|HAI LAILA ATA A US009732081B2UN MAI MULT MAI MULT (12 ) United States Patent ( 10 ) Patent No. : US 9 ,732 ,081 B2 Patil et al. (45 ) Date of Patent: Aug . 15 , 2017 ( 54) 1 ,6 -DIAZABICYCLO [3 , 2 , 1 ] OCTAN - 7 -ONE (51 ) Int. CI. DERIVATIVES AND THEIR USE IN THE C07D 471 /08 ( 2006 .01 ) TREATMENT OF BACTERIAL INFECTIONS A61K 31/ 439 (2006 .01 ) A61K 31/ 4545 ( 2006 .01 ) A61K 31 /496 ( 2006 . 01 ) ( 71 ) Applicant: WOCKHARDT LIMITED , A61K 31 /55 ( 2006 .01 ) Aurangabad ( IN ) C07D 487 / 08 ( 2006 .01 ) A61K 31/ 407 (2006 . 01) ( 72 ) Inventors : Vijaykumar Jagdishwar Patil, Solapur A61K 31/ 546 ( 2006 .01 ) ( IN ) ; Ravikumar Tadiparthi, A61K 45 / 06 ( 2006 .01 ) Auranagabad ( IN ) ; Bharat Dond , C07C 211/ 63 (2006 .01 ) Aurangabad ( IN ) ; Amol Kale , (52 ) U .S . CI. Aurangabad ( IN ) ; Loganathan CPC ...... C070 471/ 08 (2013 .01 ); A61K 31/ 407 Velupillai , Aurangabad ( IN ) ; Deepak ( 2013 .01 ); A61K 31/ 439 (2013 . 01 ) ; A61K Dekhane , Maharashtra Pune ( IN ) ; 31/ 4545 (2013 . 01 ) ; A61K 31/ 496 ( 2013. 01 ) ; Satish Shrimant Birajdar , Pin - O Latur A61K 31/ 546 ( 2013 .01 ) ; A61K 31/ 55 ( IN ) ; Mohammad Usman Shaikh , ( 2013 .01 ); A61K 45 / 06 ( 2013 .01 ) ; C07C Shrirampur ( IN ) ; Sushilkumar 211/ 63 ( 2013 .01 ) ; CO7D 487/ 08 ( 2013. 01 ) Maurya , Maharashtra Aurangabad ( IN ) ; (58 ) Field of Classification Search Piyush Ambalal Patel, Gujarat Anand CPC ...... C07D 471 /08 ( IN ) ; Prasad Dixit, Maharashtra See application file for complete search history . Aurangabad ( IN ) ; Mangesh Pawar , Maharashtra Aurangabad (IN ) ; Mahesh (56 ) References Cited Vithalbhai Patel , Aurangabad ( IN ) ; Sachin Bhagwat, M . S . Aurangabad U . S . PATENT DOCUMENTS ( IN ) 2013/ 0225554 AL 8 /2013 Maiti et al. ( * ) Notice: Subject to any disclaimer, the term of this Primary Examiner — Bruck Kifle patent is extended or adjusted under 35 (74 ) Attorney , Agent, or Firm — Bio Intellectual Property U . S . C . 154 (b ) by 0 days. Services LLC (Bio IPS ) ; O . (Sam ) Zaghmout (21 ) Appl. No. : 15/ 062, 148 (57 ) ABSTRACT Compounds of Formula ( I ) , their preparation and use in ( 22 ) Filed : Mar. 6 , 2016 preventing or treating bacterial infections are disclosed . (65 ) Prior Publication Data US 2016 / 0213655 A1 Jul . 28 , 2016 Formula ( I)

Related U . S . Application Data R3 -Z (63 ) Continuation of application No . 14 / 365 , 064 , filed as R2 application No . PCT / IB2013 /053092 on Apr. 19 , 2013 . N - R1 ( 30 ) Foreign Application Priority Data Aug. 25 , 2012 ( IN ) ...... 2471 /MUM / 2012 36 Claims, No Drawings US 9 ,732 ,081 B2 1 ,6 -DIAZABICYCLO (3 , 2 , 1 ] OCTAN - 7 -ONE or a stereoisomer or a pharmaceutically acceptable salt DERIVATIVES AND THEIR USE IN THE thereof ; TREATMENT OF BACTERIAL INFECTIONS wherein : R , is : CROSS -REFERENCE TO RELATED ( a ) SO3M , APPLICATIONS ( b ) SO2NH2, (C ) PO , M , This application is a Continuation of U . S . application Ser . ( d ) CH , COOM , No. 14 / 365 , 064, filed Jun . 12 , 2014 , now pending, which ( e ) CF , COOM , entered the National Phase of Serial No. PCT/ IB2013 / 10 ( f) CHFCOOM , or 053092 , filed Apr. 19 , 2013 , which claims priority to Indian ( g ) CF3 ; Application No . IN2012MU2471A , filed Aug. 25 , 2012 . The M is hydrogen or a cation ; entire disclosure of these prior applications are hereby R2 is : incorporated by reference . ( a ) hydrogen , 15 ( b ) (CH ) n - R3, or FIELD OF THE INVENTION ( c ) COOR3, The invention relates to nitrogen containing compounds , n is 0 , 1 or 2 ; use of these compounds as antibacterial agents , composi Rz is : tions comprising them and processes for their preparation . ( a ) hydrogen , 20 (b ) C . - C . alkyl optionally substituted with one or more BACKGROUND OF THE INVENTION substituents independently selected from halogen , OR , CN , COORS, CONRR7, NR R7, NR , COR , , Emergence of bacterial resistance to known antibacterial NR , CONRGR7, heterocyclyl, heteroaryl , cycloalkyl or agents is becoming a major challenge in treating bacterial aryl, infections. One way forward to treatat bacterial infectionsinfections , and 25 ( c ) CN , especially those caused by resistant bacteria , is to develop ( d ) NRGR7, newer antibacterial agents that can overcome the bacterial ( e ) CONRR , resistance . Coates et al. (Br . J . Pharmacol . 2007 ; 152 ( 8 ) , ( 1 ) NHCONRR , 1147 - 1154 ) have reviewed novel approaches to developing ( g ) aryl optionally substituted with one or more substitu new antibiotics . However , the development of new antibac - 30 ents independently selected from C . - C . alkyl, OR , terial agents is a challenging task . For example , Gwynn et al. NR R7, halogen , CN , CONRGR7, SO2- alkyl, SO2- aryl, ( Annals of the New York Academy of Sciences, 2010 , 1213 : OSO2- alkyl, OSO2- aryl, or NHCONRGR7, 5 - 19 ) have reviewed the challenges in the discovery of ( h ) heterocyclyl optionally substituted with one or more antibacterial agents . substituents independently selected from C - C . alkyl, Several antibacterial agents have been described in the 35 OR ., NR R7, halogen , CN , CONRGR7, SO2- alkyl, prior art ( for example , see PCT International Application SO2- aryl, OSO2- alkyl , OSO2- aryl, or NHCONRGR7, Nos. PCT /US2010 / 060923 , PCT / EP2010 / 067647, PCT / ( i) heteroaryl optionally substituted with one or more US2010 /052109 , PCT/ US2010 /048109 , PCT/ GB2009 / substituents independently selected from C1- C6 alkyl, 050609 , PCT /EP2009 /056178 and PCT/ US2009 /041200 ) . OR5, NR R7, halogen , CN , CONRGR7, SO2 - alkyl, However , there remains a need for potent antibacterial 40 SO2- aryl , OSO2- alkyl, OSO2- aryl, or NHCONRR7, agents for preventing and /or treating bacterial infections, (j ) cycloalkyl optionally substituted with one or more including those caused by bacteria that are resistant to substituents independently selected from C , -C alkyl , known antibacterial agents . ORs, NR R7, halogen , CN , CONRGR7, SO2- alkyl , The inventors have surprisingly discovered nitrogen con SO2- aryl , OSO , - alkyl , OSO , - aryl, or NHCONRR , , taining compounds with antibacterial properties . 45 ( k ) cycloalkyl substituted with C1- C6 alkylwherein C , - C6 alkyl is further substituted with one or more substitu SUMMARY OF THE INVENTION ents independently selected from OR5, NRR ,, halo gen , CN , or CONRGR7 , or Accordingly there are provided nitrogen containing com ( 1) ORS; pounds, methods for preparation of these compounds, phar - 50 R4 18 : maceutical compositions comprising these compounds, and ( a ) hydrogen , method for preventing or treating bacterial infection in a ( b ) C . -C . alkyl optionally substituted with one or more subject using these compounds . substituents independently selected from halogen , OR5, In one general aspect , there are provided compounds of CN , COOR , CONRGR7, NR R7, NR , CORg, hetero Formula (I ) : 55 cyclyl , heteroaryl, cycloalkyl or aryl, ( c ) aryl optionally substituted with one or more substitu ents independently selected from C . - C . alkyl, OR , Formula ( I) NR R7, halogen , CN , CONRR7, SO2- alkyl, SO2- aryl, OSO , - alkyl, OSO , - aryl, or NHCONRR , 60 (d ) heterocyclyl optionally substituted with one or more R3 substituents independently selected from C , - C . alkyl, Z- ORs, NR R7, halogen , CN , CONRGR7, SO2- alkyl, R2 SOZ- aryl, OSO2 -alkyl , OSO2- aryl, or NHCONRGR7, ( e ) heteroaryl optionally substituted with one or more DARI 65 substituents independently selected from C . - C . alkyl, ORs, NR R7, halogen , CN , CONRGR7, SO2- alkyl , SO2- aryl , OSO2- alkyl , OSO2- aryl, or NHCONRGR7, or US 9 ,732 ,081 B2 ( f) cycloalkyl optionally substituted with one or more thereof, and (b ) at least one beta - lactamase inhibitor selected substituents independently selected from C , - C6 alkyl, from sulbactam , tazobactam , clavulanic acid , or a pharma OR5, NR R7, halogen , CN , CONRR7, SO2- alkyl, ceutically acceptable derivative thereof. SO2- aryl, OSO2- alkyl, OSO2 - aryl, or NHCONR Rz; In another general aspect, there are provided pharmaceu R , and R , are each independently : 5 tical compositions comprising : ( a ) a compound of Formula ( a ) hydrogen , or ( I ) , or a stereoisomer or a pharmaceutically acceptable salt ( b ) C -C6 alkyl optionally substituted with one or more thereof, and ( b ) at least one antibacterial agent or a phar substituents independently selected from halogen , CN , maceutically acceptable derivative thereof. CONRR , NR R7, heterocyclyl, heteroaryl, In another general aspect , there are provided pharmaceu cycloalkyl or aryl; 10 tical compositions comprising : ( a ) a compound of Formula Ro and R , are each independently : ( I ) , or a stereoisomer or a pharmaceutically acceptable salt ( a ) hydrogen , thereof, ( b ) at least one beta - lactamase inhibitor selected (b ) C . - Cô alkyl optionally substituted with one or more from sulbactam , tazobactam , clavulanic acid , or a pharma substituents independently selected from halogen , OR , ceutically acceptable derivative thereof , and ( c ) at least one CN , COORS, CONR = R3, NR =Rs , NR ,CORg , hetero - 15 antibacterial agent or a pharmaceutically acceptable deriva cyclyl , heteroaryl , cycloalkyl or aryl, tive thereof. ( c ) aryl optionally substituted with one or more substitu - In another general aspect, there is provided a method for ents independently selected from C , - C , alkyl, OR5 , preventing or treating bacterial infection in a subject , said NR =Rg , halogen , CN , CONR Rg, SO2- alkyl, SO2- aryl, method comprising administering to said subject a pharma OSO2- alkyl , OSO2- aryl, or NHCONR Rg, 20 ceutically effective amount of a pharmaceutical composition ( d ) heterocyclyl optionally substituted with one or more comprising: ( a ) a compound of Formula ( I) , or a stereoiso substituents independently selected from C , - Co alkyl, mer or a pharmaceutically acceptable salt thereof, and ( b ) at ORS, NR Rg, halogen , CN , CONR -R3 , SO2- alkyl , least one beta - lactamase inhibitor selected from sulbactam , SO2- aryl , OSO2- alkyl , OSO2- aryl, or NHCONR = Rg, tazobactam , clavulanic acid , or a pharmaceutically accept ( e ) heteroaryl optionally substituted with one or more 25 able derivative thereof . substituents independently selected from C - C , alkyl, In yet another general aspect, there is provided a method OR5, NR :Rs , halogen , CN , CONR = Rg, SO2- alkyl, for preventing or treating a bacterial infection in a subject, SO2- aryl , OSO2- alkyl, OSO2 -aryl , or NHCONR -R3 , said infection being caused by bacteria producing one or ( f ) cycloalkyl optionally substituted with one or more more beta - lactamase enzymes, wherein the method com substituents independently selected from C . - C . alkyl, 30 prises administering to said subject a pharmaceutically OR5, NR :Rs , halogen , CN , CONR = Rg, SO2- alkyl, effective amount of a pharmaceutical composition compris SO2- aryl, OSO2- alkyl , OSO2- aryl, or NHCONR =Rs , or ing : (a ) a compound of Formula (I ) , or a stereoisomer or a ( g ) Ro and R , are joined together to form a four to seven pharmaceutically acceptable salt thereof, and ( b ) at least one member ring. beta - lactamase inhibitor selected from sulbactam , tazo In another general aspect, there are provided pharmaceu - 35 bactam , clavulanic acid , or a pharmaceutically acceptable tical compositions comprising a compound of Formula ( I) , derivative thereof. or a stereoisomer or a pharmaceutically acceptable salt In another general aspect, there is provided a method for thereof. preventing or treating bacterial infection in a subject , said In another general aspect, there is provided a method for method comprising administering to said subject a pharma preventing or treating bacterial infection in a subject, said 40 ceutically effective amountof a pharmaceutical composition method comprising administering to said subject a pharma - comprising: ( a ) a compound of Formula (I ) , or a stereoiso ceutically effective amount of a compound of Formula ( I ) or mer or a pharmaceutically acceptable salt thereof, and ( b ) at a stereoisomer or a pharmaceutically acceptable salt thereof. least one antibacterial agent or a pharmaceutically accept In another general aspect, there is provided a method for able derivative thereof. preventing or treating a bacterial infection in a subject, said 45 In yet another general aspect, there is provided a method infection being caused by bacteria producing one or more for preventing or treating a bacterial infection in a subject , beta - lactamase enzymes, wherein the method comprises said infection being caused by bacteria producing one or administering to said subject a pharmaceutically effective more beta -lactamase enzymes , wherein the method com amount of a compound of Formula ( I ) or a stereoisomer or prises administering to said subject a pharmaceutically a pharmaceutically acceptable salt thereof. 50 effective amount of a pharmaceutical composition compris In another general aspect , there is provided a method for ing : ( a ) a compound of Formula ( I ), or a stereoisomer or a preventing or treating bacterial infection in a subject , said pharmaceutically acceptable salt thereof, and (b ) at least one method comprising administering to said subject a pharma- antibacterial agent or a pharmaceutically acceptable deriva ceutically effective amount of a pharmaceutical composition tive thereof. comprising a compound of Formula ( I ) or a stereoisomer or 55 In another general aspect, there is provided a method for a pharmaceutically acceptable salt thereof. preventing or treating bacterial infection in a subject , said In yet another general aspect, there is provided a method method comprising administering to said subject a pharma for preventing or treating a bacterial infection in a subject, ceutically effective amount of a pharmaceutical composition said infection being caused by bacteria producing one or comprising : ( a ) a compound of Formula ( I ) , or a stereoiso more beta - lactamase enzymes , wherein the method com - 60 mer or a pharmaceutically acceptable salt thereof, ( b ) at least prises administering to said subject a pharmaceutically one beta - lactamase inhibitor selected from sulbactam , tazo effective amount of a pharmaceutical composition compris - bactam , clavulanic acid , or a pharmaceutically acceptable ing a compound of Formula (I ) or a stereoisomer or a derivative thereof, and (c ) at least one antibacterial agent or pharmaceutically acceptable salt thereof. a pharmaceutically acceptable derivative thereof. In another general aspect, there are provided pharmaceu - 65 In yet another general aspect , there is provided a method tical compositions comprising : ( a ) a compound of Formula for preventing or treating a bacterial infection in a subject , ( I ) , or a stereoisomer or a pharmaceutically acceptable salt said infection being caused by bacteria producing one or US 9 ,732 ,081 B2 more beta -lactamase enzymes , wherein the method com in a subject, said method comprising co - administering said prises administering to said subject a pharmaceutically antibacterial agent or a pharmaceutically acceptable deriva effective amount of a pharmaceutical composition compris tive thereof with a pharmaceutically effective amount of a ing : ( a ) a compound of Formula ( I ) , or a stereoisomer or a compound of Formula ( I ) or a stereoisomer or a pharma pharmaceutically acceptable salt thereof, ( b ) at least one 5 ceutically acceptable salt thereof. beta - lactamase inhibitor selected from sulbactam , tazo - The details of one or more embodiments of the invention bactam , clavulanic acid , or a pharmaceutically acceptable are set forth in the description below . Other features , objects derivative thereof, and ( c ) at least one antibacterial agent or and advantages of the invention will be apparent from the a pharmaceutically acceptable derivative thereof . following description including claims. In another general aspect, there is provided a method for 10 preventing or treating bacterial infection in a subject, said DETAILED DESCRIPTION OF THE method comprising administering to said subject a pharma INVENTION ceutically effective amount of : ( a ) a compound of Formula ( I ) , or a stereoisomer or a pharmaceutically acceptable salt Reference will now be made to the exemplary embodi thereof, and ( b ) at least one beta - lactamase inhibitor selected 15 ments , and specific language will be used herein to describe from sulbactam , tazobactam , clavulanic acid , or a pharma - the same. It should nevertheless be understood that no ceutically acceptable derivative thereof. limitation of the scope of the invention is thereby intended . In yet another general aspect , there is provided a method Alterations and further modifications of the inventive fea for preventing or treating a bacterial infection in a subject, tures illustrated herein , and additional applications of the said infection being caused by bacteria producing one or 20 principles of the invention as illustrated herein , which would more beta -lactamase enzymes, wherein the method com occur to one skilled in the relevant art and having possession prises administering to said subject a pharmaceutically of this disclosure , are to be considered within the scope of effective amount of: ( a ) a compound of Formula ( I ) , or a the invention . It must be noted that, as used in this specifi stereoisomer or a pharmaceutically acceptable salt thereof, cation and the appended claims, the singular forms “ a ,” and ( b ) at least one beta - lactamase inhibitor selected from 25 " an , ” and “ the ” include plural referents unless the content sulbactam , tazobactam , clavulanic acid , or a pharmaceuti- clearly dictates otherwise . All references including patents , cally acceptable derivative thereof. patent applications , and literature cited in the specification In another general aspect , there is provided a method for are expressly incorporated herein by reference in their preventing or treating bacterial infection in a subject , said entirety. method comprising administering to said subject a pharma- 30 The inventors have surprisingly discovered novel nitro ceutically effective amount of: ( a ) a compound of Formula gen containing compounds having antibacterial properties. ( 1 ) , or a stereoisomer or a pharmaceutically acceptable salt The term “ C - C . alkyl” as used herein refers to branched thereof, and ( b ) at least one antibacterial agent or a phar - or unbranched acyclic hydrocarbon radical with 1 to 6 maceutically acceptable derivative thereof. carbon atoms. Typical, non - limiting examples of “ C1 - C6 In yet another general aspect , there is provided a method 35 alkyl ” include methyl, ethyl, n - propyl, iso - propyl, n -butyl , for preventing or treating a bacterial infection in a subject, iso -butyl , tert- butyl, n -pentyl , iso -pentyl , n -hexyl and the said infection being caused by bacteria producing one or like . The “ C . - C . alkyl” may be unsubstituted , or substituted more beta - lactamase enzymes , wherein the method com - with one or more substituents. Typical, non - limiting prises administering to said subject a pharmaceutically examples of such substituents include halogen , alkoxy, CN , effective amount of: ( a ) a compound of Formula ( I) , or a 40 COOH , CONH2, OH , — NH2, — NHCOCHz, cycloalkyl, stereoisomer or a pharmaceutically acceptable salt thereof, heterocyclyl, heteroaryl, aryl and the like . and (b ) at least one antibacterial agent or a pharmaceutically The term “ cycloalkyl” as used herein refers to three to acceptable derivative thereof. seven member cyclic hydrocarbon radicals . The cycloalkyl In another general aspect, there is provided a method for group optionally incorporates one or more double or triple preventing or treating bacterial infection in a subject, said 45 bonds , or a combination of double bonds and triple bonds , method comprising administering to said subject a pharma - but which is not aromatic . Typical , non - limiting examples of ceutically effective amount of: ( a ) a compound of Formula cycloalkyl groups include cyclopropane, cyclobutane , ( 1 ) , or a stereoisomer or a pharmaceutically acceptable salt cyclopentane , cyclohexane , and cycloheptane . The thereof, ( b ) at least one beta - lactamase inhibitor selected cycloalkyl may be unsubstituted , or substituted with one or from sulbactam , tazobactam , clavulanic acid , or a pharma- 50 more substituents . Typical, non - limiting examples of such ceutically acceptable derivative thereof, and ( c ) at least one substituents include C , - Co alkyl, halogen , alkoxy, CN , antibacterial agent or a pharmaceutically acceptable deriva - COOH , CONH2, OH , NH2, NHCOCH3, heterocyclyl, het tive thereof. eroaryl, aryl , SO2- alkyl, SO2- aryl, OSO2- alkyl, OSO2 In yet another general aspect, there is provided a method aryl and the like . for preventing or treating a bacterial infection in a subject, 55 The term " heterocyclyl ” as used herein refers to four to said infection being caused by bacteria producing one or seven member cycloalkyl group containing one or more more beta - lactamase enzymes, wherein the method com - heteroatoms selected from nitrogen , oxygen or sulfur . The prises administering to said subject a pharmaceutically heterocycloalkyl group optionally incorporates one or more effective amount of: (a ) a compound of Formula (I ) , or a double or triple bonds, or a combination of double bonds and stereoisomer or a pharmaceutically acceptable salt thereof, 60 triple bonds , but which is not aromatic . Typical, non - limiting ( b ) at least one beta - lactamase inhibitor selected from sul- examples of heterocycloalkyl groups include azetidine , pyr bactam , tazobactam , clavulanic acid , or a pharmaceutically rolidine , 2 -oxo -pyrrolidine , imidazolidin - 2 - one , piperidine , acceptable derivative thereof, and ( c ) at least one antibac oxazine , thiazine , piperazine , piperazin - 2 ,3 -dione , morpho terial agent or a pharmaceutically acceptable derivative line, thiamorpholine , azapane, and the like . The heterocy thereof. 65 cloalkyl may be unsubstituted , or substituted with one or In another general aspect, there are provided methods for more substituents . Typical, non - limiting examples of such increasing antibacterial effectiveness of a antibacterial agent substituents include C . - C . alkyl, halogen , alkoxy, CN , US 9 ,732 ,081 B2 COOH , CONH2, OH , NH , NHCOCH3, heterocyclyl, het - 1 - 19 (1977 ) ), incorporated herein by reference in its entirety , eroaryl, aryl, SO2- alkyl , SO2- aryl, OSO2- alkyl , OSO2- aryl describes various pharmaceutically acceptable salts in and the like . details . The term “ aryl” as used herein refers to a monocyclic or In general, the compounds according to the invention polycyclic aromatic hydrocarbon . Typical , non - limiting 5 contain basic ( e . g . nitrogen atoms) as well as acid moieties examples of aryl groups include phenyl, naphthyl, anthra ( e . g . compounds of Formula ( I ) wherein M is hydrogen ). A cenyl, fluorenyl, phenanthrenyl, and the like. The aryl group person of skills in the art would appreciate that such com pounds, therefore , can form acidic salts ( formed with inor may be unsubstituted , or substituted with one or more ganic and / or organic acids) , as well as basic salts ( formed substituents . Typical , non -limiting examples of such sub 10 with inorganic and/ or organic bases ) . Such salts can be stituents include C , -Co alkyl, halogen , alkoxy, CN , COOH , prepared using procedures described in the art. For example , CONH2, OH , NH , NHCOCHz, heterocyclyl, heteroaryl, the basic moiety can be converted to its salt by treating a aryl, SO2- alkyl , SO2- aryl, OSO2- alkyl, OSO2- aryl and the compound with a suitable amount of acid . Typical, non like . limiting examples of such suitable acids include hydrochlo The term " heteroaryl” as used herein refers to a mono - 15 ric acid , trifluoroacetic acid , methanesulphonic acid , or the cyclic or polycyclic aromatic hydrocarbon group wherein like. Alternatively, the acid moiety may be converted into its one or more carbon atoms have been replaced with heteroa salt by treating with a suitable base . Typical non - limiting toms selected from nitrogen , oxygen , and sulfur. If the examples of such bases include sodium carbonate , sodium heteroaryl group contains more than one heteroatom , the bicarbonate , potassium carbonate , potassium bicarbonate or heteroatoms may be the same or different. Typical , non - 20 the like . In case of compounds containing more than one limiting example of heteroaryl groups include 1 , 2 , 4 -oxadi functional groups capable of being converted into salt , each azol, 1 , 3 ,4 - oxadiazol, 1 , 3 ,4 - thiadiazol, 1 , 2 , 3 , 4 - tetrazol, 1 , 3 - such functional group may be converted to salt indepen oxazol, 1, 3 -thiazole , pyridine, pyrimidine , pyrazine , dently . For example , in case of compounds containing two pyridazine, furan , pyrrol, thiophene , imidazole , pyrazole , basic nitrogen atoms, one basic nitrogen can form salt with benzofuran , benzothiophene , benzimidazole , benzoxazole , 25 one acid while the other basic nitrogen can form salt with benzothiazole , thiazole , and the like . The heteroaryl group another acid . Some compounds according to the invention contain both , acidic as well as basic moieties, and thus can may be unsubstituted , or substituted with one or more form inner salts or corresponding zwitterions. In general, all substituents . Typical , non -limiting examples of such sub pharmaceutically acceptable salt forms of compounds of stituents include C . - C . alkyl , halogen , alkoxy, CN , COOHarul , 30 Formula (I ) according to invention including acid addition CONH2, OH , NH , NHCOCH3, heterocyclyl, heteroaryl, salts , base addition salts , zwitterions or the like are contem aryl, SO2- alkyl, SO2- aryl, OSO2- alkyl, OSO2- aryl and the plated to be within the scope of the present invention and are like . generically referred to as pharmaceutically acceptable salts . The term “ stereoisomers ” as used herein refers to com The term “ halogen ” or “ halo ” as used herein refers to pounds that have identical chemical constitution , butpul dinediffer 3525 chlorine, bromine , fluorine , or iodine. with regard to the arrangement of their atoms or groups in The term “ infection ” or “ bacterial infection ” as used space . The compounds of Formula (1 ) may contain asym - herein includes presence of bacteria , in or on a subject, metric or chiral centers and , therefore , exist in different which , if its growth were inhibited , would result in a benefit stereoisomeric forms. It is intended , unless specified other to the subject. As such , the term “ infection ” in addition to wise , that all stereoisomeric forms of the compounds of 40 referring to the presence of bacteria also refers to normal Formula ( I ) as well as mixtures thereof, including racemic flora , which is not desirable . The term “ infection ” includes mixtures , form part of the present invention . In addition , the infection caused by bacteria . present invention embraces all geometric and positional The term “ treat ” , “ treating " or " treatment” as used herein isomers ( including cis and trans - forms) , as well as mixtures refers to administering a medicament, including a pharma thereof, are embraced within the scope of the invention . In 45 ceutical composition , or one or more pharmaceutically general , a reference to a compound is intended to cover its active ingredients , for prophylactic and / or therapeutic pur stereoisomers and mixture of various stereoisomers . poses . The term “ prophylactic treatment” refers to treating a The term " optionally substituted ” as used herein means subject who is not yet infected , but who is susceptible to , or that substitution is optional and therefore includes both otherwise at a risk of infection (preventing the bacterial unsubstituted and substituted atoms and moieties . A " sub - 50 infection ) . The term " therapeutic treatment” refers to admin stituted ” atom or moiety indicates that any hydrogen on the istering treatment to a subject already suffering from infec designated atom or moiety can be replaced with a selection tion . The terms “ treat” , “ treating” or “ treatment” as used from the indicated substituent group , provided that the herein also refer to administering compositions or one or normal valency of the designated atom or moiety is not more of pharmaceutically active ingredients discussed exceeded , and that the substitution results in a stable com - 55 herein , with or without additional pharmaceutically active or pound . inert ingredients , in order to : ( i) reduce or eliminate either a The term " pharmaceutically acceptable salt ” as used bacterial infection or one or more symptoms of the bacterial herein refers to one or more salts of a given compound infection , or ( ii ) retard the progression of a bacterial infec which possesses the desired pharmacological activity of the tion or of one or more symptoms of the bacterial infection , free compound and which are neither biologically nor oth - 60 or ( iii ) reduce the severity of a bacterial infection or of one erwise undesirable . In general, the " pharmaceutically or more symptoms of the bacterial infection , or (iv ) suppress acceptable salts ” refer to salts that are suitable for use in the clinical manifestation of a bacterial infection , or ( v ) contact with the tissues of human and animals without undue suppress the manifestation of adverse symptoms of the toxicity, irritation , allergic response and the like , and are bacterial infection . commensurate with a reasonable benefit / risk ratio . Pharma- 65 The term “ pharmaceutically effective amount ” or “ thera ceutically acceptable salts are well known in the art . For peutically effective amount” or “ effective amount ” as used example , S . M . Berge , et al . ( J. Pharmaceutical Sciences , 66 : herein refers to an amount, which has a therapeutic effect or US 9 ,732 ,081 B2 10 is the amount required to produce a therapeutic effect in a inhibiting or reducing ability of bacteria to multiply or subject . For example , a therapeutically or pharmaceutically remain infective in the environment. The term “ antibacterial effective amount of an antibacterial agent or a pharmaceu - agent" also refers to compounds capable of decreasing tical composition is the amount of the antibacterial agent or infectivity or virulence of bacteria . the pharmaceutical composition required to produce a 5 The term “ beta - lactam antibacterial agent” as used herein desired therapeutic effect as may be judged by clinical trial refers to compounds with antibacterial properties and con results. model animal infection studies and /or in vitro taining a beta - lactam nucleus in their molecular structure . The term " beta - lactamase ” as used herein refers to any studies ( e .g . in agar or broth media ) . The pharmaceutically enzyme or protein or any other substance that breaks down effective amount depends on several factors , including but a beta - lactam ring. The term “ beta - lactamase ” includes not limited to , the microorganism ( e. g . bacteria ) involved , 10 enzymes that are produced by bacteria and have the ability characteristics of the subject ( for example height, weight, to hydrolyze the beta -lactam ring in a beta - lactam com sex , age and medical history ) , severity of infection and the pound , either partially or completely . particular type of the antibacterial agent used . For prophy The term “ beta - lactamase inhibitor” as used herein refers lactic treatments , a therapeutically or prophylactically effec - to a compound capable of inhibiting activity of one or more tive amount is that amount which would be effective in 15 beta - lactamase enzymes , either partially or completely . preventing a microbial ( e . g . bacterial ) infection . The term “ pharmaceutically inert ingredient" or " carrier " The term “ administration " or " administering ” includes or “ excipient” refers to a compound or material used to delivery of a composition or one or more pharmaceutically facilitate administration of a compound , including for active ingredients to a subject, including for example , by any example , to increase the solubility of the compound . Typi appropriate methods, which serves to deliver the composi - 20 cal, non - limiting examples of solid carriers include , starch , tion or its active ingredients or other pharmaceutically active lactose , dicalcium phosphate , sucrose , and kaolin and so on . ingredients to the site of the infection . The method of Typical, non - limiting examples of liquid carriers include, administration may vary depending on various factors , such sterile water , saline, buffers, non - ionic surfactants , and as for example , the components of the pharmaceutical edible oils such as oil, peanut and sesame oils and so on . In composition or the nature of the pharmaceutically active or 25 addition , various adjuvants commonly used in the art may be inert ingredients , the site of the potential or actual infection , included . These and other such compounds are described in the literature , for example , in the Merck Index (Merck & the microorganism involved , severity of the infection , age Company, Rahway, N .J . ) . Considerations for inclusion of and physical condition of the subject and a like. Some various components in pharmaceutical compositions are non - limiting examples of ways to administer a composition described , for example , in Gilman et al. ( Eds . ) ( 1990 ) ; or a pharmaceutically active ingredient to a subject accord - 30 Goodman and Gilman ' s : The Pharmacological Basis of ing to this invention includes oral , intravenous , topical , Therapeutics , 8th Ed . , Pergamon Press. , which is incorpo intrarespiratory , intraperitoneal, intramuscular , parenteral , rated herein by reference in its entirety . sublingual, transdermal, intranasal, aerosol, intraocular, The term " subject” as used herein refers to vertebrate or intratracheal , intrarectal, vaginal, gene gun , dermal patch , invertebrate , including a mammal. The term “ subject” eye drop , ear drop or mouthwash . In case of a pharmaceu - 35 includes human , animal, a bird , a fish , or an amphibian . tical composition comprising more than one ingredient Typical, non - limiting examples of a “ subject” includes ( active or inert ) , one of way of administering such compo - humans, cats, dogs , horses, sheep , bovine cows, pigs, lambs , sition is by admixing the ingredients ( e. g . in the form of a rats , mice and guinea pigs . suitable unit dosage form such as tablet , capsule , solution , The term “ pharmaceutically acceptable derivative " as powder and a like ) and then administering the dosage form . 40 used herein refers to and includes any pharmaceutically Alternatively , the ingredients may also be administered acceptable salt , pro -drugs , metabolites, esters , ethers , separately ( simultaneously or one after the other ) as long as hydrates , polymorphs, solvates, complexes, enantiomers or these ingredients reach beneficial therapeutic levels such adducts of a compound described herein which , upon administration to a subject, is capable of providing (directly that the composition as a whole provides a synergistic and / or 45. or indirectly the parent compound . For example , the term desired effect. “ antibacterial agent or a pharmaceutically acceptable deriva The term “ growth ” as used herein refers to a growth of tive thereof” includes all derivatives of the antibacterial one or more microorganisms and includes reproduction or agent (such as salt , pro -drugs , metabolites , esters , ethers , population expansion of the microorganism ( e . g . bacteria ) . hydrates , polymorphs, solvates , complexes, enantiomers or The term also includes maintenance of on - going metabolic adducts ) which , upon administration to a subject, is capable processes of a microorganism , including processes that keep 50 of providing (directly or indirectly ) the antibacterial com the microorganism alive . pound . The term , " effectiveness ” as used herein refers to ability In general, the term “ cation ” includes Na , K , Mg, Ca , of a treatment or a composition or one or more pharmaceu - NH + (CH . CH ,) . N + etc . tically active ingredients to produce a desired biological In one general aspect , there are provided compounds of effect in a subject. For example , the term “ antibacterial 55 Formula ( I ) : effectiveness ” of a composition or an antibacterial agent refers to the ability of the composition or the antibacterial agent to prevent or treat the microbial ( e . g . bacterial) infec Formula ( I ) tion in a subject. The term " synergistic " or " synergy ” as used herein refers 60 to the interaction of two or more agents so that their combined effect is greater than their individual effects . ??2? The term “ antibacterial agent” as used herein refers to any substance , compound or a combination of substances or a combination compounds capable of: ( i ) inhibiting, reducing 65 or preventing growth of bacteria ; ( ii ) inhibiting or reducing OR ability of a bacteria to produce infection in a subject ; or ( iii ) US 9 ,732 , 081 B2 12 or a stereoisomer or a pharmaceutically acceptable salt ( f ) cycloalkyl optionally substituted with one or more thereof; substituents independently selected from C . - C . alkyl, wherein : OR5, NR R7, halogen , CN , CONR R7, SO2- alkyl, R , is : SO2- aryl , OSO2- alkyl, OSO2- aryl, or NHCONRR ; ( a ) SO2M , 5 R , and R , are each independently : (b ) SO NH , ( a ) hydrogen , or ( c ) POZM , ( b ) C .- C . alkyl optionally substituted with one or more ( d ) CH , COOM , substituents independently selected from halogen , CN , ( e ) CF_ COOM , CONRR , NR R7, heterocyclyl, heteroaryl, ( f ) CHFCOOM , or 10 cycloalkyl or aryl; ( g ) CFz; M is hydrogen or a cation ; Ro and R , are each independently : R2 is : ( a ) hydrogen , (a ) hydrogen , ( b ) C . - C . alkyl optionally substituted with one or more ( b ) ( CH2) n - R3, or 15 substituents independently selected from halogen , OR 5 , ( C ) COOR3, CN , COORS, CONRRs, NR Rs, NR , CORg, hetero n is 0 , 1 or 2 ; cyclyl, heteroaryl, cycloalkyl or aryl, R2 is : ( c ) aryl optionally substituted with one or more substitu ( a ) hydrogen , ents independently selected from C . -C alkyl , OR5, ( b ) C -C6 alkyl optionally substituted with one or more 20 NR Rg, halogen , CN , CONR =Rg , SO2- alkyl , SO2- aryl , substituents independently selected from halogen , OR , OSO2- alkyl , OSO2- aryl, or NHCONR ,RS , CN , COORS, CONRR7, NR R7, NR , CORE, ( d ) heterocyclyl optionally substituted with one or more NR , CONR R7, heterocyclyl, heteroaryl, cycloalkyl or substituents independently selected from C1- C6 alkyl, aryl, OR . , NR Rg, halogen , CN , CONR , RS, SO2- alkyl , (c ) CN , 25 SO2- aryl, OSO2- alkyl , OSO2- aryl, or NHCONRRs, ( d ) NRGR ,, ( e ) heteroaryl optionally substituted with one or more ( e ) CONRR , substituents independently selected from C , -C , alkyl, ( f) NHCONRR , ( g ) aryl optionally substituted with one or more substitu ORs, NR Rs, halogen , CN , CONR , RS, SO2- alkyl , ents independently selected from C . - C . alkyl , OR5, 30 SO2- aryl, OSO2- alkyl , OSO2- aryl, or NHCONR = Rg, NR R7, halogen , CN , CONRGR7, SO2- alkyl, SO2- aryl, ( f) cycloalkyl optionally substituted with one or more OSO2- alkyl , OSO2- aryl, or NHCONRGR7, substituents independently selected from C . - C . alkyl, ( h ) heterocyclyl optionally substituted with one or more OR , NR - R , , halogen , CN , CONR - R3, SO2- alkyl , substituents independently selected from C - C , alkyl, SO2- aryl, OSO2 -alkyl , OSO2- aryl , or NHCONR =Rs , or OR , NR R7, halogen , CN , CONRR7, SO2- alkyllku ,. 3635 ( g8 ) RgR . and RyR , are joined totogether to form a four to seven SO2- aryl, OSO2- alkyl, OSO2- aryl , or NHCONRR7, member ring . (i ) heteroaryl optionally substituted with one or more Typical non - limiting examples of compounds according substituents independently selected from C . - C . alkyl . to the invention include : OR , NR R ,, halogen , CN , CONRR ,, SO -alkyl , (2S ,5R )- 7 -oxo -N - [( 2S )- pyrrolidin -2 - ylmethyloxy ]- 6 -( sul SO2- aryl, OSO2- alkyl , OSO - aryl, or NHCONRR , , 40 fooxy )- 1 ,6 -diazabicyclo [ 3 .2 . 1] octane - 2 -carboxamide ; ( ) cycloalkyl optionally substituted with one or more (28 , 5R ) - 7 -oxo - N - [ ( 2R ) -pyrrolidin - 2 - ylmethyloxyl- 6 - ( sul substituents independently selected from C , -C6 alkyl, fooxy )- 1, 6 -diazabicyclo [ 3. 2 .1 ]octane - 2 - carboxamide; ORs, NR R7, halogen , CN , CONRR7, SO2- alkyl , (2S ,5R )- 7 -oxo - N -[ ( 3S ) -pyrrolidin - 3 -ylmethyloxy ]- 6 -( sul SO2- aryl, OSO2- alkyl, OSO2- aryl, or NHCONR R7, fooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxamide ; ( k ) cycloalkyl substituted with C . - C . alkyl wherein C , - C6 45 (2S ,5R ) - 7 -oxo - N - [ (3R ) -pyrrolidin - 3 -ylmethyloxy ] -6 - ( sul alkyl is further substituted with one or more substitu - fooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxamide ; ents independently selected from OR5, NR R7, halo - (2S ,5R ) - N - { [ (2S ,4R ) -4 -hydroxyl - pyrrolidin - 2 -yl ] methyl gen , CN , or CONR R7, or oxy } - 7 - oxo -6 - ( sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ] octane ( 1) OR ; 2 -carboxamide ; R4 is : 50 (2S , 5R ) - N - { [ ( 2S , 4R ) - 4 -cyano - pyrrolidin - 2 - yl] methyl ( a ) hydrogen , oxy } - 7 - oxo - 6 -( sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ] octane (b ) C . - C . alkyl optionally substituted with one or more 2 -carboxamide ; substituents independently selected from halogen , OR5, ( 2S ,5R ) - N - { [ ( 5R ) - 5 - cyanopyrrolidin - 2 -yl ] methyloxy } - 7 CN , COOR , CONRR7, NR R7, NR , CORg, hetero oxo - 6 - ( sulfooxy ) - 1 ,6 -diazabicyclo [ 3 . 2 . 1 ] octane- 2 -car cyclyl, heteroaryl, cycloalkyl or aryl, 55 boxamide ; ( c ) aryl optionally substituted with one or more substitu - (2S ,5R ) - N - { [( SR )- 5 -cyanopyrrolidin -2 - yl] methyloxy } ents independently selected from C , -C6 alkyl, OR , 7 -oxo -6 - ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - car NR R7, halogen , CN , CONRR7, SO2- alkyl, SO2- aryl , boxamide ; OSO , - alkyl, OSO , - aryl, or NHCONRR , , (2S , 5R ) - N - { [ ( 2S , 4R ) - 4 - trifluoroacetylamino - pyrrolidin ( d ) heterocyclyl optionally substituted with one or more 60 2 - yl] methyloxy } - 7 -oxo - 6 - ( sulfooxy ) - 1 ,6 -diazabicyclo substituents independently selected from C - C . alkyl, [ 3 . 2 . 1 Joctane - 2 -carboxamide ; OR5, NR R7, halogen , CN , CONRR7, SO2- alkyl, (2S ,5R ) - N - {[ (2S )- 1 - carbamimidoyl- pyrrolidin - 2 -yl ] meth SOZ- aryl, OSO2- alkyl , OSO2- aryl, or NHCONRGR7, yloxy } -7 -oxo - 6 -( sulfooxy ) - 1, 6 - diazabicyclo [3 . 2 .1 Joc ( e ) heteroaryl optionally substituted with one or more tane - 2 -carboxamide ; substituents independently selected from C . - C . alkyl, 65 ( 2S ,5R ) - 7 - oxo - N - { 1 - [ ( 2S ) -pyrrolidin - 2 - yl] ethyloxy } - 6 OR5, NR R7, halogen , CN , CONRR7, SO2- alkyl , ( sulfooxy ) - 1, 6 -diazabicyclo [ 3 . 2 . 1 ]octane - 2 -carboxam SO2- aryl, OSO2- alkyl, OSO2- aryl , or NHCONRR7, or ide; US 9 ,732 , 081 B2 13 14 (2S ,5R )- 7 -oxo -N - { [ (2S ) - 5 -oxopyrrolidin - 2 -yl ] methyloxy } - ( 2S ,5R )- N -methyloxy -7 -oxo - N - (piperidin -3 -ylmethyl ) -6 6 - ( sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxam ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxam ide; ide; ( 2S , 5R ) - N - [ ( 2S ) - azetidin - 2 -ylmethyloxy ] - 7 - oxo - 6 - ( sul (2S ,5R ) - N -methyloxy - 7 - oxo - N - (pyrrolidin - 2 -ylmethyl ) fooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1Joctane - 2 -carboxamide ; 5 6 - ( sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 Joctane - 2 -carboxam ( 2S , 5R ) - N - [ ( 2R ) - azetidin - 2 - ylmethyloxy ] - 7 - oxo -6 - ( sul ide ; fooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 - carboxamide; (2S ,5R ) - N -[ (2S ) -azetidin - 2 - ylmethyl] - N -hydroxy - 7 -oxo ( 2S ,5R ) - 7 -oxo - N - (piperidin - 4 - ylmethyloxy ) -6 - ( sulfooxy ) 6 - (sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 - carboxam 1 , 6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 -carboxamide ; ide ; ( 28 .5R ) - 7 - Oxo - N - ( ( 3R . S ) - piperidin - 3 - vlmethyloxy )- 6 - ( sul 10 (25 , 5R ) - N -hydroxy - 7 - OXO - N - [ ( 2S ) -pyrrolidin - 2 - ylm ethyl] -6 - ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 -car fooxy )- 1 ,6 -diazabicyclo [ 3 .2 . 1 ]octane - 2 -carboxamide ; boxamide ; (2S ,5R )- 7 -oxo - N -( (2R , S )piperidin - 2 -ylmethyloxy )- 6 -( sul ( 2S , 5R ) - N -hydroxy - 7 - oxo - N - [ (2S ) - piperidin - 2 - ylmethyl ] fooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 - carboxamide; 6 -( sulfooxy )- 1, 6 -diazabicyclo [ 3 .2 .1 ]octane - 2 -carboxam ( 2S , 5R ) - 7 - oxo - N - ( ( 2S ) piperidin - 2 - ylmethyloxy ) - 6 - ( sul 15 ide ; fooxy )- 1, 6 -diazabicyclo [3 .2 . 1] octane -2 -carboxamide ; (2S ,5R ) - N - [ (2S ) - azepan - 2 -ylmethyl ] - N - hydroxy - 7 -oxo - 6 (2S ,5R ) - 7 -oxo - N - ( (2S )piperidin - 2 -ylmethyloxy ) -6 - ( sul ( sulfooxy )- 1, 6 - diazabicyclo [3 . 2 .1 ]octane - 2 -carboxam fooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane- 2 - carboxamide; ide ; ( 2S ,5R )- 7 - oxo - N - { 1- [ (2S )- piperidin -2 -yl ] ethyloxy } -6 -( sul - (2S ,5R ) - N -[ ( 2R )- azetidin - 2 - ylmethyl] -N -hydroxy -7 - oxo fooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxamide ; 20 6 - (sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxam ( 2S ,5R ) - N -( azepan -2 - ylmethyloxy )- 7 - oxo - 6 -( sulfooxy )- 1 , ide ; 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxamide ; (2S ,5R ) - N -hydroxy -7 - oxo -N -[ ( 2R )- pyrrolidin -2 -ylm ( 2S ) N - ( 2 , 3 - dihydro -1H -indol - 2 - ylmethyloxy ) - 7 -oxo - 6 ethyl] - 6 - ( sulfooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 - car ( sulfooxy )- 1 ,6 -diazabicyclo [ 3. 2 . 1 ]octane - 2 -carboxam boxamide ; ide ; 25 (2S ,5R ) N -hydroxy -7 - oxo - N -[ ( 2R )- piperidin -2 -ylm (2S ,5R ) - N - {[ ( 2R ,S )- 1, 2 , 3 ,4 -tetrahydro - quinolin - 2 - yl ] ethyl] -6 - ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - car methyloxy } - 7 - oxo - 6 - ( sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ] boxamide ; octane -2 -carboxamide ; (2S , 5R ) - N -[ (2R )- azepan -2 -ylmethyl ] -N - hydroxy - 7 -oxo ( 2S ,5R ) - N -{ [( 3S ) - 1, 2 ,3 ,4 - tetrahydro - isoquinolin - 3 -yl ] 6 - ( sulfooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 Joctane - 2 -carboxam methyloxy } - 7 - oxo -6 - ( sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ] 30 or a stereoisomer or a pharmaceutically acceptable salt octane- 2 - carboxamide; thereof. ( 2S , 5R ) - N - { [ (4S )- 1 -methyl - 1 , 4 , 5 ,6 - tetrahydropyrrolo [ 3 , Typical , non - limiting examples of various salt forms of 4 - c ] pyrazol -4 - yl] methoxy } - 7 - oxo - 6 - ( sulfooxy ) - 1 , 6 -diaz the compounds according to the invention include : abicyclo [ 3 . 2 . 1 Joctane - 2 - carboxamide ; 35 Sodium salt of (2S ,5R ) - N -[ ( 2S ) - azetidin - 2 - ylmethyl] -N (2S ,5R ) - N - { [ (4S )- 1H - 1 ,4 ,5 ,6 - tetrahydropyrrolo [ 3 ,4 - c ] hydroxy -7 - oxo -6 -( sulfooxy )- 1 ,6 -diazabicyclo [ 3 .2 . 1 ]oc pyrazol- 4 - yl] methyloxy } - 7 - oxo - 6 - ( sulfooxy ) - 1 , 6 -diaz tane - 2 -carboxamide ; abicyclo [ 3 . 2 . 1 Joctane - 2 - carboxamide ; Sodium salt of (2S ,5R ) - N -hydroxy - 7 -oxo -N -[ ( 2S ) - pyrro ( 2S ) - N - [ ( 4 , 5 - dihydroxy - 1 , 4 - dihydropyridin - 2 - yl) methyl lidin - 2 - ylmethyl] - 6 - (sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] oxy ] - 7 - oxo - 6 -( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ]octane - 40 octane - 2 -carboxamide ; 2 - carboxamide ; Sodium salt of ( 2S , 5R ) - N -hydroxy - 7 - oxo - N - [ ( 2S ) -piperi (2S ,5R ) -7 -oxo -N - { [( 4S )- 2 -( 2- hydroxyphenyl ) - 4 ,5 -dihydro - din - 2 -ylmethyl ] -6 -( sulfooxy ) -1 ,6 -diazabicyclo [3 .2 . 1] oc 1 , 3 -oxazol - 4 -yl ] methyloxy } -6 - (sulfooxy ) - 1, 6 - diazabicy - tane - 2 -carboxamide ; clo [ 3 . 2 . 1 Joctane- 2 - carboxamide ; Sodium salt of ( 2S ,5R ) - N - [ ( 2S ) - azepan - 2 - ylmethyl ] - N ( 2S ,5R )- 7 -oxo -N - {[ (4S )- 2- ( (2S )- pyrrolidin -2 -yl ) - 4 ,5 -di - 45 hydroxy - 7 -oxo -6 - (sulfooxy )- 1, 6 -diazabicyclo [3 .2 . 1] oc hydro - 1 , 3 -oxazol - 4 -yl ]methyloxy } -6 -( sulfooxy )- 1 ,6 - di - tane - 2 -carboxamide ; azabicyclo [ 3 . 2 . 1 ] octane - 2 -carboxamide ; Sodium salt of (2S ,5R ) - N -[ ( 2R )- azetidin -2 - ylmethyl] - N ( 2S ,5R )- 7 -oxo - N -[ ( 3R ,S ) -pyrrolidin - 3 -yloxy ]- 6 - ( sulfooxy ) hydroxy - 7 -oxo - 6 - ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ]oc 1, 6 - diazabicyclo [ 3 .2 . 1 Joctane - 2 - carboxamide ; tane - 2 -carboxamide ; (2S ,5R ) - 7 - oxo - N -[ ( 3S ) -pyrrolidin - 3 - yloxy ] - 6 - ( sulfooxy ) - 1 , 50 Sodium salt of ( 2S , 5R ) - N - hydroxy - 7 - oxo - N - [ ( 2R ) -pyrro 6 - diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxamide ; lidin - 2 - ylmethyl] - 6 - ( sulfooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ] ( 2S , 5R ) - 7 - oxo - N -[ ( 3R ) -pyrrolidin - 3 - yloxy ] - 6 - ( sulfooxy ) - 1 , octane - 2 - carboxamideide ; 6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 - carboxamide ; Sodium salt of (2S ,5R ) - N -hydroxy - 7 - oxo - N - [ ( 2R )- piperi ( 2S ,5R ) - N - { [ (3R , 5S ) - 5 - cyanopyrrolidin - 3 - yl] oxy } - 7 - oxo din - 2 - ylmethyl ] -6 - (sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ] oc 6 - ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 Joctane - 2 - carboxam - 55 tane - 2 - carboxamide ; ide; Sodium salt of ( 2S , 5R ) - N - [ ( 2R ) -azepan - 2 - ylmethyl] - N (2S ,5R ) - N - { [ (35 ,5S ) -5 -cyanopyrrolidin - 3 -yl ] oxy } - 7 -oxo - hydroxy -7 - oxo -6 - ( sulfooxy )- 1, 6 -diazabicyclo [ 3 .2 . 1 ]oc 6 - (sulfooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 -carboxam tane - 2 - carboxamide ; ide; Sodium salt of (2S ,5R ) - 7 -oxo - N - [ ( 2S ) -pyrrolidin - 2 - ylmeth (2S ,5R ) - N - { [ (3R , 5S ) - 5 - carbamoylpyrrolidin - 3 - yl ] oxy } - 7 - 60 yloxy ] - 6 - ( sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 - car oxo - 6 - ( sulfooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ] octane - 2 - car boxamide; boxamide ; Sodium salt of (2S ,5R )- 7 -oxo - N - [( 2R ) -pyrrolidin - 2 - ylmeth (2S , 5R ) - N -( azetidin - 3 - yloxy ) - 7 -oxo -6 -( sulfooxy )- 1 ,6 -di yloxy ] -6 - ( sulfooxy ) - 1, 6 -diazabicyclo [ 3 .2 . 1 Joctane -2 -car azabicyclo [3 . 2 .1 ]octane - 2 - carboxamide ; boxamide ; (2S ,5R ) - N -methyloxy - 7 - oxo - N - (piperidin - 2 -ylmethyl ) - 6 - 65 Sodium salt of ( 2S ,5R ) - 7 -oxo - N - [ (3S ) -pyrrolidin - 3 - ylmeth (sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxam yloxy ]- 6 - ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ]octane - 2 - car ide ; boxamide ; US 9 ,732 , 081 B2 15 16 Sodium salt of (2S ,5R ) -7 -oxo - N -[ (3R )- pyrrolidin - 3 -ylmeth - Sodium salt of (2S ,5R ) - N - { [( 4S ) - 1H - 1 ,4 , 5 ,6 - tetrahydro yloxy ] -6 - ( sulfooxy )- 1 ,6 -diazabicyclo [ 3 .2 . 1 ]octane - 2 -car pyrrolo [ 3 ,4 -c ]pyrazol - 4 -yl ] methyloxy } - 7 -oxo -6 - ( sul boxamide ; fooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxamide ; Sodium salt of ( 2S , 5R ) - N - { [ (2S , 4R ) - 4 - hydroxyl- pyrroli - Sodium salt of ( 2S ) N - [ ( 4 , 5 - dihydroxy - 1 , 4 - dihydropyri din - 2 - yl] methyloxy } - 7 -oxo -6 - ( sulfooxy ) - 1 ,6 - diazabicy - 5 din - 2 - yl) methyloxy ] - 7 - oxo -6 - ( sulfooxy ) - 1 , 6 - diazabicy clo [ 3 . 2 . 1 ] octane - 2 - carboxamide ; clo [ 3 . 2 . 1 ]octane - 2 -carboxamide ; Sodium salt of ( 2S , 5R ) - N - {[ ( 2S , 4R ) - 4 - cyanol -pyrrolidin - Sodium salt of (2S ,5R ) - 7 - oxo - N - { [ ( 4S ) - 2 - ( 2 - hydroxyphe 2 - yl) methyloxy } - 7 -oxo -6 - ( sulfooxy ) - 1 , 6 - diazabicyclo nyl) -4 , 5 - dihydro - 1 , 3 - oxazol- 4 - yl] methyloxy } - 6 -( sul [ 3 . 2 . 1 ]octane - 2 -carboxamide ; fooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ] octane- 2 - carboxamide ; Sodium salt of ( 2S ,5R ) - N - {[ (5R ) - 5 -cyanopyrrolidin - 2 -yl ] " Sodium salt of ( 2S ,5R )- 7 - oxo -N - {[ (4S )- 2 -( 2S )- pyrrolidin methyloxy }- 7 -oxo - 6 -( sulfooxy )- 1, 6 -diazabicyclo [3 . 2 . 1 ] 2 - yl) - 4 , 5 -dihydro - 1 , 3 -oxazol - 4 -yl ] methyloxy } -6 - (sul octane- 2 - carboxamide ; fooxy ) - 1 ,6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxamide ; Sodium salt of (2S , 5R ) - N — { [ (SR ) - 5 - cyanopyrrolidin - 2 - Sodium salt of ( 2S , 5R ) - 7 - oxo - N - [ ( 3R , S ) - pyrrolidin - 3 yl] methyloxy } - 7 -oxo - 6 - ( sulfooxy ) - 1 ,6 -diazabicyclo 15 yloxy ] - 6 - ( sulfooxy ) - 1 ,6 -diazabicyclo [ 3 . 2 . 1 ]octane - 2 -car [ 3 . 2 . 1 ] octane - 2 - carboxamide ; boxamide ; Sodium saltof (2S , 5R ) - N - {[ ( 2S ,4R )- 4 - trifluoroacety - Sodium salt of (2S ,5R )- 7 -oxo - N - [ (3S )- pyrrolidin - 3 -yloxyl lamino -pyrrolidin -2 -yl ] methyloxy } - 7 -oxo -6 -( sulfooxy ) 6 -( sulfooxy )- 1, 6 -diazabicyclo [3 . 2 .1 ]octane - 2 -carboxam 1 , 6 - diazabicyclo [ 3 . 2 . 1 ] octane- 2 - carboxamide; ide ; Sodium salt of (2S ,5R ) - N - { [ (2S )- 1 -carbamimidoyl - pyrro - 20 Sodium salt of (2S ,5R )- 7 -oxo - N - [( 3R ) -pyrrolidin - 3 -yloxyl lidin - 2 - yl ]methyloxy } - 7 - oxo -6 - ( sulfooxy ) - 1 ,6 - diazabicy - 6 - ( sulfooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxam clo [ 3 . 2 . 1 Joctane- 2 -carboxamide ; ide; Sodium salt of (2S ,5R ) -7 -oxo - N - { 1 -[ ( 2S )- pyrrolidin - 2 -yl ] Sodium salt of (2S ,5R ) - N - {[ (3R ,5S )- 5 -cyanopyrrolidin -3 ethyloxy } -6 -( sulfooxy )- 1 ,6 - diazabicyclo [ 3 .2 .1 Joctane -2 - yl] oxy } -7 - oxo - 6 - ( sulfooxy ) - 1, 6 -diazabicyclo [ 3 . 2. 1 ]oc carboxamide ; tane - 2 - carboxamide; Sodium salt of (2S ,5R )- 7 -oxo -N -{ [ (2S ) -5 -oxopyrrolidin - 2 - Sodium salt of (2S ,5R ) - N - {[ (35 ,5S )- 5 -cyanopyrrolidin - 3 yl] methyloxy } - 6 - (sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ]oc yl] oxy } -7 -oxo -6 -( sulfooxy ) - 1, 6 -diazabicyclo [3 .2 .1 ]oc tane -2 -carboxamide ; tane -2 -carboxamide ; Sodium salt of ( 2S ,5R ) - N - [ ( 2S ) - azetidin - 2 -ylmethyloxy ] - Sodium salt of ( 2S ,5R ) - N - { [ (3R , 5S ) - 5 - carbamoylpyrroli 7 - oxo - 6 - ( sulfooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ] octane - 2 - car- 30 din - 3 - yl] oxy } - 7 - oxo -6 - ( sulfooxy ) - 1 ,6 - diazabicyclo boxamide ; [ 3 . 2 . 1 ] octane - 2 -carboxamide ; Sodium salt of (2S , 5R ) - N -[ ( 2R ) -azetidin - 2 -ylmethyloxy )- Sodium salt of (2S ,5R ) - N -( azetidin - 3 -yloxy ) -7 -oxo -6 7 -oxo - 6 - ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ]octane - 2 -car (sulfooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxam boxamide ; ide ; Sodium salt of (2S , 5R )- 7 - oxo - N - ( piperidin - 4 - ylmethyloxy ) - 35 Sodium salt of (2S , 5R ) - N -methyloxy - 7 - oxo - N - ( piperidin 6 - ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 -carboxam - 2 - ylmethyl) -6 - ( sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ]octane ide; 2 - carboxamide; Sodium salt of (2S ,5R )- 7 -oxo - N -( ( 3R , S )- piperidin - 3 -ylm - Sodium salt of (2S ,5R ) - N -methyloxy -7 -oxo - N -( piperidin ethyloxy ) -6 - ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ]octane - 2 - 3 - ylmethyl) - 6 - (sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane carboxamide ; 40 2 - carboxamide ; Sodium salt of (2S ,5R ) -7 -oxo - N -( ( 2R , S )piperidin - 2 -ylmeth - Sodium salt of (2S , 5R ) - N -methyloxy - 7 -oxo - N -( pyrroli yloxy ) - 6 - ( sulfooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 - car- din - 2 - ylmethyl) -6 - ( sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ] oc boxamide ; tane - 2 - carboxamide ; Sodium salt of (2S ,5R ) - 7 - oxo - N - ( (2S )piperidin - 2 -ylmethyl - (2S ,5R ) - N - ( 2 - aminoethyloxy ) - 7 - oxo - 6 - (sulfooxy ) - 1 , 6 - di oxy )- 6 -( sulfooxy )- 1 ,6 -diazabicyclo [ 3 .2 .1 Joctane - 2 -car - 45 azabicyclo [ 3 .2 . 1 ]octane - 2 -carboxamide trifluoroacetic boxamide ; acid salt ; Sodium salt of (2S ,5R ) - 7 -oxo - N -[ (2S )piperidin - 2 -ylmethyl - (2S ,5R ) - N -( 2 -carbamimidamidoethyloxy )- 7 -oxo -6 - (sul oxy )- 6 -( sulfooxy )- 1 ,6 -diazabicyclo [ 3 .2 .1 ]octane -2 -car fooxy )- 1 ,6 -diazabicyclo [ 3 .2 . 1] octane - 2 -carboxamide trif boxamide ; luoroacetic acid salt ; Sodium salt of (2S , 5R ) - 7 - oxo - N - { 1 - [ ( 2S ) - piperidin - 2 - yl] 50 ( 2S , 5R ) - N - ( 3 - aminopropyloxy ) - 7 -oxo - 6 -( sulfooxy ) - 1 ,6 ethyloxy } -6 -( sulfooxy )- 1 ,6 - diazabicyclo [ 3 .2 .1 ]octane -2 diazabicyclo [ 3 . 2 . 1 ]octane - 2 -carboxamide trifluoroacetic carboxamide ; acid salt ; Sodium salt of (2S ,5R ) - N - (azepan - 2 -ylmethyloxy ) - 7 -oxo - (2S ,5R ) - N - {[ (2S ) - 2 ,5 -diaminopentyl ] oxy } - 7 -oxo -6 -( sul 6 - ( sulfooxy ) - 1 ,6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxam fooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxamide trif ide ; 55 luoroacetic acid salt ; Sodium salt of (2S ) — N -( 2 ,3 -dihydro - 1H - indol -2 - ylmethyl- (2S ,5R ) - N - {[ ( 2S ,4R ) -4 - aminopyrrolidin -2 - yl] methyl oxy ) - 7 -oxo -6 - (sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ]octane oxy } - 7 -oxo - 6 - (sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane 2 -carboxamide ; 2 - carboxamide trifluoroacetic acid salt; Sodium salt of ( 2S , 5R ) - N - { [ ( 2R , S )- 1 , 2 , 3 , 4 - tetrahydro - ( 2S , 5R ) - 7 -oxo - N - [ (2S ) - piperazin - 2 -ylmethyloxy ] - 6 - ( sul quinolin - 2 - yl] methyloxy } - 7 - oxo -6 - ( sulfooxy ) - 1 ,6 - diaz - 60 fooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ] octane- 2 - carboxamide trif abicyclo [ 3 . 2 . 1 ] octane - 2 - carboxamide ; luoroacetic acid salt ; Sodium salt of (2S ,5R ) - N - {[ ( 3S ) - 1, 2 ,3 ,4 - tetrahydro - iso - (2S ,5R ) - N -methyloxy - 7 -oxo - N - (piperazin - 2 -ylmethyl )- 6 quinolin -3 -yl ]methyloxy } -7 -oxo - 6 - ( sulfooxy ) - 1, 6 -diaz ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxamide abicyclo [ 3. 2 . 1 ]octane - 2 -carboxamide ; trifluoroacetic acid salt ; Sodium salt of ( 2S ,5R ) - N - { [ (4S ) - 1 -methyl - 1 , 4 , 5 , 6 -tetra - 65 Sodium salt of (2S , 5R ) - N -methoxy - N -methyl - 7 -oxo -6 hydropyrrolo [ 3 ,4 - c ]pyrazol - 4 - yl] methoxy } - 7 - oxo - 6 - ( sul ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ]octane - 2 -carboxam fooxy )- 1 ,6 -diazabicyclo [ 3. 2 . 1] octane - 2 -carboxamide ; ide ; US 9 ,732 , 081 B2 17 18 Sodium Salt of ( 2S ,5R ) - N -methoxy -7 -oxo -6 -( sulfooxy )- 1, The intermediate compound (1b ) was subjected for 6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 - carboxamide ; hydrogenolysis in presence of a suitable catalyst ( e . g . 5 % or Sodium salt of (2S ,5R ) - N -hydroxy -7 -oxo -6 -( sulfooxy )- 1, 10 % palladium on carbon , or 20 % palladium hydroxide on 6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 -carboxamide ; carbon ) in presence of hydrogen source (such as hydrogen Sodium salt of (2S ,5R ) - N - [ ( 1 -methyl - 1H -pyrazol - 5 - yl) 5 gas , ammonium formate , cyclohexene ) in a suitable solvent methyloxy ] - 7 -oxo -6 - ( sulfooxy ) - 1 , 6 -diazabicyclo [ 3 . 2 . 1 ] ( such as methanol, ethanol, methanol - dichloromethane mix octane - 2 - carboxamide ; ture, or N , N dimethyl formamide - dichloromethane mixture ) Sodium salt of (2S ,5R ) - N -hydroxy - N -methyl - 7 -oxo -6 - at a temperature ranging from 25° C . to 60° C . for about 1 ( sulfooxy ) - 1 ,6 - diazabicyclo [ 3 . 2 . 1 ]octane - 2 - carboxam - to 14 hours to obtain intermediate compound ( 1c) . ide ; 10 The intermediate compound ( 1c ) was sulfonated by react or a stereoisomer thereof. ing it with a sulfonating reagent ( such as sulfur trioxide In general , the compounds of the invention can be pre - pyridine complex , or sulfur trioxide - N , N - dimethyl forma pared according to the following procedures . A person of mide complex ) in a suitable solvent ( such as pyridine , skills in the art would appreciate that the described methods N , N -dimethyl formamide ) at a temperature ranging from can be varied or optimized further to provide the desired and 15 about 25° C . to 90° C . for about 1 to 24 hours to obtain related compounds. In the following procedures, all vari pyridine salt of sulfonic acid which when treated with ables are as defined above. tetrabutyl ammonium sulfate provided tetrabutylammonium As described in Scheme - 1 , trans- 6 -benzyloxy - 7 -oxo - 1 ,6 - salt of sulfonic acid as an intermediate compound ( 1d ) . diaza -bicyclo [ 3 . 2 . 1 ]octane - 2 -carboxylic acid ( la ) , which is Some compounds according to the invention were iso described PCT International Publication No. WO 2009/ 20 lated as zwitterions, by treating intermediate compound ( 1d ) 091856 , was reacted with corresponding substituted with trifluoroacetic acid , in a suitable solvent such as hydroxylamines in presence of a suitable coupling agent dichloromethane , chloroform , acetonitrile ) at a temperature such as EDC hydrochloride , or dicyclohexylcarbodiimide ranging from - 10° C . to 40° C . for about 1 to 14 hours , (DCC ) in a suitable solvent such as N , N dimethyl forma especially when R in intermediate compound ( 10 ) contained mide ; N , N dimethyl acetamide; 1, 4 dioxane; chloroform ; 25 tert -butoxycarbonyl protected amine function . dichloromethane ; or dichloroethane at a temperature ranging Some other compounds according to the invention were from - 15° C . to 60° C . for about 1 to 24 hours to obtain isolated as a sodium salt , by passing a solution of interme intermediate compound ( 1b ) . diate compound ( 1d ) through a column of sodium form of

Scheme - 1

HO R3

R2 N R3ONHR2 Hydrogenolysis Coupling agent OS in diesen la

WIN R3

R2 N Sulfonating agent tha OH then Bu4NHSO4

R3 11 R3 -z -Z R2 N Sodium salt formation OSO3NBU4 OSOR R = H or Na CF3COOH (when R2, R3 contain t- Boc- amino group ) US 9 ,732 , 081 B2 19 20 Amberlite 200C resin in mixture of tetrahydrofuran -water ceutically acceptable derivative thereof, and ( c ) at least one followed by evaporation of the solvent under vacuum . antibacterial agent or a pharmaceutically acceptable deriva The required substituted hydroxyl amines were prepared tive thereof. as shown in Scheme - 2 as described in Synthesis 682 - 4 In some other embodiments , there is provided a method ( 1976 ) and U . S . Pat. No. 5 , 120 ,849 ( 1992 ) 5 for preventing or treating bacterial infection in a subject , said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical com position comprising : ( a ) a compound of Formula ( I ) , or a stereoisomer or a pharmaceutically acceptable salt thereof, OH DEAD , TPP, RT 10 and ( b ) at least one beta - lactamase inhibitor selected from R3 + HO — N sulbactam , tazobactam , clavulanic acid , or a pharmaceuti cally acceptable derivative thereof. In some other embodiments , there is provided a method for preventing or treating a bacterial infection in a subject, 15 said infection being caused by bacteria producing one or H2N - NH2 more beta - lactamase enzymes , wherein the method com R3 ZONH2 prises administering to said subject a pharmaceutically R3 effective amount of a pharmaceutical composition compris ing : ( a ) a compound of Formula ( I) , or a stereoisomer or a 20 pharmaceutically acceptable salt thereof, and ( b ) at least one beta - lactamase inhibitor selected from sulbactam , tazo In some embodiments , there are provided pharmaceutical bactam , clavulanic acid , or a pharmaceutically acceptable compositions comprising a compound of Formula ( I ) , or a derivative thereof. stereoisomer or a pharmaceutically acceptable salt thereof. In some other embodiments , there is provided a method In some other embodiments , there is provided a method 25 for preventing or treating bacterial infection in a subject , for preventing or treating bacterial infection in a subject, said method comprising administering to said subject a said method comprising administering to said subject a pharmaceutically effective amount of a pharmaceutical com pharmaceutically effective amount of a compound of For- position comprising: ( a ) a compound of Formula (I ), or a mula ( I ) or a stereoisomer or a pharmaceutically acceptable stereoisomer or a pharmaceutically acceptable salt thereof, salt thereof. 30 and ( b ) at least one antibacterial agent or a pharmaceutically In some embodiments , there is provided a method for acceptable derivative thereof. preventing or treating a bacterial infection in a subject, said In some other embodiments , there is provided a method infection being caused by bacteria producing one or more for preventing or treating a bacterial infection in a subject , beta - lactamase enzymes , wherein the method comprises said infection being caused by bacteria producing one or administering to said subject a pharmaceutically effective 35 more beta -lactamase enzymes, wherein the method com amount of a compound of Formula ( I ) or a stereoisomer or prises administering to said subject a pharmaceutically a pharmaceutically acceptable salt thereof. effective amount of a pharmaceutical composition compris In some other embodiments, there is provided a method ing : ( a ) a compound of Formula ( I ) , or a stereoisomer or a for preventing or treating bacterial infection in a subject, pharmaceutically acceptable salt thereof, and ( b ) at least one said method comprising administering to said subject a 40 antibacterial agent or a pharmaceutically acceptable deriva pharmaceutically effective amount of a pharmaceutical com - tive thereof. position comprising a compound of Formula (I ) or a ste - In some other embodiments , there is provided a method reoisomer or a pharmaceutically acceptable salt thereof . for preventing or treating bacterial infection in a subject , In some other embodiments, there is provided a method said method comprising administering to said subject a for preventing or treating a bacterial infection in a subject, 45 pharmaceutically effective amount of a pharmaceutical com said infection being caused by bacteria producing one or position comprising : ( a ) a compound of Formula (I ) , or a more beta - lactamase enzymes, wherein the method com - stereoisomer or a pharmaceutically acceptable salt thereof, prises administering to said subject a pharmaceutically ( b ) at least one beta - lactamase inhibitor selected from sul effective amount of a pharmaceutical composition compris - bactam , tazobactam , clavulanic acid , or a pharmaceutically ing a compound of Formula ( I ) or a stereoisomer or a 50 acceptable derivative thereof, and ( c ) at least one antibac pharmaceutically acceptable salt thereof. terial agent or a pharmaceutically acceptable derivative In some embodiments , there are provided pharmaceutical thereof . compositions comprising : ( a ) a compound of Formula (I ) , or In some other embodiments , there is provided a method a stereoisomer or a pharmaceutically acceptable salt thereof, for preventing or treating a bacterial infection in a subject, and (b ) at least one beta- lactamase inhibitor selected from 55 said infection being caused by bacteria producing one or sulbactam , tazobactam , clavulanic acid , or a pharmaceuti- more beta -lactamase enzymes , wherein the method com cally acceptable derivative thereof . prises administering to said subject a pharmaceutically In some other embodiments , there are provided pharma - effective amount of a pharmaceutical composition compris ceutical compositions comprising : ( a ) a compound of For - ing : ( a ) a compound of Formula ( I ) , or a stereoisomer or a mula ( 1 ) , or a stereoisomer or a pharmaceutically acceptable 60 pharmaceutically acceptable salt thereof, ( b ) at least one salt thereof, and ( b ) at least one antibacterial agent or a beta - lactamase inhibitor selected from sulbactam , tazo pharmaceutically acceptable derivative thereof. bactam , clavulanic acid , or a pharmaceutically acceptable In some other embodiments , there are provided pharma - derivative thereof, and ( c ) at least one antibacterial agent or ceutical compositions comprising : ( a ) a compound of For- a pharmaceutically acceptable derivative thereof. mula ( I) , or a stereoisomer or a pharmaceutically acceptable 65 In some other embodiments , there is provided a method salt thereof, ( b ) at least one beta - lactamase inhibitor selected for preventing or treating bacterial infection in a subject, from sulbactam , tazobactam , clavulanic acid , or a pharma said method comprising administering to said subject a US 9 ,732 ,081 B2 22 pharmaceutically effective amount of: (a ) a compound of antibacterial compounds generally classified as aminogly Formula ( I ) , or a stereoisomer or a pharmaceutically accept cosides , Ansamycins , Carbacephems, Cephalosporins, able salt thereof, and (b ) at least one beta -lactamase inhibitor Cephamycins , Lincosamides , Lipopeptides , Macrolides, selected from sulbactam , tazobactam , clavulanic acid , or a Monobactams, Nitrofurans, Penicillins , Polypeptides , Qui pharmaceutically acceptable derivative thereof . 5 nolones, Sulfonamides, Tetracyclines, Oxazolidinone and In some other embodiments, there is provided a method the like . for preventing or treating a bacterial infection in a subject , Typical, non -limiting examples of Aminoglycoside anti said infection being caused by bacteria producing one or more beta - lactamase enzymes , wherein the method com bacterial agents include Amikacin , Gentamicin , Kanamycin , prises administering to said subject a pharmaceutically 10 Neomycin , Netilmicin , Tobramycin , Paromomycin , Arbeka effective amount of: (a ) a compound of Formula ( I) , or a cin , Streptomycin , Apramycin and the like . stereoisomer or a pharmaceutically acceptable salt thereof, Typical, non - limiting examples of Ansamycin antibacte and ( b ) at least one beta - lactamase inhibitor selected from rial agents include Geldanamycin , Herbimycin and the like . sulbactam , tazobactam , clavulanic acid , or a pharmaceuti Typical, non -limiting examples of Carbacephem antibac cally acceptable derivative thereof. 15 teriallial agents include Loracarbef and the like . In some other embodiments , there is provided a method Typical , non -limiting examples of Carbapenem antibac for preventing or treating bacterial infection in a subject, terial agents include Ertapenem , Doripenem , Imipenem , said method comprising administering to said subject a Meropenem and the like . pharmaceutically effective amount of: ( a ) a compound of Typical, non - limiting examples of Cephalosporin and Formula (1 ) , or a stereoisomer or a pharmaceutically accept- 20 Cephamycin antibacterial agents include Cefazolin , Ceface able salt thereof, and ( b ) at least one antibacterial agent or trile , Cefadroxil, Cefalexin , Cefaloglycin , Cefalonium , a pharmaceutically acceptable derivative thereof. Cefaloridine , Cefalotin , Cefapirin , Cefatrizine, Cefazedone , In some other embodiments , there is provided a method Cefazaflur, Cefradine , Cefroxadine , Ceftezole , Cefaclor, for preventing or treating a bacterial infection in a subject, Cefamandole , Cefminox , Cefonicid , Ceforanide, Cefotiam , said infection being caused by bacteria producing one or 25 Cefprozil , Cefbuperazone , Cefuroxime, Cefuzonam , more beta - lactamase enzymes, wherein the method com Cephamycin , Cefoxitin , Cefotetan , Cefmetazole , Carba prises administering to said subject a pharmaceutically cephem , Cefixime, Ceftazidime, Ceftriaxone , Cefcapene, effective amount of: ( a ) a compound of Formula ( I ) , or a stereoisomer or a pharmaceutically acceptable salt thereof, Cefdaloxime, Cefdinir , Cefditoren , Cefetamet, Cefmenox and (b ) at least one antibacterial agent or a pharmaceutically 30 imeCet , Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole , acceptable derivative thereof. cally 30 Cefpiramide , Cefpodoxime, Cefsulodin , Cefteram , Ceftib In some other embodiments , there is provided a method uten , Ceftiolene , Ceftizoxime, Oxacephem , Cefepime, for preventing or treating bacterial infection in a subject, Cefozopran , Cefpirome, Cefquinome, Ceftobiprole , Ceftio said method comprising administering to said subject a fur, Cefquinome, Cefovecin , CXA - 101, Ceftaroline, Cefto pharmaceutically effective amount of: (a ) a compound of 35 Formula (I ) , or a stereoisomer or a pharmaceutically accept Typical, non -limiting examples of Lincosamide antibac able salt thereof. ( b ) at least one beta - lactamase inhibitor terial agents include Clindamycin , Lincomycin and the like . selected from sulbactam , tazobactam , clavulanic acid , or a Typical, non - limiting examples ofMacrolide antibacterial pharmaceutically acceptable derivative thereof, and ( c ) at agents include Azithromycin , Clarithromycin , Dirithromy least one antibacterial agent or a pharmaceutically accept- 40 cin , Erythromycin , Roxithromycin , Troleandomycin , able derivative thereof. Telithromycin , Spectinomycin , Solithromycin and the like . In some other embodiments , there is provided a method Typical, non - limiting examples of Monobactam antibac for preventing or treating a bacterial infection in a subject , terial agents include Aztreonam and the like. said infection being caused by bacteria producing one or Typical, non - limiting examples of Nitrofuran antibacterial more beta - lactamase enzymes , wherein the method com - 45 agents include Furazolidone , Nitrofurantoin and the like . prises administering to said subject a pharmaceutically Typical, non - limiting examples of Penicillin antibacterial effective amount of: (a ) a compound of Formula ( 1 ) , or a agents include Amoxicillin , Ampicillin , Azlocillin , Carbeni stereoisomer or a pharmaceutically acceptable salt thereof, ( b ) at least one beta -lactamase inhibitor selected from sul Methicillin , Nafcillin , Oxacillin , Penicillin G , Penicillin V , bactam , tazobactam , clavulanic acid , or a pharmaceutically 50 Piperacillin , Temocillin , Ticarcillin and the like . acceptable derivative thereof, and ( c ) at least one antibac Typical, non - limiting examples of Polypeptide antibacte terial agent or a pharmaceutically acceptable derivative rial agents include Bacitracin , Colistin , Polymyxin B and the thereof. like . In some embodiments , there are provided methods for Typical, non - limiting examples of Quinolone antibacte increasing antibacterial effectiveness of a antibacterial agent 55 rial agents include Ciprofloxacin , Enoxacin , Gatifloxacin , in a subject , said method comprising co - administering said Levofloxacin , Lomefloxacin , Moxifloxacin , Nalidixic acid , antibacterial agent or a pharmaceutically acceptable deriva - Levonadifloxacin , Norfloxacin , Ofloxacin , Trovafloxacin , tive thereof with a pharmaceutically effective amount of a Grepafloxacin , Sparfloxacin , Temafloxacin and the like. compound of Formula ( I) or a stereoisomer or a pharma Typical, non - limiting examples of Sulfonamide antibac ceutically acceptable salt thereof. 60 terial agents include Mafenide, Sulfonamidochrysoidine, In some embodiments , the compositions and methods Sulfacetamide , Sulfadiazine, Sulfamethizole , Sulfamethox according to the invention use compounds of Formula ( I ) or a zole , Sulfasalazine, Sulfisoxazole , Trimethoprim and the a stereoisomer or a pharmaceutically acceptable salt thereof like . in combination with at least one antibacterial agent or a Typical, non - limiting examples of Tetracycline antibacte pharmaceutically acceptable derivative thereof. A wide vari - 65 rial agents include Demeclocycline, Doxycycline, Minocy ety of antibacterial agents can be used . Typical, non - limiting cline , Oxytetracycline , Tetracycline , Tigecycline and the examples of antibacterial agents include one or more of like . US 9 ,732 ,081 B2 23 24 Typical, non - limiting examples of Oxazolidinone antibac - to a subject. In some other embodiments , the active ingre terial agents include Tedizolid , Linezolid , Ranbezolid , Tor dients are administered separately . Since the invention con ezolid , Radezolid etc . templates that the active ingredients agents may be admin The pharmaceutical compositions according to the inven - istered separately , the invention further provides for tion may include one or more pharmaceutically acceptable 5 combining separate pharmaceutical compositions in kit carriers or excipients or the like , Typical, non - limiting form . The kit may comprise one or more separate pharma examples of such carriers or excipient include mannitol, ceutical compositions , each comprising one or more active lactose , starch , magnesium stearate, sodium saccharine, tal ingredients . Each of such separate compositions may be cum , cellulose , sodium crosscarmellose , glucose , gelatin , sucrose, magnesium carbonate , wetting agents , emulsifying 10 present in a separate container such as a bottle , vial , agents , solubilizing agents , pH buffering agents , lubricants , syringes , boxes, bags, and the like. Typically , the kit com stabilizing agents , binding agents etc . prises directions for the administration of the separate com The pharmaceutical compositions according to this inven ponents . The kit form is particularly advantageous when the tion can exist in various forms. In some embodiments , the separate components are preferably administered in different pharmaceutical composition is in the form of a powder or a 15 dosage forms ( e. g ., oral and parenteral ) or are administere solution . In some other embodiments , the pharmaceutical at different dosage intervals. When the active ingredients are compositions according to the invention are in the form of administered separately , they may be administered simulta a powder that can be reconstituted by addition of a compat neously or sequentially . ible reconstitution diluent prior to parenteral administration . The pharmaceutical composition or the active ingredients Non -limiting example of such a compatible reconstitution 20 according to the present invention may be formulated into a diluent includes water. variety of dosage forms. Typical , non - limiting examples of In some other embodiments , the pharmaceutical compo dosage forms include solid , semi- solid , liquid and aerosol sitions according to the invention are in the form of a frozen dosage forms; such as tablets , capsules , powders , solutions, composition that can be diluted with a compatible diluent suspensions , suppositories, aerosols , granules , emulsions , prior to parenteral administration . 25 syrups , elixirs and a like . In some other embodiments , the pharmaceutical compo - In general , the pharmaceutical compositions and method sitions according to the invention are in the form ready to disclosed herein are useful in preventing or treating bacterial use for parenteral administration . infections. Advantageously , the compositions and methods In the methods according to the invention , the pharma disclosed herein are also effective in preventing or treating ceutical composition and / or other pharmaceutically active 30 infections caused by bacteria that are considered to be less ingredients disclosed herein may be administered by any or not susceptible to one or more of known antibacterial appropriate method, which serves to deliver the composition agents or their known compositions . Some non - limiting or its constituents or the active ingredients to the desired site . examples of such bacteria known to have developed resis The method of administration can vary depending on vari - tance to various antibacterial agents include Acinetobacter , ous factors , such as for example , the components of the 35 E . coli, Pseudomonas aeruginosa , Staphylococcus aureus, pharmaceutical composition and nature of the active ingre - Enterobacter , Klebsiella , Citrobacter and a like . Other non dients , the site of the potential or actual infection , the limiting examples of infections that may be prevented or microorganism ( e . g . bacteria ) involved , severity of infec - treated using the compositions and / or methods of the inven tion , age and physical condition of the subject. Some non - tion include : skin and soft tissue infections , febrile neutro limiting examples of administering the composition to a 40 penia , urinary tract infection , intraabdominal infections , subject according to this invention include oral, intravenous, respiratory tract infections , pneumonia (nosocomial ) , bac topical, intrarespiratory , intraperitoneal, intramuscular , par - teremia meningitis , surgical, infections etc . enteral , sublingual, transdermal, intranasal , aerosol, Surprisingly , the compounds , compositions and methods intraocular, intratracheal, intrarectal, vaginal, gene gun , der - according to the invention are also effective in preventing or mal patch , eye drop , ear drop or mouthwash . 45 treating bacterial infections that are caused by bacteria The compositions according to the invention can be producing one or more beta - lactamase enzymes . The ability formulated into various dosage forms wherein the active of compositions and methods according to the present ingredients and / or excipients may be present either together invention to treat such resistant bacteria with typical beta ( e . g . as an admixture ) or as separate components . When the lactam antibiotics represents a significant improvement in various ingredients in the composition are formulated as a 50 the art . mixture , such composition can be delivered by administer - In general, the compounds of Formula ( I) or a stereoiso ing such a mixture . The composition or dosage form wherein mer or pharmaceutically acceptable salt thereof according to the ingredients do not come as a mixture , but come as invention are also useful in increasing antibacterial effec separate components , such composition / dosage form may be tiveness of a antibacterial agent in a subject. The antibac administered in several ways . In one possible way , the 55 terial effectiveness of one or more antibacterial agents may ingredients may be mixed in the desired proportions and the increased , for example , by co - administering said antibacte mixture is then administered as required . Alternatively , the rial agent or a pharmaceutically acceptable salt thereof with components or the ingredients (active or inert) may be a pharmaceutically effective amount of a compound of separately administered ( simultaneously or one after the Formula ( I ) or a stereoisomer or a pharmaceutically accept other ) in appropriate proportion so as to achieve the same or 60 able salt thereof according to the invention . equivalent therapeutic level or effect as would have been It will be readily apparent to one skilled in the art that achieved by administration of the equivalent mixture . varying substitutions and modifications may be made to the Similarly , in the methods according to the invention , the invention disclosed herein without departing from the scope active ingredients disclosed herein may be administered to a and spirit of the invention . For example , those skilled in the subject in several ways depending on the requirements . In 65 art will recognize that the invention may be practiced using some embodiments , the active ingredients are admixed in a variety of different compounds within the described appropriate amounts and then the admixture is administered generic descriptions. US 9, 732 ,081 B2 25 26 EXAMPLES -continued The following examples illustrate the embodiments of the ONH , invention that are presently best known. However, it is to be understood that the following are only exemplary or illus trative of the application of the principles of the present invention . Numerous modifications and alternative compo sitions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope 10 of the present invention . The appended claims are intended Step - 1 to cover such modifications and arrangements . Thus , while A solution of DEAD ( 17 .14 ml, 1 . 092 mol) in THF ( 366 the present invention has been described above with par- ml) was cooled to - 10° C . and to this was added slowly a ticularity , the following examples provide further detail in solution of TPP ( 22 .49 gm , 1 . 092 mmol) in THF ( 36 ml) . connection with what are presently deemed to be the most 15 After stirring for 45 minutes below - 10° C . , a solution of tert - butyl ( 2S ) - 2 - hydroxymethyl) pyrrolidine - 1 - carboxy practical and preferred embodiments of the invention . late (12 . 2 gm , 0 .606 mol) in THF (36 ml) was added and after stirring for 5 minutes a solution of N -Hydroxy phthal Example - 1 imide ( 9 . 88 gm , 0 .606 mol) in THF ( 122 ml) was added . The resulting mixture was allowed to warm to RT and stirring continued further. After 16 hours, the solvent was evapo ( 2S , 5R ) - 7 - oxo - N - [ (2S ) -pyrrolidin - 2 -ylmethyloxy ] - 6 rated under reduced pressure and the residue diluted with ( sulfooxy ) - 1 , 6 - diazabicyclo [ 3 . 2 . 1 ] octane- 2 -carbox ethyl acetate (250 ml) and the ethyl acetate layer washed amide with sat . aqueous sodium bicarbonate solution (1x122 ml) , water ( 1x122 ml) and Brine (1x61 ml) . The solvent was 25 evaporated under reduced pressure and the residue was purified by column chromatography , over silica gel . Elution with 12 % Acetone in hexane and the concentration of the combined fractions gave the product as pale yellow oil , 20 . 6 gm , in 98 % yield . 30 Analysis : Mass : 347. 3 (M + H ) for MW — 346 .39 and M . F C18H22N205 Step - II: OSO3H To a solution of the Phthalimide ( 4 gm , 0 . 115 mol) in 35 ethanol (60 ml) and was added hydrazine hydrate ( 0 .84 ml, 0 . 173 mol) at RT. After stirring for 1 hour the insolubles were separated by filtration . The filtrate was concentrated Preparation of Side Chain : tert- butyl under reduced pressure and the residue was diluted with (2S ) - 2 - [ (aminooxy )methyl ] pyrrolidine- 1 DCM (40 ml) . The DCM layer was washed with water (2x40 Carboxylate 40 ml) and brine ( 1x40 ml) . The solvent was evaporated under reduced pressure to obtain 2 . 4 gm residue. This was used as such for the next coupling reaction . Coupling Reaction

4545 Step - 1 : Preparation of ( 2S , 5R )- 2 -[ (6 -benzyloxy - 7 OH oxo - 1 ,6 - diaza -bicyclo [ 3 . 2 . 1 ] octane - 2 - carbonyl ) methyloxycarbamoyl ]- ( 2S ) -pyrrolidine - 1 - carboxylic Acid Tert - Butyl Ester

50

HO - N DEAD , TPP , RT NH2 + DITHF 55 H2N - NH2 EtOH HO EDC .HCI , HOBt, NMM , DMF, RT = 3OS OBn = US 9 , 732 ,081 B2 27 28 -continued - continued

OBn OSO3NBu4 10 A solution of the Benzyl compound (2 . 1 g ,mmol ) in 1 :1 To a clear solution of ( 2S , 5R ) -6 - ( benzyloxy ) - 7 - oxo - 1 ,6 mixture of DMF: DCM ( 5 ml) , was hydrogenated over 10 % diazabicyclo [ 3 . 2 . 1 ] octane - 2 - carboxylic acid ( 3 . 06 gm , 0 . 111 Pd / C ( 125 mg) over 1 atmosphere of Hydrogen balloon . mol ) in N , N -dimethyl formamide (24 ml) , was added HOBt After stirring for 4 hours the reaction mixture was filtered ( 1 . 49 gm , 0 . 111 mol) followed by EDC hydrochloride ( 3 .18 15 over celite . The filtrate was concentrated under reduced gm , 0 . 166 mol ) and NMM ( 3 .39 , 0 . 333 mol ) at about 25° C . pressure and the residue obtained was dissolved in fresh to 35º C . under stirring . The reaction mixture was stirred for DMF (2 .5 ml) and cooled to 10° C . SO3. DMF complex (193 15 minutes and a solution of 2 - Aminooxymethyl- ( S )- pyrro mg, 12 . 6 mmol) was added and the reaction mixture was lidine - 1 - carboxylic acid t -butyl ester ( 2 . 4 gm , 0 . 100 mol) 20 allowed to warm to RT. After stirring RM at RT for 1 . 5 dissolved in N , N -dimethyl formamide ( 15 ml) . The reaction 20 hours , TBAA (379 mg, 12 .6 mmol) in water ( 1 .25 ml) was mixture was stirred at a temperature between 25° C . to 35° added to the reaction mixture and stirring continued further C . for 16 hours and the resulting mixture was poured into for 2 hours . The volatiles were removed by high vacuum water ( 120 ml) and mixture extracted with Ethyl acetate distillation and the residue co - evaporated with xylene ( 2x25 ( 3x25 ml) . The ethyl acetate layer was washed with water 25 ml) to remove traces of DMF. The residue obtained was ( 1x100 ml) and brine (1x50 ml) . The solventwas evaporated diluted with water ( 20 ml) and extracted with DCM (3x20 under reduced pressure and the residue was purified by ml) . The combined DCM layer was washed with water column chromatography over silica gel . Elution with 10 % (2x20 ml) . The DCM layer was dried and the solvent acetone in hexane and concentration of the combined frac evaporated under reduced pressure . The crude residue was tions gave the product as a whitee solid , 22 . 11 gm , 6464 % yield . 3030 triturated with Diethyl ether (3x25 ml) to obtain the product Analysis : as a white solid , 610 mg, 82 % yield . Analysis : Mass : 475 .4 ( M + H ) for MW — 474 . 56 and M . F Mass: 463 . 4 ( M - H ) for MW — 705 . 96 and M . F C24H34N406 C33H63N50 , S . ' H NMR : Solvent (CDC12 ) : 10 . 16 ( s , 1H ) , 7 . 43 - 7 . 35 ( m , 35 H NMR : Solvent (CDC1 . ) : 10 . 2 ( s . 11 ) . 4 35 ( s. 11 ) . 5H ) , 5 . 06 - 4 .88 (dd , 2H ), 4 . 12 ( s , 1H ) , 3 .94 - 393 ( d , 2H ) , 3 .83 4 . 14 ( s , 1H ). 3 . 91 - 3 . 92 ( d . 21 ). 3 .74 ( m . 11 ) . 3 .36 - 3 . 27 ( m . ( unresolved s , 1H ) , 3 . 75 - 3 . 73 ( m , 1H ) , 3 . 37 - 3 .28 (dt , 2H ) , 10H ) , 2 . 96 - 2 .88 (dd , 2H ) , 2 .31 - 2 . 26 ( m , 2H ) , 2 . 19 - 1 . 98 ( m , 3. 02 -2 .86 (dd , 2H ), 2 .29 - 2. 25 ( m , 1H ) , 1. 99 -1 .82 (m , 5H ), 2H ) , 1 . 95 - 1 . 70 ( m , 4H ) , 1. 68 - 1 .62 (p , 8H ) , 1 .49 - 1 .40 ( m , 1 .75 - 1 .61 ( m , 2H ) , 1 .45 ( s , 9H ) . 17H ) , 1 . 02 - 0 . 98 ( t , 12H ) . 40 Step - 2 : Preparation of Tetrabutylammonium Salt of Step - 3: Preparation of (2S ,5R ) -7 - oxo -N -[ (2S ) -pyr (2S ,5R )- 2 - [ (6 -sulfooxy - 7 -oxo - 1 ,6 - diaza -bicyclo rolidin -2 -ylmethyloxy ]- 6 -( sulfooxy ) -1 ,6 -diazabicy [ 3. 2 .1 Joctane - 2 -carbonyl ) -methyloxycarbamoyl ] clo [ 3 . 2 . 1 ] octane- 2 - carboxamide (2S ) -pyrrolidine - 1 -carboxylic Acid Tert -Butyl Ester 45

TFA , 50 DCM , - 10° C . MINUTE H2 — Pd / C , DMF, DCM . OSO3NBU4 55 OS OBn NH 60 SOz•DMF, OSO20H DMF TBAA , Water To a cooled (- 10° C . ) solution of TBA compound (300 65 mg, 4 . 2 mmol) in DCM ( 2 . 5 ml) was added TFA ( 2 . 5 ml) . After stirring for 30 min . at - 10° C . the solvent was BB evaporated under reduced pressure . The residue obtained US 9 ,732 ,081 B2 29 30 was triturated with diethyl ether to obtain white solid . The Examples 40 to 45 (Table 2 ) were prepared using the solid was washed with diethyl ether (3x25 ml) , Acetonitrile procedure described as in Example - 1 and using correspond (2x25 ml) and DCM ( 2x25 ml) . And the residual solid dried ing R ,CHONH2 , in place of 2 - Aminooxymethyl- ( S ) -pyr under reduced pressure ( 4 mmHg ) , to obtain the product as a white solid 140 mg, 91 % yield . rolidine - 1 -carboxylic acid t -butyl ester. These compounds Analysis : 5 were isolated as Trifluoroacetic acid salts Mass: 363 . 2 ( M - H ) for MW — 364 . 37 and M . F C12H20N _ O _ S . TH NMR : Solvent (DMSO - D6 ) : 11. 73 ( s , 1H ), 8 .62 - 8 . 83 ( d , 2H ) , 3 . 88 - 4 .00 ( m , 3H ) , 3 . 74 - 3 .81 ( m , 2H ) , 3 . 19 ( t , 2H ) , R3- 2 . 94 - 3 . 04 ( dd , 2H ), 1 . 96 - 2 . 03 ( m , 2H ), 1 . 80 - 1 .92 ( m , 3H ), 1 .54 - 1 .73 ( m , 3H ) . Examples 2 to 39 ( Table 1 ) were prepared using the procedure described as in Example - 1 and using correspond ing R , CH ONH2, in place of 2 - Aminooxymethyl- ( S ) - pyr OSO3H rolidine- 1 - carboxylic acid t- butyl ester . These compounds 15 were isolated as zwitterions . Examples 46 to 50 ( Table 3 ) were prepared using the procedure described as in Example - 1 and using correspond ing R , CHONH2, in place of 2 - Aminooxymethyl- ( S ) -pyr R3 20 rolidine- 1 - carboxylic acid t -butyl ester . These compounds were isolated as sodium salts . Procedure : A solution of intermediate sulphate compound ( 1d ) was passed through a column of sodium form of Amberlite 200C OSOH 25 resin in mixture of tetrahydrofuran -water followed by evaporation of the solvent from the combined fractions under reduced pressure ( 4 mmHg) . TABLE 1 Ex am ple Mass (ES - 1 ) No. R1 R2 R3 1H - NMR ( DMSO - do )/ D20 , values as free acid (MF ) 1 . SOOH ( DMSO - do) : 8 11. 73 ( s , 1H ) , 8 .62 - 8 . 83 ( d , 2H ) , 363. 1 3 . 88 - 4 .00 ( m , 3H ) , 3 . 74 - 3 .81 ( m , 2H ) , ( C12H20N40 S ) 3 . 19 ( t, 2H ) , 2 .94 - 3 .04 ( dd , 2H ) , 1 . 96 - 2 .03 ( m , 2H ) , 1 .80 - 1 .92 ( m , 3H ) , 1 .54 - 1 . 73 (m , 3H ) .

2 . SO2OH (DMSO - do ) : 8 11. 72 (br s , 1H ) , 8 . 88 (br s , 1H ) , 363 . 1 ( M - 1 ) H 8 .60 (br s , 1H ) , 3 .88 - 4 .04 ( m , 3H ) , 3 .72 - 3 . 84 C12H20N40 , 5 (m , 2H ) , 2 . 96 - 3 .28 (m , 4H ) , 1 .52 - 2 . 10 ( s , 8H ) . H

3 . SO ,OH ( DMSO - do ): 8 11 .50 (br s , 1H ) , 8 .60 ( br s , 2H ) , 363 . 1 ( M - 1 ) 3 .98 - 4 .02 ( m , 1H ) , 3 . 68 - 3 .82 ( m , 3H ) , 3 .30 - 3 .40 C12H20N40 5 ( m , 1H ), 2 .96 - 3 . 26 ( m , 5H ) , 2 . 54 - 2 . 60 ( m , 1H ) , 1 .94 - 2 . 08 ( m , 2H ) , 1 . 84 - 1 .88 ( m , 1H ) , 1 .64 - 1 .78 ( s , 3H ) .

4 . SO ,OH ( DMSO - do ) : 8 11 . 50 (br s , 1H ), 8 .60 (br s , 2H ) , 363 . 1 ( M - 1 ) 3 .98 - 4 .02 ( m , 1H ) , 3 . 69 - 3 . 84 ( m , 3H ) , 2 . 96 - 3 .36C12H20N407S ( m , 6H ) , 2 .54 - 2 .60 ( m , 1H ) , 1 . 94 - 2 .08 ( m , 2H ) , ? 1 .82 - 1 . 90 ( m , 1H ) , 1 . 60 - 1 .72 ( s , 3H ).

5 . SO OH HO . 379 . 1 (C12H20N4O3S )

N US 9 ,732 , 081 B2 31 TABLE 1 -continued Ex am ple Mass (ES - 1 ) No . R1 R3 1H -NMR (DMSO -ds ) /D20 , d values as free acid (MF ) 6 . SO ,OH NC 388 . 1 ( C13H19N 0 - 8 )

NH 7. SO , OH 388 . 1 NC (C13H19N5075 )

8 . SO , OH H 388. 1 NCHINI (C13H19N50 ,S ) IZ

9. SO2OH H F (DMSO -do ) : 8 11 . 6 ( s , 1H ), 9 .75 ( d , 1H ) , [ES - ] 473. 9 8 . 91 - 9 . 21 (bs , 2H ), 4 . 40 - 4 . 46 ( q , 1H ) , [ES + ] 476 . 0 FH 4 .02 ( s , 2H ) , 3 . 86 (bs , 1H ) , (C14H20N50 SF3) 3 .52 - 3 . 79 ( d , 1H ) , 3 .47 - 3 .49 (t , 1H ) , 3 . 12 - 3 . 19 ( m , 2H ), 3 .02 - 3 . 052 ( d , 1H ) , 2 . 94 2 . 96 ( d , 1H ) , 2 . 38 - 2 .45 ( m , 1H ) 2 . 003 - 2 .054 ( m , 1H ) , 1 . 87 - 1 . 89 ( m , 1H ) , 1 . 58 - 1 . 74 ( m , 2H ) , 1 . 54 - 1 . 58 ( m , 2H ) . 10. SOOH (DMSO -do ) 8 : 10 . 9 (s , 1H ), 7 .65 (d , 3H ), 405. 15 4 . 23 ( s , 1H ), 4 .403 ( m , 2H ) , 3 .87 - 3 . 92 ( m , 2H ) , (C13H22N60 . 5 ) 3 .70 - 3 . 74 ( dd , 1H ) , 3 . 47 - 3 .50 ( m , 1H ) , ** * 1114 2 .91 - 3 .02 (dd , 2H ) , 1 .83 - 1 .89 ( m , 6H ) , 1 .65 - 1 .67 ( m , 2H ) . HN NH 11 . SO OH (DMSO - d6 ) : 12 .04 (bs , 1H ) , 8 .42 - 9 . 20 (bs , 2H ), [ES - ] 377. 0 , 4 .09 (bs , 1H ) , 4 .01 ( s , 1H ) , 3 . 83 ( m , 1H ), 3 .67 [ES + ] 379 . 0 ( m , 1H ) , 3 .21 ( m , 2H ) , 2 . 92 - 3 . 03 (m , 2H ) , (C13H22N40 S ) IZ 1 .69 - 2 . 050 ( m , 8H ) , 1 . 23 - 1 .24 ( d , 3H ) .

377 . 1 12. S02OH (C12H18N4088 ) NH 13 . SO OH H 350 . 1 (M + 1 ) 2 (C11H18N40 5 ) 14 . SO2OH H 350 . 1 ( M + 1 ) (C11H18N4075 ) IZ *1111111

15 . SO ,OH H (DMSO - do) d 11 . 37 ( s , 1H ) , 8 . 39 ( bs , 1H ) , [ES - ] 377. 2 8 . 1 (bs , 1H ) , 3 .98 ( s , 1H ) , 3 .67 - 3 .68 ( d , 2H ) , JES + ] 379 . 1 3 . 64 - 3 .69 ( d , 2H ) , 3 .24 - 3 . 27 ( d , 1H ) , (C13H23N40 - 8 ) 3 .07 - 3 . 12 ( m , 1H ), 2 .99 ( s , 2H ) , 2 . 8 - 2 . 89 ( m , 2H ), 1 . 85 - 1 . 96 ( m , 4H ) , 1 .65 - 1 .67 ( m , 2H ) , 1 . 55 ( m , 1H ) , 1 . 28 - 1 . 36 ( m , 2H ) . US 9 ,732 , 081 B2 33 34 TABLE 1- continued Ex am ple Mass ( ES - 1 ) No. R1 R2 R3 ' H -NMR (DMSO -do )/ D20 , d values as free acid (MF ) 16 . SO20H ( DMSO - do) : 8 11. 43 (s , 1H ) , 8 . 48 - 8 . 50 ( d , 1H ) , 378 . 40 8 . 24 - 8 . 27 ( d , 1H ), 3 .99 (s , 1H ), 3. 61 - 3 .73 (m , (C12H2N40 S ) 3H ), 3 . 34 - 3 .37 ( m , 2H ) , 3 . 16 - 3 .21 ( m , 2H ) , --- - 2 . 99 ( s , 2H ) , 2 .68 - 2 .77 ( m , 3H ) , 1 . 85 - 2 .00 ( m , 4H ) , 1 . 65 - 1 .79 ( m , 4H ) , 1 .53 - 1 . 58 ( m , 2H ) , 1 . 20 - 1 . 30 ( m , 2H ) .

17. SO , OH H - (DMSO -do ) : 8 11 .85 (br s , 1H ), 11 .77 (br s, 377. 2 ( M - 1 ) 1H ), ( C13H » N40- S ) - 8 .47 (br s , 1H ) , 4 . 00 - 4 .04 (m , 1H ) , 3 . 80 - 3 . 95 -- ( m , NH 3H ), 2 . 76 - 3 . 18 ( m , 4H ) , 1 . 98 - 2 .06 ( m , 1H ) , 1 . 84 - 1 .94 ( m , 1H ) , 1 .62 - 1 . 80 (m , 5H ) , 1 . 28 - 1 .60 ( m , 4H ) . 18 . SOOH (DMSO - do) : d 11 .78 ( s , 1H ) , 8 . 36 - 8 .60 ( m , 2H ), 377. 0 ( M – 1 ) 3 .76 - 4 . 06 ( m , 4H ) , 2 .70 - 3 .06 ( m , 4H ) , 1 .98 - 2 .04 (C13H2N , 0 . 5 ) ( m , 1H ), 1 .84 - 1 .92 ( m , 1H ) , 1 .62 - 1 . 80 ( m , 5H ) , -- 1 . 28 - 1 .60 ( m , 4H ) . NH

19 . SO , OH (DMSO -do ) : 8 11. 90 ( s, 1H ) , 8. 40 - 8 .60 ( m , 2H ) ,379 .0 ( M + 1 ) . -- 3 . 76 - 4 .06 ( m , 4H ), 2 .70 - 3 . 06 (m , 4H ) , 1 .98 - 2 . 04 (C13H22N40 , 5 ) (m , 2H ) , 1 . 84 - 1. 92 ( m , 1H ), 1. 62 - 1 .80 ( m , 5H ) , 1 . 28 - 1 .60 ( m , 4H ) . NH

20 . SO , OH ( DMSO - do) : 8 11 .78 ( s , 1H ) , 8 . 16 - 8 .60 ( m , 2H ) , 391 . 0 ( M – 1 ) 3 .98 - 4 .03 ( m , 3H ) , 3 .78 - 3 .80 ( d , 1H ) , 3 . 23 - 3 .28 (C14H24N40 S ) ( m , 4H ) , 2 . 85 - 3 . 06 ( m , 4H ) , 1 .94 - 2 .05 ( m , 2H ) , 1 . 57 - 1 . 87 ( m , 8H ) , 1 . 30 - 1 . 49 ( m , 3H ) , 1 . 15 - 1 . 24 ( m , 4H ) . NH

21 . SO ,OH 391. 2 ( M - 1 ) (C14H24N40 - S )

--- - NH

22 . SO OH (DMSO -do D20 exchange ) : d 11 . 5 ( M , 1H ) , 411. 3 ( M – 1 ) H 7 . 128 - 7 . 012 ( m , 2H ) , 6 .76 ( m , 2H ) , 4 .12 ( m , 413. 3 ( M + 1 ) 1H ) (C16H20N40 - 8 ) 3 .98 ( s , 1H ) , 3 .90 - 3 . 73 ( m , 3H ) , 3 . 14 - 3 . 08 ( dd , 2H ) , 2 . 99 ( d , 2H ) , 2 . 78 - 2 . 72 ( m , 1H ) 2 .00 aux 1 . 98 ( m , 1H ) , 1 .85 ( m , 1H ) , 1. 71- 1 .66 ( m , 2H ) . 23 . SO OH ( DMSO -do , D20 exchange ) : 8 6 . 96 -6 .99 (m , 425 . 2 ( M - 1 ) 2H ) , 427. 2 ( M + 1 ) 6 .68 -6 .73 ( m , 2H ) , 3 . 98 ( d , 1H ) , 3 . 90 ( dd , 1H ) (C17H22N4075 ) 3 .72 - 3 . 77 ( m , 2H ) , 3 .45 - 3 .55 (m , 1H ) , 3 .05 ( d , 1H ), 2 .91 (dd , 1H ), 2 .66 - 2 .71 ( m , 2H ) , ZH 1 . 97 - 2 .04 ( m , 1H ) , 1 .85 - 1 .88 ( m , 2H ) , 1 .65 - 1 . 71 ( m , 2H ) , 1 .53 - 1 .58 ( m , 1H ) .

24 . SO , OH --- (DMSO - da ) : S 11 . 91 ( s , 1H ) , 9 . 18 (br s , 425 . 0 ( M - 1 ) H 1H ) , 7 . 19 - 7 . 27 ( m , 4H ) , 4 . 33 ( dd , 2H ) , (C17H22N4075 ) -- 3 . 83 - 4 . 11 ( m , 4H ) , 2 .99 - 3 . 08 ( m , 2H ) , 2 .94 ( d , 1H ) , 2 .83 (dd , 1H ) , 2 .02 - 2 .05 ( m , NH 1H ), 1 . 86 - 1 . 90 ( m , 1H ) , 1 .65 - 1 .76 ( m , 2H ) . US 9 , 732, 081 B2 35 36 TABLE 1 -continued

Ex aml ple Mass ( ES - 1 ) No. R1 R2 R3 IH -NMR (DMSO -ds ) / D20 , 6 values as free acid (MF ) 25. SO, OH H ( DMSO - d : 8 11 .86 (brs , 1H ) , 9 . 90) (brs , 1H ) , 415 . 1 ( M - 1 ) 7 . 29 ( s , 1H ) , 4 .89 ( dd , 1H ) , 4 .46 (dd , 2H ) , 4 .12 417. 1 ( M + 1 ) ( dd , 1H ) , 4 .01 - 4 .05 ( m , 2H ), 3 .83 ( d , 1H ), (CHNO , S ) 3 . 75 ( s , 3H ) , 298 ( dd , 2H ) , 1 . 96 - 2 .06 ( m , 1H ) , 1 . 86 - 1 .99 ( m , 1H ) 1 .63 - 1 . 77 ( m , 2H ) .

-

26 . SOOH H ? 401 . 1 ( M - 1 ) --- ? ??N 403. 1 ( M + 1 ) (C13H1gN0zS )

H

27 . SO , OH 0H 404 . 2 ( M - 1 ) ) C13H1N40 ? S (

Lz

28 . SOOH (DMSO - d6 DO exchange ) 87.50 - 7 .52 ( m , 1H ) , 457. 2 ( M + 1 ) 7 . 33 - 7 .37 ( m , 1H ), 6 .91 - 6 .94 ( m , 2H ) , ) C12H2oN40 ? S ( ? 4 . 25 - 4 .31 ( m , 3H ), 4 .15 - 4 . 17 ( m , 1H ) 3 .97 - 4 .05 ( m , 2H ) , 3 . 05- 2 . 95 ( dd , 3H ) , 2 . 05 - 97 ( m , 2H ) , 1 . 82 - 1 .85 ( m , 3H ) , = 1 . 66 - 1 .62 ( m , 2H ) .

29 . SOOH H (DMSO - d , D , 0 exchange ) 87.41 ( d , 1H , 432. 1 ( M - 1 ) 4 .20 - 4 . 14 ( m , 3H ) , 4 . 02 - 3 . 99 ( m , 2H ), 434. 2 ( M + 1 ) 3 . 86 - 3 .82 ( dd , 1H ) 3 .75 - 3 . 74 ( m , 1H ) , ( CisH23NsOgS ) 3 .68 - 3 . 64 ( dd , 1H ), 3 . 21- 3. 02 ( m , 4H ) 2 . 93 - 2 . 90 ( d , 1H ) 2 . 24 - 2 . 19 ( m , 2H ) , 2 .00 - 1 . 68 ( m , 7H )

30 . SOOH H ????? DO( ) : $ 4 . 733 ( m , 1H ) , 4 .107 ( d , 1H ) , 350. 9 ( M + 1 ) 4 .001 ( d , 1H ) , 3 .516 - 3 .481 ( d , 1H ) , 3 .371 (4H , CuHgN40 , S ) ? ? m ) , 3 .240 - 3 . 210 ( d , 1H ) , 2 . 258 - 2 . 220 ( 1H , m ) , ?????? ?? 2 .130 -1936 (3H , m ) , 1 .897 - 1 . 712 (2H , m ) .

31. SO , OH H 350 . 9 ( M + 1 ) ????????IIIIIIII (CH18N40 , S )

H US 9 ,732 , 081 B2 37 38 TABLE 1 -continued

Ex am ple Mass ( ES - 1 ) No . R1 R2 R3 'H -NMR (DMSO -d6 ) / D20 , d values as free acid (MF ) 32 . SO OH 359. 9 ( M + 1 ) (C11H18N4075 )

H

33. SO OH (DMSO - d ) : 8 11 .62 ( s , 1H ) , 9 . 77 (bs , 1H ) , FES - 1 373 . 9 4 .802 - 4 . 83 ( q , 1H ) , 4 .68 ( s , 1H ) , 4 . 001 ( s , 1H ) , FES + ] 376 . 0 ** 1 * 11111full 3 .78 - 3 .79 ( d , 1H ) , 3 .56 - 3 . 59 ( d , 1H ) , (C12H17N50 S) 3 .12 - 3 . 16 ( m , 1H ) , 3 .07 ( s , 2H ) , 2 . 55 - 2 .61 ( m , 1H ) , 2 .43 - 2 .44 ( d , 1H ) , 2 .40 - 2 .41 ( d , 1H ) , 1 .97 - 1 . 99 ( m , 1H ) , NH 1 . 86 - 1 .975 ( m , 1H ) , 1 .66 - 1 .71 ( m , 2H ) .

34 . SO OH H [ES - ] 373. 9 [ES + ] 376 .0 (C12H17N , 0 S )

35 . SO , OH (DMSO - do ) : 8 11 . 38 ( s , 1H ) , 9 . 44 ( bs , 1H ) , [ES - ] 391. 8 8 .49 (bs , 1H ) , 7 . 90 ( s , 1H ) , 7 .70 ( s , 1H ) , 4 .63 [ES + ] 394 . 1 HN "1141111111111111 ( s , 1H ) , 4 . 20 ( s , 1H ) , 3 .99 ( s , 1H ), 3 .77 - 3 .78 ( d , (C12H19N502S ) 1H ) , 3 . 54 - 3 .57 ( d , 1H ) , 3 . 02- 3 . 14 ( m , 1H ) , 2 . 99 - 3 . 02 ( d , 1H ) , 2 . 92 - 2 .95 ( d , 1H ) , 2 . 55 - 2 .60 ( m , 1H ) , 2 . 10 - 2 . 11 ( d , 1H ) , NH 2 .05 - 2 . 067 ( m , 1H ) , 1 . 85 ( m , 1H ) , 1 .61 - 1 . 72 ( m , 1H ) , 1 .55 - 1 .61 ( m , 1H ).

36 . SO , OH ( DMSO - do) : d 11 . 8 (bs , 1H ) , 8 . 85 (bs , 1H ) , [ES + ] 336 . 9 8 .52 (bs , 1H ) , 4 .73 ( m , 1H ) , 4 . 17 ( m , 2H ) , (C10H16N4075 ) mi 4 .00 ( m , 3H ) , 3 . 79 ( d , 1H ) , 2 .91 - 3 .02 ( m , 2H ) , 2 .00 ( m , 1H ) , 1 . 86 ( m , 1H ) , 1 .64 - 1 .71 ( m , 2H ) .

37 . SO ,OH (DMSO - do) : 8 8 . 2 - 8 . 24 ( d , 2H ) , 4 .02 ( s , 1H ) , 392. 42 3 . 730 ( m , 1H ) , 3 . 561 ( s , 3H ) , 3 . 18 - 3 . 37 ( m , (C14H24N40 S ) 3H ) , 2 .72 - 2 .78 ( m , 3H ) , 2 . 48 - 2 .56 ( m , 2H ) , 1 . 95 - 1 . 96 ( m , 2H ) , 1 . 726 - 1 . 787 ( m , 3H ) , 1 . 55 mm 1 .59 ( m , 2H ) , 1 .07 - 1 .17 ( m , 2H ) .

38 . SO ,OH CHZ (DMSO - do) : 8 . 4 (bs , 1H ) , 8 .08 (bs , 1H ) , [ ES - ] 391. 3 4 . 31 (bs , 1H ) , 4 .01 ( s , 1H ) , 3 . 6 . 2 - 3 .72 ( m , [ ES + ] 393. 3 4H ) , 3 .44 - 3 . 48 ( m , 1H ) , 3 . 23 (bs , 3H ) , 2 . 97 ( d , (C14H24N40 , 5 ) wim 1H ) , 2 . 84 (bs , 2H ), 1 .76 - 1 .89 ( m , 6H ) , " 1 . 22 - 1 . 33 ( m , 2H ). 39 . SO ,OH (DMSO - do) : 8 8 .95 (bs , 1H ) , 8 . 38 (bs , 1H ) , [ES ] 377 . 3 , 4 . 33 ( m , 1H ) , 4 .03 ( m , 2H ) , 3 .65 - 3 . 90 ( m , [ES + ] 379 . 2 5H ) , 3 .00 - 3 . 24 ( m , 4H ) , 2 .03 - 2 .09 ( m , (C13H22N40 , 5 ) » xmin 1H ), 1 .73 - 1 .91 ( m , 5H ) , 1 . 26 - 1 .31 ( m , 2H ) . ( 13122 US 9 ,732 , 081 B2

39 TABLE 2 40 . SO OH CF3COOH (DMSO -do ) : 8 11. 64 (s , 1H ) , 7 .78 (bs , 3H ), 323. 1 4 .01 ( s, 1H ) , 3 .95 ( t, 2H ) , 3 .82 ( d , 1H ) , ( C ,H16N40 - 5 ) 2 .95 - 3 .02 ( m , 3H ) , 2 . 92 ( d , 1H ) , 1 .89 2 .04 ( m , 1H ) , 1 . 85 - 1 .88 ( m , 1H ), mi 1 .61 - 1 .75 ( m , 2H ). 41. SO2OH .CE , COOH (DMSO - do) : 8 8 . 18 ( t , 1H ) , 7 . 59 (bs , 5H ) , 365 . 1 3 .98 ( s, 1H ), 3 .81 ( t , 2H ) , 3 . 74 ( d , 1H ) , (C10H18N60 S ) HN NHA 3 .38 ( t, 2H ) , 2 . 99 - 3 . 02 ( d , 1H ) , 2 . 82 - 2 . 85 ( d , 1H ) , 2 . 05 - 2 . 08 ( dd , 1H ) , 1 . 84 - 1 . 86 ( m , 1H ) , my 1 . 56 - 1 .69 ( m , 2H ). 42. SO ,OH •CF3COOH (DMSO -d6 ) : 11 .63 (s , 1H ) , 7 . 72 (bs , 3H ) , 337 4. 00 (s , 1H ), 3. 88 (t , 2H ) , 3. 75 (d , 1H ), (C10H13N40 - 5 ) 2 .95 - 3 . 00 ( m , 4H ) , 1 .99 ( d , 1H ), mm 1 .78 - 1 .92 ( m , 3H ) , 1 .62 - 1 . 73 (m , 2H ) .

43. SO , OH •CF3COOH (DMSO -do ): 8 11 .79 (br , 1H ), ( M – H , 394 ( SO2H ) 7 .94 - 7 . 663 ( br, 5H ) , 4 .02 ( s , 1H ) , (C13H26N50 S•C202F3) H2N ,, , m 3 .94 ( m , 1H ) , 3 . 81 ( m , 1H ) , 3 .05 - 2 .95 ( dd , 2H ), 2 . 75 ( m , 2H ) , 2 . 06 - 1 . 88 (m , 2H ), 1 .68 (m , 2H ), 1. 50 (m , 4H ) , HIN 1 .35 ( m , 2H ) .

44. SO ,OH (DMSO - do) : 8 9 .00 (bs , 2H ) , 8 . 05 (bs , 3H ) , 378 . 2 H2N °CF3COOH 3 .98 -4 .07 (m , 3H ), 3. 80 - 3. 84 (t , 2H ), ( C12H2 N OGS ) 3 .45 - 3 .50 ( dd , 1H ), 3 . 15 - 3 . 20 ( m , 1H ) , 3 .03 3 . 06 ( d , 1H ) , 2 . 93 - 2 . 96 ( d , 1H ) , 2 .41 - 2 .47 ( m , 1H ) , 2 .01 - 2 . 05 ( m , 1H ) , 1 . 88 - 1 . 90 ( m , 1H ) , mi 1. 52 - 1. 75 (m , 6 H ). H H 45 . SO ,OH H •CF3COOH (DMSO - do) : 8 11 . 9 ( s , 1H ) , 9 .00 (bs , 2H ) , [ES - ] 378 . 2 , [ES + ] 3 .94 - 4 .02 ( s , 1H ) , 3 . 79- 3 . 80 ( m , 1H ) , 380. 1 for free 3 .44 - 3 .59 ( m , 4H ), 3 .03 - 3 . 16 ( m , 4H ) , amine 2 .99 ( s , 2H ) , 1 . 99 - 2 .03 ( m , 1H ) , C12H21N50 , S•C HO2F3 1 . 88 - 1 . 91 ( m , 1H ) , 1 .65 - 1 .75 ( m , 2H ) , mm 1 .53 - 1 . 55 ( m , 1H ) , 1 . 26 - 1 . 32 ( m , 1H ) .

46 . SO ,OH •CF3COOH CHZ ( DMSO - do ) : 8 8 . 2 - 9 . 6 (bs , 3H ) , C2H24N502S•C20 F3 4 .38 ( m , 1H ) , 4 .01 ( m , 2H ) , 3 .69 ( m , 4H ) , [ES - ] 392. 2 , [ES + ] 3 .33 - 3 .58 ( m , 4H ) , 2 . 92 - 3 . 31 ( m , 5H ) , 2 .70 - 394 . 3 ww 2 .91 ( m , 1H ) , 1 . 50 - 1 .95 ( m , 4H ).

TABLE 3 47. SOONa CH3 ( DMSO -do ): 8 4. 38 ( m , 1H ), 4 .15 - 4. 20 ( m , 2H ), 3 . 58 - 3. 78 [ES ] 308. 1 , [ES + ] je ( m , 4H ), 3 .15 - 3 .42 (m , 4H ) , 1 .83 - 2 .048 ( m , 4H ) 310 . 1 for free acid ( C2H14N30 S•Na ) 48. SOONa H (DMSO -do ) : 8 11. 39 (s , 1H ), 3. 97 (s , 1H ), 3. 66 (d , 1H ), 294 for free acid 3 . 57 ( s , 3H ), 2 .99 (dd , 2H ) , 1 . 95 - 1 . 97 (m , 1H ), 1 .79 - 1 . 88 ( m , C3H12N2O2S•Na 1H ) . 1 .62 - 1 . 72 ( m , 2H ) . 49 . SOONa H = (D20 ): d 4. 10 -4 . 22 (m , 2H ), 3. 52 - 3 .64 (m , 1H ), 3 .22 - 3 . 26 280 .01 ( M - 1 ) ( m , 1H ), 1. 70 -2 . 10 (s , 4H ). C - H11N30 S US 9 ,732 , 081 B2

TABLE 3 -continued 50 . SOONa H ( DMSO -do D20 exchange ) : d 7 .32 ( d , 1H ) , 6 .29 (d , 1H ) , 374. 2 (M – 1 ) 376 . 3 4 . 83 ( M + 1 ) ( s , 2H ), 3. 95 - 3 .91 (m , 4H ) 3. 76 - 3 .66 (m , 2H ) , 2. 98 - 2 .88 (dd , (C12H16N50 S•Na ) 2H ), 1 .95 - 1 .93 ( m , 1H ), 1 .82 ( m , 1H ), 1 .67 - 1 .62 ( m , 2H ) .

51. SO20Na CHZ H 294 for free acid C3H12N207S•Na

Biological Activity 15 The invention claimed is: 1 . A compound selected from the group consisting of: The biological activity of representative compounds according to the invention against various bacterial strains was investigated . In a typical study , overnight grown bac terial cultures were diluted appropriately and inoculated on 20 the agar media containing doubling dilutions of the test HO compounds . Observation for growth or no growth was performed after 16 - 20 hours of incubation at 35 + 2° C . in ambient air. The overall procedure was performed as per EZ Clinical and Laboratory Standards Institute (CLSI ) recom 25 N mendations ( Clinical and Laboratory Standards Institute (CLSI ) , Performance Standards for Antimicrobial Suscepti OSOzH ; bility Testing , 20th Informational Supplement, M 100 -S20 , Volume 30 , No . 1, 2010 ) . 30 Table 4 describes antibacterial activity of representative compounds according to the invention against various Multi Drug Resistant (MDR ) Gram -negative bacterial strains expressing various ESBLs. The activities are expressed as MICs (mcg /ml ) . For comparison , the activity of several 35 N known antibacterial agents ( for example , Ceftazidime , Aztreonam , Imipenem , Ciprofloxacin and Tigecycline ) are also included . As can be seen , the representative compounds OSO3H ; and according to the invention exhibit antibacterial activity against various MDR strains . stereoisomers and pharmaceutically acceptable salts thereof . TABLE 4 Comparative antibacterial activity of representative compounds according to the invention against various Multi Drug Resistant (MDR ) Gram negative strains ( expressed as MICs (mcg /ml ) . Class A ESBL Class C ESBL P . aeruginosa E . Coli E . Coli E . Coli E . Coli E . Coli Ps Ps Sr. Compound W 13353 W 13351 W 13352 M 50 H 483 21 32 > 32 1 . Ceftazidime 3232 32 > 3232 > 32 > ??32 > 32 > 32 2 . Aztreonam > 32 > 32 > 32 > 32 > 32 8 8 3 . Imipenem 0 . 25 0 . 25 0 .5 1 > 32 > 32 4 . Ciprofloxacin >32 0 . 12 > 32 > 32 32 0. 12 5 . Tigecyclin 0 . 5 0 . 5 16 16 6 . Example 1 0 . 5 00 . 5 > 32 > 32 > 32 7 . Example 2 > 32 > 32 > 32 8 . Example 3 8 > 32 >> 32 >> 3232 9 . Example 4 N >????? 32 > 32 10 . Example 17 0 . 5 1 1 0 . 5 > ??32N > 32 > 3232 ? 11. Example 18 0 .5 1 1 1 > 32N >> 32 > 32 12 . Example 19 4 8 16 8 > 32N > 32 >> 32 13 . Example 30 4 8 8 4 > 32N >> 32 > 32 + 14 . Example 33 4 4 > 32 4 > 32N >> 32 > 32 15 . Example 35 4 16 8 8 > 32N > 32 > 32 US 9 , 732 , 081 B2 43 44 2 . A compound which is consisting of ceftazidime , cefixime, cefpodoxime , ceftib uten , cefepime, cefpirome, ertapenem , and pharmaceutically acceptable salts thereof. HO 11. A pharmaceutical composition comprising : ( a ) the 5 compound according to any one of claims 1 to 3 ; (b ) at least one antibacterial agent or a pharmaceutically acceptable salt thereof; and ( c ) at least one beta - lactamase inhibitor selected NH from the group consisting of sulbactam , tazobactam , clavu lanic acid , and pharmaceutically acceptable salts thereof. OSO3H , 10 12 . The pharmaceutical composition according to claim 11 , wherein the antibacterial agent is selected from the group consisting of aminoglycosides , ansamycins , carbacephems, or a stereoisomer or pharmaceutically acceptable salt cephalosporins, cephamycins, lincosamides, lipopeptides, thereof. macrolides , monobactams , nitrofurans, penicillins, polypep 3 . A compound which is tides , quinolones, sulfonamides , tetracyclines, penems, car bapenems, and oxazolidinones. NC 13 . The pharmaceutical composition according to claim 11, wherein the antibacterial agent is a beta - lactam antibac 20 terial agent. N 14 . The pharmaceutical composition according to claim 11 , wherein the antibacterial agent is selected from the group consisting of cephalothin , cephaloridine , cefaclor, cefadroxil , cefamandole , cefazolin , cephalexin , cephradine , OSO3H , 25 ceftizoxime, cefoxitin , cephacetrile , cefotiam , cefotaxime, cefsulodin , cefoperazone , ceftizoxime, cefmenoxime, cef or a stereoisomer or pharmaceutically acceptable salt metazole , cephaloglycin , cefonicid , cefodizime, cefpirome, thereof. ceftazidime, ceifriaxone , cefpiramide , cefbuperazone , cefo 4 . A pharmaceutical composition comprising the com zopran , cefepime, cefoselis , cefluprenam , cefuzonam , cef pound according to any one of claims 1 to 3 . 30 pimizole , cefclidin , cefixime, ceftibuten , cefdinir , cefpodox 5 . A pharmaceutical composition comprising : ( a ) the ime axetil , cefpodoxime proxetil , cefterampivoxil , compound according to any one of claims 1 to 3 ; and (b ) at cefetametpivoxil , cefcapenepivoxil , cefditorenpivoxil , cefu least one beta - lactamase inhibitor selected from the group roxime, cefuroxime axetil , loracarbacef, ceftaroline , pipera consisting of sulbactam , tazobactam , clavulanic acid , and cillin , ertapenem , doripenem , meropenem , imipenem , pharmaceutically acceptable salts thereof . 35 ceftolozane , latamoxef, and pharmaceutically acceptable 6 . A pharmaceutical composition comprising: ( a ) the salts thereof. compound according to any one of claims 1 to 3 ; and ( b ) at 15 . The pharmaceutical composition according to claim least one antibacterial agent or a pharmaceutically accept- 11 , wherein the antibacterial agent is selected from a group able salt thereof. consisting of ceftazidime, cefixime, cefpodoxime, ceftib 7 . The pharmaceutical composition according to claim 6 , 40 uten , cefepime, cefpirome , ertapenem , and pharmaceutically wherein the antibacterial agent is selected from the group acceptable salts thereof. consisting of aminoglycosides , ansamycins , carbacephems, 16 . A method for treating bacterial infection , comprising cephalosporins , cephamycins, lincosamides , lipopeptides, administering to a subject in need thereof a pharmaceutically macrolides ,monobactams , nitrofurans, penicillins, polypep - effective amount of the compound according to any one of tides , quinolones , sulfonamides, tetracyclines , penems, car - 45 claims 1 to 3 . bapenems, and oxazolidinones . 17 . A method for treating bacterial infection , comprising 8 . The pharmaceutical composition according to claim 6 , administering to a subject in need thereof a pharmaceutically wherein the antibacterial agent is a beta -lactam antibacterial effective amount of the pharmaceutical composition accord agent. ing to claim 4 . 9 . The pharmaceutical composition according to claim 6 , 50 18 . A method for treating bacterial infection , comprising wherein the antibacterial agent is selected from the group administering to a subject in need thereof a pharmaceutically consisting of cephalothin , cephaloridine , cefaclor, effective amount of the pharmaceutical composition accord cefadroxil , cefamandole, cefazolin , cephalexin , cephradine , ing to claim 5 . ceftizoxime , cefoxitin , cephacetrile , cefotiam , cefotaxime, 19 . A method for treating bacterial infection , comprising cefsulodin , cefoperazone, ceftizoxime, cefmenoxime, cef- 55 administering to a subject in need thereof a pharmaceutically metazole , cephaloglycin , cefonicid , cefodizime, cefpirome , effective amount of the pharmaceutical composition accord ceftazidime , ceifriaxone , cefpiramide, cefbuperazone , cefo - ing to claim 6 . zopran , cefepime, cefoselis , cefluprenam , cefuzonam , cef - 20 . A method for treating bacterial infection , comprising pimizole , cefclidin , cefixime, ceftibuten , cefdinir , cefpodox - administering to a subject in need thereof a pharmaceutically ime axetil , cefpodoxime proxetil, cefterampivoxil, 60 effective amount of the pharmaceutical composition accord cefetametpivoxil, cefcapenepivoxil , cefditorenpivoxil , cefu - ing to claim 11 . roxime, cefuroxime axetil , loracarbacef, ceftaroline, pipera - 21 . A method for treating bacterial infection , comprising cillin , ertapenem , doripenem , meropenem , imipenem , administering to a subject in need thereof pharmaceutically ceftolozane , latamoxef, and pharmaceutically acceptable effective amounts of: ( a ) the compound according to any one salts thereof. 65 of claims 1 to 3 ; and (b ) at least one beta - lactamase inhibitor 10 . The pharmaceutical composition according to claim 6 , selected from sulbactam , tazobactam , clavulanic acid , and wherein the antibacterial agent is selected from a group pharmaceutically acceptable salts thereof. US 9 ,732 ,081 B2 45 46 22 . A method for treating bacterial infection , comprising tides, quinolones, sulfonamides, tetracyclines, penems, car administering to a subject in need thereof pharmaceutically bapenems, and oxazolidi effective amounts of: ( a ) the compound according to any one 30 . The method according to claim 23 , wherein the of claims 1 to 3 ; and ( b ) at least one antibacterial agent or antibacterial agent is a beta - lactam antibacterial agent. a pharmaceutically acceptable salt thereof. 5 31 . The method according to claim 23 , wherein the antibacterial agent is selected from the group consisting of 23. A method for treating bacterial infection , comprising cephalothin , cephaloridine , cefaclor, cefadroxil, cefaman administering to a subject in need thereof pharmaceutically dole , cefazolin , cephalexin , cephradine, ceftizoxime, cefoxi effective amounts of: ( a ) the compound according to any one tin , cephacetrile , cefotiam , cefotaxime, cefsulodin , cefop of claims 1 to 3 ; ( b ) at least one beta - lactamase inhibitor erazone, ceftizoxime, cefmenoxime, cefmetazole , selected from sulbactam , tazobactam , clavulanic acid , and "0 cephaloglycin , cefonicid , cefodizime, cefpirome, ceftazi pharmaceutically acceptable salts thereof; and ( c ) at least dime, ceifriaxone , cefpiramide , cefbuperazone , cefozopran , one antibacterial agent or a pharmaceutically acceptable salt cefepime, cefoselis , cefluprenam , cefuzonam , cefpimizole , thereof . cefclidin , cefixime, ceftibuten , cefdinir , cefpodoxime axetil , 24 . A method for increasing antibacterial effectiveness of 1 cefpodoxime proxetil , cefterampivoxil , cefetametpivoxil , an antibacterial agent, comprising co - administering to a 15 cefcapenepivoxil or cefditorenpivoxil, cefuroxime, cefurox subject in need thereof said antibacterial agent or a phar ime axetil, loracarbacef , ceftaroline, piperacillin , ertapenem , maceutically acceptable salt thereof with a pharmaceutically 10doripenem ,meropenem , imipenem , ceftolozane, latamoxef , effective amount of the compound according to any one of and pharmaceutically acceptable salts thereof. claims 1 to 3 . 32 . The method according to claim 23, wherein the 25 . The method according to claim 22 , wherein the 20 antibacterial agent is selected from the group consisting of antibacterial agent is selected from the group consisting of ceftazidime, cefixime, cefpodoxime, ceftibuten , cefepime, aminoglycosides , ansamycins , carbacephems, cepha cefpirome, ertapenem , and pharmaceutically acceptable losporins , cephamycins, lincosamides, lipopeptides, salts thereof. macrolides, monobactams, nitrofurans , penicillins , polypep - 35 33 . The method according to claim 24 , wherein the tides , quinolones , sulfonamides , tetracyclines , penems, car 25 antibacterial agent is selected from the group consisting of bapenems, and oxazolidinones . aminoglycosides , ansamycins, carbacephems, cepha 26 . The method according to claim 22 , wherein the losporins, cephamycins, lincosamides, lipopeptides, antibacterial agent is a beta - lactam antibacterial agent. macrolides, monobactams, nitrofurans , penicillins, polypep 27. The method according to claim 22 , wherein the 30 tides , quinolones, sulfonamides, tetracyclines , penems, car antibacterial agent is selected from the group consisting of 30 bapenems, and oxazolidinones. cephalothin , cephaloridine , cefaclor, cefadroxil , cefaman 34 . The method according to claim 24 , wherein the dole , cefazolin , cephalexin , cephradine , ceftizoxime , cefoxi antibacterial agent is a beta - lactam antibacterial agent. tin , cephacetrile , cefotiam , cefotaxime, cefsulodin , cefop 35 . The method according to claim 24 , wherein the erazone , ceftizoxime, cefmenoxime, cefmetazole , 3 antibacterial agent is selected from the group consisting of cephaloglycin , cefonicid , cefodizime, cefpirome, ceftazi cephalothin , cephaloridine, cefaclor, cefadroxil, cefaman dime, ceifriaxone , cefpiramide, cefbuperazone, cefozopran , dole , cefazolin , cephalexin , cephradine , ceftizoxime , cefoxi cefepime, cefoselis , cefluprenam , cefuzonam , cefpimizole , tin , cephacetrile , cefotiam , cefotaxime, cefsulodin , cefop cefclidin , cefixime, ceftibuten , cefdinir , cefpodoxime axetil, erazone , ceftizoxime, cefmenoxime, cefmetazole , cefpodoxime proxetil, cefterampivoxil, cefetametpivoxil, 10 cephaloglycin , cefonicid , cefodizime, cefpirome, ceftazi cefcapenepivoxil or cefditorenpivoxil , cefuroxime, cefurox dime, ceifriaxone, cefpiramide, cefbuperazone , cefozopran , ime axetil , loracarbacef, ceftaroline , piperacillin , ertapenem , cefepime, cefoselis , cefluprenam , cefuzonam , cefpimizole , doripenem , meropenem , imipenem , ceftolozane , latamoxef, cefclidin , cefixime, ceftibuten , cefdinir , cefpodoxime axetil , and pharmaceutically acceptable salts thereof. cefpodoxime proxetil , cefterampivoxil, cefetametpivoxil , 28 . The method according to claim 22 , wherein the 45 cefcapenepivoxil or cefditorenpivoxil , cefuroxime, cefurox antibacterial agent is selected from the group consisting of ime axetil, loracarbacef , ceftaroline, piperacillin , ertapenem , ceftazidime , cefixime, cefpodoxime, ceftibuten , cefepime, doripenem , meropenem , imipenem , ceftolozane , latamoxef, cefpirome, ertapenem , and pharmaceutically acceptable and pharmaceutically acceptable salts thereof. salts thereof. 36 . The method according to claim 24 , wherein the 29 . The method according to claim 23 , wherein the 50 antibacterial agent is selected from the group consisting of antibacterial agent is selected from the group consisting of 50 ceftazidime, cefixime, cefpodoxime, ceftibuten , cefepime, aminoglycosides , ansamycins, carbacephems, cepha cefpirome, ertapenem , and pharmaceutically acceptable losporins, cephamycins, lincosamides , lipopeptides , salts thereof. macrolides, monobactams, nitrofurans , penicillins, polypep * * * * *