a substance or composition, or the value of a physical property, or the value of a parameter characterizing a process step (e.g;, the temperature at which a process step is conducted), or the like refers to variation in the numerical quantity that can occur, for example, through typical measuring, handling and sampling procedures involved in the preparation, characterization and or use of the substance or composition; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make or use the compositions or carry out the procedures; and the like. In certain embodiments, "about" can mean a variation of± 0.1, 0.2, 0.3, 0.4; 0.5, 1.0, 2.0, 3.0, 4.0, or ^" 5.0 of the appropriate unit. In certain embodiments, "about" can mean a variation of ± 1%, 2%, 3%, 4%, 5%, 10%, or 20%.

- "Aromatic ring system", as exemplified herein, by AryA, AryB and AryC, means monocyclic, bicyclic or tricyclic aromatic ring or ring system containing 5-14 ring atoms, • wherein at least one of the rings is aromatic. Aromatic ring systems, as used herein, encompass aryls and heteroaryls. The term may be used to describe. a carbocyclic ring fused to an aryl - group. For example, a 5-7-membered cycloalkyl can be fused through two adjacent ring atoms to a 5-6-membered heteroaryl containing 1, 2, or 3 heteroatom ring atoms selected from N, O, and S. In another example, a heteromonocyclic ring is fused through two ring atoms to a phenyl or 5-6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

"Aryl" means' a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 6-14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl and aphthyl.

"Cycloalkyl" means a saturated monocyclic, bicyclic or bridged carbocyclic ring, having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclohutyl, cyclopenryl, cyclohexyl, and the like. ;

"Drug resistant" means, a bacterium which is no longer susceptible to at least one previous ly.effective.drug; which has developed the ability to withstand antibiotic attack by at . . least" one previously effective drug. A drug resistant strain may ^' relay that ability to withstand to its progeny. Said resistance may be due to random genetic mutations, in the bacterial cell that alters its sensitivity to a single drug or to different drugs.

halogen" includes fluorine, chlorine, and bromine.

heteroaryl" means monocyclic, bicyclic or tricyclic ring or ring system contirining 5- 14 carbon atoms and containing at least one ring heteroatom selected from N, NH, a N as a quaternary salt, S (including SO and SO-) and O, wherein at least one of the heteroatom containing rings is aromatic. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazoiyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazoryl, benzopyrazolyl, benzo furanyl, benzothienyl (including S-oxide and dioxide), benzotriazolyl, furo(2,3-b)pyridyk quinolyl, indolyl, isoquinolyl, quinazolinyL. dibenzofuranyl, and the like.

heterocycle" means monocyclic, bicyclic or tricyclic saturated or monounsaturated ring or ring system containing 3-14 carbon atoms and containing at least one ring heteroatom selected from N, NH, a N as a quaternary salt, S (including SO and S0 ₂ ) and O. When a heterocycle contains two rings, the rings may be fused, bridged or spiro-linked. Examples of monocyclic heterocycle rings include piperazine, piperidine, and morpholine. When a heterocycle contains . two or more rings, the rings may be fused, bridged and/or spiro-linked. Examples of monocyclic heterocycle rings include piperazine, piperidine, and morpholine. Examples of tricyclic ring systems include 8-azaspiro[bicyclo[3.2.1]octane-3,3'-pyrrohdine

"Oxo" means an oxygen atom connected to another atom by a double bond and is can he represented ' -Ο".

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

Recitation or depiction of a specific compound in the claims (i.e., a species) without a specific stereoconfiguration designation, or with such a designation for less than all chiral centers, is intended to encompass the racemate, racemic mixtures, each individual enantiomer, a diastereoisomeric mixture and each individual diastereomer of the compound where such forms are possible due to the presence of one or more asymmetric centers^ With respect to a ^' compound of the invention which has one or more asymmetric centers ^' and can occur as mixtures of stereoisomers, a substantially pure compound can. be either a substantially pure mixture of the stereoisomers or a substantially pure individual diastereomer or enantiomer. All isomeric forms of these compounds, whether individually or in mixtures, are within the scope of the present invention.

When any variable (e.g., R , R¾ etc.) occurs more than one time in any constituent or in. ^* formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A squiggly line across a bond in a substituent variable represents the point of attachment. · ^'

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

In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R^ , ^, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.

The term "substituted" shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

When a group, e.g., Ci.galkyl, is indicated as being substituted, such substitutions can also be occur where such group is part of a larger substituent, e.g., and -Q.galkyl-aryl. '

In the compounds of formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. ^■ The present invention is meant to include all suitable isotopic variations of the compounds of formula I. For example, different isotopic forms of hydrogen (H) include protium ('Η) and deuterium ( ² H or D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically- enriched compounds within formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those ^" described in the EXAMPLES herein using appropriate isotopically-enriched reagents and/or intermediates. Unless expressly stated to the contrary in a particular context, any of the various cyclic rings and ring systems described hereto may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroaiom) provided that a stable compound results.

Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaromatic ring described as containing from "1 to 4 heteroatoms" means the ring can contain 1 , 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a ^• heterocyclic ring described as containing from " 1 to 4 heteroatoms" is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3

^' heteroatomSj and 4 heteroatoms. Similarly, -e when used with a chain, for example an alkyl chain, means that the chain can contain 1, 2, 3, 4, 5 or 6 carbon atoms. It also includes all ranges contained therein including C1.5, CM, CU, C^, C2-5, C3.6, C4.6, C5.6, and all other possible combinations.

. A "stable" compound is a compound which can be prepared and isolated and whose■ structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present invention are limited to stahle compounds embraced by Formula I.

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

. As indicated above, the compounds of the present invention can be employed in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptahle salt" refers to a salt which possesses the effectiveness of the parent compound and which is not hiologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). A pharmaceutically acceptahle salt can be formed, for example, by treating the compound of the invention (e.g., a compound of Formula Γ) with one molar equivalent of a mild base (e.g., sodium carhonate, sodium bicarhonate, potassium bicarbonate, or sodium acetate). In this case, M is a ^' cation, such as Na ⁺ in the event of treatment with a sodium base.

Described herein are also prodrugs of a compound of the invention, which on administration · undergo chemical conversion by metabolic processes before becorning active pharmacological substances. In general, such prodrugs will be functional derivatives of a compound of the invention that are readily convertible in vivo into compound of formula (Γ).

As set forth above, the present invention includes pharmaceutical compositions comprising a compound of Formula I of the present invention, optionally one or more other active components,, and a pharmaceutically acceptable carrier. The characteristics of the carrier will depend on the route of administration. By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition must be compatible with each other, do not interfere with the effectiveness of the active ingredient(s), and are not deleterious (e.g., toxic) to the recipient thereof. Thus, compositions according to the invention may, in addition to the inhibitor, contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art -

Also as set forth above, the present invention includes a method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The term "subjecf ' (or, alternatively, "patient") as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The term "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of Formula I mean providing the compound, or.a pharmaceutically ' acceptable salt thereof, to the individual in need of treatment. When a compound or a salt thereof is provided in combination. with one or more other active agents, "aarninistration" and its vari ants are each understood to include provision of the. compound or its salt and the other agents at the same time or at different times. .When the agents of a combination are administered at the same time, they can be administered together in a single com osition or they can be administered separately. It is understood that a "combination" of active agents can be a single composition containing all of tbe.active agents or multiple compositions each containing one or more of the active agents. In the case of two active agents a combination can be either a single composition comprising both agents or two separate compositions each comprising one of the agents; in the cas e of three active agents a combination can be either a single composition comprising all three agents, three separate compositions each comprising one of the agents, or two' compositions one ^■ of which comprises two of the agents and the other comprises the third agent; and so forth.

. The compositions and combinations of the present invention are suitably acLministered in effective amounts. The term "effective amount" as used herein with respect to a nargenicin compound means the amount of. active compound sufficient to inhibit DnaE and/or cause a bacteriocidal or bacteriostatic effect. In one embodiment, the effective amount is a

"therapeutically effective amount" meaning the amount of active compound that can overcome bacterial drug resistance and which is sufficient to inhibit bacterial replication and/or result in bacterial killing. When the active compound (i.e., active ingredient) is administered as the salt, references to ^' the amount of active ingredient are to the free acid or free base form of the compound.

The administration of a composition of the present invention is suitably parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intraocular, or intrarectal, wherein the composition is suitably formulated for administration by the selected route using formulation methods well known in the art, including, for example, the methods for preparing and adrninistering formulations described in chapters 39, 41, 42, 44 and 45 in Remington - The Science and Practice of Pharmacy, 21 ^st edition, 2006. In one embodiment, compounds of the invention are administered intravenously in a hospital setting. In another embodimem

. administration is oral in the form of a tablet or capsule or the like. The dosage of the compounds of the invention and of their pharmaceutically acceptable salts may vary within wide limits and should naturally be adjusted, in each particular case, to the individual conditions and to the pathogenic agent to be controlled. In general, for a use in the treatment of bacterial infections, the daily dose may be between 0.005 mg/kg to 100 mg/kg, 0.01 mg/kg to 10 mg kg, 0.05 mg/kg to 5 mg kg, 0.05 mg kg to 1 mg/kg. For oral administration, the compositions are preferably ■ provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

In some embodiments, the compound in the invention is provided in a pharmaceutical formulation for oral intravenous, intramuscular, nasal, or topical administration. Thus, in some embodiments, the formulation can be prepared in a dosages form, such as but not limited to, a tablet, capsule, liquid (solution or suspension), suppository, οϊηπηεηζ cream, or aerosol. In some embodiments, the presently disclosed subject matter provides such compounds and or formulations that have been lyophilized and that can be reconstituted to form pharmaceutically ■ acceptable formulations for administration, for example, as by intravenous or intramuscular injection.

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

The methods of the presently disclosed subject matter are useful for treating these conditions in that they inhibit the οη$εζ growth, or spread of the condition, cause regression of the condition, cure the condition, or otherwise improve the general well-being of a subject afflicted with, or at risk of, contracting the condition. Thus, in accordance with the presently disclosed subject matter, the terms "treat", "treating", and grammatical variations thereof, as well as the phrase "method of treating", are meant to encompass any desired therapeutic intervention, including but not limited to a method for treating an existing infection in a subject, and a method for the prophylaxis (i.e., preventing) of infection, such as in a subject that has been exposed to a . microbe as disclosed herein or that has an expectation of being exposed to a microbe as disclosed herein.

Infections that may be treatable by the compounds of the invention can be caused by a variety of microbes, including fungi, algae, protozoa, bacteria, and viruses. In some

embodiments, the infection is a bacterial infection. Exemplary microbial infections that may be treated by the methods of the invention include, but are not limited to, infections caused by one or more of Staphylococcus aureaus, Enter ocbccus faecalis, Bacillus anthracis, a Streptococcus species (e.g., Streptococcus pyogenes arid Streptococcus pneumoniae), Escherichia coli, Pseudomonas aeruginosa, Burkholderia cepacia, a Proteus species (e.g., Proteus mirabilis and Proteus vulgaris), Klebsiella pneumoniae, Acinetobacter baumannii, and Strenotrophomonas maltophillia.

In certain embodiments, the infection is an infection of a bacterium selected from · Pseudomonas spp. , Klebsiella spp., Enterobacter spp., Escherichia spp., Morganella spp., Citrobacter spp., Serratia spp. or Acintetobacter spp.

In some embodiments, the compound of Formula (Γ), (la) or (lb), is administered •prophylacticaJly to prevent or reduce the incidence of one of: (a) a bacterial infection in a subject at risk of infection; (b) a recurrence of a bacterial infection; and (c) combinations thereof. In some embodiments, the compound of Formula (I), (la) or (lb), is administered to treat an existing bacterial infection. In some embodiments, the compound of Formula ((I), (la) or (lb), is

' administered to treat an infection of a multi-drug resistant strain of bacterial (i.e., a strain that is resistant to two or more previously known anti-bacterial drugs, such as i) Carbapenemase producing Enterobacteriaceae that are resistant to Cephalosporins and certain carbapenems; ii) Extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae that are resistant to cephalosporins and penicillins; iii) Aminoglycoside and Fluoroquinolone resistant

Enterobacteriaceae; iv) Extended spectrum β-lactamase (ESBL) producing P. aeruginosa and v) Aminoglycoside and Fluoroquinolone resistant P. aeruginosa.. In some embodiments, the compound of Formula (I), (la) or (lb), has a minimum inhibitory concentration (MIC) against one or bacterial species of 25 or less. In some embodiments, the compound of Formula (I ^a ) ^or (lb), is adininistered to treat an infection of a multi-drug resistant strain.

In some embodiments, the compound of Formula I, la, has a minimum inhibitory concentration (MIC) against one or more bacterial species of 25 ]i§JraL or less. MICs can he determined via methods known in the art, for example, as described in Hurdle et al., 2008, J. A ntimicrob. Chem other..62 : 1037- 1045.

In some embodiments, the methods of the invention further comprise admim^tering to the

^' subject an additional therapeutic compound. In some embodiments, the compound of the ■ invention is aitainistered to the subject before, after, or at the same time as one or more additional therapeutic compounds. In some embodiments, the additional therapeutic compound is an antibiotic.

The invention thus provides in a further aspect, a combination comprising a compound of Formula I, or a. pharmaceutically acceptable salt thereof, together with one or more additional therapeutic agents. Examples of such one or more additional therapeutic agents include, but not limited to, β- lactams, aminoglycosides, tetrac clines, macrocycles, oxazolidinones,

glycopepudes, Upopeptides, quinolones, etc., ^"

Thus, the other antibiotic which may be combined with the compounds of. formula I or la or lb are, for example, Vancomycin, Linezolid, Tedizolid, Ceftaroline, Ceftobiprole,

Ceftalozane, Daptomycin, Dalbavancin, Telavancin, Oritavancin, Aztreonam, Delafloxacin, . GSK2140944, Piazomicin, Tigecycline, Solithromycin etc.,

Abbreviations employed herein include the following: . AC = acetonitrile; aq. = aqueous; Bn = benzyl; Boc = tert-butoxy carbonyl;.CDCl ₃ = deuterated chloroform; CDI =

carbodiimidazole; DCE = 1,2-dichJoroethane; DCM = dichloromethane; DIAD = diisopropyl azodicarboxylate; DIPEA = diisopropylethylamine; DMAP = 4-dimethylaminopyridine or N,N- dimethy laminopyridine; DMF =. ,N-dimethylformamide; DMSO = dimethyl sulfoxide; Et = ethyl; EtOAc = ethyl acetate; ¾ = hydrogen gas, HPLC = high-performance liquid

chromatography; LC-MS = liquid chromatograpby/mass spectrometry; Me = methyl; MeCN = acetonitrile; MeOH = methanol; MIC = minimum inhibitory concentration; MW = molecular weight; MS = mass spectrometry; Pd C = palladium on carbon; PNB - p-nitrobenzyl; PNZ =]p nitrobenzyl carbamate; PPh ₃ = triphenylphosphine; RB = round bottom flask; RT = room temperature; TBDMS= tert-butyl dimethylsilyl; TBTU =NNN',N-te1xamemyl-0-(benzotriazol- 1-yl) uroniumtetrafluoroborate; TEA = triethylamine; TFA = trifluoroacetic ^' acid; THF = tetrahy drofnran; ^" TLC = thin layer chromatography.- The compounds disclosed herein can be prepared according to the following reaction schemes and EXAMPLES, or modifications thereof; using readily available, starting materials, re gents and conventional synthesis procedures. In these reactions, it is also possible to make use of variations which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds disclosed herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and EXAMPLES.

Described below are processes for the preparation of a compound of formula ((I), (la) or (lb) as shown in the general schemes 1 , 2, 2a and 3, wherein all the groups are as defined earlier.

Step 1: The Compound of formula (1) was prepared according to known' methods available in the literature. The reaction was carried out in the presence of base, alkaline carbonates such as sodium carbonate, potassium carbonate and the like in a suitable solvent such as tetrahydrofuran (THF), dimethoxyethane, ether, dichloromethane (DCM), dimethylformamide (D F), acetone . and the like.

Step 2: The silyl group in compound of formula (1) was deprotected by mineral acids such as HC1, H2SO4 and the like in presence of solvent such as tetrahydrofuran,. dioxane, acetonitrile (A CN), dimethylformamide and the like to yield the compound of formula (2). - Step 3: The compound of formula (3) was obtained by reacting a compound of formula (2) with triphenylphosphine (ΡΡΙ¾), formic acid and Diisopropyl azodicarbox late (DIAD) in the presence of THF.

Step 4: The compound of formula (3) was hydrolyzed according to the procedure given in Bull Chem Soc Japan, 1976, 4 _. 9. 510 to yield the compound of formula (4).

Step 5: The compound of formula (4) was reacted with triphenylphosphine, hydrazoic acid and DIAD according to the procedure given in Tetrahedron Letters, 1983, 49 ₍ 54, to yield the ' compound of formula (5).

Step, 6: Reducing the Compound of formula (5) using reducing reagents such as

triphenylphosphine, trimemylphosphine, triethylphosphine, tributylphosphine, methyl m^henylphosphinite or ethy ldiphenylphosphinite and the like in presence of aqueous organic solvents such as tetrahydrofuran (THF), dioxane, acetonitrile (ACN), acetone, or

dimethylformamide (DMF) containing about 1% to 50% water, preferably about 5% to 10% water and the like according to known Staudinger reaction gave the compound of formula (6). Step 7: The compound of formula (7) was synthesized by reacting a compound of formula (6) with amino protecting group in presence of organic base such as sodium bicarbonate and the like and water soluble snlvents such as THF, dioxane and acetone followed by hydrolyzing using base such as LiOH and the like. Suitable amino-protecting groups include, for example, acyl groups such as formyl, acetyl and substituted acetyl (e.g., halogenated acetyl), benzoyl and substituted benzoyl, alkoxycarbonyl, halogenated alkoxycarbonyl, alkenyloxycarbonyl, aralkoxycarbonyl, halogenated aralkoxy carb ony 1, benzyl and benzyl derivatives, trityl and trityl derivatives, sulfenyl derivatives, sulfonyl derivatives, diacyl derivatives such as phthalimido or succinimido or derivatives thereof and Schiff bases formed with aldehydes or ketones.

Carbamate protection was done by using di-tert-butoxycarbonylanhydride (BOC anhydride) and . - inorganic base such as sodium bicarbonate in water soluble solvent such as tetrahydrofuran, dioxan and acetone.

Step 8: The Compound of formula (7) was reacted with carbodiimidazole and magnesium mono p-nitrobenzyl malonate ester by a known method given in D. G. Melillo et al., Tetrahedron Letters, 1980, 21, 2783 to yield the compound of formula (8). The reaction of a magnesium malonate with the activated carboxy- moiety was carried out in organic solvent such as tetrahydrofuran, dioxane, dichloromethane, acetonitrile, benzene, toluene and the like.

Step 9: The compound of formula (8) was subjected to a diazo-transfer reaction to yield compound of formula (9). The compound of formula (8) was treated with an azide such as dodecabenzenesulfonylazide, 4-carboxybenzenesulfonylazide, p-toluenesulfonylazide, methanesulfonylazide and the like in presence of a base such as triethylamine (TEA),

diemylarnine, pyridine or lutidine and the like and solvent such as acetonitrile, dichloromethane, toluene, benzene and the like to yield the Compound of formula (9).

Step 10: The compound of formula (10) was synthesized by treating the compound of formula (9) with acids such as trifluoroacetic acid (TFA) or HCl and the like in presence of solvents such as dioxane or- ether and the like,

Step-1 la: Reacting compound of formula (10) with R ^A COOH in the presence of coupling agents such as c-u-bodiimides, phosphonium, uronium, guanidinium salts and the like and solvents such as ethyl acetate (EtOAc) and the like gave the compound of formula (11).

Step l i b: Reacting compound of formula (10) with R ^A X (X is CI, Br, F, I) in the presence of acid binding agents such as alkali acetate, alkali hydroxide, calcium oxide, calcium carbonate, magnesium carbonate or organic bases such as pyridine, N-methyl morpholine,

d ^opropylemylarnine (DEPEA), TEA and the like and solvents such as DCM, dioxane, toluene, and the like gave the compound of formula ( 11).

Step 11c: The compound of formula (10) was reacted with carbonylating agent such as phosgene; diphosgene, triphosgene, N,N'-carbonyldiimidazole (CDI), thiophosgene, thjocarbonyldiimida-zole and the like in presence of bases such as pyridine, N-methyl morpholine, DEPEA, TEA and the like in solvents such as DCM, 1,2-dichloromethane, toluene, ACN and the like and successively treated with R ^A OH/R ^A NH ₂ to yield the compound of formula (1 1). ^" ·

. SCHEME 2a

Ste

triphenylphbsphine and DIAD in solvents such as THF and the like to obtain a compound of formula (11). '

Step 1 le: The compound of formula (b) was reacted with compound (c) in presence of copper iodide and DEPEA in solvents such as toluene and the like to obtain a compound of formula (11).

SCHEME 3

Step 12: The compound of formula (12) was prepared by reacting a ^' compound of formula (11) with the compound of general formula H-SR ¹ , wherein the R ¹ is as defined earlier in presence of activating agent such as diphenyl chlorophosphate, dimemylaniinopyridine (DMAP) and the like and catalyst such as bis(acet lacetonate)Cu(n), copper sulfate, copper powder, rhodium acetate [Rh ₂ (OAc) ₄ ], rhodium(n)octanoate, Pd(OAc) ₂ , Pb(OAc) ₄ and the like and solvents such as tetfahydrofuran, ethyl acetate, benzene, toluene, hexane, cyclohexane and the like.

Step 12a: Reacting the compound of formula (12) with 2-iodoacetamide or iodomethane and the like in presence of solvents such as THF-acetone and the like gave the compound of formula (I), (la) or (lb).

Step 13: The compound of formula (I), (la) or (lb), was prepared by reducing the compound of ■ formula (12) or the compound of formula (12a) with Pd C in presence of solvents such as THF- water and the like under pressure. ^'

Step 14: Hydroxymethylation by a cross coupling reaction between carbapenem-2Ttriflate and Bu ₃ SnC¾OH. ^' -

Step 15: Allylic carbonate (14) was prepared by isobutylchloroformate in presence of DIPEA, DMAP. and in solvents like dichloromethane and tetrahydrofuran.

Step 16: AUylic amine (15) was prepared by reaction of allylic carbonate (14) and amine in presence of Palladium catalyst

Step 17: Formula (la) was prepared by reducing the compound of formula (15) with Pt C in presence of solvents such as THF-water and the like under pressure.

The examples below are provided by way of illustration only and should not be considered to limit the scope of the invention. EXAMPLES

Preparation 1: (H Benzyl 2-((2.y^,S 3-((.¾-l-(^butyldiinethyk^

2-yl)propanoate

To a mixture of (2y-2-((2,S,3iS 3-((i9-l-(/-butyi^

y propanoic acid (1 g, 3.32 mmoles), potassium carbonate (0.68 g, 4.95 mmoles) and acetone (10 mL), benzyl bromide ( 0.63 g, 3.67 mmoles) was added and heated to reflux for 5 hours. The reaction mixture. was filtered and the residue was washed with ethyl acetate (25 mL). The organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated to afford the title compound as oil. (1.2 g, 92.3 %j. 'HNMR. (T>MSO-d ₆ ) δ pm: 0.01 (d, 6H), 0.79 (s, 9H), 1.04 (d, 6H), 2.37-2.46 (m, 1H), 2.84 (t, 1H), 3.63-3.65 (d, . lH), 4.02-4.07 (m, 1H), 4.83-4.84 (m, 2H), 7.30-7.38 (ra, 5H), 8.06 (s, 1H).

Preparation 2: (i-)-Benzyl-2-((2S'^5)-3-((i-)-l-hydro^eaiyl)-4-oxoazendin-2 -yl) propanoate

Aqueous hydrochloric acid (2 N, 10 mL) was added to 10 g

butyldimemyIsDyloxy)emyl)-4-oxoazeu ^' din-2-yl)propanoate (10 g) dissolved in acetonitrile (100 mL) and stirred at room temperature for 3 hours. Reaction mixture was concentrated to obtain .crude oil, which was dissolved in ethyl acetate (250 mL). The organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated under vacuum. The residue thus obtained was triturated with hexane (100 mL), filtered and dried to give the product as a white solid (6.2 g, 87.5 %). Ή NM (DMSO-de) δ ppm: 1.08-1.09 (d, 3H), 1.17-1 :18 (d, 3H), 2.66-2.73 (m, 1H), 2.86 _: 2.87 (d, 1H), 3.63-3.65 (d, 1H), 3.86-3.91 (m, 1H), 4.85-4.86 (d, 1H), 5.08-5.31 (m, 2H), 7.35-7.42 (m, 5H), 8.17 (s, 1H).

Preparation 3: ( -Benzyl 2-((2S^-S 3-((^-Hformyloxy)ethyI)-4-oxoazetidin-2-yl) propanoate _.

To a solution of (SJ-benzyl 2-((25,3¾-3-((2y-l-hy(koxyemyl)-4-oxoazetidin-2-yl) propanoate

(10 g, 36.05 mmoles) in tetrahydrofuran (100 mL), was added triphenylphosphine (15.2 g, 57.95 mmoles) and 98 % formic acid (3.33- g, 72.34 mmoles) at ice-cold condition.

Diisopropylazodicarboxylate (11.7 g, 57.86 mmoles) was then added to the reaction mixture, slowly over a.period of 15 minutes. The reaction mixture was further stirred at ice-cold condition for a period of 30 minutes. Subsequently, water (50 mL) was added and the reaction mixture was extracted withi ethyl acetate (100 mL). The organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated under vacuum. · The residue thus obtained was stirred with toluene (100 mL) and filtered. The filtrate was concentrated to yield oily crude. The crude thus obtained was purified by column

' chromatography to yield the product as an oily substance (3.32 g, 30.2 %). 'H NM fDMSO-de) δ ppm: 1.036 (d, 3H), 1.13 (d, 3H), 2.49-2.5 (q, 1H), 2.65 (t, 1H), 2.81-2.83 (q, 3.58-3.6 (q, 1H), 3.8 1-3.85 (q, 1H), 4.80 (br, 1H), 5.03-5.12 (dd, 2H), 7.30-7.38 (rn, 5H), 8.12 (s, 1H).

Preparation 4: (SJ-Benzyl propanoate

To a solution of (R)-benz l 2-((2S,3S)-3-((S l-(formy]oxy)ethyl 4-oxoazetidin-2-y])propanoate (10 g, 32.75 mmoies) in tetrahydrofuran (100 mL), lithium hydroxide (0.768 g,

32.07 mmoies) dissolved in 30 mL water was added at ice cold condition. After completion of the reaction, the reaction mixture was concentrated and diluted with ethyl acetate (150 mL). The organic layer was washed with water and brine. After drying over, sodium sulphate, the organic layer was concentrated. The crude product thus obtained was purified by column

chromatography to yield the product as white color solid. (8 g, 88.1 %). ^: H N R (DMSO-de) <S ppm: 1.12 (d, 3H), 1 ,17 (d, 3H), 2.65-2.70 (q, 1H), 2.84 (q, 1H), 3.48-3.51 (m, 1H), 3.81-3.85 (m, 1H), 5.09 (dd, 2H),

Preparation 5: (BJ.-Be

To a solution of (7^-benzyl 2-((2S,35)-3-(('S l-hy ^Q roxyemylH- ^ox o^tidin- ² - propanoate (10 g, 36.05 mmoies) in 200 mL of tetrahydrofuranitoluene (1 :1) was added triphenylphosphine (15.14 g, 57.72 mmoies) and 85 mL of 0.85 M hydrazoic acid (3.1 g, 72.09 mmoies) at -10 ^D C under nitrogen atmosphere. To the above, diisopropylazodicarbox late (1 1.7 g, 57.86 mmoies) was added slowly over a period of 15 minutes. The mixture was further stirred at ice-cold condition for a period of 30 minutes. To the reaction mixture, water (50 mL) was added and concentrated to half of the volume. Then the reaction mixture was extracted with ethyl acetate ^■ (300 mL). The organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated. The residue thus obtained was stirred with toluene (100 mL) and filtered. The filtrate was concentrated to obtain the oily crude. The crude thus obtained was purified by column chromatography to yield the product as an oily substance. (7.95 g, 72.9 %). ^] H NMR (DMSO-di) δ ppm: 1.12-1.19 (m, 6Ή), 2.65-2.71 (q, IH), 3.01-3.03 (q, IH),

Triphenylphosphine (6.51 g, 24.8 mmoles) was added to a solution of (¾)-benzyl 2-((2£, 35 -3- ((7^-l-a23doethyl)-4-oxoazetidin-2-yl)propanoate (5 g, 16.6 mmoles) in tetrahydrofuran (25 mL) and the mixture was stirred at room temperature for 5 hours under nitrogen atmosphere. To the reaction mixture, water (5 mL) was ^{^} added and it was stirred at room temperature for a period of 16 hours. Brine solution (50 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL). The organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated. The residue thus obtained was stirred with toluene (100 mL) and filtered. The filtrate was concentrated to obtain oily crude. The crude thus obtained was purified by column chromatography to yield the product as an oily substance. (4 g, 87.5 %). Ή NMR (DMSO-d ₆ ) <5 ppm: 0.963-0.98 (d, 3H), 1.00-1.12 (d, 3H), 2.62-2.66 (m, IH), 2.69-2.72 (m, IH), 2.96-2.98 (m, IH), 3.52-3.54 (m, IH), 5.08-5.09 (dd, 2H), 7.30-7.39 (m, 5H), 8.15 (s, IE).

Preparation 7: (K BenzyI 2-((2iS,3jR)-3-((3¾)-l-(/-butoxycarbonyIamino)ethyI)-4- oxoazetidin-2-yI)propanoate

To a mixture of sodium bicarbonate (6.1 g, 72.04 mmoles) and (¾J-benzyi 2-((25,3Λ)-3-((7^-Ι- aminoethyl)-4-oxoazetidin-2-yl)propanoate (10 g, 36.18 mmoles) in 150 mL of teb-ahydrofuran : water (2:1), di-i-butyldicarbonate (9.5 g, 43.47 mmoles) was added and stirred at room .

temperature for 6 hours. The reaction mixture was filtered and extracted with ethyl acetate (250 mL). The organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated to obtain the product as a white solid, (10 g, 73.4 %). Ή

NMR (D SO-di) <5 ppm: 1.09-1.112 (m, 6Ή), 1.36 (s, 9H), 2.65-2.70 (m, IH), 2.92 (m, IH), 3.51-3.53 (m, IH), 3.60-3.74 (m, IH), 5.10-5.16 (dd, 2¾ 6.73-6.75 (d, IH), 7.32-7.37 (m, 5H), 8.2 (2, IH).

Preparation 8 : (R)-2-{(2S^R)-3-{(R) -I- (t- toxyca r bonylam ino)ethyI)-4-oio a retidinr2- yl)propanoic acid Lithium hydroxide (0.768 g, 32.07 mmoles) was added to the solution of (2¾)-benzyl 2-((25,3R 3-((7^-I-(/-butDxycarbonylarrimo)ethyl)^oxo2-zetidin-2-yl)pr opanoate (10 g, 26.56 mmoles) in 50 mL of tetiahyajofuran: methanol: water (1: I : 0.5) at ice-cold condition. The reaction mixture was continued to be stirred at room temperature for 1 hour. The reaction ^' mixture was concentrated and diluted with water (150 mL). The aqueous layer was washed with EtOAc (1 50 mL). The separated aqueous layer was now acidified with citric acid to pH 2 and extracted with ethyl acetate (250 mL). The organic layer was washed with water and brine. After drying over sodium sul hate the organic layer was concentrated to give the product as a white solid. (7.05 g, 92.7 %). Ή NMR (DMSO-d ₆ ) δ ppm: 1.09-1.112 (m, 6Ή), 1.39 (s, 9H), .2.50-2.51 (m; 1H), 2.88-2:91 (m, 1H), 3.4-3.58 (m, IH), 3.69-3.75 (m, 1H), 6.7 (d, 1H), 8.15 (s, 1H), 12.35 (s, IH). ^{" ' ^}

Preparation 9: (R 4-Nitrobenzyl ^((ZA^/ii-S-ffK -l-fi-butox carbonylaminoJethyl) -4- . oxoazetidin-2-yI)-3-oxopentanoa

To a solution of (K 2-((2-? _J 3if)-3-((R)- l-(tert-butoxycarbonylarnmo)e l)-4-oxoazetidin-2- . yl)propanoic acid (10 g; 34.93 mmoles) in acetonitrile (100 mL), Ι, Γ-carbonylaiirnidazole (6.52 g, 40.21 mmoles) was added and continued to stir for a period of 1 hour at ice-cold condition under nitrogen atmosphere. The above obtained solution was added slowly to a suspension of magnesium salt of mono-p-nitroben2ylmalonate (20.32 g, 77.26 mmoles) in acetonitrile (100 mL) and stirred for 5 hours at room temperature and heated to 50 °C for a further period of 6 hours under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated and the obtained crude was diluted with ethyl acetate. The organic layer was washed with water. and brine. After drying over sodium sulphate, the organic layer was.

concentrated to give oily crude. The crude thus obtained was purified by column

chromatography to yield the product as a white solid (10 g, 61.78%). Ή NMR (DMSO-di) δ ppm: 1.09-1.1 12 (m,;6H), 1.39 (s, 9H), 2.87-2.91 (m, 1H), 2.99-3.00 (m, 1H), 3.5-3.52 (m, 1H), 3.73-3.77 (m, IH), 3.8-J3.93 (dd, 2H), 5.29 (s, 2H), 6.7 (d, IH), 7.60-7.66 (d, 2H), 8.09 (s, 1 H), 8.23-8.26 (d, 2H). ^' '

Preparation 10: (R)-4-Nirxobeiizyl 4-((2J? _r 3^)-3-((K l-(i-butoxycarbonylamino) etbyl)-4- oxoazetidin-2-yl)-2-diazo-3-oxopen tanoate

To a solution of (7^-4-m ^' trobenzyl 4-((2i¾3R 3-((7^-l-^butoxycarbonylamino) ethyl)-4- oxoazetidu 2-yl)-3-oxopentanoate (10 g, 21.57 mmoles) in acetonitrile (50 mL) was added successively dodecabenzenesulfonylazide (70% in toluene, 13 mL, 25.9 mmoles) and triemylamine (12.7 mL, 1.1 mmoles) at ice-cold condition. The reaction mixture was stirred for 1 hour and then it was concentrated and diluted with ethyl acetate (150 mL). The organic layer was washed with water and brine. After dr ing over sodium sulphate, the organic layer was concentrated to give oily crude. The crude thus obtained was purified by column

chromatography to yield the product as a white solid ( 10 g, 94.69%). Ή NMR (DMSO-de) δ ppm: 1.00-1.02 (d, 3H), 1.06-1.08 (d, 3H), 1.39 (s, 9H), 3.01-3.03 (m, 1H), 3.47-3.49 (m, 1H), 3.63-3.66 (m, 1H), 3.71-3.73 (m, 1H), 5.43 (s, 2H , 6.55 (d, 1H), 7.69-7.72 (d, 2H), 8.15 (s, 1H) ^' , 8.25-8.27 (d, 2H). .

Preparation 11: (R 4-Nitrobenzyl 4-((2J?,3ii 3-( K l-aminoethy])-4-oxoazetidin-2-y] 2- diazo-3-oxopentanoate

Trifluoroacetic acid (1.40 g, 12.3 4- (2R,

(50 mL) was. stirred at room temperature for 30 minutes under nitrogen atmosphere. To the reaction mixture (R)-4-nitrobenzyl 4-((2R, 3R)-3-((R)-l-ammoemyl)-4-oxoazetidin-2-yl)-2- diazo-3-oxopentanoate (1.2 g, 3.08 mmoles) was added and it was stirred for a further period of 30 nunutes. The reaction mixture was treated with water (20 mL) and extracted withEtOAc (50 mL). The separated organic layer was washed with water and brine. After drying over sodium sulphate the organic layer was concentrated to give the product as an off-white solid. ^l H N (D SO-de) δ ppm: 1.47-1.49 (m, 9H), 1.55 (s, 3H), 2.06-2.08 (d, IK), 3.06 (t, IH), 3.64-3.72 (d, IH), 4.31-4.34 (q, IH), 5.43 (s, 4H), 7.29-7.34 (s, 2H , 7.70-7.77 (dd, 4H), 8.25-8.32 (dd, 4H . Preparation 13: f¾l-4-NitrobenzyI 2-0Jazo-4-((2i-^S)-3-(f3y-l-(methylsnlfonamido) ethyl)- 4-oxoazetidin-2-yl)-3-oxop

Methane sulfonyl chloride (0.1 mL, 25.7 mmoles) was added to a mixture of (KJ-4- mtrobenzyl4-((2fl,3fi)-3-((7y- l-arninoethyl)-4-oxoazetidin-2-yl)-2-diazo-3-oxopentanoate (1 g, 2.57 mmoles) and diisopro ^' pyletbylamine (0.92 mL, 51.4 mmoles) in dichloromethane (20 mL) at ice-cold condition under nitrogen atmosphere. The reaction mixture was treated with water (20 mL) and extracted with dichloromethane (50 mL). The separated organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated to obtain crude, which on purification by column chromatography yielded the product as an off-white solid. ^ NMR pMSO-ds^ ppm: 1.14-1.18 (d, 3H), 1.19-1.22 (d, 3H), 2.85 _: 2.89 (d, 1H), 2.91 (s, 3H), 3.52-3.57 (m, 2H), 3.69-3.72 (m, IH), 5.39-5÷47 (dd, 2H), 7.08-7.10 (d, IK), 7.70-7.72 (d, 2H), 8.25-8.27 (dd, 3H).

Preparation 14: (2y-4-Nitrobenzyi 2-dia20-4-((2 -^i-)-3-(f2y-l-(methoxycarbonyl amino)

Methyl chloroformate (0.2 mL, 2.58 mmoles) was added to a mixture of f3¾)-4-nitrobenz l-4- (pfi^R S-ff^-l- mmoemylJ^-oxoazetio^^-yl^-dia-^S-oxo pentanoate (1 g, 2.57 mmoles) and o isopropylethylainine (0.92 mL, 51.4 mmoles) in dichloromethane (20 mL) at ice-cold condition under nitrogen atmosphere. The reaction mixture was treated with water (20 mL) and extracted with dichloromethane (50 mL). The separated organic layer was washed with water and hrine. After drying over sodium sulphate the organic layer was concentrated to obtain crude which on column purification yield an off-white solid. ^J H NMR (DMSO-dg) <5 ppm: 1.01-1.02 (d, 3H), 1.06- 1.09 (d, 3H), 2.82-2.85 (d, IK), 3.44-3.48 (m, IK), 3.49 (s, 3H), 3.65-3.69 (m, 2H), 5.41-5.44 (m, 2H), 7.10-7.12 (d, IH), 7.69-7.73 (d, 2H), 8.25-8.27 (m, 3H).

Preparation 15: (7y-4-Nitrobenzyl 2-d zo^((2 l^R)-3-{(R)-l-(miihoxycaTbono thioylamino)ethyl)-4-oxoazetidiii-2-yl)-3-oxopentanoate.

-To an ice-cold solution of (2iJ-4-nitroben2yl 4-((2R,3-?)-3-((7y-l-am oemyl)-4-oxoazetidin-2- yl)-2-diazo-3-oxopentanoate (1 g, 2.57 mmoles) in dichloromethane (10 mL) was added aqueous solution of NaHCC> ₃ (0.6 g in 10 mL, 7.14 mmoles). Thiophosgene (0.25 mL, 3.34 mmoles) was added to the ahove and stirred for 1 hour. After, completion of the reaction, the reaction mixture was filtered. The organic layer was washed with water ^" and evaporated to obtain a crude product. The crude thus obtained was purified by column chromatography. The compound obtained was dissolved in methanol (10 mL) and heated to reflux for 5 hours. The reaction mixture was evaporated and purified by column chromatography to obtain the title compound. Ή N

(DMSO-de) <5 pm: 1.10-1.15 (d, 3H), 1.21-1.22 (d, 3H), 2.00 (d, ^' lH), 2.88-2.89 (d, 1H), 3.50- 3.51 (m, 1H), 3.61-3.62 (s, 3H), 3.68-3.70 (m, 1H), 5.42 (m, 2H), 6.89-6.90 (d, 1H), 7.70-7.75 (d, 2H), 8.24-8.26 (d, 2H), 8.34 (s, 1H). _

Preparation 16: (¾ -4-Nitrobenzyl 2-diazo-4-((2i?,3i?)-3-((R)-l-(2-meitlioxy-2-oxo acetamido)ethyl)-4-oxoazetidm-2-yl)-3-oxopentaDOate

A mixture of 2-methoxy-2-oxoacetic acid (0.14.g, 1.35 mmoles), N.NJV'.N'-tetramethyl-O- (benzotriazol-l-yl)urohium tetrafluoroborate (TBTU, 0.43 g, 1.35 mmoles) and diisopropyl ethylamine (0.25 mL; 1.46 mmoles) in ethyl acetate (10 mL)^vas stirred for 30 minutes. To the above reaction mixture a solution of f7¾ -4-nitrohenzyl 4-((2R, 3-¾)-3-(^-l-aminoethyl)-4- oxoaz£tidin-2-yl)-2-diazo-3-oxopentanoate (0,6 g, 1.22 mmoles) in ethyl acetate (5 mL) was added and stirred for 2 hours. After completion of the reaction, the reaction mixture was diluted with water. The organic layer was separated and washed with water and brine successively. After drying over sodium sulphate, the organic layer was concentrated to obtain crude which on purification hy column chromatography yielded the product as oily substance. (0.25 g— 42.8%). *H NMR (DMSO-di) <5 ppm: 1.11-1.18 (d, 3H), 1.20-1.21 (d, 3H), 2.08 (d, 1H), 2.86-2.88 (d, 1H), 3.50-3.51 (m, 1H), 3.61-3.62 (s, 3H), 3.65-3.70 (m, 1H), 5.42 (m, 2H), 6.91-6:96 (d, 1H), 7.70-7.71 (d, 2H), 8.22-8.25 (d, 2H), 8.13 (s, 1H). , - Preparation 17: (¾-4-Nitrobenzyl 2-ΰϊ2ζο-4-((2Λ^Λ)-3-((2ξ)-1-(2^- dilluoroacetamido)ethyl)-4-oxoa2etidin-2-yi)-3-dxopentanoate

By following the procedure provided in preparation 16, (KJ-4-nitrobenzyl 4-((2Λ,3Λ)-3-(ίϊζ)-1- ammoethyl)-4-oxoazetidin-2-yl)-2--diazo-3-oxopentanoate (5 g, 12.84 mmoles) was derivatised with difluoroacetic acid to yield the title product (3.7 g.78.7 ). Ή NMR (DMSO-ds) δ p ^' pm: 1.10-1.12 (d, 3H), 1.21-1.23 (d, 3H , -2.06 (d, IH), 2.87-2.91 (d, 1H), 3.51-3.55 (m, 1H), 3.67- 3.69 (in, 1H), 5.43 (m, 2H), 6.94-6.96 (t, 1H), 7.70-7.72 (d, 2H), 8.14-8.16 (d, 2H , 8,20 (s, 1H). Preparation 18: (R)-4-nitro benzyl 4-((2R,3R)-3-((R)-l-cyanamidoethyl)-4-oxoazetidin-2- yl)-2-diazo-3-oxopentanoate

Cyanogen bromide (0.l4g, 1 ,28mmol) was added to a solution of (R)-4-mtrobenzyl 4-((2R,3R)-

3-((R)-l-arninoemyl)-4-oxoa2etidin-2-yl)-2-diazo-3-oxopen tanoate (0.5g, 1.28 mmol) in dichlororaethane (10 mL) at ice cold condition. Triethyl amine (0.3n L, 2.15 mmol) was added to • above and stirred at ice-cold condition for 1 hour. After completion of the reaction, the reaction mixture was treated with water. The organic layer was separated and washed with water and- brine solution. After drying over sodium sulphate, the organic layer was concentrated to obtain crude which on purification by column chromatography yields the product as a white solid.

(0.33g, 62%). 'HNMR (DMSO-di) δ ppm: 1.1 1-1.18 (d, 3H), 1.21-1.23 (d, 3H), 2.08 (d, l _. H), _.

2.87-2.89 (d, 1H), 3.51-3.54 (q, 1H), 3.68-3.71 (q, 1H), 5.43 (S. 2H), 6.95-6.96 (d, 1H , 7.69- ¹

7.71 (d, 2H), 8.24 8.26 (d, 2H), 8.34 (s, 1H).

Preparation 19; ( O-i-diazo^filii^^S-f^l-Cisoxazol-S- lox ieth iy^oxoazetid-n-Z- yl)-3-oxopentanoic

To a solution of (R)-4-nitrobenzyl 2-diazo-4-((2R,3S)-3-((S)-l-hydroxyemylH-oxoazendin-2- yl)-3-oxopentanoate (2.15 g, 5.34 mmoles) in tetrahydrofuran (10 mL) was added

tripbenylphosphine (2.24 g, 8.54 mmoles) and isoxazol-3-ol (0.9 g, 10.62 mmoles) at 0 "C. Diisopropyl azodicarboxylate (1.73 g, 8.56 mmoles) was added slowly at 0 °C for 10 minutes. The reaction mixture was stirred for 5 hours at room temperature. On completion of reaction (as measured by TLC), the reaction mixture was diluted with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and the solvent was evaporated to obtain the crude as an oily substance. The crude product was treated with toluene (10 mL) and stirred at 0 °C for 30 minutes, filtered and washed with 10 mL of toluene (cold). The filtrate and the washings were mixed together and concentrated to obtain crude product. The crude product on purification by column chromatography (15% EtOAc in

To a mixture of p-nitrobenzyloxycarbonyl-Sarcosine (l Og, 37.28 mmoles)

diisopropylemylamine (9.3 mL, 56.26 mmoles) in ethyl acetate (60 mL) was added TBTU ( 14.36 g, 44.72 mmoles) and stirred for 0.5 hour at room temperature. A solution of (R)-4-nitrobenzyl 4-((2R,3R)-3-((R)-l-aiiimoe l)-4-oxoa^ (14.5 g, 37.24 mmoles) in EtOAc (25 mL) was added to the above at 0 °C and the reaction mixture was stirred for 3 hours at room temperature. After completion of the reaction, the reaction mixture was • diluted with EtOAC (150 mL) and.washed with water and brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to obtain crude product as an oily substance. The crude product on purification by column chromatography (20 % acetone in dichloromethane) yields the title compound as a pale yellow solid. (10.7 g, 65 %). Preparation 22: l-(2-ammo^2-oxoethyI^l-methyI-^((2S,4S)-4-((4R,5S,6S^4-methy l-6-((R . l-(methylsulfonamido)ethyl)-2-((4-nitrobenzyloxy)carbonyI)-7 -oxo-l-azabicyclo[3.2.0] hept- 2-en-3-ylthio)-l-((4-riitroben-yloxy)carbony])pyro

iodide

(4R,5S,6S)-4-nitrobenzyl 4-methyl-3-((3S,5S)-5-(4-methylpipera2ine-l-carbonyl)- 1-((4- nitrobenzyloxy)carbonyl)pyrrolidin-3-ylthio)-6-((R)-l-(methy lsulfpn.^

a2abicyclo[3.2.0]hept-2-ene-2-caiboxylate (0.5 g, 0.6 mmoles) was dissolved in tetrabydrofuran ^■ (2 mL) and acetone (5 mL). 2-Iodoacetamide (0.55 g, 2.97 mmoles) was added to the reaction mixture and heated to reflux for 4 hours. The reaction mixture was concentrated under vacuum and triturated with ethyl acetate (10 mL) to obtain solid. The solid obtained was filtered and dried to obtain the product as an off-white solid. (0.36g, 60%). Ή NMR (DMSO-de) δ ppm: ■1.15-1.19 (d, 3H), 1.24-1.28 (d, 3H), 2.92 (s, 3H), 3.16-3.29 (m, 2H), 3.54-3.57(s, 2H), 3.61- 3.66 (m, 4H), 3.73-3.82 (m, 4H), 3.86 - 3.91 (m, 3H), 4.0-4.03 (m, 3H), 4.15-4.23 (m, 4H), 5.21-5.47 (m, 4H), 7.33-7.35. (d, IH), 7.52-7,54 (d, IH), 7.64-7.66 (d, IH), 7.69-7.71 (d, IH), 7.76-7.79 (d, IH), 8.22-8.24 (4H).

Preparation 23: (R)- -nitrobenzyl 2-d zo-4-((2K^R)-3^(R)-l-(2-ethoxy-2- oxoethylamino)ethyl)-4-oxoazetidin-2-yl)-3-oxopentanoate

Ethyl bromoacetate a mixture of solution of (¾)-4-mtrobenzyl 4-((2R, 3R)-3-((7^-l-arm^oethy])-4-oxoa.Ktidm-2-yI)-2-dia20-3-oxopen tanoate ( 1 g, 2.05 mmoles), diisopropylethylamine (0.45 mL, 2.58 mmoles) and catalytic amounts, of

dimethylaminopyridine in dichloromethane (15 mL) at 0 °C and stirred for 16 hours at room temperature. After regular work up, the crude obtained was purified by chromatography to obtain the title compound (0.37g, 30%).Ή NMR (DMSO-di) S ppm: 1.08 (d, 3H), 1.12 (d, 3H), , 1.29 (t, 3H), 2.85 (d, IK), 3.40-3.42 (m, IH), 3.63-3.66 (m, IH), 3.77 (s, 2H), 3.99 (m, IK), 4.13

(q, 2Hj, 5.44 (s, 2H), 8.25 (m, 2H), 8.32 (s, 2H).

4- oles) in dimethylformamide (20 mL) was heated at 50-55°C for 16 hr. After regular work up, the crude obtained was purified by chromatography to obtain (R)-4-riitrobenzyl 4-((2R,3R)-3-((R)-l- (buty larriino)ethy l)-4-oxoazetidin-2-yI 2-diazo-3-oxopentanoate (0.5g, 43.7%). Ή NMR (CDCI ₃ ) S ppm: 0.93 (t, 3H), 1.27 (m, 6H), 1.42 (m, 3H), 1.60 (m, 3H), 2.88 (d, 1H), 3.42 (m, 1H), 3.74 (m, 1), 3.80 (m, ΪΗ), 5.35 (s, 2H), .6.01 (s, 1H),7.53 (m, 2H), 8.25 (m, 2H).

Step (ii): 4-nitrobenzylchlorofonnate (0.42g, 1.96mmoles) was added to a mixture of solution of ^■ (R)-4-nitrobenzyl 4-((2R,3R)-3-((R)-l-(butylammo)etbyl)-4-oxoazeudin-2-yl)-2-d ia^

oxopentanoate (0.5g, 1.12 rnmoles), triethylamine (0.34g, 2.45 mmoles) and catalytic amount of dimemyl-miinopyridine at 0°C and stirred at room temperature for 16 hr. .After regular work up, the crude obtained was purified by column chromatography to obtain the title compound (0.31g . 44.2%). ^] H NMR (DMSO-ds) <5 ppm: 0.84 (t, 3H), 1.1 (d, 3H), 1.26 (m, 6H) 1.50 (m, 3H), 3.08 · (m, 1H), 3.47 (m, 1H), 3.56 (m^ 1), 4.01 (m, 1H), 5.19 (dd, 2H), 5.34 (s, 2H), ^' 7.60 (m, 2H), 7.67 (m, 2H), 8.24 (m, 4H).

Preparation ^■ 25: . E·thyl 2-pivala ·

0-(lH-Benzotriazol-l-yl)-N,N, T,N'-tetramethyluroriium tetrafluoroborate (TBTU, 70.8 g, 0.22 ^■ mol) was added to a mixture of pivalic acid (15 g, 0.147 mol) and triethylamine (35 mL, 0.25 mol) in ethyl acetate (150 mL) and stirred for 0.5 hour at room temperature. Glycine ethyl ester HC1 (20.52 g, 0.147.mol) was added to the above at 0°C and the reaction mixture was stirred for 16 hours at room temperature. After the completion of the reaction, the reaction mixture was diluted with EtOAC ( 50 mL) and washed with. water and brine. After drying over sodium sulphate, the organic layer was evaporated under reduced pressure to obtain crude product as oil.

ane) yielded (s, 9H), 1.41 .

solution of eth 2-pivalamidoacetate (10 g, 0.053 mol) in acetonitrile (200 mL) was treated with sodium azide (14 g, 0.22 mol) and tetrachlorosilane (10 mL, 0.087 mol). The solution was heated to 90°C under nitrogen for 16 hours. A further amount of sodium azide (7g, 0.1 mol) and tetrachlorosilane (6 mL, 0.052 mol) were added and.continued the reflux for additional 16 hours. The reaction mixture was poured into cold 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate (150 mL x 3). The organic layers were combined, dried over sodium by δ - 1.29

At 0°C, a solution of ethyl 2-(5-tert-butyl- lH-tetrazol-l-yl)acetate (9g, 0.042 mol) in tetrahydrofuran -MeOH (90 mL : 45 mL) was treated with a solution of lithium hydroxide monohydrate (2.68 g 0.064 mol) in 45 mL of water. The reaction. mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was neutralized with IN HCl to pH= 6-7 and concentrated. The crude was treated with aqueous lithium hydroxide (2.6 g in 100 mL) and a washed with ethyl acetate (150 mL). The aqueous layer was acidified with IN HCl to pH 2 and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine solution (150 mL). The organic layer was evaporated after drying over sodium sulphate to ohtain the title product as a white solid (6.8 g, 87%). 'H N R (DMSO-d ₆ ) δ = 1.39 (s, 9H), 5.46 (s, 2H), 13.78 (brs, 1H).

Example 1: (4 ^,6S)-3-((3-y,5S 5-pimethylca rbamoyl)pyrrolidiii-3-ylthio)-4-niethyl-6- ((K^-l-(methyIsulfonamido)ethyl)-7-o∑o-l-azabicyclo[3.2.0] hept-2-ene-2-carbo _-- ylic acid

Step 1: (4ii,5S,65 -4-Nitrobenzyl.3-((35,55>r5-(dimethylcarbanioyl)-l-((4- ^"

riirxoben.ylo:_y)carbonyl)pyrrobdm-3-ylthio)-4-m^

etbyl)-7-oxo-l-azabicycio[3

To a solution of (7y-4-mtrobenzyl-2-diazo-4-((2-? _J 3S)-3-((-¾-l-(methyl sulfpnamido)ethyl)-4- oxoazetidin-2-yl)-3-oxopentanoate (preparation 13) in acetone (10 mL), Rhodium octanoate (0.008 g, 0.01 mmoles) was added and heated to reflux/for 1 hour. The reaction mixture was cooled to room temperature and then to -50 to -40 °C using dry ice-acetone bath. - Diisopropylethyiamine (0.25 mL, 1.43 mmoles), catalytical amount of dimethylaniinopyridine and diphenylchlorophosphate (0.26 mL, 1.28, mmoles) were added successively to the reaction mixture and stirred for 30 minutes at -50 to -40 °C. (25, 45)-4-nitrobenzyl-2- (d memylcarbamoyl)-4-mercaptopyn ajLne-l-carboxylate (0.374 g; 1.06 mmoles) and dusoprop lefty lainine (0.25 mL, 1.43 mmoles) were added to the reaction mixture and continued stirring at -20 °C for 1 hour. The reaction mixture was then warmed to 0 °C and the stirring was continued for a further period of 3 hours. The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (50 mL). The separated organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated to obtain the crude, which on purification hy column chromatography, yielded a white solid 0.4 g - 48% (compound eluted with 20 - 30 % acetone in dichloromethane). ^! H NMR (DMSO-d ₆ ) <5 ppm: 1.14-1.18 (d, 6H), 1.6-1.8 (m, 1H), 2.83-2.86 (m, 3H),.2.94 (m, ^' lH), ^' 2.99-3.01 (d, 3H), 3.20 (m, 1H), 3.40-3.43(m, 1H), 3.59-3.61 (m, 2H), 3.88-4.22 (m, 3H), 4.23- 4.27 (m, 2H) 4.78-4.88 (m, 1H), 5.09-5.32 (d, 2H), 5,43-5.47 (d, 1H), 5.47-5.5 (d, 1H), 7.20-7.21 (d, 1Η)7.55-7.57 (d, 1H), 7.66-7.68 (d, 1H), 7.73-7.75 (m, 2H), 8.13-8.15 (d, 1H), 8.25-8.27 (m, 4H). -

Step 2: (4K,5S,6S)-3-((3£,5S 5-(Dimethylcarbamoy^

(methyIsulfonainido)ethyl)-7-oxo-l-azabicyclo[3.2.0]hept-2-e ne-2-carbo _-- ylic acid

To a solution of (4^55,6.7 4-nitrobenzyl 3-((3S,5 ₁ S 5-(<-imethylcarbamoyl)-l-((4- nitrobenzyloxy)c rbonyl)pyrrohd -3-ylt^

. oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate obtained from step 1 (0.2 g, 0.258 mmoles) in THF: water (15 mL, 1 : 1) was subjected to hydrogenation in the presence of Pd C . The reaction mixture was filtered over celite. The filtrate was washed with EtOAc (30 mL x 6). The aqueous layer was then lyophilised to yield the title compound as a white solid (90 mg, 75%). Ή NMR (I¾0) δ ppm: 1.21-1,23 (d, 3H), 1.33-1.39 (d, 3H), 1.92-1.96 (m, 1H); 2.99-3.00 (s, 3H), 3.01- ■ 3.03 (m, 1H),.3,1.1 (m, 1H), 3.47 (s, 6H), 3.46-3.48 (m ^' ,- 2H), 3.97-3.99(m, 2H), 4.03-4.21 (d, 1H), 4.73-4.75 (d, 1H), 4.8-4.86(d, 1H). . MS m/z: 460.7.

■ · Examples 2-6, 17, 21, 26, 28, 31, 32, 35, 37-38, 40, 42-46, 49-50, 53-56, 58-68, 70-85 and 87- 94 were prepared by treating the.compound of formula (10) with appropriate R ^A COOH according to the procedure given in the preparations 12, 16 and 17, followed by the procedure given in Example 1.

-Examples 7-16, 18-19, 23-25, 27, 29-30, 33-34, 39, 48, 51, 57 and 86 were prepared by treating the compound of formula (10) with appropriate R ^A X according to the procedure given in preparation 13 and 14, followed by the procedure given in Example 1.

Examples 20, 22, 36, 41, 47, 52 and 69 were prepared by treating the compound of formula (10) with appropriate carbonylating agents according to the procedure given in the preparation 15 followed by the procedure given in example 1. The quaternization of the heterocyclic rings in Examples 39, 45, 46, 80 and 94 were carried out according to the procedure given in preparation

19.

azabicydo[3.2.01hept-2-ene-2-carboxylic acid

ene-2-carboxytic acid

methy!pyridinium iodide Example 95: (^SS _j eii^-iP-RjSS^S-Klc^-ammopyrro^

ylthio)-4-mettyI-6-((-^l-(2-(methylamm^

2-ene-2-carboxylic acid

Step-1: (4Λ,5Λ,6Λ)-4-ηίττο benzyl 3-(diphenoxyphosphoryloxy)-4-mcthyI-6-((i?)-l-(2- (methyl((4-nitrobenzyIoxy)carbonyI)amino)acetainido)cthy ^] )-7-oxo-l-a2abicyclo[3.2.0]hept- 2-ene-2-carboxylate

Rhodium octanoate (0.1 g, 0.128 mmoles) was added to a solution of ( )-4-nitrobenzyl 2-diazo- 4-((2R,3R)-3-((R l-(2-(methyl((4-nitrob _. erizyloxy)carbonyl)aniino) acetaraido) ethyl)-4- oxoazetidin-2-yl)-3-oxopentanoate (3 g, 4.69 mmoles) in acetone (60 mL) and heated to reflux for 1.5 hours. The reaction mixture was cooled to -50 to -40 ^C C and diphenyl chlorophosphate

(1.64 g, 6.1 mmoles), cmsopropylethylamine (1.1 mL, 6.71 mmoles) and dimethylaminopyridine

(0.05 g, 0.41 mmoles) were added successively and continued stirring for a period of 1 hour at - 10 °C, The reaction mixture was treated with 0.5 M phosphate buffer (pH 7.4) and extracted with ethyl acetate (150 mL). The organic layer was separated and washed with water and brine.

After drying over sodium sulphate the organic la er was evaporated to obtain the oily product.

^• The crude product on purification by column chromatography yields the title compound as a pale yellow solid. (2 g, 49.6 %).

Step-2: (4i?,S5,6i?)-4-nitrobenzyl4-methyl-6-((-?)-l-(2-(methyl((4-n itrobenzyIoxy) carbonyI)am o)acetamido)ethyI)-3-((3S,5S)-l-((4^^

nitrobenzylo-ry)carbonyIamino)pyrroUdine-l-carbonyl)pyrrolid in-3-ylthio)-7-oxo-l-

A cooled solution (0 °C) of (41^51^6TR.)-4-nitroben2yl3-(diphenoxyphbsphoryloxy) -4-methyl- ((R)-l-(2-(methyl((4-rutroben-^loxy)carbonyI)-unmo)acetamido )ethyl)- -1- azabicyclo[3.2.0]hept-2-ene-2-carboxylate (5 g, 8.72 mmoles) and (2S,4R)-4-nitrobenzyl4- mercapto-2-((R)-3 -((4-nitrobenzy loxy) carbony 1 amino)pyrrolidine- 1 - carbony l)pyrrol idine- 1 - ^' carboxylate (7.5 g, 8.72 mmoles) in acetonitrile was degassed using nitrogen for 1G minutes and Ν,Ν-chisopropylethylamine (2.2mL, 13.3mM) was added and degassed using nitrogen for a further period of 10 minutes. The reaction mixture was stirred for 3 hours at 0 °C under nitrogen. The reaction mixture was treated with 0.5 M phosphate buffer (pH 7.4) and extracted with EtOAc (150 mL). The organic layer was separated and washed with water and brine. After drying over sodium sulphate the organic, layer was evaporated to obtain the oily product. The crude product on purification by column chromatography (15-17 % methanol in

dichloromethane) yields the title compound as an off-white solid. (6.2 g, 60 %)

Step-3: (4R,5S,61l)-3-((3R ₎ 5S 5-( R)-3-ammopyrrolidine-l-carbonyl)pyrrolidin-3-ylthio) - 4-methyl-6-((B)-l-(2-(methyIainino)acetamido)etliyl)-7-oxo-l -a2abicyclo(3.2.0] hept-2-ene- 2-carboxylic acid

(4R,5S,6R)-4-mtroberj2yl4-memyl-6-((R)-l-(2-(methyl((4-m^

carbonyl)amino)acetamido)emyl)-3-((3S,5S)-l-(4-nitroberLzylo xy)carboriyl)r5-((R 3-((4- mtrobenzyloxy)carbonylammo)pynOlidme-l-c^

azabicy clo[3.2.0jhept-2-ene-2-carboxylate (0.5 g) in 20 rnL of tetrahydrofuran:water (2: 1) mixture and suspension of PdVC (2 g) was hydrogenated for a period of 1,5 hours. The reaction mixture was filtered over celite and washed with 30 rnL of tetrahydrofuraniwater (2: 1) mixture.

The filtrate was washed with EtOAc (30 rnL x 6). The aqueous layer was treated with charcoal (1 g) and filtered. The filtrate was lyophilized to yield the title compound (0.1 g, 50 %). Ή MR (D ₂ 0) - 1.07-1.08 (d, 3H), 1.20-1.29 (d, 3H), 1.92 (m, 1H), 2.12 (m, 2H), 2.46 (m, 2H), .

2.76 (s, 3H), 2.92 (m, 1H), 3.34-3.38 (m, 2H), 3.40 (d, 3H), 3.60-3.64 (d, 2H), 3.76-3.78 (d, 3H),

3.93-3.96 (m, IH), 4.02 (m, 1H), 4.48 (m, IH). MS m/z: 493.6 (M-l).

Examples 96, 97,.100-135, 137-145, 147-166, 168- 176, 178-186, 188-200, 202, 205-206, 209- 231, 235-238, 241-273, 275-292, 294-297, 299-312, 314-318, 320-325, 329-361 and 363-368 were prepared by treating the compound of formula (10) with appropriate R ^A COOH according to the procedure given in the preparations 12, 16 and 17, followed by the procedure given in Example 1.

Examples 136, 201, 203, 204, 239, 240 and 362 were prepared by following the procedure provided in preparation 13.

Example 187 was prepared by following the procedure provided in preparation 19.

Example 98 and 99 were prepared by following the procedure given in preparation 23.

Examples 146, 167, 177, 207, 208, 232-234 were prepared by following the procedure described in the preparation 20 using appropriate alkynes (cf. Scheme 2a). Exam le 274 and 293 were prepared by following the procedure provided in preparation 24.

tar boxy lie acid (4R,5S ₎ 6R)^-{(R l-(2 ₁ 2-Difluoroacelaniido)et yI)-4- mel yI-3-((3S ₁ 5S>5-((R>3-(2- (mcthylamino)a ctamido)pyrrolidkic- 1- carbonylJpyrroUdin-3-yltbao)-7-oxo- 1- ' azabicyclo[3.2.0]bcpt-2-ene-2-carboxylic acid

Ή NMR (D ₂ 0) 8 ppm: 1.17-1.19 (d, 3H), 1.21-1.29 (d, 3H). 2.99-3.00 (m,3H), 3.07- 3:09 (d, 3H), 3.37-3.46 (ra, 3H), 3.51-3.52

O " O H ₃ C . J ^' (m, 3H), 3.81-3.82 (m, 2H), 4.01-4.15 (m,

0 0 2H), 4.43-4.45 (m, 2H), 4.57 (d, 1H , 6.02-

(4R,5S,6R)-6-({R i-(2-(2-Amino-2- 6.29 (t, lH). MS m/z: 495.6 (M-l) • oxoethylaiiiino)acetamido)ethyl)-3-((3S,5S)-5- (dimetbyIca--bamoyl)pyrrolidiii-3-ylthio)-4-methyl-7- oxo- 1 -azabicy clo[3.2.0] hept-2-ene-2-carboxy li c acid

H,C ^NH Ή NMR (DjO) 8 ppm: 1.19-1.21 (d, 3H),

1.32-1.37 (d, 3H), 2.86 (m, 1H), 3.19-3.22 H H Y |] (m, 2H), 3.32-3.37 (d,3H), 3.46-3.57 (m,

THJV 5H), 3.61-3.62 (m, 4H),.3.90 (m, 1H), 4.14- 0 1 ^■ 4.16 (m, 1H), 4.36-4.38 (m, 1H) 6.02 (t,

(4R,5S,6 )-3-((3S,5S)-5-(4-Carbamimidoylpipcraziiie- 1H). MS m/z: 544.6 (M+I)

1 -carbonyl)pynoUdin-3-yltbio)-6-((R)- 1 -(2,2- difluorq acetamido)e1by l)-4-me1byl- 7-oxo- 1- azabicyclor3.2.01hcpt-2-ene-2-carboxylic acid

'H NMR (D.O) 8 ppm: 1.19-1.27 (d, 3H), 1.30- 1.37 (d, 3H), 2.91 (s, 3H), 3.31-3.33 (m, 2H), 3.54-3.56 (m, 3H), 3.5-3.57 (m, 4H), 3.63-3.68 (d, 4H), 3.94 (d, 4H), 4.14- 4.19 (m,2H), 4.55 (m.IH), 6.02-6.29 (t,lH).

(4R,5S,6R)-6-((R)-l-(2,2-difluoroacetamido)cthyl)-4- MS m z: 573.6 (M+I)

mctbyl-3-((3S ₁ 5S)-5-(4-(2-(methylaniino)- acetyl)piper_--ine-l-carbonyl)pynOlidin-3-ylthio)-7- oxo-I-azabicycloF3.2.0]bept-2-ene-2-cai oxylic acid

von Ή NMR DiO) δ ppm: 1.21-1.27 (d, 3H),

1.29-1.35 (d, 3H), 2.89-2.91 (m, 3H), 3.27-

H H Y l 3.33 (d, 2H), 3.35-3.37 (d, 3H), 3.57-3.59

(d, 3H), 3.62-3.64 (d, 2H), 3.70-3.71 (d,

0 H)C j 2H), 3.92-3.98 (d, 2H), 4.05-4.06 (d, 1H),

{4R,5S,6R)-3- 1((3S,5S)-5-(4-(2- ^■ 4.14-4.16 (d, 1H), 4.75-4.81 (d, 2H), 6.02- AmiiioacctylJpiper-aine-l-carbonylJpyirolidin-S- 6.29 (t, IH). MS m/z: 559.60 (M+l) lthio)-6-(0tH-(¾ ² - ^t ^ ^{uoroacetaraido} ) ^eth y ^! H- methy 1-7-oxo- 1-azab icyclo[3.2.0]hept-2-cnc-2- caiboxy!ic acid

a2abicyclnf3.2.01hept-2-enc-2-carboxylic acid

l-azabicyclof3.2.01hept-2-ene-2-carboxylic acid

a2abicyclo[3.2.01hept-2-ene-2-carboxylic acid

azabicyclo f3.2.0]hept-2-ene-2-carboxylic acid

azabicyclor3.2.01hept-2-ene-2-carboxylic acid

azabicycloP.2.0]bept-2-∞e-2-carboxylic acid

azabicyclo 3.2.01hept-2-eiie-2-earboxylic acid

oxo-l-azabicyclof3.2.0]hept-2-ene-2-carbox lie acid

Preparation of example 298: (4R,5S,6R 6-((R)-l-(2-(iH-tetrazol-l-yl) acetamido)ethyl)-3- ((3S,5 S^S-i^J-S-aminopyrrolidine- 1-ca rbonyl)pyrro lidin-3-y lthio)-4-methy l-7-o∑o- 1- azabicyclo [3.2.0] hept-2~ene-2-carboxylic acid

Step 1: (R -Nitrobenzyl.4-((2;R^R)-3-((R)^^

oxoa zeti din-2-y l)-2-diazo-3-oxopentanoate lH-Tetrazole-1 -acetic acid (6.33 g, 49 mmol) was taken in a RB. To this ethylacetate (1.5 L), TBTU (18.7 g, 58 mmol), dusopropylemylaniine (14 mL, 80.38 mmol). was added under N ₂ atmosphere and reaction mixture was stirred for 1 hour. Trifluoroacetate salt of (R)-4- nitrobenzyl 4-((2R,3R)-3-((R)-l-ammoemyl)-4~oxoazeu^b-2-yl)-2-dia2o-3-ox open1anoate (17.5 g, 44 mmol) was diluted with ethyl acetate (75 mL) and was neutralized using

diisopropylethylamine (5 mL) at 0°C. This solution was then added to the aforementioned reaction mixture at 0° C under N2 atmosphere. After the addition was complete the reaction mixture was brought to room temperature and stirred for 14 hours under N2 atmosphere. After the completion of the reaction, the reaction mixture was diluted with water and extracted by ethyl acetate. The organic layer was dried using sodium sulphate and evaporated under vacuum. The crude was then purified by column chromatography to give the product (14 g, 63%). Ή NMR (DMSO-de, 400 MHz): 9.35 (IH, s), 8.44-8.42 (IH, d), 8.31 (IH, s), 8,27-8.25 (2H, d), 7.72-7.70 (2H, d), 5.45-5.44 (2H, d), 5.23-5.09 (2H, m), 4.08-4.02 (IH, m), 3.64-3.63 (IH, t), 3,45-3.43 (IH, q), 2.94-2.78 (IH, q), 1.2-1.19 (3H, d), 1.17-1.16 (3H, d).

Step 2: (4R,5R,6R 4-Nitrobenzyl 6-(( )-l-(2-(iH-tetrazol-l-yl)acetaniido)ethyI)-3- (dipheno-ryphosphoiyloiy)-^methyl-7-oxo-l azabicyclo[3.2.0]hept-2-ene-2-carbo-cylate

(R)-4-Nifroben-^1 4-((2R,3R)-3-((R)-H^

yl)-2-diazo-3-oxopentanoate (4 g, 8 mmol) was _. dissolved in 100 mL of acetone

under N ₂ atmosphere. To this solution was added rhodium octanoate (100 mg, 0.128 mmoles) and heated to 60°C for 2.5 hours. After the completion of the reaction, the reaction mixture was then cooled to -30°C and diphenylchlorophosphate (2.72 mL, .12.8 mmoles),

diisopropylemylamine (2.6 mL, 13.6 mmol) and catalytic amount of dimemylarj-inopyridiiie

(292 mg, 2.4 mmol) was added successively. The reaction mixture was then stirred for 1 hour at -10° C. Diisopropylemylamine (1.7 mL) and buffer solution pH = 7 was added and the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane and the organic layer evaporated under vacuum at room temperature. The crude thus obtained was purified by colum chromatography to give the product as a solid (2.7 g, 47 %). Ή NMR: 9.35 (IH, s), 8.62-8.60 (IH, d), 8.14-8.12 (2H, m), 7.62-7.60 (2H, d), 7.46-7.37 (4H, m), 7.32-7.20 (6H, m), 5.33-5.31 (2H, d), 5.28-5.24 (2H, q) 4.23-4.21 (IH, d), 4.17-4.14 (IH, m), 3.59-3.56 (IH, q), 3.5-3.4 (IH, d), 1.23- 1.21 (3H, d), 1.18-1.17 (3H, d). Step 3: (4R,5S,6R 4-nitrobenzyl 6-((H)-l-(2-(lH-tetrazol-l-yI)acetamido)ethyl)-4-methyl- 3-((3S,5S l-((4-Ditrobenzyloiy)carbonyl)-5-(CR)-3-((4- nitrobenzy loiy)ca rbonyla in ino)pyr ro lidine-l-ca rbonyI)pyrrol idin-3-ylthio)-7-oxo-l- azabicyclo [3.2.0] he t-2-ene-2-carboiylate

(4R,5R,6R)-4-nitrobenzyl 6-(CR)-l-(2-(lH-tetrazol-l-yl)acetamido)ethyl)-3- (diphenoxyphosphory.loxy)^-methy 1-7-oxo- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate ( 1.5 g, 21 mmoles) was taken in acetonitrile (150 mL) at 0°C. The solution was then degassed for 10 minutes using N2 atmosphere. To this solution was added the thiol (1.22 g, 21 mmoles) at 0°C under N2 followed by addition of dhsopropylethylamine (0.58 mL, 1.5 eq.). The resultant solution was degassed again for 15 minutes. The reaction mixture was stirred under 2 at 0°C for 2 hours. After the completion of reaction, the reaction rj uLxture was quenched using water ^' and extracted by ethyl acetate. The organic layer was then washed with water, brine, dried over sodium sulphate and evaporated under vacuum to give the crude. The crude reaction mixture was purified by column chromatography to give the product (1.45 g, 66%) as a solid. M S: 1027 (M+l); HPLC: 85.35 %; _, *HNMR (DMSO-d6, 400 MHz): 9.345 (1H, d), 8.64-8.61 (1H, t), 8.24-8.22 (5H, m), 7.77-7.70 (2H, t), 7.65-7.60 (2H, t), 7.54-7.52 (1H, d), 7.49-7.47 (1H, d), 5.76-5.45 (2H, d), 5.33-5.29 (2H, d), 5.24-5.20 (1H, d), -5.17-5.12 (2H, d), 5.07-5.04 (2H, d), ^" 4.64-4.62 (1H, d), 4.21-4.12 (4H, m), 3.91-3.83 (2H, d), 3.59-3.53 (2H,.d), 3.46-3.45 (2H, d), 3.23-3.14 (2H; m), 2.85-2.80 (2H, d), 1.70-1.68 (3H, t), 1.24-1.23 (3H, d), 1.19-1.17 (3H, d) Step 4: (4R,5S,6R)-6-{(R l-(2-(lH-tetrazol-l-yl)acetarjiido)ethyl)-3-((3S,5S)-S-((R)- 3- aminopyrroUdine-l-carbonyl)pvrrolidin-3-ylthio)-4-methyl-7-o xo-l-azabicyclo[3.2.0]hept- 2-ene-2-carbo∑ybc acid

(4R,5S,6R)-4-nitrobenzyl 6-((R>l-(2-(lH-tetra2»l-l-yl)acetajD-ddo)emyl)-4-methyl- 3-((3S,5S)- l- ((4-mtroben2yloxy)carbonyl)-5-((R)-3-((4-rdtrobenzyloxy)carb onyl amino)pyrrolidine- 1- carbonyl)pyn-olidm-3-yltbio)-7-oxo-l-a2abicyclo[3.2.0]hept-2 -ene-2-carboxylate (1.45 g, 1 mmol) was taken in a Parr shaker vessel and to this was added 80 mL of THF, 40.mL of water and 4.35 g of Pd/C. The reaction was kept for 1.5 hours at 5 Kg hydrogen pressure. The reaction mixture was then filtered through'filter paper and was washed with ethyl acetate (5 x 50 mL). The reaction mixture was treated with charcoal and filtered. The, aquoues layer was again given ethyl acetate .washing and was kept under lyophilization for 2 days to give the final product as a white solid (400 mg, 51.34 ).

The compounds of Examples 299-312 were prepared according to the procedure for Example

aminopyrrolidine- !-carbon !)p n lidin-3- y!thio)-4-raettiy!-6-{(R}-H2-(2-nietliyl-2H- tetraz»l-5-y!)ac*tainido)ethyl}-7-oxo- 1- azabicyc!o[3.2.01hept-2-ene-2-carboxylic acid

'HNMR (D ₂ 0) - 1.21 {d,3 H), 1.45 {d, 3H), 2.99- 3.02 {s, 3H), 3.04-3.09 {m, 2H), 3.33-3.36 (s, 3H), 3.40-3.42 (m, 2H) 3.65-3.71 (m, 2H), 4.25 (d, 2H), 4.65-4.72 (m, 2H), 8.74-8.85 {m; 2H), 9. !7 (s, 1H).

0 Mass (488.56) 489.6

(4R,5S,6R)-3-{(3S,5S}-5- (dimethylcarba-noyl)pynOlidin-3-ylthio)-4- methyl-7-oxo-6-({R)-l-(pyrazine-2- carboxamido)ethy!)-l-azabicyclo[3.2.0]hept-2- ene-2-carboxy!ic acid

!H MR fl¼0) - 1.22 (d, 3H), 1.33 {d, 3H), 2.99- 3.02 {s, 3H), 3.09-3.1 1 (m, 4H), 3.34-3.38 (s, 3H), 3.46-3.56 (m, 3H), 3.58-3.65 {m, 2H), 3.74-3.78 (in, 3H), 4.02 (d, 2H), 4.31-4.38 {m, IH). Mass

0 {506.58) 507.2

{4R,5S,6R)-3-((3S,5S)-5- (dimethy]carb£_-ioyl)pyrrolidin-3-ylthio)-4- methy!-6-{(R> l-{2-{l-methyl-l H-tetrazol-5- yl)acetamido)ethyl)-7-oxo- 1- azabicyclq[3.2.0]hept-2-ene-2-carbox lic acid

'HNMR fl¼0) - 1.16 (d, 3H), 1.35 {d, 3H), 3.32- 3.45 (m, 2H), 3.56-3.58 (m, 3H), 3.68-3.73 (m, 3H), 3.95-4.04 (m, 2H), 4.14 {d, IH), 4.38-4.72 (m.lH), 5.41 {d, 2H), 9.26 {s, IH). Mass (529.59) 530.6

{4R,5S,6R}-6-{(R)-l-{2-(lH-tctrazol-l- y!)acetamido)ethy!)-4-methyl-7-oxo-3- (3S,5S}- 5-{{s-JF-unoyla.nLno)methyl)pynOlidin-3-ylthio)- l-azabicyclo[3.2.0]hept-2-ene-2-cartjoxy]ic acid

'HNMR (D ₂ 0) - 1.24 {d, 3H), 1.35 (d, 3H), 3.35- 3.39 {m, IH), 3.64-3.65 (m, 2H), 4.22 {d, 2H), 4.43- 4.45 {m, 2H), 5.05-5.14 <m, 2H), 5.43 {d, 2H), 9.03 (d, IH), 9.26 {d, IH). Mass {459.48) 460

(4R,5S,6R}-6-({R)-l- 2-{lH-tetrazol- 1- yl)acetamido)ethy!)-3-(6,7-dibydro-5H- pyr-aolotl^-alfl^^jtriazoM-ium-fi-y!thio)^

methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxy!ate

*> · 'HNMR (D ₂ 0) - 1.21 (d, 3H), 1.35 (d, 3H), 2.97- 2.99 {s, 3H), 3.08 (d, 3H), 3.32-3.38 {m, 2H), 3.55- 3.59 {m, 2H), 3.98 {m, 2H), 4.13 (d, IH), 4.15-4.17 {m, IH), 4.42 (d, 2H), 5.61-5.63 {m, 2H), 8.85 {s, IH). Mass {492.55) 493.1

0

{4R,5S,6R}-6-({R)-l-{2-{2H-tctrazol-2- yl)acetamido)ethy! -3-{{3S,5S}-5- (dimethyicait>amoyl)pyrrolidin-3-ylthio)-4- metbyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- carboxylic acid azabicyclo[3.2,0]hept- 2-ene- 2-carboxylic acid

Preparation of example 313: (4 ,SS,6S)-6-((R)-l-(lH-tetrazol-l-yl)ethyl)-3-((3S,5S)-5- (dimethyIcarbamoyI)pyrrolidin-3-ylthio)^methyl-7-oxo-l-azahi cyclo[3.2.0]hept-2-ene-2 carhoxylic acid

Steps 2B & 3

Similar to the - ((R)-l-(2H-tetrazol-2-yl)ethyl)-4-oxoa2e din-2-yl)-2-diazo-3-oxopentanoate (600 mg) to (4R,5S,6S)-4-nitrobenzyl 6-((R)- l-(2H-tetrazol-2-yl)ethyl)-3 _r ((3S,5S)-5-(dimethylcarbamoyl)-l- ((4-nitroben2yloxy)carbonyl)pyiTolidin-3-ylthio)-4-methyl-7- oxo-l- azabicyclo[3.2.0]bept-2-ene-2-carboxylate was converted to its enol ^' phosphate (0.28 g, 39.9%) and then finally to the ^' titled product (270 mg, 27%). 'H NMR; 9.53 (IH, s), 8.21 -8.26 (4H, m), 7.71 (2H, m), 7.64-7.62 ( IH, m), 7.53-7.51 (IH, d), 5.47-5.43 (IH, m), 5.29-5.20 (2H, m), 5.06- 5.02 (2H, m), 4.83-4J2 (IH, m), 4.26-4.21 (IH, m), 4,12-4.08 (IH, m), 4.01-4.00 (IH, m), 3.85- 3.81 (IH, m), 3.59-3.53 (IH, m), 3.18-3.12 (IH, m), 3.01-2.95 (3H, d), 2.86 (3H, d), 2.80 (IH, m), 1.70 (3H, d), 1.62-1.60 (lH, m), 1.14 (3H, d).

Step 4B: (4R ₁ 5S,6S)-6-((R)-l-(2H-tetrazoI-2-yI)ethyl)-3-((3S,5S)-5- (dimethyIcarhamoyl)- pyrrolidin-3-ylthio)-4-methyI-7-oxo-l-azahicyclo[3.2.0]hept- 2-ene-2-carbO-cylic acid (4R,5S,6S)-4-nitrobenzyl 6-((R)-l-(2H-tet^l-2-yl)e1hyl)-3-((3S,5S)-5-(dimethylcart)am oyl)-l- ((4-mtroben2yloxy)carbonyl)pyrrolidin-3-yltm^

(4R,5S,6S)-6-((R 1 -(2H-tetra∞l-2-yI)ethyl>3- ((3S,5S)-5-(dimethylcarbamoyl)pyiTolidiii-3-

•ylthio)-4-methyl-7-oxo- 1- azabicyclo .2.01hept-2-ene-2-carboxylic acid

'HNMR (I¾0) - 1.26 (d, 3H), 1.34 (d, 3H), 1.8S-1.92 (m, 1H), 2.94-3.26 (m, 2H), 3.46- 3.49 (m, 4H>; 3.57-3.58 (m, 2H), 3,62-3.72 (m, 1H), 3.73-3.76. (m, 1Ή), 3.80-3.84 (m, 2H), 3.87-3.92 (m, 1H), 3.94-4.13 (m, 1H),

314 (4R,5 S,6R)-6- (( 1 -(2-( 1 H-tetrazol- 1- 4.30 (d, 1H), 4.43-4.49 (m, 1H) _S 4.51-4.53 yl)acetamido)ethyl)-4-methyl-7-oxo-3- {m, 1H), 5.47 (m, 2H), 9.27 (s, 1H). Mass ((3S,5S)-5-(piperazine-l-carbonyl)pyn lidin-3- {533.60) 534.6 ·

ylthio)- 1 -azabicy clo[3.2.0]hept-2-ene-2- carboxylic acid

'HNMR (D.D) - 1.20 (d, 3H), 1.34 (d, 3H), 1.89-1.92 (m, 1H), 2.99 (s, 3H), 3.07 {s, 3H), 3.32-3.36 (ra, 2H), 3.56 (d, 1H), 3.66 (m, 1H), 3.98 (ra, 1H), 4.14 (d, 1H), 4.40- 4.42 (m, 1H), 4:60-4.62 (m, 2H), 5.34 (d,

315 2H). Mass (507.57) 508.2

(4R,5S,6 )-6-((R> l-( -(5-ai-iino-2H-tBtrazol-

. 2-yl)acetamido)ethyl)-3-((3S,5S)-5- . (dimethy!carbamoyl)pyrrolidin-3-ylthio)-4- raethy 1-7-oxo- 1 -azabicy clo[3.2.0]hept-2-ene-2- . carboxylic acid

'HNMR (DjO) - 1.20 (d, 3H), 1.34 (d, 3H), 1.80-1.85 (m, 1H), 2.08-2.30 (m, 2H), 2.44-2.48 (m, 2H), 2.70-3.00 (m, 3H), 3.19 (d, 3H> 3.29-3.57 (m, 3H), 3.54-3.78 (m,

^■ ° o 2H), 4.14 (4 1H), 4.38-4.42 (m, 1H), 5.29-

316 (4R,5S,6R)-6-(CR)- l-(2-(5-amino-2H-tetrazol- 5.32 (m, 1H). Mass (548.62) 549.1

2-yl)acetamido)ethyl)-3-((3S,5S)-5-((R)-3- aminopyrrolidine- 1 -carbony l)pyrroiidin-3- y lthio)-4-methy l-7-Όχο- 1 - azabicyclo[3.2.0lhept-2-ene-2-carboxylic acid

'HNMR- (D20) - 1.12 (d, 3H), 1.33 (d, 3H), 2.25-2.26 (m, 2H), 2.48-2.50 (ra, 1H), 2.60-2.67 (m, 1H),. 2.8-3.00 (m, 1H), 3.34 (d, 2H), 3.55 (d, 2H), 3.65 (d, 2H), 3.76 (d,' o < 2Η),· 3.88 (d, 2H), 3.94 (d, 1H), 4.13-4.15

(4R,5S,6R)-6-((R)- l-(2-(5-amino-3- {m, 1H), 4.41-4.57 (m, 2H). Mass (615.63)

3 17

' (trifluoromethyl)- lH-l,2,4-tria2ol-l- 616.1

yi)acetamido)ethyi)-3-((3S,5S)-5-((R)-3- aminopyrrolidine- 1 -carbony l)pyirolidin-3- ylt-iio)-4-methyl-7-oxo-l- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

0 'HNMR (I¼0) -1.15 (d, 3H), 1.35 (d, 3H),

1.88-1.93 (s, 6H), 3.01 (s, 3H), 3.07 (s, 3H), 3.34-3.40 (m, .2H), 3.49 (d, 2H), 3.63- 3.64 (m, 2H), 4.00-4.17 (m, 2H), 4.37-4.41

318 (m, 1H), 4.67-4.71 (ώ, 1H), 9.36 (s, 1H).

^■ ° c? - Mass - (520.61) 521

(4R,5S,6R 3-((3S,5S>5- (dimethylcarbamoyl)pyrTolidin-3-ylthio)-4- methyl-6-((R)r l-(2-methyl-2-( 1 H-tetrazol- 1- yl)prop._aamido)ethyl)-7~oxo- 1 - azabicyclo[3.2.01hept-2-ene-2-carboxylic acid

Preparation of example 319: (4R ₁ 5S,6S)-6-((R)-l-(lH-tetrazol-l-yl)ethyl 3-((3S,5S)-5- (d imethylca rbam oyl)pyrrol id in-3-y ltfaio)-4-methy 1-7-oxo-l-aza bicy do [3.2.0] h ept-2-ene-2- carboxylic acid .

Step 1: (R)-4-nitrobenzyl 4-((2R^S 3-((¾ l-(lH-tetrazol-l-yl)ethy -4rOxoazetidin-2-yl)-2-

tetrazole (193 nig, 2.768 mmol) in tetrahydrofuran (9 mL) was added. Then

diisopropylazodicarboxylate (746 mg, 3.691 mmol) at 0°C was added to the reaction mixture and was brought to room temperature and stirred for 10 hours. After the completion of the reaction, the reaction mixture was quenched with water and the crude product extracted with ethyl acetate. The organic layer was evaporated to get the crude product which was purified by column chromatography to obtain products A (300 mg, 29.3%) and B (480 mg, 47%). Ή NMR:

Product A: (D SO-ds, 400 MHz) : 9.36 (s, 1H), 8.50 (s, 1H), 8.27-8.25 (d, 2H), 8.28-7.70 (d, 2H), 5.43 (s, 2H), 5.16-5.12 (t; 1H) 3.54 (s, 2H), 3.45-3.42 (d, 1H), 1.59-1.57 (d, 3H), 0.98-0.96 (d, 3H). Product B: (DMSO-d _s , 400 MHz) : 8.95 Cs, 'lH¾ 8.48 (s, 1H), 8.27-8.25 (d, 2H), 5.43 (s, 2H), 3.56-3.47 (m, 2H), 1.61-1.59 (d, 3H), 0.96-0.95 (d, 3H).

(R)-4-nitrobeiizyl 4-((2R,3S)-3-(( )-I-(2H-tetrazol-2-yl)ethyl>4-oxoazetidm-2-yl)-2-diazo-3- oxopentanoate (530 mg, 1.19 mmol) was taken in 30 mL of acetone under >½ atmosphere. To this solution was added rhodium octaiioate (0.025 g, 0.0324 mmol) and the resultant reaction mixture was heated to 65-70°C for 1.5 hours. After the completion nf reaction, the reaction mixture was cooled to -40°C followed by addition of diphenylchlorophosphate (0.4 mL, 1.93 ^' mmol), diisopropylethyl amine (0.35 mL, 2 mmol) and catalytic amount of

■ dimethylaminopyridine.. The reaction mixture was brought to -20°C and stirred for 1 hour. At - • 20°C Disopropylethyiamine (0.35 mL) was added to the reaction mixture and was quenched with water and extracted with dichloromethane. The organic layer was then dried over sodium sulphate and concentrated under vacuum at room temperature to give the crude product. This crude product was purified by column chromatography to give the product as a solid (250 mg, 32.2%).

Step 3A: (4R,SS,6S 4-nitrobenzyl 6-((R l-(lH-tetrazoI-l-yI)ethyi)-3-((3S,SS 5- (duBetliylcar bam oyl)-l-((4-nitroben i^Ioi )

azabicycIo[3.2.0]hept-2-ene-2-carboxylate

The product obtained (0.25 g, 0.39 mmol) from step 2A was taken in 10 mL of acetonitrile and cooled to 0°C and degassed for 10 minutes. To this reaction mixture was added the thiol (0.22 g, 0.39 mmol) followed by diisopropylethylamine (0.1 mL, 0.57 mmol) under N2 atmosphere. The reaction mixture was again degassed for 10-15 minutes. Further the reaction mixture was stirred ' at 0°C for 2 hours. After the completion of reaction, the reaction mixture was added with water and extracted using ethyl acetate. The organic layer was concentrated and the resultant crude mixture was purified by column chromatography to give the product (260 mg, 33.6%). 'H N R: (D SO-di, 400 MHz) : 9.05 (1H, s), 8.26 -8.21 (4H, m), 7.72 -7.51 (4Η, ^' m), 5.65 -5.61 (1H, q), 5.47 -5.06 (4H, m), 4.81-4.72 (1H, m), 4.06-4.05 (1H, m), 3.83-3.81 (2H, m), 3.58-3.56 (2H, m), _. 3.10 (1H, m), 3.02-2.95 (3H, d), 2.81 (3H, d), 2.80 (1H, m) l.73-1.71 (3H, d), 1.60 (1H, m), 1.18- 1.16 (3H, d). ^'

Step 4A: (4R,5S,6S)-6-((R)-i-(lH-terra^

(dimethylcarbamoy})pyrroUdin-3-yithio)-4-met^

carboxylic acid

(4R,5S,6S)-4-mtro

l-((4-nitrobeiizyloxy)carbony])pyrrolidin-3-y]mio)-4-meth yl-7-oxo-l-azabicyd^

ene-2-carbox late (250 mg, 0.33 mmol) was hydrogenated using Pd/C (500 mg) in a mixture of THF - ¾0 (20 mL : 10 rnL) for 1.5 hours at 5 Kg hydrogen pressure. After the regular work up, the titled compound was obtained (70 mg, 49%).

Examples 326-328 were prepared by following the procedure described in preparations 313 & 319 using appropriately substituted tetrazoles.

Example 328 was prepared by reacting compound obtained by Step 2A with appropriate RpSH group followed by the procedure of steps 3 A and 4A or Example 319.

Examples 334 and 335 ^: were prepared by reacting compound obtained by Step 2 with appropriate -SH group followed by the procedure in step 3 of Example 347.

0 'HNMR (D ₂ 0) - 1.23 (d, 3H), 1.32

(d, 3H), 1.42 (m, 3H), 2.12 (m, 1H), 2.24 (m, 1H), 2.49 (m, 1H), 2.90 (m, 1H), 3.34 (m, 1H), 3.37-3.39 (m, 2H), 3.57-3.60 (m, 2H), 3.70-3.75

(4R,5S,6R 3-((3S,5S>5-((R 3-_jninopyiTolidine-l- (m, 2H), 3.88 (m, 2H), 4.07 (m, 1H), carbonyl)pyrrolidin-3-y!thio)-6-((R)-l-(2-(5- 4.29 (m, 1ΕΓ), 4.35 (m, 2H), 4.52 (ra, (ethoxycarbony 1)- 1 H-tetrazo!- 1 -y l)acetamido)ethyl)-4- 2H), 5.65 (d, 2H). Mass (605.67) - me^yl-7-oxo-l-az^icyclo[3.2.0]hept-2-cne-2-caiboxylic 606.1

acid

0 'HNMR (I¾0) 1.21 (d, 3H), 1.33

(d.- 3H), 1.57-1.60 (m, 2H), 1.84 (m, 1H), 2.17 (m, 2H), 2.93 (m, 2H), 3.29-3.37 (m, 3H), 3.50-3.58 (m, 3H), 3.96 (m, 2H), 4.16 (d, lH), 4.42

(4R,5S ₎ 6R)-6-((R)-l-( ⁰ 2-(lHf-tEtra2oH-yi)acetamido)ethyl> (m, 1H), 4.48-4.57. (m, 2H), 5.44 (d, 3-((3 S,5 S)- 5-(4-aminopiperidine- l-carbonyl)pyrroIidin-3- 2H), 9.28 (s, 1H). Mass (547.63) ylthio)r4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- 548.2

carboxylic acid

'HNMR (I¾0) - 1.18 (d, 3H), 1.32 (d, 3H), 1.66-1.8 (m, 2H), .1.92 (s, 3H), 2,90-2.93 (ra, 1H), 3.13-3.19

V- ^N_ V-,OH (m, lH), 3.27-3.43 (m, 3H), 3.45- 0 3.50 (m, 2H), 3.56 (d, lH), 3.70-3.73

(4R,5S,6R)'6-((R)-l-(2-(lH-tetrazoi-l-yi)acetamido)ethyl} - (m, lH), 3.93 (d, lH), 4.15 (d, lH), 3-((3S,SS)-S-((S)-3--unLaopiperi(ibe-l-cai onyl)pyiToUdiii- 4.36-4.47 (m, 2H), 4.50-4.80 (ra, 3-ylthio)-4-niethyl-7-Oxo-l-azabicycIo[3.2.0]hept-2-enc-2- 1H), 5.38-5.48 {m, 2H), 9.27 (s, 1H).

carboxylic acid Mass(547.63) 548.2

'HNMR (DjO) - 1.20 (d, 3H), 1.34 (d, 3H), 1.76-1.81 (ra, lH), 1.91 (m, 1H), 2.83-2.89 (ra,. 2¾ 2.99-3.02 (m, 2H), 3.19-3.3S (m, 3H), 3.45- 3.49 (ra, 3H), 3.58 (m, 3H), 3.87-

(4 R,5S,6R)-6-((R)- 1 -{2-( 1 H-tetrazol- 1-y l)acetara ido)ethyl> 3.97 (ra, 3H), 4.04 (d, 2H), 4.14 (d, 3-((3 S ,5S)-5-(4-(3-aminoazetidLn- 1 -yl)piperi dine- 1 - 1H), 4.40-4.43 (in, 2H), 4.47-4.54 carbonyl)pyrroUdin-3-yIthio)-4-niethyl- 7-oxo-l- (m, 1H), 5.43 (d, 2H), 9.27 (s, 1H). azabicyclo[3.2.0]hept _: 2-ene-2-carboxylic acid Mass (602.71) 603.2.

'HNMR (DjO) - 1.26 (d, 3H), 1.32 (d, 3H), 1.81 (m, 1H), 1.91 (ra, lH), 2.00 (m, 3H), 2.81-2.90 (m, 3H), 3.02 (d, 2H), 3.18-3.35 (m, 5H), 3.48-3.57 (m, 4H), 3.87-3.95 (3H),

(4R.5 S,6R)-6-((R)- 1 - (2-(lH-tetrazol- l-yJ)acetamido)ethyl 4.14 (d, lH), 4.42-4.53 (m, 3H), 5.43 3-{(3 S,5S)-5-(4-(3 -(amraomethyl)azetidin- 1 -y IJpiperidine- 1- (d, 2H), 9.27 (s, 1H) C _a ,H«M AS; carbonyl)pyrrolidin-3-ylthio)-4-methyl-7-oxo-l- HPLC - 96.6%; Mass (616.74) 617.2 azabicycto[3.2.01hept-2-ene-2-carboxylic acid

'HNMR (I¾0) - 1.20 (d, 3H), 1.32 (d, 3H), 1.80-1.82 (m, 1H), 1.92 (m, 1H), 2.74 (m, .1H), 3.12 (m, IH), 3.35 (d, 2H), 3.54 (d, 2H), 3.74-3.85 (ID, 2H), 4.04-4.15 (m, 1H), 4.32 (d,'

(4R,5S _> 6R)-6-((R)-l-(2-(lH-tetrazol-l-yi)acetaniido)ethyl)- 2H), 4.42 (ra, 1H), 4.56 (d, 2H), 5.44 3-((3S,SS)-5-(3-(aniiiiomelhyl)-3-fluoroazetidme-l- (d, 2H), 9.27 (s, 1H). Mass (551.59) carbonyl)pyrrolidin-3 -ylthio)-4-methyl-7-oxo- 1 - 552.1

azabicyc!o P .2.0]hept-2-enc-2-carboxylic acid

Preparation of C: ffi c

Step (i): Ethyl 2-(2,2,2-tnfluoroacetainido)acetate

Ethyl trifluoroacetate (10.7 g, 0.075 moles) was dissolved in methanol (mL) and cooled to 0°C. Glycine ester hydrochloride (10.5 g, 0.075 mol) was added to this solution and the reaction mixture was stirred for 5 _. minutes. Triethylamine (15.7 mL, 0.1 12 moles) was added dropwise at 0°C and stirred for 15 minutes. The reaction mixture was then brought to room temperature and stirred overnight. The solvent of the reaction mixture was evaporated under vacuum and water was added to the crude followed by extraction with ethyl acetate. The organic layer was then washed with water, brine, dried over sodium sulphate and concentrated to give the crude product (15g). NMR: (CDCI3, 400 MHz): 6.85 (s, 1H), 4.25-4.30 (m, 2H), 4.12-4.15 (m, 2H), 1.30-1.33 (m, 3H).

Step (ii): Ethyl 2-(2,2,2-trifluoroethanethioamido)acetate

(20 mL) minutes. P2S5 (10 g, 0.045 mmol, 0.6 eq.) was added portion wise very slowly and stirred for 10 minutes at 0°C. The reaction mixture was then heated to 70°C for 6 hours. After the completion of reaction, the reaction mixture was brought to room temperature and quenched with water slowly at 0°C and extracted with ethyl acetate. The organic layer was washed with 5% NaHC(¼ solution, water and brine respectively and dried over sodium sulphate. The crude reaction mixture was then concentrated under vacuum and the product was isolated by column chromatography (11 g, 67.8%). Ή NMR: (CDC13, 400 MHz): 8.46 (s, 1H), 4.29-4.38 (m, 2H), 4.12-4. Γ5 (m, 2H), 1.30- 1.35 (m, 3H).

Step (iii): Ethyl 2-(5-(trifluoroiiiethyl)-lH-tetrazol-l-yl)acetate

Ethyl 2-(2,2,2-ίτϊι]ηοΓ06ώ3ηείηϊθ3Γηί£ΐο)3οε ΐ3ΐε (11 g, 0.051 mol) was dissolved in

dichloromethane (110 mL) at ambient temperature. Azidotrirnethylsilane (13.5 ml, 0.102 mol) was added dropwise to this solution and stirred for 10 minutes. A solution of SnCU (13.3 mL, 0.127 mmol) in dichloromethane (mL) was added dropwise and stirred for 1 S minutes. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was then quenched with saturated NaHC0 ₃ solution slowly at 0°C, filtered through celite bed, washed . with dichloromethane. The organic layer was then separated, washed with water, brine, dried over sodium sulphate and concentrated under vacuum to give the crude product. The crude product was then purified by column chromatography to give the product (6 g, 52.6%). ^! H NMR

2-(5-(Trifluoromethyl)-lH-tetrazol-l-yl)acetic acid (7.3 g, 0.033 moles) was dissolved in THF (70 mL). A solution of LiOHH ₂ 0 (1.5 g, 0.036 mol) in water (80 mL) was added dropwise at room temperature and the resultant reaction mixture was stirred for 2 hours. After the completion of reaction, the solvent was evaporated under vacuum and the resultant crude was dissolved in water. The aqueous layer was washed with ethyl acetate and was then acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under vacuum to give the desired product (5.6 g, 87.6%). Ή MR (DMSO-d^ 400 MHz) : 14.00 (br s, lH), 5.69 (s^ 2H).

Preparation of Example 347 (4R,5S,6R)-3-((3S,5S 5-((R)-3-aminopyrrolidine-l- carbonyl)pyrroUoin-3-yUhio)-4'methyl-7^oxo-6-((R)-l-(2-(5-(t rifluoromethyl)-lH-tetra-»l- l-yI)acetamido)ethyl)-l-azabicyclo[3.2.0]hept-2-ene-2-carbox ylic acid

Step 1: (R)^Nitrobeiizyl2^iazo-3-oxo-4-((2R^ ^

lH-tetrazol-l-yl)acetamido)ethyI)azetidui~2-yI)pentanoate

TETTU, DSPEA.

OoC-RT

5-TrLfluoro-Tetrazole acetic acid (2.1 g, 0.011 mol) was dissolved in ethyl acetate (mL) cooled to 0°C and to this solution was added TBTU (4.47 g, 0.014 mol) and stirred for 5 minutes at the same temperature. Diisopropylemylamine (3.8 ml, 0.022 mol) was added dropwise and stirred for 10 minutes at 0°C. The reaction mixture was then brought to room temperature and further stirred for 1 hour. The reaction mixture was again cooled to 0°C and to it was added a solution' _, of the trifluoroacetate salt of (R)-4-nitrobenzyl 4-((2R,3R)-3-((R) l-am oethyl)-4-oxoazetidin- 2-yl)-2-diazo-3-oxopentanoate, (3.7 g, 0.007 mol) in ethyl acetate (25 mL) followed by dusopropylethylamine (3.8 mL) drop wise and stirred for 10 minutes at 0°C. The reaction mixture was then brought to room temperature and stirred overnight. After the completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, followed by brine, dried over sodium sulphate and concentrated under vacuum to give the crude which was then purified by column

chromatography to give the product (1 g, 23.9%). Ή NMR (CDCI3, 400 MHz): 1.19-1.21 (3H, d), 1.35-1.37 (3H, d), 2.86-2.88 (1H, m), 3.58-3.69 (2H, m), 4.24-4.33 (1H, m), 5.22-5.29 (2H, m), 5.35 (2H, s), 6.04 (1H, s), 6.71-6.73 (1H, d), 7.53-7.55 (2H, d), 8.25-8.28 (2H, d).

Step 2: (4R,5R,6R)-4-nitrobenzyl 3-(diphenoxyphosphoryloxy)-4-methyl-7-oxo-6-((R)-l-(2- (5-(rrifluoromethyl)-:tH-tetra-»l-l-yl)aceta

carboxylate

(R)-4-nitrobenzyl 2-diazo-3-oxo-4-((2R,3R)-4-oxo-3-((R)-l-(2-(5-(trifluorometh yl)-lH-tetrazol ]-yl)acetamido)ethyl)azetidin-2-yl)pentanoate (l .l g, 1.94 mmol) was dissolved in 50 mL of acetone under N2 atmosphere. To this solution was added rhodium octanoate (40 mg, 0.051 mmol) and heated to 70°C for 1 hour. The reaction mixture was then cooled to -40 ^D C and diphenylchlorophosphate (0.64 mL, 3.1mmol), diisopropylethyl amine (0.6mL, 3.44 mmol) and catalytic amount of dimemylaminopyridine was added successively. The reaction mixture-was then stirred for 1 hour at -20°C. Diisopropylemylamine (0.6mL) was again added to the reaction mixture and was quenched with water. The aqueous layer was extracted with dichloromethane and the organic layer evaporated under vacuum at room temperature. The crude thus obtained was purified by column chromatography to give the product as a solid (850 mg).

Step 3: (4R,5S,6R)- -Nirro benzyl -methyl-3-((3S,5S)-l-((4-nitroberjzyloxy) carbonyl)-5-

(trifluo romethyl)- 1 H-tetrazo 1- 1 -y )acetami o)et y 1)- 1 -aza icyc o .2. ept-2-ene-2-carboxylate (500 mg, 0.65 mmol) was taken in acetonitrile (10 mL) at 0°C. The solution was then degassed for 10 minutes using N2 atmosphere. To this solution was added the thiol (0.372 g, 0.65 mmol) at 0°C under N ₂ atmosphere followed by addition of du ^' sopropyleth lainine (0.2 mL, 1.15 mmol). The resultant solution was degassed again for 15 minutes. The reaction mixture was stirred under N2 at 0°C for 2 hours. After the completion of reaction, the reaction mixture was quenched using water and extracted by ethyl acetate. The organic layer was then washed with water, brine, dried over sodium sulphate and evaporated under vacuum to give the crude. The crude reaction mixture was purified by-column chromatography to give the product (450 mg, 64%) as a solid. ^! H NM (DMSO-ά _ί , 400 MHz) 3 1.18-1.19 (3H, d), 1.22- 1.24 (3H, d), 1.73 (2H, m), 2.83 (1H, m), 3.14-3.17 (2H, m), 3.47-3.69 (4H, m), 3.88-3.90 (2H, m), 4.12-4.22 (4H, m), 4.54 (1H, m), 5.07-5.09 (1H, m), 5.17-5.2 (3H, m), 5.41-5.44 (1H, d), 5.48-5.52 (3H, m), 7.47-7.49 (2H, m), 7.52-7.54 (2H, m), 7 _r 60-7.62 (3H, m), 7.70-7.72 (1H, m), 8.20-8.24 (6H, m), 8.75-8.77 (ΪΗ, d). ^{' "}

Example 348 was prepared by reacting compound obtained by Step 2 with appropriate R'-SH

Example Structure AnalyticaLData

347 'HNMR (D ₂ 0)- 1.27 (d, 3H), 1.36 (d,

3H), 1.86 (m, 1H), 2.49 (d, 1H), 2.89 (m, 2H), 3.43 (m, 2H), 3.58 (m, 2H), 3.62 (d, 2H), 3.73 (d, 2H), 4.06 (d, 2H), 4.16 (d, 1H), 4.28-4.42 (m, 2H),

(4R,5S,6 >3-((3S,5S>5-((R)-3-amiiiop irolidine-l- 5.62 (m, 2H). Mass (601.60) 602.5 . carbonyl)p3rroUdin-3-yl& ^" o)- -methyI-7-oxcHi-({R)-l-(2-(5- (trifluoromethyl)- lH-tetrazol-l-yl)acctamidn)ethyl)- 1-

-_Eabicyclo[3.2.01bep(-2-enE-2-carboxylic acid

Examples 369-378 and 383-451 were prepared by treating the compound of formula (10) with appropriate R ^A COOH according to the procedure given in the preparations 12, 16. arid 17, followed by the procedure given in Example I .

The cyclisation to obtain carbapenem and reaction of its enolic phosphate with.various R'-SH is similar to that described for preparation of Example 1 (S tep I & Step 2) or Example 95 (Step 1 to 3) or Example 298 (Step 2 to 4). ■

Example Structure Analytical Data

'HNMR (D ₂ 0) - 1.11 (d, 3H), 1.23 (d, 3H), 2.04-2.08 (m, IH), 2.51-2.72 (m, 2H), 2.95 (m, IH), 3.07-3.19 (m, 2H), 3.34-3.46 (m, 3H); 3.63-3.70

369

0 (m, 6H), 3.73 (m, IH), 3.78 (m, 2H; ,

(4R,5S,6R)-6-(( l-(3-(lH-tetrazol-l- 3.8-4.28 (m, 3H), 9.24 (s, IH); yl)propaiamido)- yl)-3-((3S,5S)-5-{(R)-3---i-^ C23H33N905S; HPLC 98.9%; Mass

1 -carbo nyI)pyrrolidin-3-y lthio)-4-methyl-7-oxo- 1- 548.3 (M+l) azabicyc [3.2.0]bept-2-en--2-carboxylic acid

2-enc-2- carboxylic acid

azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Mass 563.4 (M+l)

azahicyclof3.2.01hcpt-2-ene-2-carboxylic acid

The following examples 452- 601 were prepared adopting the procedure for synthesizing example 298.

. . 460 ^J HNMR (D ₂ 0) - 1.17 (d, 3H), 1.32 yo ^{' '} (d, 3H), 1.89 (m, 1H), 2.72-2.77 (m,

3H), 2.94-2.97 (m, 1H), 3.07-3.10 (m, 1H), 3.23-3.33 (m, 2H), 3.54- 3.56 (m, 2H , 3.70-3.75 (m, 2H), 3.95 (m, 1H), 4.11-4.13 (m, 1H),

(4R,5S )-6-((R)-l-(2-(lH-tetr-^l-l-yl)acetamido)ethyl)-3' 4.37-4.41 (m, 2H), 4.60-4.80 (m, ((3S,5S^5-((R)-2- aIninometbyl)πlό hol-πe- - 2H), 5.35-5.45 (m, 2H), 8.43 (m, carbonyl)pyrrolid-n-3-yltmo)-4-methyl-7-oxo-l- 1H), 9.23 (s, 1H) C23H33N906S azabicydo[3.2.0]hept-2-ene-2-carboxyiic acid HPLC 90%, Mass (M+l) 564.1

461 f- 'H R (D ₂ 0) -1.17 (d, 3H), 1.32

^■ V (d, 3H), 1.87 (m, 1H), 2.68-2.73 (m,

3H), 2.90-2.94 (ra, 1H), 3.02-3.08 (m, 1H), 3.28-3.42 (m, 2H), 3.58- 3.62 (m, 2H), 3.72-3.78 (ra, 2H), 4.01 (m, 1H), 4.14-4.18 (ra, 1H),

(4R,5S,6R)-6-((R)- 1 -(2-( 1 H-tetrazoH-yl)acetaraido)ethy 1>3- 4.40-4.44 (ra, 2H), 4.72-4.94 (m, ((SS.SSJ-S-CiSH-taminometh moi holine^- 2H), 5.44-5.48 (m, 2H), 8.52 (m, carbonyljpynol idin-3-ylthio)-4-methyl-7-oxo- 1 - 1H), 9.26 (s, 1H) C23H33N906S B2abicydo[3.2.0]hept-2-ene-2-carboxylic acid HPLC 95.1%, Mass (M+l) 564.1

462 ■ 'HNMR (D ₂ 0) - U7 (d, 3H), 1.32

(d, 3H), 2.58-2.62 (m, 3H), 2.66-2.70 (m, 4H), 2.82-2.87 (m, 2H), 2.93- 2.99 (m, 1H), 3.25-3.29 (m, 3H), 3.35-3.39 (m, 3H), 3.55-3.60 (m, 1H), 3.72-3.99 (m, 1H), 4.0-4.13 (to,

(4R,5 S,6R)-6-((R)- 1 -(2-(lH-tetrazol- 1 -y l)acetamido)ethy 1 3- 1H), 4.33-4.65 (m, 1H), 4.67-4.80 ((3S 5S>5-(4^(S)-3-amino-2-fluorOpropyl)piperaziBe-l- (m, 1H), 5.1 (ra, 1H), 5:3 (m, 1H), carbonyl)pynoUdin-3-ylthio)-4-methyI-7-oxo- 1- 5.4 (m, 2H), 9.25 (s, 1H) azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid C25H37F 10O5S

HPLC 95.6%, Mass 609.5 (M+l)

463 'HNMR (PjO) - 1.27 (d, 3H), 1.33

(d, 3H); 1.65-1.80 (m, 1H), 2.44-2.48 (m ,1H), 3.13-3.14 (ra, 1H), 3.30- 3.36 (m, 1H), 3.52-3.58 (m, 3Η),· . 3.62-3.65 (m, 3H), 3.71-3.77 (m,

(4R,5S )-6-((R)-l-(2-(lH-tetrazoi-l-yi)acetamido)ethy] 3- 3H), 3.99 (m, 2H), 4.13-4.15 (m, ((3S,5S)-5-(4-(ammomethyl)^-(hydmxymethyl)pipcridiiie-l- 3H), 4.31 -4.39 (m, 2H), 4.40-4.69 carbonyI)pynoUdin-3-ylthio)-4-methyi-7-oxo-l- (m, 1H), 4.79 (m,, lH), 5.30-5.46 (m, azabicycio(3.2.0]hept-2-ene-2-carboxylic acid . ^• 2H), 9.25 (s, 1H) C25H37N906S

HPLC 90%, Mass 591.7 (M+1)

464 o 'HNMR (DiO) - 1.17 (d, 3H), 1.31

(d, 3H), 1.89-1.96 (m, 1H), 2.42-2.44 (m, 2H) 2.59-2.76 (m, 1H), 2.78 (m,

⁰ . ν,ίι- 1Η), 3.11 _η 3.14 (ιο, 1H), 3.22-3.29

^■ o _o ° ^H (m, 2H), 3.41-3.46 (m, 2H), 3.48- 3.49 (ra, 1H), 3.54-3.55 (m, 2H),

(4R,5S,6R)-6-((R)- 1 -(2-(lH-tetra2ol- l-yl)acetamido)etbyl)-3- 3.75 (m, 2H), 3.94-4.12 (m, 2H) ((3S ,5 S SKiSJ^-C-aiiinoi cthy yTTOlid ne- 1 - 4.29-4.37 (m, 2H), 5.40-5.44 (d, 2H), carbooyl)pyrroHdin-3-ylthio)-4-metbyl-7-oxo-l- 9.23 (s, 1H) C23H33N905S azabicyclo[3.2.0]hept-2-ene-2-car oxylic acid

HPLC 90%, Mass (M+l) 548.2

465 ^l HNMR (D ₂ 0) -1.17 (d, 3H), 1.30

(d, 3H), 1.92 (m, 1H), 2.43-2.46 (m, 2H) 2.60-2.74 (m, 1H), 2.80-2.82 (m, IH), 3.14-3.}6 (m, 1H), 3.28-3.32 (m, 2H), 3.42-3.45 (m, 2H), 3.49- 471 'H MR φ ₂ 0) - 1.19 (d, 3H), 1.33 ^■

(d, 3H), 1.81-1.84 (m, 1H), 2.86-2.92 (m, lH), 3.31-3.34 (m, 2H), 3.37- 3.40 (m, 1H), 3.47-3.53 (m; 4H), 3.55-3.62 (m, 3H), 3.94 (m, 1H), 4.02-4.04 (m, 1H), 4.12-4.14 (ra,

(4R, 5S,6R)-6-((R>- 1 -(2-{l H-tetrazol- l ^' -yl) acetamic!o)ethyl)-4- lH), 4.31†4.38 (m, 2H), 4.40-4.42 methyl-3-((3S,5S}:5-((4aR,7aS)-octahydropyrrolo[3,4- (m, 1 H), 4.56-4.57 (m, 1H), 5.02- b][i;4]oxazine-4-carbonyl)p Trolidiii-3-ylthio)-7-oxo-l- 5.04 (m. l ^' H), 5.44-5.46 (m; 2H), azahicyclo[3.2.0]hept-2-ene-2-carboxylic acid 9.26 (s, 1H) C23H33N906S

HPLC 90.3%, Mass (M+l) 564.1

472 'HNMR (D ₂ 0) - 1,19 (d, 3H), 1.33

(d, 3H , L82-1.85 (m, 2H), 2.16-2.30 (m, 1H), 2.4-2.6 (m, 1H), 2.93 (m,

· 4 Yy Lm 1H), 3.10-3.13 (m, 2H), ,3.32-3.33

(m, 2H), 3.56-3.57 (m, 2H), 3.63-

(4¾5S,6R)-6-((R)-i-(2-(lH-tetrazol-]-yl)acetaraido)ethyl )-3- 3.65 (m, 1H), 3.71-.379 (m, 2H), ((3S,5S)-5-((S)-3-(amLaomcthyl)pyrT ilidin -l- 3.96 (m, ]H), 4.12-4.14 (<L 2H), carbon l)pyrrolidin-3-ylthio)-4-methy 1-7-oxo- 1 - 4.40- 4.42 (m, 2H), 5.43-5.44 (d, azab!cycloi3.2.0]hept-2-ene-2-carboxylic acid 2H), 9.26 (s, 1H) C23H33N905S

HPLC 90.9%, Mass 548.3 (M+l)

473 ^l HNMR {DiO) -1.18 (d, 3H), 1.33

(d, 3H), 1.78-1.80 (m, 1H), 2.42-2.44 (m, l H), 2.80-2.84 (m, 1H , 3.15- 3.18 (m, 2H), 3.30-3.36 (m, 3H), 3.54-3.56 (m, 2H), 3.70-3.77 (m, o <f . 1H), 3.84-3.94 (m, 3H), 4.11-4.12

(4R,5 S,6R)-6-((R)- 1 -(2-(l H-tetrazol- l-yl)acetamido)ethyl>- 3- ((3S,5S 5-((2¾4R)-4-amino-2-(aniinOmethyl)pyiTOlidine-l- (m, 1H), 4.23 (m, 1H), 4.30-4.39 (m,

2H), 5.43-5.45 (d, 2H), 9.25 (s, 1H) carbonyl)pyrrolidijti-3-yl-hio)-4-iDethyl-7-oxo-l- C23H34N10O5S

azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

HPLC 90.0%, Mass (M+l) 563.2

474 'HNMR (DjO) 1.19 (4 3H), 1.32 (d,

3H), 2.4.(ra, lH), 2.78 (m, 1H), 2.88 (m, 1H), 3.22-3.25 (m, 2H , 3.31- 3.33 (m, 1H), 3.4 (m, 2H , 3.54-3.56 (m, 2H), 4.0 (m, 2H), 4.3-4.39 (m,

^" (4R,SS,6R)-6-((R)-l-(2-(lH-tetrazol-l-yl)acetamido)eth yl)-3- 2H), 4.40-4.79 (in, 3H), 5.3-5.4 (m, ((3S, 5S)-S-((2R,4R)-4½nino-2-(hydroxyiii ethyl)pyrro Lidine- 3H), 9.23 (s, 1H) C23H33N906S, 1 -caf bony l)jj^olidLn-3-ylthio)-4-inethyl-7-oxo- 1- HPLC 90.5%, Mass 564.3 (M+l) azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid

475 'HNMR iDjOJ - I.lS id. SH), 1.31

(d, 3H), 3.30-3.45 (tn, 5H), 3.50-3.79 (m, 5H), 4.10-4.18 (m, 4H), 4.30- 4.38 (m, 4H), 5.30-5.41 (m, 4H), 9.24 (s, 1H) C24H35N906S

(4R,5S,6R)-6-((R)- 1-(2-( 1 H-tetrazol- 1 -yl)acetamido)ethy 0-3- HPLC 94%, Mass 578.3 (M+l) . ((3S,5S)-5-(4-ambo- -(hydroxymethyl)piperidine-l- carbonyl)pyiToli diet- 3-yl tbio)-4-niethyl-7-oxo- 1 - azabicyclo [3.2.0] hept-2-ene-2-carbox lic acid

476 'HNMR (D ₂ 0) - 1.18 (d, 3H), 1.33

(43H), 1.68-1.81 (m, 8H), 1.96-2.0 (m, 1H), 2.98-3.05 (m ,3H), 3.21- 3.26 (m, 3H), 3.28-3.30 (m, 2H),

(4R,5S,6R 3-((3S,5S>-5-(l,9-diazaspiro[5.5]m)decane 3.41 (m, 2H), 3.48 (m, 2H), 3.55- l-carbonyl)pyrroUdin-3-yithio 6-((R> l-(2-( lH-tetrazol- 1- 3.57 (m, 2H), 4.12-4.15 (m, 2H), 492 'HNMR (p ₂ 0) -1.20 (d, 3H), 1.34

(d, 3H), 1.-80-1.83 (m, 2H), 2.20-2.23 (m, 1H), 2.66-2.69 (m, 2H), 2.81- 2.98 (m, 1H), 3.24-3.29 (m, 3H), 3.33-3.37 (m, 1H), 3.41-3.48 (m, lH), 3.52-3.61 (m, 3H), 3.72-3.78

(4R,5S,6 )-6-(CR)- HH 1 H-tetrazol- l-y])acctamido)elhy] 3- (m, 2H), 3.91-3.93 (m, 1H), 4.13- ((SS.SSJ-S-iCR^S-iS-amino ro anajnidoJ yrrolidine-l- .·

4.15 (m, 1H), 4.28 (m, 1H), 4.38- carbony!)pyTrolidin-3-ylthio)-4-methyl-7-oxo-l- 4.41 (m, 2H , 5.41-5.42 (m, 2H , azabicyclo[3.2.0]hept-2-en ^' e-2-carboxylic acid

9.29 (s, 1H) C25H36N10O6S HPLC 97% Mass (M+l) 605.1

493 0 , i NH 'HNMR (D _J O) - 1.09 (d, 3H), 1.23

(d, 3H), 1.76-1.77 (m, 1H), 1.93-2.04 (m, 4H), 2.86 (m, 1H), 3.20-3.27 (m, 4H), 3.34-3.37 (m, 3H),-3.40-3.43 (m, 3H), 3.45-3.48 (m, lH), 3.51- .

0 —OH 3.58 (m, 1H), 3.85-3.88 (m, 1H), 0 4.02-4.04 (m, 1H), 4.27-4.33 (m,

(4R,5S,6R) 6-(C )-l-(2-(lH-tetrazol-l-yl)acetamido)ethyl)-3- 2H), 5.30-5.31 (m, 2H , 9.26 (s, 1H) ((3S,5S)-5-(¾7-diazaspiio[4.4]non-uic-2-carbony pyrrolidin- C25H35N905S

3-y lthio)-4-methyl-7-oxo- 1 -azabicycloi3.2.0]hept-2-ene- 2- HPLC 97.9% Mass 574.3 (M+l) carboxylic acid

494 •?* N 'HNMR (DjO) - 1.19 (d, 3H), 1.30

H H ?*> I (d, 3H), 2.20-2.23 (m, 1H), 2.95 (m,

2H), 3.20-3.27 (m, 2H), 3.28-3.31 (ra, 2H), 3.38-3.40 (m, 2H), 3.43 (s,

(4R,5S,6 )-6-(CR)-l-(2-(lH-tetiazo!-l-yl)acctaraido)ethyl)-3- 3H), 3.44-3.47 (m, 1H), 3.54-3.91 ((3S,5S)-5-((3S,4S)-3-a -ao-4-niethoxypyrrolidLne-l- (rii, 3H), 3.97 (m, 1H), 4.13-4.15 (m, carbonyl)pyrroUdin-3-ylthio)-4-methyl-7-oxo-l- 2H), 4.39-4.42 (m, 1H), 4.50-4.52 a-ahicyclo[3.2.0]hept-2-eae-2-carboxylic acid (m, I H), 5:42-5.44 (d, 2H), 9.26 (s,

1H) C25H35N905S .

HPLC 96.2% Mass (M+l) 574.2

495 o . 'HNMR (D.O)— 1.19 (d, 3H), 1.33 .

(d,-3H), 1.77-1.80 (m, 2H), 2.14-2.20 (m ,2H), 2.65 (ra, 1H), 2.98-3.08 (m, 1H), 3.29-3.33 (ra, 2H), 3.36-3.37 (ra, 1H), 3.39-3.49 (m, 2H), 3.52 (m,

° 0 ■ 1H), 3.58-3.69 (m, 2H), 3.71 (m,

(4R.5 S,6R)-6-((R)- 1 -(2-(l H-tetrazol- 1 -yl)acetamido)ethyl)-4- 2H), 3.88 (m, lH), 3.99-4.05 (m, me l-3-((3S,5S>5-(oct-Aydro-lH-pyiTolo[¾3-c]pyridine-6- 3H), 4.12-4. L5 (d, lH), 4.38-4.40 (m, caibonyl)pyirolidin-3-ylthio)-7-oxo-l-azabicyclo[3.2.0]hept- 1H), 5.40-5.41 (d,.2H), 9.26 (s, 1H) ^■ 2-ene-2-carboxylic acid . C25H35N905S

HPLC 95.8% Mass (M+l) 574.3

496 'HNMR (D,0) -1.09 (d, 3H), 1.18

(d, 3H), 2.01-2J24 (m, 2H), 2.98 (m, 1H), 3.20-3.23 (m, 2H), 3.46-3.47 (m, 2H), 3.50-3.51 (m, 2H), 3.58- 3.65 (m, 3H), 3.68-3.73 (m, 2H), 3.86 (m, 1H), 4.02-4.04 (m, 1H),

(4R,5S,6R>6-((R)-l-(2-(lH-tetrazol-l-yl)acctamido)cthy l)-3- 4.28-4.32 (m, 2H), 5.30-5.31 (d, 2H), ((3S,5S)-5-(3-amii»-3-(hydroxymethyl)pynolidinc-l- 9.16 (s, 1H) C23H33N906S carhwayl)pyrroUdin-3-ylthio)-4-methy l-7-oxo- 1 - HPLC 99% Mass (M+l) 564.6 azahicyclo[3.2.0]hcpt-2-enc-2-carboxy lie acid 497 'HNMR (D ₂ 0) -1.19 (d, 3H), 1.33

(d, 3H), 2.21-2.25 (m, 2H), 2.96-2.98 (m, 1Η),·3.22-3.25 (m, 2H), 3.47- 3.49 (m, 2H , 3.51-3.54 (m, 2H), 3.59-3.65 (m, 3H), 3.71-3.76 (m, 2H), 3.92- 3.96 (m, 1H), 4:04-4.06

(4R,5S,6R)-(5-((R)-l-(2-(lH-tetrazol-I-yl)acetamido)ethyl )-3- (m, 1H)6 4.30-4.34 (m, 2H), 5.32- ((SS _j SSJ-S-fS-ajiiino-S-ihydroxymethylJpyrrolidinc-l- 5.33 (d, 2H), 9.25 (s, 1H) carbony l)pyrrolidin-3-y Ittiio)-4-methyl-7-oxo- 1 - C23H33N906S

a2abicydo[3.2.0]hept-2-erie-2-c-irbox lie acid HPLC 0.3% Mass (M+l) 564.2

498 'HNMR (D ₂ 0) - 1.09 (d, 3H), 1.23

(d, 3H), 1.81 (in, 1H), 2.89-2.92 (m, 2H), 3.23-3.28 (m, 2H), 3.29 (m, 2H), 3.46-3.48 (m, 2H), 3.51-3.53

O (m, 2H), 3.83-3.89 (ra, 3H), 4.02-

(4R,5S,6R)-6-((R)-l-(2-(lH-tetrazoi-l-yl)acetaiiiido)ethy l)-3- 4.04 (ni, 1H), 4.28-4.32 (m, 1H), ((3S,5S)-5-((3S,4R)-3-amino-4-fluoropyrrolidine-l- 5.30-5.31 (d, 2H), 9.16 (s, 1H) carbonyl)pyrrolidin-3-ylthio)-4-methyl- 7-oxo-l- C22H30FN9O5S HPLC 99% azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Mass (M+l) 552.2 ■ m 'HNMR (D ₂ 0) -1.1 (d, 3H), 1.34

(d, 3H), 1.85-1.97 (m, 5H), 2.03-2.04 (ra, 3H), 2.91-2.97 (m, 1H), 3.27- 3.37 (m, 6H), 3.42-3.46 (m, 1H), 3.51-3.58 (m, 4H), 3.72 (m, 1H),

. ^■ o ■ 4.13-4.15 (ra, 1H), 4.40-4.41 (m, ^' (4R, 5S,6R)-6-((R)-l-(2-(l H-tetrazol- 1-y l)acetamido)ethy l)-3- 2H), 5.42-5.47 (d, 2H), 9.27 (s, 1H) ((3S,5S)-5-(2,8-diazaspiro[4.S]dec^e-2-c^bonyl)p)TTolidin- C26H37N905S

3-ylthio)-4-metbyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- HPLC 8.8% Mass (M+l) 588.1 carboxylic acid

500 'HNMR (D.O) - 1.19 (d, 3H), 1.33

(m, 9H), 2.21-2.25 (m, 2H), 2.96- 2.98 (m, 1H), 3.22-3.25 (m, ^' 2H), 3.47-3.49 (m, 2H), 3.51-3.54 (m, 2H), 3.59-3.65 (in, 3H), 3.71-3.76 (m, 1H), 3.92- 3.96 (m, 1H), 4.04-

(4R,5S _I 6R)-6-((R)-l-(2-(lH-tctrazol-l-yl)acetamido)ethyl)-3- 4.06 (m, IH) 4.30-4.34 (m, 2H), ((3S,5S)-5-((R)-3-(2-amiiiopropan-2-yl)pyrTOlidiiie-l- 5.32-5.33 (d, 2H), 9.25 (s, IH) carbonyl)pyrroUdLQ-3Tyltbjo)-4-methyl-7-oxo-l- C25H37N905S ^■

azabicyclo[3.2.0]hept-2-cne-2-carboxylic acid

HPLC 97.9% Mass (M+l) 576.3

501 'HNMR (D ₂ 0) - 1.09 (d, 3H), 1.23

(d, 3H), 1.76-1.77 (m, IH), 1.93-2.04 (m, 2H), 2.86 (ra, IH), 3.20-3.27 (m, 4H), 3.34-3.37 (m, 3H), 3.40-3.43 (m, 3H), 3.45-3.48 (m, IH), 3.51- 3.58 (m, IH), 3.85-3.88 (m, IH),

(4R,5S,6R)-6-((R)- 1-(2-( IH-tetrazol- l-yl)acetamido)-thyl)-3- 4.02-4.04 (m, IH), 4.27-4.33 (m, ((3S,5S)-5-(2,6^di_-^piro[3.4]octan_-2-carbonyl)p TTolidin- 2H), 5.30-5.31 (d, 2H), 9.26 (s, IH) 3-ylthio)-4-raethyl-7-oxo- 1 -azabicyclot3.2.0]hept-2-ene-2- C24H33N905S

caiboxylic acid HPLC 97.9% Mass (M+l) 560.4

502 'HNMR 0¼Ο) - 1.19 (d, 3H), 1.33

(d, 3H), 1.88 (m, IH), 2.02-2.04 (m, 2H), 2.84-2.86 (m, IH), 3.22-3.29 (m, H 3.35-3.38 (m, 3H), 3.41- 3.44 (m, 3H), 3.46-3.49 (ra, IH), 3.52-3.59 (m, 1H 3.86-3.89 (m, ^■ 513 'HNMR (D ₂ 0) - 1.18 (d, 3H), 1.32

(d, 3H), 1.85-1.88 (m, 2H), 2 _: 18-2.32 (m, IH), 2.42-2.46 (m, IH), 2.89- 2.93 (m, IH), 3.12-3.15 (m, 2H), o 3.33-3.34 (m, 2H), 3.57-3.58 (m,

(4R,5S,6R)-6-{(R)-l-{2-(lH-tetrazol-l-yl)acetainido)ethyl )-4- 2H), 3.63-3.65 (m, IH), 3.71-.379 me l _r 7-oxo-3-((3S,5S)-5-((R)-pyrroIidin-3- (m, 2H), 3.96 (m, IH), 4.12-4.14 (d, ylmethyIcarbamoyl)pyrTolidiB-3-yltbio)-I- 2H), 4.40- 4.42 (m, 2H), 5.43-5.44 azabicyclo[3.2.0]hept-2-tne-2-caitioxylic acid (d, 2H), 9.26 (s, IH) C23H33N905S - HPLC 97.9% Mass (M+l) 548.3

514 'H MR (D _J O) - 1.20 (d, 3H), 1.34

(d, 9H), 1.79- 1.82 (m, IH), 2.08-2.11 (ra, IH), 2.35-2.38 (m, IH), 3.33- 3.40 (m, IH), 3.67-3.71 (m, IH), 3.73 (m, IH), 3.78 (d, 2H), 3.90 (m,

(4R,5S,6R)-3-((3S, 5S>5-((R 3-am inopyrrolidine- 1 - IH),.4.12-4.14 (m, 2H), 4.14-4.15 . carbonyl)pynoUdin-3-ylthio)-6-((R)- 1 -((Z)-2-(2- (m, 2H), 4 16 (d, lH), 4.41 (d, IH), aminotbiazol-4-yl)-2-(2-carboxypropan-2- 4.60 (d, 1H), 4.84 (d, IH), 8.54 (s, y xyimino)acetamido)ethyl)-4-methyl-7-oxo-I- IH), C28H38N808S2 azabicycio[3.2.0]hept-2-cne-2-carboxylic acid HPLC 90% Mass (M+l) 679.1

515 HjC ¹ HNMR (t ⁾ ₂ 0) - 1.28 (d, 3H), 1.34

(d, 3H), 2.86 (m, IH), 3.02-3.06 (m, IH), 3.44-3.48 (m, IH), 3.57-3.60 (m, IH), 3.73-3.77 (m, IH), 4.05 (m, l O . 2H), 4.27-4.33 (m, 2H), 5.42 (d, (4R,5S,6R)-6-((R>l-<2-{lH-tetra2ol-l-yl)acetamido)cthy l)-3- 2H), 9.27 (s, IH)

(l-c^ba-iiiniidoylazetidin-3-yltbio)-4-mcthyI-7-oxo-l- C17H23N904S

azabicycIo[3.2.0]hept-2-ene-2½arboxylic acid HPLC 95.1% Mass (M+l) 450.4

516 o 'HNMR (D ₂ 0) - 1.20 (d, 3H), 1.34

(d, 3H), 1.85-1.92 (ra, lH),-2.94-3.26 (m, 4H), 3.46-3.49 (ra, 4H), 3.57- 3.58 (m, 2H), 3.62-3.72 (m, IH), o 3.73-3.76 (ra, IH), 3.80-3.84 (m,

(4R,5S,6 )-3-((3S,5S)-5-(l ,4-diazepane-l- 2H), 3.87-3.92 (m, IH), 3.94-4.13 cajbonyOpynOlidin-S-ylt oJ-e-iCRH^-tlH-tetrazol-l- (m, IH), 4.30 (d, IH), 4.43-4.49 (in, yI)acetamid )ethyl)-4-mi;thyl-7-oxo-l-azabicyclo[3.2.0]hept- IH), 4.51-4,53 (m, 1H), 5.47 (ra, 2-ene-2-carboxylfc arid 2H), 9.27 (s, IH)

C23H33N905S

HPLC 97.9% Mass (M+l) 548.1

517 'HNMR (DjO) 1.20 (d, 3H), 1.34 (d,

,3H), 1.88-1.95 (m, IH), 3.12-3.34 (m, 4H), 3.48-3.51 (m, 4H), 3.59- 3.60 (m, 2H), 3.64-3.74 (m, IH),

(4R,5S,6R)-6-(CR)-l-(2-(lH-tetrazol-l-yI)acetamido)etbyl) -3- 3.75-3.78 (m, IH), 3.82-3.86 (m, ((3 S, 5S)-5-(4-carbamimidoy i- 1 ,4-di azcpane- 1 - 2H), 3.88-3.93 (m, IH), 4.12-4.15 carbonyi)pyrrolidin-3-y ltbio)-4-niethyl-7-oxo- 1 - (m, IH), 4.38 (d, IH), 4.48-4.52 (m, azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid IH), 4.58-4.60 (ra, IH), 5.48 (m,

2H), 9.27 (s, IH) ^' C24H35N1105S HPLC 97.9%. Mass (M+l) 590.2

51S 0 'HNMR (DjO) - 1.21 (d, 3H), 1.29

(d, 3H), 1.94-2.0 (m, IH), 3.00 (s, 3H), 3.03 (s, 3H), 3.28 (s, 3H), 3.35- 3.37 (m, IH), 3.41 (s, 3H), 3.57-3.58 (m, IH), 3.60-3.62 (m, 2H), 3.72-

(4R,5S,6R 3-((3S,5S)-5-Cdijncthylcarbamoyl)pyiToiidin-3- ^" 3.73 (m, 3H), 3.90-3.91 (m, 2H),

carbonyl)pyirolidin-3-ylthio)-7-oxo- l-azabicyclof3.2.01hept-

2-ene-2-carboxylic acid

azabicyclo[3.2.0]hept-2-cne-2-carboxylic acid 'HNMR (D ₂ O) -1.07 (d, 3H), 1.21

(d, 3H), 1.67-1.79 (m, 4H), 1.93-1.98 (m, IH), 2.39-2.40 (m, IH), 2.77- 2.78 (m, I H), 2.89-2.95 (m, IH), 3.14-3.15 (m, IH), 3.22-3.23 (m, IH), 3.29-3.37 (m, 3H), 3.43-3.45

0 (in, 2H), 3.51-3.57 (m, IH), 3.60-

(4R,5S,6R)-6-((R)-l-(2-(lH-tetra2ol-l-yl)acetamido)et yl)-3- 3.67 (m, IH), 3.80-3.81 (m, IH), ((3 S,5S)-5-(( 1 R, 7R)-3 ,8-Diaza-tri cyclo[5.2.1.01 ,5]decane-8- • 4.00-4.02 (m, IH), 4.14-4.17 (m, carbony l)-pyrrolidin-3-ylraio)-4-methyl-7-oxo- 1 - IH), 4.27-4.33 (in, 2H), 5.25-5.34 azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid · (m, 2H), 9.14 (s, IH)

C26H35N905S

HPLC 97.9% Mass (M+1) 586.2

'ΗΝΜΚ (0 ₂ 0) - 1.15 ( 3H), 1.22 (d, 3H), 1.45-1.52 (m, 2H), 1.67-1.69 (m, IH); 1.78-1.8-7 (m, 3H), 2.52- 2.53 (m, IH), 2.74.-2.80 (m, 3H), 2.99-3.02 (m, I H), 3.02-3.22 (m ^' , 3H), 3.35-3.36 (m, IH), 3.38-3.44

(4R,5S,6R)-6-((R)-l-(2-(lH-tetrazol-l-yl)acetamido)ethy]) -3- (m, IH), 3.60-3.64 (m, IH), 3.74- ((3S,5S)-5-(4-(3-amino-2- 3,77 (m, IH), 3.84-3.85 (m, 2H), hydroxypropy lcaibamoyl)piperidi ne- 1 -carbohyl)pyrroli din-3- 4.00-4.02 (m, IH), 4.21-4.70 (m, ylthio)-4-methyl-7-oxo-l-az-ibicyclo(3.2.0]hept-2-ene-2- 3H), 5.25-5.34 (m, 2H), 9.13 (s, IH) carboxylic acid C27H40N10O7S

HPLC 96.5% Mass (M+1) 649.2

¾NMR (D ₂ 0) - 1. 1 (d, 3H), 1.24 (d, 3H), 1.48-1.55 (m, 2H), 1.70-1.72 (m, IH), 1.81-1.90 (m, 3H), 2.55-2.56 (ra, IH), 2.77-2.83 (m, 3H), 3.02-3.05 (m, IH), 3.05-3.25 (m, 3H), 3.38-3.39 (tn, IH), 3.41-3.47 (m, IH), 3.63-3.67 (m,

(4R.5 S,6R)-6-((R> l-(2-(l H-tetrazol-1 -yl)acetamido)et yl>-3- IH), 3.77-3.81 (m, IH), 3.87-3.88 (m, ((3S,5S)-5-(4-(3-amino-2- 2H), 4.03-4.05 (m, IH), 4.24-4.73 (ra, hydroxypropylc^amoyl)piperidine-l-caibonyl)pyiTolidin-3- 3H), 5.28-5.37 (m, 2H), 9.15 (s, IH) yithio)-4-meti3yl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2- C27H40N10O7S

carboxylic acid HPLC 97.9% Mass (M+1) 648.73

'HNMR (DiO) - 1.07 (d, 3H), 1.21 (d, 3H), 1.64-1.69 (m, 2H), 1.70-1.78 (m, 2H), 1.84-1.95 (m, IH), 2.09-2.10 (m, I H), 2.33-2.35 (m, IH), 2.42-2.46 (m ,1H), 2.76-2.77 (ra, IH), 3.08-3.09 (tn, IH), 3.18-3.19 (m, lH), ^' 3.20-3.22 (m,

(4R,5S,6R)-6-((R)-l-(2-(lH-tctr- Ml-l^l)a«tamido)etbyl)-3- 2H), 3.27-3.30 (m, IH), 3.43-3.46 (tn, ((3S,5S 5^(3aS,5S,6_R)-3¾5-diaininooctahydrocyclo- IH), 3.44-3.50 (m, 2H), 3.60-3.66 (m, penta(c]pyTro]e- 2-carbonyl)pyrrolidin-3-ylthio)-4-mcthyl-7- IH), 3.91-3.99 (ra, 2H), 5.27-5.29 (m, oxo- 1 -azabi cyclo[3 ,2.0]hept-2-ene-2-carbox lie acid 2H), 9.14 (s, IH) C25H36N10O5S

HPLC 91.8% Mass (M+1) 589.1

'HNMR (D.O-1.05 (d, 3H), 1.20 (d, 3H), 1.73 (m, IH), 1.94 (m, 2H), 2.04 (tn, IH), 2.32 (m, 2H>, 2.49 (m, IH), 3.24 (m, 2H), 3.44-3.55 (m, 3H), 3.59 (m, IH), 3.82 (m, IH), 4.01-4.03 (tn, IH), 4.19-4.28 (m, IH), 4.34 (m, IH),

(4R, 5S,6R)-6- ((R)- 1-{2-( 1 H-tetrazol- 1 -yl)acetamido)ethyI}-3- 5.28r5.29 (d, 2H), 9.13 (s, IH) ((3S, 5S)-5-(((U}-3-aminopynOlidin- 1 -yl j (imino)- C23H33N1 105S

methylcarbamoyl)rpyrroUdin-3-yl-thio)-4-methyl-7-ox( -l- HPLC 97.1% Mass (M+1) 576.4 azabicyclo-[3.2.01-hept-2-ene-2-carboxylic acid 0

azabicyclo[3.2.0]hept-2-cne-2-carboxyLic acid 591 'HNMR (D ₂ 0)- 1.28(d, 3H), 1.33 (d,

VCD"" 3H), 1.81-1.99 (m, 2H), 2.86-2.87 (m

,1H), 3.22-3.24 (m, 1H), 3,35-3.43 (ra, 1H), 3.50-3.55 (m, IH), 3.75-3.76 (m, 2H), 3.92-3.93 (m, IH), 3.99-4.00 (m,

(4R,5S,6R)^-((R)-l-(2 lH-tetr.JM)l-l-yl)acctamido)ethyl>3- 2H), 4.01-4.02 (m, IH), 4.12-4.14 (m, ' {(3S,5S 5-(3,6-diazabicyclo[3.2.0]heptane-3- IH), 4.20-4.28 (ra, 2H), 4.38-4.48 (m, carbony l)pyrro lidin-3-ylthio)-4-methyl-7-oxo- 1 - 2H), 5:05-5.12 (m, IH), 5.32-5.46 (d, azabicyclo[3.2.0]hept-2-enc-2-carboxylic acid 2H), 9.25 (s, IH) C23H31N905S

HPLC 96.1% Mass (M+l) 546.2

592 'HNMR (DiO) - 1.17 (d, 3H), 1.32 (d,

3H), 1.83-1.97 (m, IH), 2.75-2.96 (ra ,2H , 3.28-3.34 (ra, 2H), 3.42-3.45 (m, 3H), 3.52-3.54 (ra, 2H), 3.67-3.78 (ra, , 4H), 3.84-3.87 (m, 2H), 4.39-4.81 (m,

(4R,5S,6R)- ⁰ 6-(( f)- l-(2-(lH-tetrazol-l-yl)acetamido)cthyl)-3- 2H), 5.35-5.44 (d, 2H), 9.24 (s, IH) ((3 S ,5S)-5-((3R,4S)-3-guani dino-4- C24H35N1106S 27

(hydroxymcthyl)pyrrolidinc- 1 -carbonyl)pyrTolidin-3-ylthio)-4- HPLC 90% Mass (M+l) 606.2 racthyl-7-oxo- l---!abicyclo[3.2.0]hept-2-ene-2-carboxylic acid

593 1 'HNMR p _! O) -0.97 (d, 3H), 1.29 (d,

3H), 1.78-1.80 (ra, 1H), 1.94-1.98 (m, 2H), 2.14-2.22 (m ,1H), 2.86-2.96 (m, 2H), 3.05-3.10 (m, IH), 3.34-3.44 (m,

(4R.5 S,6R)-6-((R)-l -(2-( 1 H-tetrazoi- 1 -y l)acetamido)ethy 1 4" 2H), 3.96-3.99 (m, JH), 4.31-4.33 (m, methy i-7-nxo-3-{l -((R)-pymi lidin-3-y Lraethy 1)- 1 H-pyrazol-4- 3H), 5.36-5.40 (m, 2H), 7.70-7.73 (m, ylthio)- l-azabicycln[3.2.0]hcpt-2-cne-2-carboxylic acid 1H), 7.93-7.97 (m, 1H), 9.23 (s, IH)

C21H27N904S

HPLC 91.35% Mass (M+l) 502.3

594 'HNMR (D ₂ 0) - 1.13 (d, 3H), 1.28 (d,

3H), 2.20-2.29 (in, 3H), 2.97 (m, 2H), 3.87-3.88 (m, 2H), 3.47-3.48 (m, 3H), 3.87-3.88 (ra, 3H), 3.99-4.15 (m, 2H),

(4R, 5S ,6R)-6- ((R)- 1 -(2-(lH-tetrazol- l-yl)acetamido)ethy 1 3- 4.30 (m, 2H), 5.36 (d, 2H), 7.43-7.44 (1 -(( I -(2-aminncthyl)-l-methylpipcridinium-4-yl)methyl)- 1H- (m, 2H), 7.54-7.56 (m, 2H), 7.93 (s, pyrazol-4rylthio)-4-methyl-7-oxo-l-azabicyc!o[3.2.0]hept-2- IH), 8.04 (s, IH), 9.22 (s, IH) ene-2-carboxylate C25H36N10O4S

HPLC 91.4% Mass (M+l) 573.1

595 'HNMR (DiO) - 0.86-0.88 (d, 3H),

1.68 (d, 3H), 2.18-2.19 (m, 2H), 3.02- 3.06 (ra, 2H), 3.31-3.32 (m, 2H), 3.47- 3.48 (m, 2H), 3.86-3.87 (m, IH), 4.1 1- 4.13 (m, 2H), 4.23-4.24 (m, IH), 5.27-

(4R,5S,6R)-6-((R)-l-(2-(lH-tetrazol-l--yl)acetan!ido)cthy l)-3- 5.28 (m, 2H), 7.63 (m, 2H), 7.84 (m, (4-( 1 - (3-aminopropyl)- 1 H-pyrazol-4-yl)benzy lthio)-4-methyl- 2H), 8.39 (s, IH), 8.43 (s, IH) 9.14 (s, 7-oxo- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid IH) C26H3IN904S

HPLC 94.4% Mass (M+l) 566.2

596 'HNMR (DjO) - 1.00 (d, 3H), 1.18 (d,

3H), 2.22-2.23 (d, 2H), 3.00-3.01 (m, 2H), 3.31-3.33 (m, IH), 3.69-3.71 (m, 2H), 3.91-3.92 (m, IH), 3.99-4.01 (m, IH), 4.07 (s, 3H), 4.20-4.21 (m, IH), 4.47-4.49 (m, I H), 5.25-5.26 (ra, 2H),-

(4R,5S,6R)^-((R) -(2^1H-tctr _--- ol-i-yl)aKtamido)cthyl)-3- 7.35-7.37 (m, 2H), 7.43-7.47 (ra, 2H), ^" (4-( 1 - (3-aminopropy l)-2-methyi- lH-pyrazol-2-ium-4- . 8.44 (s, IH), 8.50 (s, IH), 9.12 (s, IH) yl)benzyithio)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hcpt-2-ene- C27H33N904S HPLC 96.7% _ 2-carboxylate (M+l) 580.2

mcthyl-7-oxo- l-azabicyclo[3 ^, .2.0]hept-2-ene-2-carboxylic acid

Example 600: Synthesis _, of (4S,5R,6R>6-((R)-l-(2-(lH-tetrazol-l-yI)acetamido)ethyl 3- (((3S,4S 3-guanidino-4-hydro _-- ypyrrolidin-l-yl)methyl)-4-methyl-7-oxo-l- .

azabicyclp[3.2.0]hept-2-ene-2-carboxylic acid

(R 4-Nitrober^l 4-((2R,3R)-3-(C )-l-(2-(lH-tetrazol-l-yl)acetam

yl)-2-diazo-3-oxopentanoate (10 g, 20 mmol) was dissolved in 200 mL of acetone under N2 atmosphere. To this solution was added rhodium octanoate (750 mg, 0.96 mmoles) and heated' to 60 ^D C for 2.5 hours. After the completion of the reaction, the reactio mixture was then cooled to -40 °C and trifljc anhydride (4.6 mL, 28 mmoles), diisopropylethylamine (8.8 mL, 50.9 mmol) and catalytic amount of dimethylaminopyridine (750 mg, 6.14 mmol) was added successively. The reaction mixture was then stirred for 1 hour at -40°C. The reaction mixture was quenched with addition of 0.1M phosphate buffer (pH = 7). The aqueous layer was extracted with dichloromethane and the organic layer evaporated under vacuum at room temperature to obtain crude. Partial purification of the crude was done by column chromatography to yield (4R,5R,6R)-4-rutroberjzyI 6-((R)-l-(2-(lH-tetrazol-l-yl)acetamido)ethyl)-4-methyl-7-ox o-3- (trifluoromethylsulfonyloxy)-l-azabicyclo[3.2.0]hept-2-ene-2 -carboxylate (2.7 g, 47 %).

A mixture containing (4R,5R,6R)-4-nitrobenzyl 6-((R)-l-(2-(lH-tetrazol-l-yl)acetamido)ethyl)- 4-memyl-7-oxo-3-(trifluoromemylsulfonyloxy)-^

(2.6g), tri-n-hutylstannylmethanol (5.48g, 17.1 mmol) and hexamethylphosphoramide

(degassed) was stirred for 30 minutes. To the above a separately prepared solution containing tris(2-furyl)phosphine (0.32g, l ^' .38 mmol), Pd(dba) ₃ (0.513g, 0.56mmol) and zinc chloride

(0.513g, 3.77 mmol) in 10 mL of hexamethylphosphoramide (degassed) was added and heated to 70 °C for 1 hour in a sealed tube. Reaction mixture was diluted with diethyl ether and water. The organic layer was separated and concentrated to obtain the crude. Column chromatographic purification of the crude was done to obtain lg of (4S,5R,6R)-4-nitrobenzyl 6-((R)-l-(2-(lH- tetrazol-l-yl)acetamido)emyl)-3-(hydroxymem^

ene-2-carboxylate. 'HNMR CDCI3 1.17 (d, 3H), 1.39 (d, 3H), 3.22-3.24 (m, 1H), 3.41-3.43 (m, 1H), 4.09-4.12 (d. ^' lH), 4.34-4.37 (m, 1H), 4.38 -4.39 (m, 1H), 4.58-4.62 (m, 1H), ^' 5.12-5.13 (d, 2H), 5.26-5.29 (dd, 1H), 5.49-5.52 (dd, 1H), 6.13 (br s, 1H), 7.64-7.66 (m, 2H), 8.22-8.24 (d, 2H), 8.93 (s, 1H).

A mixture of N,N-diisopropylthylamine (1.36 mL, 7.85mmol) and dimethylaminopyridine

(0.015 g, 0.13 mmol) in tetrahydrofuran (30 mL) was cooled to 0 °C and isobutyl-chloroformate (0.5 mL, 3.84 mmol) was added and stirred for 5 minutes. To the above, a solution of

(4S,5R,6R)-4-rurroberL?yl 6-((R)-l-(2-(lH-tetra∞l-l-yl)acetamido)emyl)-3-(hydroxymet hyl)-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.6 g, 1.24 mmol) dissolved in tetrahydrofuran (10 tnL) was added at 0 °C and continued stirring at room temperature for 24 h. Reaction mixture was concentrated under vacuo and purified the crude by column chromatography to obtain the titled compound, 0.4g. 'HNMR CDCI3 - 0.94-0.96 (d, 6H), 1.18 . (d, 3H), 1.38 (d, 3H), 1.94-2.01 (m, 1H), 3.10-3.11 (m, 1H), 3.30-3.34 (m, -lH), 3.93-3.94 (d, 2H), 4.10-4.12 (d, 1H), 4.38-4.42 (m, 1H), 4.78 -4.82. (m, 1H), 5.17 (d, 2H), 5.25-5.29 (m, 1H), 5.47-5.51 (m, 2H), 6.67-6.68 (br s, 1H), 7.63-7.65 (in, 2H), 8.23-8.25 (d, 2H), 8.87 (s, 1H).

Preparation 29: (4S,5R,6R)-4-rutrobenzyl 6-((R)-l-(2-(lH-tetrazol-l-yl)acetamido)ethyl)-3-

(((3S,4S)-3-((E)-2,3-bis((4-nitrobeii2yloxy)carbonyl^

yl)methyl)-4-raethyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene- 2-carbox late PNZ

Pd(dba) ₃ CHCI ₃ (0.026g, 0.025mmol), triethylphosphite (0.18ml, 0.l04mmol) and a mixture of 10 mL of tetrahydrofuran - toluene (degassed, 1 : 9) was stirred for 30 minutes. To the above, a solution containing mixture of 4-pjtroben2yl ((3S,4S)-4-hydroxypyrrolidm-3-yl-im-no)((4- nitrobeiizyloxy)carbonylainino)methylenecarbamate, trifluoroacetate salt (0.085g, 0.102mmol, neutralized with diisopropylethylamine) arid (4S,5 ,6R)-4-nitrobenzyl 6-((R)-l-(2-(lH- tetrazoll-yl)acetainido)ethyl)-3-((isobutoxycarbonyloxy) methyl)-4-methyl-7-oxo- 1- azabicyclo[3.2.0]hept-2-ene-2-carboxyIate (O. lg, 0.17mmol) in 5 mL of tetrahydrofuran- toluene (degassed 1 : 9) was added and stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and 0.1 phosphate buffsr 7.0. Organic layer was separated and washed with water and brine. After drying over sodium sulphate, organic layer was concentrated to obtain crude. The crude was purified by column chromatography to obtain the titled compound (0.06g). 'HNMR CDC1 ₃ 1.14 (d, 3H), 1.38 (d, 3H), 1.98-1.99 (in, 1H), 2.52-2.24 (m, 1H), 3.08 (m, 1H), 3.34 (m, 1H), 3.41 (m, 1H), 4.06 (m, ,1H), 4.11-4.13 (m, 1H), 4.43 (m, 1H), 4.91-4.94 (m, 2H), 5.Π-5.21 (m, 4H , 5.24-5.30 (nt, 4H), 5. 3-5.49 (m, 2H , 6.65 (br s , 1H , 7.51-7.56 (m, 6H), 8.19-8.24 (m, 6H), 8.87 (s, 1H) ^■

The above compound was hydrogenated similar to Step 4 of example 298 to obtain the required compoimd (4S,5R,6R)-6-((R l-(2-(lH-te^^

4-hydroxypyrrolidin- 1 -yl)methyl)-4-methy 1-7-oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxyl ic acid. 'HNMR (D ₂ 0) - 1.16 (d, 3H), 1.26 (d, 3H), 3.19-3.21 (m, 2H), 3.23 (m, 1H), 3.47 (m, 1H), 3.51 (m, IH), 3.84-3.86 (m, IH), 3.98-4.05 (m, IH), 4.12 _: 4.16 (m, 2H), 4.22 (m, 2H , 4.49 (m, IH), 5.30-5.46 (m, 2H , 9.25 (s, IH) C19H28N10O5 HPLC 90% Mass (M+l) 477.1

Example 601: Synthesis of (5R,6R)-6-((R)-l-(2-{lH-tetrazol-l-yl)acetamido)ethyl)-3- ((3S,5S)-5-(octahydro-lH-pyrrolo[3,2-c]pyridine-l-carbonyl)p yrroIidin _r 3-ylthio)-7-oxo-l- azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid

To a solution of (5)-4-phenyl-3-ace-yl-2-oxazolidinone (42.8 g, 0.21 mol) in dichlorometbane (250 mL), TiCL( (50 g, 0.26 mol) was added dropwise in 30 ruin at -20 to -25°C. After stirring the mixture for 30 min at -20 to -25 °C, diisopropyl ethylamine (56 g, 0.24 mol) was added dropwise, and stirring continued for lh at same temperature. To the above, (3 ?,4 ?)-4-acetoxy-3- [(.S)-l-((terrbutyldimethylsilyr) oxy)ethyl]-2-azetidinone (50 g, 0.17 mol) dissolved in dichloromethane (100 mL) was added at -15 to -10°C over a period of 20 minutes. Then the mixture was stirred at room temperature for 3 h. Reaction mixture was diluted with

dichioromethane (300 mL) and washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated under vacuum to obtain a residue. The residue was purified ' by. column chromatography (Eluant - 15% acetone in hexane) to obtain (4S)-3-(2-((2R)-3-((R)- l-(tert-butyldimemylsUyloxy)emyl)-4-oxoazen^m _: 2-yl)acetyl)-4-phenyloxazolidin-2-one (28.5g). This compound (28.5g) was dissolved in 300 mL of mixture of acetone and water (2 : 1 ) and cooled to 0 °C. Cooled hydrogen peroxide (30%, 22 mL) was added followed by dropwise addition of IN sodium hydroxide solution (200 mL) at 0 °C in 30 minutes. After stirring for 15 minutes at the same temperature, the reaction was diluted with water (1L). The aqueous layer was washed with ethyl acetate (500 mL' x 2). The aqueous layer was cooled to 0 °C and the pH was adjusted with 6 N HCl to 8. The aqueous layer was washed with ethyl acetate (500 mL x 2). The aqueous layer was acidifed to pH 3 with dil HCl and extracted with ethyl acetate (400 mL x 2). After drying over sodium sulphate the organic layer was evaporated to obtain 2-((2R)-3-((R)-l-(tert-butyldimemylsilyloxy)e ^ acid, J 1.5g

'HN R - CDCl ₃ - 0.05 (d, 6H),O.8 (s, 9H), 1.21 (d, 3H), 2.53-2.62 (m, 1H), 2.76-2.78 (m, 1H), 2.82-2.84 (d, 1H), 3.96-3.98 (d, lH), 4.12-4.14 (m, IH), 6.68 (br s. NH)

Scheme 1 was followed for preparing the below compound by using the starting material obtained above (2-((2R)-3-((R)-l-(tert-butyldrniemylsilyloxy)ethyl)-4-oxoaz eodm-2-yl)acetic acid)

'HNMR (J¾0) - 1.32 (d, 3H), 1.68-1.69 (m, IH), 1.83-1.87 (ra, 2H),1.97 (m, IH), 2.12-2.17 (m, 3H), 2.48-2.52 (m, IH), 2.64 (m, 3H), 3.00-3.07 (ra, 3H), 3.27-3.31 (m, 2H), 3.42-3.43 (d, 3H), 3.65-3.70 (m, 3H), 4.01 (m, IH), 4.11-4.13 (d, IH), 4.28-4.30 (m, IH), 4.37-4.40 (m, IH), 4.53- 4.57 (m, IH), 5.40 (d, 2H), 9.25 (s, IH), C25H37N906S, HPLC 90%

Mass 592.2 (M+l)

Antibacterial Activity:

Compounds were evaluated for their antibacterial activity against.Gram positive and Gram negative bacterial strains. These strains include methicillin-sensitive Staphylococcus aureus, carbapenem sensitive Escherichia coli, extended spectrum β lactamase (ESBL) SHV 8 producing Klebsiella pneumoniae, carbapenemase producing K. pneumoniae, Enterobacter spp; Morganello spp citrobacter spp serratia spp acinetobacter and carbapenem sensitive

Pseudomonas aeruginosa.

Experimental:

Antibacterial activity was evaluated by detennining the minimum inhibitory concentration (MIC) of these compounds by broth micro-dilution method (CLSI guidelines, M7- A7/Jan 2006, M100-S18/Jan 2008). Two-fold serial dilutions of the test compounds in Mueller- Hinton broth were prepared in 96 well micro-titre plates. ^' To these dilutions, equal amount of ^■ , Mueller-Hintori broth containing bacterial suspensions were added to obtain a 5 x 10 ^s colony forming units per mL. MIC of the test compounds was determined after incubating micro-titre plates at 35 °C for 22 hours. The minimum concentration of the compound that inhibited visible growth of bacteria is defined as MIC.

Results:

MIC of test compounds is presented in table 1.

Table 1 : MIC of test compounds

Example Pheno type- Organism

MSSA ESBL+ve PC-2 ESBL -ve Meropenem■

(SHV-18) susceptible

S. aureus K. K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922. ATCC27853

ATCC700603 1705

MIC DATA ^g/mL)

17 4 . >128 ■ ^■ 32 .16 ^{; "} 128

18 ^' 8 64 8 4 32

19 ^■ 1 8 >128 1. 128 _. ^■

20 2 8 16 1 ^{" ■} 128

21 2 • 4 4-16 2 . >128

22 2 64-128 ^' 32 8 >128

23 16 I 8 ^• _, 0.5 32- 128

24 16 ^■ 1 4 0.5 .32- 64 ·

25 . 4 8 8 1 128

26 4 4-8 8 1 128

. 27 16 1 4 0.5 64-128

28 8 2 4-8 2 4-8

29 ' 4 8 >128 1 128

30 2 8 ,. 8 1 128

31 16 16 4 4 >128 ^'

32 1 1 1 0.5 32

33 4 32 16 .4 >128

' 34 4 8 8 1 128

35 ■ 1 4 2-4 1 >128

36 1 16 16 2 128

37 16 1 16 1 >128

38 0.25 1 2-4 ^' 1 32-64

39 16 16 16 4 16

40 4 8 4-8 1 >128

41 2 16 16 1 >128 Example Pheno type- Organism

MSSA ESBL+ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible

S. aureus K. K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCCBAA- ATCC25922 ATCC27853

ATCC700603 1705 .

M IC DATA ^g/mL)

42 2 1 8 . 1 128

43 ^■ 2 4 8 - 1 64

^• 44 32 4 8 4 16

45 1 4 · 16 1 4

46 1 4 8 1 16

47 2 · 128 64 2 >128

48 16 1 64 0.5 · 8

49 2 2 >128 1 >128

50 1 , 8- 16 2-4 1-2 - 16-32

51 8 32 ^' .32 ^■ 4 >128

52 . 1 128 >128 8 >128

54 Γ >128 >128 8 >128

56 64 16 16 - 8 64

57 32 16 128 4 ' >128

58 32 >128 >128 16 . >128

59 · 32 16 >128 2 32

60 ^■ 32 32 64 .16 >128 .

61 1 16 16 1 >128

63 _. 8-16 16-32 8.-16 1-2 >128

64 2 8 8 1-2 64

66 8 8 4-8 2 ^" >128 .

67 4 >128 >128 8 >128

68. .32 8 >128 4 ^• 32 - 64

70 16 8 16 4 >128

71 8 128 64 16. >128 Example Pheno type- Organism

MSSA . ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-I8) susceptible

S. aureus K- K. pneumoniae £ coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705

^• MIC DATA g/ L)

72 32 >128 >128 · 32 ^■ · >128

73 4 4 . ' 8 1-2 4-16

74 8-16 1-2 . 4 ^' -2 8 .

75 4. - 8 ^" 16 ■ .1 . >128

76 2 8 8 1 . >128 .

77 4-8 1 A 0.5 - 1 32 - 64

78 8 2 >128 1 128

79 4 >128 >128 32 >128

80 4 32 64 4 . >128

81 1 8 8 1 64

82 8 2 8 1 128

83 2 >128 >128 64 >128

84 4 ^' 4 16 1 128

85 1 2 2 0.5 64

86 2 8 8. 1 128

87 2 8 8 1 64

88 0.25 >128 >128 128 >128

89 0.5 8 4 0.5 128

90 1 32 4 1. 128

91 ^■ 16 32 32 4 >128

92 1 4 4' 0.5 32

93 !6 >128 >128 128 >128

94 0.25 ^' >128 >128 64 >128

95 32 2 2 1 2

- 96 1 64 32 4 >128 Example Pheno type- Organism

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible

S. aureus K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705 .

MIC DATA ^g/mL

122 1 4 4 1 ^■ 16

123 2 2 4 0.5 64

124 _. 2 4 4 1 4

125 2 32 16 2 128

126 2 8 8 2 16

127 2 8 16 2 32

128 16 8 . 8 4 64

129 32 32 8 4 8

130 2 ^" 8 · 4 1 32

131 4 2 8 0.5 16

132 2 4 4 _. 1 4

133 4 4 8 1 8

134 2 4 4 1 16

135 2 4 4 1 8

136 >128 16 . 16 ^' 4 32

137 4 8 8 1 >128

138 32 ^' 32 · 64 ^■ 4 >128

139 32 ' 4 . 4 1 32

140 2 1 2 0.5 32

141 4-8 4-8 4-8 I 64

142 4-8 8 8 1 16-32

143 2 8 8 1 32-64

145 0.5 8-16 8 2 32

146. 1-4 1-2 2 1 64

147 2 2 4-8 ■ 1 64-128 Example Pheno type- Organism ^'

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible

S. aureus K. K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 ^■ 1705

MIC DATA ( g mL)

148 1-2 . 1 2-4 0.5 32-64

149 2 8 8 ^' 1 4

150 4 64 ^• 16 4 64

151 4 16 8 2 32

153 · 8 2 8 1 64

154 4 ^• 2 8 1 • 64

155 2 8 8 1 ^■ 32

156 32 16 32 8 >128

157 2 8 - 4 ^• 1 4

158 2 ^' 4 4 1 8

159 2 .. 4 4 1 8

160 4 8 8 1 16

161 0.5 8 4 0.5 8

162 1 4 4 0.5 16

163 1 4 4 1 8

164 1 1 4 0.25 32

165 64 4 2 2 32

166 64 8 8 ^' 4 32

167 2 4 4 4 32

168 16 2 2 1 2

169 8 16 2 1 ' 4

170 2 4 8 1 32

171 2 128 128 4 >128

172 4 8 8 1 . 64

173 4 16 . 8 _. 2 16 Example Pheno type- Organism

MSSA . ESBL +ve KP.C-2 ESBL -ve Meropenem

(SHV-18) susceptible

S. aureus K. K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 . ATCC27853

ATCC700603 1705

. MIC DATA ^ /mL)

174 4 16 8 2 32

175 2 2 4 1 16

176 2 4 8 1 8

177 8 2 2 2 32

178 32 4 4 2 4

179 128 ^' 16 8 2 16

180 128 32 ^■ 32 4 16

181 >128 >128 ^■ 64 8 . 128

182 128 16 16 8 8

183 8 32 16 2 64

184 2 4 8 0.5 4

185 2 64 16 2 64

186 4 4 ^■ 4 0.5 8

187 4 8 64 2 128

188 128 16 8 8 16

189 >128 32 8 ^■ 4 ^■ 16

190 64 16 4 2 4

191 64 32 8 8 32

^• 192 ^■ 64 2 2 1 4

193 64 8 4 4 8

194 8 8 16 2 16

195 ^■ 2 1 4 0.5 8

196 2 4 8 1 32

197 16 16 16 4 · 32

198 2 1 4 0.25 32 Example Pheno type- Organism

MSSA ESBL +ve PC-2 ESBL -ve Meropenem • (SHV-18) susceptible

S. aureus . K. K pneumoniae E. coll ■P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705

M 1C DATA ^g/mL) ^■

199 · 32 4 2 1 4

200 128 8 ^' 4 2 4 .

201 16 16 64 ^■ 2 16

202 64 64 16 4 8

203 ^' 16 1 4 0.5 128

204 32 ^• >128 ^' >128 8 >128

205 32 2 • 4 1 8

206 64 4 4 4 4

207 2 8 8 2 >128

^• 208 64 8 8 4 >128

209 2 2 2 0.5 64

_, 210 2 4 4 1 64

21 1 - 2 4 4 r 16

212 1 . 2 4 0.5 8

213 1 2 4 0.5 8

214 32 32 16 4 >128

215 8 ^• 32 8 2 >128

216 32 16 4 1 4

217 16 1 1 0.5 2

-218 16 2 2 1 ^■ 2

219 2 - 4 . 4 1 4

220 32 2 2 1 2

221 32 2 2 - 2 4

222 64 8 4 2 8

225 16 32 2 ^■ 1 64 Example Pheno type- Organism

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible

S. aureus ^' K. K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705

MIC DATA ( g mL)

226 32 32 8 I 64

227 64 8 4 2 32

228 64 ^" 4 . 8 1 64

229 128 64 64 16 32

230 32 ^' 8 4 1 8

231 ^■ 32 4 2 1 16

232 2 . 8 8 . ■ 2 >128

233 4 4 4 Γ >128

234 0.5 4 4 0.5 >128

235 2 - 16 2. >128

236 2 - 4 ^■ 2 128

237 - 1 - 4 2 128

238 16 - NT 16 >128

241 16 - 2 2 32

242 16 - 2 2 8

243 32 - 32 16 >128

244 1 - 4 ^• 1 64

245 8 - 4 2 . 4

246 - 32 - 128 8 >128

247 32 - 32 4 >128

248 1 -. 4 1 >128

251 0.5 - 0.5 0.25 32

252 16 - 4 · 2 . 16

253 32 - - 16 16 16

254 64 - 16 8 128 Example Pheoo type- Organism

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible

S. aureus K K pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705

MIC DATA ^g mL)

255 8 8 4 32

256 4 - 2 1 32

257 >128 - 16 4 128

258 1 - 16 . 4 128

259 2 - 16 4 >128·

260 1 - 8 4 32

261 2 - 16 2 64

^• 262 32 - 16 4 64

263 ^' 0.25 - 2 0.25 128

264 16 - 4 2 8

265 2 - 8 2 >128

266 64 - 8 2 128

267 ^• 0.5 2 1 >128

268 8 - 4 2 32

269 16 - 4 4 128

270 4 - 4 1 64

271 2 - 4 1 8

272 128 - 64 64 >128

273 128 · - 32 16 128

274 32 ^" - 16 ^' 16 >128

275 64 - 64 16 >128

276 32 - 4 2 8

277 64 - 4 2 16

278 16 - 2 2 4

279 >128 - 16 4 >128 Example Pheno type- Organism

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible■

S. aureus K K. pneumoniae E. coli P, aeruginosa ATCC29213 . pneumoniae ATCC BAA- ATCC25922 ATCC27853 .

ATCC700603 1705

MIC DATA ^g/mL)

306 2 - 1 0.25 4

307 ^■ . 1 - 4 0.25 . 128

309 . 16 - 4 1 32

310 32 - . 4 1 64

3 1 1 ^■ 32 - 32 8 >128

3 12 16 - 4 1 64

3 13 4 - 16 1 >128

314 4. - 2 0.25 4

315 4 - 2 0.125 64

^• 316 4 - 16 0.25 16

317 2 - 8 0.5 128

318 16 - 128 2 >128

319 2 - 1 0.25 32

320 2 4 1 128

321 2 - 8 1 >128

322 16 - 16 2 . ^■ >128

323 . 16 - 8 2 >128.

324 4 - 4 0.5 4

325 ^" 8 - 64 4 > 128

326 2 - 16 1 64

327 1 - 32 2 64 ·

328 4 - 4 ^• 2 32

329 8 - 2 0.25 8

330 8 - 2 0.25 64

331 4 - 4 0.25 8 Example Pheno type- Organism

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem ^"

(SHV-18) susceptible

S. aureus K. K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705

MIC DATA ^g/mL) ^'

332 . 8- - 4 1 ^' 8 .

333 8 - 4 ^' 0.5 4

334 4 - 32 0.5 128

335 4 ^■ -. 64 1 >128

336 A - 4 - 1 . 8 '

337 2- - 1 0.5 32

338 8 - 32 2 128

339 8 - 32 1 32

340 8 - 4 1 4

341 4 - 4 1 8

342 16 - 8 2 8

343 ^■ 16 - 8 2 8

344 16 - 16 1 16 ■

345 64 - 32 8 128

346 16 - 8 1 16 -

347 4 ■ 16 0.5 >128 ^"

348 8 . - 16 1 >128

349 4 - 4 0.25 32

350 2 - 1 0.25 128 ^"

351 16 - 4 1 >128

352 4 ^■ - 2 0.25 2

353 16 - 2 0.25 16

354 2 - 1 0.125 32

355 4 - 16 ^' 1 128

356 4 - 16 1 >128 Example Pheno type- Organism

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible

^■ S. aureus ^■ K. K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae' ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705

MIC DATA ^g mL)

357 2 ' - 32 1 > 128 .

358 1 - 32 1 > 128

359 ^■ 8 - 2 0.5 16

360 8 - 2 0.5 1

36.1 . 8 4 2 1 2

362 8 4 4 0.25 4

363 4 2 0.25 1

364 4 2 0.25 1

365 . . 4 2 ^■ 0.25 2

366 4 2 0.25 2

367 2 2 0.25 . 1

■ 368 2 2 0.25 1

369 2 - ^' 8 0.25 ^' 16

370 . 8 64 4 ^* >128

. 371 16 - 4 1 64

372 ^' . 4 - 8 0.5 64

373 - >128 32 128

374 8 - >128 32 >128

375 16 - 8 2 4

376 8 - 16 0.25 >128

377 . 4 - 2 .0.25 ^' 8

378 4 - 2 0.25 128

379 16 16 0.5 >128

380 32 - 8 1 32

381 16 - 4 1 >128 Example Pheno type- Organism

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible

S. aureus K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853 .

ATCC700603 1705

MIC DATA (|ig mL)

382 16 - 4 1 128

383 4 - 4 0.25 >128

38 .4 -. 4 0.5 64

385 4 - 2 0.25 64

386 2 - 8 0.125 8

387 8 - 8 0.25 ^{■ "} 32

388 8 - 8 2 ^• >128

389 8 - 4 1 >128

390 4 - 16 1 128 .

39l ^' 1 0-5 0.5 4

392 4 - 4 1 64

393 4 - 1 ^" 0.125 8

394 8 32 2 128

395 2 - 1 0.125 1

396 4 - 1 . 0.125 4

397 ^{" ■} 2 . . - 1 0.25 2

398 4 ^' 1 .0.25

399 2 - ^• 2 - 0.125 8 ^'

400 4 - 1 0.125 1

401 8 - 2 0.5 2

402 I - 1 0.06 32

403 4 - 8 0.5 16

404 1 - 0.5 0.25 1

405 4 - 2 0.-125 4

406 ^' 4 - 2 0.25 16 Example Pheno type- Organism

MSSA ^■ ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18 ¹ ) . susceptible

S. aureus K K, pneumoniae 2Γ. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705

MIC DATA (με/mL)

407 2 - . 1 0.5 8

408 . 4 - 2 ' 1- 2

409- 4 - 2 1 4

410 2 - 4 0.5 4

411 2 - 1 0.25 1

412 2 - 2 0.25 1

413 2 - 2 0.25 2

414 4 - 2 0.5 4

415 4 - 1 2 16

416 4 ^' - 2 0.5 8

417 8 - 2 0.5 16

418 8 ' - 4 1 8 .

419 4 1 0.25 1

420 4 - 1 ^' 0.25 2

421 4 - 2 0.125 32

422 4 - 2 0.25 4

423 8 - 2 0.5 32

424 16 - 2 0.25 16

. 425 4 - 2 .0.25 2

426 4 - ^• 1 0.25 2

427 2 - - ^■ 1 0.25 2

428 4 - 4 , 0.5 2

429 . 4 - 2 0.25 2

430 4 - 2 0.5 4

431 2 - 0.5 0.25 1 Example Pheno type- Organism

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible

S. aureus • K. K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700

432 2 - I 0.25 1

433 2 - 1 0.25 1

434 2 - 2 0.5 2

435 2 - 1 0.25 .. 1 ^* .

436 8 - .1 0.25 8

437 2 - 1 0.25 2

438 2 - 1 0.25 2

. 439 2 1 0.25 1

440 2 - I . 0.25 t

441 4 - 2 0.25 8

442 · . 2 - r 0.125 0.5

443 4 - 2 0.5 1

444 2 - •2 0.5 2

445 2 . - I 0.25 1

446 2 - 1 0.25 ¹ 4

447 16 - . 4 0.5 16

448 4 ■ - 8 0.5 >128

449 4 - ' 4 0.5 64

450 8 - 1 0.25 1

451 8 - 1 0.25 2

452 2 - I 0.25 2

453 16 - _, 2 0.125 8

454 8 - 4 0.5 4

455 4 - 2 0.5 - 4

456 2 - 2 0.5 2 Example Pbeno type- Organism

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible

S. aureus K K. pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705

MIC DATA ^ mL)

457 2 - 1 0.25 1

458 16 - 1 0.5 ^■ 16.

459 1 - 1 0.125 ^■ 2

460 4 - . 2 0.5 ^■ 4

461 4 . - ^■ 2 0.5 4

462 4 - 1 0.25 2

463 4 - 1 0.5 2

464 4 - 4 1 16

465 ^" 4 - ■ 2 0.5 16

466 4 - 2 0.5 4

467 8 - 2 1 8

468 4 - 2 . ^■ 0.5 8

469 4 - 2 ,0.5 4

470 4 ■ - 2 0.5 4

471 2 - 2 0.5 4

472 4 - 2 0.5 2

^' 473 4 - 2 0.5 4

474 ^■ 4 - 2 0.25 2

475 4 - ■ 2 0.5 . 2

476 2 - 2 1 32

477 2 2 0.5 64

. 478 8 - 1 0.125 8

479 8 - 2 - 0.25 16

480 2 - 1 0.25 2

481 2 - 2 0.125 2 Example Pheno type- Organism

MSSA ESBL +ve PC-2 ESBL -ve Meropenem

CSHV-18 susceptible

S. aureus K. K. pneumoniae £. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705

M IC DATA ^g/mL)

507 2 . - 8 1 64

508 16 - 8 2 128

509 32 - 4 ^{■ ■} 32

510 . 4 - ·. 4 0.25 1

511 4 - 2 0.25 1

512 8 - 64 2 >128

513 4 . - 1 0.25 16

514 .16 - ^■ 16 0.5 ^' 32

515 2 - 1 0.25 ^' 16

516 . . 2 - 2 0.25 ^■ 2

517 4 - 2 0.5 .4

518 8 - 4 1 128

519 16 - 16 2 ^• >128

520 16 - 16 2 >128

521 2 0.5 0.5 ^" 2

522 4 - 2 ^' 0.25 1

523 2 - 1 0.125 1

524 4 - 2 0.25 1

525 .4 - 2 0.25 . . 0.5

526 4 ^' - 2 . 0.25 1 ^'

527 4. ^' - 1 0.125 1

528 ^' 4- - 1 0.25 1

529 4 - 2 0.25 _. 1

530 2 - 1 0.25 0.5

531 4 ^■' - 2 0.125 1 ample Pheno type- Organism

^■ MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

. (SHV-18) susceptible

S. aureus K. K pneumoniae E. coli P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 1705

M tic DATA gftnL)

532 4 - ^' 2 0.25 2

533 4 - 2 0.25 . 2

534 2 1 0.125 . 1

535 2 - 2 0.25 1

536 2 - 2 0.25 4

537 4 - 2 0.25 2

538 4 - ■2 0.25 1

539 4 - 1 0.25 2

540 4 - . 2 0.25 1

541 2 - 1 0.25 1

542 4 - 2 0.25 2

543 2 - 1 0.5 2

544 1 - 0.5 0.25 1

545 1 - 0.5 0.125 1 546 1 1 0.25 2

547 4 - 2 0.5 2

548 ^" 8 - ■ 1 0.25 4

549 4 - 1 0.125 1

550 1 - 2 0.25 8

551 4 - 2 0.25 2

552 · 4 - 2 0.25 2

553 2 1 0.25 2

554 4 - 2 0.5 2

555 4 - 1 0.25 2

556 2 - 1 0.125 4 Example Pheno type- Organism

MSSA ESBL +ve KPC-2 ESBL -ve Meropenem

(SHV-18) susceptible

S. aureus K K. pneumoniae E. coli ^' P. aeruginosa ATCC29213 pneumoniae ATCC BAA- ATCC25922 ATCC27853

ATCC700603 ■ 1705

MIC DATA ^ /mL)

557 4 - 4 0.1-25 16

558 16 - 2 0.5 128

55? 1 - 1 0.25 4

560 . 1 - 0.5 0.125 _. 1

561 4 - ^• 2 0.5 8

562 16 - - 2 0.5 2

563 16 - 2 . 0.25 2 ·

564 2 ^' - 1 0.125 1

565 . 2 2 0.25 1

566 0.5 - 0.5 0.06 0.25

567 1 - 0.5 0.125 1

568 16 2 1 4

569 2 . 1 0.25 ■ ^■ 2

570 1 - 1 0.125 2

571 1 - . 0.5 0.06 1

572 4 - 2 0.25 4

573 4 - 2 0.125 1

574 8 - 4 0.5 2

575 16 - 0.5 0.125 >128

576 1 - 0.5 0.125 0.25

■ 577 ^' 4 - 2 0.25 4

578 2 - 1 0.25 4

579 4 1 0.25 16

580 2 1 0.25 0.5

581 8 - 8 0.5 64