WO2013110643A1 - Amidine substituted beta - lactam compounds, their preparation and use as antibacterial agents - Google Patents

Amidine substituted beta - lactam compounds, their preparation and use as antibacterial agents Download PDF

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Publication number
WO2013110643A1
WO2013110643A1 PCT/EP2013/051217 EP2013051217W WO2013110643A1 WO 2013110643 A1 WO2013110643 A1 WO 2013110643A1 EP 2013051217 W EP2013051217 W EP 2013051217W WO 2013110643 A1 WO2013110643 A1 WO 2013110643A1
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Prior art keywords
amino
thiazol
imino
ethoxy
methyl
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PCT/EP2013/051217
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French (fr)
Inventor
Burkhard Klenke
Irith WIEGAND
Guido Schiffer
Heike Broetz-Oesterhelt
Samarendra N. Maiti
Jehangir Khan
Andhe REDDY
Zhixiang Yang
Mostafa HENA
Guofeng Jia
Ou LIGONG
Hong Liang
Judy Yip
Chuanjun Gao
Sabiha TAJAMMUL
Rahim Mohammad
Ganguli BISWAJEET
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Aicuris Gmbh & Co. Kg
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Publication date
Priority to CA2862338A priority Critical patent/CA2862338C/en
Priority to MX2014008915A priority patent/MX346602B/en
Priority to SI201330299A priority patent/SI2806873T1/en
Priority to LTEP13701246.4T priority patent/LT2806873T/en
Priority to EP13701246.4A priority patent/EP2806873B1/en
Priority to CUP2014000090A priority patent/CU24273B1/en
Priority to AP2014007880A priority patent/AP2014007880A0/en
Priority to BR112014017968A priority patent/BR112014017968A8/en
Priority to ES13701246.4T priority patent/ES2592403T3/en
Priority to NZ626951A priority patent/NZ626951A/en
Priority to EA201400838A priority patent/EA027126B1/en
Priority to DK13701246.4T priority patent/DK2806873T3/en
Priority to MYPI2014002088A priority patent/MY173843A/en
Priority to MEP-2016-191A priority patent/ME02532B/en
Priority to UAA201409319A priority patent/UA110880C2/en
Priority to AU2013211575A priority patent/AU2013211575B2/en
Application filed by Aicuris Gmbh & Co. Kg filed Critical Aicuris Gmbh & Co. Kg
Priority to CN201380016121.9A priority patent/CN104203237A/en
Priority to IN1640MUN2014 priority patent/IN2014MN01640A/en
Priority to RS20160764A priority patent/RS55210B1/en
Priority to US14/374,325 priority patent/US9556165B2/en
Priority to JP2014553696A priority patent/JP5869701B2/en
Priority to SG11201403930XA priority patent/SG11201403930XA/en
Priority to KR1020147020410A priority patent/KR102036393B1/en
Publication of WO2013110643A1 publication Critical patent/WO2013110643A1/en
Priority to TNP2014000297A priority patent/TN2014000297A1/en
Priority to ZA2014/05057A priority patent/ZA201405057B/en
Priority to PH12014501671A priority patent/PH12014501671B1/en
Priority to IL233805A priority patent/IL233805A/en
Priority to MA37280A priority patent/MA35905B1/en
Priority to HK15104018.3A priority patent/HK1203389A1/en
Priority to CY20161100851T priority patent/CY1117955T1/en
Priority to HRP20161171TT priority patent/HRP20161171T1/en
Priority to SM201600354T priority patent/SMT201600354B/en
Priority to US15/382,986 priority patent/US9782390B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to novel 3-lactam compounds, their preparation and use.
  • this invention relates to novel ⁇ -lactam compounds which are amidine substituted monobactam derivatives useful as antimicrobial agents and their preparation.
  • the present invention relates to compounds of formula (I)
  • R 1 and R 2 independently of one another represent hydrogen, aminocarbonyl or (Ci-C 4 )-alkyl, or
  • R 1 and R 2 together with the carbon atom to which they are bonded form a (C 3 - C 8 )-cycloalkyl
  • R 3 represents -(CH 2 ) m -(S0 2 )OH or -0-(CH 2 ) 0 -(S0 2 )OH, wherein m and o independently of one another represent an integer 0, 1, 2 or 3, and wherein any CH 2 -group contained in the residues which R 3 represents may be substituted with one or two (Ci-C 4 )-alkyl-residues,
  • X represents CR 4 or N
  • R 4 represents hydrogen or halogen
  • Z represents a bond or an alkyl-chain having one, two, three or four carbon atoms, whereby the alkyl-chain may be substituted with one, two, three or four substituents, selected independently of one another from the group consisting of carboxy, aminocarbonyl and (Ci-C 4 )-alkyl, whereby alkyl in turn may be substituted with a substituent selected from the group consisting of hydroxy, carboxy and aminocarbonyl,
  • Y represents a bond, O, NH or S, represents (C6-Cio)-aryl or 5- to 10-membered heteroaryl, whereby aryl and heteroaryl are substituted with a substituent of the following formula
  • R lb , R 2b and R 3b independently of one another represent hydrogen, amino, hydroxy, (Ci-C 4 )-alkyl, (0-C 4 )-alkoxy, (C3-C 6 )- cycloalkyl, 4-, 5-, 6- or 7-membered heterocyclyl or 5- or 6- membered heteroaryl, whereby amino and hydroxy may be substituted with one or two substituents selected independently of one another from the group consisting of carbonyl, (G-C 4 )- alkylcarbonyl, mono- or di-(Ci-C4)-alkylaminocarbonyl, and (Ci-G -alkyl, whereby alkoxy, heterocyclyl and heteroaryl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, (G-C 4 )- alkylcarbonyl, (G-C 4 )-alkoxy, mono-
  • R 2b and R 3b together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle including one, two or three further heteroatoms selected from the series N, O and S and R lb is as defined above,
  • R S represents hydrogen or (G-C 4 )-alkyl
  • Q represents a bond, CH 2 or NH, k represents an integer 1 or 2, and
  • aryl and heteroaryl further may be substituted with one or two substituents selected independently of one another from the group consisting of halogen, cyano, amino, hydroxy, (G-C 4 )-alkyl, (G-C 4 )- alkoxy, mono- or di-(Ci-C 4 )-alkylamino, amino-(Ci-C 4 )-alkyl, hydroxy- (Ci-C4)-alkyl or carboxy, whereby alkyl, alkoxy, alkylamino, aminoalkyl, hydroxyalkyl and carboxy in turn may be substituted with a substituent selected from the group consisting of halogen, (Ci-C 4 )-alkyl and carbonyl, and
  • 1 represents an integer 0, 1, 2 or 3, and the salts thereof, the solvates thereof and the solvates of the salts thereof.
  • Compounds of the invention are the compounds of formula (I) and the salts, solvates and solvates of the salts thereof, as well as the compounds which are encompassed by formula (I) and are mentioned hereinafter as exemplary embodiments), and the salts, solvates and solvates of the salts thereof, insofar as the compounds encompassed by formula (I) and mentioned hereinafter are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore also encompasses the enantiomers or diastereomers and respective mixtures thereof.
  • the stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers.
  • the compounds of the invention may occur in tautomeric forms, the present invention encompasses all tautomeric forms.
  • Salts preferred for the purposes of the present invention are physiologically acceptable salts of the compounds of the invention. Also encompassed however are salts which are themselves not suitable for pharmaceutical applications but can be used for example for the isolation or purification of the compounds of the invention.
  • Examples of pharmaceutically acceptable salts of the compounds of formula (I) include salts of inorganic bases like ammonium salts, alkali metal salts, in particular sodium or potassium salts, alkaline earth metal salts, in particular magnesium or calcium salts; salts of organic bases, in particular salts derived from cyclohex- ylamine, benzylamine, octylamine, ethanolamine, diethanolamine, diethylamine, triethylamine, ethylenediamine, procaine, morpholine, pyrroline, piperidine, N- ethylpiperidine, N-methylmorpholine, piperazine as the organic base; or salts with basic amino acids, in particular lysine, arginine, ornithine and histidine.
  • inorganic bases like ammonium salts, alkali metal salts, in particular sodium or potassium salts, alkaline earth metal salts, in particular magnesium or calcium salts
  • salts of organic bases in particular salts
  • Examples of pharmaceutically acceptable salts of the compounds of formula (I) also include salts of inorganic acids like hydrochlorides, hydrobromides, sulfates, phosphates or phosphonates; salts of organic acids, in particular acetates, formates, propionates, lactates, citrates, fumarates, maleates, benzoates, tartrates, malates, methanesulfonates, ethanesulfonates, toluenesulfonates or benzenesulf- onates; or salts with acidic amino acids, in particular aspartate or glutamate.
  • inorganic acids like hydrochlorides, hydrobromides, sulfates, phosphates or phosphonates
  • salts of organic acids in particular acetates, formates, propionates, lactates, citrates, fumarates, maleates, benzoates, tartrates, malates, methanesulfonates, ethanes
  • Solvates for the purposes of the invention refer to those forms of the compounds of the invention which in the solid or liquid state form a complex by coordination with solvent molecules. Hydrates are a specific form of solvates in which the coordination takes place with water.
  • alkyl refers to branched or straight-chain (Ci-C 6 )-alkyl, preferably (G-C 4 )-alkyl, such as in particular methyl, ethyl, propyl, butyl, isopropyl, isobutyl and tert.-butyl.
  • alkylamino refers to an alkyl substituent linked via an amino group.
  • alkylcarbonyl refers to an alkyl substituent linked via a carbonyl group.
  • alkylaminocarbonyl refers to an alkylamino substituent linked via a carbonyl group.
  • cycloalkyl refers to aliphatic C3-C8, preferably C3-C6, rings such as in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkoxy refers to branched or straight-chain (Ci-C 6 )-alkoxy, preferably (Ci-C 4 )-alkoxy, such as in particular methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy and tert.-butoxy.
  • alkoxycarbonyl refers to an alkoxy substituent linked via a carbonyl group.
  • heteroaryl refers to cyclic heteroaromatic groups with 5-10 ring atoms, preferably with 5-6 ring atoms, and with up to 4, preferably with up to 2, heteroatoms selected from the group consisting of N, O, S, in which N can also form an N-oxide.
  • Many other suitable heteroaryl groups for the purpose of the invention are known to the person skilled in the art or can be readily found in the literature.
  • heterocyclyl refers to saturated or partially unsaturated heterocyclic groups with 4-10 ring atoms, preferably with 5-6 ring atoms, and with up to 3, preferably with up to 2, heteroatoms selected from the group consisting of N, O, S, SO and S0 2 , in which N can also form an N-oxide.
  • Many other suitable heterocyclyl groups for the purpose of the invention are known to the person skilled in the art or can be readily found in the literature.
  • halogen refers to fluorine, chlorine, bromine or iodine; preferably fluorine or chlorine.
  • aminocarbonyl refers to an amino group linked via a car- bonyl group.
  • carbonylamino refers to a carbonyl group linked via an amino group.
  • carboxy refers to a carboxylic acid group, i.e. a -COOH group.
  • carbonyloxy refers to a carbonyl group linked via an oxygen.
  • the present invention also relates to compounds of formula (I) in which
  • R 1 and R 2 independently of one another represent hydrogen or (G-C 4 )-alkyl, or
  • R 1 and R z together with the carbon atom to which they are bonded form a (C 3 - C 8 )-cycloalkyl
  • R 3 represents -(CH 2 ) m -(S0 2 )OH or -0-(CH 2 )o-(S0 2 )OH, wherein m and o independently of one another represent an integer 0, or 1 and wherein any CH2-group contained in the residues which R 3 represents may be substituted with one or two (G-C4)-alkyl-residues, represents CR 4 or N, represents hydrogen or halogen, represents a bond or an alkyl-chain having one, two or three carbon atoms, whereby the alkyl-chain may be substituted with one, two or three sub- stituents, selected independently of one another from the group consisting of carboxy, aminocarbonyl and (Ci-C 4 )-alkyl, whereby alkyl in turn may be substituted with a substituent selected from the group consisting of hydroxy and carboxy, represents a bond, O, NH or S, represents (C 6 -Cio)-aryl or 5- to 10-membered
  • R 2b and R 3 together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle including one, two or three further heteroatoms selected from the series N, O and S and R lb is as defined above,
  • R 5b represents hydrogen or (G-C 4 )-alkyl
  • Q represents a bond, CH2 or NH
  • k represents an integer 1 or 2
  • aryl and heteroaryl further may be substituted with one or two substituents selected independently of one another from the group consisting of halogen, cyano, amino, hydroxy, (Ci-C 4 )-alkyl, (G-C 4 )- alkoxy, mono- or di-(Ci-C 4 )-alkylamino, amino-(Ci-C 4 )-alkyl, hydroxy- (Ci-C 4 )-alkyl or carboxy, whereby alkyl, alkoxy, alkylamino, aminoalkyl, hydroxyalkyl and carboxy in turn may be substituted with a substituent selected from the group consisting of halogen, (G-C 4 )-alkyl and carbonyl, and represents an integer 0 or 1 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
  • the present invention also relates to compounds of formula (I) in which
  • R 1 and R 2 independently of one another represent hydrogen or (G-C 4 )-alkyl, or
  • R 1 and R z together with the carbon atom to which they are bonded form a (C3- C 8 )-cycloalkyl
  • R 3 represents -(S0 2 )OH or -0-(CH 2 ) 0 -(S0 2 )OH, wherein o is an integer 0 or 1, and wherein any CH2-group contained in the residues which R 3 represents may be substituted with one or two (G-C 4 )-alkyl-residues,
  • X represents CH
  • Z represents an alkyl-chain having two or three carbon atoms, whereby the alkyl-chain may be substituted with one or two substitu- ents selected independently of one another from the group consisting of carboxy, aminocarbonyl, methyl, hydroxymethyl, hydroxyethyl, represents O represents phenyl or 5- or 6-membered heteroaryl, whereby phenyl and heteroaryl are substituted with a substituent of the following formula
  • R 2b and R 3 together with the nitrogen atom to which they are bonded form a 6-membered heterocycle including one or two nitrogen atoms and R lb is hydrogen,
  • R 4b represents hydrogen or amino, whereby amino may be substituted with one or two (Ci-C 4 )-alkyl substituents,
  • R 5b represents hydrogen
  • Q represents a bond
  • k represents an integer 1 or 2
  • * is the linkage site to the residue represented by A, and whereby phenyl und heteroaryl further may be substituted with one or two substituents selected independently of one another from the group consisting of halogen, cyano, amino, hydroxy, (Ci-C 4 )-alkyl or hydroxy-(G-C 4 )-alkyl, whereby hydroxyalkyl in turn may be susbstituted with a carbonyl sub- stituent, and represents 0 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
  • the present invention also relates to compounds of formula (I) in which independently of one another represent hydrogen or methyl, represents -(S0 2 )OH or -0-(S0 2 )OH, represents CH, represents an alkyl-chain having two or three carbon atoms, whereby the alkyl-chain may be substituted with one or two substitu- ents, selected independently of one another from the group consisting of carboxy and methyl, represents O, represents phenyl or 6-membered heteroaryl, whereby phenyl and heteroaryl are substituted with a substituent of the following formula
  • R l and R 2b represent hydrogen
  • * is the linkage site to the residue represented by A, and whereby aryl and heteroaryl further may be substituted with one sub- stituent selected from the group consisting of halogen, cyano, amino, hydroxy, (Ci-C 4 )-alkyl or hydroxy-(CrC4)-alkyl
  • the present invention also relates to compounds of formula (I) in which
  • R 1 and R 2 represent methyl
  • R 3 represents -0-(S02)OH
  • X represents CH
  • Z represents an alkyl-chain having two carbon atoms, whereby the alkyl-chain may be substituted with a carboxy substituent
  • Y represents O
  • A represents phenyl substituted with a substituent of the following formula
  • R lb and R 2b represent hydrogen, represents aminoethyl, azetidine, pyrrolidine or piperi- dine
  • * is the linkage site to the residue represented by A, and 1 represents 0 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
  • the present invention also relates to compounds of formula (I) in which
  • R 1 and R 2 represent methyl
  • R 3 represents -0-(S0 2 )OH
  • X represents CH
  • Z represents a two carbon alkyl-chain, substituted with a carboxy substit- uent
  • A represents phenyl substituted with a substituent of the following formula
  • R lb and R 2 represent hydrogen, R 3b represents aminoethyl, azetidine, pyrrolidine or piperi- dine,
  • A represents a group selected from the following formulae
  • the present invention also relates to methods for the preparation of compounds of formula (I).
  • the compounds of the present invention may be prepared by removing the protecting group from compounds of formula
  • Pg represents a protecting group and P ⁇ -R 3 , A, 1, X, Y and Z are as defined above, under acidic conditions.
  • Acidic conditions may involve treating the compounds of formula (II) with formic acid, acetic acid, trifluoroacetic acid or hydrochloric acid at temperatures ranging from 0°C to 100°C for a time ranging from 10 min to 16 hours, preferably with 90% formic acid at a temperature of 30-60°C for 30-60 min.
  • R 1 , R 2 and R 3 are as defined above.
  • the reaction generally takes place in inert solvents in the presence of a coupling reagent and where applicable with addition of a base at a temperature ranging from -20°C to 80°C for 1-24 hours, preferably at a temperature of 20-30°C overnight.
  • Inert solvents are for example dichloromethane (DCM), trichloromethane, benzene, toluene, tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide (DMA), N-methylpyrrolidin-2-one (NMP) and ace- tonitrile as well as mixtures of the aforementioned solvents.
  • DCM dichloromethane
  • THF trichloromethane
  • benzene toluene
  • THF tetrahydrofuran
  • 1,4-dioxane N,N-dimethylformamide
  • DMA
  • a preferred solvent is N,N-dimethylformamide.
  • Suitable coupling reagents are for example carbodiimides such as ⁇ , ⁇ '-diethyl-, ⁇ , ⁇ ,'-dipropyl-, ⁇ , ⁇ '-diisopropyl-, ⁇ , ⁇ '-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl)-N'-ethylcarbodiimid-hydrochloride (EDC), N-cyclohe- xylcarbodiimid-N'-propyloxymethyl-polystyrene (PS-Carbodiimide) or carbonyl compounds such as carbonyldiimidazole (CDI), or 1,2-oxazolium compounds such as 2-ethyl-5 -phenyl- l,2-oxazolium-3-sulf ate or 2-tert.-butyl-5-methyl-isoxazolium-per-
  • Suitable bases are for example carbonates and bicarbonates, triethylamine, diisopropylethylamine, N-methylmorpholine, N- methylpiperidine or 4-dimethylaminopyridine.
  • reactions are carried out with a mixture of a carbodiimide and 1-hydroxybenzotriazole with or without the addition of sodium bicarbonate as base.
  • the compounds of formula (III) can be prepared selectively with the preferred Z-orientation of the oxime by reacting compounds of formula
  • the reaction generally takes place in protic solvents or in solvent mixtures containing at least one protic solvent at a temperature ranging from 0°C to 100°C for 1-24 hours.
  • Suitable protic solvents are for example methanol, ethanol, iso- propanol, tert.-butanol, water or acetic acid.
  • Solvents suitable to form mixtures are for example dichloromethane, trichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile and ⁇ , ⁇ -dimethylformamide.
  • the reaction is carried out in a mixture of anhydrous ethanol and chloroform at 20-30°C overnight.
  • the deprotection reaction generally takes place with hydrazine, ammonia or methylamine or a salt or a solvate thereof in protic solvents or in solvent mixtures containing at least one protic solvent at a temperature ranging from 0°C to 100°C for 1-24 hours.
  • Protic solvents are for example methanol, ethanol, iso- propanol, tert.-butanol, water or acetic acid.
  • Suitable solvents to form mixtures are for example dichloromethane, trichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile and ⁇ , ⁇ -dimethylformamide.
  • the reactions are carried out with hydrazine monohydrate in anhydrous ethanol at 20-30°C for 2-6 hours.
  • the compounds of formula (VII) can be prepared by reacting compounds of formula (VII).
  • reaction in which Lg represents a leaving group and A, 1, Y and Z are as defined above with N-hydroxy-phthalimide.
  • Alkylation type reactions generally take place in the presence of an inorganic or organic base in aprotic solvents at a temperature ranging from 0°C to 100°C for 1-24 hours.
  • Mitsunobu type reactions are generally carried out in the presence of triphenylphosphine and an alkyl azodicarboxylate in aprotic solvents at a temperature ranging from 0°C to 100°C for 1-24 hours.
  • aprotic solvents are for example acetonitrile, tetrahydrofuran, dichloromethane, trichloromethane, 1,4- dioxane, N,N-dimethylformamide, JV,N-dimethylacetamide and JV-methyl-pyrolidin- 2-one.
  • reaction takes place under alkylation conditions in the presence of potassium carbonate or 1,8-diazabi- cyclo[5.4.0]undec-7-ene (DBU) in acetonitrile or ⁇ , ⁇ -dimethylformamide at 20°C to 80°C for 2-16 hours.
  • DBU 1,8-diazabi- cyclo[5.4.0]undec-7-ene
  • Examples for preferred compounds of formula (VIII) are compounds of formulae
  • Pg represents an alkyl- or arylalkylester protecting group into the required substituted or unsubstituted amidine functionality.
  • One possibility is to treat the cyano(hetero)aryl with hydrochloric acid gas in a protic solvent, like methanol or ethanol, at 0°C to 30°C for 2-24 hours.
  • the formed O-alkyl amidate intermediate is then treated with an ammonia solution or an amine in the same solvent at 20°C to 50°C for 1-16 hours.
  • Hydrochloric acid gas may also be formed in-situ from acetylchloride or thionylchloride; ammonium chloride in the presence of a base like triethylamine or diisopropylethylamine may also be used instead of an ammonia solution.
  • a further possibility is to react the cyano(hetero)aryl with an amine, ammonium chloride or an amine salt in the presence of trimethylaluminium in a non-protic solvent, like toluene or dichlorobenzene, at 20°C to 120°C for 1-16 hours.
  • a non-protic solvent like toluene or dichlorobenzene
  • a further option is to treat the cyano(hetero)aryl with hydroxylamine in polar solvents, like ethanol, water or dimethylsulfoxide or a mixture of the aforementioned solvents, at 20°C to 80°C for 1-16 hours.
  • polar solvents like ethanol, water or dimethylsulfoxide or a mixture of the aforementioned solvents.
  • the formed amidoxime intermediate is then de-oxygenated using hydrogen over palladium on carbon in acetic acid at 20°C to 50°C for 4-24 hours.
  • Hydroxylamine hydrochloride in the presence of triethylamine or diisopropylethylamine may be used instead of hydrox- ylamine; the de-oxygenation may also be carried out using a co-solvent, like methanol, ethanol or 1,4-dioxane, or with the additional acetic acid anhydride.
  • a further option is to treat the cyano(hetero)aryl with sodium alk- oxide in the corresponding alcohol, preferably with sodium methoxide in methanol, at 20°C to 50°C for 2-20 hours.
  • the formed O-alkyl amidate intermediate is then treated with an ammonia solution or an amine as described above.
  • a further option is to treat the cyano(hetero)aryl with lithium hex- amethyldisilazide in an inert solvent like tetrahydrofuran at 0°C to 20°C for 2-20 hours.
  • the formed silyl protected amidine intermediate is then de-protected by treating with an acid in a polar solvent, preferably with hydrochloric acid in ethanol, at 0°C to 20°C for 1-16 h.
  • the lithium hexamethyldisilazide may thereby be formed in-situ e.g. from n-butyl lithium and hexamethyldisilazane.
  • compounds of formula (X) may also first be converted to the corresponding amidine using the methods detailed above.
  • the compounds of the invention show a valuable range of pharmacological effects which could not have been predicted.
  • the compounds of the present invention are distinguished in particular by an advantageous range of antibacterial effects.
  • the present invention therefore further relates to the use of the compounds of the invention for the treatment and/or prophylaxis of diseases caused by bacteria, especially gram-negative bacteria.
  • the present invention further relates to the use of the compounds of the invention for the treatment and/or prophylaxis of diseases, especially of the diseases mentioned below.
  • the present invention further relates to the use of the compounds of the invention for the manufacture of a medicament for the treatment and/or prophylaxis of diseases, especially of bacterial infections and in particular the diseases mentioned below.
  • the present invention further relates to a method for the treatment and/or prophylaxis of diseases, especially of bacterial infections and in particular the diseases mentioned below, using a therapeutically effective amount of the compounds of the invention.
  • the compounds of the invention exhibit an antibacterial spectrum against gram-negative bacteria and selected gram-positive bacteria combined with low toxicity.
  • Compounds of this invention are particularly useful in human and veterinary medicine for the prophylaxis and treatment of local and systemic infec- tions which are caused for example by the following pathogens or by mixtures of the following pathogens:
  • Aerobic gram-positive bacteria Including but not limited to Staphylococcus spp. (S. aureus), Streptococcus spp. (S. pneumoniae, S. pyogenes, S. agalactiae, Streptococcus group C and G) as well as Bacillus spp. and Listeria monocytogenes.
  • Staphylococcus spp. S. aureus
  • Streptococcus spp. S. pneumoniae, S. pyogenes, S. agalactiae, Streptococcus group C and G
  • Bacillus spp. Listeria monocytogenes.
  • Aerobic gram-negative bacteria Enter obacteriaceae, including but not limited to Escherichia spp. (E. coli), Citrobacter spp. (C. freundii, C. diversus), Klebsiella spp. (K. pneumoniae, K. oxytoca), Enterobacter spp. (E. cloacae, E. aerogenes), Morganella morganii, Hafhia alvei, Serratia spp. (5. marcescens), Proteus spp. (P. mirabilis, P. vulgaris, P. penneri), Providencia spp. (P. stuartii, P.
  • Yersinia spp. Y. enter ocolitica, Y. pseudotuberculosis
  • Salmonella spp. Shigella spp. and also non-fermenters including but not limited to Pseudomonas spp. (P. aeruginosa), Burkholderia spp. (B. cepacia), Stenotrophomonas maltophilia, and Acinetobacter spp. (A. baumannii, Acinetobacter gen. sp. 13TU, Acinetobacter gen. sp. 3) as well as Bordetella spp. (B.
  • Aeromonas spp. Haemophilus spp. (H. influenzae), Neisseria spp. (N. gonorrhoeae, N. meningitidis) as well as Alcaligenes spp. (including A. xylosoxidans) , Pasteurella spp. (P. multocida), Vibro spp. (V. cholerae), Campylobacter jejuni and Helicobacter pylori.
  • the antibacterial spectrum also covers strictly anaerobic bacteria including but not limited to Bacteroides spp. (B. fragilis), Peptostreptococcus spp. (P. anaerobius), Prevotella spp., Brucella spp. (B. abortus), Porphyromonas spp., and Clostridium spp. (Clostridium perfringens).
  • pathogens are merely exemplary and in no way to be regarded as limiting.
  • diseases which may be caused by the said pathogens and which may be prevented, improved or cured by the compounds according to the invention are, for example: [0068] Respiratory tract infections such as lower respiratory tract infections, lung infection in cystic fibrosis patients, acute exacerbation of chronic bronchitis, community aquired pneumonia (CAP), nosocomial pneumonia (including ventilator- associated pneumonia (VAP)), diseases of the upper airways, diffuse panbronchiolitis, tonsillitis, pharyngitis, acute sinusitis and otitis including mastoiditis; urinary tract and genital infections for example cystitis, uretritis, pyelonephritis, endometritis, prostatitis, salpingitis and epididymitis; ocular infections such as conjunctivitis, corneal ulcer, iridocyclitis and post-operative infection
  • bacterial infections can also be treated in animals, such as primates, pigs, ruminants (cow, sheep, goat), horses, cats, dogs, poultry (such as hen, turkey, quail, pigeon, ornamental birds) as well as productive and ornamental fish, reptiles and amphibians.
  • animals such as primates, pigs, ruminants (cow, sheep, goat), horses, cats, dogs, poultry (such as hen, turkey, quail, pigeon, ornamental birds) as well as productive and ornamental fish, reptiles and amphibians.
  • the compounds of the invention may act systemically and/or locally. They can for this purpose be administered in a suitable way, such as, for example, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermal- ly, transdermally, conjunctivally, otically or as an implant or stent.
  • parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption step (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • Suitable for the other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops, solutions, sprays; tablets, films/wafers or capsules, for lingual, sublingual or buccal administration, suppositories, preparations for ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as for example patches), milk, pastes, foams, dusting powders, implants or stents.
  • pharmaceutical forms for inhalation inter alia powder inhalers, nebulizers
  • nasal drops solutions, sprays
  • tablets films/wafers or capsules
  • suppositories preparations for ears or eyes
  • vaginal capsules vaginal capsules
  • aqueous suspensions such as for example patches
  • lipophilic suspensions ointments
  • creams such as for example patches
  • the compounds of the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, non-toxic, pharmaceutically acceptable excipients.
  • excipients include inter alia carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colors (e.g. inorganic pigments such as, for example, iron oxides) and taste and/or odor corrigents.
  • carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • the present invention further relates to medicaments which comprise at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically acceptable excipients, as well as to their use for the aforementioned purposes.
  • the present invention further relates to medicaments which comprise at least one compound of the invention in combination with at least one further active compound, as well as to their use for the aforementioned purposes.
  • Examples for the further active compound include / ⁇ -lactamase inhibitors.
  • Suitable /3-lactamase inhibitors to be used in combination with the compounds of the invention include clavulanic acid, tazobactam, sulbactam, avibactam (NXL-104), and MK-7655.
  • the minimum amount of the compounds of the invention to be administered is a therapeutically effective amount.
  • therapeutically effective amount means an amount of compound which prevents the onset of, alleviates the symptoms of, stops the progression of, and/or eliminates a bacterial infection in humans or animals.
  • an effective dosing schedule of the compounds of the invention for adults is about 50 mg to about 3000 mg of a compound of formula (I) in a single dose; in another embodiment, an effective single dose is about 100 mg to about 2000 mg. In another embodiment, an effective single dose is about 500 mg to about 1200 mg. Typically the dosages are given 1 to 4 times per day. In one embodiment, the dosages are given 3 times per day. In some cases, it may be necessary to use dosages outside these limits.
  • NMR spectra were recorded on a Varian Oxford AS 400 NMR operating at 400 MHz for ⁇ , and 376 MHz for 19 F respectively. NMR data is recorded in chemical shifts relative to tetramethylsilane (TMS) as internal standard. NMR spectra were run either in CDCI3 containing 0.05 % TMS, CD3OD containing 0.05 % TMS, or DMSO-de containing 0.03 % TMS.
  • HPLC analyses were performed using a Waters 2695 Separation Module and a Waters 2996 Photodiode Array Detector system or a Waters 600 Controller including a Waters 717plus Autosampler and a Waters 2996 Photodiode Array Detector system on an Atlantis ⁇ 3- ⁇ 8-3 ⁇ -4.6 ⁇ 150 ⁇ column with an acetonitrile/aqueous 0.1 % H 3 PO4 gradient at 22°C, and a flow rate of 1 mL/minute.
  • Preparative HPLC was performed on a Waters Prep LC 2767 System utilizing a Waters Prep HPLC Controller, and a Waters 2487 Dual Wave Absorbance Detector on a ⁇ - 18-10 ⁇ -50 ⁇ 100 ⁇ (flow rate of 70 mL/minute), X-Bridge-C- 18-5 ⁇ -30 ⁇ 100 ⁇ (flow rate of 42 mL/minute), Ace-C-18 ⁇ m-30x250mm (flow rate of 40 mL/minute), or GemNX-C-18- ⁇ m-50x250mm (flow rate of 80 mL/minute) column, using an acetonitrile/aqueous 0.1 % trifluoroacetic acid gradient or an acetonitrile/aqueous 0.1 % formic acid gradient at 22 °C.
  • Mass spectra were recorded on a Waters 2795 Separation Module using either ES " or ES + ionization modes.
  • Compound 1_1_1 was synthesized according to David M. Floyd, Alan W. Fritz, Josip Pluscec, Eugene R. Weaver, Christopher M. Cimarusti /. Org. Chem., 1982, 47 (26), 5160-5167.
  • Compound 1_3_1 was synthesized according to David M. Floyd, Alan W. Fritz, Josip Pluscec, Eugene R. Weaver, Christopher M. Cimarusti /. Org. Chem., 1982, 47 (26), 5160-5167.
  • reaction mixture was stirred at room temperature for 24 h and filtered through a celite bed, washed with ethyl acetate (2 x 50 mL), and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30-40 % ethyl acetate in hexane to give compound 1_5_6 (24.5 g, 84.5 %) as a colorless solid.
  • Methanesulfonyl chloride (MsCl, 0.72 g, 6.3 mmol) was added dropwise via a syringe to a solution of 1_6_5 (2.0 g, 5.71 mmol) in pyridine (60 mL) at 0°C. The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in water (10 mL), tetrabu- tylammonium hydrogensulfate (1.87 g, 5.5 mmol) was added, the pH was adjusted to 3 with IN sulfuric acid, and the mixture was extracted with chloroform (5 x 30 mL).
  • Compound 1_9_1 was synthesized according to M. Sendai, S. Hashiguchi, M. Tomimoto, S. Kishimoto, T. Matsuo, M. Ochiai; Chemical & Pharmaceutical Bulletin 1985, 33 (9), 3798-3810 and EP 73061. Synthesis of amino-thiazole and amino-thiadiazole building blocks Oxo [2- (tritylamino) - 1 , 3-thiazol-4-yl]acetic acid
  • Compound 2_1_1 was synthesized according to Sakagami, Kenji; Iwamatsu, Katsuyoshi; Atsumi, Kunio; Hatanaka, Minoru; Chemical & Pharmaceutical Bulletin, 1990, 38(12), 3476 - 3479.
  • Compound 2_2_1 was synthesized according to Yamawaki, Kenji; Nomura, Takashi; Yasukata, Tatsuro; Uotani, Koichi; Miwa, Hideaki; Takeda, Kei; Nishitani, Yasuhiro; Bioorganic & Medicinal Chemistry, 2007, 38 (21), 6716-6732. [5-Chloro-2-(tritylamino)-l,3-thiazol-4-yl](oxo)acetic acid
  • Compound 2_3_1 was synthesized according to: a) Sakagami, Kenji; Iwamatsu, Katsuyoshi; Atsumi, Kunio; Hatanaka, Minoru;
  • Step 2 4- ⁇ 2-[(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]ethoxy ⁇ benzonitrile (3_1_3)
  • Step 3 2-[2-(4-Aminophenoxy)ethoxy]-lH-isoindole-l,3(2H)-dione (3_8_4)
  • Trifluoroacetic acid (TFA, 14.3 mL) was added to a solution of compound 3_8_3 (7.4 g, 18.6 mmol) in dichloromethane (150 mL). The mixture was stirred for 2.5 hours at room temperature, and concentrated. The residue was then triturated with diethyl ether and the solid was collected to give the desired compound 3_8_4 (7.5 g, 97 % yield, trifluoroacetic acid salt) as a pink solid.
  • Step 4 tert-Butyl ⁇ (E)-[(tert-butoxycarbonyl)amino] [(4- ⁇ 2-[(l,3-dioxo-l,3-dihydro-2H- isoindol-2-yl)oxy]ethoxy ⁇ phenyl)amino]methylidene ⁇ carbamate (3_8_5)
  • Trifluoroacetic acid (6 mL, 43.2 mmol) was added to a suspension of compound 3_8_4 (7.4 g, 14.1 mmol) in acetonitrile (200 mL), and the mixture was stirred for 30 minutes at room temperature.
  • Compound 3_9_6 was prepared using the procedure described above for compound 3_8_6 using 1,3-dibromopropane instead of 1,2-dibromoethane in step 1.
  • Step 2 4- ⁇ [2-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)ethyl]sulfanyl ⁇ benzonitrile
  • Triphenyl phosphine (5.85 g, 0.0223 mol) was added to a solution of compound 3_10_2 (4.00 g, 0.0223 mol) and N-hydroxyphalimide (Phth.OH, 3.64 g, 0.223 mol) in tetrahydrofuran (100 mL), followed by diethyl azodicarboxylate (3.66 mL, 0.0223 mol) slowly over 20 minutes. The mixture was stirred at room temperature for 24 hours then concentrated to give a residue. The residue was purified by column chromatography to afford compound 3_10_3 (4.6 g, 62 % yield).
  • Step 5 4- ⁇ [2-(Aminooxy)ethyl]sulfanyl ⁇ benzenecarboximidamide (3_10_6)
  • Compound 3_12_6 was prepared using the procedure described above for compound 3_11_6 using methylamine instead of isopropylamine.
  • Compound 3_13_6 was prepared using the procedure described above for compound 3_11_6 using 2-aminoethanol instead of isopropylamine.
  • Compound 3_15_6 was prepared using the procedure described above for compound 3_11_6 using tert-butyl 2-aminoethylcarbamate instead of isopropylamine.
  • Compound 3_17_6 was prepared using the procedure described above for compound 3_11_6 using 2-aminomethyl pyridine instead of isopropyla- mine.
  • Compound 3_18_6 was prepared using the procedure described above for compound 3_11_6 using N-Boc protected piperizane instead of isopropyl- amine.
  • Compound 3_20_6 was prepared using the procedure described above for compound 3_11_6 using amino acetic acid instead of isopropylamine.
  • Compound 3_22_6 was prepared using the procedure described above for compound 3_11_6 using tert-butyl (2-amino-3- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ propyl)carbamate instead of isopropylamine.
  • Step 1 4- ⁇ [(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]methyl ⁇ benzonitrile (3_24_2)
  • N-Hydroxyphthalimide (PhthOH, 7.12 g, 55 mmol), triphenyl- phosphine (14.41 g, 55 mmol) and diethyl azodicarboxylate (DEAD, 9 mL, 55 mmol) were slowly added to a solution of 4-hydroxymethyl benzonitrile 3_24_1 (8.15 g, 50 mmol) in tetrahydrofuran (100 mL). The mixture was stirred at room temperature for 15 hours. The solid was collected by filtration, washed with tetrahydrofuran and dried to give compound 3_24_2 (10 g, 72 % yield) as a solid.
  • Step 2 4- ( ⁇ 2- [( 1 , 3-Dioxo- 1 , 3-dihydro-2H-isoindol-2-yl)oxy] ethyl ⁇ amino)benzonitrile (3_25_3)
  • Triphenylphosphine (1.61 g, 6.16 mmol) was added to a solution of compound 3_25_2 (1.00 g, 6.16 mmol) and N-hydroxyphthalimide (Phth-OH, 1.05 g, 6.16 mmol) in tetrahydrofuran (100 mL), followed by the slow addition of diethyl azodicarboxylate (1.02 mL, 6.16 mmol) over 20 minutes. The mixture was stirred at room temperature for 24 hours and concentrated to yield a residue which was purified by column chromatography to afford compound 3_25_3 (1.1 g, 58 % yield).
  • Step 3 4- ⁇ [2-(Aminooxy)ethyl]amino ⁇ benzonitrile (3_25_4) [00206] Hydrazine hydrate (0.255 mL, 10.90 mmol) was added to a suspension of compound 3_25_3 (3.35 g, 10.90 mmol) in ethanol (80 mL) and the mixture was stirred at 45°C for 14 hours. The solid was removed by filtration and the filtrate was concentrated. The residue was diluted with dichloromethane (20 mL). The solid was removed by filtration and the filtrate was concentrated to give compound 3_25_4 (1.9 g, 97 % yield) as an oil.
  • Step 4 4- ⁇ [2-(Aminooxy)ethyl]amino ⁇ benzenecarboximidoate (3_25_5)
  • Step 5 4- ⁇ [2-(Aminooxy)ethyl]amino ⁇ benzenecarboximidamide (3_25_6)
  • Zinc cyanide (15.2 g, 0.129 mmol) was added to a solution of (4- bromo-thiophen-2-yl)-methanol 3_26_2 (25.0 g, 0.129 mol) in ⁇ /, ⁇ -dimethylform- amide (150 mL). After degassing for 10 minutes, tetrakis(triphenylphosphine)- palladium(O) (7.48g, 6.47 mmol) was added and the reaction mixture was stirred at 80°C for 4 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography to give the desired product (13.67 g, 76 % yield).
  • Triphenylphosphine (9.9 g, 37.7 mmol) and carbon tetrabromide (12.59 g, 37.7 mmol) were added to a solution of 5-hydroxymethyl-thiophene-3- carbonitrile 3_26_3 (5.0 g, 35.9 mmol) in tetrahydrofuran (150 mL), at room temperature. After stirring for 4 hours, the mixture was concentrated to dryness. The residue was purified by column chromatography to give the desired product (4.85 g, 67 % yield) as a colorless oil.
  • reaction mixture was neutralized to pH 7 using diluted hydrochloric acid at 0°C and the mixture was extracted with ethyl acetate and the extract was washed with brine, dried over sodium sulfate and concentrated to dryness to give the product (4.12 g, 9 % yield) as a colorless oil.
  • N-Hydroxyphthalimide (Phth-OH, 1.44 g, 8.83 mmol) and triphe- nylphosphine (2.53 g, 9.63 mmol) were added to a solution of 3-amino-4-(2-hydroxy- ethoxy)-benzonitrile 3_28_3 (1.43 g, 8.02 mmol) in anhydrous tetrahydrofuran (40 mL) at room temperature.
  • Diethyl azodicarboxylate (1.68 g, 9.63 mmol) was added dropwise to the resulting solution at 20°C and the resulting mixture was stirred at room temperature overnight.
  • Step 6 3-Amino-4-(2-aminooxy-ethoxy)-benzamidine (3_28_7)
  • HMTA Hexamethylenetetramine
  • TFA trifluoroacetic acid
  • the mixture was heated at 100°C for 16 hours, cooled to room temperature, quenched with 50 % sulfuric acid (210 mL) and water (1260 mL), extracted with ethyl acetate, dried and concentrated. The residue was purified by chromatography to give compound 3_29_2 (12 g, 19 % yield) as an off- white solid.
  • Sodium borohydride (67 mg, 1.77 mmol) was added in portions to a cooled (0°C) solution of compound 3_29_3 (224 mg, 0.89 mmol) in methanol (5 mL). After the addition, the mixture was stirred at 0°C for 40 minutes, quenched with a saturated ammonium chloride solution, diluted with ethyl acetate (30 mL), washed with water (5 mL), dried over sodium sulfate and concentrated to give compound 3_29_4 (170 mg, 75 % yield) as a gum.
  • Step l 6-(2-Hydroxyethoxy)pyridazine-3-carboximidic acid 2-hydroxy-ethyl ester (3_30_2)
  • Ammonium chloride (0.899 g, 16.8 mmol) was added to a mixture of 6-(2-hydroxy-ethoxy)-pyridazine-3-carboximidic acid 2-hydroxy-ethyl ester 3_30_2 (3.185 g, 14.0 mmol) in methanol (120 mL). The mixture was refluxed overnight and then concentrated to dryness. The residue was dissolved in water, neutralized to pH 9 using a saturated sodium bicarbonate solution and lyophilized to give the crude product. The material was purified by flash column chromatography to give the desired product (2.1 g, 82 % yield) as a white solid.
  • BOC2O di- tert-butyldicarbonate
  • Step 4 tert-Butyl [(6- ⁇ 2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]ethoxy ⁇ pyrid- azin-3-yl)(imino) methyl] carbamate (3_30_5)
  • N-Hydroxyphthalimide (Phth-OH, 0.814 g, 4.99 mmol) and triphenylphosphine (1.427 g, 5.44 mmol) were added to a solution of ⁇ [6-(2-hydroxy- ethoxy)-pyridazin-3-yl]-imino-methyl ⁇ -carbamic acid tert-butyl ester 3_30_4 (1.28 g, 4.53 mmol) in anhydrous tetrahydrofuran (40 mL) at room temperature and a solution of diethyl azodicarboxylate (0.948 g, 5.44 mmol) in tetrahydrofuran (20 mL) was added dropwise to the resulting solution at 20°C.
  • Step l 5-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-pyridine-2-carbonitrile (3_32_2)
  • Triphenylphosphine (4.36 g, 16.65 mmol) was added to a solution of N-(2-hydroxyethoxy)phthalimide (3.45 g, 16.65mmol) and 2-cyano-5-hydroxy- pyridine 3_32_1 (2.0 g, 16.65 mmol) in tetrahydrofuran (200 mL), followed by the slow addition of diethyl azodicarboxylate (2.73 mL, 16.65 mmol) over 20 minutes and the mixture was stirred at room temperature for 24 hours. After removal of the solvent, the residue was purified by crystallization from tetrahydrofuran to afford compound 3_32_2 (3.0 g, 58 % yield).
  • Triethylamine (5.42 g, 53.3 mmol) was added to a suspension of compound 3_35_2 (10.0 g, 53.3 mmol) in methanol (200 mL) followed by tert-butyl hydrazinecarboxylate (Boc-Hydrazine, 14.1 g, 106.6 mmol).
  • the resulting clear solution was heated at 40° C for 2 hours, it was then evaporated and purified by column chromatography to obtain compound 3_35_3 (9.2 g, 69 % yield) as a white solid.
  • Step 3 tert-Butyl 2-[(5- ⁇ 2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]ethoxy ⁇ phen- yl)(imino)methyl]hydrazinecarboxylate (3_35_4)
  • N-Hydroxyphthalimide (8.36 g, 51.27 mmol) was added dropwise to a solution of compound 3_36_1 (10.0 g, 51.26 mmol) in dry ⁇ , ⁇ -dimethylformamide (70 mL) followed by l,8-diazabicyclo[5.4.0]undec-7-ene (7.7 mL, 51.27 mmol) during 20 minutes.
  • LAH Lithium aluminium hydride
  • Step l 2-(4-Cyano-phenoxy)-2-methyl-propionic acid ethyl ester (3_37_2)
  • Potassium carbonate 14.16 g. 102.5 mmol
  • a solution of compound 3_37__1 (10.0 g, 51.27 mmol) in dry ⁇ , ⁇ -dimethylformamide (70 mL) followed by 4-cyanophenol (6.7 g, 61.52 mmol) at room temperature and the reaction mixture was heated at 60°C for 16 hours.
  • the reaction mixture was cooled to room temperature, filtered, washed with ⁇ , ⁇ -dimethylformamide and the filtrate was concentrated under vacuum.
  • Triphenylphosphine (2.31 g, 8.79 mmol) was added to a mixture of compound 3_37_3 (1.6 g, 8.37 mmol) and JV-hydroxyphthalimide (1.43 g, 8.79 mmol) in tetrahydrofuran (20 mL), and the mixture was sonicated for 20 minutes, and treated with diisopropyl azodicarboxylate (DIAD, 1.73 mL, 8.79 mmol). The reaction mixture was stirred at room temperature for 20 hours, concentrated and the residue was purified by column chromatography to give compound 3_37_4 (1.6 g, 57 % yield) as an off-white solid, which was used in the next step without further purification.
  • DIAD diisopropyl azodicarboxylate
  • Step 5 4-(2-Aminooxy-l,l-dimethyl-ethoxy)-benzimidic acid methyl ester (3_37_6)
  • Step 6 4-(2-Aminooxy-l,l-dimethyl-ethoxy)-benzamidine (3_37_7)
  • Step l 2-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboxylic acid ethyl ester (3_38_2)
  • reaction mixture was neutralized to pH 7 using acetic acid at 0°C, diluted with ethyl acetate (150 mL) and washed with brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give the desired product (99.4 g, 73 % yield) as a white solid.
  • Triethylamine (TEA, 1.22 g, 12.07 mmol) was added to a solution of 2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboxylic acid 3_38_3 (3.0 g, 11.0 mmol) in tetrahydrofuran (60 mL), followed by ethyl chloroformate (1.31 g, 12.07 mmol) slowly at -10°C. After stirring at room temperature for 1.5 hour, concentrated ammonium hydroxide (0.80 g, 13.17 mmol) was slowly added to the reaction mixture at 0°C and the resulting mixture was stirred at room temperature for 1 hour.
  • Step 4 2-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carbonitrile (3_38_5)
  • Triethylamine (TEA, 7.625 g, 75.3 mmol) was added to a solution of 2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboxylic acid amide 3_38_4 (1.71 g, 6.28 mmol) in dichloromethane (50 mL) at 0°C.
  • Phosphorus oxychloride (2.407 g, 15.70 mmol) was slowly added to the reaction mixture at 0°C and the resulting mixture was stirred at room temperature for 1 hour.
  • Step 5 2-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboximidic acid 2- hydroxy-ethyl ester (3_38_6)
  • Step 8 ⁇ [2-(2-Hydroxy-ethoxy)-thiazol-4-yl]-imino-methyl ⁇ -carbamic acid tert-butyl ester (3_38_9)
  • a saturated sodium bicarbonate solution (15 mL) and a solution of di-tert-butyldicarbonate (BOC 2 0, 1.346 g, 6.17 mmol) in 1,4-dioxane (10 mL) were added to a solution of 2-(2-hydroxy-ethoxy)-thiazole-4-carboxamidine hydrochloric acid 3_38_8 (0.92 g, 4.11 mmol) in water (5 mL) at room temperature.
  • Step 9 ( ⁇ 2-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-thiazol-4-yl ⁇ -imino- methyl)-carbamic acid tert-butyl ester (3_38_10)
  • N-Hydroxyphthalimide 0.393 g, 2.41 mmol
  • triphenylphos- phine 0.690 g, 2.63 mmol
  • ⁇ [2-(2-hydroxy-ethoxy)- thiazol-4-yl]-imino-methyl ⁇ -carbamic acid tert-butyl ester 3_38_9 0.63 g, 2.19 mmol
  • anhydrous tetrahydrofuran 40 mL
  • Step 10 3.38. tert-Butyl [ ⁇ 2-[2-(aminooxy)ethoxy]-l,3-thiazol-4-yl ⁇ (imino)methyl]- carbamate (3_38_11)
  • CuBr 2 (18.06 g, 80.1 mmol) was added to a suspension of 5-amino- [l,3,4]thiadiazole-2-carboxylic acid ethyl ester 3_39_1 (7 g, 40.5 mmol) in 150 mL of acetonitrile, the mixture was stirred for 15 min, t-BuONO (9.6 mL, 80.1 mmol) was added over 20 min., and the mixture was heated at 60°C for 0.5 h.
  • Step 3 5-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-[l,3,4] thiadiazole-2-carboxylic acid amide (3_39_4)
  • Step 4 5 - [2- (Tetrahydro-pyran-2-yloxy)-ethoxy] -[1,3,4] thiadiazole-2-carbonitrile
  • Trifluoroacetic anhydride (TFAA, 1.13 mL, 8.46 mmol) was added to a solution of compound 3_39_4 (2.1 g, 7.69 mmol) and triethylamine (TEA, 1.13 mL, 8.64 mmol) in tetrahydrofuran (20 mL) at 0°C, and the mixture was warmed to room temperature, and stirred for 1 hour.
  • TFAA Trifluoroacetic anhydride
  • TEA triethylamine
  • Step 5 5 - [2- (Tetrahydro-pyran-2-yloxy)-ethoxy] -[1,3, 4] thiadiazole-2-carboxamidine (3_39_6)
  • Step 7 ⁇ [5-(2-Hydroxy-ethoxy)-[l,3,4]thiadiazol-2-yl]-imino-methyl ⁇ -carbamic acid tert-butyl ester (3_39_8)
  • Triphenylphosphine (0.37 g, 1.5 mmol) and diisopropyl azodicar- boxylate (0.3 mL, 1.5 mmol) were added to a solution of compound 3_39_8 (0.3 g, 1 mmol) and N-hydroxyphalimide (0.17 g, 1 mmol) in 10 mL of tetrahydrofuran, at 0 °C, and the mixture was stirred at room temperature for 1.5 h, diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution and brine, dried over Na2S0 4 , filtered and concentrated to give a residue. The residue was purified by column chromatography to give compound 3_39_9 (0.4 g, 92 % yield).
  • Step 9 tert-Butyl [ ⁇ 5-[2-(aminooxy)ethoxy]-l,3,4-thiadiazol-2-yl ⁇ (imino)methyl]carb- amate (3_39_10)
  • Triethylamine (66 mL, 474.4 mmol) was added to a solution of methylhydrazine sulfuric acid salt (30.4 g, 211 mmol) in water (150 mL) and methanol (300 mL) at room temperature. The mixture was stirred for 0.5 hour at room temperature, but-2-ynedioic acid dimethyl ester (30 g, 211 mmol) was added and the mixture was stirred for 18 hours at 70°C. The reaction mixture was kept at room temperature for two days and the solid was collected by filtration and dried to give 12 g of the desired compound. The filtrate was concentrated, treated with ice and the solid was collected by filtration, and dried to give an additional 5 g of the desired compound 3_41_2 (17 g, 52 % yield) as a yellow solid.
  • Step 2 2-Methyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-2H-pyrazole-3-carboxylic acid ethyl ester (3_ 1_3)
  • Diisopropyl azodicarboxylate (DIAD, 41.6 mL, 205.8 mmol) was added to a solution of 3_41_2 (10.7 g, 68.6 mmol), 2-(tetrahydro-pyran-2-yloxy)- ethanol (17 mL, 102.9 mmol) and triphenylphosphine (53.9 g, 205.8 mmol) at 0°C, and the mixture was stirred at room temperature for 16 hours.
  • DIAD Diisopropyl azodicarboxylate
  • the reaction mixture was heated at 80°C for 16 hours, more 2-(tetrahydro-pyran-2-yloxy)-ethanol (3.75 mL), triphenylphosphine (5.3 g) and diisopropyl azodicarboxylate (3 mL) were added, and the reaction mixture was refluxed for 16 hours, concentrated and treated with diethyl ether and hexanes (2:3, 500 mL) to give a precipitate, which was removed by filtration. The filtrate was concentrated and the residue obtained was purified by column chromatography to give compound 3_41_3 (26.6 g, >100 % yield, contaminated with diisopropyl azodicarboxylate) as a yellow oil.
  • ethyl 2,3-epoxypropanoate (3.0 g, 25.8 mmol) were added to a solution of 4-hydroxybenzonitrile 3_45_1 (12.31 g, 0.103 mmol) in acetonitrile (100 mL). After refluxing for 4 hours, the resulting mixture was cooled and filtered.
  • Step 3 3-(4-Carbamimidoyl-phenoxy)-2-hydroxy-propionic acid methyl ester (3_45_4)
  • Ammonia (7N in methanol, 3.0 mL, 20.97 mmol) was added to a mixture of 2-hydroxy-3-(4-methoxycarbonimidoyl-phenoxy)-propionic acid methyl ester hydrochloric acid salt 3_45_3 (2.43 g, 8.39 mmol) in anhydrous methanol (30 mL) at 0°C and the resulting mixture was stirred at 40°C for 5 hours.
  • the reaction mixture was concentrated to dryness to give the crude product of compound 3_45_4 (2.39 g, >100% yield) as a white solid which was used without purification.
  • Step 4 3-[4-(tert-Butoxycarbonylamino-imino-methyl)-phenoxy]-2-hydroxy- propionic acid methyl ester (3_45_5)
  • a saturated sodium carbonate solution (lOmL) and di-tert- butyldicarbonate (BOC 2 0, 2.197 g, 10.07 mmol) were added to a solution of 3-(4- carbamimidoyl-phenoxy)-2-hydroxy-propionic acid methyl ester 3_45_4 (2.35 g, crude material from previous step, 8.39 mmol) in tetrahydrofuran (30 mL) at room temperature. After stirring at room temperature for 3.5 hours, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The residue was purified by column chromatography to give the desired product (2.0 g, 66 % yield) as a white solid.
  • Step 5 3-[4-(tert-Butoxycarbonylamino-imino-methyl)-phenoxy]-2-hydroxy- propionic acid (3_45_6)
  • a solution of sodium hydroxide (0.189 g, 4.73 mmol) in water (4 mL) was added to a solution of 3-[4-(tert-butoxycarbonylamino-imino-methyl)- phenoxy]-2-hydroxy-propionic acid methyl ester 3_45_5 (0.8 g, 2.36 mmol) in tetrahydrofuran (10 mL) at 0°C. After stirring at this temperature for 15 minutes, the reaction mixture was neutralized to pH 7 using acetic acid and concentrated to dryness to afford the crude desired product (1.12 g) as a white solid.
  • Step 6 3-[4-(tert-Butoxycarbonylamino-imino-methyl)-phenoxy]-2-hydroxy- propionic acid benzhydryl ester (3_45_7)
  • Step 7 3-[4-(tert-Butoxycarbonylamino-imino-methyl)-phenoxy]-2-(l,3-dioxo-l,3- dihydro-isoindol-2-yloxy)-propionic acid benzhydryl ester (3_45_8)
  • N-Hydroxyphthalimide (0.205 g, 1.26 mmol
  • triphenylphos- phine 0.359 g, 1.37 mmol
  • 3-[4-(tert-butoxycarb- onylamino-imino-methyl)-phenoxy]-2-hydroxy-propionic acid benzhydryl ester 3_45_7 (0.56 g, 1.14 mmol) in anhydrous tetrahydrofuran (10 mL) at room temperature.
  • Step 8 Diphenylmethyl 2-(aminooxy)-3- ⁇ 4-[N-(tert-butoxycarbonyl)carbamimidoyl]- phenoxyjpropanoate (3_45_9)
  • Step 2 ⁇ [4-(2-Hydroxyethoxy)-pyridin-2-yl]-iminomethyl ⁇ carbamic acid tert-butyl ester (3_47_3)
  • Step 3 ( ⁇ 4-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-pyridin-2-yl ⁇ -imino- methyl)carbamic acid tert-butyl ester (3_47_4)
  • Step 1 3,5-Bis-isopropylideneaminooxy-pyridine-2-carbonitrile (3_49_2)
  • Step 5 ( ⁇ 5-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-3-hydroxy-pyridin-2- yl ⁇ -imino-methyl)-carbamic acid tert-butyl ester (3_49_6)
  • Triethylamine (1.465 g, 14.47 mmol) was added to a solution of N- (2-hydroxyethoxy)phthalimide (2.0 g, 9.65 mmol) in dichloromethane (20 mL) at 0°C.
  • Methanesulfonyl chloride (1.657 g, 14.47 mmol) was slowly added to the reaction mixture at 0°C.
  • Step 6 tert-Butyl [ ⁇ 5-[2-(aminooxy)ethoxy]-3-hydroxypyridin-2-yl ⁇ (imino)methyl]- carbamate (3_49_7)
  • Step 1 tert-Butyl 4- ⁇ [(4-hydroxyphenyl)(imino)methyl]amino ⁇ piperidine-l- carboxylate (3_51_2)
  • Step 3 tert-Butyl 4- ⁇ (tert-butoxycarbonyl)[(4-hydroxyphenyl)(imino)methyl]amino ⁇ - piperidine- 1 -carboxylate (3_51_4)
  • Step l (2-Pyrrolidin-l-yl-ethyl)-carbamic acid tert-butyl ester (3_54_2)
  • Step 2 l-(2-tert-Butoxycarbonylamino-ethyl)-l-methyl-pyrrolidinium iodide (3_54_3)
  • Step 3 l-(2-Ammo-ethyl)-l-methyl-pyrrolidinium chloride hydrochloride salt (3_54_4)
  • Step 1 tert-Butyl ⁇ 2- [4-(benzyloxy)phenyl] - 1 ,4,5, 6-tetrahydropyrimidin-5-yl ⁇ carb- amate (3_55_2)
  • Step 2 tert-Butyl 2-[4-(benzyloxy)phenyl]-5-[(tert-butoxycarbonyl)amino]-5,6- dihydropyrimidine-l(4H)-carboxylate (3_55_3)
  • Step 2 Di-tert-butyl 4- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ pyrazolidine-l,2-dicarboxylate (3_57_3)
  • Step 4 Di-tert-butyl 4-[(methylsulfonyl)oxy]pyrazolidine-l,2-dicarboxylate (3_57_5)
  • Step 6 Di-tert-butyl 4-aminopyrazolidine-l,2-dicarboxylate (3_57_7)
  • Step 3 4- ⁇ [tert-Butyl (dimethyl)silyl] oxy ⁇ -3- [(1 , 3-dioxo- 1 , 3-dihydro-2H-isoindol-2- yl)oxy]butyl acetate (3_58_4)
  • Triphenylphosphine (16.4 g, 62.8 mmol) was added to a solution of compound 3_58_3 (13 g, 48.3 mmol) and iV-hydroxyphthalimide (11 g, 67.6 mmol) in tetrahydrofuran (200 mL), and diisopropyl azodicarboxylate (14.6 mL, 72.5 mmol) at 0°C, and the mixture was stirred at room temperature for 3 hours and concentrated to give a residue, which was purified by column chromatography to give compound 3_58_4 (20 g, 99 % yield) as a yellow solid.
  • Step 4 3-[(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]-4-hydroxybutyl acetate (3_58_5)
  • Step 5 4- ⁇ 4-[N-(tert-Butoxycarbonyl)carbamimidoyl]phenoxy ⁇ -3-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)oxy]butyl acetate (3_58_6)
  • Step 6 3-(Aminooxy)-4- ⁇ 4-[N-(tert-butoxycarbonyl)carbamimidoyl]phenoxy ⁇ butyl acetate (3_58_7)
  • Step l 3- ⁇ 4-[N-(2-tert-Butoxycarbonylamino-ethyl)-carbamimidoyl]-phenoxy ⁇ -2- hydroxy-propionic acid methyl ester (3_59_1)
  • Triethylamine (1.295 g, 12.8 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (1.76 g, 11.0 mmol) were added to a mixture of compound 3_45_3 (3.09 g, 10.7 mmol) in anhydrous methanol (50 mL) at 0°C and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography to give the desired product (3.09 g, 76 % yield) as a white solid.
  • Step 2 3-(4- ⁇ [tert-Butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)-amino]-imino- methyl ⁇ -phenoxy)-2-hydroxy-propionic acid methyl ester (3_59_2)
  • Butyllithium (1.6N in hexane, 168 mL, 269 mmol) was added to a solution of hexamethyldisilazane (56.5 mL, 269 mmol) in tetrahydrofuran (250 mL) at 0°C, and stirred at 0°C for 1 hour to form lithium hexamethyldisilazide (LHMDS).
  • LHMDS lithium hexamethyldisilazide
  • a solution of compound 3_60_2 (22.6 g, 107.6 mmol) in tetrahydrofuran (250 mL) was added slowly at 0°C, and the mixture was warmed to room temperature slowly and stirred for 16 hours at room temperature.
  • Step 3 Amino-(5-benzyloxy-pyridin-2-yl)-methylene]-carbamic acid tert-butyl ester (3_60_4)
  • Step 4 Amino-(5-hydroxy-pyridin-2-yl)-methylene]-carbamic acid tert-butyl ester (3_60_5)
  • Step 5 3-[6-(tert-Butoxycarbonylamino-imino-methyl)-pyridin-3-yloxy]-2-hydroxy- propionic acid ethyl ester (3_60_6)
  • Step 2 4-(2,3-Dihydroxy-propoxy)-benzimidic acid methyl ester hydrochloric acid salt (3_61_3)
  • Step 3 4-(2,3-Dihydroxy-propoxy)-benzamidine (3_61_4)
  • a saturated sodium carbonate solution (8mL) and di-tert-butyldi- carbonate (Boc 2 0, 6.52 g, 30 mmol) were added to a solution of compound 3_61_4 (3.70 g, crude, 12.5 mmol) in methanol (30 mL) and tetrahydrofuran (20 mL) at 0 °C. After stirring at room temperature overnight, the resulting mixture was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated. The residue was washed with a small volume of cold ethyl acetate to give the desired product (3.10 g, 80 % yield) as a white solid.
  • Step 5 ( ⁇ 4-[3-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-propoxy]-phenyl ⁇ -imino- methyl)-carbamic acid tert-butyl ester (3_61_6)
  • Step l (R)-3-(4-Cyano-phenoxy)-2-hydroxy-propionic acid ethyl ester (3_62_2)
  • Step 2 (#)-2-Hydroxy-3-(4-methoxycarbonimidoyl-phenoxy)-propionic acid methyl ester hydrochloric acid salt (3_62_3)
  • Step 3 (i?)-tert-Butyl 4-(4-(2-hydroxy-3-methoxy-3-oxopropoxy)benzimidamido)pip- eridine-l-carboxylate (3_62_4)
  • Triethylamine (1.537 g, 15.2 mmol) and tert-butyl 4-amino- piperidine-l-carboxylate (2.765 g, 13.8 mmol) were added to a mixture of compound 3_62_3 (4.0 g, 13.8 mmol) in anhydrous methanol (50 mL) at 0°C and the resulting mixture was stirred at room temperature overnight.
  • the reaction mixture was concentrated to dryness to give the crude desired product (7.81 g, >100 % yield) as a white foam, which was used without purification.
  • Step 5 (R)-tert-Butyl 4-(4-(3-(benzhydryloxy)-2-hydroxy-3-oxopropoxy)benzimid- amido)piperidine-l-carboxylate (3_62_6)
  • Step 6 (S)-tert-Butyl 4-(4-(3-(benzhydryloxy)-2-((l,3-dioxoisoindolin-2-yl)oxy)-3-oxo- propoxy)benzimidamido)piperidine-l-carboxylate (3_62_7)
  • N-Hydroxyphthalimide 0.573 g, 3.51 mmol
  • tri- phenylphosphine 1.005 g, 3.83 mmol
  • Step 7 2-Aminooxy-3-(4- ⁇ [tert-butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)- amino]-imino-methyl ⁇ -phenoxy)-propionic acid benzhydryl ester (3_62_8)
  • Step l Methyl 3- ⁇ 4-[N-(tert-butoxycarbonyl)carbamimidoyl]phenoxy ⁇ -2-[(l ; 3-dioxo- l,3-dihydro-2H-isoindol-2-yl)oxy]propanoate (3_83_1)
  • Step 1 3- ⁇ [tert-Butyl(dimethyl)silyl]oxy ⁇ -2-hydroxypropyl acetate (3_84_2)
  • Step 2 2- ⁇ 4-[N-(tert-Butoxycarbonyl)carbamimidoyl]phenoxy ⁇ -3- ⁇ [tert-butyl(dimeth- yl)silyl]oxy ⁇ propyl acetate (3_84_3)
  • Triphenylphosphine (4.33 g, 16.53 mmol) was added to a mixture of compound 3_84_2 (3.5 g, 14.11 mmol) and tert-butyl [(4-hydroxyphenyl)(imino)- methyl] carbamate (3.26 g, 13.78 mmol) in tetrahydrofuran (100 mL), and diisopro- pyl azodicarboxylate (4.17 mL, 20.67 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to give a residue, which was purified by column chromatography eluting with 30% EtOAc in hexane to give compound 3_84_3 (6.5 g, 99 % yield) as a yellow solid.
  • Tetra-n-butylammonium fluoride (TBAF, IN in tetrahydrofuran, 39.9 mL, 39.9 mmol) was added to a solution of compound 3_84_3 (9.3 g, 19.9 mmol) in tetrahydrofuran (100 mL) under cooling, and the mixture was stirred at room temperature for 2 h and concentrated to give a residue, which was purified by column chromatography to give compound 3_84_4 (3.6 g, 51 % yield) as a gum.
  • TBAF Tri-n-butylammonium fluoride
  • Step 4 2- ⁇ 4-[N-(tert-Butoxycarbonyl)carbamimidoyl]phenoxy ⁇ -3-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)oxy]propyl acetate (3_84_5)
  • Step 5 3-(Aminooxy)-2- ⁇ 4-[N-(tert-butoxycarbonyl)carbamimidoyl]phenoxy ⁇ propyl acetate (3_84_6)
  • Hydrazine monohydrate (0.34 g, 6.84 mmol) was added to a solution of 3_84_5 (3.4 g, 6.84 mmol) in anhydrous ethanol (40 mL) under cooling and the resulting mixture was stirred at room temperature for 5 h and filtered and the filtrate was concentrated to afford crude compound 3_84_6 (2.4 g, 96 % yield) as a solid, which was used without purification.
  • Step 6 tert-Butyl [(4- ⁇ [l-(aminooxy)-3-hydroxypropan-2-yl]oxy ⁇ phenyl)(imino)meth- yl] carbamate (3_84_7)
  • Step 4 3-[(3-Amino-l,2-benzoxazol-6-yl)oxy]-2-hydroxypropanoate (3_85_5)
  • Step 5 3-(4-Carbamimidoyl-3-hydroxyphenoxy)-2-hydroxypropanoate (3_85_6)
  • 5% palladium on charcoal 140 mg was added to a degassed solution of 3_85_5 (330 mg, 1.24 mmol) in methanol (30 mL). The mixture was stirred under hydrogen with a balloon for 2 hours and filtered through a pad of Celite. The filtrate was concentrated to give compound 3_85_6 (310 mg, 93 % yield).
  • Ketoacid 2_x (1.7 mmol) was added to a solution of compound 3_x (1.7 mmol) in anhydrous ethanol (30 mL) and chloroform (10 mL) and the resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was re-crystallized from ethanol or purified by column chromatography to afford compound 4_3 (24 % - 91% yield) as a yellow solid.
  • the compounds 4_6 of Examples 1-111 were prepared according to the procedures detailed above.
  • the compound of Example 38 was prepared by treating the compound of Example 24 with isopropyl formimidate hydrochloride in the presence of potassium carbonate (conditions see e.g. US 2009/0012054).
  • the compound of Example 43 was prepared by treating the compound of Example 39 with ethanimidoate hydrochloride in the presence of potassium carbonate (conditions see e.g. US 2009/0012054).
  • the compound of Example 46 was prepared by oxidizing the compound of Example 81 with Jones reagent (conditions see e.g. Kenneth Bowden, I. M. Heilbron, E. R. H. Jones and B. C. L. Weedon, J. Chem.
  • the compounds of Example 87 were prepared by oxidizing the compound of Example 112 with Jones reagent (conditions see e.g. Kenneth Bowden, I. M. Heilbron, E. R. H. Jones and B. C. L. Weedon, J. Chem. Soc, 1946, 39-45) followed by a standard de-protection and HPLC separation.
  • the compound of Example 78 was prepared by treating the compound of Example 24 with diisopropylethylamine followed by di-tert-butyl [(Z)-IH- pyrazol-l-yl-methylylidene]biscarbamate at room temperature for 15 hours (conditions see e.g. WO 2009/49028 Al).
  • the compound of Example 60 was prepared by treating the compound of Example 59 with formic acid as formylating agent.
  • the compound of Example 63 was prepared by treating the compound of Example 64 with formic acid as formylating agent.

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Abstract

The present invention relates to novel β-lactam compounds of formula (I), their preparation and use. In particular, this invention relates to novel β-lactam compounds which are amidine substituted monobactam derivatives useful as antimicrobial agents and their preparation.

Description

AMIDINE SUBSTITUTED BETA - LACTAM COMPOUNDS, THEIR PREPARATION AND USE AS ANTIBACTERIAL AGENTS
[0001] This invention relates to novel 3-lactam compounds, their preparation and use. In particular, this invention relates to novel ^-lactam compounds which are amidine substituted monobactam derivatives useful as antimicrobial agents and their preparation.
[0002] Public health experts and officials consider the emergence and spread of antibiotic resistant bacteria as one of the major public health problems of the 21st century. Although not a new phenomenon per se, the spread of antibiotic resistant bacteria has reached an unprecedented dimension. While the most resistant isolates continue to emerge in the hospital setting, physicians and epidemiologists are encountering increasing numbers of resistant bacteria in the community among people without previous healthcare contact. The number of patients who are dying from untreatable nosocomial infections continues to grow. Therapeutic options are especially limited for infections due to multi-drug-resistant Gram-negative pathogens including Enterobacteriaceae and non-fermenters, a situation made worse by the fact that the pipelines of the pharmaceutical industry contain few compounds with promising resistance breaking profiles (H.W. Boucher et al.; Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America; Clin Inf Dis 2009, 48, 1-12).
[0003] The highly successful and well-tolerated class of ^-lactam antibiotics has historically been one mainstay for the treatment of infections caused by Gram- negative pathogens. Among these especially 3rd-generation cephalosporins, car- bapenems and monobactams are extensively used for the treatment of infections with Gram-negative bacteria. However, a vast array of more than 1000 ^-lactamases (a constantly updated list of ^-lactamases can be found under http://www.lahey.org-/Studies/) and further resistance mechanisms severely endanger the mid-term usability of the current compounds in these subclasses. Especially extended-spectrum 2-lactamases (ESBLs) and carbapenemases are important drivers of resistance. New /3-lactams with resistance breaking properties are urgently needed to fill the gap.
[0004] With aztreonam as the single FDA approved monobactam used worldwide and a second analogue marketed exclusively in Japan (tigemonam), the monobactams are a clearly under-explored subclass among the /^-lactams. Reviews on aztreonam are available: W.C. Hellinger, N.S. Brewer; Carbapenems and Monobactams - Imipenem, Meropenem and Aztreonam; Mayo Clin. Proc. 1999, 74, 420-434. R.B. Sykes, D.P. Bonner; Discovery and Development of the monobactams; Rev. Infect. Dis. 1985, 7 (Suppl. 4), 579-593. [0005] The attempt to enhance the cellular uptake of the /^-lactams by using iron-siderophore uptake systems in microorganisms is one concept that has been explored in the monobactam field by Basilea (WO 2007065288), Naeja Pharmaceuticals (WO 2002022613) and Squibb & Sons (US 5290929, EP 531976, EP 484881). The heteroaryl units mimicing siderophores can also be attached to the side-chain as hydrazides as demonstrated by Squibb & Sons (US 5318963, US 5112968). Recently, Pfizer re-investigated monocarbams, mono-cyclic J-lactams that carry a sulfonyla- minocarbonyl activating group at the Nl-position (WO 2010070523). Additionally, in WO 2008116813 Basilea has described combination therapy approaches using a combination of monobactams with carbapenems.
[0006] In view of the increasing resistance development of pathogenic bacteria against known antibacterial agents, including multiple resistances, there is an ongoing need to find novel antibacterial substances, in particular compounds that have different structural motives.
[0007] The present invention relates to compounds of formula (I)
Figure imgf000004_0001
in which R1 and R2 independently of one another represent hydrogen, aminocarbonyl or (Ci-C4)-alkyl, or
R1 and R2 together with the carbon atom to which they are bonded form a (C3- C8)-cycloalkyl,
R3 represents -(CH2)m-(S02)OH or -0-(CH2)0-(S02)OH, wherein m and o independently of one another represent an integer 0, 1, 2 or 3, and wherein any CH2-group contained in the residues which R3 represents may be substituted with one or two (Ci-C4)-alkyl-residues,
X represents CR4 or N,
R4 represents hydrogen or halogen,
Z represents a bond or an alkyl-chain having one, two, three or four carbon atoms, whereby the alkyl-chain may be substituted with one, two, three or four substituents, selected independently of one another from the group consisting of carboxy, aminocarbonyl and (Ci-C4)-alkyl, whereby alkyl in turn may be substituted with a substituent selected from the group consisting of hydroxy, carboxy and aminocarbonyl,
Y represents a bond, O, NH or S, represents (C6-Cio)-aryl or 5- to 10-membered heteroaryl, whereby aryl and heteroaryl are substituted with a substituent of the following formula
Figure imgf000006_0001
wherein
Rlb, R2b and R3b independently of one another represent hydrogen, amino, hydroxy, (Ci-C4)-alkyl, (0-C4)-alkoxy, (C3-C6)- cycloalkyl, 4-, 5-, 6- or 7-membered heterocyclyl or 5- or 6- membered heteroaryl, whereby amino and hydroxy may be substituted with one or two substituents selected independently of one another from the group consisting of carbonyl, (G-C4)- alkylcarbonyl, mono- or di-(Ci-C4)-alkylaminocarbonyl, and (Ci-G -alkyl, whereby alkoxy, heterocyclyl and heteroaryl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, (G-C4)- alkylcarbonyl, (G-C4)-alkoxy, mono- or di-(G-C4)- alkylamino, mono- or di-(Ci-C4)-alkylaminocarbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), -C(=NH)CH3 and (G- C4)-alkyl, and whereby alkyl and cycloalkyl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, carbonyloxy, ami- nocarbonyl, carbonylamino, (Ci-C4)-alkylcarbonyl, (G- C4)-alkoxy, mono- or di-(0-C4)-alkylamino, mono- or di- (Ci-C4)-alkylaminocarbonyl, -NH-CH(=NH), -NH-C(=NH)- (NH2), -CH(=NH)CH3, (C6-C10)-aryl, 5- or 6-membered heteroaryl and 5- or 6-membered heterocyclyl, whereby heteroaryl and heterocyclyl in turn may be substituted with (Ci-C4)-alkyl, whereby amino in turn may be substituted with 5- or 6-membered heteroaryl, or
R2b and R3b together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle including one, two or three further heteroatoms selected from the series N, O and S and Rlb is as defined above,
R4 represents hydrogen, amino, hydroxy, (Ci-C4)-alkyl or (G- C4)-alkoxy, whereby amino and hydroxy may be substituted with one or two substituents selected independently of one another from the group consisting of (G-C4)- alkylcarbonyl, mono- or di-(Ci-C4)-alkylaminocarbonyl and (Ci-C4)-alkyl, whereby alkoxy may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, (G-C4)-alkylcarbonyl, (G-C4)-alkoxy, mono- or di-(Ci-C4)-alkylamino, mono- or di-(G-C4)- alkylaminocarbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), -CH(=NH)CH3 and (Ci-C4)-alkyl, and whereby alkyl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, aminocarbonyl, (C1-C4)-alkylcarbonyl, (Ci-C4)-alkoxy, mono- or di-(Ci-C4)-alkylamino, mono- or di-(Ci-C4)-alkylaminocarbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), -CH(=NH)CH3, (C1-C4)-alkyl, (C6-C10)- aryl and 5- or 6-membered heteroaryl,
RS represents hydrogen or (G-C4)-alkyl,
Q represents a bond, CH2 or NH, k represents an integer 1 or 2, and
* is the linkage site to the residue represented by A, and whereby aryl and heteroaryl further may be substituted with one or two substituents selected independently of one another from the group consisting of halogen, cyano, amino, hydroxy, (G-C4)-alkyl, (G-C4)- alkoxy, mono- or di-(Ci-C4)-alkylamino, amino-(Ci-C4)-alkyl, hydroxy- (Ci-C4)-alkyl or carboxy, whereby alkyl, alkoxy, alkylamino, aminoalkyl, hydroxyalkyl and carboxy in turn may be substituted with a substituent selected from the group consisting of halogen, (Ci-C4)-alkyl and carbonyl, and
1 represents an integer 0, 1, 2 or 3, and the salts thereof, the solvates thereof and the solvates of the salts thereof.
[0008] Compounds of the invention are the compounds of formula (I) and the salts, solvates and solvates of the salts thereof, as well as the compounds which are encompassed by formula (I) and are mentioned hereinafter as exemplary embodiments), and the salts, solvates and solvates of the salts thereof, insofar as the compounds encompassed by formula (I) and mentioned hereinafter are not already salts, solvates and solvates of the salts.
[0009] The compounds of the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore also encompasses the enantiomers or diastereomers and respective mixtures thereof. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers.
[0010] If the compounds of the invention may occur in tautomeric forms, the present invention encompasses all tautomeric forms.
[0011] Salts preferred for the purposes of the present invention are physiologically acceptable salts of the compounds of the invention. Also encompassed however are salts which are themselves not suitable for pharmaceutical applications but can be used for example for the isolation or purification of the compounds of the invention.
[0012] Examples of pharmaceutically acceptable salts of the compounds of formula (I) include salts of inorganic bases like ammonium salts, alkali metal salts, in particular sodium or potassium salts, alkaline earth metal salts, in particular magnesium or calcium salts; salts of organic bases, in particular salts derived from cyclohex- ylamine, benzylamine, octylamine, ethanolamine, diethanolamine, diethylamine, triethylamine, ethylenediamine, procaine, morpholine, pyrroline, piperidine, N- ethylpiperidine, N-methylmorpholine, piperazine as the organic base; or salts with basic amino acids, in particular lysine, arginine, ornithine and histidine.
[0013] Examples of pharmaceutically acceptable salts of the compounds of formula (I) also include salts of inorganic acids like hydrochlorides, hydrobromides, sulfates, phosphates or phosphonates; salts of organic acids, in particular acetates, formates, propionates, lactates, citrates, fumarates, maleates, benzoates, tartrates, malates, methanesulfonates, ethanesulfonates, toluenesulfonates or benzenesulf- onates; or salts with acidic amino acids, in particular aspartate or glutamate.
[0014] Solvates for the purposes of the invention refer to those forms of the compounds of the invention which in the solid or liquid state form a complex by coordination with solvent molecules. Hydrates are a specific form of solvates in which the coordination takes place with water.
[0015] In the context of this invention the substituents have the following definitions unless specified otherwise.
[0016] The term alkyl refers to branched or straight-chain (Ci-C6)-alkyl, preferably (G-C4)-alkyl, such as in particular methyl, ethyl, propyl, butyl, isopropyl, isobutyl and tert.-butyl. The term alkylamino refers to an alkyl substituent linked via an amino group. The term alkylcarbonyl refers to an alkyl substituent linked via a carbonyl group. The term alkylaminocarbonyl refers to an alkylamino substituent linked via a carbonyl group.
[0017] The term cycloalkyl refers to aliphatic C3-C8, preferably C3-C6, rings such as in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0018] The term alkoxy refers to branched or straight-chain (Ci-C6)-alkoxy, preferably (Ci-C4)-alkoxy, such as in particular methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy and tert.-butoxy. The term alkoxycarbonyl refers to an alkoxy substituent linked via a carbonyl group.
[0019] The term heteroaryl refers to cyclic heteroaromatic groups with 5-10 ring atoms, preferably with 5-6 ring atoms, and with up to 4, preferably with up to 2, heteroatoms selected from the group consisting of N, O, S, in which N can also form an N-oxide. Preferred are monocyclic heteroaryl groups with 5-6 ring atoms including up to 2 hetero atoms selected from the group consisting of N, O and S, such as in particular thiophene, benzothiophene, furan, benzofuran, pyrrole, pyrazole, imidazole, thiazole, thiadiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyri- dazine, indole, isoindole, purine, quinoline or isoquinoline. Many other suitable heteroaryl groups for the purpose of the invention are known to the person skilled in the art or can be readily found in the literature.
[0020] The term heterocyclyl refers to saturated or partially unsaturated heterocyclic groups with 4-10 ring atoms, preferably with 5-6 ring atoms, and with up to 3, preferably with up to 2, heteroatoms selected from the group consisting of N, O, S, SO and S02, in which N can also form an N-oxide. Preferred are saturated monocyclic heterocyclyl groups with 5-6 ring atoms including up to 2 hetero atoms selected from the group consisting of N, O and S, such as in particular pyrrolidine, pyrroline, tetrahydrofuran, tetrahydrothiophene, thiazolidine, imidazolidine, imidazoline, piperidine, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, mor- pholine, thiomorpholine, piperazine, piperidazine. Many other suitable heterocyclyl groups for the purpose of the invention are known to the person skilled in the art or can be readily found in the literature.
[0021] The term halogen refers to fluorine, chlorine, bromine or iodine; preferably fluorine or chlorine.
[0022] The term aminocarbonyl refers to an amino group linked via a car- bonyl group.
[0023] The term carbonylamino refers to a carbonyl group linked via an amino group.
[0024] The term carboxy refers to a carboxylic acid group, i.e. a -COOH group.
[0025] The term carbonyloxy refers to a carbonyl group linked via an oxygen.
[0026] The present invention also relates to compounds of formula (I) in which
R1 and R2 independently of one another represent hydrogen or (G-C4)-alkyl, or
R1 and Rz together with the carbon atom to which they are bonded form a (C3- C8)-cycloalkyl,
R3 represents -(CH2)m-(S02)OH or -0-(CH2)o-(S02)OH, wherein m and o independently of one another represent an integer 0, or 1 and wherein any CH2-group contained in the residues which R3 represents may be substituted with one or two (G-C4)-alkyl-residues, represents CR4 or N, represents hydrogen or halogen, represents a bond or an alkyl-chain having one, two or three carbon atoms, whereby the alkyl-chain may be substituted with one, two or three sub- stituents, selected independently of one another from the group consisting of carboxy, aminocarbonyl and (Ci-C4)-alkyl, whereby alkyl in turn may be substituted with a substituent selected from the group consisting of hydroxy and carboxy, represents a bond, O, NH or S, represents (C6-Cio)-aryl or 5- to 10-membered heteroaryl, whereby aryl and heteroaryl are substituted with a substituent of the following formula
Figure imgf000013_0001
wherein
Rl , R2b and R3b independently of one another represent hydrogen, amino, hydroxy, (G-C4)-alkyl, 4-, 5-, 6- or 7-membered het- erocyclyl or 5- or 6-membered heteroaryl, whereby heterocyclyl and heteroaryl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, (G-C4)- alkylcarbonyl, (G-C4)-alkoxy, mono- or di-(G-C4)- alkylamino, mono- or di-(Ci-C4)-alkylaminocarbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), -C(=NH)CH3 and (G- C4)-alkyl, and whereby alkyl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, carbonyloxy, aminocarbonyl, carbonyl- amino, (C1-C4)-alkylcarbonyl, (G-C4)-alkoxy, mono- or di-(Ci-C4)-alkylamino, mono- or di-(G-C4)-alkylamino- carbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), -CH(=NH)CH3, (C6-Cio)-aryl, 5- or 6-membered heteroaryl and 5- or 6-membered heterocyclyl, whereby heteroaryl and heterocyclyl in turn may be substituted with (G-C4)-alkyl, or
R2b and R3 together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle including one, two or three further heteroatoms selected from the series N, O and S and Rlb is as defined above,
R4b represents hydrogen, amino, hydroxy, (G-C4)-alkyl or (G- C4)-alkoxy, whereby amino and hydroxy may be substituted with one or two substituents selected independently of one another from the group consisting of (G-C4)- alkylcarbonyl, mono- or di-(Ci-C4)-alkylaminocarbonyl and (Ci-C4)-alkyl, and whereby alkyl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, car- bonyl, carboxy, aminocarbonyl, (G-C^-alkylcarbonyl, (Ci-C4)-alkoxy, mono- or di-(Ci-C4)-alkylamino, mono- or di-(Ci-C4)-alkylaminocarbonyl, -NH-CH(=NH), -NH- C(=NH)(NH2), -CH(=NH)CH3, (G-C4)-alkyl, (C6-Ci0)-aryl and 5- or 6-membered heteroaryl,
R5b represents hydrogen or (G-C4)-alkyl,
Q represents a bond, CH2 or NH, k represents an integer 1 or 2, and
* is the linkage site to the residue represented by A, and whereby aryl and heteroaryl further may be substituted with one or two substituents selected independently of one another from the group consisting of halogen, cyano, amino, hydroxy, (Ci-C4)-alkyl, (G-C4)- alkoxy, mono- or di-(Ci-C4)-alkylamino, amino-(Ci-C4)-alkyl, hydroxy- (Ci-C4)-alkyl or carboxy, whereby alkyl, alkoxy, alkylamino, aminoalkyl, hydroxyalkyl and carboxy in turn may be substituted with a substituent selected from the group consisting of halogen, (G-C4)-alkyl and carbonyl, and represents an integer 0 or 1 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
[0027] The present invention also relates to compounds of formula (I) in which
R1 and R2 independently of one another represent hydrogen or (G-C4)-alkyl, or
R1 and Rz together with the carbon atom to which they are bonded form a (C3- C8)-cycloalkyl,
R3 represents -(S02)OH or -0-(CH2)0-(S02)OH, wherein o is an integer 0 or 1, and wherein any CH2-group contained in the residues which R3 represents may be substituted with one or two (G-C4)-alkyl-residues,
X represents CH,
Z represents an alkyl-chain having two or three carbon atoms, whereby the alkyl-chain may be substituted with one or two substitu- ents selected independently of one another from the group consisting of carboxy, aminocarbonyl, methyl, hydroxymethyl, hydroxyethyl, represents O represents phenyl or 5- or 6-membered heteroaryl, whereby phenyl and heteroaryl are substituted with a substituent of the following formula
Figure imgf000017_0001
wherein
Rlb, R2b and R3b independently of one another represent hydrogen, amino, hydroxy, (Ci-C4)-alkyl or 4-, 5-, 6- or 7-membered heterocyclyl, whereby heterocyclyl may be substituted with one or two substituents selected independently of one another from the group consisting of amino, carboxy, mono- or di-(Ci-C4)-alkylamino, and (G-C4)-alkyl, and whereby alkyl may be substituted with one or two substituents selected independently of one another from the group consisting of hydroxy, amino, carboxy, car- bonyloxy, aminocarbonyl, carbonylamino, mono- or di- (Ci-C4)-alkylamino, mono- or di-(Ci-C4)-alkylamino- carbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), phenyl, 6- membered heteroaryl and 5- or 6-membered heterocy- clyl, or
R2b and R3 together with the nitrogen atom to which they are bonded form a 6-membered heterocycle including one or two nitrogen atoms and Rlb is hydrogen,
R4b represents hydrogen or amino, whereby amino may be substituted with one or two (Ci-C4)-alkyl substituents,
R5b represents hydrogen,
Q represents a bond, k represents an integer 1 or 2, and
* is the linkage site to the residue represented by A, and whereby phenyl und heteroaryl further may be substituted with one or two substituents selected independently of one another from the group consisting of halogen, cyano, amino, hydroxy, (Ci-C4)-alkyl or hydroxy-(G-C4)-alkyl, whereby hydroxyalkyl in turn may be susbstituted with a carbonyl sub- stituent, and represents 0 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
[0028] The present invention also relates to compounds of formula (I) in which independently of one another represent hydrogen or methyl, represents -(S02)OH or -0-(S02)OH, represents CH, represents an alkyl-chain having two or three carbon atoms, whereby the alkyl-chain may be substituted with one or two substitu- ents, selected independently of one another from the group consisting of carboxy and methyl, represents O, represents phenyl or 6-membered heteroaryl, whereby phenyl and heteroaryl are substituted with a substituent of the following formula
Figure imgf000019_0001
wherein
Rl and R2b represent hydrogen,
R3b represents hydrogen, amino, hydroxy, (Ci-C4)-alkyl or 4-, 5- or 6-membered nitrogen-containing heterocyclyl, whereby alkyl may be substituted with a substitu- ent selected from the group consisting of hydroxy, amino, carboxy, carbonyloxy, mono- or di-(0-C4)- alkylamino, -NH-CH(=NH), -NH-C(=NH)(NH2), 5- or 6-membered nitrogen-containing heteroaryl and 5- or 6-membered nitrogen-containing heterocyclyl,
Q represents a bond,
* is the linkage site to the residue represented by A, and whereby aryl and heteroaryl further may be substituted with one sub- stituent selected from the group consisting of halogen, cyano, amino, hydroxy, (Ci-C4)-alkyl or hydroxy-(CrC4)-alkyl
1 represents 0 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
[0029] The present invention also relates to compounds of formula (I) in which
R1 and R2 represent methyl, R3 represents -0-(S02)OH, X represents CH, Z represents an alkyl-chain having two carbon atoms, whereby the alkyl-chain may be substituted with a carboxy substituent,
Y represents O, A represents phenyl substituted with a substituent of the following formula
Figure imgf000021_0001
wherein
Rlb and R2b represent hydrogen, represents aminoethyl, azetidine, pyrrolidine or piperi- dine
Q represents a bond,
* is the linkage site to the residue represented by A, and 1 represents 0 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
[0030] The present invention also relates to compounds of formula (I) in which
R1 and R2 represent methyl,
R3 represents -0-(S02)OH,
X represents CH,
Z represents a two carbon alkyl-chain, substituted with a carboxy substit- uent,
Y represents O,
A represents phenyl substituted with a substituent of the following formula
Figure imgf000022_0001
wherein
Rlb and R2 represent hydrogen, R3b represents aminoethyl, azetidine, pyrrolidine or piperi- dine,
Q represents a bond,
* is the linkage site to the residue represented by A, and
1 represents 0 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
[0031] In particular the present invention relates to compounds of formula (I) in which
A represents a group selected from the following formulae
Figure imgf000024_0001
Figure imgf000025_0001
and the salts thereof, the solvates thereof and the solvates of the salts thereof.
[0032] The present invention also relates to methods for the preparation of compounds of formula (I). The compounds of the present invention may be prepared by removing the protecting group from compounds of formula
Figure imgf000026_0001
in which Pg represents a protecting group and P^-R3, A, 1, X, Y and Z are as defined above, under acidic conditions.
[0033] Acidic conditions may involve treating the compounds of formula (II) with formic acid, acetic acid, trifluoroacetic acid or hydrochloric acid at temperatures ranging from 0°C to 100°C for a time ranging from 10 min to 16 hours, preferably with 90% formic acid at a temperature of 30-60°C for 30-60 min.
[0034] The compounds of formula (II) can be synthesized by reacting compounds of formula
Figure imgf000027_0001
in which Pg represents a protecting group and A, 1, X, Y and Z are as defined above, with compounds of formula
Figure imgf000027_0002
in which R1, R2 and R3 are as defined above.
[0035] The reaction generally takes place in inert solvents in the presence of a coupling reagent and where applicable with addition of a base at a temperature ranging from -20°C to 80°C for 1-24 hours, preferably at a temperature of 20-30°C overnight. Inert solvents are for example dichloromethane (DCM), trichloromethane, benzene, toluene, tetrahydrofuran (THF), 1,4-dioxane, N,N-dimethylformamide (DMF), Ν,Ν-dimethylacetamide (DMA), N-methylpyrrolidin-2-one (NMP) and ace- tonitrile as well as mixtures of the aforementioned solvents. A preferred solvent is N,N-dimethylformamide. [0036] Suitable coupling reagents are for example carbodiimides such as Ν,Ν'-diethyl-, Ν,Ν,'-dipropyl-, Ν,Ν'-diisopropyl-, Ν,Ν'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl)-N'-ethylcarbodiimid-hydrochloride (EDC), N-cyclohe- xylcarbodiimid-N'-propyloxymethyl-polystyrene (PS-Carbodiimide) or carbonyl compounds such as carbonyldiimidazole (CDI), or 1,2-oxazolium compounds such as 2-ethyl-5 -phenyl- l,2-oxazolium-3-sulf ate or 2-tert.-butyl-5-methyl-isoxazolium-per- chlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l,2-dihydro- chinoline, or propanphosphonic acid anhydride, or isobutylchloroformate, or bis-(2- oxo-3-oxazolidinyl)-phosphorylchloride, or 0-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HBTU), 2-(2-oxo-l-(2H)-pyridyi)-l, 1,3,3- tetramethyluroniumtetrafluoroborate (TPTU) or 0-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluroniumhexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-l-yloxytris(dimethylamino)-phosphoniumhexafluoropho- sphate (BOP), or benzotriazol-l-yloxytris(pyrrolidino)-phosphoniumhexafluoropho- sphate (PyBOP), or N-hydroxysuccinimide as well as mixtures of the aforementioned coupling reagents with or without the addition of a base. In the latter case both inorganic and organic bases may be used. Suitable bases are for example carbonates and bicarbonates, triethylamine, diisopropylethylamine, N-methylmorpholine, N- methylpiperidine or 4-dimethylaminopyridine. Preferably, reactions are carried out with a mixture of a carbodiimide and 1-hydroxybenzotriazole with or without the addition of sodium bicarbonate as base.
[0037] The compounds of formula (III) can be prepared selectively with the preferred Z-orientation of the oxime by reacting compounds of formula
Figure imgf000028_0001
in which Pg represents a protecting group, and X is as defined above with compounds of formula
A
(CH2),
r
I
.0
(VI), in which A, 1, Y and Z are as defined above.
[0038] The reaction generally takes place in protic solvents or in solvent mixtures containing at least one protic solvent at a temperature ranging from 0°C to 100°C for 1-24 hours. Suitable protic solvents are for example methanol, ethanol, iso- propanol, tert.-butanol, water or acetic acid. Solvents suitable to form mixtures are for example dichloromethane, trichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile and Ν,Ν-dimethylformamide. Preferably, the reaction is carried out in a mixture of anhydrous ethanol and chloroform at 20-30°C overnight.
[0039] Compounds of formula (IV) can be synthesized according to the following literature references: J. Org. Chem. 1982, 47 (26), 5160-5167; WO 2007/65288; J. Antibiotics 1985, 38 (11), 1536-1549; WO 2008/116813; Org. Proc. Res. Dev. 2002, 6 (6), 863-868; EP 336667; DE 3336262; BE 904699 or by adapting the referenced procedures in a way known to a person skilled in the art.
[0040] Compounds of formula (V) can be synthesized according to the following literature references: Chem. & Pharm. Bull., 1990, 38(12), 3476 - 3479; Bioorg. Med. Chem., 2007, 38 (21), 6716-6732; Chem. & Pharm. Bull., 1990, 38(12), 3476 - 3479 or Bioorg. Med. Chem., 2007, 38(21), 6716-6732.
[0041] The compounds of formula (VI) can be prepared by deprotecting compounds of formula
Figure imgf000030_0001
in which A, 1, Y and Z are as defined above.
[0042] The deprotection reaction generally takes place with hydrazine, ammonia or methylamine or a salt or a solvate thereof in protic solvents or in solvent mixtures containing at least one protic solvent at a temperature ranging from 0°C to 100°C for 1-24 hours. Protic solvents are for example methanol, ethanol, iso- propanol, tert.-butanol, water or acetic acid. Suitable solvents to form mixtures are for example dichloromethane, trichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile and Ν,Ν-dimethylformamide. Preferably, the reactions are carried out with hydrazine monohydrate in anhydrous ethanol at 20-30°C for 2-6 hours.
[0043] The compounds of formula (VII) can be prepared by reacting compounds of formula
Figure imgf000030_0002
(VIM) in which Lg represents a leaving group and A, 1, Y and Z are as defined above with N-hydroxy-phthalimide. [0044] The reaction can be performed as an alkylation type (Lg = halide, mesylate, tosylate, triflate or similar) or a Mitsunobu type (Lg = OH) reaction. Alkylation type reactions generally take place in the presence of an inorganic or organic base in aprotic solvents at a temperature ranging from 0°C to 100°C for 1-24 hours.
[0045] Mitsunobu type reactions are generally carried out in the presence of triphenylphosphine and an alkyl azodicarboxylate in aprotic solvents at a temperature ranging from 0°C to 100°C for 1-24 hours. Suitable aprotic solvents are for example acetonitrile, tetrahydrofuran, dichloromethane, trichloromethane, 1,4- dioxane, N,N-dimethylformamide, JV,N-dimethylacetamide and JV-methyl-pyrolidin- 2-one. Preferably, the reaction takes place under Mitsunobu conditions (Lg = OH) in the presence of triphenylphosphine and diisopropyl azodicarboxylate in anhydrous tetrahydrofuran at 0°C to 30°C for 2-6 hours.
[0046] In an alternative preferred method the reaction takes place under alkylation conditions in the presence of potassium carbonate or 1,8-diazabi- cyclo[5.4.0]undec-7-ene (DBU) in acetonitrile or Ν,Ν-dimethylformamide at 20°C to 80°C for 2-16 hours. Examples for preferred compounds of formula (VIII) are compounds of formulae
Figure imgf000031_0001
in which Pg represents an alkyl- or arylalkylester protecting group and A is as defined above. [0047] The compounds of formula (Villa) and (VHIb) can be synthesised by converting the cyano group in compounds of formula
Figure imgf000032_0001
in which Pg represents an alkyl- or arylalkylester protecting group into the required substituted or unsubstituted amidine functionality.
[0048] The conversion of the cyano(hetero)aryl to the corresponding ami- dine can be achieved under a range of different acidic and alkaline conditions.
[0049] One possibility is to treat the cyano(hetero)aryl with hydrochloric acid gas in a protic solvent, like methanol or ethanol, at 0°C to 30°C for 2-24 hours. The formed O-alkyl amidate intermediate is then treated with an ammonia solution or an amine in the same solvent at 20°C to 50°C for 1-16 hours. Hydrochloric acid gas may also be formed in-situ from acetylchloride or thionylchloride; ammonium chloride in the presence of a base like triethylamine or diisopropylethylamine may also be used instead of an ammonia solution.
[0050] A further possibility is to react the cyano(hetero)aryl with an amine, ammonium chloride or an amine salt in the presence of trimethylaluminium in a non-protic solvent, like toluene or dichlorobenzene, at 20°C to 120°C for 1-16 hours.
[0051] A further option is to treat the cyano(hetero)aryl with hydroxylamine in polar solvents, like ethanol, water or dimethylsulfoxide or a mixture of the aforementioned solvents, at 20°C to 80°C for 1-16 hours. The formed amidoxime intermediate is then de-oxygenated using hydrogen over palladium on carbon in acetic acid at 20°C to 50°C for 4-24 hours. Hydroxylamine hydrochloride in the presence of triethylamine or diisopropylethylamine may be used instead of hydrox- ylamine; the de-oxygenation may also be carried out using a co-solvent, like methanol, ethanol or 1,4-dioxane, or with the additional acetic acid anhydride.
[0052] A further option is to treat the cyano(hetero)aryl with sodium alk- oxide in the corresponding alcohol, preferably with sodium methoxide in methanol, at 20°C to 50°C for 2-20 hours. The formed O-alkyl amidate intermediate is then treated with an ammonia solution or an amine as described above.
[0053] A further option is to treat the cyano(hetero)aryl with lithium hex- amethyldisilazide in an inert solvent like tetrahydrofuran at 0°C to 20°C for 2-20 hours. The formed silyl protected amidine intermediate is then de-protected by treating with an acid in a polar solvent, preferably with hydrochloric acid in ethanol, at 0°C to 20°C for 1-16 h. The lithium hexamethyldisilazide may thereby be formed in-situ e.g. from n-butyl lithium and hexamethyldisilazane.
[0054] Compounds of formula (IXa) and (IXb) can be synthesized from compounds of formula
/-(Hetero)Aryr
HO
(X) by adapting alkylation procedures reported in the literature, e.g. in /. Am . Chem. Soc. 2009, 131 (10), 3762-3771 and WO 2008096189, or by adapting epoxide ring opening procedures reported in the literature, e.g. in ChemMedChem. 2007, 2 (5), 641-654; Heterocycles 2005, 65 (11), 2667-2674 and Tetrahedron Lett. 2001, 42 (50), 8743-8745.
[0055] Before carrying out the alkylation or epoxide opening, compounds of formula (X) may also first be converted to the corresponding amidine using the methods detailed above. [0056] The compounds of the invention show a valuable range of pharmacological effects which could not have been predicted.
[0057] They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and animals.
[0058] The compounds of the present invention are distinguished in particular by an advantageous range of antibacterial effects.
[0059] The present invention therefore further relates to the use of the compounds of the invention for the treatment and/or prophylaxis of diseases caused by bacteria, especially gram-negative bacteria.
[0060] The present invention further relates to the use of the compounds of the invention for the treatment and/or prophylaxis of diseases, especially of the diseases mentioned below.
[0061] The present invention further relates to the use of the compounds of the invention for the manufacture of a medicament for the treatment and/or prophylaxis of diseases, especially of bacterial infections and in particular the diseases mentioned below.
[0062] The present invention further relates to a method for the treatment and/or prophylaxis of diseases, especially of bacterial infections and in particular the diseases mentioned below, using a therapeutically effective amount of the compounds of the invention.
[0063] The compounds of the invention exhibit an antibacterial spectrum against gram-negative bacteria and selected gram-positive bacteria combined with low toxicity. Compounds of this invention are particularly useful in human and veterinary medicine for the prophylaxis and treatment of local and systemic infec- tions which are caused for example by the following pathogens or by mixtures of the following pathogens:
[0064] Aerobic gram-positive bacteria: Including but not limited to Staphylococcus spp. (S. aureus), Streptococcus spp. (S. pneumoniae, S. pyogenes, S. agalactiae, Streptococcus group C and G) as well as Bacillus spp. and Listeria monocytogenes.
[0065] Aerobic gram-negative bacteria: Enter obacteriaceae, including but not limited to Escherichia spp. (E. coli), Citrobacter spp. (C. freundii, C. diversus), Klebsiella spp. (K. pneumoniae, K. oxytoca), Enterobacter spp. (E. cloacae, E. aerogenes), Morganella morganii, Hafhia alvei, Serratia spp. (5. marcescens), Proteus spp. (P. mirabilis, P. vulgaris, P. penneri), Providencia spp. (P. stuartii, P. rettgeri), Yersinia spp. (Y. enter ocolitica, Y. pseudotuberculosis), Salmonella spp., Shigella spp. and also non-fermenters including but not limited to Pseudomonas spp. (P. aeruginosa), Burkholderia spp. (B. cepacia), Stenotrophomonas maltophilia, and Acinetobacter spp. (A. baumannii, Acinetobacter gen. sp. 13TU, Acinetobacter gen. sp. 3) as well as Bordetella spp. (B. bronchiseptica), Moraxel- la catarrhalis and Legionella pneumophila; furthermore, Aeromonas spp., Haemophilus spp. (H. influenzae), Neisseria spp. (N. gonorrhoeae, N. meningitidis) as well as Alcaligenes spp. (including A. xylosoxidans) , Pasteurella spp. (P. multocida), Vibro spp. (V. cholerae), Campylobacter jejuni and Helicobacter pylori.
[0066] Moreover, the antibacterial spectrum also covers strictly anaerobic bacteria including but not limited to Bacteroides spp. (B. fragilis), Peptostreptococcus spp. (P. anaerobius), Prevotella spp., Brucella spp. (B. abortus), Porphyromonas spp., and Clostridium spp. (Clostridium perfringens).
[0067] The above listing of pathogens is merely exemplary and in no way to be regarded as limiting. Examples of diseases which may be caused by the said pathogens and which may be prevented, improved or cured by the compounds according to the invention are, for example: [0068] Respiratory tract infections such as lower respiratory tract infections, lung infection in cystic fibrosis patients, acute exacerbation of chronic bronchitis, community aquired pneumonia (CAP), nosocomial pneumonia (including ventilator- associated pneumonia (VAP)), diseases of the upper airways, diffuse panbronchiolitis, tonsillitis, pharyngitis, acute sinusitis and otitis including mastoiditis; urinary tract and genital infections for example cystitis, uretritis, pyelonephritis, endometritis, prostatitis, salpingitis and epididymitis; ocular infections such as conjunctivitis, corneal ulcer, iridocyclitis and post-operative infection in radial keratotomy surgery patients; blood infections, for example septicaemia; infections of the skin and soft tissues, for example infective dermatitis, infected wounds, infected burns, phlegmon, folliculitis and impetigo; bone and joint infections such as osteomyelitis and septic arthritis; gastrointestinal infections, for example dysentery, enteritis, colitis, necrotis- ing enterocolitis and anorectal infections; intraabdominal infections such as typhoid fever, infectious diarrhea, peritonitis with appendicitis, pelviperitonitis, and intraabdominal abscesses; infections in the oral region for example infections after dental operations; other infections for example, meliodosis, infectious endocarditis, hepatic abscesses, cholecystitis, cholangitis, mastitis as well as meningitis and infections of the nervous systems.
[0069] In addition to humans, bacterial infections can also be treated in animals, such as primates, pigs, ruminants (cow, sheep, goat), horses, cats, dogs, poultry (such as hen, turkey, quail, pigeon, ornamental birds) as well as productive and ornamental fish, reptiles and amphibians.
[0070] The compounds of the invention may act systemically and/or locally. They can for this purpose be administered in a suitable way, such as, for example, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermal- ly, transdermally, conjunctivally, otically or as an implant or stent.
[0071] For these administration routes the compounds of the invention can be administered in suitable administration forms. [0072] Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption step (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
[0073] Suitable for the other administration routes are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops, solutions, sprays; tablets, films/wafers or capsules, for lingual, sublingual or buccal administration, suppositories, preparations for ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as for example patches), milk, pastes, foams, dusting powders, implants or stents.
[0074] The compounds of the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, non-toxic, pharmaceutically acceptable excipients. These excipients include inter alia carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as, for example, ascorbic acid), colors (e.g. inorganic pigments such as, for example, iron oxides) and taste and/or odor corrigents.
[0075] The present invention further relates to medicaments which comprise at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically acceptable excipients, as well as to their use for the aforementioned purposes. [0076] The present invention further relates to medicaments which comprise at least one compound of the invention in combination with at least one further active compound, as well as to their use for the aforementioned purposes.
[0077] Examples for the further active compound include /^-lactamase inhibitors.
[0078] Examples for suitable /3-lactamase inhibitors to be used in combination with the compounds of the invention include clavulanic acid, tazobactam, sulbactam, avibactam (NXL-104), and MK-7655.
[0079] The minimum amount of the compounds of the invention to be administered is a therapeutically effective amount. The term "therapeutically effective amount" means an amount of compound which prevents the onset of, alleviates the symptoms of, stops the progression of, and/or eliminates a bacterial infection in humans or animals.
[0080] Typically, an effective dosing schedule of the compounds of the invention for adults is about 50 mg to about 3000 mg of a compound of formula (I) in a single dose; in another embodiment, an effective single dose is about 100 mg to about 2000 mg. In another embodiment, an effective single dose is about 500 mg to about 1200 mg. Typically the dosages are given 1 to 4 times per day. In one embodiment, the dosages are given 3 times per day. In some cases, it may be necessary to use dosages outside these limits.
[0081] It may nevertheless be necessary where appropriate to deviate from the stated amounts, in particular as a function of body weight, administration route, individual response to the active ingredient, type of preparation and time or interval over which administration takes place. Thus, in some cases it may be sufficient to make do with less than the aforementioned minimum amount, whereas in other cases the upper limit mentioned must be exceeded. In the case of an administration of larger amounts, it may be advisable to distribute these in a plurality of single doses over the day.
[0082] The percentage data in the following tests and examples are, unless indicated otherwise, percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid/liquid solutions are based in each case on volume. The statement "w/v" means "weight/volume". Thus, for example, "10% w/v" means: 100 ml of solution or suspension contain 10 g of substance.
Examples
Abbreviations
δ: chemical shift in ppm
br s: broad singlet in NMR
CDC13: deuterated chloroform
d: doublet in NMR
dd: doublet of doublet in NMR
DCM: dichloromethane
DMF: Ν,Ν-dimethylformamide
DMSO: dimethyl sulfoxide
EtOAc: ethyl acetate
ES~: negative ion mode in electrospray ionization mass spectrometry
ES+: positive ion mode in electrospray ionization mass spectrometry g: gram(s)
h: hour(s)
HPLC: high performance liquid chromatography
Hz: hertz
J: coupling constant in NMR
L: liter(s)
M: molarity
m: multiplet in NMR
mg: milligram(s)
MHz: megahertz
min: minute(s)
mL: milliliter(s)
mmol: millimole(s)
mol: mole(s)
MS: mass spectrometry
N: normality
NMR: nuclear magnetic resonance
q: quartet in NMR s: singlet in NMR
t: triplet in NMR
f-BuOH: tert-butyl alcohol
TFA: trifluoroacetic acid
THF: tetrahydrofuran
TLC: thin layer chromatography
TMS: tetramethylsilane
Analytical Methods
[0083] All ¾ and 19F NMR spectra were recorded on a Varian Oxford AS 400 NMR operating at 400 MHz for Ή, and 376 MHz for 19F respectively. NMR data is recorded in chemical shifts relative to tetramethylsilane (TMS) as internal standard. NMR spectra were run either in CDCI3 containing 0.05 % TMS, CD3OD containing 0.05 % TMS, or DMSO-de containing 0.03 % TMS.
[0084] HPLC analyses were performed using a Waters 2695 Separation Module and a Waters 2996 Photodiode Array Detector system or a Waters 600 Controller including a Waters 717plus Autosampler and a Waters 2996 Photodiode Array Detector system on an Atlantis Τ3-Ο8-3μπι-4.6χ150πιηι column with an acetonitrile/aqueous 0.1 % H3PO4 gradient at 22°C, and a flow rate of 1 mL/minute.
[0085] Preparative HPLC was performed on a Waters Prep LC 2767 System utilizing a Waters Prep HPLC Controller, and a Waters 2487 Dual Wave Absorbance Detector on a Οεπι- 18-10μπι-50χ100πιπι (flow rate of 70 mL/minute), X-Bridge-C- 18-5μπι-30χ100πιπι (flow rate of 42 mL/minute), Ace-C-18^m-30x250mm (flow rate of 40 mL/minute), or GemNX-C-18-^m-50x250mm (flow rate of 80 mL/minute) column, using an acetonitrile/aqueous 0.1 % trifluoroacetic acid gradient or an acetonitrile/aqueous 0.1 % formic acid gradient at 22 °C.
[0086] Mass spectra were recorded on a Waters 2795 Separation Module using either ES" or ES+ ionization modes.
[0087] Column chromatography was performed using Desican Inc. Silica Gel: CC Grade (230 - 400 Mesh).
[0088] Commercial solvents and reagents were generally used without further purification. All products were dried before characterization and use in subsequent synthetic steps. General Synthetic Methods
Synthesis of the ?-lactam building blocks ( S/45)-3-Amino-4-methyl-2-oxoazetidine-l-sulfonic acid
Figure imgf000043_0001
[0089] Compound 1_1_1 was synthesized according to David M. Floyd, Alan W. Fritz, Josip Pluscec, Eugene R. Weaver, Christopher M. Cimarusti /. Org. Chem., 1982, 47 (26), 5160-5167.
1.2 (35/4S)-3-Amino-4-methyl-l-(sulfooxy)azetidin-2-one
Figure imgf000043_0002
1 2 1
[0090] Compound 1_2_1 was synthesized according to WO 2007/65288
1.3 ( 5/4/?)-3-Amino-4-methyl-2-oxoazetidine-l-sulfonic acid
Figure imgf000043_0003
[0091] Compound 1_3_1 was synthesized according to David M. Floyd, Alan W. Fritz, Josip Pluscec, Eugene R. Weaver, Christopher M. Cimarusti /. Org. Chem., 1982, 47 (26), 5160-5167.
1.4 (3S,4R) -3-Amino-4-methyl-l-(sulfooxy)azetidin-2-one
Figure imgf000044_0001
- ot reon ne
Figure imgf000044_0002
[0092] To a solution of potassium hydroxide (2.53 g, 45.1 mmol, in 28 mL of water) at room temperature was added L-allothreonine (3.0 gm, 25.1 mmol) and the mixture was cooled to 24°C using an ice-bath. A dz'-teri-butyl dicarbonate solution (Boc20, 6.02 g in 15 mL of t-BuOH) was then added portionwise over 20 minutes to the colorless reaction mixture without cooling to form a white cloudy solution. The reaction mixture was then stirred at room temperature for 5 h until TLC (acetoni- trile/acetone/acetic acid, 15:15:1) indicated the absence of any starting material. O- benzyloxyhydroxylamine hydrochloride (6.0 g, 37.6 mmol) was then added in portions over 7 min, 6.0 N HC1 (4 mL) was then added in portions maintaining pH 4 (white fumes), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.81 g, 25.1 mmol) was then added in portions to the reaction mixture while cooling. The reaction mixture was left stirring at room temperature overnight, saturated with sodium chloride and extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, dried over MgS04, filtered, evaporated to dryness and dried under vacuum to afford 1_4_2 (6.5 g, 79.5 %) as viscous oil.
[0093] Ή NMR (400 MHz, DMSO-rf6): δ = 1.02 (d, / = 5.8 Hz, 3 H), 1.36 (s, 9 H), 3.49 - 3.83 (m, 1 H), 3.56 - 3.70 (m, 1 H), 4.70 - 4.81 (m, 2 H), 4.86 (d, / = 4.6 Hz, 1 H), 6.73 (d, / = 8.5 Hz, 1 H), 7.29 - 7.42 (m, 5 H), 11.09 (s, 1 H).
[0094] Diethyl azodicarboxylate (DEAD, 0.51 mL. 3.08 mmol) was added dropwise to a solution of compound 1_4_2 (1.0 g, 3.08 mmol) and tri- phenylphosphine (0.81 g, 3.08 mmol) in THF (40 mL) at room temperature over 5 min. The reaction mixture was heated at 50°C for 6 h and concentrated to give a viscous oil which was purified by column chromatography eluting with ethyl ace- tate/hexane (40: 60) to give compound 1_4_3 (0.30 g, 31.7 %).
[0095] Ή NMR (400 MHz, DMSO-dg): δ = 1.01 (d, / = 5.8 Hz, 3 H), 1.38 (s, 9 H), 3.87 - 4.11 (m, 1 H), 4.62 (dd, / = 9.3 and 5.1 Hz, 1 H), 4.78 - 5.02 (m, 2 H), 7.21 - 7.51 (m, 5 H), 7.64 (d, / = 9.3 Hz, 1 H).
[0096] 10 % Pd/C (100 mg, wet) was added to a solution of compound 1_4_3 (1.0 g, 3.26 mmol) in ethanol (100 mL) and the mixture was hydrogenated at 30 psi for 3 h. TLC (1:1, ethyl acetate in hexanes) showed completion of the reaction. The catalyst was removed by filtration through a bed of celite and was washed with methanol (2 x 50 mL). The filtrate was concentrated under vacuum resulting in compound 1_4_4 as a solid (0.7 g, 99 %) which was used in the next step without further purification.
[0097] Ή NMR (400 MHz, DMSO-c¾: δ = 1.05 (d, / = 6.2 Hz, 3 H), 1.37 (s, 9 H), 3.69 - 4.09 (m, 1 H), 4.60 (dd, / = 8.9 and 5.1 Hz, 1 H), 7.62 (d, / = 9.3 Hz, 1 H), 9.92 - 10.40 (m, 1 H). [0098] Sulfur trioxide-pyridine complex (1.76 g, 11.09 mmol) was added to a solution of compound 1_4_4 (2.0 g, 9.24 mmol) in anhydrous pyridine (20 mL) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum resulting in a foam, which was triturated with dichloromethane (10 mL) and hexane (30 mL) to give compound 1_4_5 as a white solid (3.46 g) which was used directly for the next step.
[0099] Compound 1_4_5 (3.46 g, 9.21 mmol) was dissolved in a 0.5 M solution of potassium dihydrogen phosphate (100 mL), extracted with ethyl acetate (2 x 100 mL), and the ethyl acetate extract was discarded. Tetra-n-butyl ammonium sulfate (3.13 g, 9.21 mmol) was added to the aqueous layer in one portion. The mixture was stirred at room temperature for 1 h and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum resulting in compound 1_4_6 as a foam (4.0 g) which was used directly for the next step.
[00100] Compound 1_4_6 (4.00 g, 7.41 mmol) was dissolved in 98 % formic acid (16 mL) and the mixture was stirred at room temperature for 3 h. A white precipitate began to form after few minutes. Dichloromethane (30 mL) was added to the reaction mixture and the mixture was cooled to 0-5 °C, and kept overnight in the fridge. The white precipitate formed was isolated by filtration and dried under vacuum to give compound 1_4_7 (1.00 g, 75.8 %).
[00101] ¾ NMR (400 MHz, DMSO-c¾: δ = 1.32 (d, / = 6.2 Hz, 3 H), 4.30 - 4.42 (m, 1 H), 4.50 (d, / = 5.0 Hz, 1 H), 8.31 - 9.20 (m, 3 H). 1.5 (3S)-3-Amino-4,4-dimethyl-l-(sulfooxy)azetidin-2-one
Figure imgf000047_0001
TEMPO, NaCI02 BnONH2-HCI
S03-Pyridine complex NaCIO (cat.) ΒθεΝΗ'· θΗ ° HC
N∞aHCO0 pyri
j BT dine / 0»C/2 h
Sodium phosphate Buffer Me
acetonitrile/water OH D F K2C03, EtOAc
Figure imgf000047_0002
1 5 5 1 5 6
KH2P04 Bu„NHSO,
Figure imgf000047_0003
[00102] Acetyl chloride (AcCI, 96.0 mL, 1.35 mol) was added dropwise over 15 min to pre-cooled methanol (650 mL) at 0°C. The solution was stirred for an additional 5 min, and then solid D-serine (51.0 g, 0.49 mol) was added in portions. The resulting mixture was heated under reflux for 2 h, then cooled to room temperature and the solvent was removed under reduced pressure. The solid obtained was triturated with 3:1 hexane/ether (300 mL) to give compound 1_5_2 as an off-white solid, which was thoroughly dried overnight in an oven under vacuum to give compound 1_5_2 (87.0 g, 99 %) as a white solid.
[00103] Ή NMR (400 MHz, Methanol-^): δ = 3.72 (s, 3H), 3.81 (br. s, 2H), 4.07 (s, 1H), 5.6 (br. s, 1H), 8.78 (br. s, 2H). [00104] Triethylamine (TEA, 183 mL, 1.3 mol) was added dropwise to a solution of compound 1_5_2 (94.0 g, 0.605 mol) in THF (3 L) at 0°C. To the resulting thick white suspension a solution of rfz'-fert-butyldicarbonate (135.0 g, 0.65 mol) in THF (500 mL) was added dropwise over a period of 1.5 h at the same temperature. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was partitioned between diethyl ether (3 L) and a saturated aqueous sodium bicarbonate solution (3 L). The aqueous layer was extracted with diethyl ether (3 x 2 L), the organic extracts were combined and dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 1_5_3 (134.0 g, 75 %) as a viscous oil.
[00105] ¾ NMR (400 MHz, CDC13): δ = 1.42 (s, 9H), 3.80 (s, 3H), 3.90 (m, 2H), 4.38 (br. s, 1H), 5.44 (br. s, 1H).
[00106] A 3.0 M solution of MeMgBr in diethyl ether (450 mL, 1.35 mol) was added dropwise to a cooled solution of compound 1_5_3 (50.0 g, 0.23 mol) in diethyl ether (2 L) at -78°C. The reaction mixture was allowed to reach room temperature, stirred at room temperature for 1 h, and then poured into a saturated aqueous ammonium chloride solution (2.5 L). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 2 L). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether/hexane (1:2, 500 mL) and cooled in an ice bath. The precipitated solid was isolated by filtration to give compound 1_5_4 (33.0 g, 66 %) as a colorless solid.
[00107] ¾ NMR (400 MHz, CDC13): δ = 1.25 (s, 3 H), 1.35 (s, 3 H), 1.43 - 1.48 (m, 9 H), 2.49 (br. s, 1 H), 2.62 (br. s, 1 H), 3.47 (d, / = 8.9 Hz, 1 H), 3.76 - 3.86 (m, 1 H), 3.98 - 4.09 (m, 1 H), 5.37 (br. s, 1 H).
[00108] 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO, 2.3 g, 15 mmol) was added to a mixture of compound 1_5_4 (33.0 g, 150 mmol) in acetonitrile (750 mL) and sodium phosphate buffer (600 mL, 0.7 M solution, pH 6-7) and the resulting mixture was heated to 35°C. The mixture was then treated by a simultaneous addition of a sodium chlorite solution (34.2 g in 150 mL of water) and 60 drops of a very dilute sodium hypochlorite solution (3 mL of commercial solution in 100 mL of water). The mixture was stirred at 35°C overnight, cooled to room temperature, treated with citric acid (-15 g, pH 3), saturated with sodium chloride and extracted with ethyl acetate (3 x 2 L). The organic extracts were combined and concentrated under reduced pressure. The residue was dissolved in 1.5 L of a 2 M sodium carbonate solution and washed with ethyl acetate (2 x 2 L). The aqueous layer was cooled to 0°C, the pH was adjusted to 3.0 using a 2 M solution of H3P04 and the solution was saturated with sodium chloride. The resulting mixture was extracted with ethyl acetate (3 x 2 L), the organic phases were combined, dried, filtered and concentrated under reduced pressure to give compound 1_5_5 (28.4 g, 81 %) as a colorless solid.
[00109] Ή NMR (400 MHz, DMSO-d6): δ = 1.15 (s, 3 H), 1.17 (s, 3 H), 1.39 (s, 9 H), 3.86 (d, / = 8.6 Hz, 1 H) 6.52 (d, / = 8.9 Hz, 1 H).
[00110] Dicyclohexylcarbodiimide (DCC, 19.5 g, 94.3 mmol) was added to a solution of compound 1_5_5 (20.0 g, 85.7 mmol) in Ν,Ν-dimethylformamide at room temperature followed by 1-hydroxybenzotriazole (HOBt, 12.7 g, 94.3 mmol). The resulting mixture was stirred at room temperature for 30 min, and O-benzyl- hydroxylamine hydrochloride (15.1 g, 94.3 mmol) was added followed by sodium bicarbonate (18.0 g, 214.3 mmol). The reaction mixture was stirred at room temperature for 24 h and filtered through a celite bed, washed with ethyl acetate (2 x 50 mL), and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 30-40 % ethyl acetate in hexane to give compound 1_5_6 (24.5 g, 84.5 %) as a colorless solid.
[00111] Ή NMR (400 MHz, DMSO-rf6): δ = 1.05 (s, 3 H), 1.08 (s, 3 H), 1.26 (s, 9 H), 3.74 (d, / = 9.3 Hz, 1 H), 4.62 (br. s, 1 H), 4.72 (s, 2 H), 6.42 (d, / = 8.9 Hz, 1 H), 7.26 - 7.47 (m, 5 H), 11.03 (br. s, 1 H). [00112] Sulfur trioxide-pyridine complex (58.7 g, 0.368 mol) was added to a solution of compound 1_5_6 (96.0 g, 0.283 mol) in pyridine (1 L) at 0°C in portions and the mixture was stirred for 2 h. The pyridine was removed under vacuum and the residue was triturated with diethyl ether/hexanes (1:10, 1 L) to remove the major portion of the pyridine. A solution of potassium carbonate (240 g in 1.2 L of water) and 500 mL of ethyl acetate were added to the solid intermediate. The resulting mixture was heated under reflux for 2 h, cooled down to room temperature and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 200 mL) and the combined ethyl acetate layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography eluting with 30-40 % ethyl acetate in hexanes. The desired fractions were combined and concentrated. The residue was triturated with 10 % ether in hexane (-400 mL) to give compound 1_5_7 (58.1 g, 64 %) as a colorless solid.
[00113] ¾ NMR (400 MHz, CDC13): δ = 1.08 (s, 3H), 1.32 (s, 3H), 1.43 (s, 9H), 4.30 (d, / = 6.8 Hz, 1H), 4.96 (s, 2H), 7.40 (m, 5H).
[00114] 5 % Pd/C (6.0 g, wet, -50 % water) was added to a solution of compound 1_5_7 (30.0 g, 93.6 mmol) in methanol (600 mL) and the mixture was hydro- genated at 50 psi for 1 h. TLC (1:1, ethyl acetate in hexanes) showed completion of the reaction. The catalyst was removed by filtration through a bed of celite and was washed with methanol (2 x 100 mL). The filtrate was concentrated under vacuum and the resulting solid was triturated with 10 % ether in hexanes (100 mL), filtered and dried in vacuum to give compound 1_5_8 (21.9 g, quant.) as a colorless solid.
[00115] Ή NMR (400 MHz, DMSO-c¾: δ = 1.17 (s, 3H), 1.31 (s, 3H), 1.41 (s, 9H), 4.21 (d, / = 6.8 Hz, 1H), 7.71 (d, / = 6.8 Hz, 1H), 10.01 (br. s, 1H).
[00116] Sulfur trioxide-pyridine complex (39.7 g, 0.249 mol) was added to a solution of compound 1_5_8 (50.0 g, 0.217 mol) in pyridine (500 mL) at 0°C. The resulting mixture was stirred at room temperature for 1.5 h and concentrated under vacuum to give compound 1_5_9 (106.0 g) as a foam, which was dissolved in 4 L of a 0.5 M solution of KH2P04 and extracted with dichloromethane (2 x 400 mL). The aqueous layer was cooled to 0°C and tetra-n-butyl ammonium sulfate (84.8 g, 0.249 mol) was added. The resulting mixture was stirred at 0-5°C for 1 h and extracted with dichloromethane (5 x 500 mL). The combined dichloromethane layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give intermediate 1_5_10 (115.0 g) as a foam which was dissolved in 96 % formic acid (500 mL) and the resulting mixture was stirred at room temperature for 4 h. A white precipitate began to form after few minutes. Dichloromethane (500 mL) was added to the reaction mixture and the mixture was cooled to 0-5°C, and kept in the fridge over the weekend. The white precipitate was isolated by filtration and dried under vacuum to afford compound 1_5_11 (24.5 g, 53 % over 3 steps) as a colorless solid.
[00117] Ή NMR (400 MHz, DMSO-rf6): δ = 1.42 (s, 3H), 1.43 (s, 3H), 4.15 (s, 1H), 8.80 (br. s, 2H).
1.6 {[(3S,4S)-3-Amino-4-methyl-2-oxoazetidin-l-yl]oxy}methanesulfonic acid
Figure imgf000051_0001
1_6 8 1 6 9 [00118] Di-tert-butyl dicarbonate (56.7 g, 59.7 mL, 0.23 mol, Aldrich) was added dropwise to a solution of L-threonine 1_6_1 (23.8 g, 0.2 mol) in THF (200 mL) and a 2 N aqueous sodium hydroxide solution (120 mL) at 0°C. The resulting mixture was stirred at 0°C to room temperature overnight and concentrated under reduced pressure to remove the solvent. The residue was saturated with solid ammonium chloride, cooled to 0°C, acidified with 1 N hydrochloric acid to pH 3, and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was treated with hexane (300 mL) and filtered to give 1_6_2 (39.7 g, 91 %) as a colorless solid.
[00119] Ή NMR (400 MHz, DMSO-d6): δ = 1.06 (d, J = 6.2 Hz, 3 H), 1.37 (s, 9 H), 3.86 (dd, J = 9.1 and 3.3 Hz, 1 H), 3.98 - 4.08 (m, 1 H), 6.29 (d, J = 9.3 Hz, 1 H).
[00120] (Aminooxy)methanesulfonic acid compound 1_6_3 (5.9 g, 46.4 mmol) was added to a solution of compound 1_6_2 (9.4 g, 42.9 mmol) in THF (50 mL) and water (100 mL) at 0°C, the pH of the mixture was adjusted to 4.5 using a IN aqueous potassium hydroxide solution, and a solution of N-(3-dimethyl- aminopropyl)-N-ethylcarbodiimide hydrochloride (EDCI, 9.3 g, 47.1 mmol) in water (30 mL) was added slowly over 20 min. The resulting mixture was stirred at room temperature for 3 h while adjusting to pH 4.0-4.5 with IN sulfuric acid. Tetrabu- tylammonium hydrogensulfate (14.5 g, 42.9 mmol, Aldrich) was added, the pH was adjusted to 3 using IN sulfuric acid and the mixture was extracted with chloroform (5 x 100 mL). The combined chloroform layers were dried over sodium sulfate and concentrated under reduced pressure to give crude compound 1_6_4 (17.5 g) which was dissolved in water (20 mL) and purified on a Dowex 50WX4 Na form ion exchange resin (200 mL) column eluting with water. The first 400 mL of water fractions were collected and lyophilized to give 1_6_5 (6.93 g, 46 %) as a yellow solid. [00121] m NMR (400 MHz, DMSO-i¾: δ = 1.01 (d, J = 6.2 Hz, 3 H), 1.38 (s, 9 H), 3.72 - 3.91 (m, 2 H), 4.24 (s, 2 H), 4.85 (br. s, 1 H), 6.37 (d, J = 8.6 Hz, 1 H), 7.40 (s, 1 H), 11.25 (br. s, 1 H).
[00122] Methanesulfonyl chloride (MsCl, 0.72 g, 6.3 mmol) was added dropwise via a syringe to a solution of 1_6_5 (2.0 g, 5.71 mmol) in pyridine (60 mL) at 0°C. The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in water (10 mL), tetrabu- tylammonium hydrogensulfate (1.87 g, 5.5 mmol) was added, the pH was adjusted to 3 with IN sulfuric acid, and the mixture was extracted with chloroform (5 x 30 mL). The combined chloroform layers were dried over sodium sulfate and concentrated under reduced pressure to give a light brown solid. MS indicated that the product obtained was a mixture of compound 1_6_6, a Ν,Ν,Ν-tributylbutan-l-amonium salt of compound 1_6_5 and a di-Ms by-product. The mixture was used in the next step without further purification.
[00123] A solution of 1_6_6 (3.1 g, 4.8 mmol) in acetone (10 mL) was added dropwise to a suspension of potassium carbonate (3.0 g, 21.7 mmol) in acetone (90 mL) under reflux. The resulting mixture was kept under reflux for 4 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give crude intermediate 1_6_7 which was dissolved in a 0.5 M aqueous KH2P04 solution (15 mL), the pH was adjusted to 3 using IN sulfuric acid, and the mixture was extracted with dichloromethane (6 x 50 mL). The combined dichloromethane layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and purified on a Dowex 50WX4 Na form ion exchange resin (200 mL) column eluting with water. The first 500 mL of water fractions were collected and lyophilized to give 1.3 g of crude product as a yellow solid. MS indicated that the product obtained was a mixture of compound 1_6_8 and compound 1_6_5. This mixture was used in the next step without further purification. [00124] Trifluoroacetic acid (TFA, 10 mL) was added to a suspension of compound 1_6_8 from the previous step as mixture (1.2 g, 3.6 mmol) in dichloro- methane (5 mL) and anisole (5 mL) at 0°C. The resulting mixture was stirred at 0°C for 1 h and concentrated under reduced pressure. The residue was stirred with benzene (10 mL) and evaporated twice, washed with dichloromethane, and dried in vacuum to give crude compound 1_6_9 (1.6 g, quant, with small amount of residual trifluoroacetic acid). This material was used as 47 % pure in next step without further purification.
[00125] The Ή NMR was complex as the product obtained was a mixture of compound 1_6_9 and compound 1_6_5.
[00126] MS (ES ) m/z: [M-Na]- calcd for C5H9N2O5S: 209.02. Found: 209.11.
1.7 {[(3S)-3-Amino-4,4-dimethyl-2-oxoazetidin-l-yl]oxy}methanesulfonic acid
Figure imgf000054_0001
1 7 4 1 7 5
[00127] Chloromethyl methyl sulfide (1.15 mL, 13.8 mmol) was added dropwise to a solution of potassium iodide (2.29 g, 13.8 mmol) in N,N-dimethyl- formamide (40 mL) at room temperature. The resulting mixture was stirred at room temperature for 0.5h, and ferf-butyl {(35)-4,4-dimethyl-l-hydroxy-2-oxoazetidin-3- yljcarbamate 1_7_1 (1.60 g, 6.94 mmol) was added followed by potassium carbonate (1.90 g, 13.8 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was poured into ice water (200 mL) and extracted with ethyl acetate (3 x 30 mL). The combined ethyl acetate layers were washed with water and brine, dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 6:1 ~ 3:1 hexane - ethyl acetate to give compound 1_7_2 (1.73 g, 86 %) as a yellow oil.
[00128] Ή NMR (400 MHz, CDC13): δ = 1.33 (s, 3 H), 1.45 (s, 9 H), 1.54 (s, 3 H), 2.28 (s, 3 H), 4.39 (d, / = 6.6 Hz, 1 H, 4.96 (s, 2 H), 5.10 (d, / = 6.6 Hz, 1 H).
[00129] Sulfuryl dichloride (0.71 mL, 8.78 mmol) was added dropwise to a solution of compound 1_7_2 (1.70 g, 5.85 mmol) in dichloromethane (50 mL) at -78°C. The resulting mixture was stirred at -78°C for 15 min and then at room temperature for 15 min. The reaction mixture was cooled to -78°C and N- ethyldiisopropylamine (DIPEA, 10.1 mL, 58.5 mmol) was added dropwise followed by thioacetic acid (AcSH, 2.1 mL, 29.3 mmol). The resulting mixture was stirred at -78°C for 15 min and then at -78°C to room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (200 mL) and extracted with dichloromethane (3 x 50 mL). The combined dichloromethane layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 6: 1 ~ 3: 1 hexane - ethyl acetate to give compound 1_7_4 (1.25 g, 67 %) as a yellow solid.
[00130] ¾ NMR (400 MHz, CDC13): δ = 1.32 (s, 3 H), 1.45 (s, 9 H), 1.52 (s, 3 H), 2.42 (s, 3 H), 4.36 (d, / = 6.6 Hz, 2 H), 5.03 (d, / = 6.6 Hz, 1 H), 5.36 (s, 2H).
[00131] Compound 1_7_4 (1.10 g, 3.45 mmol) was added to a solution of 3- chloroperoxybenzoic acid (mCPBA, 4.0 g, 13.8 mmol) in dichloromethane (50 mL). The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was treated with formic acid (96 %, 20 mL) and stirred at room temperature for 4 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was treated with dichloromethane (50 mL), stirred at room temperature for 0.5 h and filtered. The filtrate was concentrated under reduced pressure to give crude compound 1_7_5 (0.9 g, 100 %, 0.77 g expected) as a pale yellow solid which was used as it is in the next step.
[00132] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.46 (s, 3 H), 1.48 (s, 3 H), 4.14 (s, 1 H), 4.42 (AB, / = 8.0 and 32.0 Hz, 2 H), 8.72 (br s, 1 H).
1.8 3- Amino- 1 - (sulf ooxy) - 1 -azaspiro [3.4]octan-2-one
Figure imgf000056_0001
[00133] A mixture of N-(ferf-butoxycarbonyl)glycine 1_8_1 (10 g, 57.14 mmol), benzyl chloride (BnCI, 7.30 mL, 62.85 mmol), feira-n-butylammonium bromide (TBAB, 0.19 g, 0.57 mmol) and potassium bicarbonate (6.87 g, 68.57 mmol) in Ν,Ν-dimethylformamide (100 mL) was stirred at room temperature for 72 hours and filtered. The filtrate was concentrated under vacuum. The residue was treated with water and the solid was collected and dried to give compound 1_8_2 (10 g, 67 %). [00134] ¾ NMR (400 MHz, DMSO-c¾: δ = 1.40 (s, 9H), 3.75 (d, / = 6.8 Hz, 2H), 5.10 (s, 2H), 7.20 (t, / = 6.8 Hz, 1H), 7.33 (m, 5H).
[00135] n-Butyl lithium (35.85 mL, 1.6 M in hexane) was added to a cooled (-40°C) solution of dz'-isopropylamine (7.23 mL, 51.23 mmol) in THF (40 mL). The mixture was stirred at -40°C for 30 min to form lithium diisopropylamide (LDA). A solution of compound 1_8_2 (5.43 g, 20.49 mmol) in THF (20 mL) was added at -78°C. The mixture was stirred at -78°C for 30 min and cyclopentanone (dried over molecular sieves, 2.07 mL, 24.59 mmol) was added. The resulting mixture was stirred at -78°C for 20 min, gradually warmed up to -20°C over 30 min and then to 0°C over 20 min, quenched with a solution of acetic acid (2.70 mL, 47.13 mmol) in THF (10 mL), poured into water (50 mL), extracted with ethyl acetate (200 mL), dried and concentrated. The residue was purified by column chromatography to give compound 1_8_3 (5.65 g, 79 %).
[00136] Ή NMR (400 MHz, DMSO-i6): δ = 1.40 (s, 9H), 1.50 - 1.90 (m, 8H), 2.20 (s, 1H), 4.25 (d, / = 7.7 Hz, 1H), 5.20 (m, 2H), 5.50 (d, / = 7.7 Hz, 1H), 7.40 (m, 5H).
[00137] 10% Pd/C (0.52 g) was added to a degassed solution of compound 1_8_3 (5.65 g, 16.19 mmol) in methanol (100 mL). The mixture was stirred under a hydrogen balloon for 3 h and filtered through a pad of celite. The filtrate was concentrated to give compound 1_8_4 (4.1 g) which was used in the next step without further purification.
[00138] Ή NMR (400 MHz, DMSO-d6): δ = 1.40 (s, 9H), 1.50 - 2.00 (m, 8H), 4.20 (br. s, 1H), 5.95 (br. s, 1H).
[00139] 1-Hydroxybenzotriazole (HOBT, 2.19 g, 16.19 mmol) and dicyclo- hexylcarbodiimide (DCC, 3.34 g, 16.19 mmol) was added to a cooled (0°C) solution of compound 1_8_4 (4.1 g) in THF (20 mL). The mixture was stirred at 0°C for 2 hours. A solution of O-benzyl hydroxylamine (made from 7.76 g of its corresponding hydrogen chloride salt and an aqueous sodium hydroxide solution, 47.89 mmol) in THF (10 mL) was added and the mixture was stirred at room temperature for 5 h and filtered. The filtrate was concentrated and the residue was purified by column chromatography to give compound 1_8_5 (4.7 g, 80 %)
[00140] Ή NMR (400 MHz, CDC13): δ = 1.40 (s, 9H), 1.50 -2.00 (m, 8H), 3.60 (d, / = 7.8 Hz, 1H), 3.90 (s, 1H), 4.90 (s, 2H), 5.62 (d, / = 7.8 Hz, 1H), 7.40 (m, 5H), 9.02 (s, 1H).
[00141] A mixture of compound 1_8_5 (4.66 g, 12.80 mmol) and sulfur tri- oxide-pyridine complex (3.71 g, 23.25 mmol) in pyridine (50 mL) was heated at 50- 55°C for 2 h and concentrated. The residue was diluted with acetonitrile (20 mL) and concentrated. The residue was dried under high vacuum for 2 h, diluted with ethyl acetate (150 mL) and treated with a solution of potassium carbonate (19.67 g, 143 mmol) in water (54 mL). The resulting mixture was refluxed for 2 h, cooled to room temperature and the phases were separated. The organic phase was washed with a 5% aqueous sodium hydrogen sulfate solution (20 mL), dried and concentrated. The residue was purified by column chromatography to give compound 1_8_6 (2.5 g, 56 %) as colorless solid.
[00142] Ή NMR (400 MHz, CDC13): δ = 1.42 (s, 9H), 1.43 - 2.00 (m, 8H), 4.43 (d, / = 8.0 Hz, 1H), 4.90 - 5.00 (m, 3H), 7.40 (m, 5H).
[00143] 10 % Pd-C (100 mg) was added to a degassed solution of compound 1_8_6 (1.0 g, 2.89 mmol) in methanol (20 mL). The mixture was stirred under a hydrogen balloon for 1 h and filtered through a pad of celite. The filtrate was concentrated to give compound 1_8_7 (0.70 g, 100 %) which was used in the next step without further purification. [00144] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.39 (s, 9H), 1.50 - 2.00 (m, 8H), 4.28 (d, / = 7.9 Hz, 1H), 7.72 (d, / = 7.9 Hz, 1H).
[00145] A mixture of compound 1_8_7 (0.74 g, 2.89 mmol) and sulfur triox- ide-pyridine complex (1.43 g, 8.96 mmol) in pyridine (20 mL) was stirred at room temperature for 2 h, and concentrated. The residue was treated with a 10 % aqueous potassium dihydrogenphosphate solution (10 mL) and the mixture was stirred with tetra-n-butylammonium hydrogensulfate (1.08 g, 3.18 mmol) at 0°C for 30 min. The reaction mixture was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were concentrated. The residue was dissolved in 98 % formic aid (10 mL) and stirred at room temperature for 4 h, diluted with dichloromethane (30 mL) and left in the fridge for 16 h. The solid was collected and dried to give compound 1_8_8 (380 mg, 56 %).
[00146] Ή NMR (400 MHz, DMSO-c¾: δ = 1.40 - 2.00 (m, 6H), 2.20 (m, 2H), 4.37 (s, 1H).
(3S,4S)- 3-Amino-4-(aminocarbonyl)-2-oxo-l-azetidinesulfonic acid
Figure imgf000059_0001
1_9_1
[00147] Compound 1_9_1 was synthesized according to M. Sendai, S. Hashiguchi, M. Tomimoto, S. Kishimoto, T. Matsuo, M. Ochiai; Chemical & Pharmaceutical Bulletin 1985, 33 (9), 3798-3810 and EP 73061. Synthesis of amino-thiazole and amino-thiadiazole building blocks Oxo [2- (tritylamino) - 1 , 3-thiazol-4-yl]acetic acid
Figure imgf000060_0001
2 1 1
[00148] Compound 2_1_1 was synthesized according to Sakagami, Kenji; Iwamatsu, Katsuyoshi; Atsumi, Kunio; Hatanaka, Minoru; Chemical & Pharmaceutical Bulletin, 1990, 38(12), 3476 - 3479.
2.2 {5-[(teri-Butoxycarbonyl)amino]-l,2,4-thiadiazol-3-yl}(oxo)acetic acid
Figure imgf000060_0002
2 2 1
[00149] Compound 2_2_1 was synthesized according to Yamawaki, Kenji; Nomura, Takashi; Yasukata, Tatsuro; Uotani, Koichi; Miwa, Hideaki; Takeda, Kei; Nishitani, Yasuhiro; Bioorganic & Medicinal Chemistry, 2007, 38 (21), 6716-6732. [5-Chloro-2-(tritylamino)-l,3-thiazol-4-yl](oxo)acetic acid
Figure imgf000061_0001
2 3 1
[00150] Compound 2_3_1 was synthesized according to: a) Sakagami, Kenji; Iwamatsu, Katsuyoshi; Atsumi, Kunio; Hatanaka, Minoru;
Chemical & Pharmaceutical Bulletin, 1990, 38(12), 3476 - 3479. b) Yamawaki, Kenji; Nomura, Takashi; Yasukata, Tatsuro; Uotani, Koichi; Miwa, Hideaki; Takeda, Kei; Nishitani, Yasuhiro; Bioorganic & Medicinal Chemistry, 2007, 38(21), 6716-6732.
3. Synthesis of aryl and heteroaryl amidine side chains
3.1 4-[2-(Aminooxy)ethoxy]benzenecarboximidamide
Figure imgf000061_0002
Step 1: 4-(2-Bromoethoxy)benzonitrile (3_1_2)
[00151] 1,2-Dibromoethane (471 g, 2.52 mol) and potassium carbonate (232 g, 1.68 mol) were added to a solution of 4-hydroxybenzonitrile 3_1_1 (100 g, 0.84 mol) in acetonitrile (4 L). The mixture was refluxed for 18 hours, the solid was removed by filtration and the filtrate was concentrated to give a residue which was purified by chromatography (3:1 hexanes/ethyl acetate) to give compound 3_1_2 (74.4 g, 40 % yield) as a solid.
[00152] Ή NMR (400 MHz, CDC13): δ = 3.66 (t, J = 6.0 Hz, 2H), 4.34 (t, J = 6.2 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 7.61 (d, J = 8.9 Hz, 2H).
Step 2: 4-{2-[(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]ethoxy}benzonitrile (3_1_3)
[00153] l,8-Diazabicyclo[5.4.0]undec-7-ene (49.4 mL, 0.33 mmol) was added slowly over 20 minutes to a solution of compound 3_1_2 (74.3 g, 0.33 mol) and N- hydroxyphthalimide (Phth-OH, 53.6 g, 0.33 mol) in N,N-dimethylformamide (470 mL) and the mixture was heated at 46°C for 6 hours. After removal of the solvent, the residue was treated with IN HC1 (1 L) which resulted in a precipitate. The precipitate was collected by filtration, washed with water and dried to give compound 3_1_3 (98.0 g, 96 % yield) as a white solid.
[00154] Ή NMR (400 MHz, CDC13): δ = 4.31 - 4.43 (m, 2H), 4.51 - 4.63 (m, 2H), 6.91 (m, J = 8.5 Hz, 2H), 7.57 (m, J = 8.5 Hz, 2H), 7.75 - 7.87 (m, 4H).
Step 3: 4-[2-(Aminooxy)ethoxy]benzonitrile (3_1_4)
[00155] Hydrazine hydrate (11.5 mL, 0.236 mol) was added to a suspension of compound 3_1_3 (72.7 g, 0.236 mol) in ethanol (800 mL) and the mixture was stirred at 45°C for 14 hours. The solid was removed by filtration and the filtrate was concentrated. The residue was diluted with ethyl acetate (300 mL), the solid was removed by filtration and the filtrate was concentrated to give compound 3_1_4 (40.0 g, 96 % yield) as a white solid.
[00156] Ή NMR (400 MHz, CDC13): δ = 4.03 (t, J = 4.8 Hz, 2H), 4.21 (t, J = 4.8 Hz, 2H), 5.58 (s, 2H), 6.98 (d, J = 6.0 Hz, 2H), 7.59 (d, J = 6.0 Hz, 2H).
Step 4: Methyl 4-[2-(aminooxy)ethoxy]benzenecarboximidoate (3_1_5)
[00157] Hydrogen chloride gas was bubbled through a solution of compound 3_1_4 (15.0 g, 84.7 mmol) in dry methanol (330 mL) at 0°C for 1 hour and the mixture was stirred at room temperature for 14 hours (NMR showed 50 % conversion). Hydrogen chloride gas was bubbled through the solution for another 40 minutes at 0°C, and the reaction mixture was stirred for 24 hours to give a suspension. Compound 3_1_5 (23.0 g, 96 % yield, hydrochloride salt) was collected by filtration as a white solid.
[00158] lH NMR (400 MHz, CDC13): δ = 3.95 - 4.08 (m, 2H), 4.13 - 4.25 (m, 2H), 5.55 (br s, 2H), 6.99 (m, J = 8.5 Hz, 2H), 7.26 (s, 1H), 7.59 (m, J = 8.5 Hz, 2H).
Step 5: 4-[2-(Aminooxy)ethoxy]benzenecarboximidamide (3_1_6)
[00159] Ammonia (7 N in methanol, 53.3 mL) was added to a solution of compound 3_1_5 (11.5 g, 37.3 mmol) in dry methanol (150 mL). The mixture was stirred at 50°C for 2 hours and at room temperature for 14 hours. After removal of the solvent, the residue was purified by chromatography to give compound 3_1_6 (6.2 g, 85 % yield) as a solid.
[00160] Ή NMR (400 MHz, Methanol-^): δ = 3.97 - 4.05 (m, 2H), 4.24 - 4.37 (m, 2H), 7.16 (d, J = 8.9 Hz, 2H), 7.79 (d, J = 8.9 Hz, 2H). [00161] Using the conditions described above under 3.1 the following ami- dine side chains were prepared:
Figure imgf000064_0001
3.8 tert-Butyl {({4-[2-(aminooxy)ethoxy]phenyl}amino)[(tert-butoxycarbonyl)- amino]methylidene}carbamate
Figure imgf000065_0001
Step 1: tert-Butyl [4-(2-bromoethoxy)phenyl] carbamate (3_8_2)
[00162] A mixture of tert-butyl (4-hydroxyphenyl)carbamate 3_8_1 (25 g, 119.6 mmol), 1,2-dibromoethane (41 mL, 478.5 mmol) and potassium carbonate (33 g, 239.2 mmol) in acetonitrile (500 mL) was refluxed for 24 hours (TLC showed 50 % conversion). Addditional 1,2-dibromoethane (20 mL, 239 mmol) and potassium carbonate (16 g, 120 mmol) was added and the mixture was refluxed for another 23 hours. Further potassium carbonate (16 g, 120 mmol) was added and the mixture was refluxed for another 5 hours. The solid was removed by filtration and the filtrate was concentrated to give a residue. The residue was purified by chromatography to give compound 3_8_2 (15.6 g, 41 % yield) as a solid.
[00163] Ή NMR (CDC13): δ = 1.51 (s, 9H), 3.61 (t, J = 6.0 Hz, 2H), 4.26 (t, J = 6.0 Hz, 2H), 4.26 (t, J = 6.0 Hz, 2H), 6.34 (s, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H). Step 2: fert-Butyl (4-{2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]ethoxy}phenyl)- carbamate (3_8_3)
[00164] l,8-Diazabicyclo[5.4.0]-undec-7-ene (9 mL, 59.3 mmol) was added to a solution of compound 3_8_2 (15.6 g, 49.4 mmol) and N-hydroxyphalimide (Phth- OH, 12.1 g, 74 mmol) in N,N-dimethylformamide (80 mL) at room temperature. The mixture was stirred at 45°C for 15 hours, concentrated, extracted with ethyl acetate, washed with a saturated sodium bicarbonate solution, IN hydrochloric acid and brine, dried over sodium sulfate, filtered and concentrated. The residue was triturated with hexanes and the solid was collected to give compound 3_8_3 (17.1 g, 86 % yield) as a white solid.
[00165] Ή NMR (CDC13): δ = 1.50 (s, 9H), 4.32 (t, J = 6.4 Hz, 2H), 4.56 (t, J = 6.4 Hz, 2H), 6.33 (s, 1H), 6.75 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 H, 2H), 7.83 (m, 2H), 7.52 (m, 2H).
Step 3: 2-[2-(4-Aminophenoxy)ethoxy]-lH-isoindole-l,3(2H)-dione (3_8_4)
[00166] Trifluoroacetic acid (TFA, 14.3 mL) was added to a solution of compound 3_8_3 (7.4 g, 18.6 mmol) in dichloromethane (150 mL). The mixture was stirred for 2.5 hours at room temperature, and concentrated. The residue was then triturated with diethyl ether and the solid was collected to give the desired compound 3_8_4 (7.5 g, 97 % yield, trifluoroacetic acid salt) as a pink solid.
[00167] Ή NMR (MeOH-d4): δ = 4.36 (m, 2H), 4.55 (m, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 7.83 (s, 4H).
Step 4:tert-Butyl {(E)-[(tert-butoxycarbonyl)amino] [(4-{2-[(l,3-dioxo-l,3-dihydro-2H- isoindol-2-yl)oxy]ethoxy}phenyl)amino]methylidene}carbamate (3_8_5) [00168] Trifluoroacetic acid (6 mL, 43.2 mmol) was added to a suspension of compound 3_8_4 (7.4 g, 14.1 mmol) in acetonitrile (200 mL), and the mixture was stirred for 30 minutes at room temperature. Di-terf-butyl [(Z)-lH-pyrazol-l- ylmethylylidenejbiscarbamate (3.2 g, 10.8 mmol) was added and the mixture was stirred for 15 hours at room temperature, concentrated and the residue was extracted with ethyl acetate, washed with brine, filtered and concentrated to give a residue. The residue was purified by chromatography to give compound 3_8_5 (3.82 g, 50 % yield) as a solid.
[00169] ¾ NMR (CDC13): δ = 1.49 (s, 9H), 1.53 (s, 9H), 4.32 (t, J = 4.4 Hz, 2H), 4.57 (t, J = 4.4 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.84 (m, 2H), 7.75 (m, 2H), 10.18 (s, 1H), 11.63 (s, 1H).
Step 5:tert-Butyl {({4-[2-(aminooxy)ethoxy]phenyl}amino)[(tert-butoxycarbonyl)am- ino] methylidenejcarbamate (3_8_6)
[00170] Hydrazine hydrate (0.35 mL, 7.1 mmol) was added to a suspension of compound 3_8_5 (3.82 g, 7.1 mmol) in ethanol (200 mL) and the mixture was stirred at 35°C for 18 hours. The solid was removed by filtration and the filtrate was concentrated to give a residue. The residue was purified by chromatography (1:1 ethyl acetate/hexanes) to give a crude product (3.1 g), which was washed with dichloromethane and filtered. The filtrate was concentrated to give pure product 3_8_6 (2.7 g, 97 % yield) as a white solid.
[00171] Ή NMR (CDCI3): δ = 1.49 (s, 9H), 1.53 (s, 9H), 4.01 (t, J = 4.4 Hz, 2H), 4.14 (t, J = 4.4 Hz, 2H), 5.54 (s, 2H), 6.89 (d, J = 9.2 Hz, 2H), 7.49 (d, J = 9.2 Hz, 2H), 10.19 (s, 1H), 11.64 (s, 1H). 3.9 tert-Butyl {({4-[2-(aminooxy)propoxy]phenyl}amino)[(tert-butoxycarb- onyl)amino]methylidene}carbamate
Figure imgf000068_0001
[00172] Compound 3_9_6 was prepared using the procedure described above for compound 3_8_6 using 1,3-dibromopropane instead of 1,2-dibromoethane in step 1.
3.10 4- {[2- (Aminooxy)ethyl]sulf anyljbenzenecarboximidamide
Figure imgf000068_0002
Step l:4-[(2-Hydroxyethyl)sulfanyl]benzonitrile (3_10_2)
[00173] 2-Mercaptoethanol (4.10 g, 0.0525 mmol) and potassium carbonate (7.25 g, 0.0525 mol) was added to a solution of 4-fluorobenzonitrile 3_10_1 (4.22 g, 0.035 mol) in acetonitrile (50 mL) and the mixture was stirred at room temperature for 18 hours. The solid was removed by filtration and the filtrate was concentrated to give a residue, which was purified by column chromatography to give compound 3_10_2 (4.0 g, 64 % yield) as an oil.
[00174] Ή NMR (400 MHz, CDC13): δ = 1.92 (t, J = 6.1 Hz, 1H), 3.22 (t, J = 5.9 Hz, 2H), 3.86 (q, J = 6.0 Hz, 2H), 7.38 (m, J = 8.6 Hz, 2H), 7.55 (m, J = 8.2 Hz, 2H).
Step 2:4-{[2-(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)ethyl]sulfanyl}benzonitrile
(3_10_3)
[00175] Triphenyl phosphine (5.85 g, 0.0223 mol) was added to a solution of compound 3_10_2 (4.00 g, 0.0223 mol) and N-hydroxyphalimide (Phth.OH, 3.64 g, 0.223 mol) in tetrahydrofuran (100 mL), followed by diethyl azodicarboxylate (3.66 mL, 0.0223 mol) slowly over 20 minutes. The mixture was stirred at room temperature for 24 hours then concentrated to give a residue. The residue was purified by column chromatography to afford compound 3_10_3 (4.6 g, 62 % yield).
[00176] Ή NMR (400 MHz, CDC13): δ = 3.42 (s, 2H), 4.38 (s, 2H,), 7.41 (m, J = 8.2 Hz, 2H), 7.56 (m, J = 8.2 Hz, 2H), 7.79 (d, J = 3.1 Hz, 2H), 7.85 (br s, 2H).
Step 3: 4-{[2-(Aminooxy)ethyl]sulfanyl}benzonitrile (3_10_4)
[00177] Hydrazine (0.804 mL, 0.0256 mol) was added to a suspension of compound 3_10_3 (4.6 g, 0.0256 mol) in ethanol (100 mL) and the mixture was stirred at 45 °C for 14 hours. The solid was removed by filtration and the filtrate was concentrated. The residue was diluted with dichloromethane (20 mL) and the solid was removed by filtration. The filtrate was concentrated to give compound 3_10_4 (3.5 g, 70 % yield) as an oil.
[00178] Ή NMR (400 MHz, CDC13): δ = 3.25 (t, J = 6.6 Hz, 2H), 3.88 (t, J = 6.6 Hz, 2H), 5.49 (br s., 2H), 7.37 (m, J = 8.2 Hz, 2H), 7.54 (m, J = 8.6 Hz, 2H). Step 4: 4-{[2-(Aminooxy)ethyl]sulfanyl}benzenecarboximidoate (3_10_5)
[00179] Hydrogen chloride gas was bubbled through a solution of compound 3_10_4 (3.5 g, 0.0180 mol) in dry methanol (100 mL) at 0 °C for 10 minutes. The mixture was stirred at room temperature for 14 hours to give a suspension. The white solid (3.0 g, 74 % yield, hydrochloride salt) was collected by filtration.
[00180] Ή NMR (400 MHz, MeOH-rf4): δ = 3.47 (s, 2H), 4.27-4.40 (m, 5H), 7.57 (d, J = 9.0 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H).
Step 5: 4-{[2-(Aminooxy)ethyl]sulfanyl}benzenecarboximidamide (3_10_6)
[00181] Ammonia (7N in methanol, 10 mL) was added to a solution of compound 3_10_5 (3.0 g, 73.7 mol) in dry methanol (20 mL) and the mixture was heated at 50 °C for 2 hours. After removal of the solvent, the residue was purified by chromatography to give compound 3_10_6 (1.5 g, 54 % yield) as a solid.
[00182] Ή NMR (400 MHz, MeOH-rf4): δ = 3.32 (br s, 2H), 3.86 (s, 2H), 7.53 (m, J = 8.6 Hz, 2H) 7.71 (m, J = 8.60 Hz, 2H).
3.11 4-[2-(Aminooxy)ethoxy]-N-(propan-2-yl)benzenecarboximidamide
Figure imgf000070_0001
[00183] Isopropylamine (2 mL) was added dropwise at 0°C to a suspension of compound 3_1_5 (1 g, 3.57 mmol) in methanol (10 mL) in a sealed tube and the mixture was heated at 50°C for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was lyophilized to give compound 3_11_6 (1.0 g, 75 % yield) as a yellow foam.
3.12 4 - [2- (Aminooxy) ethoxy ]-N-methy lbenzenecarboximidamide
Figure imgf000071_0001
[00184] Compound 3_12_6 was prepared using the procedure described above for compound 3_11_6 using methylamine instead of isopropylamine.
3.13 4-[2-(Aminooxy)ethox -N-(2-hydroxyethyl)benzenecarboximidamide
Figure imgf000071_0002
[00185] Compound 3_13_6 was prepared using the procedure described above for compound 3_11_6 using 2-aminoethanol instead of isopropylamine.
3.14 2-{[{4-[2-(Aminooxy)ethoxy]phenyl}(imino)methyl]amino}ethyl formate
Figure imgf000071_0003
[00186] Compound 3_14_7 was prepared from compound 3_13_6 using a standard literature reported formylation method using formic acid, see e.g. Chem. Commun. 2007, (28), 2977-2979.
3.15 N- (2- (tert-Butoxycarbony lamino) ethyl) -4- [2- (aminooxy)ethoxy ]benzene- carboximidamide
Figure imgf000072_0001
[00187] Compound 3_15_6 was prepared using the procedure described above for compound 3_11_6 using tert-butyl 2-aminoethylcarbamate instead of isopropylamine.
3.16 4- [2- (Aminooxy) ethoxy ]-N- (3- (tert-butoxycarbony lamino) propyl) benzene- carboximidamide
Figure imgf000072_0002
H2N 3_16_6
[00188] Compound 3_16_6 was prepared using the procedure described above for compound 3_11_6 using tert-butyl 2-aminopropylcarbamate instead of isopropylamine. 3.17 4-[2-(Aminooxy)ethoxy]-N-(pyridin-2-ylmethyl)benzenecarboximidamide
Figure imgf000073_0001
[00189] Compound 3_17_6 was prepared using the procedure described above for compound 3_11_6 using 2-aminomethyl pyridine instead of isopropyla- mine.
3.18 l-{4-[2-(Aminooxy)ethoxy]phenyl}-l-[4-(tert-butoxycarbonylpiperazin-l- y 1) ]methanimine
Figure imgf000073_0002
[00190] Compound 3_18_6 was prepared using the procedure described above for compound 3_11_6 using N-Boc protected piperizane instead of isopropyl- amine.
3.19 4-[2-(Aminooxy)ethoxy]-N-[2-(dimethylamino)ethyl]benzenecarboximid- amide
Figure imgf000073_0003
H2N 3_19 6 [00191] Compound 3_19_6 was prepared using the procedure described above for compound 3_11_6 using 2-(N,N-dimethylamino)ethylamine instead of isopropylamine.
3.20 N- [{4- [2- (Aminooxy)ethoxy]pheny 1} (imino) methy l]glycine
Figure imgf000074_0001
[00192] Compound 3_20_6 was prepared using the procedure described above for compound 3_11_6 using amino acetic acid instead of isopropylamine.
3.21 4-[2-(Aminooxy)ethoxy]-N-(l/3-di(tert-butoxycarbonylamino)propan-2- yl)benzenecarboximidamide
Figure imgf000074_0002
[00193] Compound 3_21_6 was prepared using the procedure described above for compound 3_11_6 using di-tert-butyl (2-aminopropane-l,3- diyl)biscarbamate instead of isopropylamine. 3.22 N-(l-(tert-butoxycarbonylamino)-3-hydroxypropan-2-yl)-4-[2-(amino- oxy)ethoxy]benzenecarboximidamide
Figure imgf000075_0001
[00194] Compound 3_22_6 was prepared using the procedure described above for compound 3_11_6 using tert-butyl (2-amino-3-{[tert- butyl(dimethyl)silyl]oxy}propyl)carbamate instead of isopropylamine.
3.23 4-(2-Aminooxy-ethoxy)-N-hydroxy-benzamidine
Figure imgf000075_0002
[00195] Hydroxylamine hydrogen chloride (1.36 g, 19.6 mmol) was added to a mixture of compound 3_1_4 (1 g, 5.61 mmol) and sodium carbonate (1.07 g; 10.1 mmol) in ethanol / water (3 mL : 23 mL). The reaction mixture was stirred at room temperature for 72 hours, diluted with brine (40 mL), extracted into ethyl acetate (3 χ 100 mL) and the combined organic extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was triturated with dichloromethane, filtered, rinsed with dichloromethane and dried in vacuum to give compound 3_23_5 (0.3 g, 25 % yield) as a white powder.
[00196] Ή NMR (400 MHz, DMSO-rf6): δ = 3.82 (br s, 2H), 4.11 (br s, 2H), 5.69 (s, 2H), 6.08 (s, 2H), 6.91 (d, J = 8.99 Hz, 2H), 7.57 (d, J = 8.99 Hz, 2H), 9.42 (s, 1H). [00197] MS: m/z (ES+, %) 212 (M+H, 100), 179 (5), 153 (10), 124 (15), 103
(25).
4-[(Aminooxy)methyl]benzenecarboximidamide
Figure imgf000076_0001
3 24 4 3 24 5
Step 1: 4-{[(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]methyl}benzonitrile (3_24_2)
[00198] N-Hydroxyphthalimide (PhthOH, 7.12 g, 55 mmol), triphenyl- phosphine (14.41 g, 55 mmol) and diethyl azodicarboxylate (DEAD, 9 mL, 55 mmol) were slowly added to a solution of 4-hydroxymethyl benzonitrile 3_24_1 (8.15 g, 50 mmol) in tetrahydrofuran (100 mL). The mixture was stirred at room temperature for 15 hours. The solid was collected by filtration, washed with tetrahydrofuran and dried to give compound 3_24_2 (10 g, 72 % yield) as a solid.
Step 2:4-[(Aminooxy)methyl]benzonitrile (3_24_3)
[00199] Hydrazine hydrate (0.336 g, 6.2 mmol) was added to a suspension of compound 3_24_2 (1.55 g, 5.6 mmol) in ethanol (20 mL) and the mixture was stirred at room temperature for 15 hours. The solid was removed by filtration and the filtrate was concentrated. The residue was diluted with dichloromethane (30 mL), the solid was removed by filtration and the filtrate was concentrated to give compound 3_24_3 (0.88 g, 100 % yield) as a solid.
Step 3:Methyl 4-[(aminooxy)methyl]benzenecarboximidoate (3_24_4)
[00200] Hydrogen chloride gas was bubbled through a solution of compound 3_24_3 (0.88 g, 5.6 mmol) in methanol (30 mL) at 0 °C for 5 minutes and the mixture was stirred at room temperature for 20 hours. The solid was collected by filtration, washed with methanol and dried to give compound 3_24_4 (0.54 g, 38 % yield) as a white solid.
Step 4:4-[(Aminooxy)methyl]benzenecarboximidamide (3_24_5)
[00201] Compound 3_24_4 (0.54 g, 2.13 mmol) in methanol (5 mL) was added slowly to a solution of ammonia (7N in methanol, 7 mL, 21 mmol) in methanol (10 mL) and the mixture was stirred at room temperature for 18 hours. After removal of the solvent, the residue was diluted with dichloromethane (30 mL), and the solid was collected by filtration to give compound 3_24_5 (0.42 g, 83 % yield) as a white solid.
3.25 4-{[2-(Aminooxy)ethyl]amino}benzenecarboximidamide
Figure imgf000077_0001
Step l:4-[(2-Hydroxyethyl)amino]benzonitrile (3_25_2)
[00202] 2-Aminoethanol (3.0 mL, 49.48 mmol) and potassium carbonate (6.84 g, 49.48 mmol) were added to a solution of 4-fluorobenzonitrile 3_25_1 (5.0 g, 41.24 mmol) in dimethyl sulfoxide (30 mL). The mixture was stirred at 100°C for 18 hours, poured onto ice-water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated to give a residue which was purified by column chromatography to give compound 3_25_2 (3.0 g, 45 % yield) as an oil.
[00203] Ή NMR (400 MHz, CDC13): δ = 1.80 (t, J = 5.3 Hz, 1H), 3.34 (q, J = 5.5 Hz, 2H), 3.87 (q, J = 5.2 Hz, 2H), 4.61 (br s., 1H), 6.60 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H).
Step 2: 4- ({2- [( 1 , 3-Dioxo- 1 , 3-dihydro-2H-isoindol-2-yl)oxy] ethyl} amino)benzonitrile (3_25_3)
[00204] Triphenylphosphine (1.61 g, 6.16 mmol) was added to a solution of compound 3_25_2 (1.00 g, 6.16 mmol) and N-hydroxyphthalimide (Phth-OH, 1.05 g, 6.16 mmol) in tetrahydrofuran (100 mL), followed by the slow addition of diethyl azodicarboxylate (1.02 mL, 6.16 mmol) over 20 minutes. The mixture was stirred at room temperature for 24 hours and concentrated to yield a residue which was purified by column chromatography to afford compound 3_25_3 (1.1 g, 58 % yield).
[00205] Ή NMR (400 MHz, DMSO-rf6): δ = 3.50 (d, J = 5.5 Hz, 2H), 4.29 (t, J = 5.47 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 6.79 (s, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.86 (s, 4H).
Step 3: 4-{[2-(Aminooxy)ethyl]amino}benzonitrile (3_25_4) [00206] Hydrazine hydrate (0.255 mL, 10.90 mmol) was added to a suspension of compound 3_25_3 (3.35 g, 10.90 mmol) in ethanol (80 mL) and the mixture was stirred at 45°C for 14 hours. The solid was removed by filtration and the filtrate was concentrated. The residue was diluted with dichloromethane (20 mL). The solid was removed by filtration and the filtrate was concentrated to give compound 3_25_4 (1.9 g, 97 % yield) as an oil.
[00207] Ή NMR (400 MHz, DMSO-i/6): δ = 3.27 (d, J = 5.7 Hz, 2H), 3.58-3.71 (m, 2H), 6.04 (s, 2H), 6.66 (d, J = 8. Hz, 3H), 7.43 (d, J = 8.9 Hz, 2H).
Step 4: 4-{[2-(Aminooxy)ethyl]amino}benzenecarboximidoate (3_25_5)
[00208] Hydrogen chloride gas was bubbled through a solution of compound 3_25_4 (1.9 g, 10.72 mmol) in dry methanol (50 mL) at 0 °C for 10 minutes. The mixture was stirred at room temperature for 14 hours to give compound 3_25_5 as a white solid (1.0 g, 45 % yield, hydrochloride salt) which was collected by filtration.
[00209] Ή NMR (400 MHz, MeOH-d4): δ = 3.60 (s, 2H), 4.18-4.30 (m, 5H), 6.79 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H).
Step 5: 4-{[2-(Aminooxy)ethyl]amino}benzenecarboximidamide (3_25_6)
[00210] Ammonia (7N in methanol, 5 mL) was added to a solution of compound 3_25_5 (1.0 g, 4.78 mmol) in dry methanol (10 mL) and the mixture was heated at 50°C for 2 hours. After removal of the solvent, the obtained product (930 mg, 100 % yield) was used without further purification.
[00211] Ή NMR (400 MHz, MeOH-rf4): δ = 3.40 (t, J = 5.5 Hz, 2H), 3.82 (t, J = 5.5 Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H). 3.26 5-{[2-(Aminooxy)ethoxy]methyl}thiophene-3-carboximidamide
Figure imgf000080_0001
3_26_5 3_26_6
Step l:(4-Bromothiophen-2-yl)methanol (3_26_2):
[00212] Sodium borohydride (5.20 g, 0.137 mol) was added to a solution of 4-bromo-thiophene-2-carbaldehyde 3_26_1 (25.0 g, 0.131 mol) in anhydrous tetra- hydrofuran (400 mL) at room temperature and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by carefully adding a saturated ammonium chloride solution (100 mL) at room temperature. The mixture was extracted into ethyl acetate and the extract was washed with brine, dried over sodium sulfate, and concentrated to give the product (25.02 g, 99% yield) which was used in the next step without further purification.
[00213] Ή NMR (400 MHz, CDC13): δ = 1.93 (br. s., 1H), 4.79 (s, 2H), 6.93 (s, 1H), 7.18 (d, J = 1.5 Hz, 1H).
Step 2:5-(Hydroxymethyl)thiophene-3-carbonitrile (3_26_3)
[00214] Zinc cyanide (15.2 g, 0.129 mmol) was added to a solution of (4- bromo-thiophen-2-yl)-methanol 3_26_2 (25.0 g, 0.129 mol) in Λ/,Ν-dimethylform- amide (150 mL). After degassing for 10 minutes, tetrakis(triphenylphosphine)- palladium(O) (7.48g, 6.47 mmol) was added and the reaction mixture was stirred at 80°C for 4 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography to give the desired product (13.67 g, 76 % yield).
[00215] Ή NMR (400 MHz, CDC13): δ = 1.98 (t, 1H), 4.86 (d, J = 6.1 Hz, 2H), 7.17 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H).
Step 3:5-(Bromomethyl)thiophene-3-carbonitrile (3_26_4)
[00216] Triphenylphosphine (9.9 g, 37.7 mmol) and carbon tetrabromide (12.59 g, 37.7 mmol) were added to a solution of 5-hydroxymethyl-thiophene-3- carbonitrile 3_26_3 (5.0 g, 35.9 mmol) in tetrahydrofuran (150 mL), at room temperature. After stirring for 4 hours, the mixture was concentrated to dryness. The residue was purified by column chromatography to give the desired product (4.85 g, 67 % yield) as a colorless oil.
Step 4: 5-[(2-Hydroxyethoxy)methyl]thiophene-3-carbonitrile (3_26_5)
[00217] Sodium (0.824 g, 35.8 mmol) was added to a solution of ethylene glycol (14.8 g, 0.239 mol) in tetrahydrofuran (20 mL) at room temperature. After all the sodium was consumed, 5-bromomethyl-thiophene-3-carbonitrile 3_26_4 (4.83 g, 23.9 mmol) in tetrahydrofuran (20 mL) was added at -10°C and the reaction mixture was stirred at room temperature for 9.5 hours. The reaction mixture was neutralized to pH 7 using diluted hydrochloric acid at 0°C and the mixture was extracted with ethyl acetate and the extract was washed with brine, dried over sodium sulfate and concentrated to dryness to give the product (4.12 g, 9 % yield) as a colorless oil.
[00218] Ή NMR (400 MHz, CDC13): δ = 1.90 (t, 1H), 3.58 - 3.65 (m, 2H), 3.73 - 3.88 (m, 2H), 4.62 - 4.81 (m, 2H), 7.18 (d, J = 1.2 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H).
[00219] MS (ES+) m/z: [M+H]+ calcd for C8Hi0NO2S: 184.23. Found: 184.93. [00220] Following the procedures as described under 3_24 and using 5-(2- hydroxy-ethoxymethyl)-thiophene-3-carbonitrile (3_26_5) in place of 4-hydroxy- methyl benzonitrile (3_24_1), compound 3_26_6 was prepared.
3.27 5-[(Aminooxy)methyl]thiophene-3-carboximidamide
Figure imgf000082_0001
3 26 3
3 27 6
[00221] Following the procedures as described under 3_24 and using 5- (hydroxymethyl)-thiophene-3-carbonitrile (3_26_3) in place of 4-hydroxymethyl benzonitrile (3_24_1), compound 3_27_6 was prepared.
3.28 3- Amino-4 - (2-aminooxy-ethoxy) -benzamidine
Figure imgf000082_0002
Step l:4-(2-Hydroxy-ethoxy)-3-nitro-benzonitrile (3_28_2)
[00222] Sodium (1.038 g, 45.2 mmol) was added to a mixture of ethylene glycol (28.03 g, 0.451 mol) in tetrahydrofuran (20 mL) at room temperature. After all sodium was consumed, 4-fluoro-3-nitro-benzonitrile 3_28_1 (5.0 g, 30.1 mmol) in tetrahydrofuran (10 mL) was added at -10°C and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched by adding ice- water and neutralized to pH 7 using dilute hydrochloric acid at 0°C. The mixture was extracted with ethyl acetate and the extract was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by crystallization from ethyl acetate/hexanes to give the desired product (4.45 g, 71 % yield) as a light yellow solid.
[00223] Ή NM (400 MHz, DMSO-d6): δ = 3.60-3.79 (m, 2H), 4.17-4.37 (m, 2H), 4.94 (t, J = 5.3 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 8.09 (dd, J = 8.9, 2.2 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H).
[00224] MS (ES ) m/z: [M-H]' calcd for C9H7N2O4: 207.18. Found: 206.90.
Step 2: 3-Amino-4-(2-hydroxy-ethoxy)-benzonitrile (3_28_3)
[00225] Palladium on charcoal (10 %, 0.4g) was added to a solution of 4-(2- hydroxy-ethoxy)-3-nitro-benzonitrile 3_28_2 (2.7 g, 12.97 mmol) in ethanol (40 mL) and tetrahydrofuran (40 mL). The mixture was hydrogenated on a Parr Shaker apparatus at room temperature for 3 hours. After filtration, the filtrate was concentrated and the residue was purified by flash column chromatography to give the desired product (1.50 g, 65 % yield) as a white solid.
[00226] Ή NMR (400 MHz, DMSO-d6): δ = 3.71 (m, 2H), 3.98 (t, J = 4.7 Hz, 2H), 4.93 (t, J = 6.3 Hz, 1H), 5.30 (s, 2H), 6.77 - 6.98 (m, 3H). [00227] MS (ES+) m/z: [M+H]+ calcd for C9H11N2O2: 179.19. Found: 178.99.
Step 3:3-Amino-4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-benzonitrile (3_28_4)
[00228] N-Hydroxyphthalimide (Phth-OH, 1.44 g, 8.83 mmol) and triphe- nylphosphine (2.53 g, 9.63 mmol) were added to a solution of 3-amino-4-(2-hydroxy- ethoxy)-benzonitrile 3_28_3 (1.43 g, 8.02 mmol) in anhydrous tetrahydrofuran (40 mL) at room temperature. Diethyl azodicarboxylate (1.68 g, 9.63 mmol) was added dropwise to the resulting solution at 20°C and the resulting mixture was stirred at room temperature overnight. After the evaporation of the tetrahydrofuran, the residue was dissolved in acetone (25 mL) and diluted with hexanes (33 mL). The white precipitate was collected and washed with a miminum amount of acetone to give the desired product (1.91 g, 74 % yield) as a white solid.
[00229] ¾ NMR (400 MHz, DMSO-d6): δ = 4.34 (m, 2H), 4.54 (ddd, J = 3.9, 2.2, 2.0 Hz, 2H), 5.21 (s, 2H), 6.83 - 7.03 (m, 3H), 7.86 (s, 4H).
Step 4:3-Amino-4-(2-aminooxy-ethoxy)-benzonitrile (3_28_5)
[00230] Hydrazine monohydrate (0.338 g, 6.76 mmol) was added to a solution of 3-amino-4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-benzonitrile 3_28_4 (1.90 g, 5.88 mmol) in anhydrous ethanol (15 mL) and tetrahydrofuran (30 mL) at 0°C and the resulting mixture was stirred at room temperature for 6.5 hours. After concentration, the residue was stirred with ether (40 mL) for 1 hour and filtered. The filtrate was concentrated to give crude compound 3_28_5 (1.31 g, crude) as a white solid.
[00231] Ή NMR (400 MHz, DMSO-rf6): δ = 3.77-3.91 (m, 2H), 4.12-4.22 (m, 2H), 5.13 (s, 2H), 6.09 (br s., 2H), 6.82-7.00 (m, 3H). Step 5: 3-Amino-4-(2-aminooxy-ethoxy)-benzimidic acid methyl ester dihydrochloric acid salt (3_28_6)
[00232] Hydrogen chloride gas was introduced into a solution of 3-amino-4- (2-aminooxy-ethoxy)-benzonitrile 3_28_5 (1.30 g, 6.73 mmol) in anhydrous methanol (200 mL) at 0°C for 15 minutes and the resulting mixture was stirred at room temperature overnight. After concentration, the residue was stirred with ether (60 mL) for 0.5 hour and the precipitate was collected and dried to give the desired product (1.33 g, 66 % yield) as a white solid.
[00233] Ή NMR (400 MHz, DMSO-d6): δ = 4.23 (s, 3H), 4.34-4.51 (m, 8H), 7.12 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.61 (br s., 1H), 8.05 (br s., 1H).
Step 6: 3-Amino-4-(2-aminooxy-ethoxy)-benzamidine (3_28_7)
[00234] Ammonia (7N in methanol, 9.6 mL, 66.9 mol) was added to a suspension of 3-amino-4-(2-aminooxy-ethoxy)-benzimidic acid methyl ester dihydrochloric acid salt 3_28_6 (1.33 g, 4.46 mmol) in anhydrous methanol (35 mL) at 0°C and the resulting mixture was stirred at 50 °C for 3 hours. After concentration, the residue was stirred with ethanol for 1 hour. After filtration, the filtrate was concentrated to dryness to afford the desired product (1.2 g, >100% yield) as a white solid, which was used without further purification.
3.29 4-[2-(Aminooxy)ethoxy]-3-(hydroxymethyl)benzenecarboximidamide
Figure imgf000086_0001
Step l:3-Formyl-4-hydroxybenzonitrile (3_29_2)
[00235] Hexamethylenetetramine (HMTA, 117.6 g, 840 mmol) was added to a cooled (0°C) solution of 4-cyanophenol 3_29_1 (50 g, 420 mmol) in trifluoroacetic acid (TFA, 340 mL). After the addition, the mixture was heated at 100°C for 16 hours, cooled to room temperature, quenched with 50 % sulfuric acid (210 mL) and water (1260 mL), extracted with ethyl acetate, dried and concentrated. The residue was purified by chromatography to give compound 3_29_2 (12 g, 19 % yield) as an off- white solid.
Step 2:4-(2-Bromoethoxy)-3-formylbenzonitrile (3_29_3)
[00236] A mixture of compound 3_29_2 (0.5 g, 3.4 mmol), 1,2-dibromo- ethane (0.85 mL, 10.20 mmol) and K2CO3 (2.35 g, 17 mmol) in acetonitrile was refluxed for 2 h, cooled to RT, filtered and concentrated. The residue was purified by chromatography to give compound 3_29_3 (650 mg, 76 % yield) as a colorless oil.
Step 3:4-(2-Bromoethoxy)-3-(hydroxymethyl)benzonitrile (3_29_4) [00237] Sodium borohydride (67 mg, 1.77 mmol) was added in portions to a cooled (0°C) solution of compound 3_29_3 (224 mg, 0.89 mmol) in methanol (5 mL). After the addition, the mixture was stirred at 0°C for 40 minutes, quenched with a saturated ammonium chloride solution, diluted with ethyl acetate (30 mL), washed with water (5 mL), dried over sodium sulfate and concentrated to give compound 3_29_4 (170 mg, 75 % yield) as a gum.
[00238] Following the procedures as described under 3_1 and using 4-(2- bromoethoxy)-3-(hydroxymethyl)benzonitrile (3_29_4) instead of 4-(2-bromoeth- oxy)benzonitrile (3_1_2), compound 3_29_5 was prepared.
3.30 tert-Butyl [{6-[2-(aniinooxy)ethoxy]pyridazin-3-yl}(imino)methyl]carbamate
Figure imgf000087_0001
Step l: 6-(2-Hydroxyethoxy)pyridazine-3-carboximidic acid 2-hydroxy-ethyl ester (3_30_2)
[00239] Sodium (0.593 g, 0.0258 mmol) was added to a flask containing ethylene glycol (13.34 g, 0.215 mol) at 0°C. After all sodium was consumed, 6-fluoro- pyridazine-3-carbonitrile 3_30_1 (3.0 g, 0.0215 mmol) in tetrahydrofuran (10 mL) was added at 0°C and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filter cake was washed with cold tetrahydrofuran and dried to afford the desired product 3_30_2 (4.32 g, 88 % yield) as a white solid.
[00240] ¾ NMR (400 MHz, DMSO-d6): δ = 3.65-3.86 (m, 4H), 4.23-4.34 (m, 2H), 4.47 - 4.57 (m, 2H), 4.82-5.03 (m, 2H), 7.37 (d, J = 9.0 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 9.23 (s, 1H).
[00241] MS (ES+) m/z: [M+H]+ calcd for C9H14N3O4: 228.22. Found: 228.07.
Step 2: 6-(2-Hydroxyethoxy)pyridazine-3-carboxamidine (3_30_3)
[00242] Ammonium chloride (0.899 g, 16.8 mmol) was added to a mixture of 6-(2-hydroxy-ethoxy)-pyridazine-3-carboximidic acid 2-hydroxy-ethyl ester 3_30_2 (3.185 g, 14.0 mmol) in methanol (120 mL). The mixture was refluxed overnight and then concentrated to dryness. The residue was dissolved in water, neutralized to pH 9 using a saturated sodium bicarbonate solution and lyophilized to give the crude product. The material was purified by flash column chromatography to give the desired product (2.1 g, 82 % yield) as a white solid.
[00243] Ή NMR (400 MHz, DMSO-i¾: δ = 3.78 (m, 2H), 4.41 - 4.57 (m, 2H), 4.88-4.99 (m, 1H), 6.87 (br. s., 3H), 7.29 (d, J = 9.1 Hz, 1H), 8.24 (d, J = 9.4 Hz, 1H). Step 3:tert-Butyl {[6-(2-hydroxyethoxy)pyridazin-3-yl](imino)methyl}carbamate (3_30_4)
[00244] A saturated sodium bicarbonate solution (8 mL) and a solution of di- tert-butyldicarbonate (BOC2O, 2.753 g, 12.6 mmol) in 1,4-dioxane (10 mL) were added to a solution of 6-(2-hydroxy-ethoxy)-pyridazine-3-carboxamidine 3_30_3 (1.915 g , 10.5 mmol) in water (10 mL) at room temperature. After stirring at room temperature overnight, more di-tert-butyldicarbonate (1.0 g) was added and the mixture was stirred for another 16 hours. The resulting mixture was concentrated and the white solid was collected, washed with water and dried to give the desired product (1.29 g, 44 % yield) as an off-white solid.
[00245] ¾ NMR (400 MHz, DMSO-d6): δ = 1.45 (s, 9H), 3.68 - 3.89 (m, 2H), 4.41 - 4.61 (m, 2H), 4.95 (t, J = 5.4 Hz, 1H), 7.32 (d, J = 9.4 Hz, 1H), 8.22 (d, J = 9.1 Hz, 1H), 9.03 (br s., 2H).
[00246] MS (ES+) m/z: [M+H]+ calcd for C12H19N4O4: 283.30 Found: 283.25.
Step 4:tert-Butyl [(6-{2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]ethoxy}pyrid- azin-3-yl)(imino) methyl] carbamate (3_30_5)
[00247] N-Hydroxyphthalimide (Phth-OH, 0.814 g, 4.99 mmol) and triphenylphosphine (1.427 g, 5.44 mmol) were added to a solution of {[6-(2-hydroxy- ethoxy)-pyridazin-3-yl]-imino-methyl}-carbamic acid tert-butyl ester 3_30_4 (1.28 g, 4.53 mmol) in anhydrous tetrahydrofuran (40 mL) at room temperature and a solution of diethyl azodicarboxylate (0.948 g, 5.44 mmol) in tetrahydrofuran (20 mL) was added dropwise to the resulting solution at 20°C. The resulting mixture was stirred at room temperature for 2 hours. After evaporation of half of the tetrahydrofuran, the white precipitate was collected, washed with a small volume of cold tetrahydrofuran and dried to afford the product 3_30_5 (1.412 g, 73 % yield) as a white solid. [00248] ¾ NMR (400 MHz, DMSO-d6): δ = 1.53 (s, 9H), 4.50 - 4.66 (m, 2H), 4.73-4.89 (m, 2H), 7.29 (d, J = 9.1 Hz, 1H), 7.86 (s, 4H), 8.23 (d, J = 9.1 Hz, 1H), 9.03 (br s., 2H).
[00249] MS (ES+) m/z: [M+H]+ calcd for CzoHzzNsOe: 428.42. Found: 428.22. Step 5:tert-Butyl [{6-[2-(aminooxy)ethoxy]pyridazin-3-yl}(imino)raethyl]carbamate
(3_30_6)
[00250] Hydrazine monohydrate (0.178 g, 3.55 mmol) was added to a solution of ({6-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-pyridazin-3-yl}-imino- methyl)-carbamic acid tert-butyl ester 3_30_5 (1.381 g, 3.23 mmol) in anhydrous ethanol (20 mL) and tetrahydrofuran (20 mL) at 0°C and the resulting mixture was stirred at room temperature for 2.5 hours. After concentration, the residue was purified by flash column chromatography to give compound 3_30_6 (0.960 g, 100 %) as a white solid.
[00251] Ή NMR (400 MHz, DMSO-<¾: δ = 1.44 (s, 9H), 3.80-3.96 (m, 2H), 4.58-4.70 (m, 2H), 6.12 (s, 2H), 7.31 (d, J = 9.4 Hz, 1H), 8.19 (d, J = 9.1 Hz, 1H).
[00252] MS (ES+) m/z: [M+H]+ calcd for G2H20N5O4: 298.32. Found: 298.27.
3.31 tert-Butyl [ {5 - [2- (Aminooxy) ethoxy ]py razine-2-yl} (imino) methy l]carb- amate
Figure imgf000090_0001
[00253] Using the procedure as described under 3.30 but using 5-chloro- pyrazine-2-carbonitrile (3_31_1) instead of 6-fluoro-pyridazine-3-carbonitrile (3_30_1), compound 3_31_6 was prepared.
3.32 5-[2-(Aminooxy)ethoxy]pyridine-2-carboximidamide
Figure imgf000091_0001
Step l:5-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-pyridine-2-carbonitrile (3_32_2)
[00254] Triphenylphosphine (4.36 g, 16.65 mmol) was added to a solution of N-(2-hydroxyethoxy)phthalimide (3.45 g, 16.65mmol) and 2-cyano-5-hydroxy- pyridine 3_32_1 (2.0 g, 16.65 mmol) in tetrahydrofuran (200 mL), followed by the slow addition of diethyl azodicarboxylate (2.73 mL, 16.65 mmol) over 20 minutes and the mixture was stirred at room temperature for 24 hours. After removal of the solvent, the residue was purified by crystallization from tetrahydrofuran to afford compound 3_32_2 (3.0 g, 58 % yield). [00255] Ή NMR (400 MHz, DMSO-rf6): δ = 4.51 (dd, J = 17.5, 5.7 Hz, 4H), 7.60 (dd, J = 8.9, 2.9 Hz, 1H), 7.87 (s, 4H), 8.02 (d, J = 8.9 Hz, 1H), 8.39 (d, J = 2.9 Hz, 1H).
Step 2:5-(2-Aminooxy-ethoxy)-pyridine-2-carbonitrile (3_32_3)
[00256] Hydrazine hydrate (0.310 mL, 9.69 mmol) was added to a suspension of compound 3_32_2 (3.0 g, 9.69 mmol) in ethanol (100 mL) and the mixture was stirred at 45°C for 14 hours. The solid was removed by filtration and the filtrate was concentrated. The residue was diluted with dichloromethane (20 mL), the solid was removed by filtration and the filtrate was concentrated to give compound 3_32_3 (1.3 g, 75 % yield) as an oil.
[00257] Ή NMR (400 MHz, DMSO-c¾: δ = 3.80-3.90 (m, 2H), 4.24-4.34 (m, 2H), 6.13 (s, 2H), 7.61 (dd, J = 8.7, 3.0 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 8.45 (d, J = 2.5 Hz, 1H).
Step 3:5-(2-Aminooxy-ethoxy)-pyridine-2-carboximidic acid methyl ester (3_32_4)
[00258] Sodium meth oxide (23 mg, 0.418 mmol) was added to a solution of compound 3_32_3 (150 mg, 0.837 mmol) in 5 mL of dry MeOH. The mixture was stirred at room temperature for 16 hours, and the solvent was evaporated to give compound 3_32_4 as a white solid (0.176 mg, 100 % yield).
[00259] XH NMR (400 MHz, MeOH-d4): δ = 3.94 (s, 3 H), 3.93-4.03 (m, 2H), 4.19-4.38 (m, 2H), 7.45 (dd, J = 8.6, 2.74Hz, 1H),7.84 (d, J = 8.6 Hz, 1H), 8.35 (d, J = 2.7 Hz, 1H). Step 4:5-(2-Aminooxy-ethoxy)-pyridine-2-carboxamidine (3_32_5)
[00260] Ammonium chloride (31 mg, 0.568 mmol) was added to a solution of 3_32_4 (100 mg, 0.437 mmol) in methanol (5 mL) and the mixture was stirred at room temperature for 6 hours. After the removal of the solvent, the residue was washed with tert-butyl methyl ether (10 mL), and stirred with ammonia (6N in methanol, 1 mL) for 1 hour. The solvents were then evaporated to give compound 3_32_5 (0.10 g, crude) as a solid.
[00261] Ή NMR (400 MHz, DMSO-rf6): δ = 4.31 (b. s., 2H), 4.35-4.43 (m, H), 6.01 (br. s., 2H), 7.42-7.51 (m, 1H), 7.74-7.82 (m, 1H), 8.30 (br s., 1H).
3.33 tert-Buty 1 (2- { [ {5 - [2- (aminooxy) ethoxy ]py ridin-2-y 1} (imino)methyl]- amino}ethyl)carbamate
Figure imgf000093_0001
[00262] Following the procedure described under 3.32 but using N- diethylamine instead of ammonium chloride compound 3_33_5 was prepared.
6-[2-(Aminooxy)ethoxy]pyridine-3-carboximidamide
H2N
Figure imgf000093_0002
[00263] Following the procedure described under 3.32 but using 5-cyano-2- hydroxypyridine instead of 2-cyano-5 -hydroxypyridine (3_32_1) compound 3_34_5 was prepared.
3.35 tert-Buty 1 2- [{ 5 - [2- (aminooxy)ethoxy ]pheny 1} (imino) methy l]hydrazine- carboxylate
Figure imgf000094_0001
Step l:4-Hydroxy benzenecarboximidoate (3_35_2)
[00264] A suspension of 4-cyanophenol 3_35_1 (20.0 g, 167.9 mmol) in methanol (300 mL) was cooled to 0°C and a stream of hydrogen chloride gas was passed through until the solution became saturated. The reaction mixture was stirred overnight at room temperature and the solid was collected by filtration to obtain compound 3_35_2 (28.6 g, 90 % yield, hydrochloride salt) as a white solid.
[00265] ¾ NMR (400 MHz, DMSO-i¾: δ = 4.22 (s, 3H), 6.99 (d, J = 8.6 Hz, 2H), 8.02 (d, J = 9.0 Hz, 2H), 11.18 (br s, 1H), 11.68 (br s, 1H).
[00266] MS (ES+) m/z: [M+H]+ calcd for C8Hi0NO2: 152.07; found: 152.13. Step 2:tert-Butyl 2-[(5-hydroxyphenyl)(imino)methyl]hydrazinecarboxylate (3_35_3)
[00267] Triethylamine (5.42 g, 53.3 mmol) was added to a suspension of compound 3_35_2 (10.0 g, 53.3 mmol) in methanol (200 mL) followed by tert-butyl hydrazinecarboxylate (Boc-Hydrazine, 14.1 g, 106.6 mmol). The resulting clear solution was heated at 40° C for 2 hours, it was then evaporated and purified by column chromatography to obtain compound 3_35_3 (9.2 g, 69 % yield) as a white solid.
[00268] Ή NMR (400 MHz, DMSO-rf6): δ = 1.42 (s, 9H), 6.08 (br s, 2H), 6.71 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 8.80 (br s, 1H), 9.60 (s, 1H).
[00269] MS (ES+) m/z: [M+H]+ calcd for C12H18N3O3: 252.13; found: 252.17.
Step 3: tert-Butyl 2-[(5-{2-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]ethoxy}phen- yl)(imino)methyl]hydrazinecarboxylate (3_35_4)
[00270] To a suspension of compound 3_35_3 (3.2 g, 12.8 mmol), triphenylphosphine (3.7 g, 14.1 mmol), and N-(2-hydroxyethoxy)phthalimide (2.9 g, 14.1 mmol) in tetrahydrofuran (20 mL) was added diisopropyl azodicarboxylate (2.8 g, 14.1 mmol) dropwise with sonication in an ultrasonic bath. The mixture was sonicated for an additional 15 minutes, stirred overnight at room temperature, evaporated and purified by column chromatography to obtain compound 3_35_4 (4.4 g, 79 % yield) as a white solid.
[00271] ln NMR (400 MHz, DMSO-d6): δ = 1.43 (s, 9H), 4.18-4.37 (m, 2H), 4.37-4.57 (m, 2H), 6.15 (s, 2H), 6.81 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H), 7.85 (s, 4H), 8.86 (br s, 1H).
[00272] MS (ES+) m/z: [M+H]+ calcd for C22H25N4O6: 441.18; found: 441.20. Step 4:tert-Butyl 2-[{5-[2-(aminooxy)ethoxy]phenyl}(irnino)methyl]hydrazinecarb- oxylate (3_35_5)
[00273] Hydrazine hydrate (0.68 g, 20.2 mmol) was added to a suspension of compound 3_35_4 (4.5 g, 10.1 mmol) in ethanol and the resulting mixture was slowly heated to 45°C with vigorous stirring until a precipitate formed. The slurry was allowed to cool to room temperature and stirred for 4 hours. After the solid was removed by filtration, the filtrate was evaporated and purified by column chromatography to obtain compound 3_35_5 (2.7 g, 87 % yield).
[00274] Ή NMR (400 MHz, DMSO-c¾: δ = 1.42 (s, 9H), 3.82 (d, J = 4.44 Hz, 2H), 4.11 (d, J = 4.8 Hz, 2H), 6.08 (s, 2H), 6.15 (br s, 2H), 6.90 (d, J = 8.9 Hz, 2H), 7.64 ( d, J =8.9 Hz, 2H), 8.86 (br s, 1H).
3.36 4-(2-Aminooxy-2-methyl-propoxy)-benzamidine
Figure imgf000096_0001
Step l:2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yloxy)-2-methyl-propionic acid ethyl ester (3_36_2) [00275] N-Hydroxyphthalimide (8.36 g, 51.27 mmol) was added dropwise to a solution of compound 3_36_1 (10.0 g, 51.26 mmol) in dry Ν,Ν-dimethylformamide (70 mL) followed by l,8-diazabicyclo[5.4.0]undec-7-ene (7.7 mL, 51.27 mmol) during 20 minutes. The mixture was stirred at 35°C for 3 days, concentrated under vacuum and the residue was suspended in ethyl acetate (200 mL) and washed successively with cold 0.5 M hydrochloric acid, water and brine. The organic extract was dried over anhydrous sodium sulfate and evaporated to afford the title compound 3_36_2 (14.0 g, 98 % yield), which was used in the next step without further purification.
[00276] Ή NMR (400 MHz, DMSO-c?6): δ = 1.21 (t, J = 7.0 Hz, 3H), 1.50 (s, 6H), 4.12 (d, J = 7.0 Hz, 2H), 7.86 (s, 4H).
[00277] MS: m/z (ES+ %) 278 (M+H, 35) 204 (100), 186 (20), 164 (35), 115
(45).
Step 2:2-Aminooxy-2-methyl-propionic acid ethyl ester (3_36_3)
[00278] Hydrazine hydrate (1.01 mL, 18.7 mmol) was added to a suspension of compound 3_36_2 (4.95 g, 17.8 mmol) in absolute ethanol (50 mL) and the mixture was stirred at 40°C for 2 hours. The suspension was cooled to 20°C, filtered, washed with ethanol and the filtrate was evaporated. The residue obtained was triturated with ethyl acetate (50 mL) and filtered. The filtrate was concentrated to obtain compound 3_36_3 (1.9 g, 73 % yield) as a white solid.
[00279] Ή NMR (400 MHz, DMSO-d6): δ = 1.18 (t, J = 7.1 Hz, 3H), 1.25 (s, 6H), 4.06 (q, J = 70 Hz, 2H), 5.81 (br s, 2H).
[00280] MS: m/z (ES+, %) 148 (M+H, 100) Step 3:N-Boc-2-Aminooxy-2-methyl-propionic acid ethyl ester (3_36_4)
[00281] Di-tert-butyldicarbonate (BOC20, 2.82g, 12.92 mmol) was added to a solution of compound 3_36_3 (1.9 g, 12.92 mmol) in dry tetrahydrofuran (25 mL) and the mixture was stirred at room temperature for 16 hours and evaporated under vacuum. The residue obtained was purified by chromatography to obtain compound 3_36_4 (2.3 g, 72 % yield) as a clear thick oil.
[00282] H N R (400 MHz, DMSO-c/6): δ = 1.10-1.29 (m, 3H), 1.32 (s, 3H),
I.39 (s, 3H), 1.47 (s, 9H), 3.96-4.19 (m, 2H), 9.55 (s, 1H).
[00283] MS: m/z (ES", %) 248 (M+H, 60), 192 (100), 175 (8), 115 (18). Step 4:N-Boc-2-Aminooxy-2-methyl-propan-l-ol (3_36_5)
[00284] Lithium aluminium hydride (LAH, IM in tetrahydrofuran, 13.45 mL,
II.33 mmol) was added dropwise to a cold (0°C) solution of compound 3_36_4 (1.9 g, 7.68 mmol) in dry diethyl ether (35 mL) over 15 minutes. The reaction mixture was stirred at 0°C for 5 hours and quenched by pouring into a cold (0°C) saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (2 x 75 mL) and the combined organic extracts were filtered through Celite, washed with water, brine, dried over anhydrous sodium sulfate and evaporated to yield compound 3_36_5 (1.1 g, 70 % yield) as a solid.
[00285] Ή NMR (400 MHz, DMSO-c¾: δ = 1.05 (s, 6H), 1.40 (s, 9H), 3.21 (d, J = 6.6 Hz, 2H), 4.43 (t, J = 6.6 Hz, 2H), 9.58 (d, J = 3.9 Hz, 1H).
Step 5:N-Boc-4-(2-Aminooxy-2-methyl-propoxy)-benzonitrile (3_36_6)
[00286] Sodium hydride (60 % in mineral oil, 0.41g, 10.24 mmol) was added in portions to a cold (10°C) solution of compound 3_36_5 (0.7 g, 3.41 mmol) in dry tetrahydrofuran (9 mL) under a nitrogen atmosphere. After stirring for 15 minutes 4- fluorobenzonitrile (0.496 g, 4.09 mmol) was added dropwise and the mixture was refluxed for 3 hours, stirred at 50°C for 16 hours, cooled to room temperature, poured into cold water, acidified with acetic acid (1.5 mL) and extracted into ethyl acetate (3 χ 75 mL). The combined organic extracts were filtered through Celite, washed with water and brine, dried over anhydrous sodium sulfate, evaporated and the residue was purified by column chromatography to obtain compound 3_36_6 (0.75 g, 72 % yield) as an off-white solid.
[00287] ¾ NMR (400 MHz, DMSO-c¾: δ = 1.23 (s, 6H), 1.37 (s, 9H), 3.94 (s, 2H), 7.09 (m, J = 8.9 Hz, 2H), 7.76 (m, J = 8.9 Hz, 2H), 9.55 (s, 1H).
[00288] MS: m/z (ES", %) 305 (M+H, 98), 218 (100), 204 (8).
Step 6:4-(2-Aminooxy-2-methyl-propoxy)-benzimidic acid methyl ester hydrochloride salt (3_36_7)
[00289] A solution of compound 3_36_6 (0.75 g, 2.45 mmol) in anhydrous methanol (20 mL) in a pressure reaction vessel (100 mL) at -10°C was saturated with dry hydrogen gas and the sealed vessel was stirred at room temperature for 18 hours. The reaction mixture was concentrated to half the volume, diluted with diethyl ether (75 mL), stirred, filtered, washed with diethyl ether and dried under vacuum to obtain compound 3_36_7 (0.7 g, 70 % yield) as a white powder, which was used in the next step without purification.
[00290] ¾ NMR (400 MHz, DMSO-c¾: δ = 1.44 (s, 6H), 4.14 (br s, 3H), 4.22- 4.38 (m, 2H), 7.24 (m, J = 8.9 Hz, 2H), 8.16 (m, J = 8.9 Hz, 2H), 11.08 (br s, 3H).
[00291] MS: m/z (ES+ %) 239 (ΜΉ, 45), 206 (100), 174 (15), 152 (90), 104
(30) Step 7:4-(2-Aminooxy-2-methyl-propoxy)-benzamidine (3_36_8)
[00292] Ammonia (7N in methanol, 3.0 mL) was added to a suspension of compound 3_36_7 (0.70 g, 2.55 mmol) in anhydrous methanol (10 mL) at 20°C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was triturated with hexanes/ether (1:1, 50 mL), filtered, washed with hexanes/ether (1:1) and dried under vacuum to obtain the title compound 3_36_8 (0.55g, quant.) as a white powder.
[00293] Ή NMR (400 MHz, DMSO-rf6): δ = 1.17 (s, 6H), 3.99 (s, 2H), 7.15 (d, J = 9.0 Hz, 2H), 7.82 (d, J = 9.0 Hz, 2H), 8.96 (br s, 2H), 9.19 (br s, 1H).
[00294] MS: m/z (ES+ %) 224 (ΜΉ, 100), 199 (74), 191 (82), 137 (7).
3.37 4- (2- Aminooxy- 1 , 1 -dimethy 1-ethoxy) -benzamidine
Figure imgf000100_0001
Step l: 2-(4-Cyano-phenoxy)-2-methyl-propionic acid ethyl ester (3_37_2) [00295] Potassium carbonate (14.16 g. 102.5 mmol) was added to a solution of compound 3_37__1 (10.0 g, 51.27 mmol) in dry Ν,Ν-dimethylformamide (70 mL) followed by 4-cyanophenol (6.7 g, 61.52 mmol) at room temperature and the reaction mixture was heated at 60°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, washed with Ν,Ν-dimethylformamide and the filtrate was concentrated under vacuum. The residue was dissolved in ethyl acetate (300 mL), washed with a cold, aqueous 0.5 M sodium hydroxide solution (3 x 30 mL), water and brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography to afford compound 3_37_2 (3.1 g, 26 % yield) as a clear liquid.
[00296] Ή NMR (400 MHz, DMSO-d6): δ = 1.12 (t, J = 7.03 Hz, 3H), 1.58 (s, 6H), 4.15 (d, J = 7.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H).
Step 2:4-(2-Hydroxy-l,l-dimethyl-ethoxy)-benzonitrile (3_37_3)
[00297] Sodium borohydride (2.3 g, 60.76 mmol) was added in portions to a cold (5°C) solution of compound 3_37_2 (4.7 g, 20.17 mmol) in anhydrous methanol (50 mL) over 10 minutes. The mixture was stirred at room temperature for 16 hours and the suspension was concentrated to remove most of the methanol. The residue was partitioned between a cold saturated ammonium chloride solution and ethyl acetate (150 mL each). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The crude product obtained was purified by column chromatography to give compound 3_37_3 (3.2 g, 79 % yield) as a colorless liquid.
[00298] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.26 (s, 6H), 3.41 (d, J = 5.86 Hz, 2H), 5.00 (t, 1H), 7.16 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H). Step 3 : 4- [2-(l , 3-Dioxo- 1 ,3-dihydro-isoindol-2-yloxy)- 1 , 1 -dimethyl-ethoxy] - benzonitrile (3_37_4)
[00299] Triphenylphosphine (2.31 g, 8.79 mmol) was added to a mixture of compound 3_37_3 (1.6 g, 8.37 mmol) and JV-hydroxyphthalimide (1.43 g, 8.79 mmol) in tetrahydrofuran (20 mL), and the mixture was sonicated for 20 minutes, and treated with diisopropyl azodicarboxylate (DIAD, 1.73 mL, 8.79 mmol). The reaction mixture was stirred at room temperature for 20 hours, concentrated and the residue was purified by column chromatography to give compound 3_37_4 (1.6 g, 57 % yield) as an off-white solid, which was used in the next step without further purification.
Step 4:4-(2-Aminooxy-l,l-dimethyl-ethoxy)-benzonitrile (3_37_5)
[00300] Hydrazine hydrate (0.24 mL, 4.99 mmol) was added to a solution of compound 3_37_4 (1.6 g, 4.75 mmol) in absolute ethanol (30 mL) and the mixture was stirred at 35°C for 2 hours. The resulting suspension was cooled to 20°C, filtered, washed with ethanol and evaporated. The residue was triturated in ethyl acetate (50 mL), filtered and the filtrate was evaporated to obtain compound 3_37_5 (1.0 g, 100% yield), which was used in the next step without purification.
[00301] Ή NMR (400 MHz, DMSO-d6): δ = 1.29 (s, 6H), 3.61 (s, 2H), 6.17 (s, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H).
Step 5:4-(2-Aminooxy-l,l-dimethyl-ethoxy)-benzimidic acid methyl ester (3_37_6)
[00302] A solution of compound 3_37_5 (1.6 g, 4.85 mmol) in anhydrous methanol (20 mL) at -10°C was saturated with dry hydrogen chloride gas and the sealed vessel was stirred at room temperature for 18 hours. The reaction mixture was concentrated to half the volume, diluted with diethyl ether (75 mL), stirred, filtered, washed with diethyl ether and dried under vacuum to obtain compound 3_37_6 (1.6 g, >100% yield) as a white powder, which was used in the next step without purification.
[00303] Ή NMR (400 MHz, DMSO-d6): δ = 1.37 (s, 6H), 4.13 (s, 2H), 4.24 (s, 3H), 7.27 (d, J = 8.9 Hz, 2H), 8.07 (d, J = 8.9 Hz, 2H).
Step 6: 4-(2-Aminooxy-l,l-dimethyl-ethoxy)-benzamidine (3_37_7)
[00304] Ammonia (7 N in methanol (7.5 mL, 52.5 mmol) was added to a suspension of compound 3_37_6 (1.6 g, 4.85 mmol) in anhydrous methanol (150 mL) at 20°C and the mixture was stirred at 35°C for 1.5 hours and concentrated. The residue was triturated in a mixture of hexanes/ether (50 mL, 1:1), filtered, washed with hexanes/ether (1:1) and dried under vacuum to afford compound 3_37_7 (1.0 g, 93 % yield) as a white powder.
3.38 tert-Butyl [{2-[2-(aminooxy)ethoxy]-l,3-thiazol-4-yl}(imino)methyl]carb- amate
Figure imgf000103_0001
Figure imgf000103_0002
Step l:2-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboxylic acid ethyl ester (3_38_2)
[00305] Sodium hydride (60 % dispersion in oil, 1.69 g, 42.4 mmol) was added to a solution of 2-(tetrahydro-pyran-2-yloxy)-ethanol (6.19 g, 42.4 mmol) in N,N- dimethylformamide (20 mL). After stirring at 0°C for 1 hour, 2-bromo-thiazole-4- carboxylic acid ethyl ester 3_38_1 (10.0 g, 42.4 mmol) in Ν,Ν-dimethylformamide (10 mL) was added at 0°C and the resulting mixture was stirred at 0°C for 2.5 hours. The reaction mixture was neutralized to pH 7 using acetic acid at 0°C, diluted with ethyl acetate (150 mL) and washed with brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give the desired product (99.4 g, 73 % yield) as a white solid.
[00306] Ή NMR (400 MHz, DMSO-rf6): δ = 1.28 (t, J = 7.2 Hz, 3H), 1.37 - 1.53 (m, 4H), 1.56-1.78 (m, 2 H), 3.38-3.48 (m, 1H), 3.66-3.80 (m, 2H), 3.85 - 3.98 (m, 1H), 4.26 (q, J = 7.0 Hz, 2H), 4.37 - 4.46 (m, 1H), 4.52 - 4.59 (m, 1H), 4.64 (br s, 1H), 7.93 (s, 1H).
Step 2:2-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboxylic acid (3_38_3)
[00307] A solution of lithium hydroxide (1.26 g, 52.6 mmol) in water (35 mL) was added to a solution of 2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole- 4-carboxylic acid ethyl ester 3_38_2 (3.17 g, 10.5 mmol) in tetrahydrofuran (45 mL). After stirring at room temperature for 2 hours, the reaction mixture was neutralized to pH 7 using dilute hydrochloric acid at 0°C, diluted with ethyl acetate (150 mL) and washed with brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give the desired product (2.9 g, 100 % yield) as a white solid. [00308] Ή NMR (400 MHz, DMSO-d6): δ = 1.35-1.54 (m, 4H), 1.57-1.76 (m, 2H), 3.39-3.47 (m, 1H), 3.67-3.81 (m, 2H), 3.90-3.98 (m, 1H), 4.50-4.58 (m, 2H), 4.64 (br s, 1H), 7.85 (s, 1H).
Step 3:2-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboxylic acid amide (3_38_4)
[00309] Triethylamine (TEA, 1.22 g, 12.07 mmol) was added to a solution of 2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboxylic acid 3_38_3 (3.0 g, 11.0 mmol) in tetrahydrofuran (60 mL), followed by ethyl chloroformate (1.31 g, 12.07 mmol) slowly at -10°C. After stirring at room temperature for 1.5 hour, concentrated ammonium hydroxide (0.80 g, 13.17 mmol) was slowly added to the reaction mixture at 0°C and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, diluted with ethyl acetate (150 mL) and washed with brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give the desired product (1.76 g, 59 % yield) as a white solid.
[00310] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.33-1.53 (m, 4H), 1.55-1.79 (m, 2H), 3.38-3.51 (m, 1H), 3.66-3.82 (m, 2H), 3.87-4.00 (m, 1H), 4.43-4.74 (m, 3H), 7.44- 7.57 (m, 2H), 7.62 (s, 1H).
[00311] MS (ES+) m/z: [M+H]+ calcd for C11H17N2O4S: 273.33. Found: 273.24.
Step 4: 2-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carbonitrile (3_38_5)
[00312] Triethylamine (TEA, 7.625 g, 75.3 mmol) was added to a solution of 2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboxylic acid amide 3_38_4 (1.71 g, 6.28 mmol) in dichloromethane (50 mL) at 0°C. Phosphorus oxychloride (2.407 g, 15.70 mmol) was slowly added to the reaction mixture at 0°C and the resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with ice-water (20 mL), extracted with ethyl acetate and the extract was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column to give the desired product (1.42 g, 88.9 %) as a white solid.
[00313] Ή NMR (400 MHz, DMSO-rf6): δ = 1.38-1.55 (m, 4H), 1.57-1.79 (m, 2H), 3.38-3.51 (m, 1H), 3.67-3.79 (m, 2H), 3.87-4.00 (m, 1H), 4.49-4.71 (m, 3H), 8.25 (s, 1H).
[00314] MS (ES+) m/z: [M+H]+ calcd for G1H15N2O3S: 255.31. Found: 255.20.
Step 5:2-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboximidic acid 2- hydroxy-ethyl ester (3_38_6)
[00315] Sodium (0.036 g, 1.56 mmol) was added to a flask containing ethylene glycol (1.33 g, 5.23 mmol) at room temperature. After all sodium was consumed, 2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carbonitrile 3_38_5 (1.33 g, 5.23 mmol) in tetrahydrofuran (10 mL) was added at 0°C and the reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized to pH 7 using acetic acid and diluted with ethyl acetate. The mixture was washed with brine, dried and concentrated to afford the desired product (1.52 g, 92% yield) as a white solid, which was used without purification.
[00316] Ή NMR (400 MHz, DMSO-rf6): δ = 1.35-1.53 (m, 4H), 1.58-1.76 (m, 2H), 3.41-3.48 (m, 1H), 3.66-3.79 (m, 4H), 3.89-3.98 (m, 1H), 4.19 (t, J = 5.0 Hz, 2H), 4.54-4.61 (m, 3H), 4.64 (d, J = 2.9 Hz, 2H), 7.48 (s, 1H), 8.31 (br s, 1H).
[00317] MS (ES+) m/z: [M+H]+ calcd for GsH^NzOsS: 317.38. Found: 317.27. Step 6: 2-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboxamidine (3_38_7)
[00318] Ammonium chloride (0.302 g, 5.65 mmol) was added to a mixture of 2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboximidic acid 2-hydroxy- ethyl ester 3_38_6 (1.49 g, 4.71 mmol) in methanol (40 mL) and the mixture was refluxed for 6.5 hours and concentrated to dryness to afford the crude product which was purified by column chromatography to give the desired product (1.35 g, 100 %) as a white solid.
[00319] ¾ NMR (400 MHz, DMSO-c¾: δ = 1.44 (m, 4H), 1.54-1.79 (m, 2H), 3.38-3.48 (m, H), 3.66-3.80 (m, H), 3.85-4.00 (m, 1H), 4.54-4.73 (m, 3H), 8.39 (s, 1H), 9.20 (br s, 4H).
[00320] MS (ES+) m/z: [M+H]+ calcd for CnH18N303S: 272.34. Found: 272.23.
Step 7:2-(2-Hydroxy-ethoxy)-thiazole-4-carboxamidine hydrochloric acid (3_38_8)
[00321] Concentrated hydrochloric acid (0.1 mL) was added to a mixture of 2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-thiazole-4-carboxamidine 3_38_7 (1.25 g; 4.61 mmol) in methanol (10 mL) and the mixture was stirred at room temperature for 1 hour and concentrated to dryness to afford compound 3_38_8 as crude product (0.92 g, 91 % yield) as a white solid.
[00322] Ή NMR (400 MHz, DMSO-d6): δ = 3.67-3.77 (m, 2H), 4.43-4.53 (m, 2H), 8.40 (s, 1H), 9.14 (s, H), 9.24 (s, 2H).
[00323] MS (ES+) m/z: [M+H]+ calcd for CeHioNsOzS: 188.22. Found: 188.20.
Step 8:{[2-(2-Hydroxy-ethoxy)-thiazol-4-yl]-imino-methyl}-carbamic acid tert-butyl ester (3_38_9) [00324] A saturated sodium bicarbonate solution (15 mL) and a solution of di-tert-butyldicarbonate (BOC20, 1.346 g, 6.17 mmol) in 1,4-dioxane (10 mL) were added to a solution of 2-(2-hydroxy-ethoxy)-thiazole-4-carboxamidine hydrochloric acid 3_38_8 (0.92 g, 4.11 mmol) in water (5 mL) at room temperature. After stirring at room temperature overnight, the resulting mixture was concentrated and the residue was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to give the desired product (0.68 g, 58 % yield) as a white solid.
[00325] Ή NMR (400 MHz, DMSO-rf6): δ = 1.42 (s, 9H), 3.65-3.78 (m, 2H), 4.47 (t, J = 4.7 Hz, 2H), 4.96 (t, J = 5.4 Hz, 1H), 7.79 (s, 1H), 8.32 (br s, 1H), 9.09 (br s, 1H).
[00326] MS (ES+) m/z: [M+H]+ calcd for CnH18N304S: 288.34. Found: 288.20.
Step 9:({2-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-thiazol-4-yl}-imino- methyl)-carbamic acid tert-butyl ester (3_38_10)
[00327] N-Hydroxyphthalimide (0.393 g, 2.41 mmol) and triphenylphos- phine (0.690 g, 2.63 mmol) were added to a solution of {[2-(2-hydroxy-ethoxy)- thiazol-4-yl]-imino-methyl}-carbamic acid tert-butyl ester 3_38_9 (0.63 g, 2.19 mmol) in anhydrous tetrahydrofuran (40 mL) at room temperature. A solution of diethyl azodicarboxylate (DEAD, 0.458 g, 2.63 mmol) in tetrahydrofuran (20 mL) was added dropwise to the resulting solution at 20°C and the resulting mixture was stirred at room temperature overnight. After evaporation of the tetrahydrofuran, the crude product was purified by column chromatography to give the desired product (1.02 g, 100 % yield) as a white solid.
[00328] XH NMR (400 MHz, DMSO- ): δ = 1.41 (s, 9 H), 4.53-4.65 (m, 2 H), 4.70 - 4.83 (m, 2 H), 7.81 (s, 1 H), 7.85 (s, 4 H). [00329] MS (ES+) m/z: [M+H]+ calcd for Ci9H2iN406S: 433.46. Found: 433.34.
Step 10: 3.38. tert-Butyl [{2-[2-(aminooxy)ethoxy]-l,3-thiazol-4-yl}(imino)methyl]- carbamate (3_38_11)
[00330] Hydrazine monohydrate (0.127 g, 2.54 mmol) was added to a solution of ({2-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-thiazol-4-yl}-imino- methyl)-carbamic acid tert-butyl ester 3_38_10 (1.0 g, 2.31 mmol) in anhydrous ethanol (15 mL) and tetrahydrofuran (10 mL) at 0°C and the resulting mixture was stirred at room temperature for 2.5 hours. After concentration, the residue was stirred with ethyl acetate/hexanes (2:1, 20 mL) and filtered. The filtrate was concentrated to afford the desired product (0.6 g, 86 % yield) as a white solid.
[00331] ¾ NMR (400 MHz, DMSO-c/6): δ = 1.42 (s, 9H), 3.78 - 3.89 (m, 2H), 4.57-4.64 (m, 2H), 6.12 (s, 2H), 7.79 (s, 1H), 8.36 (br s, 1H), 9.09 (br s, 1H).
3.39 tert-Butyl [{5 -[2-(aminooxy)ethoxy]- 1, 3,4-thiadiazol-2-yl} (imino)methyl]- carbamate
Figure imgf000109_0001
Step l:5-Bromo-[l,3,4]thiadiazole-2-carboxylic acid ethyl ester (3_39_2) [00332] CuBr2 (18.06 g, 80.1 mmol) was added to a suspension of 5-amino- [l,3,4]thiadiazole-2-carboxylic acid ethyl ester 3_39_1 (7 g, 40.5 mmol) in 150 mL of acetonitrile, the mixture was stirred for 15 min, t-BuONO (9.6 mL, 80.1 mmol) was added over 20 min., and the mixture was heated at 60°C for 0.5 h. Water and ethyl acetate were added, the mixture was stirred until the dark color disappeared and filtered through celite, and the organic layer was washed with brine, dried over Na2S04, filtrated and concentrated to give compound 3_39_2 (7.56 g, 79 % yield) as a yellow solid.
[00333] Ή NMR (400 MHz, DMSO-d6): δ = 1.32 (t, J = 7.14 Hz, 3 H), 4.41 (q, J = 7.30 Hz, 2 H);
Step 2:5-Bromo-[l,3,4]thiadiazole-2-carboxylic acid amide (3_39_3)
[00334] NH4OH (50 % aq solution, 6.45 mL) was added to a solution of compound 3_39_2 (7.56 g, 31.8 mol) in 70 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 16 h and concentrated to give a solid, which was triturated with ether, filtered, and dried to give compound 3_39_3 (6.5 g, 98 % yield) as a yellow solid.
[00335] Ή NMR (400 MHz, DMSO-rf6): δ = 8.26 (br. s., 1 H), 8.64 (br. s., 1 H).
Step 3: 5-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-[l,3,4] thiadiazole-2-carboxylic acid amide (3_39_4)
[00336] NaH (1.6 g, 40.2 mmol) was added to a solution of compound 3_39_3 (4.16 g, 20.1 mmol) in 20 mL of Ν,Ν-dimethylformamide, and the mixture was stirred at room temperature for 20 min. 2-(Tetrahydro-pyran-2-yloxy)-ethanol (3.81 mL, 26.1 mmol) was added, and the mixture was heated at 50-60°C for 3 h, concentrated, diluted with ethyl acetate, washed with brine, dried over Na2S04, filtered and concentrated to give a residue, which was purified by column chromatography to give compound 3_39_4 (2.15 g, 40 % yield) as a gum.
[00337] Ή NMR (400 MHz, CDC13): δ = 1.45 - 1.70 (m, 4 H), 1.69 - 1.92 (m, 2 H), 3.54 (m, 1 H), 3.79 - 3.94 (m, 2 H), 4.05 - 4.15 (m, 1 H), 4.68 (t, J = 3.49 Hz, 1 H), 4.77 (dt, J = 6.03, 3.01 Hz, 2 H), 5.90 (br. s., 1 H), 7.08 (br. s., 1 H).
Step 4: 5 - [2- (Tetrahydro-pyran-2-yloxy)-ethoxy] -[1,3,4] thiadiazole-2-carbonitrile
(3_39_5)
[00338] Trifluoroacetic anhydride (TFAA, 1.13 mL, 8.46 mmol) was added to a solution of compound 3_39_4 (2.1 g, 7.69 mmol) and triethylamine (TEA, 1.13 mL, 8.64 mmol) in tetrahydrofuran (20 mL) at 0°C, and the mixture was warmed to room temperature, and stirred for 1 hour. Additional 0.4 mL of trifluoroacetic anhydride and 3 mL of triethylamine were added and the mixture was stirred at room temperature for 16 h, diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution and brine, dried over Na2SC>4, filtered, and concentrated to give a residue. The residue was purified by column chromatography to give compound 3_39_5 (1.3 g, 68 % yield) as a yellow oil.
[00339] ¾ NMR (400 MHz, CDC13): δ = 1.48 - 1.66 (m, 4 H), 1.68 - 1.88 (m, 2 H), 3.55 (t, J = 5.39 Hz, 1 H), 3.81 - 3.91 (m, 2H), 4.06 - 4.17 (m, 1 H), 4.67 (t, J = 2.86 Hz, 1 H), 4.78 - 4.93 (m, 2 H).
Step 5 : 5 - [2- (Tetrahydro-pyran-2-yloxy)-ethoxy] -[1,3, 4] thiadiazole-2-carboxamidine (3_39_6)
[00340] NaOMe (0.08 g, 1.5 mmol) was added to solution of compound 3_39_5 (0.77 g, 3.02 mmol) in 15 mL of dry MeOH, and the mixture was stirred at room temperature for 0.5 h. NH4C1 (7.6 g, 30.1 mmol) was added, and the reaction mixture was refluxed for 20 h, concentrated, diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution and brine, dried over Na2S04, filtered and concentrated to give compound 3_39_6 (0.41 g 50 % yield) as a brown gum.
[00341] Ή NMR (400 MHz, DMSO-</6 with one drop of trifluroacetic acid): δ = 1.32 - 1.52 (m, 4 H), 1.53 - 1.72 (m, 2 H), 3.42 (m, 1 H), 3.67 - 3.87 (m, 2 H), 3.93 - 4.04 (m, 1 H), 4.59 - 4.69 (m, 1 H), 4.75 (m, 2 H), 9.66 (br. s., 2 H), 9.87 (br. s., 2 H).
Step 6: 5-(2-Hydroxy-ethoxy)-[l,3,4]thiadiazole-2-carboxamidine (3_39_7)
[00342] 3 mL of IN HC1 were added to a solution of compound 3_39_6 (0.41 g, 1.5 mmol) in 15 mL of MeOH at 0 °C, and the mixture was stirred at 20 °C for 2 h, concentrated and lyophilized to give crude compound 3_39_7 (0.51 g, >100% yield) as a solid, which was used in the next step without purification.
[00343] ¾ NMR (400 MHz, DMSO-c¾ with one drop of trifluroacetic acid): δ = 3.77 (d, J = 4.12 Hz, 2 H), 4.59 (t, J = 4.44 Hz, 2 H), 9.64 (br. s., 2 H), 9.88 (br. s., 2 H).
Step 7: {[5-(2-Hydroxy-ethoxy)-[l,3,4]thiadiazol-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (3_39_8)
[00344] Di-tert-butyldicarbonate (Boc20, 0.5 g, 2.25 mmol) was added to a solution of compound 3_39_7 (0.5 g crude as obtained above) in 3 mL of a saturated sodium bicarbonate solution, 5 mL of dioxane and 2.5 mL of water, and the mixture was stirred for 16 h at room temperature, concentrated, diluted with ethyl acetate, washed with brine, dried over Na2S04, filtered, and concentrated to give compound 3_39_8 (0.3 g, 69 % yield over two steps) as a brown oil.
[00345] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.42 (s, 9 H), 3.75 (d, J = 4.12 Hz, 2 H), 4.52 (d, J = 4.12 Hz, 2 H), 5.06 (s, 1 H). Step 8: ({5-[2-(l;3-Dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-[l,3;4]thiadiazol-2-yl}- imino-methyl)-carbamic acid tert-butyl ester (3_39_9)
[00346] Triphenylphosphine (0.37 g, 1.5 mmol) and diisopropyl azodicar- boxylate (0.3 mL, 1.5 mmol) were added to a solution of compound 3_39_8 (0.3 g, 1 mmol) and N-hydroxyphalimide (0.17 g, 1 mmol) in 10 mL of tetrahydrofuran, at 0 °C, and the mixture was stirred at room temperature for 1.5 h, diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution and brine, dried over Na2S04, filtered and concentrated to give a residue. The residue was purified by column chromatography to give compound 3_39_9 (0.4 g, 92 % yield).
[00347] Ή NMR (400 MHz, CDC13): δ = 1.55 (s, 9 H), 4.55 - 4.67 (m, 2 H), 4.88 - 5.00 (m, 2 H), 7.70 - 7.91 (m, 4 H).
Step 9:tert-Butyl [{5-[2-(aminooxy)ethoxy]-l,3,4-thiadiazol-2-yl}(imino)methyl]carb- amate (3_39_10)
[00348] Hydrazine hydrate (0.1 mL, 2 mmol) was added to a suspension of compound 3_39_9 (1.5 g, 2 mmol) in 6 mL of EtOH, and the mixture was stirred at room temperature for 4 h. The solid was removed by filtration, and the filtrate was concentrated to give a residue. The residue was dissolved in dichloromethane, filtered to remove the solid, and the filtrate was concentrated to give compound 3_39_10 (0.43 g, 71 % yield) as an oil.
[00349] Ή NMR (400 MHz, CDC13): δ = 1.54 (s, 9 H), 4.04 (d, J = 4.44 Hz, 2 H), 4.79 (d, J = 4.12 Hz, 2 H), 6.34 (br. s., 2 H). 3.40 tert-Butyl [{3-[2-(aminooxy)ethoxy]-l,2-oxazol-5-yl}(imino)methyl]carb- amate
Figure imgf000114_0001
3 40 10
[00350] Following the procedure as described above under 3.38 but using ethyl 3-bromo-isoxazole-5-carboxylate instead of ethyl 2-bromo-thiazole-4-carb- oxylate 3_38_1 compound 3_40_10 was prepared.
3.41 tert-Butyl [{3-[2- (aminooxy)ethoxy]- 1 -methyl-1 H-pyrazol-5-yl} (imino)- methyl]carbamate
Figure imgf000114_0002
3 41 10
Step l:Methyl 3-hydroxy-l-methyl-lH-pyrazole-5-carboxylate (3_41_2)
[00351] Triethylamine (66 mL, 474.4 mmol) was added to a solution of methylhydrazine sulfuric acid salt (30.4 g, 211 mmol) in water (150 mL) and methanol (300 mL) at room temperature. The mixture was stirred for 0.5 hour at room temperature, but-2-ynedioic acid dimethyl ester (30 g, 211 mmol) was added and the mixture was stirred for 18 hours at 70°C. The reaction mixture was kept at room temperature for two days and the solid was collected by filtration and dried to give 12 g of the desired compound. The filtrate was concentrated, treated with ice and the solid was collected by filtration, and dried to give an additional 5 g of the desired compound 3_41_2 (17 g, 52 % yield) as a yellow solid.
[00352] ¾ NMR (400 MHz, DMSO-c¾: δ = 3.79 (s, 3H), 3.88 (s, 3H), 6.01 (s, 1H), 10.05 (s, 1H).
Step 2: 2-Methyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-2H-pyrazole-3-carboxylic acid ethyl ester (3_ 1_3)
[00353] Diisopropyl azodicarboxylate (DIAD, 41.6 mL, 205.8 mmol) was added to a solution of 3_41_2 (10.7 g, 68.6 mmol), 2-(tetrahydro-pyran-2-yloxy)- ethanol (17 mL, 102.9 mmol) and triphenylphosphine (53.9 g, 205.8 mmol) at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was heated at 80°C for 16 hours, more 2-(tetrahydro-pyran-2-yloxy)-ethanol (3.75 mL), triphenylphosphine (5.3 g) and diisopropyl azodicarboxylate (3 mL) were added, and the reaction mixture was refluxed for 16 hours, concentrated and treated with diethyl ether and hexanes (2:3, 500 mL) to give a precipitate, which was removed by filtration. The filtrate was concentrated and the residue obtained was purified by column chromatography to give compound 3_41_3 (26.6 g, >100 % yield, contaminated with diisopropyl azodicarboxylate) as a yellow oil.
[00354] Ή NMR (400 MHz, CDC13): δ = 1.45-1.90 (m, 6H), 3.52 (d, ]=UA Hz, 1H), 3.79-3.92 (m, 5H), 3.95-4.10 (m, 5H), 4.31 (t, J=4.9 Hz, 2H), 4.69 (t, J=3.5 Hz, 1H), 6.21 (s, 1H).
[00355] Following the procedure as described above under 3.38 intermediate 3_41_3 was converted to compound 3_41_10. 3.42 tert-Butyl [{5-[2-(aminooxy)ethoxy]-l-methyl-lH-pyrazol-3-yl}(imino)- methyljcarbamate
Figure imgf000116_0001
[00356] Using ethyl 5-hydroxy-l-methyl-lH-pyrazole-3-carboxylate 3_42_1 (EP 1990336, 2008) as the starting material and following the conditions described under 3.41 and 3.38 compound 3_42_10 was prepared.
3.43 4-[2-(Aminooxy)ethoxy]-5-methyl-l,3-thiazole-2-carboximidamide
Figure imgf000116_0002
Step l: 5-Hydroxy-l-methyl-lH-pyrazole-3-carboxylic acid ethyl ester (3_43_2)
[00357] Pyridine (2 mL) was slowly added to a mixture of 2-mercapto- propionic acid (10 g, 94 mmol) and nitriloacetic acid ethyl ester 3_43_1 (8.77 g, 94 mmol) at 0°C, and the mixture was stirred for 1 hour and then heated at 100°C for 2 hours. After cooling, ethanol (100 mL) was added and the reaction mixture was stirred at room temperature for 1 hour to give a suspension, which was collected by filtration, washed with diethyl ether, and dried to give compound 3_43_2 (104 g, 60 % yield) as a white solid.
[00358] ¾ NMR (400 MHz, DMSO-i6): δ = 1.27 (td, J = 7.2, 1.9 Hz, 3H), 2.23 (d, J = 1.9 Hz, 3H), 4.29 (dd, J = 7.0, 1.9 Hz, 2H). [00359] Following the conditions as described under 3.41 and 3.38 the intermediate 3_43_2 was converted to compound 3_43_10.
3.44 4-[2-(Aminooxy)ethoxy]-2-hydroxybenzenecarboximidamide
Figure imgf000117_0001
Step l:2-Fluoro-4-(2-hydroxy-ethoxy)-benzonitrile (3_44_2)
[00360] Anhydrous potassium carbonate (10.0 g, 72.4 mmol) was added to a solution of 2-fluoro-4-hydroxy-benzonitrile 3_44_1 (5.0 g, 36.5 mmol) in N,N- diemthylformamide (50 mL). The resulting mixture was stirred at room temperature for 10 minutes, and 2-bromoethanol (13.5 g, 7.7 mL, 108.0 mmol) was added drop- wise over 15 minutes. The resulting mixture was stirred at room temperature for 3 days. TLC showed the reaction was incomplete. Additional 2-bromoethanol (3 mL) was added and the reaction mixture was stirred for another day, poured into water (300 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate layers were washed with a saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 3_44_2 (5.0 g, 76 % yield) as a white solid. [00361] Ή NMR (CDC13, 400 MHz): δ = 3.99 - 4.01 (m, 2H), 4.02 - 4.14 (m, 2H), 6.73 - 6.81 (m, 2H), 7.51 - 7.55 (m, 12H).
Step 2 and 3: 2-(3-Amino-benzo[d]isoxazol-6-yloxy)-ethanol (3_44_4)
[00362] Potassium tert-butoxide (6.5 g, 58.0 mmol) was added in portions to a solution of acetone acetone oxime (4.2 g, 58.05 mmol) in Ν,Ν-dimethylformamide (100 mL). The resulting mixture was stirred at room temperature for 1 hour, and a solution of compound 3_44_2 (5.0 g, 27.6 mmol) in Ν,Ν-diemthylformamide (20 mL) was added dropwise. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated ammonium chloride solution (600 mL) and extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate layers were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give crude intermediate 3_44_3 (5.3 g, yellow oil). The intermediate 3_44_3 was dissolved in ethanol (100 mL) and 2N hydrochloric acid solution (100 mL) and heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (200 mL), and washed with a saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 3_44_4 (1.9 g, 35 % yield) as a white solid.
[00363] Ή NMR (MeOH-d4, 400 MHz): δ = 3.90 (t, J = 4.8 Hz, 2H), 4.11 (t, J = 4.8 Hz, 2H), 6.87 - 6.93 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H).
Step 4:2-Hydroxy-4-(2-hydroxy-ethoxy)-benzamidine (3_44_5)
[00364] Palladium on charcoal (5 % wet, 1.5 g, -50 % water) was added to a solution of compound 3_44_4 (1.9 g, 7.7 mmol) in methanol (100 mL) and the mixture was hydrogenated at 1 atmosphere with a balloon for 31 hours. TLC showed completion of the reaction. The catalyst was removed by filtration through a bed of celite and washed with methanol (2 x 10 mL). The filtrate was concentrated under reduced pressure to give compound 3_44_5 (1.4 g, 73 % yield) as an off-white solid which was used without further purification.
[00365] Ή NMR (MeOH-rf4, 400 MHz): δ = 3.84 (t, J = 4.8 Hz, 2H), 4.03 (t, J = 4.8 Hz 2H), 6.14 - 6.19 (m, 2H), 7.45 (d, J = 8.8 Hz, 1H).
[00366] MS: m/z (ES+, %) 197 (M++H, 100).
[00367] Following the conditions described in the previous examples intermediate 3_44_5 was converted via a Mitsunobu reaction with N-hydroxyphthalimide and consecutive phthalimide deprotection to compound 3_44_6.
3.45 Diphenylmethyl 2- (aminooxy) -3 - {4- [N- (tert-butoxy carbony l)carb- amimidoy l]phenoxy} propanoate
Figure imgf000119_0001
Step l:3-(4-Cyano-phenoxy)-2-hydroxy-propionic acid ethyl ester (3_45_2) [00368] Potassium carbonate (10.705 g, 77.5 mmol), lithium perchlorate (5.497 g, 51.7 mmol) and ethyl 2,3-epoxypropanoate (3.0 g, 25.8 mmol) were added to a solution of 4-hydroxybenzonitrile 3_45_1 (12.31 g, 0.103 mmol) in acetonitrile (100 mL). After refluxing for 4 hours, the resulting mixture was cooled and filtered. The filtrate was diluted with ice-water and neutralized to pH 7 using dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give the desired compound 3_45_2 (2.92 g, 48 % yield) as a thick colorless oil.
[00369] Ή NMR (400 MHz, DMSO-d6): δ = 1.18 (t, J = 1.7 Hz, 3H), 4.03-4.19 (m, 2H), 4.25 (d, J = 4.4 Hz, 2H), 4.38-4.51 (m, 1H), 5.89 (d, J = 5.9 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H).
[00370] MS (ES+) m/z: [M+H]+ calcd for Ci2Hi4N04: 236.24. Found: 236.16.
Step 2:2-Hydroxy-3-(4-methoxycarbonimidoyl-phenoxy)-propionic acid methyl ester hydrochloric acid salt (3_45_3)
[00371] Hydrogen chloride gas was introduced into a solution of 3-(4-cyano- phenoxy)-2-hydroxy-propionic acid ethyl ester 3_45_2 (2.10 g, 8.93 mmol) in anhydrous methanol (70 mL) at 0°C for 10 minutes and the resulting mixture was stirred at room temperature overnight. After concentration, the residue was stirred with diethyl ether (20 mL) for 0.5 hour and the precipitate was collected and dried to give the desired product (2.43 g, 94 % yield) as a white solid.
[00372] Ή NMR (400 MHz, DMSO-rf6): δ = 3.66 (s, 3H), 4.24 (s, 3H), 4.27- 4.30 (m, 2H), 4.48 (t, J = 4.4 Hz, 1H), 7.16 (d, J = 9.1 Hz, 2H), 8.09 (d, J = 9.1 Hz, 2H).
Step 3:3-(4-Carbamimidoyl-phenoxy)-2-hydroxy-propionic acid methyl ester (3_45_4) [00373] Ammonia (7N in methanol, 3.0 mL, 20.97 mmol) was added to a mixture of 2-hydroxy-3-(4-methoxycarbonimidoyl-phenoxy)-propionic acid methyl ester hydrochloric acid salt 3_45_3 (2.43 g, 8.39 mmol) in anhydrous methanol (30 mL) at 0°C and the resulting mixture was stirred at 40°C for 5 hours. The reaction mixture was concentrated to dryness to give the crude product of compound 3_45_4 (2.39 g, >100% yield) as a white solid which was used without purification.
[00374] Ή NMR (400 MHz, DMSO-d6): δ = 3.65 (s, 3H), 4.22-4.31 (m, 2H), 4.47 (q, J = 4.7 Hz, 1H), 5.99 (d, J = 5.9 Hz, 1H), 7.13 (d, J = 8.9 Hz, 2H), 7.85 (d, J = 8.9 Hz, 2H), 9.16 (br. s., 3H).
[00375] MS (ES+) m/z: [M+H]+ calcd for CnHlsN204: 239.25. Found: 239.23.
Step 4: 3-[4-(tert-Butoxycarbonylamino-imino-methyl)-phenoxy]-2-hydroxy- propionic acid methyl ester (3_45_5)
[00376] A saturated sodium carbonate solution (lOmL) and di-tert- butyldicarbonate (BOC20, 2.197 g, 10.07 mmol) were added to a solution of 3-(4- carbamimidoyl-phenoxy)-2-hydroxy-propionic acid methyl ester 3_45_4 (2.35 g, crude material from previous step, 8.39 mmol) in tetrahydrofuran (30 mL) at room temperature. After stirring at room temperature for 3.5 hours, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried and concentrated. The residue was purified by column chromatography to give the desired product (2.0 g, 66 % yield) as a white solid.
[00377] Ή NMR (400 MHz, DMSO-d6): δ = 1.42 (s, 9H), 3.66 (s, 3H), 4.14- 4.25 (m, 2H), 4.45 (t, J = 4.4 Hz, 1H), 5.88 (s, 1H), 6.98 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H).
Step 5: 3-[4-(tert-Butoxycarbonylamino-imino-methyl)-phenoxy]-2-hydroxy- propionic acid (3_45_6) [00378] A solution of sodium hydroxide (0.189 g, 4.73 mmol) in water (4 mL) was added to a solution of 3-[4-(tert-butoxycarbonylamino-imino-methyl)- phenoxy]-2-hydroxy-propionic acid methyl ester 3_45_5 (0.8 g, 2.36 mmol) in tetrahydrofuran (10 mL) at 0°C. After stirring at this temperature for 15 minutes, the reaction mixture was neutralized to pH 7 using acetic acid and concentrated to dryness to afford the crude desired product (1.12 g) as a white solid.
[00379] XH NMR (400 MHz, DMSO-d6): δ = 3.77-3.79 (m, 2H), 3.84-3.95 (m, 1H), 4.13-4.29 (m, 1H), 6.94 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H).
[00380] MS (ES+) m/z: [M+H]+ calcd for Ci5H2iN206: 325.34. Found: 325.22.
Step 6:3-[4-(tert-Butoxycarbonylamino-imino-methyl)-phenoxy]-2-hydroxy- propionic acid benzhydryl ester (3_45_7)
[00381] A solution of diazo(diphenyl)methane (0.459 g, 2.36 mmol) was slowly added to a solution of 3-[4-(tert-butoxycarbonylamino-imino-methyl)-phen- oxy]-2-hydroxy-propionic acid 3_45_6 (1.12 g, crude, 2.36 mmol) in methanol (10 mL). The resulting mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified by column chromatography to give the desired product (0.571 g, 49 % yield) as a white solid.
[00382] Ή NMR (400 MHz, DMSO-d6): δ = 1.42 (s, 9H), 4.20-4.30 (m, 1H), 4.30-4.43 (m, 1H), 4.61 (d, J = 4.4 Hz, 1H), 6.00 (d, J = 4.4 Hz, 1H), 6.85 (s, 1H), 6.95 (d, J = 9.1 Hz, 2H), 7.20-7.45 (m, 10H), 7.93 (d, J = 8.8 Hz, 2H).
[00383] MS (ES+) m/z: [M+H]+ calcd for CzsHsiNzOe: 491.56. Found: 491.23.
Step 7:3-[4-(tert-Butoxycarbonylamino-imino-methyl)-phenoxy]-2-(l,3-dioxo-l,3- dihydro-isoindol-2-yloxy)-propionic acid benzhydryl ester (3_45_8) [00384] N-Hydroxyphthalimide (0.205 g, 1.26 mmol) and triphenylphos- phine (0.359 g, 1.37 mmol) were added to a solution of 3-[4-(tert-butoxycarb- onylamino-imino-methyl)-phenoxy]-2-hydroxy-propionic acid benzhydryl ester 3_45_7 (0.56 g, 1.14 mmol) in anhydrous tetrahydrofuran (10 mL) at room temperature. A solution of diethyl azodicarboxylate (0.238 g, 1.37 mmol) in tetrahydrofuran (5 mL) was added dropwise to the resulting solution at 20°C and the resulting mixture was stirred at room temperature overnight. After evaporation of the tetrahydrofuran, the crude product was purified by column chromatography to give the desired product (0.79 g, 88 % yield) as a white solid.
[00385] Ή NMR (400 MHz, DMSO-d6): δ = 1.43 (s, 9H), 4.51-4.66 (m, 2H), 5.43 (t, J = 3.2 Hz, 1H), 6.92 (s, 1H), 6.95 (d, J = 2.6 Hz, 2H), 7.19-7.46 (m, 10H), 7.85 (s, 4H), 7.94 (d, J = 8.8 Hz, 2H), 8.98 (br s, 2H).
[00386] MS (ES+) m/z: [M+H]+ calcd for C36H34N3O8: 366.68. Found: 366.34.
Step 8: Diphenylmethyl 2-(aminooxy)-3-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]- phenoxyjpropanoate (3_45_9)
[00387] Hydrazine monohydrate (0.067 g, 1.35 mmol) was added to a solution of 3- [4-(tert-butoxycarbonylamino-imino-methyl)-phenoxy]-2-(l ,3-dioxo- 1,3- dihydro-isoindol-2-yloxy)-propionic acid benzhydryl ester 3_45_8 (0.78 g, 1.23 mmol) in anhydrous ethanol (15 mL) and tetrahydrofuran (10 mL) at 0°C and the resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was stirred with dichloromethane (10 mL) and filtered. The filtrate was concentrated to afford the desired product (0.76 g, >100% yield) as a white solid, which was used without purification.
[00388] Ή NMR (400 MHz, DMSO-d6): δ = 1.42 (s, 9H), 4.28-4.46 (m, 2H), 4.60 (t, J = 4.1 Hz, 1H), 6.43 (s, 2H), 6.89 (s, 1H), 6.94 (d, J = 8.5 Hz, 2H), 7.19-7.47 (m, 10H), 7.92 (d, J = 8.8 Hz, 2H), 8.98 (br s, 2H). 3.46 4-[2-(Aminooxy)ethoxy]-2-methylbenzenecarboximidamide
Figure imgf000124_0001
Step l:4-(2-Hydroxyethoxy)-2-methylbenzonitrile (3_46_2)
[00389] Sodium hydride (60 %, 0.62 g, 40.8 mmol) was added slowly to ethylene glycol (40 mL) and the resulting mixture was stirred at room temperature for 0.5 hour. 4-Bromo-2-methylbenzonitrile 3_46_1 (2.0 g, 10.2 mmol) was then added followed by copper(I) bromide (0.44 g, 3.06 mmol) and the reaction mixture was heated at 120°C for 2 hours, cooled to room temperature, poured into water (300 mL), and extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate layers were washed with water (2 x 200 mL) and brine (1 x 200 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 3_46_2 (1.6 g, 88 % yield) as a pale yellow solid.
[00390] ¾ NMR (400 MHz, CDC13): δ = 2.51 (s, 3H), 3.94-4.04 (m, 2H), 4.07- 4.15 (m, 2H), 6.74-6.87 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H).
[00391] Using intermediate 3_46_2 and following the conditions as described in the previous examples, compound 3_46_3 was prepared. 3.47 tert-Butyl [{4-[2-(aminooxy)ethoxy]pyridin-2-yl}(imino)methyl]carbamate
Figure imgf000125_0001
Step l:4-(2-Hydroxyethoxy)-pyridine-2-carbonitrile (3_47_2)
[00392] 2-(Tetrahydropyran-2-yloxy)ethanol (3.50 g, 22 mmol) was added dropwise to a cooled (0°C) suspension of sodium hydride (530 mg, 60 % in mineral oil, 21 mmol) in Ν,Ν-dimethylformamide. After the addition was over, the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0°C and 4-chloro-pyridine-2-carbonitrile 3_47_1 (2.77 g, 20 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 2 hours and the mixture was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with water, dried and concentrated. The residue was dissolved in methanol (30 mL) and treated with a IN hydrochloric acid solution (10 mL) at 0°C. The mixture was stirred at room temperature for 2 hours, extracted with ethyl acetate (150 mL), dried and concentrated. The residue was purified by column chromatography to give 3_47_2 (2.04 g, 62 % yield) as a white solid.
[00393] Ή NMR (CDC13, 400MHz): δ
1H), 4.27 (m, 2H), 4.00 (m, 2H), 2.00 (t, 1H). Step 2: {[4-(2-Hydroxyethoxy)-pyridin-2-yl]-iminomethyl}carbamic acid tert-butyl ester (3_47_3)
[00394] A solution of compound 3_47_2 (1.0 g, 6.10 mmol) in methanol (10 mL) was added to a freshly prepared solution of sodium methoxide (0.28 g of sodium in methanol (10 mL) at 0°C and the reaction mixture was stirred at room temperature for 90 minutes. Ammonium chloride (1.30 g, 24.4 mmol) was added and the reaction mixture was heated at reflux for 16 hours. A saturated aqueous sodium bicarbonate solution (20 mL) and di-tert-butyl dicarbonate (Boc20, 4.17 g, 18.3 mmol) were added to the cooled (0°C) mixture. The resulting mixture was stirred at room temperature for 16 hours, extracted with ethyl acetate (150 mL), dried and concentrated. The residue was purified by column chromatography to give compound 3_47_3 (1.53 g, 90 % yield) as viscous oil.
[00395] Ή NMR (CDC13, 400MHz): δ = 9.40 (br s, 1H), 8.44 (d, 2H), 8.00 (s, 1H), 7.00 (d, 1H), 4.30 (d, 2H), 4.00 (m, 2H), 2.00 (br s, 1H), 1.60 (s, 9H).
Step 3: ({4-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-pyridin-2-yl}-imino- methyl)carbamic acid tert-butyl ester (3_47_4)
[00396] Diisopropyl azodicarboxylate (1.28 mL, 6.53 mmol) was added dropwise to a cooled mixture of compound 3_47_3 (1.53 g, 5.44 mmol), N-hydroxy- phthalimide (0.98 g, 5.98 mmol) and triphenylphosphine (1.71 g, 6.53 mmol) in tetrahydrofuran. After the addition, the mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by column chromatography to give compound 3_47_4 (1.66 g, 72 % yield) as a white solid.
[00397] Ή NMR (CDC13, 400MHz): δ = 9.40 (br s, 1H), 8.37 (d, 2H), 7.91 (s, 1H), 7.85 (m, 2H), 7.78 (m, 2H), 6.91 (d, 1H), 4.90 (m, 2H), 4.49 (m, 2H). Step 4:tert-Butyl [{4-[2-(aminooxy)ethoxy]pyridin-2-yl}(imino)methyl]carbamate (3_47_5)
[00398] Ammonia (2.5 mL, 2N in methanol) was added to a solution of compound 3_47_4 (210 mg, 0.5 mmol) in methanol (1 mL). The mixture was stirred for 16 hours, filtered and the filtrate was concentrated. The residue was diluted with dichloromethane and filtered. The filtrate was concentrated to give compound 3_47_5 (160 mg, >100 % yield) which was used in the next step without further purification.
[00399] Ή NMR (CDC13, 400 MHz): δ = 9.30 (br s, 1H), 8.40 (m, 2H), 8.00 (s, 1H), 7.00 (d, 1H), 5.60 (s, 2H), 4.40 (m, H), 4.10 (m, 2H), 1.60 (s, 9H).
3.48 tert-Butyl [{2-[2-(aminooxy)ethoxy]pyridin-4-yl}(imino)methyl]carbamate
Figure imgf000127_0001
[00400] Following the procedure as described under 3.47 but using 2-chloro- 4-cyano-pyridine 3_48_1 as the starting material instead of 4-chloro-2-cyano- pyridine 3_47_1 compound 3_48_5 was prepared.
3.49 tert-Butyl [{5-[2-(aminooxy)ethoxy]-3-hydroxypyridin-2-yl}(imino)meth- yl]carbamate
Figure imgf000128_0001
3_49_7
Step 1 : 3,5-Bis-isopropylideneaminooxy-pyridine-2-carbonitrile (3_49_2)
[00401] Sodium hydride (0.875 g, 21.89 mmol, 60 % in mineral oil) was added to a solution of acetone acetone oxime (1.60 g, 9.95 mmol) in Ν,Ν-dimeth- ylformamide (30 mL) at 0°C and the resulting mixture was stirred at room temperature for 1 hour. A solution of 5-bromo-3-fluoro-pyridine-2-carbonitrile 3_49_1 (2.0 g, 9.95 mmol) in Ν,Ν-dimethylformamide (10 mL) was added at 0°C and the reaction mixture was stirred at room temperature overnight. After the removal of most of the Ν,Ν-dimethylformamide, the mixture was cooled to 0°C and water (40 mL) was added and the mixture was stirred for 0.5 hour. The white precipitate was collected, washed with cold water and dried to give the desired product (2.55 g, 100 % yield) as a white solid.
[00402] ¾ NMR (400 MHz, DMSO-d6): δ = 2.05 (s, 3H), 2.06 (s, 3H), 2.09 (s, 3H), 2.13 (s, 3H), 7.69 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H).
[00403] MS (ES+) m/z: [M+H]+ calcd for C12H15N4O2: 247.27. Found: 247.12. Step 2:Propan-2-one 0-(3-amino-isoxazolo[4,5-b]pyridin-6-yl)-oxime (3_49_3)
[00404] Cone, hydrochloric acid (1:1, 32 mL) was added to a mixture of 3,5- bis-isopropylideneaminooxy-pyridine-2-carbonitrile 3_49_2 (4.8 g, 19.49 mmol) in methanol (80 mL) and the resulting mixture was stirred at 60°C for 4 hours. After cooling to room temperature, the white precipitate was collected, washed with water, and dried to give the desired product (3.50 g, 87 % yield) as a white solid.
[00405] Ή NMR (400 MHz, CDC13): δ = 2.01-2.04 (m, 3H), 2.06-2.09 (m, 3H), 6.42 (s, 2H), 7.63 (d, J = 2.0 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H).
[00406] MS (ES+) m/z: [M+H]+ calcd for C9H11N4O2: 207.21. Found: 207.11.
Step 3:3,5-Dihydroxy-pyridine-2-carboxamidine (3_49_4)
[00407] Palladium on carbon (2.0 g, 10 wt. %, wet) was added to a solution of propan-2-one 0-(3-amino-isoxazolo[4,5-b]pyridin-6-yl)-oxime 3_49_3 (3.67 g, 17.80 mmol) in anhydrous tetrahydrofuran (30 mL), methanol (30 mL) and N,N- dimethylformamide (150 mL) and the resulting mixture was hydrogenated under 1 atmosphere at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness to afford the crude compound 3_49_4 (4.08 g, >100 % yield) as a white solid, which was used in the next step without purification.
[00408] Ή NMR (400 MHz, DMSO-d6): δ = 6.08 (d, J = 2.3 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.53 (br s, 2H).
[00409] MS (ES+) m/z: [M+H]+ calcd for CeHgNsOz: 154.14. Found: 154.15. Step 4: [(3,5-Dihydroxy-pyridin-2-yl)-imino-methyl]-carbamic acid tert-butyl ester (3_49_5)
[00410] Di-tert-butyl dicarbonate (Boc20, 5.826 g, 26.70 mmol) was added to a suspension of 3,5-dihydroxy-pyridine-2-carboxamidine 3_49_4 (4.08 g, crude, 17.8 mmol), in methanol (40 mL) and tetrahydrofuran (60 mL) followed by sodium carbonate (3.77 g, 35.61 mmol) in water (20 mL) at room temperature. After stirring at room temperature overnight, the resulting mixture was filtered and the filtrate was concentrated, diluted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution and brine, dried and concentrated to give the desired product (2.90 g, 64 % yield) as a white solid.
[00411] ¾ NMR (400 MHz, DMSO-d6): δ = 1.48 (s, 9H), 6.55 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.85 (br s, 2H).
[00412] MS (ES+) m/z: [M+H]+ calcd for C11H14N3O4: 252.26. Found: 252.19.
Step 5: ({5-[2-(l,3-Dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-3-hydroxy-pyridin-2- yl}-imino-methyl)-carbamic acid tert-butyl ester (3_49_6)
[00413] Triethylamine (1.465 g, 14.47 mmol) was added to a solution of N- (2-hydroxyethoxy)phthalimide (2.0 g, 9.65 mmol) in dichloromethane (20 mL) at 0°C. Methanesulfonyl chloride (1.657 g, 14.47 mmol) was slowly added to the reaction mixture at 0°C. After stirring at room temperature for 3 hours, the reaction mixture was washed with brine, dried over sodium sulfate and concentrated to dryness to give methanesulfonic acid 2-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)- ethyl ester (2.46 g, 89 % yield) as a white solid.
[00414] Potassium carbonate (0.994 g, 7.19 mmol) was added to a solution of [(3,5-dihydroxy-pyridin-2-yl)-imino-methyl]-carbamic acid tert-butyl ester 3_49_5 (0.911 g, 3.60 mmol) in Ν,Ν-dimethylformamide (20 mL). After stirring at 60°C for 15 minutes, a solution of methanesulfonic acid 2-(l,3-dioxo-l,3-dihydro-isoindol-2- yloxy)-ethyl ester (1.026 g, 3.60 mmol) in Ν,Ν-dimethylformamide (30 mL) was slowly added at 60°C and the mixture was stirred at 60°C for 4 hours before it was neutralized to pH 7 using dilute hydrochloric acid and diluted with cold water. The precipitate was collected and purified by column chromatography to give the desired product (0.243 g, 15 % yield) as a white solid.
[00415] Ή NMR (400 MHz, DMSO-d6): δ = 1.49 (s, 9H), 4.39 (br s, 2H), 4.44- 4.57 (m, 2H), 6.76 (br s, 1H), 7.67 (br s, 1H), 7.87 (s, 4H), 9.03 (br s, 2H).
[00416] MS (ES+) m/z: [M+H]+ calcd for C21H23N4O7: 443.43. Found: 443.11.
Step 6: tert-Butyl [{5-[2-(aminooxy)ethoxy]-3-hydroxypyridin-2-yl}(imino)methyl]- carbamate (3_49_7)
[00417] Hydrazine monohydrate (0.0445 g, 0.890 mmol) was slowly added to a solution of ({5-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yloxy)-ethoxy]-3-hydroxy- pyridin-2-yl}-imino-methyl)-carbamic acid tert-butyl ester 3_49_6 (0.358 g, 0.809 mmol) in tetrahydrofuran (3 mL) and ethanol (5 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated. The resulting solid was stirred with dichloromethane (25 mL) for 15 minutes and filtered. The filtrate was concentrated to give the desired product (0.320 g, >100 % yield) as a white solid, which was used for the next step without further purification.
[00418] Ή NMR (400 MHz, DMSO-d6): δ = 1.49 (s, 9H), 3.77-3.91 (m, 2H), 4.10-4.26 (m, 2H), 6.12 (s, 2H), 6.79 (br s, 1H), 7.80 (br s, 1H).
[00419] MS (ES+) m/z: [M+H]+ calcd for Ci3H2iN405: 313.33. Found: 313.13. 2-{4-[2-(Aminooxy)ethoxy]phenyl}-4,5-dihydro-lH-imidazole
3 50 4
Step l:tert-Butyl [2-(4-cyanophenoxy)ethoxy]carbamate (3_50_2)
[00420] A mixture of 4-[2-(aminooxy)ethoxy]benzonitrile 3_50_1 (5.0 g, 28.0 mmol), di-tert-butyl dicarbonate (B0C2O, 6.1 g, 28.0 mmol) and triethyl amine (2.8 g, 28.0 mmol) in dichloromethane (300 mL) was stirred overnight at room temperature. The mixture was evaporated and the residue suspended in ether (200 mL). The resulting white precipitate was collected to obtain compound 3_50_2 (7.1 g, 91 % yield).
[00421] Ή NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 4.02 (dd, J=5.2, 3.0 Hz, 2H), 4.21 (dd, J=5.2, 3.3 Hz, 2H), 7.10 (d, J=8.9 Hz, 2H), 7.75 (d, J=8.9 Hz, 2H), 10.08 (br s, 1H)
[00422] MS (ES+) m/z: [M+H]+ calcd for C14H19NZ04: 279.13; found: 279.12.
Step 2:tert-Butyl {2-[4-(4,5-dihydro-lH-imidazol-2-yl)phenoxy]ethoxy}carbamate (3_50_3)
[00423] Sodium hydrogen sulfide (0.16 g, 2.16 mmol) was added to a suspension of tert-butyl [2-(4-cyanophenoxy)ethoxy]carbamate 3_50_2 (6.0 g, 21.6 mmol) and ethylenediamine (20 mL). The resulting mixture was heated at 120°C for 2 hours, cooled to room temperature and poured into crushed ice to form a white solid. The solid was collected and dried under vacuum to obtain compound 3_50_3 (3.8 g, 55 %) as a white solid.
[00424] Ή NMR (400 MHz, DMSO-d6): δ = 1.14-1.67 (m, 9H), 3.55 (s, 4H), 3.91-4.10 (m, 2H), 4.08-4.29 (m, 2H), 6.79-7.09 (m, 3H), 7.54-7.87 (m, 3H)
[00425] MS (ES+) m/z: [M+H]+ calcd for C16H24N3O4: 322.18; found: 322.15
Step 3:2-{4-[2-(Aminooxy)ethoxy]phenyl}-4,5-dihydro-lH-imidazole (3_50_4)
[00426] A solution of tert-butyl {2-[4-(4,5-dihydro-lH-imidazol-2- yl)phenoxy]ethoxy}carbamate 3_50_3 (3.8 g, 12.0 mmol) in dichloromethane (50 mL) was treated with trifluoroacetic acid (TFA, 3.8 mL). The resulting solution was stirred overnight at room temperature, evaporated to remove excess trifluoroacetic acid and diluted with dichloromethane (200 mL). The solution was washed with an aqueous sodium bicarbonate solution (10 ml), dried and evaporated to obtain compound 3_50_4 (2.17 g, 81 % yield) as a gum.
[00427] Ή NMR (400 MHz, DMSO-d6): δ = 3.69 (s, 4H), 3.77 - 3.94 (m, 2H), 4.10-4.30 (m, 2H), 6.11 (br s, 2H), 6.90-7.17 (m, 2H), 7.59-7.96 (m, 3H).
[00428] MS (ES+) m/z: [M+H]+ calcd for CnHieNsOz: 222.12; found: 222.14. 3.51 tert-Butyl 4-{[{4-[2-(aminooxy)ethoxy]phenyl}(imino)methyl](tert-butoxy- carbonyl)amino}piperidine- 1 -carboxylate
Figure imgf000134_0001
Step 1 : tert-Butyl 4-{[(4-hydroxyphenyl)(imino)methyl]amino}piperidine-l- carboxylate (3_51_2)
[00429] A suspension of compound 3_51_1 (1.0 g, 4.46 mmol) in methanol (10.0 mL) was treated with triethylamine (1.20 mL, 0.86 mmol) at 0°C to give a clear yellow solution. The solution was treated with tert-butyl 4-aminopiperidine-l- carboxylate (0.90 g, 4.46 mmol) in methanol (2.0 mL) and stirred at room temperature overnight. The mixture was concentrated in vacuo to a yellow foam. The foam was purified by column chromatography to afford compound 3_51_2 (1.20 g, 85 % yield) as an off-white solid.
[00430] Ή NMR (400 MHz, DMSO-d6): δ = 1.22 (t, J = 7.03 Hz, 2H), 1.42 (s, 9H), 1.46-1.55 (m, 2H), 1.88-1.93 (m, 2H), 3.05-3.10 (m, 1H), 3.80-4.11 (m, 2H), 6.95 (d, J = 8.99 Hz, 2H), 7.61 (d, J = 8.99 Hz, 2H), 9.02 (br s, 1H), 10.53 (br s, 1H).
[00431] MS (ES+) m/z: [M+H]+ calcd for G7H26N3O3: 320.20. Found: 320.21. Step 2: tert-Butyl 4-{(tert-butoxycarbonyl) [{4- [(tert-butoxycarbonyl)oxyjphenyl}- (imino)methyl]amino}piperidine-l-carboxylate (3_51_3)
[00432] A solution of compound 3_51_2 (2.40 g, 7.51 mmol) in 1,4-dioxane (100 mL) was treated with a saturated sodium carbonate solution (100 mL) followed by di-tert-butyl dicarbonate (B0C2O, 8.20 g, 37.57 mmol) at 0°C. The mixture was stirred at room temperature overnight and then extracted with ethyl acetate. The organic extracts were filtered through a short plug of silica gel and the pad was rinsed with ethyl acetate. The filtrate was concentrated to afford compound 3_51_3 (2.40 g, 62 % yield) as a white solid.
[00433] Ή NMR (400 MHz, DMSO-</6): δ = 1.18 (s, 9H), 1.24-1.40 (m, 2H), 1.40 (s, 9H), 1.49 (s, 9H), 1.84-1.89 (m, 2H), 2.67-2.90 (m; 2H), 3.81-3.90 (m, 3H), 7.26 (d, J = 8.60 Hz, 2H), 7.38 (d, J = 8.60 Hz, 2H), 7.75 (d, J = 6.25 Hz, 1H).
[00434] MS (ES+) m/z: [M+H]+ calcd for C27H42N3O7: 520.30. Found: 520.30.
Step 3: tert-Butyl 4-{(tert-butoxycarbonyl)[(4-hydroxyphenyl)(imino)methyl]amino}- piperidine- 1 -carboxylate (3_51_4)
[00435] A colorless solution of compound 3_51_3 (2.40 g, 4.62 mmol) in tet- rahydrofuran (50 mL) and methanol (50 mL) was treated with lithium hydroxide monohydrate (0.58 g, 13.86 mmol) in water (5.0 mL) at 0°C. The mixture was stirred at room temperature for 2 hours and concentrated in vacuo to remove organic solvents. The residue was diluted with water and extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated in vacuo to provide a white solid which was purified by column chromatography to give compound 3_51_4 (1.70 g, 88 % yield) as a white solid. [00436] Ή NMR (400 MHz, DMSO-d6): δ = 1.19 (s, 9H), 1.21-1.31 (m, 2H), 1.38 (s, 9H), 1.78-1.84 (m, 2H), 2.70-2.80 (m, 2H); 3.80-3.95 (m, 3H), 6.74 (d, J = 8.60 Hz, 2H), 7.17 (d, J = 8.60 Hz, 2H), 7.40-7.50 (m, 1H).
[00437] MS (ES+) m/z: [M+H]+ calcd for C22H34N3O5: 420.25. Found: 420.25.
[00438] Using the intermediate 3_51_4, compound 3_51_5 was prepared using the conditions as described in the previously cited examples.
3.52 tert-Butyl 4-{[{4-[(3S)-3-(aminooxy)ethoxy]phenyl}(imino)methyl](tert- butoxycarbonyl)amino}pyrrolidine-l-carboxylate
Figure imgf000136_0001
3 52 5
[00439] Using conditions as described under 3.51 but using fert-butyl (3S)-3- aminopyrrolidine-l-carboxylate instead of ierr-butyl 4-aminopiperidine-l-carboxyl- ate, compound 3_52_5 was prepared.
3.53 tert-Butyl (2S,4S)-4-{[{4-[2-(Aminooxy)ethoxy]phenyl}(imino)methyl](tert- butoxycarbonyl)amino} -Ν,Ν-dimethyl-prolinamide- 1 -carboxylate
Figure imgf000136_0002
3_53_5
[00440] Using conditions as described under 3.51 but using iert-butyl (2S,4S)- 4-amino-2-(dimethylcarbamoyl)pyrrolidine-l -carboxylate instead of iert-butyl 4- aminopiperidine-1 -carboxylate, compound 3_53_5 was prepared. 3.54 l-(2-{[{4-[2-(Aminooxy)ethoxy]phenyl}(imino)methyl]amino}ethyl)-l- methylpyrrolidinium trifluoroacetate
Figure imgf000137_0001
Step l:(2-Pyrrolidin-l-yl-ethyl)-carbamic acid tert-butyl ester (3_54_2)
[00441] A solution of di-tert-butyldicarbonate (Boc20, 10.512 g, 48.2 mol) in tetrahydrofuran (20 mL) was added to a solution of 2-pyrrolidin-l-yl-ethylamine 3_54_1 (5.0 g, 43.8 mol) in tetrahydrofuran (40 mL) at 0°C. After stirring at room temperature overnight, the resulting mixture was concentrated to give the desired product (9.45 g, 100% yield) as a colorless oil, which was used in the next step without purification.
[00442] ¾ NMR (400 MHz, CDC13): δ = 1.45 (s, 9H), 1.74 - 78 (m, 4H), 2.48- 2.58 (m, 6H), 3.22-3.26 (3, 2H), 5.08 (br s, 1H).
Step 2: l-(2-tert-Butoxycarbonylamino-ethyl)-l-methyl-pyrrolidinium iodide (3_54_3)
[00443] Iodomethane (20 mL) was added to a solution of compound 3_54_2 (9.45 g, crude, 43.8 mmol) in dichloromethame (30 mL) at -10°C. The resulting solution was sealed, stirred at 60 °C overnight and concentrated to give the desired product (16.79 g, >100 % yield) as a light yellow sticky solid, which was used in the next step without purification. [00444] ¾ NMR (400 MHz, DMSO-d6): δ = 1.38 (s, 9H), 2.06 (br s, 4H), 2.98 (s, 3H), 3.34-3.37 (m, 4H), 3.42-3.46 (m, 2H), 3.47-3.54 (m, 2H), 7.18 (br s, 1H).
Step 3: l-(2-Ammo-ethyl)-l-methyl-pyrrolidinium chloride hydrochloride salt (3_54_4)
[00445] Hydrogen chloride gas was introduced into a solution of compound 3_54_3 (16.79 g, crude, 47.1 mmol) in dichloromethane (100 mL) at 0°C for 10 minutes. After stirring at room temperature for 1 hour, the resulting solid was filtered off, washed with dichloromethane and then dissolved in methanol (10 mL). Ether (30 mL) was added to the solution and the precipitate was collected and dried to give the desired product (10.1 g, 100 % yield) as an off-white solid.
[00446] ¾ NMR (400 MHz, DMSO-d6): δ = 2.06-2.11 (m, 4H), 3.05 (s, 3H), 3.27-3.33 (m, 2H), 3.48-3.56 (m, 2H), 3.57-3.65 (m, 4H), 8.60 (br s, 2H).
[00447] Using the intermediate 3_54_4 and following the procedure as described under 3.11 compound 3_54_5 was prepared.
3.55 tert-Butyl 2-{4-[2-(aminooxy)ethoxy]phenyl}-l-tert-butoxycarbonyl- 1,4,5 , 6-tetrahy dropy rimidin- 5 -carbamate
Figure imgf000138_0001
Step 1 : tert-Butyl {2- [4-(benzyloxy)phenyl] - 1 ,4,5, 6-tetrahydropyrimidin-5-yl}carb- amate (3_55_2)
[00448] 4-(Benzyloxy)benzaldehyde 3_55_1 (1.00 g, 4.71 mmol) was treated with tert-butyl (l,3-diaminopropan-2-yl)carbamate (0.94 g, 4.97 mmol) in dichloro- methane (47.0 mL). The mixture was stirred at room temperature for 7 h, cooled to 0°C, and treated with N-bromosuccinimide (0.88 g, 4.94 mmol). The suspension was stirred at 0°C to room temperature overnight, and quenched with a saturated sodium metabisulfite solution and a IN sodium hydroxide solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography to afford compound 3_55_2 (1.05 g, 59 % yield) as a light yellow solid.
[00449] Ή NMR (400 MHz, CD3OD): δ = 1.45 (s, 9H), 3.42 (dd, J = 13.3, 5.1 Hz, 2H), 3.65 (dd, J = 12.9, 3.9 Hz, 2H), 4.05-4.09 (m, 1H), 5.18 (s, 2H), 7.15 (d, J = 8.6 Hz, 2H), 7.30-7.75 (m, 5H), 7.66 (d, J = 9.0 Hz, 2H).
Step 2: tert-Butyl 2-[4-(benzyloxy)phenyl]-5-[(tert-butoxycarbonyl)amino]-5,6- dihydropyrimidine-l(4H)-carboxylate (3_55_3)
[00450] A solution of compound 3_55_2 (1.05 g, 2.75 mmol) in a mixture of dioxane/methanol/tetrahydrofuran (1.0 mL / 2.0 mL / 53.0 mL) and a saturated sodium carbonate solution (50.0 mL) was cooled to 0°C, and treated with di-tert- butyl dicarbonate (B0C2O, 2.86 g, 13.1 mmol) in portions. The suspension was stirred at room temperature overnight, concentrated in vacuo to remove the organic solvents, and diluted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated to give a yellow oil. The oil was purified by column chromatography to afford compound 3_55_3 (1.10 g, 87 % yield) as a yellow solid. [00451] ¾ NMR (400 MHz, CD3OD): δ = 1.08 (s, 9H), 1.43 (s, 9H), 3.37 (dd, J = 16.0, 5.9 Hz, 1H), 3.68-3.81 (m, 3H), 3.84-3.37 (m, 1H), 5.15 (s, 2H), 7.00 (d, J = 9.0 Hz, 2H), 7.25-7.45 (m, 7H).
Step 3:tert-Butyl 5-[(tert-butoxycarbonyl)amino]-2-(4-hydroxyphenyl)-5,6-dihydro- pyrimidine- 1 (4H)-carboxylate (3_55_4)
[00452] A solution of compound 3_55_3 (2.50 g, 5.19 mmol) in methanol was treated with palladium on carbon (10 % wet, 0.25 g), and hydrogenated at 15 psi of hydrogen gas for 3 hours. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography to afford compound 3_55_4 (1.50 g, 74 % yield) as a white solid.
[00453] Ή NMR (400 MHz, DMSO-d6): δ = 1.09 (s, 9H), 1.39 (s, 9H), 3.25- 3.39 (m, 2H), 3.64-3.73 (m, 3H), 6.73 (d, J = 9.0 Hz, 2H), 7.00-7.04 (m, 1H), 7.27 (d, J = 9.0 Hz, 2H), 9.67 (br s, 1H).
[00454] The above intermediate 3_55_4 was used to prepare compound 3_55_5 by following the conditions as described before.
3.56 tert-Butyl 1 - (2- {4- [2- (Aminooxy)ethoxy]phenyl} - 1 -tert-butoxycarbony 1-4, 5 - dihydro-lH-imidazol-5-yl)methancarbamate
Figure imgf000140_0001
3 56 5 [00455] Using the conditions as described under 3.55 but using ferf-butyl (2,3-diaminopropan-l-yl)carbamate in place of terf-butyl (l,3-diaminopropan-2- yl)carbamate, compound 3_56_5 was prepared.
3.57 Di-tert-butyl 4-{[{4-[2-(aminooxy)ethoxy]phenyl}(imino)methyl]amino}- py razolidine- 1 , 2-dicarboxy late
Figure imgf000141_0001
Step l:tert-Butyl[(l,3-dibromopropan-2-yl)oxy]dimethylsilane (3_57_2)
[00456] Imidazole (19.69 g, 289 mmol) was added in portions to an ice-cold solution of l,3-dibromopropan-2-ol 3_57_1 (25.2 g, 115 mmol) and tert-butyl- dimethylsilyl chloride (TBDMSCl, 20.92 g, 138 mmol) in Ν,Ν-dimethylformamide (116 mL) and the resulting solution was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, and washed with water and brine. The organic phase was dried and concentrated under reduced pressure. Vacuum distillation afforded compound 3_57_2 (27.6 g, 72 % yield).
Step 2: Di-tert-butyl 4-{[tert-butyl(dimethyl)silyl]oxy}pyrazolidine-l,2-dicarboxylate (3_57_3)
[00457] A solution of di-tert-butyl hydrazine-l,2-dicarboxylate (BocNH- NHBoc, 1.51 g, 6.492 mmol) in N,iV-dimethylformamide (32 mL) was treated with sodium hydride (60 % in mineral oil, 0.262 g, 6.446 mmol) to give a yellow slurry. The mixture was stirred for 1.75 hours, treated with compound 3_57_2 (2.135 g, 6.428 mmol) and stirred for another 1.75 hours. Another portion of sodium hydride (60 % in mineral oil, 0.270 g, 8.484 mmol) was added and the mixture was heated at 90°C for 2 hours. The mixture was cooled to room temperature, another portion of sodium hydride was added (60 %, in mineral oil, 0.103 g, 2.57 mmol) and the mixture was heated at 90°C for 1 hour. The solvent was removed under reduced pressure, and the mixture was quenched with methanol and extracted with ethyl acetate. The organic extract was washed with water and brine, dried and concentrated under vacuum to afford crude compound 3_57_3 (2.1 g, 80% yield) as an oil.
Step 3:Di-tert-butyl 4-hydroxypyrazolidine-l,2-dicarboxylate (3_57_4)
[00458] A solution of compound 3_57_3 (9.05 g, 22.48 mmol) in tetrahydro- furan (225 mL) was cooled to 0°C, then treated with glacial acetic acid (3.87 mL, 67.46 mmol) followed by the addition of tetra-n-butylammonium fluoride (TBAF, IN in tetrahydrofuran, 47.6 mL, 47.6 mmol). The mixture was heated at 50°C for 4.5 hours, cooled to room temperature and extracted with ethyl acetate. The extract was washed with a saturated sodium bicarbonate solution, dried and concentrated in vacuo to afford the crude compound 3_57_4 (6.48 g, 100 % yield), which was used without purification.
Step 4:Di-tert-butyl 4-[(methylsulfonyl)oxy]pyrazolidine-l,2-dicarboxylate (3_57_5)
[00459] A solution of compound 3_57_4 (6.48 g, 22.48 mmol) in dichloro- methane (112 mL) at 0°C was treated with triethylamine (TEA, 6.27 mL, 44.96 mmol) followed by methanesulfonyl chloride (MsCl, 2.62 mL, 11.24 mmol). The resulting mixture was stirred for 1.5 hours, washed with a saturated sodium bicarbonate solution, water and brine. The extract was dried and concentrated in vacuo to afford the crude compound 3_57_5 (8.24 g, 100 % yield). Step 5: Di-tert-butyl 4-azidopyrazolidine-l,2-dicarboxylate (3_57_6)
[00460] A solution of compound 3_57_5 (8.24 g, 22.48 mmol) in N,N- dimethylformamide was treated with sodium azide (4.38 g, 67.44 mmol). The resulting mixture was heated at 50°C for 20 hours, then extracted with ethyl acetate (225 mL) and washed with water and brine. The extract was dried and concentrated in vacuo to afford the crude compound 3_57_6 (7.02 g, 100 % yield).
Step 6: Di-tert-butyl 4-aminopyrazolidine-l,2-dicarboxylate (3_57_7)
[00461] A solution of compound 3_57_6 (0.125 g, 0.40 mmol) and palladium on charcoal (5 %, 0.10 g) in methanol (6 mL) was hydrogenated at 42 psi of hydrogen for 4.5 hours. The mixture was filtered through a bed of Celite and the filtrate was concentrated in vacuo to afford crude compound 3_57_7 (0.103 g, 90 % yield).
[00462] Treating the intermediate 3_1_5 with the above compound 3_57_7 instead of ammonia as described under 3.1 gave the desired compound 3_57_8.
3.58 tert-Butyl [(4- {[2-(aminooxy)-4-hydroxybutan- 1 -yl]oxy} phenyl) (imino)- methyl]carbamate
Figure imgf000144_0001
Step l:3,4-Dihydroxybutyl acetate (3_58_2)
[00463] A mixture of compound 3_58_1 (WO2005/70874, 30 g, 159.6 mmol) in acetic acid (150 mL) and water (100 mL) was heated at 60 °C for 2.5 hours and concentrated to dryness to give crude compound 3_58_2 (25 g, >100 % yield) as an oil, which was used in the next step without further purification.
[00464] Ή NMR (400 MHz, CDC13): δ = 1.78 (m, 2H), 1.97-2.18 (m, 5H), 3.45 (m, IH), 3.67 (dd, J=11.3, 3.1 Hz, IH), 3.80 (tt, J=8.0, 3.7 Hz, IH), 4.03-4.25 (m, IH), 4.38 (m, IH).
Step 2:4-{[tert-Butyl(dimethyl)silyl]oxy}-3-hydroxybutyl acetate (3_58_3)
[00465] Tert-butyldimethylchlorosilane (TBSC1, 24 g, 152.0 mmol) was added portionwise to a solution of compound 3_58_2 (crude 25 g), triethylamine (32.7 g, 235.2 mmol) and 4-dimethylaminopyridine (1.2 g, 9.8 mmol) in dichloromethane (250 mL). The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, filtered again to remove the solid and the filtrate was concentrated to give a residue, which was purified by column chromatography to give compound 3_58_3 (13 g, 30 % yield) as an oil.
[00466] ¾ NMR (400 MHz, CDC13): δ = 0.01 (s, 6H), 0.82 (s, 9H), 1.70 (m, 2H), 1.98 (s, 3H), 2.41 (d, J = 3.6 Hz, 1H), 3.38 (m, 1H), 3.54 (m, 1H), 3.63 (m, 1H), 4.16 (m, 1H).
Step 3 : 4-{ [tert-Butyl (dimethyl)silyl] oxy} -3- [(1 , 3-dioxo- 1 , 3-dihydro-2H-isoindol-2- yl)oxy]butyl acetate (3_58_4)
[00467] Triphenylphosphine (16.4 g, 62.8 mmol) was added to a solution of compound 3_58_3 (13 g, 48.3 mmol) and iV-hydroxyphthalimide (11 g, 67.6 mmol) in tetrahydrofuran (200 mL), and diisopropyl azodicarboxylate (14.6 mL, 72.5 mmol) at 0°C, and the mixture was stirred at room temperature for 3 hours and concentrated to give a residue, which was purified by column chromatography to give compound 3_58_4 (20 g, 99 % yield) as a yellow solid.
[00468] Ή NMR (400 MHz, CDC13): δ = 0.02 (s, 6H), 0.80 (s, 9H), 2.10 (m, 5H), 3.81 (m, 1H), 3.96 (m, 1H), 4.42 (m, 3H), 7.78 (m, 2H), 7.82 (m, 2H).
Step 4:3-[(l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)oxy]-4-hydroxybutyl acetate (3_58_5)
[00469] Hydrogen fluoride-pyridine complex (HF-pyridine, 5 ml) was added to a solution of compound 3_58_4 (10 g, 24.1 mmol) in tetrahydrofuran (100 mL) under cooling, and the mixture was stirred at room temperature for 16 hours, and concentrated to give a residue, which was purified by column chromatography to give compound 3_58_5 (6.4 g, 91 % yield) as a yellow solid.
[00470] ¾ NMR (400 MHz, CDC13): δ = 1.96 (m, 1H), 2.04 (s, 3H), 2.30 (m, 1H), 3.51 (m, 1H), 3.60 (m, 1H), 3.80 (m, 1H), 4.31 (m, 2H), 4.45 (m, 1H), 7.79 (m, 2H), 7.86 (m, 2H).
Step 5:4-{4-[N-(tert-Butoxycarbonyl)carbamimidoyl]phenoxy}-3-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)oxy]butyl acetate (3_58_6)
[00471] Diisopropyl azodicarboxylate (5.93 mL, 29.4 mmol) was added to a solution of compound 3_58_5 (5.74 g, 19.58 mmol), tert-butyl-N-[(4-hydroxyphen- yl)iminomethyl] -carbamate (4.64 g, 19.58 mmol) and triphenylphosphine (6.1 g, 23.49 mmol) in tetrahydrofuran (100 mL) at 0°C and the mixture was stirred at room temperature for 16 hours and concentrated to give a residue, which was purified by column chromatography to give compound 3_58_6 (8.76 g, 78 % yield) as a gum.
[00472] Ή NMR (400 MHz, CDC13): δ = 1.54 (s, 9H), 2.21 (s, 3H), 2.27 (m, 2H), 4.25 (m, 1H), 4.38 (m, 2H), 4.52 (m, 1H), 4.70 (m, 1H), 6.78 (d, J = 6.4 Hz, 2H), 7.81 (m, 6H).
Step 6:3-(Aminooxy)-4-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]phenoxy}butyl acetate (3_58_7)
[00473] Hydrazine monohydrate (0.13 g, 2.6 mmol) was added to a solution of compound 3_58_6 (1.4 g, 2.73 mmol) in anhydrous ethanol (15 mL) under cooling. The resulting mixture was stirred at room temperature for 16 hours, filtered and the filtrate was concentrated to afford crude compound 3_58_7 (1 g, 96 % yield) as a white solid. [00474] Ή NMR (400 MHz, CDC13): δ = 1.54 (s, 9H), 1.98 (m, 2H), 2.28 (s, 3H), 4.00 (m, IH), 4.15 (m, 2H), 4.23 (m, 2H), 5.42 (br s, 2H), 6.85 (d, J = 6.4 Hz, 2H), 7.81 (d, J = 6.4 Hz, 2H).
Step 7:tert-Butyl [{4-[2-(aminooxy)-4-hydroxybutoxy]phenyl}(imino)methyl]carb- amate (3_58_8)
[00475] Potassium carbonate (0.13 g, 2.6 mmol) was added to a solution of compound 3_58_7 (1 g, 2.62 mmol) in anhydrous methanol (30 mL) under cooling, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give compound 3_58_8 (0.18 g, 20 % yield) as a gum.
[00476] Ή NMR (400 MHz, DMSO-d6): δ = 1.42 (s, 9H), 1.43 (m, IH), 1.78 (m, IH), 3.50 (m, IH), 3.80 (m, IH), 4.16 (m, 2H), 4.42 (m, IH), 5.95 (s, 2H), 7.22 (d, J=6.4 Hz, 2H), 7.96 (d, J=6.4 Hz, 2H).
3.59 Diphenylmethyl 2-(aminooxy)-3-{4-[N-(tert-butoxycarbonyl)-N-{2-[(tert- butoxycarbonyl)amino]ethyl}carbamimidoyl]phenoxy}propanoate
Figure imgf000147_0001
Step l: 3-{4-[N-(2-tert-Butoxycarbonylamino-ethyl)-carbamimidoyl]-phenoxy}-2- hydroxy-propionic acid methyl ester (3_59_1)
[00477] Triethylamine (1.295 g, 12.8 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (1.76 g, 11.0 mmol) were added to a mixture of compound 3_45_3 (3.09 g, 10.7 mmol) in anhydrous methanol (50 mL) at 0°C and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography to give the desired product (3.09 g, 76 % yield) as a white solid.
[00478] ¾ NMR(400 MHz, DMSO-d6): δ = 1.35 (s, 9H), 3.18-3.27 (m, 2H), 3.38-3.47 (m, 2H), 3.65 (s, 3H), 4.23 - 4.28 (m, 2H), 4.44-4.50 (m, 1H), 5.95 (d, J = 6.2 Hz, 1H), 7.12 (d, J = 9.1 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 8.96 (br. s., 1H), 9.36 (br s, 1H), 9.55 (br s, 1H).
Step 2: 3-(4-{[tert-Butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)-amino]-imino- methyl}-phenoxy)-2-hydroxy-propionic acid methyl ester (3_59_2)
[00479] A saturated solution of sodium carbonate (20 mL) and di-tert- butyldicarbonate (Boc20, 3.519 g, 16.1 mmol) in 1,4-dioxane (25 mL) were added to a solution of compound 3_59_1 (2.05 g, 5.37 mmol) in water (30 mL) at 0 °C. After stirring at room temperature for 4.5 hours, the resulting mixture was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated. The residue was purified by column chromatography to give the desired product (0.66 g, 26% yield) as a white solid.
[00480] Ή NMR (400 MHz, DMSO-d6): δ = 1.21 (s, 9H), 1.37 (s, 9H), 3.05- 3.14 (m, 2H), 3.17-3.25 (m, 2H), 3.64 (s, 3H), 4.13-4.19 (m, 2H), 4.44 (m, 1H), 5.87 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.31 (d, / = 8.8 Hz, 2 H). [00481] Using compound 3_59_1 and following the procedure as described under 3.45 compound 3_59_3 was prepared.
3.60 Diphenylmethyl 2-(aminooxy)-3-[(6-{tert-butoxycarbonyl-carbamimido- yl}pyridin-3-yl)oxy]propanoate
Η
3
Figure imgf000149_0001
60 5
Step l:5-Benzyloxy-pyridine-2-carbonitrile (3_60_2)
[00482] A mixture of 5-hydroxy-pyridine-2-carbonitrile 3_60_1 (14 g, 116 mmol) and potassium carbonate (32.2 g, 233 mmol) in Ν,Ν-dimethylformamide (140 mL) was heated at 60°C for 0.5 hours. Benzylbromide (13.9 g, 116 mmol) was added and the mixture was stirred at 66°C for 1 hour, and filtered and the filtrate was concentrated, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with diethyl ether and hexanes to give a precipitate, which was collected to give compound 3_60_2 (21 g, 85 % yield) as a solid.
[00483] Ή NMR (400 MHz, DMSO-d6): δ = 5.27 (s, 2H), 7.33-7.50 (m, 5H), 7.65 (dd, J=8.8, 2.9 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 8.50 (d, J = 3.2 Hz, 1H). Step 2:5-Benzyloxy-pyridine-2-carboxamidine (3_60_3)
[00484] Butyllithium (1.6N in hexane, 168 mL, 269 mmol) was added to a solution of hexamethyldisilazane (56.5 mL, 269 mmol) in tetrahydrofuran (250 mL) at 0°C, and stirred at 0°C for 1 hour to form lithium hexamethyldisilazide (LHMDS). A solution of compound 3_60_2 (22.6 g, 107.6 mmol) in tetrahydrofuran (250 mL) was added slowly at 0°C, and the mixture was warmed to room temperature slowly and stirred for 16 hours at room temperature. A IN hydrochloric acid solution (300 mL) was added to the reaction mixture to give a precipitate which was collected to give pure compound 3_60_3 (17 g, 70 % yield). From the mother liquor an additional amount of crude compound 3_60_3 (10 g) was obtained as a gum.
[00485] Ή NMR (400 MHz, DMSO-d6): δ = 5.32 (s, 2H), 7.32-7.52 (m, 5H), 7.78 (dd, J = 8.8, 2.9 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 2.7 Hz, 1H), 9.18 (s, 2H), 9.32 (s, 2H).
Step 3:Amino-(5-benzyloxy-pyridin-2-yl)-methylene]-carbamic acid tert-butyl ester (3_60_4)
[00486] Sodium bicarbonate (7.78 g, 92.5 mmol) was added to a suspension of compound 3_60_3 (14 g, 61.67 mmol) in a mixture of dioxane (200 mL) and water (200 mL) at room temperature, and the mixture was stirred at room temperature for 20 minutes. Di-tert-butyl dicarbonate (Boc20, 13.4 g, 61.44 mmol) was added, and the mixture was stirred for 16 hours at room temperature to give a precipitate. The precipitate was collected, dissolved in ethyl acetate and washed with brine, dried over sodium sulfate and concentrated to give pure compound 3_60_4 (5 g, 25 % yield). The filtrate was concentrated to remove dioxane, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated to give a solid, which was triturated with diethyl ether to give further compound 3_60_4 (6.2 g, 31 % yield) as a yellow solid. [00487] Ή NMR (400 MHz, CDC13): δ = 1.56 (d, J = 5.1 Hz, 9H), 7.31 (dd, J = 8.8, 2.9 Hz, 1H), 7.34-7.46 (m, 5H), 8.32 (d, J = 2.7 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 9.33 (br s, 1H).
Step 4:Amino-(5-hydroxy-pyridin-2-yl)-methylene]-carbamic acid tert-butyl ester (3_60_5)
[00488] A mixture of compound 3_60_4 (5 g, 15.3 mmol) and palladium on charcoal (10 %, wet, 1 g) in a mixture of methanol (80 mL) and ethyl acetate (10 mL) was hydrogenated at room temperature under 35 psi for 3 hours. The reaction mixture was filtered and concentrated to give compound 3_60_5 (3.4 g, 97 % yield) as a brown solid.
[00489] ¾ NMR (400 MHz, CDC13): δ = 1.57 (s, 9H), 5.15 (s, 2H), 7.51 (dd, J = 8.8, 2.5 Hz, 1H), 8.27 (d, J = 2.7 Hz, 1H), 8.73 (d, J = 9.0 Hz, 1H).
Step 5:3-[6-(tert-Butoxycarbonylamino-imino-methyl)-pyridin-3-yloxy]-2-hydroxy- propionic acid ethyl ester (3_60_6)
[00490] Potassium carbonate (5.46 g, 39.6 mmol) was added to a solution of compound 3_60_5 (3 g, 13.2 mmol) in acetonitrile (50 mL) and the mixture was heated at 93°C for 0.5 hours. Ethyl 2,3-epoxypropanoate (4.6 g, 39.6 mmol) was added to the reaction mixture. After refluxing for 48 hours, the resulting mixture was cooled and filtered and the filtrate was concentrated to give a residue which was purified by column chromatography to give compound 3_60_6 (2 g, 21 % yield) as a brown solid.
[00491] Ή NMR (400 MHz, DMSO-d6): δ = 1.18 (t, J = 7.0 Hz, 3H), 1.45 (m, 9H), 4.15 (dd, J = 7.0, 1.5 Hz, 2H), 4.29-4.37 (m, 2H), 4.48 (q, J = 4.7 Hz, 1H), 5.92 (d, J = 5.9 Hz, 1H), 7.55 (dd, J = 8.8, 2.9 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 8.35 (d, J = 2.7 Hz, 1H), 8.75 (br. s., 1H), 9.02 (br. s, 1H). [00492] Using the above alcohol 3_60_6 and following the procedure as described under 3.45 compound 3_60_7 was prepared.
3.61 tert-Buty 1 ( 1 - {4- [2- (aminooxy) - 3 - (tert-butyl-dimethy l-silanyloxy)-propox- y]-phenyl}-iminomethyl)-carbamate
Figure imgf000152_0001
3 61 7
Step l:4-(2,2-Dimethyl-[l,3]dioxolan-4-ylmethoxy)-benzonitrile (3_61_2)
[00493] 2,2-Dimethyl-l,3-dioxolane-4-methanol (3.66 g, 27.7 mmol) and triphenylphosphine (7.93 g, 30.2 mmol) were added to a solution of 4-hydroxy- benzonitrile 3_61_1 (3.0 g, 25.2 mmmol) in anhydrous tetrahydrofuran (80 mL) at room temperature. Diethyl azodicarboxylate (5.26 g, 30.2 mmol) was added dropwise to the resulting solution at 20°C and the resulting mixture was stirred at room temperature overnight. After evaporation of the tetrahydrofuran, the crude product was purified by column chromatography to give the desired product (5.65 g, 96 % yield) as a white solid. [00494] lH NMR (400 MHz, DMSO-d6): δ = 1.28 (s, 3H), 1.33 (s, 3H), 3.69- 3.79 (m, 1H), 3.99-4.18 (m, 3H), 4.33-4.47 (m, 1H), 7.11 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H).
Step 2: 4-(2,3-Dihydroxy-propoxy)-benzimidic acid methyl ester hydrochloric acid salt (3_61_3)
[00495] Hydrogen chloride gas was introduced into a solution of compound 3_61_2 (3.02 g, 12.9 mmol) in anhydrous methanol (80 mL) at 0°C for 10 minutes and the resulting mixture was stirred at room temperature overnight. After concentration, the residue was stirred with diethyl ether (60 mL) for 0.5 hours and the precipitate was collected and dried to give the desired product (3.26 g, 97 % yield) as a white solid.
[00496] ¾ NMR (400 MHz, DMSO-d6): δ = 3.37-3.48 (m, 2H), 3.75-3.84 (m, H), 4.00 (dd, J = 10.1, 6.3 Hz, 1H), 4.13 (dd, J = 10.3, 3.8 Hz, 1H), 4.23 (s, 3H), 7.14- 7.19 (m, 2H), 8.06 (d, J = 8.8 Hz, 2H).
Step 3: 4-(2,3-Dihydroxy-propoxy)-benzamidine (3_61_4)
[00497] Ammonia (27 mL, 7N in methanol, 0.187 mol) was added to a solution of compound 3_61_3 (3.26 g, 12.5 mmol) in anhydrous methanol (20 mL) at 0°C and the resulting mixture was stirred at 40 °C for 3 hours. The reaction mixture was concentrated to dryness to give the crude desired product (2.92 g, >100 % yield) as a white solid, which was used without purification.
[00498] XH NMR (400 MHz, DMSO-d6): δ = 3.45 (br s, 2H), 3.81 (br. s, 1H), 3.99 (dd, J = 10.3, 6.2 Hz, 1H), 4.12 (dd, J = 10.1, 4.0 Hz, 1H), 4.74 (br. s, 1H), 5.04 (d, J = 4.7 Hz, 1H), 7.12-7.19 (m, 2H), 7.79-7.86 (m, 2H), 8.90 (s, 2H), 9.19 (s, 2H). Step 4: {[4-(2,3-Dihydroxy-propoxy)-phenyl] mino-methyl}-carbamic acid tert-butyl ester (3_61_5)
[00499] A saturated sodium carbonate solution (8mL) and di-tert-butyldi- carbonate (Boc20, 6.52 g, 30 mmol) were added to a solution of compound 3_61_4 (3.70 g, crude, 12.5 mmol) in methanol (30 mL) and tetrahydrofuran (20 mL) at 0 °C. After stirring at room temperature overnight, the resulting mixture was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated. The residue was washed with a small volume of cold ethyl acetate to give the desired product (3.10 g, 80 % yield) as a white solid.
[00500] Ή NMR (400 MHz, DMSO-d6): δ = 1.44 (s, 9H), 3.41-3.48 (m, 2H), 3.80 (d, J = 5.0 Hz, 1H), 3.93 (dd, J = 9.8, 6.3 Hz, 1H), 3.99-4.11 (m, 1H), 4.70 (t, J = 5.7 Hz, 1H), 4.99 (d, J = 5.0 Hz, 1H), 7.00 (d, J = 9.1 Hz, 2H), 7.94 (d, J = 9.1 Hz, 2H).
Step 5: ({4-[3-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-propoxy]-phenyl}-imino- methyl)-carbamic acid tert-butyl ester (3_61_6)
[00501] Imidazole (1.44 g, 21.1 mmol) and tert-butyldimethylsilyl chloride (TBDMS-C1, 1.592 g, 10.6 mmol) were added to a solution of compound 3_61_5 (2.98 g, 9.60 mmol) in Ν,Ν-dimethylformamide (15 mL) at 0 °C. After stirring at room temperature overnight, the reaction mixture was quenched by adding ice-water (30 mL) and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and concentrated to dryness to afford the crude desired product (4.81 g, >100 % yield) as an off-white sticky solid, which was used without purification.
[00502] Ή NMR (400 MHz, DMSO-d6): δ = 0.05-0.14 (m, 6H), 0.87-0.92 (m, 9H), 1.48 (s, 9H), 3.68 (d, J = 5.9 Hz, 2H), 3.82-3.91 (m, 1H), 3.95-4.04 (m, 1H), 4.05- 4.14 (m, 1H), 5.11 (d, J = 5.0 Hz, 1H), 6.99-7.07 (m, 2H), 7.94-8.01 (m, 2H). [00503] Using the above alcohol 3_61_6 and following the procedure as described under 3.45 compound 3_61_7 was prepared.
3.62 tert-Butyl 4-{[(4-{[(2S)-2-(aminooxy)-3-(diphenylmethoxy)-3-oxopropyl]- oxy}phenyl)(imino)methyl]amino}piperidine-l-carboxylate
Figure imgf000155_0001
Step l : (R)-3-(4-Cyano-phenoxy)-2-hydroxy-propionic acid ethyl ester (3_62_2)
[00504] A mixture of a Co(III)-catalyst (0.26 g, 0.31 mmol, ref: /. Am. Chem. Soc. 1999, 121, 6086-6087), and 4A molecular sieves (2 g) was treated with 4- hydroxybenzonitrile 3_62_1 (1.0 g, 8.4 mmol) and ethyl oxirane-2-carboxylate (2.0 g, 17 mmol) followed by tert-butyl methyl ether (3.0 mL) under a stream of nitrogen. The suspension was stirred at room temperature overnight and filtered through a pad of Celite. The filtrate was concentrated to give a dark brown liquid. The liquid was purified by column chromatography to afford compound 3_62_2 (1.9 g, 96 % yield) as a brown oil. [00505] Ή NMR (400 MHz, DMSO-d6): 8 = 1.18 (t, J = 1.7 Hz, 3H), 4.03 - 4.19 (m, 2H), 4.25 (d, J = 4.4 Hz, 2H), 4.38-4.51 (m, 1H), 5.89 (d, J = 5.9 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H).
Step 2: (#)-2-Hydroxy-3-(4-methoxycarbonimidoyl-phenoxy)-propionic acid methyl ester hydrochloric acid salt (3_62_3)
[00506] A mixture of compound 3_62_2 (1.1 g, 4.7 mmol) in methanol (50 mL) was cooled to 0°C in a sealed vessel. Anhydrous hydrogen chloride gas was bubbled through the solution until the mixture was saturated. The flask was sealed and stirred at 0°C to room temperature overnight. The mixture was concentrated in vacuo and diluted with diethyl ether to give a suspension. The suspension was stirred for 15 minutes and compound 3_62_3 (1.1 g, 81 % yield) as a white solid was collected after drying under high vacuum.
[00507] NMR (400 MHz, DMSO-d6): δ = 3.66 (s, 3H), 4.24 (s, 3H), 4.27- 4.30 (m, 2H), 4.48 (t, J = 4.4 Hz, 1H), 7.16 (d, J = 9.1 Hz, 2H), 8.09 (d, J = 9.1 Hz, 2H).
Step 3: (i?)-tert-Butyl 4-(4-(2-hydroxy-3-methoxy-3-oxopropoxy)benzimidamido)pip- eridine-l-carboxylate (3_62_4)
[00508] Triethylamine (1.537 g, 15.2 mmol) and tert-butyl 4-amino- piperidine-l-carboxylate (2.765 g, 13.8 mmol) were added to a mixture of compound 3_62_3 (4.0 g, 13.8 mmol) in anhydrous methanol (50 mL) at 0°C and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness to give the crude desired product (7.81 g, >100 % yield) as a white foam, which was used without purification.
[00509] Ή NMR(400 MHz, DMSO-d6): δ = 1.38 (s, 9H), 1.54-1.43 (m, 2H), 1.82-1.93 (m, 2H), 2.60-2.90 (m, 2H), 3.64 (s, 3H), 3.90-4.00 (m, 3H), 4.12-4.28 (m, 2H), 4.44-4.50 (m, 1H), 5.98 (s, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H). Step 4: (R)-3-(4-(N-(l-(tert-Butoxycarbonyl)piperidin-4-yl)carbamimidoyl)phenoxy)-2- hydroxypropanoic acid (3_62_5)
[00510] A solution of sodium hydroxide (0.552 g, 13.8 mmol) in water (20 mL) was added to a solution of compound 3_62_4 (3.905 g, crude, 6.90 mmol) in tetrahydrofuran (50 mL) at 0°C. After stirring at this temperature for 90 minutes, the reaction mixture was neutralized to pH 7 using 4iV hydrogen chloride in dioxane. The mixture was concentrated and dried to afford the crude desired product (5.20 g, >100 % yield) as a white solid, which was used in the next step without purification.
Step 5: (R)-tert-Butyl 4-(4-(3-(benzhydryloxy)-2-hydroxy-3-oxopropoxy)benzimid- amido)piperidine-l-carboxylate (3_62_6)
[00511] A solution of diazo(diphenyl)methane (Ph2CN2, 2.00 g, 10.35 mmol) in methanol (15 mL) was slowly added to a solution of compound 3_62_5 (5.20 g, crude, 6.90 mmol) in methanol (100 mL). The resulting mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified by column chromatography to give the desired product (1.8 g, 46 % yield) as a white solid.
[00512] ¾ NMR (400 MHz, DMSO-d6): δ = 1.39 (s, 9H), 1.42-1.52 (m, 2H), 1.87-1.92 (m, 2H), 2.82 (br. s, 2H), 3.90-4.00 (m, 3H), 4.30-4.42 (m, 2H), 4.62-4.65 (m, 1H), 6.48 (d, J = 7.6 Hz ,1H), 6.84 (s, 1H), 7.09 (d, J = 8.8 Hz, 2H), 7.22-7.41 (m, 10H), 7.69 (d, J = 8.8 Hz, 2H), 9.10 (br. s, 1H), 9.38 (br. s, 1H).
[00513] MS: 574.14 (M+l).
Step 6: (S)-tert-Butyl 4-(4-(3-(benzhydryloxy)-2-((l,3-dioxoisoindolin-2-yl)oxy)-3-oxo- propoxy)benzimidamido)piperidine-l-carboxylate (3_62_7) [00514] N-Hydroxyphthalimide (0.573 g, 3.51 mmol) and tri- phenylphosphine (1.005 g, 3.83 mmol) were added to a solution of compound 3_62_6 (1.831 g, 3.19 mmol) in anhydrous tetrahydrofuran (60 mL) at room temperature. A solution of diethyl azodicarboxylate (0.667 g, 3.83 mmol) in tetrahydrofuran (5 mL) was added dropwise to the resulting solution at 20°C. The resulting mixture was stirred at room temperature for 2.5 hours. After evaporation of the tetrahydrofuran, the crude product was purified by column chromatography to give the desired product (1.5 g, 65 % yield) as a white solid.
[00515] ¾ NMR (400 MHz, DMSO-d6): δ = 1.42 (s, 9H), 1.44-1.53 (m, 2H), 1.92-1.96 (m, 2H), 2.82 (br. s, 2H), 3.92-4.16 (m, 3H), 4.68 (br. s, 2H), 5.48 (br m., 1H), 6.98 (s, 1H), 7.11 (d, J = 8.6 Hz, 2H), 7.26-7.48 (m, 10H), 7.75 (d, J = 8.6 Hz, 2H), 7.86 (s, 4H), 9.24 (br. s, 1H), 9.40 (b. s, 1H).
[00516] MS: 719.18 (M+l).
Step 7:2-Aminooxy-3-(4-{[tert-butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)- amino]-imino-methyl}-phenoxy)-propionic acid benzhydryl ester (3_62_8)
[00517] Hydrazine monohydrate (0.114 g, 2.28 mmol) was added to a solution of compound 3_62_7 (1.49 g, 2.07 mmol) in anhydrous ethanol (35 mL) and tetrahydrofuran (20 mL) at 0°C and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness and the residue was stirred with dichloromethane (10 mL) at room temperature for 15 minutes and filtered. The filtrate was concentrated to afford the crude desired product (1.4 g, >100 % yield) as an off-white foam, which was used in the next step without purification.
[00518] ¾ NMR (400 MHz, DMSO-d6): δ = 1.42 (s, 9H), 1.44-1.53 (m, 2H), 1.89-1.94 (m, 2H), 2.85 (br. s, 2H), 3.92-4.02 (m, 3H), 4.36-4.47 (m, 2H), 4.62-4.66 (m, 1H), 6.45 (s, 2H), 6.91 (s, 1H), 7.09 (d, J = 8.8 Hz, 2H), 7.26-7.45 (m, 10H), 7.72 (d, J = 8.8 Hz, 2H), 9.25 (br. s, 2H).
[00519] Following the procedure detailed above under 3.62 but using the amines R-NH2 shown in the table below instead of tert-butyl 4-aminopiperidine-l- carboxylate in step 3 of the synthesis, compounds 3_63_8 to 3_79_8 were prepared.
Figure imgf000159_0001
Figure imgf000159_0002
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
[00520] Following the procedure detailed above under 3.62 but using the enantiomer of 3_62_3 and amines R-NH2 shown in the table below instead of tert- butyl 4-aminopiperi dine- 1-carboxylate in step 3 of the synthesis, compounds 3_80_8 to 3_82_8 were prepared.
Figure imgf000162_0002
Figure imgf000162_0003
Figure imgf000163_0001
3.83 tert-Butyl [{4-[3-amino-2-(aminooxy)-3-oxopropoxy]phenyl}(imino)- methyl]carbamate
Figure imgf000163_0002
Step l:Methyl 3-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]phenoxy}-2-[(l;3-dioxo- l,3-dihydro-2H-isoindol-2-yl)oxy]propanoate (3_83_1)
[00521] Diisopropyl azodicarboxylate (0.39 g, 2.41 mmol) was added drop- wise to a mixture of methyl 3-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]phenoxy}-2- hydroxypropanoate 3_45_5 (0.68 g, 2.01 mmol), N-hydroxy-phthalimide (PhthN- OH, 0.68g, 2.01 mmol) and triphenylphosphine (0.63 g, 2.41 mmol) in tetrahydrofu- ran. After the addition was complete, the mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by column chromatography to give compound 3_83_1 (1.0 g, 100 % yield) as yellow foam. [00522] ¾ NMR (400 MHz, DMSO-d6): δ = 1.42 (s, 9H), 3.77 (s, 3H), 4.45 (m, 1H), 4.58 (m, 1H), 5.22 (m, 1H), 6.97 (d, J = 8.2 Hz, 2H), 7.85 9s, 4H), 7.92 (d, J = 8.2 Hz, 2H).
[00523] MS (m/z, ES+): 484.17
Step 2:tert-Butyl [{4-[3-amino-2-(aminooxy)-3-oxopropoxy]phenyl}(imino)methyl]- carbamate (3_83_2)
[00524] Compound 3_83_1 (1.0 g, 4.29 mmol) was dissolved in a methanolic solution of 7N ammonia (10 mL), stirred at room temperature for 24 hours and filtered. The filtrate was concentrated to give compound 3_83_2 (0.7 g, 100 % yield), which was used in the next step without further purification.
[00525] Ή NMR (400 MHz, DMSO-d6): δ = 1.42 (s, 9H), 4.20-4.50(m, 3H), 6.40 (br. s, 2H), 6.97 (d, J = 8.2 Hz, 2H), 7.85 (s, 4H), 7.92 (d, J = 8.2 Hz, 2H).
[00526] MS (m/z, ES+): 339.11
3.84 tert-Butyl [(4-{[l-(aminooxy)-3-hydroxypropan-2-yl]oxy}phenyl)(imino)- methyl]carbamate
Figure imgf000164_0001
Step 1: 3-{[tert-Butyl(dimethyl)silyl]oxy}-2-hydroxypropyl acetate (3_84_2)
[00527] Tert-butyldimethylchlorosilane (TBSC1, 28.2 g, 180.1 mmol) was added portion wise to a mixture of compound 3_84_1 (27 g, 189.6 mmol; ref.: /. Med. Chem. 1989, 2104-2110), triethylamine (36.9 mL, 265.4 mmol) and 4- dimethylaminopyridine (1.38 g, 11.4 mmol) in dichloromethane (250 mL). The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was concentrated. The residue was dissolved in EtOAc, filtered again to remove any solid, and the filtrate was concentrated to give a residue, which was purified by column chromatography eluting with 30% EtOAc in hexane to give compound 3_84_2 (22 g, 46 % yield) as an oil.
[00528] ¾ NMR (400 MHz, CDC13): δ = 0.07 (s, 6 H), 0.89 (s, 9 H), 2.08 (s, 3 H), 2.49 (d, J=5.5 Hz, 1 H), 3.57 - 3.65 (m, 1 H), 3.65 - 3.73 (m, 1 H), 3.82 - 3.93 (m, 1 H), 4.04 - 4.21 (m, 2 H).
Step 2:2-{4-[N-(tert-Butoxycarbonyl)carbamimidoyl]phenoxy}-3-{[tert-butyl(dimeth- yl)silyl]oxy}propyl acetate (3_84_3)
[00529] Triphenylphosphine (4.33 g, 16.53 mmol) was added to a mixture of compound 3_84_2 (3.5 g, 14.11 mmol) and tert-butyl [(4-hydroxyphenyl)(imino)- methyl] carbamate (3.26 g, 13.78 mmol) in tetrahydrofuran (100 mL), and diisopro- pyl azodicarboxylate (4.17 mL, 20.67 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to give a residue, which was purified by column chromatography eluting with 30% EtOAc in hexane to give compound 3_84_3 (6.5 g, 99 % yield) as a yellow solid.
[00530] Ή NMR (400 MHz, CDC13): δ = 0.09 (m, 6 H), 0.87 (s, 9 H), 1.55 (s, 9 H), 2.04 (s, 3 H), 3.75 - 3.86 (m, 2 H), 4.25 - 4.41 (m, 2 H), 4.51 - 4.64 (m, 1 H), 6.98 (d, J = 9.0 Hz, 2 H), 7.83 (d, J = 9.0 Hz, 2 H). Step 3:2-{4-[N-(tert-Butoxycarbonyl)carbamimidoyl]phenoxy}-3-hydroxypropyl acetate (3_84_4)
[00531] Tetra-n-butylammonium fluoride (TBAF, IN in tetrahydrofuran, 39.9 mL, 39.9 mmol) was added to a solution of compound 3_84_3 (9.3 g, 19.9 mmol) in tetrahydrofuran (100 mL) under cooling, and the mixture was stirred at room temperature for 2 h and concentrated to give a residue, which was purified by column chromatography to give compound 3_84_4 (3.6 g, 51 % yield) as a gum.
[00532] ¾ NMR (400 MHz, CDC13): δ = 1.55 (s, 9 H), 2.06 (s, 3 H), 3.85 (dd, J = 5.1, 2.3 Hz, 2 H), 4.24 - 4.32 (m, 1 H), 4.35 - 4.45 (m, 1 H), 4.62 (t, J = 5.1 Hz, 1 H), 7.01 (d, J = 9.0 Hz, 2 H), 7.84 (d, J = 9.0 Hz, 2 H).
Step 4:2-{4-[N-(tert-Butoxycarbonyl)carbamimidoyl]phenoxy}-3-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)oxy]propyl acetate (3_84_5)
[00533] Diisopropyl azodicarboxylate (3.11 mL, 15.42 mmol) was added to a solution of compound 3_84_4 (3.62 g, 10.28 mmol), N-hydroxyphthalimide (PhthN- OH, 2.34 g, 14.39 mmol) and triphenylphosphine (3.50 g, 13.36 mmol) in tetrahydrofuran (100 mL) at 0°C, and the mixture was stirred at room temperature for 4 h. The mixture was concentrated, extracted with EtOAc, washed with a saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated to give a residue, which was purified by column chromatography to give compound 3_84_5 (3.4 g, 66 % yield) as a white solid.
[00534] ¾ NMR (400 MHz, CDC13): δ = 1.54 (s, 9 H), 2.08 (s, 3 H), 4.41 - 4.50 (m, 4 H), 4.91 - 5.00 (m, 1 H), 6.98 (d, J = 9.0 Hz, 2 H), 7.70 - 7.86 (m, 6 H).
Step 5: 3-(Aminooxy)-2-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]phenoxy} propyl acetate (3_84_6) [00535] Hydrazine monohydrate (0.34 g, 6.84 mmol) was added to a solution of 3_84_5 (3.4 g, 6.84 mmol) in anhydrous ethanol (40 mL) under cooling and the resulting mixture was stirred at room temperature for 5 h and filtered and the filtrate was concentrated to afford crude compound 3_84_6 (2.4 g, 96 % yield) as a solid, which was used without purification.
[00536] NMR (400 MHz, CDC13): 5 = 1.55 (s, 9 H), 2.05 (s, 3 H), 3.81 - 3.94 (m, 2 H), 4.26 - 4.37 (m, 2 H), 4.82 - 4.87 (m, 1 H), 7.04 (d, J = 9.0 Hz, 2 H), 7.83 (d, J = 9.0 Hz, 2 H).
Step 6: tert-Butyl [(4-{[l-(aminooxy)-3-hydroxypropan-2-yl]oxy}phenyl)(imino)meth- yl] carbamate (3_84_7)
[00537] Potassium carbonate (0.9 g, 6.53 mmol) was added to a solution of compound 3_84_6 (2.4 g, 6.53 mmol) in anhydrous methanol (40 mL) under cooling and the resulting mixture was stirred for 1 h, concentrated, extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, and filtered and the filtrate was concentrated to give compound 3_84_7 (1.57 g, 74 % yield) as a gum, which was used without further purification.
[00538] Ή NMR (400 MHz, DMSO-d6): δ = 1.42 (s, 9 H), 3.56 (m, 2 H), 3.72 (m, 2 H), 4.62 (t, J = 5.2 Hz, 1 H), 4.90 (s, 1 H), 6.10 (s, 2 H), 7.02 (d, J = 8.4 Hz, 2 H), 7.90 (d, J = 8.4 Hz, 2 H).
3.85 Diphenylmethyl 2-(aminooxy)-3-{3-hydroxy-4-[N-(tert-butoxycarbonyl)- carbamimidoyl] -phenoxy } -propanoate
Figure imgf000168_0001
Step 1 : 2-Fluoro-4-(tetrahydro-2H-pyran-2-yloxy)benzonitrile (3_85_2)
[00539] 3,4-Dihydro-2H-pyran (DHP, 7.20 mL, 79.12 mmol) was added to a mixture of 2-fluoro-4-hydroxy-benzonitrile (5.42 g, 39.56 mmol) and pyridium p- toluenesulfonate (PPTS, 170 mg, 0.68 mmol) in dry dichloromethane (100 mL) and the mixture was stirred at room temperature for 16 hours and concentrated. The residue was purified by column chromatography to give compound 3_85_2 (8.9 g, 100 % yield) as a clear oil.
Step 2: 6-(Tetrahydro-pyran-2-yloxy)-benzo[d]isoxazol-3-ylamine (3_85_3)
[00540] Potassium tert-butoxide (8.96 g, 80 mmol) was added in portions to a solution of N-hydroxy acetamide (6.00 g, 80 mmol) in N,N-dimethylformamide (40 mL). After the addition was complete, the resulting mixture was stirred at room temperature for 1 hour. A solution of 2-fluoro-4-(tetrahydro-2H-pyran-2-yloxy)benzo- nitrile 3_85_2 (8.90 g, 40 mmol) in ,Ν-dimethylformamide (20 mL) was added and the resulting mixture was stirred at room temperature for 24 hours and concentrated. The residue was diluted with ethyl acetate (200 mL), washed with water (20 mL) and brine (20 mL), dried and concentrated. The residue was purified by column chromatography to give compound 3_85_3 (6.5 g, 69 % yield).
Step 3:3-Amino-l,2-benzoxazol-6-ol (3_85_4)
[00541] IN hydrochloric acid solution (10 mL) was added to a solution of 6- (tetrahydro-pyran-2-yloxy)-benzo[d]isoxazol-3-ylamine 3_85_3 (6.5 g, 27.77 mmol) in methanol (30 mL) and the mixture was stirred at room temperature for 1 hour and concentrated. The residue was purified by column chromatography to give compound 3_85_4 (4.10 g, 100 % yield) as a white solid.
[00542] Ή NMR (400 MHz, DMSO-d6): δ = 6.20 (br. s, 2H), 6.70 (m, 2H), 7.59 (d, J = 9.4 Hz, 1H), 10.05 (br. s, 1H).
Step 4: 3-[(3-Amino-l,2-benzoxazol-6-yl)oxy]-2-hydroxypropanoate (3_85_5)
[00543] A mixture of 3_85_4 (7.31 g, 63 mmol) and potassium carbonate (11.60 g, 84 mmol) in dry acetonitrile (40 mL) was refluxed for 5 hours and filtered. The filtrate was concentrated and purified by column chromatography to give compound 3_85_5 (1.43 g, 26 % yield) as a sticky gum.
[00544] Ή NMR (400 MHz, CDC13): δ = 1.27 (t, J = 9.5 Hz, 3H), 3.20 (d, J = 2 Hz, 1H), 4.20-4.40 (m, 4H, 4.59 (m, 1H), 6.83 (d, J = 8.6 Hz, 1H), 7.28 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H).
Step 5:3-(4-Carbamimidoyl-3-hydroxyphenoxy)-2-hydroxypropanoate (3_85_6) [00545] 5% palladium on charcoal (140 mg) was added to a degassed solution of 3_85_5 (330 mg, 1.24 mmol) in methanol (30 mL). The mixture was stirred under hydrogen with a balloon for 2 hours and filtered through a pad of Celite. The filtrate was concentrated to give compound 3_85_6 (310 mg, 93 % yield).
[00546] Ή NMR (400 MHz, CD3OD): δ = 1.23 (t, J = 8.8 Hz, 3H), 4.20-4.30 (m, 4H), 4.50 (m, 1H), 6.15 (d, J = 9.2 Hz, 1H), 6.20 (s, 1H), 7.43 (d, J = 9.2 Hz, 1H).
[00547] MS (ES+): 269.10 (Calcd: 268.11)
[00548] Following the same procedure as described above under 3.45 but using intermediate 3_85_6 instead of 3_45_4 compound 3_85_7 was obtained.
4. Oxime formation, coupling reaction and de-protection
Figure imgf000170_0001
[00549] Ketoacid 2_x (1.7 mmol) was added to a solution of compound 3_x (1.7 mmol) in anhydrous ethanol (30 mL) and chloroform (10 mL) and the resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was re-crystallized from ethanol or purified by column chromatography to afford compound 4_3 (24 % - 91% yield) as a yellow solid. [00550] Dicyclohexylcarbodiimide (DCC; 0.29 g, 1.41 mmol) and 1- hydroxybenzotriazole (HOBT, 0.14 g, 1.41 mmol) were added to a solution of compound 4_3 (0.706 mmol) in N,N-dimethylformamide (15 mL) at room temperature. After stirring at room temperature for 30 minutes, 3-amino-azetidin-2-one l_x (1.06 mmol) was added followed by sodium bicarbonate (0.23 g, 2.8 mmol). The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure at 40°C. The residue was purified by column chromatography eluting with 5-10 % methanol in dichloromethane to give compound 4_5 (8 % - 90 % yield) as a yellow solid.
[00551] A solution of compound 4_5 (0.42 mmol) in 90 % formic acid (15 mL) or trifluoroacetic acid / dichloromethane (1: 1, 10 mL) was stirred at 40°C for 40 min. After concentrating to dryness under reduced pressure, the residue was stirred with water (20 mL) for 20 min. After filtration, the filtrate was lyophilized to give the crude product which was purified by prep-HPLC to afford compound 4_6 (5 % - 78 % yield) as formate or TFA salt as a colorless solid.
[00552] The compounds 4_6 of Examples 1-111 were prepared according to the procedures detailed above. The compound of Example 38 was prepared by treating the compound of Example 24 with isopropyl formimidate hydrochloride in the presence of potassium carbonate (conditions see e.g. US 2009/0012054). The compound of Example 43 was prepared by treating the compound of Example 39 with ethanimidoate hydrochloride in the presence of potassium carbonate (conditions see e.g. US 2009/0012054). The compound of Example 46 was prepared by oxidizing the compound of Example 81 with Jones reagent (conditions see e.g. Kenneth Bowden, I. M. Heilbron, E. R. H. Jones and B. C. L. Weedon, J. Chem. Soc, 1946, 39-45). The compounds of Example 87 were prepared by oxidizing the compound of Example 112 with Jones reagent (conditions see e.g. Kenneth Bowden, I. M. Heilbron, E. R. H. Jones and B. C. L. Weedon, J. Chem. Soc, 1946, 39-45) followed by a standard de-protection and HPLC separation. [00553] The compound of Example 78 was prepared by treating the compound of Example 24 with diisopropylethylamine followed by di-tert-butyl [(Z)-IH- pyrazol-l-yl-methylylidene]biscarbamate at room temperature for 15 hours (conditions see e.g. WO 2009/49028 Al). The compound of Example 60 was prepared by treating the compound of Example 59 with formic acid as formylating agent. The compound of Example 63 was prepared by treating the compound of Example 64 with formic acid as formylating agent.
[00554] For the convenience of the reader the structures of the final compounds as well as used building blocks (l_x, 2_x and 3_x) are provided in table 3, which is followed by analytical data for all examples.
Table 3. Structures of final compounds and used building blocks
Example Structure BB 1 (1_x) BB 2 (2_x) BB 3 (3_x)
Figure imgf000172_0001
ı72
Figure imgf000173_0001
ı73
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000179_0002
Figure imgf000179_0003
Figure imgf000180_0001
)
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
NH
NH,
Figure imgf000185_0002
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
[00555] Analytical data for examples 1-112 (structures shown above):
Example 1
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-3-hydroxyphenoxy)eth- oxy]imino}-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00556] Ή NMR (400 MHz, DMSO-c¾: δ = 1.23 (s, 3 H), 1.40 (s, 3 H), 4.19 (m, 2H), 4.38 (m, 2H), 4.59 (d, / = 8.0 Hz, IH), 6.49 (s, 1 H), 6.57 (d, / = 8.8 Hz, IH,), 6.76 (s, 1 H), 7.21 (br s, 2 H), 7.57 (d, / = 8.8 Hz, IH), 9.49 (d, / = 8.0 Hz, IH).
[00557] MS (ES+) m/z: [M+H]+ calcd for G9H24N7O9S2: 558.11. Found: 558.14.
[00558] HPLC: 98.63 %
Example 2
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-3- hydroxyphenoxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00559] Ή NMR (400 MHz, DMSO-d6): δ = 1.33 (d, / = 6.2 Hz, 3 H), 3.67 (m., 1 H), 4.22 (m, 2H), 4.35 (m, 2H), 4.41 (m, IH), 6.45 (br. s, IH,), 6.52 (m, IH), 6.79 (s, 1 H), 7.22 (m, 2H), 7.56 (d, / = 8.8 Hz, IH), 9.32 (m, IH).
[00560] MS (ES ) m/z: [M-H]- calcd for C18H20N7O8S2: 526.08. Found: 526.13.
[00561] HPLC: 91.43 % Example 3
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2 (6-carbamimidoylpyridin-3- yl)oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00562] ¾ NMR (400 MHz, DMSO-<¾): δ = 1.35 (d, / = 6.2 Hz, 3 H), 3.66 (dd, / = 6.0 and 2.5 Hz, 1 H), 4.26 - 4.57 (m, 5 H), 6.78 (s, 1 H), 7.76 (dd, / = 8.9 and 2.7 Hz, 1 H), 8.26 (d, / = 8.9 Hz, 1 H), 8.52 (d, / = 2.3 Hz, 1 H), 8.95 (s, 2 H), 9.21 - 9.49 (m, 3 H).
[00563] MS (ES ) ra/z: [M-H]" calcd for C17H20N8O7S2: 512.09. Found: 512.53. [00564] HPLC: 96.60 % Example 4
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(6-carbamimidoylpyridin-3-yl)oxy]ethoxy}- imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00565] Ή NMR (400 MHz, DMSO-rf6): δ = 1.23 (s, 3 H), 1.40 (s, 3 H), 3.77 (d, / = 3.9 Hz, 1 H), 4.42 (d, / = 4.6 Hz, 3 H), 4.59 (d, / = 7.8 Hz, 1 H), 7.21 (s, 2 H), 7.74 (dd, / = 8.7 and 2.9 Hz, 1 H), 8.12 - 8.40 (m, 2 H), 8.49 (d, / = 2.7 Hz, 1 H), 9.44 (d, / = 8.2 Hz, 3 H).
[00566] MS (ES ) ra/z: [M-H]" calcd for GsHziNgO Sz: 541.09. Found: 541.23. [00567] HPLC: 88.45 % Example 5
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2 (5-carbamimidoylpyridin-2-yl)- oxy] ethoxy}imino)acetyl] amino}-2-methyl-4-oxoazetidine- 1-sulfonic acid [00568] ¾ NMR (400 MHz, DMSO-</6): δ = 1.33 (d, / = 6.2 Hz, 3 H), 3.61 (dd, / = 6.0 and 2.5 Hz, 1 H), 4.35 - 4.49 (m, 3 H), 4.49 - 4.71 (m, 2 H), 6.79 (s, 1 H), 7.12 (d, / = 8.9 Hz, 1 H), 8.10 (dd, / = 8.7 and 2.5 Hz, 1 H), 8.64 (d, / = 1.9 Hz, 1 H), 8.86 (s, 4 H), 9.12 - 9.43 (m, 2 H).
[00569] MS (ES ) m/z: [M-H]" calcd for Ci7H19N807S2: 511.08. Found: 511.13.
[00570] HPLC: 96.6 %
Example 6
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(4-carbamimidoylphenyl)sulf- anyl] ethoxy}imino)acetyl] amino}-2-methyl-4-oxoazetidine-l -sulfonic acid
[00571] Ή NMR (400 MHz, DMSO-rf6): δ = 1.40 (d, / = 5.8 Hz, 3 H), 3.28 - 3.40 (m, 2 H), 3.73 (dd, / = 6.0 and 2.5 Hz, 1 H), 4.25 (t, / = 6.2 Hz, 2 H), 4.44 (dd, / = 7.8 and 2.3 Hz, 1 H), 6.78 and 8.16 (2s, 1 H), 7.22 (br. s, 2 H), 7.57 (m, 2 H), 7.76 (m, 2 H), 8.85 (br. s, 2 H), 9.26 (s, 2 H), 9.21 (s, 1 H).
[00572] MS (ES+) m/z: [M+H]+ calcd for CieHzzN/OeSs: 528.08. Found: 527.97.
[00573] HPLC: 98.3 %
Example 7
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(4-carbamimidoylphenyl)sulfanyl]eth- oxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00574] Ή NMR (400 MHz, DMSO-rf6): δ = 1.29 (s, 3 H), 1.43 (s, 3 H), 3.38 (t, / = 6.6 Hz, 2 H), 4.25 (t, / = 6.6 Hz, 2 H), 4.61 (d, / = 7.8 Hz, 1 H), 6.82 (s, 1 H), 7.5 (br. s, 2H), 7.55 (d, / = 8.6 Hz, 2 H), 7.75 (d, / = 8.6 Hz, 2 H), 8.82 (s, 2 H), 9.23 (s, 2 H), 9.46 (d, / = 7.8 Hz, 1 H). [00575] MS (ES+) m/z: [M+H]+ calcd for
Figure imgf000196_0001
558.09. Found: 558.09. [00576] HPLC: 92.85 % Example 8
(2S;3S)-3-{[(2Z)-2-(2-Amino-l/3-thiazol-4-yl)-2-({2-[(4-carbamimidoylphenyl)amino]- ethoxyjimino) acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00577] Ή NMR (400 MHz, DMSO-c¾: δ = 1.36 (d, / = 6.2 Hz, 3 H), 3.45 (t, / = 4.8 Hz, 2 H), 3.66 (dd, / = 6.2 and 2.3 Hz, 1 H), 4.20 (t, / = 5.0 Hz, 2 H), 4.45 (dd, / = 8.0 and 2.5 Hz, 1 H), 6.66 - 6.86 (m, 3 H), 7.65 (d, / = 8.9 Hz, 2 H), 8.28 (br. s, 2 H), 8.77 (s, 2 H), 9.27 (d, / = 7.8 Hz, 1 H).
[00578] MS (ES+) m/z: [M+H]+ calcd for
Figure imgf000196_0002
511.12. Found: 510.96.
[00579] HPLC: 95.40 %
Example 9
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)eth- oxy] imino} acetyl] amino}-2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00580] l NMR (400 MHz, DMSO-rf6): δ = 1.33 (d, / = 6.3 Hz, 3 H), 3.64 (dd, / = 6.1 and 2.7 Hz, 2 H), 4.34 (d, / = 5.3 Hz, 2 H), 4.36 - 4.49 (m, 3 H), 6.78 (s, 1 H), 7.21 (d, / = 8.8 Hz, 2 H), 7.80 (d, / = 8.8 Hz, 2 H), 8.67 (s, 2 H), 9.13 (s, 2 H), 9.31 (d, / = 9.2 Hz, 1 H).
[00581] MS (ES+) m/z: [M+H]+ calcd for C18H21N7O7S2: 512.09. Found: 512.13. [00582] HPLC: 99.00 %
Example 10 (2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4 arbamimidoylphenoxy)ethoxy]imino}-N- [(2R;3S)-2-methyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00583] Ή NMR (400 MHz; DMSO-rf6): δ = 1.11 (d, / = 6.2 Hz, 3 H), 4.20 - 4.44 (m, 5 H), 4.85 - 5.04 (m, 1 H), 6.79 (s, 1 H), 7.18 (d, / = 8.2 Hz; 3 H), 7.80 (d, / = 8.9 Hz, 2 H), 8.67 (s, 2 H), 9.15 (s, 2 H), 9.34 (d, / = 8.6 Hz, 1 H).
[00584] MS (ES+) m/z: [M+H]+ calcd for CisHzzN/OsSz: 528.10. Found: 527.90.
[00585] HPLC: 92.10 %
Example 11
(2R,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4 arbamimidoylphenoxy)eth- oxy] imino}acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00586] Ή NMR (400 MHz, DMSO-rf6): δ = 1.33 (d, / = 6.2 Hz, 3 H), 3.64 (dd, / = 6.0 and 2.1 Hz, 1 H), 4.33 (br. s, 2 H), 4.35 - 4.47 (m, 3 H), 6.76 (s, 1 H), 7.15 - 7.27 (m, 4 H), 7.80 (d, / = 8.5 Hz, 2 H), 8.65 (br. s, 2 H), 9.12 (br. s, 2 H), 9.29 (d, / = 8.2 Hz, 1 H).
[00587] MS (ES ) m/z: [M-H]" calcd for
Figure imgf000197_0001
510.09. Found: 510.02. [00588] HPLC: 95.60 % Example 12
{[(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)eth- oxy]imino}acetyl]amino}-2-methyl-4-oxoazetidin-l-yl]oxy}methanesulfonic acid
[00589] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.30 (d, / = 7.8, 1 H), 3.96 (dd, / = 6.2 and 1.9 Hz, 1 H), 4.25 - 4.35 (m, 2 H), 4.35 - 4.47 (m, 4 H), 6.76 (s, 1 H), 7.11 - 7.29 (m, 4 H), 7.82 (d, / = 8.9 Hz, 2 H), 9.03 (br. s, 4 H), 9.25 (d, / = 7.8 Hz, 1 H). [00590] MS (ES ) m/z: [M-H]" calcd for CwHzzNyOsSz: 540.10. Found: 540.10. [00591] HPLC: 98.51 % Example 13
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-3-methylphenoxy)eth oxy]imino}-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00592] Ή NMR (400 MHz, DMSO-rf6): δ - 1.23 (s, 3 H), 1.41 (s, 3 H), 2.37 (s, 3 H), 4.20 - 4.31 (m, 2 H), 4.40 (t, / = 4.3 Hz, 2 H), 4.59 (d, / = 7.8 Hz, 1 H), 6.79 (s, 1 H), 6.89 - 7.06 (m, 1 H), 7.40 (d, / = 8.6 Hz, 1 H), 8.85 (s, 2 H), 9.11 (s, 2 H), 9.48 (d, / = 7.8 Hz, 1 H).
[00593] MS (ES ) m/z: [M-H]" calcd for C2oH24N708Sz: 554.11. Found: 554.14. [00594] HPLC: 97.18 % Example 14
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-3-methylphen- oxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00595] ¾ NMR (400 MHz, DMSO-d6): δ - 1.34 (d, J = 6.2 Hz, 3 H), 2.36 (s, 3 H,) 3.60 (dd, / = 6.0 and 2.5 Hz, 1 H), 4.24 - 4.31 (m, 2 H), 4.35 - 4.40 (m, 2 H), 4.43 (dd, / = 8.2 and 2.7 Hz, 1 H), 6.75 (s, 1 H), 6.92 - 7.05 (m, 2 H), 7.21 (s, 2 H), 7.39 (d, / = 8.6 Hz, 1 H), 8.90 (br. s, 2 H), 9.09 (br. s, 2 H), 9.27 (d, / = 8.2 Hz, 1 H).
[00596] MS (ES ) m/z: [M-H]' calcd for C19H22N7O7S2: 524.10. Found: 524.06.
[00597] HPLC: 96.56 % Example 15
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(2-carbamimidoylpyridin-4-yl)oxy]ethoxy}- imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00598] ¾ NMR (400MHz, DMSO-d6): 5 = 1.22 (s, 3H), 1.40 (s, 3H), 4.36 - 4.44 (m, 4H), 4.57 (d, J = 2.3 Hz, 1H), 6.76 (s, 1H), 7.19 (s, 2H), 7.36 (m, 1H), 7.86 (s, 1H), 8.61 (m, 1H), 9.20 - 9.40 (br. s, 2H), 9.45 (m, J = 8.2 Hz, 1H).
[00599] MS (ES+) m/z: [M+H]+ calcd for GsHaNeC^: 543.11. Found: 543.08.
[00600] HPLC: 98.52 %
Example 16
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)ethoxy]imino}-N- [2-oxo- l-(sulf ooxy)- 1 -azaspiro [3.4]oct-3-yl] ethanamide
[00601] Ή NMR (400 MHz, DMSO-c?6): δ = 1.20 - 1.60 (m, 4H), 1.70 - 1.90 (m, 3H), 2.10 - 2.20 (m, 1H), 4.30 (br. s, 2H), 4.40 (br. s, 2H), 4.65 (d, / = 8.3 Hz, 1H), 6.96 (s, 1H), 7.20 (m, 4H), 7.80 (d, / = 9.2 Hz, 2H), 8.80 (br. s, 2H), 9.10 (br. s, 2H), 9.48 (d, / = 8.3 Hz, 1H).
[00602] MS (ES+) m/z: [M+H]+ calcd for
Figure imgf000199_0001
568.13. Found: 568.17.
[00603] HPLC: 97.04 %
Example 17
(25,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)-2- methylpropoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid [00604] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.24 - 1.47 (d, 3H), 3.71 (br. s, 1H), 4.15 (s, 2H), 4.44 (br. s, 1H), 6.74 (s, 1H), 7.25 (d, / = 8.5 Hz, 2H), 7.22 (br. s, 2H), 7.77 (d, / = 8.5 Hz, 2H,) 8.96 (br. s, 1H), 9.36 (br. s, 1H).
[00605] MS (ES+) m/z: [M+H]+ calcd for C20H26N7O7S2: 540.13. Found: 540.17.
[00606] HPLC: 92.38 %
Example 18
(25,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({[l-(4-carbamimidoylphenoxy)-2- methylpropan-2-yl]oxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00607] Ή NMR (400 MHz, DMSO-i¾: δ = 1.28 - 1.46 (m, 9H), 3.66 (dd, / = 6.1 and 2.3 Hz, 1H), 4.10 (d, / = 1.9 Hz, 2H), 4.44 (dd, / = 7.9 and 2.5 Hz, 1H), 6.72 (s, 1H), 7.09 - 7.31 (m, 4H), 7.80 (d, / = 8.8 Hz, 2H), 8.65 (br. s, 2H), 8.98 - 9.20 (m, 3H).
[00608] MS (ES+) m/z: [M+H]+ calcd for C20H26N7O7S2: 540.13. Found: 540.08.
[00609] HPLC: 97.8 %
Example 19
(25,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-2-fluorophen- oxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00610] Ή NMR (400 MHz, DMSO-rf6): δ - 1.34 (d, / = 6.0 Hz, 3H), 4.27 - 4.52 (m, 4H), 6.77 (s, 1H), 7.40 - 7.54 (m, 1H), 7.78 (d, / = 2.5 Hz, 1H), 7.75 (s, 1 H), 8.80 (br. s, 2H), 9.19 (br. s, 2H), 9.31 (s, 1H).
[00611] MS (ES ) m/z: [M-H]' calcd for C18H19N7O7S2: 528.08. Found: 528.06. [00612] HPLC: 97.7 % Example 20
(25,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-2- chlorophenoxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00613] Ή NMR (400 MHz, DMSO-d6): δ = 1.35 (d, / = 5.8 Hz, 3H), 3.66 (dd, / = 6.0 and 2.5 Hz, 1H), 4.44 (s, 4H), 6.76 (s, 1H), 7.22 (s, 2H), 7.41 (d, / = 8.6 Hz, 1H), 7.69 - 7.89 (m, 1H), 7.96 (d, / = 1.9 Hz, 1H), 9.28 (d, / = 7.4 Hz, 4H).
[00614] MS (ES+) m/z: [M+H]+ calcd for C18H21CIN7O7S2: 546.06. Found: 546.15.
[00615] HPLC: 99.0 %
Example 21
(2S,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[4-(N-hydroxycarbamimidoyl)- phenoxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00616] Ή NMR (400 MHz, DMSO-tfc): δ = 1.33 (d, / = 6.0 Hz, 3H), 3.64 (m, 1H), 4.25 (m, 2H), 4.40-4.42 (m, 3H), 6.78 (s, 1H), 7.20 (d, / = 8.8 Hz, 2H), 7.40 (br. s, 2H), 7.68 (d, / = 9.2 Hz, 2H), 8.85 (br. s, 1H), 9.20 (br. s, 1H) 9.31 (d, / = 7.6 Hz, 2H), 10.97 (s, 1H).
[00617] MS (ES+) m/z: [M+H]+ calcd for
Figure imgf000201_0001
528.10. Found: 528.15. [00618] HPLC: 95.6 % Example 22
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(4-carbamimidoylpyridin-2-yl)oxy]eth- oxy}imino)-N-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide [00619] Ή NMR (400 MHz, DMSO-c¾: δ = 1.23 (s, 3H), 1.40 (s, 3H), 4.38 - 4.41 (m, 2H), 4.50 - 4.54 (m, 2H), 4.58 (d, / = 7.8 Hz, 1H), 6.75 (s, 1H), 7.20 (s, 2H), 7.22 (s, 1H), 7.32 (d, / = 5.0 Hz, 1H), 8.40 (d, / = 5.4 Hz, 1H), 9.30 (br. s, 1H), 9.45 (d, / = 8.2 Hz, 1H).
[00620] MS (ES+) ra/z: [M+H]+ calcd for GeHaNeOeSz: 543.11. Found: 542.98. [00621] HPLC: 91.72 % Example 23
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl] -2- [(2-{4- [JV- (piperidin-4-yl)carbamimidoyl] phenoxy} ethoxy)imino] ethanamide
[00622] ¾ NMR (400 MHz, DMSO-c¾: δ = 1.21 (s, 3H), 1.39 (s, 3H), 1.51 - 1.57 (m, 2H), 1.82 - 1.90 (m, 2H), 2.52 - 2.68 (m, 2H), 3.04 - 3.13 (m, 2H), 3.66 - 3.79 (m, 1H), 4.26 - 4.32 (m, 2H), 4.40 - 4.43 (m, 2H), 4.58 (d, / = 7.8 Hz, 1H), 6.77 (s, 1H), 7.16 (d, / = 8.9 Hz, 2H), 7.21 (s, 2H), 7.70 (d, / = 8.6 Hz, 2H), 9.44 (d, / = 8.2 Hz, 1H).
[00623] MS (ES ) ra/z: [M-H]" calcd for CMHSINSOSSZ: 623.17. Found: 622.94.
[00624] HPLC: 96.71 %
Example 24
(2Z)-2-[(2-{4-[N-(2-Aminoethyl)carbamimidoyl]phenoxy}ethoxy)imino]-2-(2-amino- l,3-thiazol-4-yl)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethan amide
[00625] Ή NMR (400 MHz, DMSO-rf6+TFA): δ = 1.18 (s, 3H), 1.38 (s, 3H), 2.48 (t, / = 1.7 Hz, 2H), 3.95 (s, 4H), 4.29 - 4.45 (m, 2H), 4.44 - 4.58 (m, 2H), 4.59 (d, / = 7.8 Hz, 1H), 6.96 (s, 1H), 6.97 (s, 1H), 7.08 (s, 1H), 7.14 - 7.27 (m, 4H), 7.89 (d, / = 8.9 Hz, 2H), 9.68 (d, / = 7.8 Hz, 1H), 10.27 (s, 1H). [00626] MS (ES ) m/z: [M-H]' calcd for C2iH27N808S2: 583.14. Found: 583.14
[00627] HPLC: 98.64 % Example 25
(2Z -2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[4-(4;5-dihydro-lH-imidazol-2-yl)phenoxy]- ethoxy}imino)-N-[(35)-2)2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00628] Ή NMR (400 MHz, DMSO-rf6 +TFA): δ = 1.19 (s, 3H), 1.38 (s, 3H), 3.94 (s, 4H), 4.33 - 4.43 (m, 2H), 4.47 - 4.56 (m, 2H), 4.60 (d, / = 7.8 Hz, 1H), 6.98 (s, 1H), 7.18 (d, / = 8.6 Hz, 2H), 7.89 (d, / = 8.6 Hz, 2H), 9.69 (d, / = 7.4 Hz, 1H), 10.26 (s, 1H), 12.05 - 12.49 (m, 3H).
[00629] MS (ES ) m/z: [M-H] calcd for C21H24N7O8S2: 566.11: Found: 566.16
[00630] HPLC: 98.64 %
Example 26
(25 and 2i?)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(2S,3S)-2-methyl-4-oxo-l-sulfo- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-carbamidinoyl-phenoxy)prop- anoic acid
Epimer A
[00631] NMR (400 MHz, DMSO-<26): δ - 1.29 (d, / = 6.2 Hz, 3H), 3.61 (dd, / = 5.7 and 2.8 Hz, 1H), 4.31 - 4.55 (m, 3H), 4.82 (br. s., 1H), 6.53 (s, 1H), 6.79 (s, 1H), 7.11 - 7.30 (m, 4H), 7.78 (d, / = 9.1 Hz, 2H), 8.85 (br. s., 2H), 9.08 (br. s., 2H).
[00632] MS (ES ) m/z: [M-H]" calcd for G9H20N7O9S2: 554.08. Found: 554.20.
[00633] HPLC: 99.59 % (RT: 11.050 min). Epimer B
[00634] Ή NMR (400 MHz, DMSO-rf6): δ = 1.33 (d, / = 6.2 Hz, 3H), 3.75 (br. s., 1H), 4.33 - 4.58 (m, 3H), 4.85 (br. s., 1H), 6.51 (s, 1H), 6.82 (s, 1H), 7.15 - 7.29 (m, 4H), 7.78 (d, / = 9.1 Hz, 2H), 8.75 - 8.91 (m, 2H), 9.09 (s, 2H).
[00635] MS (ES ) m/z: [M-H]- calcd for C.9H20N7O9S2: 554.08. Found: 554.20.
[00636] HPLC: 98.82 % (RT: 11.168 min).
Example 27
(25 and 2¾-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l- (sulfooxy)azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4- carbamimidoylphenoxy)propanoic acid
Epimer A
[00637] Ή NMR (400 MHz, DMSO-rf6): δ = 1.10 (s, 3H) 1.40 (s, 3H), 4.40 (m, 2H), 4.60 (d, / = 6.6 Hz, 1H), 5.0 (m, 1H), 6.80 (s, 1H), 7.17 (d, / = 8.8 Hz, 2H), 7.24 (br. s, 2H), 7.80 (d, / = 8.8 Hz, 2H), 8.60 (s, 2H), 9.27 (s, 2H), 9.40 (d, / = 6.6 Hz, 1H). 19 F NMR: - 74.
[00638] MS (ES ) m/z: [M-H]- calcd for C20H22N7O10S2: 584.09. Found: 584.08. [00639] HPLC: 97.15 %. Epimer B
[00640] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.24 (s, 3H) 1.420 (s, 3H), 4.45 (m, 2H), 4.60 (d, / = 6.6 Hz, 1H), 5.0 (m, 1H), 6.80 (s, 1H), 7.20 (d, / = 8.8 Hz, 2H), 7.24 (br. s, 2H), 7.80 (d, / = 8.8 Hz, 2H), 8.64 (s, 2H), 9.18 (s, 2H), 9.40 (d, / = 6.6 Hz, 1H). 19 F NMR: - 74.
[00641] MS (ES ) m/z: [M-H]" calcd for C20H22N7O10S2: 584.09. Found: 584.08. [00642] HPLC: 97.08 %. Example 28
(25,35)-3-{[(2Z)-2-(2-Amino-l,3 hiazol-4-yl)-2-({2-[(6-carbamimidoylpyridazin-3- yl)oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00643] Ή NMR (400 MHz, DMSO-c¾: δ = 1.35 (d, / = 6.2 Hz, 3H), 3.62 (dd, / = 6.3 and 2.8 Hz, 1H), 4.42 (dd, / = 7.9 and 2.6 Hz, 1H), 4.48 (t, / = 4.4 Hz, 2H), 4.69 - 4.85 (m, 2H), 6.76 (s, 1H), 7.22 (s, 2H), 7.64 (d, / = 9.4 Hz, 1H), 8.31 (d, / = 9.4 Hz, 1H), 9.26 (d, / = 7.9 Hz, 1H).
[00644] MS (ES ) m/z: [M-H]- calcd for GeHigNgCvSz: 512.51. Found: 512.08.
[00645] HPLC: 92.31 %.
Example 29
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(6-carbamimidoylpyridazin-3-yl)oxy]- ethoxy}imino)-]V-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00646] ¾ NMR (400 MHz, DMSO-c¾: δ = 1.24 (s, 3H), 1.40 (s, 3H), 4.45 - 4.52 (m, 2H), 4.56 (d, / = 7.6 Hz, 1H), 4.68 - 4.84 (m, 2H), 6.79 (s, 1H), 7.62 (d, / = 9.4 Hz, 1H), 8.31 (d, / = 9.4 Hz, 1H), 9.23 (br. s., 2H), 9.46 (br. s, 1H), 9.69 (br. s, 2H).
[00647] MS (ES ) m/z: [M-H]- calcd for GyHzoNgOsSz: 542.54. Found: 542.13.
[00648] HPLC: 91.40 %.
Example 30
(25,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(5-carbamimidoylpyrazin-2- yl)oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid [00649] ¾ NMR (400 MHz, DMSO-cie): δ = 1.36 (d, / = 6.2 Hz, 3H), 3.64 (dd, / = 6.3 and 2.5 Hz, 1H), 4.32 - 4.54 (m, 3H), 4.60 - 4.77 (m, 2H), 6.80 (s, 1H), 8.58 (d, / = 1.2 Hz, 1H), 9.01 (d, / = 1.2 Hz, 1H), 9.11 (s, 2H), 9.31 (d, / = 7.9 Hz, 1H), 9.47 (s, 2H).
[00650] MS (ES ) m/z: [M-H]" calcd for GeHisNgC Sz: 512.51. Found: 512.20. [00651] HPLC: 95.45 %. Example 31
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(4-carbamimidoyl-l,3-thm yl)oxy]ethoxy}immo)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00652] ¾ NMR (400 MHz, DMSO-rfe): δ = 1.37 (d, / = 6.2 Hz, 3H), 3.58 - 3.72 (m, 1H), 4.36 - 4.55 (m, 3H), 4.64 - 4.76 (m, 2H), 6.79 (s, 1 H), 8.26 (s, 1H), 8.91 (s, 2H), 9.14 (s, 2H), 9.33 (d, / = 7.9 Hz, 1H).
[00653] MS (ES ) m/z [M-H]- calcd for GsHi/NsO/Ss: 517.55. Found: 517.23.
[00654] HPLC: 98.78 %.
Example 32
(25,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-(2-[(4-carbamimidoylthiophen-2- yl)methoxy] imino)acetyl] amino}-2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00655] Ή NMR (400 MHz, DMSO-rf6): δ = 1.38 (d, / = 6.2 Hz, 3 H), 3.68 (dd, / = 6.2 and 2.6 Hz, 1H), 4.42 (dd, / = 7.9 and 2.6 Hz, 1H), 5.29 (s, 2H), 6.79 (s, 1H), 7.23 (s, 2H), 7.61 (s, 1H), 8.49 (d, / = 1.5 Hz, 1H), 8.66 (s, 2H), 9.17 (s, 2H), 9.34 (d, / = 7.6 Hz, 1H).
[00656] MS (ES+) m/z: [M+H]+ calcd for GsHigNzOeSs: 488.54. Found: 488.00. [00657] HPLC: 95.07 %.
Example 33
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(6-carbamimidoyl-5-hydroxypyridin-3- yl)oxy]ethoxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]ethanamide
[00658] Ή NMR (400 MHz, DMSO-c/6): δ = 1.23 (s, 3H), 1.40 (s, 3H), 4.34 (t, / = 4.4 Hz, 2H), 4.44 (t, / = 4.1 Hz, 2H), 4.60 (d, / = 8.2 Hz, 1H), 6.79 (s, 1 H), 6.97 (d, / = 2.6 Hz, 1H), 8.04 (d, / = 2.3 Hz, 1H), 8.61 (s, 2H), 8.84 (s, 2H), 9.45 (d, / = 7.9 Hz, 1H).
[00659] MS (ES ) m/z: [M-H]- calcd for QgHziNgOgSz: 557.55. Found: 557.08. [00660] HPLC: 94.21 %. Example 34
(25 and 2ii)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l- (sulf ooxy)azetidin-3-yl] amino}-2-oxoethylidene] amino} oxy)-3 - (4-carbamimidoyl-3 - hydroxyphenoxy)propanoic acid
Epimer A
[00661] Ή NMR (400 MHz, DMSO-c¾: δ = 1.19 (s, 3H), 1.41 (s, 3H), 4.30 - 4.40 (m, 2H), 4.60 (d, / = 8.4 Hz, 1H), 4.95 (m, 1H), 6.51 (s, 1H), 6.60 (m, 1H), 6.80 (s, 1H), 7.25 (br s, 2H), 7.57 (d, / = 9.2 Hz, 1H), 8.48 (s, 2H), 8.82 (s, 2H), 9.40 (d, / = 8.4 Hz, 1H), 11.29 (s, 1H). 19 F NMR: - 74 ppm.
[00662] MS (ES ) m/z [M-H]" calcd for C20H22N7O11S2: 600.08. Found: 600.06.
[00663] HPLC: 91.6 %. Epimer B
[00664] ¾ NMR (400 MHz, DMSO-d6): δ = 1.24 (s, 3H) 1.420 (s, 3H), 4.45 (m, 2H), 4.60 (d, / = 6.6 Hz, 1H), 5.0 (m, 1H), 6.80 (s, 1H), 7.20 (d, / = 8.8 Hz, 2H), 7.24 (br s, 2H), 7.80 (d, / = 8.8 Hz, 2H), 8.64 (s, 2H), 9.18 (s, 2H), 9.40 (d, / = 6.6 Hz, 1H). 19F NMR: - 74 ppm.
[00665] MS (ES ) m/z: [M-H]" calcd for C20H22N7O11S2: 600.08. Found: 600.06. [00666] HPLC: 95.4 %. Example 35
(2S,35)-3-{[(2Z)-2-{[2-(2-Amino-4-carbamimidoylphenoxy)ethoxy]imino}-2-(2-amino- 1 , 3-thiazol-4-yl) acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00667] Ή NMR(400 MHz, DMSO-i¾: δ = 1.32 (d, / = 6.4 Hz, 3H), 3.52 - 3.69 (m, 1H), 4.25 - 4.35 (m, 2H), 4.37 - 4.50 (m, 3H), 6.79 (s, 1H), 6.92 - 7.12 (m, 3H), 8.56 (s, 2H), 8.99 (s, 2H), 9.32 (d, / = 7.3 Hz, 1H).
[00668] MS (ES ) m/z: [M-H]" calcd for C18H21N8O7S2: 525.55. Found: 525.16.
[00669] HPLC: 98.17 %.
Example 36
(25 and 2JR)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l- (sulfooxy)azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-[(6-carbamimidoyl- pyridin-3-yl)oxy] propanoic acid
Epimer A
[00670] Ή NMR (400 MHz, DMSO-<¾): δ = 1.21 (s, 3H), 1.42 (s, 3H), 4.56 (m, 2H), 4.66 (d, / = 8.6 Hz, 1H), 4.76 - 4.98 (br, 1H), 6.54 (s, lH)s, 6.81 (s, 1H), 7.19 (s, 1H), 7.78 (dd, / = 8.8 and 2.9 Hz, 2H), 8.25 (d, / = 8.6 Hz, 1H), 8.53 (s, / = 2.3 Hz, 1H), 9.09 (br. s, 2H), 9.34 (br. s, 2H).
[00671] MS (ES ) m/z: [M-H]- calcd for Ci9H22N8OioS2: 585.10. Found: 585.15.
[00672] HPLC: 92.9 %.
Epimer B
[00673] Ή NMR (400 MHz, DMSO- ): δ = 1.28 (s, 3H), 1.42 (s, 3H), 4.35 - 4.49 (m, 1H), 4.59 (d, / = 8.2 Hz, 2H), 4.72 - 4.91 (m, 1H), 6.54 (s, 1H), 6.84 (s, 1H), 7.19 (s, 2H), 7.80 (d, / = 2.7 Hz, 1H), 8.25 (d, / = 9.0 Hz, 1H), 8.51 (d, / = 2.3 Hz, 1H), 9.13 (br. s, 2H), 9.33 (br. s, 2H).
[00674] MS (ES ) m/z: [M-H]- calcd for CwHzzNgOioSz: 585.10, Found: 585.15.
[00675] HPLC: 91.5 %.
Example 37
(25, 3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[{3-(4-carbamimidoylphenoxy)prop- oxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00676] Ή NMR (400 MHz, DMSO-c/6): δ = 1.27 (d, / = 8.20 Hz, 3H), 2.01 - 2.11 (m, 2H), 3.58 - 3.68 (m, 1H), 4.10 - 4.17 (m, 2H), 4.22 (t, / = 5.66 Hz, 2H), 4.43 (dd, / = 8.20, 2.73 Hz, 1H), 6.75 (s, 1H), 7.14 (d, / = 8.98 Hz, 2H), 7.78 (d, / = 8.59 Hz, 2H), 8.66 (br. s., 2H), 9.07 (br. s., 2H), 9.33 (d, / = 8.20 Hz, 1H).
[00677] MS (ES+) m/z: [M+H]+ calcd for G9H23N7O7S2: 525.57. Found: 526.27.
[00678] HPLC: 98.74 % Example 38
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(35)-l-hydroxy-^^
2-({2-[4-(N-{2-[(iminomethyl)amino]ethyl}carbam
ethanamide
[00679] Ή NMR (400 MHz, DMSO-rf6 + TFA): δ = 1.18 (s, 3H), 1.38 (s, 3H), 3.56 (br s, 4H), 4.340 - 4.37 (m, 2H), 4.50 - 4.52 (m, 2H), 4.60 (d, / = 7.6 Hz, 1H), 6.98 (s, 1H), 7.15 - 7.18 (m, 2H), 7.71 - 7.73 (m, 2H), 7.96 - 7.98 (m, 1H), 8.11 (s, 1H), 9.00 - 9.10 (m, 2H), 9.32 - 9.53 (m, 2H), 9.61 - 9.69 (m, 2H).
[00680] MS (ES+) m/z: [M+H]+ calcd for C22H30N9O8S2: 612.17. Found: 612.01.
[00681] HPLC: 90.08 %
Example 39
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl] -2-{ [2-(4-{N- [(3S)-pyrrolidin-3-yl] carbami
amide
[00682] Ή NMR (400 MHz, DMSO-d6): δ = 1.21 (s, 3H), 1.39 (s, 3H), 1.79 - 1.97 (m, 1H), 2.12 - 2.20 (m, 1H), 2.80 - 2.97 (m, 1H), 3.00 - 3.15 (m, 3H), 4.14 - 4.20 (m, 1H), 4.26 - 4.30 (m, 2H), 4.38 - 4.42 (m, 2H), 4.58 (d, / = 7.82 Hz, 1H), 6.77 (s, 1H), 7.14 (d, / = 9.0 Hz, 2H), 7.21 (s, 1H), 7.71 (d, / = 9.0 Hz, 2H), 9.44 (d, / = 7.8 Hz, 1H).
[00683] MS (ES+) m/z: [M-H]' calcd for CzsHzgNgOsSz: 609.16. Found: 609.00.
[00684] HPLC: 91.82 % Example 40
(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-{[2-(4-{N-[2-(dimethylamino)ethyl]carbamim yl}phenoxy)ethoxy]imino}-]V-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yljethanamide
[00685] Ή NMR (400 MHz, DMSO-rf6): δ = 1.19 (s, 3H), 1.39 (s, 3H), 2.50 (s, 6H), 3.34 - 3.53 (m, 2H), 3.68 - 3.84 (m, 2H), 4.21 - 4.37 (m, 2H), 4.37 - 4.50 (m, 2H), 4.59 (d, / = 7.8 Hz, 1H), 6.81 (s, 1H), 7.19 (d, / = 8.99 Hz, 2H), 7.53 (br. s, 1H), 7.79 (d, = 8.9 Hz, 2H), 9.10 (s, 1H), 9.48 (d, / = 7.8 Hz, 1H), 9.57 (br. s, 2H), 9.84 (br. s, 1H).
[00686] MS (ES ) m/z: [M-H]" calcd for
Figure imgf000211_0001
611.17. Found: 611.01
[00687] HPLC: 97.87 %
Example 41
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4 arbamimidoylphenoxy)ethoxy]imino}-N- [(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00688] Ή NMR (400 MHz, DMSO-rf6): δ = 1.21 (s, 3H) 1.39 (s, 3H) 4.19 - 4.50 (m, 4H) 4.59 (d, / = 7.8 Hz, 1H) 6.79 (s, 1H) 7.06 - 7.31 (m, 2H) 7.81 (d, / = 8.9 Hz, 2H) 8.67 (s, 2H) 9.14 (s, 2H) 9.47 (d, / = 7.8 Hz, 1H).
[00689] MS (ES+) m/z: [M+H]+ calcd for G9H23N7O8S2: 542.10. Found: 542.01.
[00690] HPLC: 92.4 %.
Example 42
(4S)-4-{[{4 2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2/2-dimethyl-4-oxo-l-
(sulfooxy)azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)ethoxy]phen- yl}(imino)methyl]amino}-N,N-dimethyl-L-prolinamide [00691] Ή NMR (400 MHz, DMSO-i¾: δ = 1.19 (s, 3H), 1.38 (s, 3H), 2.03- 2.10 (m, IH), 2.40-2.50 (m, IH), 2.80-3.10 (m, 2H), 2.94 (s, 3H), 3.00 (s, 3H), 4.27- 4.32 (m, 2H), 4.40-4.43 (m, 2H), 4.44-4.53 (m, lH), 4.57 (d, / = 8.2 Hz, IH), 4.65-4.75 (m, IH), 6.78 (s, IH), 7.20 (d, / = 8.2 Hz, 2H), 7.20-7.39 (m, IH), 7.73 (d, / = 8.2 Hz, 2H), 8.71-8.85 (m, IH), 9.18 (br. s, IH), 9.35-9.47 (m, 2H), 9.59 (br. s, IH), 9.89-10.01 (m, IH).
[00692] MS (ES ) ra/z: [M-H]" calcd for C26H34N9O9S2: 680.19. Found: 680.05. [00693] HPLC: 91.92 % Example 43
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]-2-{[2-(4-{N-[(35)-l-ethanimidoylpyrrolidin-3-yl]carbamimidoyl}phenoxy)ethoxy]- imino} ethanamide
[00694] ¾ NMR (400 MHz, DMSO- ): δ = 1.19 (s, 3H), 1.39 (s, 3H), 2.25 (d, / = 5.4 Hz, 3H), 3.49-3.65 (m, 2H), 3.69-3.83 (m, 3H), 3.85-3.98 (m, IH), 4.28-1.30 (m, 2H), 4.40-4.42 (m, 2H), 4.47-4.49 (m, IH), 4.57 (d, / = 8.2 Hz, IH), 6.78 (s, IH), 7.18 (d, / = 9.0 Hz, 2H), 7.24-7.40 (m, IH), 7.72 (d, / = 8.2 Hz, 2H), 8.45 (s, IH), 9.15-9.35 (m, 2H), 9.44 (d, / = 7.4 Hz, IH), 9.45-9.55 (m, IH), 9.61-9.70 (m, IH).
[00695] MS (ES+) ra/z: [M+H]+ calcd for C25H34N9O8S2: 652.20. Found: 651.92.
[00696] HPLC: 86.7 %
Example 44
(2R flnrf 25)-3-{4-[N-(2-Aminoethyl)carbamimidoyl]phenoxy}-2-({[(lZ)-l-(2-amino-l,3- thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]amino}-2-oxoeth- ylidene]amino}oxy)propanoic acid Epimer A
[00697] Ή NMR (400 MHz, DMSO-rf6): δ = 1.26 (s, 3H), 1.35 (s, 3H), 3.14 -
3.21 (m, 2H), 3.57 - 3.62 (m, 2H), 4.37 - 4.46 (m, 2H), 4.57 (d, / = 8.0 Hz, IH), 4.95 - 4.96 (m, IH), 6.51 (br. s, IH), 6.78 (s, IH), 7.18 (d, / = 8.8 Hz, 2H), 7.23 (br. s, 2H), 7.80 (d, / = 8.8 Hz, 2H), 7.87 (br. s, 3H), 8.98 (br. s, IH), 9.38 (d, / = 7.3 Hz, IH), 9.48 (br. s, 2H).
[00698] MS (ES ) m/z: [M-H]" calcd for C22H27N8OioS2: 627.13. Found: 626.99. [00699] HPLC: 97.08 % (RT: 8.435 min). Epimer B
[00700] Ή NMR (400 MHz, DMSO-c/6): δ = 1.22 (s, 3H), 1.37 (s, 3H), 3.15 -
3.22 (m, 2H), 3.57 - 3.62 (m, 2H), 4.42 - 4.44 (m, 2H), 4.56 (d, / = 7.6 Hz, IH), 4.95 - 4.99 (m, IH), 6.50 (br. s, IH), 6.80 (s, IH), 7.18 - 7.22 (m, 4H), 7.80 (d, / = 8.8 Hz, 2H), 7.84 (br. s, 3H), 8.98 (br. s, IH), 9.35 (d, / = 7.3 Hz, IH), 9.43-9.47 (br. s, 2H).
[00701] MS (ES ) m/z: [M-H]" calcd for
Figure imgf000213_0001
627.13. Found: 626.99.
[00702] HPLC: 97.02 % (RT: 8.793 min).
Example 5
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({[(2i? and 2S)-l-(4-carbamimidoylphenoxy)-3- hydroxypropan-2-yl]oxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yljethanamide
Epimer A
[00703] Ή NMR (400 MHz, DMSO-i6): δ = 1.20 (s, 3H), 1.40 (s, 3H), 3.59 - 3.77 (m, 2H), 4.21 - 4.29 (m, 2H), 4.38 - 4.44 (m, IH), 4.56 (d, / = 7.6 Hz, IH), 6.78 (s, IH), 7.18 (d, / = 8.8 Hz, 2H), 7.81 (d, / = 9.1 Hz, 2H), 8.66 (s, 2H), 9.14 (s, 2H), 9.37 (d, / = 7.6 Hz, IH). [00704] MS (ES ) m/z: [M-H]" calcd for C20H24N7O9S2: 570.11. Found: 570.08. [00705] HPLC: 87.39 % (RT: 2.210 min). Epimer B
[00706] Ή NMR (400 MHz, DMSO-i¾: δ = 1.21 (s, 3H), 1.36 (s, 3H), 3.65 - 3.72 (m, 2H), 4.15 - 4.22 (m, 1H), 4.24 - 4.30 (m, 1H), 4.38 - 4.44 (m, 1H), 4.56 (d, / = 7.6 Hz, 1H), 6.78 (s, 1H), 7.16 (d, / = 9.1 Hz, 2H), 7.79 (d, / = 9.1 Hz, 2H), 8.64 (s, 2H), 9.12 (s, 2H), 9.34 (d, / = 7.6 Hz, 1H).
[00707] MS (ES ) m/z: [M-H]" calcd for C20H24N7O9S2: 570.11. Found: 570.08.
[00708] HPLC: 92.48 % (RT: 2.317 min).
Example 46
3-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-4-(4-carbamimidoylphen- oxy)butanoic acid
[00709] Ή NMR (400 MHz, DMSO-rf6): δ = 1.24 (d, 3H), 1.40 (s, 3H), 2.65 - 2.76 (m, 2H), 4.26 (d, / = 5.5 Hz, 2H), 4.57 (dd, / = 7.6 and 3.7 Hz, 1H,) 4.77 (br. s, 1H), 6.79 (s, 1H), 7.18 (dd, / = 9.0 and 3.1 Hz, 2H), 7.23 - 7.32 (br. s, 2H), 7.81 (d, / = 7.4 Hz, 2H), 8.70 (br. s, 2H), 9.13 (s, 2H), 9.36 (m, 1H).
[00710] MS (ES+) m/z: [M+H]+ calcd for C2iH25N;OioS2: 600.11. Found: 599.98.
[00711] HPLC: 95.2 %.
Example 47
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)ethoxy]imino}-N- [(2S,35)-2-methyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide [00712] lH NMR (400 MHz, DMSO-rf6): δ = 1.32 (d, / = 6.2 Hz, 3H), 3.90 (m, 1H), 4.28 - 4.48 (m, 2H), 4.40 - 4.48 (m, 3H), 6.78 (s, 1H), 7.28 - 7.32 (m, 3H), 7.80 (d, / = 8.9 Hz, 2H), 8.67 (s, 2H), 9.15 (s, 2H), 9.44 (d, / = 8.6 Hz, 1H).
[00713] MS (ES+) m/z: [M+H]+ calcd for C18H22N7O8S2: 528.10. Found: 528.10
[00714] HPLC: 92.75 %.
Example 48
(2«,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[3-(4-carbamimidoylphenoxy)prop- oxy] imino} acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00715] Ή NMR (400 MHz, DMSO-rf6): δ = 1.30 (d, / = 6.2 Hz, 3H), 2.08 (m, 2H), 3.17 - 4.25 (m, 5H), 4.44 (dd, / = 2.4 and 7.8 Hz, 1H), 6.77 (s, 1H), 7.11 (d, / = 9.0 Hz, 2H), 7.80 (d, / = 9.0 Hz, 2H), 8.68 (s, 2H), 9.09 (s, 2H), 9.35 (d, / = 8.2 Hz, 1H).
[00716] MS (ES+) m/z: [M+H]+ calcd for G9H24N7O7S2: 526.12. Found: 526.08.
[00717] HPLC: 94.79 %.
Example 49
(25,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(2-bromo-4-carbamimidoyl- phenoxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00718] ¾ NMR (400 MHz, DMSO-i?6): δ = 1.36 (d, / = 6.2 Hz, 3H), 3.67 (dd, / = 2.7 and 5.8 Hz, 1H), 4.36 - 4.52 (m, 5H), 6.79 (s, 1H), 7.37 (d, / = 8.9 Hz, 1H), 7.86 (d, / = 1.9 Hz, 1H), 8.10 (d, / = 2.3 Hz, 1H), 8.80 (br. s., 2H), 9.20 (br. s, 2H), 9.30 (br. s, 1H).
[00719] MS (ES ) m/z: [M-H]" calcd for Gs^oBr^CvSz: 590.00; found: 589.88. [00720] HPLC: 93.93 %. Example 50
(25;3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidamidophenoxy)eth- oxy] imino} acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00721] Ή NMR (400 MHz, OMSO-d6): δ = 1.35 (d, / = 6.4 Hz, 2H), 3.64 (m, 1H), 4.24 (m, 2H), 4.42 (m, 2H), 4.44 (m, 1H), 6.80 (s, 1H), 7.03 (d, / = 8.4 Hz, 2H), 7.17 (s, 6H), 9.34 (s, 1H), 9.36 (s, 1H).
[00722] MS (ES+) m/z: [M+H]+ calcd for GsHzzNgC Sz: 527.10. Found: 527.02.
[00723] HPLC: 93.93 %.
Example 51
(2S,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[3-(4-carbamimidamidophenoxy)- propoxy] iminojacetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00724] ¾ NMR (400 MHz, DMSO-c¾: δ = 1.35 (d, / = 6.0 Hz, 2H,), 2.07 (m, 2H), 3.65 (m, 1H), 4.06 (t, / = 6.0 Hz, 2H), 4.23 (t, / = 6.0 Hz, 2H), 4.50 (m, 1H), 6.78 (s, 1H), 7.01 (d, / = 8.8 Hz, 2H), 7.16 (br. s, 6H), 9.33 (s, 1H), 9.36 (d, / =8.8 Hz, 1H).
[00725] MS (ES+) m/z: [M+H]+ calcd for G9H24N8O7S2: 541.12. Found: 541.01.
[00726] HPLC: 95.00 %.
Example 52
(2Z)-2-(5-Amino-l,2,4-thiadiazol-3-yl)-2-{[2-(4-carbamimidoylphenoxy)ethoxy]- imino}-N-[(2S,3S)-l-hydroxy-2-methyl-4-oxoazetidin-3-yl]ethanamide [00727] Ή NMR (400 MHz, DMSO- ): δ = 1.32 (d, / = 6.0 Hz, 3H), 3.57 (m, 2H), 4.34 (m, 2H), 4.40 (dd, / = 2.4 and 7.6 Hz, 2H), 4.49 (m, 2H), 7.21 (d, / = 8.8 Hz, 2H), 7.80 (d, / = 8.8 Hz, 2H), 8.16 (s, 2H), 8.67 (s, 2H), 9.13 (s, 2H), 9.33 (s, 2H).
[00728] MS (ES+) m/z: [M+H]+ calcd for G7H20N8O7S2: 512.09. Found: 512.85.
[00729] HPLC: 91.20 %.
Example 53
(25,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(3-carbamimidoylphenoxy)eth- oxy] iminojacetyi] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00730] ¾ NMR (400 MHz, DMSO-d6): δ = 1.33 (d, / = 6.0 Hz, 3H), 3.66 (qd, / = 2.5 and 6.0 Hz, 1H), 4.26 - 4.36 (m, 2H), 4.36 - 4.51 (m, 3H), 6.82 (s, 1H), 7.30 - 7.41 (m, 3H), 7.51 (t, / = 8.0 Hz, 1H), 8.94 (br. s, 2H), 9.25 (br. s, 2H), 9.37 (d, / = 7.9 Hz, 1H).
[00731] MS (ES ) m/z: [M-H]- calcd for C18H21N7O7S2: 512.09. Found: 511.97. [00732] HPLC: 90.81 %. Example 54
(25,35)-3-({(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[(2-{4-[N-(propan-2-yl)carbamimido- yl]phenoxy}ethoxy)imino]acetyl}amino)-2-methyl-4-oxoazetidine-l-sulfonic acid
[00733] Ή NMR (400 MHz, DMSO-rf6): δ = 1.23 (d, / = 6.4 Hz, 6H), 1.31 (d, / = 6.4 Hz, 3H), 3.6 (m, 1H), 3.9 (m, 1H), 4.29 (d, / = 4.0 Hz, 2H), 4.39 (m, 3H), 6.73 (s, 1H), 7.17 (m, 4H), 7.65 (d, / = 8.8 Hz, 2H), 8.68 (s, 2H), 9.06 (br. s, 1H), 9.26 (d, / = 8.0 Hz, 1H).
[00734] MS (ES ) m/z: [M-H]" calcd for C2iH26N707S2: 552.13. Found: 551.90. [00735] HPLC: 94.27 %. Example 55
(25;3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[(4-carbamimidoylbenzyl)oxy]imino}- acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00736] ¾ NMR (400 MHz, DMSO-d6): δ = 1.38 (d, / = 6.4 Hz, 3H), 3.65 (dd, / = 2.5 and 6.0 Ηζ,ΙΗ), 4.45 (dd, / = 2.9 and 7.9 Ηζ,ΙΗ), 5.26 (s, 1H), 6.78 (s, 1H), 7.28 (br. s, 2H), 7.59 (d, / = 8.5 Hz, 2H), 7.79 (d, / = 8.5 Hz, 2H), 8.86 (s, 2H), 9.24 (s, 1H), 9.44 (d, / = 7.9 Hz, 1H).
[00737] MS (ES+) ra/z: [M+H]+ calcd for G7H20N7O6S2: 482.09. Found: 481.93.
[00738] HPLC: 96.47 %.
Example 56
(25,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(4-carbamimidoylthiophen-2- yl)methoxy] ethoxy}imino)acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00739] Ή NMR (400 MHz, DMSO-d6): δ = 1.36 (d, 3H), 3.61 - 3.80 (m, 3H), 4.16 - 4.28 (m, 2H), 4.41 (dd, / = 7.9, 2.6 Hz, 1H), 4.71 (s, 2H), 6.72 (s, 1 H), 7.20 (s, 2H), 7.55 (s, 1H), 8.45 (d, / = 1.5 Hz, 1H), 8.70 (br. s, 2H), 9.10 (br. s, 2H), 9.28 (d, / = 7.6 Hz, 1H).
[00740] MS (ES ) m/z: [M-H]" calcd for G7H20N7O7S3: 530.59. Found: 530.07. [00741] HPLC: 97.62 %. Example 57
(2Z)-2-(2-Amino- 1 ,3-thiazol-4-yl)-2-{ [(4-carbamimidoylbenzyl)oxy] imino}-N- [(3S)-2,2- dimethyl-4-oxo- 1 -(sulf ooxy) azetidin-3-yl] ethanamide [00742] Ή NMR (400 MHz, DMSO-c/6): δ = 1.22 (s, 3H), 1.43 (s, 3H), 4.60 - 4.66 (m, 1H), 5.25 (s, 2H), 6.75 (s, 1H), 7.20 (s, 2H), 7.59 (d, / = 8.6 Hz, 2H), 7.78 (d, / = 8.6 Hz, 2H), 8.22 (s, 1H), 9.07 - 9.17 (m, 2H), 9.19 - 9.27 (m, 1H), 9.59 (d, / = 7.9 Hz, 1H).
[00743] MS (ES ) m/z: [M-H]" calcd for C18H20N7O7S2: 510.08. Found: 510.16. [00744] HPLC: 99.75 %. Example 58
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[3-(4 arbamimidoylphenoxy)propoxy]imino}-N- [(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00745] Ή NMR (400 MHz, DMSO-</6): δ = 1.23 (s, 3H), 1.39 (s, 3H), 2.03 - 2.13 (m, 2H), 4.17 (t, / = 8.0 Hz, 2H), 4.23 (t, / = 8.0 Hz, 2H), 4.60 (d, / = 7.9 Hz, 1H), 6.76 (s, 1H), 7.16 (d, / = 9.2 Hz, 2H), 7.81 (d, / = 8.9 Hz, 2H), 8.67 (s, 2 H), 9.12 (s, 2H), 9.49 (d, / = 7.9 Hz, 1H).
[00746] MS (ES+) m/z: [M+H]+ calcd for CzoHzsN/OsSz: 556.12. Found: 556.14.
[00747] HPLC: 98.10 %.
Example 59
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[4-carbamimidoyl-2-(hydroxymethyl) phenoxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00748] ¾ NMR (400 MHz, METHANOL-^): δ = 1.45 (d, / = 8.0 Hz , 2H), 3.82 (dd, / = 2.7 and 6.1 Hz, 1H), 4.39 - 4.49 (m, 1H), 4.50 - 4.62 (m, 2H), 4.66 - 4.81 (m, 2H), 6.85 (s, 1H), 7.19 (d, / = 8.5 Hz, 1H), 7.74 (dd, / = 2.3 and 8.7 Hz, 1H), 7.85 (d, / = 1.9 Hz, 1H). [00749] MS (ES-) m/z: [M-H]~ calcd for C19H23N708S2: 540.1. Found: 540.1.
[00750] HPLC: 86.90 %. Example 60
(2S,3S)-3-({(2Z)-2-(2-Amino-l,3-to
methyl]phenoxy}ethoxy)imino]acetyl}amino)-2-methyl-4-oxoazetidine-l-sulfoni acid
[00751] Ή NMR (400 MHz, DMSO-rf6): δ = 1.33 (d, / = 6.2 Hz, 3H), 3.62 (dd, / = 2.5 and 6.0 Hz, 1H), 4.27 - 4.50 (m, 3H), 5.23 (s, 2H), 6.75 (s, 2H), 7.21 (s, OH), 7.31 (d, / = 8.9 Hz, 1H), 7.65 - 7.93 (m, 3H), 8.27 - 8.43 (m, 2H), 9.11 (br. s, 1H), 9.28 (d, 2H).
[00752] MS (ES ) m/z: [M-H]" calcd for C20H22N7O9S2: 568.09. Found: 568.09. [00753] HPLC: 86.60 %. Example 61
(25,35)-3-{[(2Z)-2-(2-Amino-5-chloro-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphen- oxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00754] Ή NMR (400 MHz, DMSO-t 6): δ = 1.31 (d, / = 6.3 Hz, 3H), 3.60 (m, 1H), 4.38 (m, 2H), 4.40 (m, 1H), 4.42 (m, 2H), 7.21 (d, / = 8.9 Hz, 2 H), 7.80 (d, / = 9.2 Hz, 2H), 8.66 (s, 2H), 9.12 (s, 2H), 9.30 (d, / = 8.4 Hz, 1H).
[00755] MS (ES ) m/z: [M-H]" calcd for C18H20CIN7O7S2: 544.05. Found: 544.14.
[00756] HPLC: 97.10 %.
Example 62 (25;35)-3-{[(2Z -2-({2-[4-(2-Amino-2-iminoethyl)phenoxy]ethoxy}imino)-2-(2-am
1 , 3 -thiazol-4-yl)acetyl] amino}-2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00757] Ή NMR (400 MHz, DMSO-d6): δ = 1.23 - 1.46 (m, 3H), 2.49 (br. s., 1H), , 3.56 - 3.75 (m, 2H), 4.09 - 4.27 (m, 2H), 4.27 - 4.52 (m, 2H), 6.56 - 6.83 (m, 1H), 6.86 - 7.04 (m, 2H), 7.17 - 7.43 (m, 3H), 8.32 - 8.53 (m, 2H), 8.82 - 9.10 (m, 2H), 9.26 (s, 1 H).
[00758] MS (ES+) m/z: [M+H]+ calcd for C19H24N7O7S2: 526.12. Found: 526.13. [00759] HPLC: 95.50 %. Example 63
(2S,35)-3-({(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[(2-{4-[(2-formylhydrazinyl)(imino)- methyl]phenoxy}ethoxy)imino]acetyl}amino)-2-methyl-4-oxoazetidine-l-sulfonic acid
[00760] Ή NMR (400 MHz, DMSO-c¾: δ = 1.34 (d, / = 6.2 Hz, 3H), 3.44 (br. s., 2H), 3.61 - 3.73 (m, 1H), 4.30 - 4.38 (m, 2H), 4.38 - 4.48 (m, 3H), 6.78 (s, 1H), 7.25 (d, / = 8.9 Hz, 2H), 7.78 (d, / = 8.9 Hz, 2H), 8.23 (s, 1H), 9.32 (d, / = 7.8 Hz, 1H), 9.41 (br. s, 1H), 9.80 (br. s, 1H), 10.73 (s, 1H).
[00761] MS (ES+) m/z: [M+H]+ calcd for CwHaNsC^: 555.56. Found: 555.23.
[00762] HPLC: 92.05 %.
Example 64
(2S,3S)-3-({(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[(2-{4-[hydrazinyl(imino)methyl]phen- oxy } ethoxy)imino] acetyl} amino)-2-methyl-4-oxoazetidine- 1 -sulfonic acid [00763] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.40 (d, / = 6.2 Hz, 3H), 3.58 - 3.71 (m, 1H), 4.26 - 4.36 (m, 2H), 4.35 - 4.51 (m, 3H), 5.13 - 5.31 (m, 1H), 6.73 (s, 1H), 7.28 (br. s, 2H), 7.69 (d, 2H), 7.78 (d, / = 8.9 Hz, 2H), 8.72 (br. s, 1H), 9.26 (br. s, 2H), 10.75 (br. s, 1H).
[00764] MS (ES-) ra/z: [M-H]" calcd for
Figure imgf000222_0001
525.54. Found: 525.31. [00765] HPLC: 96.80 %. Example 65
(25,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(5-carbamimidoyl-l,3,4-thiadiazol- 2-yl) oxy] ethoxy}imino)acetyl] amino}-2-methyl-4-oxoazetidine- 1 -sulfonic acid
[00766] Ή NMR (400 MHz, DMSO- ): δ = 1.39 (d, /=6.25 Hz, 3H), 3.64 (dd, / = 6.1 and 2.5 Hz, 1H), 4.38 - 4.52 (m, 3H), 4.81 (d, / = 4.7 Hz, 2H), 6.78 (s, 1H), 9.29 (d, / = 8.2 Hz, 1H), 9.42 (s, 2H), 9.78 (s, 2H).
[00767] MS (ES ) m/z: [M+H]" calcd for Ci4Hi7N907S3: 518.04. Found: 518.17.
[00768] HPLC: 94.0 %.
Example 66
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)- ethoxy]imino}acetyl]amino}-2-carbamoyl-4-oxoazetidine-l-sulfonic acid
[00769] ¾ NMR (400 MHz, DMSO-c¾: δ = 4.35 (m, 4H), 5.26 - 5.43 (m, 1H), 6.97 (s, 1H), 7.19 - 7.24 (m, 2H), 7.85 (m, 2H), 8.55 - 8.82 (m, 2H), 9.05 - 9.33 (m, 2H).
[00770] MS (ES+) m/z: [M+H]+ calcd for
Figure imgf000222_0002
541.09. Found: 541.23. [00771] HPLC: 91.2 %. Example 67
(25,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2 {2-[(3-carbamimidoyl-l,2-oxazol-5- yl)oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00772] Ή NMR (400 MHz, DMSO-d6): δ = 1.38 (d, / = 6.2 Hz, 3H), 3.67 (d, / = 2.3 Hz, 1H), 4.32 - 4.51 (m, 5H), 6.76 (s, 1H), 6.87 (s, 1H), 7.23 (s, 3H), 8.32 (s, 2H), 9.31 (d, / = 8.2 Hz, 1H).
[00773] MS (ES+) m/z: [M+H]+ calcd for GsHisNsOsSz: 503.06. Found: 503.20.
[00774] HPLC: 91.9 %.
Example 68
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[4-(N-methylcarbamimidoyl)- phenoxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00775] Ή NMR (400 MHz, DMSO-rf6): δ = 1.33 (d, / = 6.2 Hz, 3H), 2.97 (s, 3H), 3.61 - 3.67 (m, 1H), 4.29 - 4.35 (m, 2H), 4.38 - 4.42 (m, 2H), 4.43 (d, / = 2.7 Hz, 1H), 6.75 (s, 1H), 7.20 (d, / = 8.9 Hz, 2H), 7.21 (s, 2H), 7.72 (d, / = 8.9 Hz, 2H), 8.41 - 8.47 (ra, 1H), 9.28 (d, / = 8.2 Hz, 1H).
[00776] MS (ES ) m/z: [M-H]" calcd for G9H22N7O7S2: 524.55. Found: 524.25.
[00777] HPLC: 97.51 %.
Example 69
(2S,3S)-3-({(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[(2-{4-[N-(2-hydroxyethyl)carbami- midoyl]phenoxy}ethoxy)imino]acetyl}amino)-2-methyl-4-oxoazetidine-l-sulfonic acid [00778] ¾ NMR (400 MHz, DMSO- ): δ = 1.32 (d, / = 6.2 Hz, 3H), 3.42 - 3.48 (m, 2H), 3.56 - 3.71 (m, 2H), 4.22 - 4.36 (m, 3H), 4.36 - 4.51 (m, 4H), 6.74 (s, 1H), 7.11 - 7.26 (m, 4H), 7.71 (d, / = 8.6 Hz, 2H), 8.30 (s, 1H), 9.27 (d, / = 7.8 Hz, 1H).
[00779] MS (ES ) m/z: [M-H]" calcd for C20H24N7O8S2: 554.58. Found: 554.26.
[00780] HPLC: 97.00 %.
Example 70
(2S,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2- amimidoyl}phenoxy)ethoxy]imino}acetyl]am
acid
[00781] ¾ NMR (400 MHz, DMSO-<¾: δ = 1.31 (d, / = 6.2 Hz, 3H), 3.40 - 3.42 (m, 2H), 3.58 - 3.71 (m, 2H), 4.26 - 4.36 (m, 4H), 4.36 - 4.44 (m, 3H), 6.74 (s, 1H), 7.15 - 7.24 (m, 4H), 7.68 (d, / = 8.9 Hz, 2H), 8.26 (s, 1H), 8.31 (s, 1H), 9.27 (d, / = 7.8 Hz, 1H).
[00782] MS (ES ) m/z: [M-H]" calcd for C21H24N7O9S2: 582.59. Found: 582.27. [00783] HPLC: 91.79 %. Example 71
(2S,35)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(3-carbamimidoyl-l-methyl-lH- pyrazol-5-yl)oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00784] NMR (400 MHz, DMSO-rf6): δ = 1.37 (d, / = 5.8 Hz, 3H), 3.65 - 3.68 (m, IH), 3.71 (s, 3H), 4.30 - 4.37 (m, 2H), 4.41 (m, 3H), 6.50 (s, 1H), 6.76 (s, 1H), 7.21 (s, IH), 8.36 (br. s., IH), 9.34 (d, / = 8.0 Hz , IH). [00785] MS (ES+) m/z: [M+H]+ calcd for
Figure imgf000225_0001
516.10. Found: 516.10.
[00786] HPLC: 96.30 %.
Example 72
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl^
pyrazol-3-yl)oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
[00787] Ή NMR (400 MHz, DMSO-rf6): δ = 1.35 (d, / = 6.2 Hz, 3H), 3.53 - 3.72 (m, 1H), 3.80 (s, 3H), 4.34 (d, / = 5.5 Hz, 4H), 4.38 - 4.51 (m, 1H), 6.32 (s, 1H), 6.75 (s, 1H), 7.21 (br. s., 2H), 8.17 (s, 1H), 9.27 (d, / = 8.0 Hz , 1H).
[00788] MS (ES ) m/z [M-H]- calcd for Ci6H21N907S2: 514.10, Found: 514.16.
[00789] HPLC: 97.70 %.
Example 73
N-[{4-[2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfo- oxy)azetidin-3-yl] amino} -2-oxoethylidene] amino}oxy)ethoxy] phenyl} (imino)- methyljglycine
[00790] lH NMR (400 MHz, DMSO-rf6): δ = 1.22 (s, 3H), 1.38 (s, 3H), 2.31 (dt, / = 1.9 and 3.6 Hz, 1H), 2.61 - 2.68 (m, 2H), 4.24 - 4.31 (m, 2H), 4.35 - 4.41 (m, 2H), 6.58 (s, 2H), 6.75 (s, 1H), 7.14 (d, / = 8.9 Hz, 2H), 7.19 (s, 2H), 7.71 (d, / = 8.9 Hz, 2H), 8.42 (br. s., 1H), 9.43 (d, / = 8.2 Hz, 1H).
[00791] MS (ES ) m/z: [M-H]- calcd for C21H24N7O10S2: 598.59, Found: 598.12.
[00792] HPLC: 84.19 %. Example 74
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(2 arbam
yl)oxy]ethoxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]eth- anamide
[00793] 1H NMR (400 MHz, DMSO-d6): δ = 1.22 (s, 3H), 1.40 (s, 3H), 2.34 (s, 3H), 4.38 (d, / = 4.7 Hz, 2H), 4.54 (q, / = 4.4 Hz, 2H), 4.57 (d, / = 7.8 Hz, 1H), 6.74 (s, 1H), 7.19 (s, 2H), 8.17 (s, 1H), 9.45 (d, / = 7.8 Hz, 1H).
[00794] MS (ES+) m/z: [M+H]+ calcd for CiyHzzNgOsSs: 563.07. Found: 563.09.
[00795] HPLC: 98.60 %.
Example 75
2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azet- idin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-carbamimidoylphenoxy)prop- anamide
[00796] Ή NMR (400 MHz, DMSO-rf6): δ = 1.15 (s, 3H), 1.34(s, 3H), 4.33 - 4.47 (m, 1H), 4.56 - 4.66 (m, 2H), 4.80 - 4.91 (m, 1H), 6.82 (s, 1H), 7.12 - 7.23 (m, 2H), 7.74 - 7.90 (m, 2H), 8.74 (s, 1H), 9.20 (s, 1H), 9.70 (s, 1H).
[00797] MS (ES ) m/z: ΓΜ-Η]- calcd for CaoHzsNsOgSz: 583.10. Found: 582.90.
[00798] HPLC: 75.70 %.
Example 76
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]-2-[(2-{4-[N-(pyridin-2-ylmethyl)carbamimidoyl]phenoxy}ethoxy)imino]eth- anamide [00799] Ή NMR (400 MHz, DMSO-d6): δ - 1.22 (s, 3H), 1.40 (s, 3H), 4.29 (br. s., 2H), 4.41 (d, / = 4.6 Hz, 2H), 4.59 (d, / = 8.2 Hz, 1H), 4.74 (s, 2H), 6.77 (s, 1H), 7.11 - 7.25 (m, 4H), 7.36 (d, / = 4.6 Hz, 1H), 7.47 (d, / = 7.8 Hz, 1H), 7.71 - 7.92 (m, 3H), 8.38 (s, 1H), 8.58 (d, / = 3.9 Hz, 1H), 9.45 (d, / = 7.8 Hz, 1H).
[00800] MS (ES ) m/z: [M-H]" calcd for CzsHzyNsOsSz: 631.66. Found: 631.06.
[00801] HPLC: 95.66 %.
Example 77
{ [(25,35)-3-{[(2Z)-2- [(2-{4- [N-(2-Aminoethyl)carbamimidoyl] phenoxy} ethoxy)imino] - 2-(2-amino- 1 ,3-thiazol-4-yl)acetyl]amino}-2-methyl-4-oxoazetidin- 1 - yl]oxy}methanesulfonic acid
[00802] Ή NMR (400 MHz, DMSO-d6): δ = 1.37 (d, / = 5.8 Hz, 3H), 3.17 - 3.31 (m, 2H), 3.64 - 3.76 (m, 2H), 3.96 - 4.06 (m, 1H), 4.33 - 4.53 (m, 6 H), 4.60 (d, / = 4.6 Hz, 1H), 7.10 (s, 1H), 7.17 (s, 1H), 7.26 (d, / = 8.6 Hz, 2H), 7.82 - 7.92 (m, 2H), 8.00 (br. s, 2H), 9.08 (br. s, 1H), 9.46 - 9.64 (m, 3H).
[00803] MS (ES ) m/z: [M-H]" calcd for
Figure imgf000227_0001
583.14. Found: 582.75.
[00804] HPLC: 87.53 %.
Example 78
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[(2-{4-[N-(2 arbamimidamidoethyl)carbami- midoyl]phenoxy}ethoxy)imino]-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]ethanamide
[00805] Ή NMR (400 MHz, DMSO-rf6): δ = 1.19 (s, 3H), 1.39 (s, 3H), 3.35 - 3.41 (m, 2H), 3.47 - 3.53 (m, 4H), 4.25 - 4.35 (m, 2H), 4.36 - 4.46 (m, 2H), 4.58 (d, / = 7.8 Hz, 1H), 6.78 (s, 1H), 7.18 (d, / = 8.9 Hz, 2H), 7.25 (br. s, 2H), 7.71 - 7.77 (m, 3H), 8.96 (s, 1H), 9.41 (br. s, 1H), 9.44 (d, / = 7.8 Hz, 1H), 9.57 (t, / = 5.0 Hz, 1H).
[00806] MS (ES+) m/z: [M+H]+ calcd for C22H31N10O8S2: 627.18. Found: 626.92.
[00807] HPLC: 91.16 %.
Example 79
l-(2-{[{4-[2-({[(lZ)-l 2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l-(sulfo- oxy)azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)ethoxy]phenyl}(imino)-meth- yl]amino}ethyl)-l-methylpyrrolidinium chloride
[00808] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.17 (s, 3H), 1.38 (s, 3H), 2.13 (br. s, 4H), 3.49 - 3.56 (m, 2H), 3.59 - 3.63 (m, 2H), 3.67 - 3.71 (m, 2H), 3.87 - 3.89 (m, 2H), 4.31 - 4.33 (m, 2H), 4.41 - 4.43 (m, 2H), 4.57 (d, / = 8.0 Hz, 1H), 6.78 (s, 1H), 7.21 (d, / = 8.8 Hz, 2H), 7.26 (br.s, 2H), 7.73 (d, / = 8.8 Hz, 2H), 9.14 (br. s, 1H), 9.43 (d, / = 7.6 Hz, 1H), 9.60 - 9.63 (m, 2H).
[00809] MS (ES+) m/z: M+ calcd for CzeHszNgOgSz: 653.22. Found: 653.05.
[00810] HPLC: 96.65 %.
Example 80
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl] -2- [(2-{4- [imino(piperazin- 1 -yl)methyl] phenoxy} ethoxy)imino] ethan amide
[00811] ¾ NMR (400 MHz, DMSO-d6): δ = 1.16 (s, 3H), 1.38 (s, 3H), 3.26 (br. s., 2H), 3.59 (br. s., 2H), 3.88 (br. s., 2H), 4.30 (br. s., 2H), 4.42 (d, / = 4.6 Hz, 2H), 4.57 (d, / = 7.8 Hz, 1H), 6.77 (s, 1H), 7.19 (d, / = 8.9 Hz, 2H), 7.24 (s, 1H), 7.26 - 7.33 (m, 1H), 7.60 (d, / = 8.5 Hz, 2H), 9.09 (br. s., 2H), 9.32 (br. s., 1H), 9.44 (d, / = 7.8 Hz, 1H), 9.64 (s, 1H). [00812] MS (ES ) m/z: [M-H]" calcd for CaH^NeOeSa: 609.15. Found: 609.13. [00813] HPLC: 89.11 %. Example 81
(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-({[l-(4-carbamimidoylphenoxy)-4-hydroxybutan- 2-yl]oxy}imino)-N-[(35)-2,2-dirnethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
Epimer A
[00814] Ή NMR (400 MHz, DMSO-i 6): δ = 1.27 (s, 3H), 1.41 (s, 3H), 1.84 (m, 1H), 1.91 (m, 1H), 3.54 (m, 2H), 4.21 (m, 2H), 4.55 (m, 1H), 4.58 (d, / = 8.0 Hz, 1H), 6.74 (s, 1H), 7.14 (, / = 8.8 Hz, 2H), 7.21 (s, 2H), 7.79 (d, / = 8.8 Hz, 2H), 8.46 (br. s, 4H), 9.42 (d, / = 7.2 Hz, 1H).
[00815] MS (ES ) m/z [M-H]" calcd for C21H27N7O9S2: 584.13. Found: 584.01.
[00816] HPLC: 95.20 %.
Epimer B
[00817] Ή NMR (400 MHz, DMSO-c 6): δ = 1.23 (s, 3H), 1.42 (s, 3H), 1.86 (m, 1H), 2.51 (m, 1H), 3.54 (m, 2H), 4.22 (m, 2H), 4.55 (m, 1H), 4.60 (d, / = 8.8 Hz, 1H), 6.74 (s, 1H), 7.14 (, / = 8.8 Hz, 2H), 7.221 (s, 2H), 7.79 (d, / = 8.8 Hz, 2H), 8.49 (br. s, 4H), 9.38 (d, / = 7.2 Hz, 1H).
[00818] MS (ES ) m/z: [M-H]" calcd for C21H27N7O9S2: 584.13. Found: 584.01.
[00819] HPLC: 92.70 %. Example 82
(2Z)-2-{[2-({6-[N-(2-Aminoethyl)carbamimidoyl]pyridin-3-yl}oxy)ethoxy]imino}-2-(2- amino-l;3-thiazol-4-yl)-N-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethan- amide
[00820] Ή NMR (400 MHz, DMSO-c 6): 5 = 3.15 (dd, / = 4.1 and 10.4 Hz, 2H), 3.69 (dd, / = 5.9 and 12.1 Hz, 2H), 4.41 - 4.45 (m, 4H), 4.58 (d, / = 7.8 Hz, 1H), 6.78 (s, 1H), 7.20 - 7.26 (m, 2H), 7.76 - 7.86 (m, 4H), 8.25 (d, / = 9.0 Hz, 1H), 8.51 (d, / = 2.7 Hz, 1H), 9.25 (br. s, 1H), 9.43 (d, / = 7.8 Hz, 1H), 9.72 (br. s, 1 H), 9.80 (s, 1H).
[00821] MS (ES+) m/z: [M+H]+ calcd. for CzoHzsNgOgSz: 586.15. Found: 586.14.
[00822] HPLC: 94.78 %.
Example 83
(2Z)-2 (2-{4-[N-(3-Aminopropyl)carbamimidoyl]phenoxy}ethoxy)imino]-2-(2-amino- l,3-thiazol-4-yl)-N-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
[00823] ¾ NMR (400 MHz, DMSC 6): δ = 1.20 (s, 3H), 1.39 (s, 3H), 1.81 - 1.98 (m, 2H), 2.80 - 3.00 (m, 2H), 3.41 - 3.48 (m, 2H), 4.24 - 4.36 (m, 2H), 4.37 - 4.47 (m, 2H), 4.58 (d, / = 7.8 Hz, 1H), 6.78 (s, 1H), 7.02 (s, 1H), 7.18 (d, / = 8.9 Hz, 2H), 7.27 (s, 1H), 7.73 (d, / = 8.9 Hz, 2H), 7.76 - 7.89 (m, 2H), 8.92 (br. s., 1H), 9.37 (br. s., 1H), 9.46 (d, / = 7.8 Hz, 1H), 9.59 (br. s., 1H).
[00824] MS (ES+) m/z: [M+H]+ calcd for CzzHaiNgOgSz: 599.17. Found: 599.23.
[00825] HPLC: 90.78 %.
Example 84 (2Z)-2-(2-Amino-l/3-thiazol-4-yl)-2-[(2-{4-[N-(l,3-diaminopropan-2-yl)carbamimid oyl]phenoxy}ethoxy)imino]-N-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]eth- anamide
[00826] Ή NMR (400 MHz, DMSO- ): δ = 1.17 (s, 3H), 1.39 (s, 3H), 3.10 - 3.32 (m, 4H), 3.57 - 3.64 (m, 4H), 4.25 - 4.37 (m, 2H), 4.37 - 4.47 (m, 2H), 4.58 (d, / = 7.8 Hz, 1H), 6.79 (s, 1H), 7.22 (d, / = 8.9 Hz, 2H), 7.23 - 7.33 (m, 1H), 7.89 (d, / = 8.9 Hz, 2H), 8.09 (br. s, 2H), 9.03 (br. s, 1H), 9.32 (d, / = 7.0 Hz, 1H), 9.44 (d, / = 7.8 Hz, 1H), 9.76 (br. s, 1H).
[00827] MS (ES ) m/z: [M-H]" calcd for C22H30N9O8S2: 612.17. Found: 612.20.
[00828] HPLC: 90.51 %.
Example 85
(2Z)-2-{[2-(4-{N-[(2ii)-l-Amino-3-hydroxypropan-2-yl]carbamirnidoyl}pherioxy)eth- oxy]imino}-2-(2-amino-l,3-thiazol-4-yl)-N-[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]ethanamide
[00829] Ή NMR (400 MHz, DMSO-i6): δ = 1.22 (s, 3H), 1.42 (s, 3H), 3.20 (m, 2H), 4.10 (m, 1H), 4.30 (m, 2H), 4.40 (m, 2H), 4.60 (d, / = 8.8 Hz, 1H), 6.80 (s, 1H), 7.20 (d, / = 8.8 Hz, 2H), 7.22 (s, 2H), 7.79 (d, / = 8.8 Hz, 2H), 8.00 (br. s., 3H), 9.00 (s, 1H), 9.38 (d, / = 7.2 Hz, 1H), 9.50 (m, 2H).
[00830] MS (ES ) m/z: [M-H]' calcd for C22H29N809S2: 613.15. Found: 613.10.
[00831] HPLC: 92.70 %.
Example 86 (2Z)-2-({2-[4-(5-Amino-l;4,5;6-tetrahydropyrimidin-2-yl)phenoxy]ethoxy}imin
(2-amino-l;3-thiazol-4-yl)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]eth- anamide
[00832] Ή NMR (400 MHz, DMSO-rf6): δ = 1.16 (s, 3H), 1.38 (s, 3H), 3.50- 3.57 (m, 2H), 3.72-3.79 (m, 2H), 3.98-4.04 (m, 1H), 4.28-4.32 (m, 2H), 4.41-4.45 (m, 2H), 4.57 (d, / = 7.8 Hz, 1H), 6.79 (s, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.22-7.44 (m, 1H), 7.70 (d, 7 = 8.6 Hz, 2H), 8.22-8.42 (br. m, 3H), 9.44 (d, J = 7.8 Hz, 1H), 10.00 (br. s, 2H).
[00833] MS (ES-) m/z: [M-H]" calcd for
Figure imgf000232_0001
595.14. Found: 595.09. [00834] HPLC: 93.67 %. Example 87
3-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azet- idin-3-yl]amino}-2-oxoethylidene]amino}oxy)-2-(4-carbamimidoylphenoxy)prop- anoic acid
Epimer A
[00835] Ή NMR (400 MHz, DMSO-rf6): δ = 1 .20 (s, 3H), 1.37 (s, 3H), 4.4 - 4.5 (m, 2H), 4.57 (d, J = 8.0 Hz, 1H), 5.02 (m, 1H), 6.76 (s, 1H), 7.05 (d, J = 9.0 Hz, 2H), 7.2 (s, 2H), 7.8 (d, 7 = 9.0 Hz, 2H), 8.9 (s, 2H), 9.1 (s, 2H), 9.43 (d, J = 8.0 Hz, 1H).
[00836] MS (ES+) m/z: [M+H]+ calcd for C20H23N7O10S2: 584.09. Found: 584.13.
[00837] HPLC: 87.90 %.
Epimer B
[00838] Ή NMR (400 MHz, DMSO-c¾: δ = 1.20 (s, 3H), 1.39 (s, 3H), 4.37 - 4.52 (m, 2H), 4.56 (d, J = 8.2 Hz, 1H), 4.90 - 5.09 (m, 1H), 6.76 (s, 1H), 7.06 (d, J = 9.0 Hz, 2H), 7.22 (s, 2H), 7.75 (d, / = 9.0 Hz, 2H), 8.87 (s, 2H), 9.08 (s, 2H), 9.47 (d, / = 7.2 Hz, 1H).
[00839] MS (ES ) m/z: [M-H]- calcd for C20H23N7O10S2: 584.09. Found: 584.13. [00840] HPLC: 91.10 %. Example 88
(25)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[(3J?)-piperidin-3-yl]carb- amimidoyl}phenoxy)propanoic acid
[00841] ¾ NMR (400 MHz, DMSO-</6): δ = 1.24 (s, 3H), 1.44 (s, 3H), 1.64 - 1.76 (m, 2H), 1.90 - 2.04 (m, 2H), 2.84 - 2.98 (m, 2H), 3.06 - 3.16 (m, 1H), 3.86 (br. s, 1H), 4.19 (d, /=10.55 Hz, 1H), 4.35 - 4.46 (m, 1H), 4.69 - 4.77 (m, 2H), 6.84 (s, 1H), 7.08 (d, /=8.99 Hz, 2H), 7.19 (br. s, 2H), 7.61 (d, 7=8.60 Hz, 2H), 8.17 (s, 2H), 8.97 (br. s, 1H), 9.24 - 9.82 (m, 3H), 10.59 (br. s, 1H).
[00842] MS (ES ) m/z: [M-H]' calcd CzsHszNsOioSz: 668.17. Found: 667.05.
[00843] HPLC: 98.6 %
Example 89
(2ii)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dirnethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[(3^)-piperidin-3-yl]carb- amimidoyl}phenoxy)propanoic acid
[00844] Ή NMR (400 MHz, OM O-de): δ = 1.22 (s, 3H), 1.40 (s, 3H), 1.52 (s, 3H), 1.69 (br. s, 2H), 1.71 - 1.83 (m, 2H), 1.83 - 2.00 (m, 2H), 2.74 - 2.88 (m, 2H), 2.87 - 3.03 (m, 2H), 3.81 - 3.95 (m, 2H), 3.95 - 4.08 (m, 1H) 4.18 - 4.36 (m, 1H), 4.67 (d, 7=8.59 Hz, 2H), 6.82 (s, 1H), 7.09 (d, 7=8.98 Hz, 2H), 7.16 (br. s, 1H), 7.71 (d, 7=8.98 Hz, 2H), 8.14 (s, 1H).
[00845] MS (ES-) ra/z: [M-H]" calcd C25H32N8O10S2: 668.17. Found: 667.05.
[00846] HPLC: 98.0 %
Example 90
{[(35)-3-{[(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-{[(4-carbamimidoylbenzyl)oxy]- imino}acetyl]amino}-2,2-dimethyl-4-oxoazetidin-l-yl]oxy}methanesulfonic acid
[00847] Ή NMR (400 MHz, DMSO-c¾: δ = 1.16 (s, 3H), 1.41 (s, 3H), 4.22 - 4.32 (m, 3H), 4.37 - 4.43 (m, 3H), 4.54 (d, J = 7.6 Hz, 1H), 6.79 (s, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 8.66 (br. s, 2H), 9.13 (br. s, 2H), 9.39 (d, J = 7.6 Hz, 1H).
[00848] MS (ES+) m/z: [M+H]+ calcd for C20H26N7O8S2: 556.13. Found: 556.06. [00849] HPLC: 98.76 %. Example 91
(2Z)-2-[(2-{4-[5-(Aminomethyl)-4,5-dihydro-lH-imidazol-2-yl]phenoxy}ethoxy)- imino]-2-(2-amino-l,3-thiazol-4-yl)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-
3-yl]ethanamide
[00850] Ή NMR (400 MHz, DMSO-d6): δ = 1.16 (s, 3H), 1.37 (s, 3H), 3.16 (t, J = 5.0 Hz, 2H), 3.44 (br. s, 2H), 3.87 (dd, 7 = 7.2 and 11.5 Hz, 1H), 4.13 (t, J = 11.7 Hz, 1H), 4.29 - 4.36 (m, 2H), 4.39 - 4.45 (m, 2H), 4.57 (d, J = 7.8 Hz, 1H), 6.78 (s, 1H), 7.26 (d, 7 = 8.9 Hz, 2H), 7.91 (d, J = 9.3 Hz, 2H), 8.03 (br. s, 2H), 9.43 (d, J = 8.2 Hz, 1H), 10.37 (br. s, 1H), 10.55 (br. s, 1H). [00851] MS (ES ) m/z: [M-H]" calcd for CzzHzyNgOgSz: 595.14. Found: 595.22. [00852] HPLC: 93.28 %. Example 92
(35)-3-({(2Z)-2-(2-Amino-l/3-thiazol-4-yl)-2-[(2-{4 N-(pyrazolidin-4-yl)carbamimid- oyl]phenoxy}ethoxy)imino]acetyl}amino)-2,2-dimethyl-4-oxoazetidine-l-sulfonic acid
[00853] NMR (400 MHz, DMSO-rf6): δ = 1.17 (s, 3H), 1.36 (s, 3H), 3.00- 3.80 (4H, masked by H20), 4.26-4.48 (m, 5H), 4.56 (d, / = 7.4 Hz, 1H), 6.77 (s, 1H), 7.12 (d, / = 8.0 Hz, 2H), 7.64 (d, / = 8.0 Hz, 2H), 9.03 (d, / = 2.3 Hz, 1H), 9.34 - 9.45 (m, 3H).
[00854] MS (ES ) m/z: [M-H]- calcd for CzzHzgNgOsSz: 610.16. Found: 610.19. [00855] HPLC: 90.14 %. Example 93
(2S)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l- sulfoazetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{iV-[(35)-pyrrolidin-3- yl]carbamimidoyl}phenoxy)propanoic acid
[00856] lU NMR (400 MHz, DMSO-d6): δ = 1.08 (s, 3H), 1.37 (s, 3H), 2.08 - 2.36 (m, 2H), 3.17 - 3.62 (m, 4H), 4.35 - 4.48 (m, 3H), 4.60 (d, / = 7.8 Hz, 1H), 4.88 - 5.04 (m, 1H), 6.81 (s, 1H), 7.20 (d, / = 8.9 Hz, 2H), 7.35 (br. s, 1H), 7.76 (d, / = 8.9 Hz, 2H), 8.82 - 9.10 (m, 1H), 9.15 (br. s, 1H), 9.45 (d, / = 8.2 Hz, 1H), 9.57 (br. s, 2H).
[00857] MS (ES ) m/z: [M-H]- calcd. for C24H30N8O10S2: 653.15. Found: 652.99.
[00858] HPLC: 94.26 %. Example 94
(25)-3-{4-[N-(2-Amino-2-methylpropyl)carbamimidoyl]phenoxy}-2-({[(lZ)-l-(2-ami- no-l;3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]amino}-2- oxoethylidene]amino}oxy)propanoic acid
[00859] Ή NMR (400 MHz, DMSO-c¾: δ = 1.09 (s, 3H), 1.33 (s, 6H), 1.37 (s, 3H), 3.58 (d, / = 6.3 Hz, 2H), 4.37-4.42 (m, 1H), 4.44-4.50 (m, 1H), 4.60 (d, / = 7.8 Hz, 1H), 4.95-5.01 (m, 1H), 6.82 (s, 1H), 7.21 (d, / = 9.0 Hz, 2H), 7.39 (br. s, 1H), 7.85 (d, / = 9.0 Hz, 2H), 8.00 (br. s, 2H), 9.09 (br. s, 1H), 9.46 (d, / = 7.8 Hz, 1H), 9.55 (br. s, 1H), 9.61 (br. s, 1H).
[00860] MS (ES ) m/z: [M-H]" calcd for C24H3iN8OioS2: 655.16. Found: 654.93.
[00861] HPLC: 94.85 %.
Example 95
(2S)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[2-(methylamino)ethyl]- carbamimidoyl}phenoxy)propanoic acid
[00862] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.20 (s, 3H), 1.40 (s, 3H), 2.35 (s, 1H), 3.65-3.75 (m, 3H), 3.60-3.80 (m, 2H), 4.30 - 4.50 (m, 2H), 4.60 (d, / = 7.8 Hz, 1H), 4.95-5.00 (m, 1H), 6.80 (s, 1H), 7.18 (d, / = 8.9 Hz, 2H), 7.27 (br. s, 2H), 7.80 (d, / = 8.9 Hz, 2H), 8.45 (br. s, 2H), 9.05 (br. s, 1H), 9.40-9.60 (m, 3H).
[00863] MS (ES+) m/z: [M+H]+ calcd for C23H31N8O10S2: 643.16. Found: 643.02.
[00864] HPLC: 95.18 %.
Example 96 (25)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2;2-dimethyl-4-oxo-l- sulfoazetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[(3^)-pyrrolidin-3- yl]carbamimidoyl}phenoxy)propanoic acid
[00865] Ή NMR (400 MHz, DMSO-rf6): δ = 1.24 (s, 3H), 1.43 (s, 3H), 2.17 (m, 1H), 2.23 - 2.34 (m, 1H), 3.19 - 3.27 (m, 2H), 3.54 (d, / = 1.6 Hz, 2H), 4.05 (d, / = 11.6 Hz , 1H), 4.20 - 4.29 (m, 1H), 4.48 (br. s, 1H), 4.66 (d, / = 7.8 Hz, 1H), 4.71 (dd, / = 2.0 and 8.6 Hz, 1H), 6.84 (s, 1H), 7.07 (d, / = 8.6 Hz, 2H), 7.19 (br. s, 2H), 7.76 (d, / = 9.0 Hz, 2H), 10.51 (br. s, 1H).
[00866] MS (ES ) m/z: [M-H]" calcd for C24H3oN8OioS2: 653.15. Found: 653.02.
[00867] HPLC: 97.20 %.
Example 97
(2S)-2-({ [(1Z)- 1 -(2-Amino- 1 ,3-thiazol-4-yl)-2-{ [(35)-2,2-dimethyl-4-oxo- 1 -(sulfo- oxy)azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(piperidin-3-yl)carb- amimidoyl]phenoxy}propanoic acid
[00868] Ή NMR (400 MHz, DMSO-rf6): δ = 1.08 (s, 3H), 1.36 (s, 3H), 1.53 - 2.11 (m, 4H), 2.77 - 3.54 (m, 4H), 3.94 (br. s, 1H), 4.41 - 4.57 (m, 2H), 4.62 (dd, / = 1.5 and 7.8 Hz, 1H), 5.08 (d, / = 1.9 Hz, 1H), 6.93 - 7.26 (m, 3H), 7.71 (br. s, 2H), 8.02 (d, / = 16.7 Hz, 1H), 8.56 (br. s, 1H), 8.84 (br. s, 1H), 9.13 (br. s, 1 H), 9.33 - 9.57 (m, 2H), 9.57 - 9.76 (m, 1H).
[00869] MS (ES ) m/z: [M-H]- calcd for CzsHsiNeOioSz: 667.16. Found: 667.02.
[00870] HPLC: 96.60 %. Example 98
(2S)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2;2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(pyrrolidin-2-ylmethyl)- carbamimidoyl]phenoxy} propanoic acid
[00871] Ή NMR (400 MHz, DMSO-c¾: δ = 1.24 (d, 3H), 1.43 (s, 3H), 1.52 - 1.67 (m, 1H), 1.77 - 1.98 (m; 2H), 2.05 - 2.17 (m, 1H), 3.08 - 3.25 (m, 2H), 3.46 - 3.76 (m, 2H), 3.77 - 3.90 (m, 1H), 4.17 (m, 1H), 4.26 - 4.39 (m, 1H), 4.64 - 4.75 (m, 2H), 6.82 - 6.87 (m; 1H), 7.05 (d, / = 8.7 Hz, 1H), 7.11 (d, / = 8.4 Hz, 1H), 7.20 (br. s, 2H), 7.26 - 7.26 (m, 1H), 7.72 - 7.80 (m, 2H).
[00872] MS (ES ) ra/z: [M-H]" calcd for CzsHsiNsOioS 667.16. Found: 667.02.
[00873] HPLC: 89.04 %.
Example 99
(2S)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(piperidin-2-ylmethyl)carb- amimidoyl]phenoxy}propanoic acid
[00874] Ή NMR (400 MHz, DMSO-c¾: δ = 1.08 (s, 3H), 1.37 (s, 3H), 1.36- 1.62 (m, 3H), 1.62-1.81 (m, 2H), 1.90-2.00 (m, 1H), 2.85-3.00 (m, 1H), 3.30-3.42 (m, 2H), 3.42-3.61 (m, 2H), 4.38-4.49 (m, 2H), 4.60 (d, / = 7.8 Hz, 1H), 4.96-5.00 (m, 1H), 6.81 (s, 1H), 7.21 (d, / = 8.6 Hz, 2H), 7.21-7.40 (br. s, 2H), 7.83 (d, / = 9.0 Hz, 2H), 8.40-8.60 (br. s, 2H), 9.05 (br. s, 1H), 9.41 (d, / = 7.8 Hz, 1H), 9.56 (br. s, 2H).
[00875] MS (ES+) m/z: [M+H]+ calcd for C26H33N8O10S2: 681.18. Found: 681.05.
[00876] HPLC: 96.45 %.
Example 100 (2S)-3-{4-[ -(ir «5-2-Aminocyclopropyl)carbamimidoyl]phenoxy}-2-({[(lZ)-l-(2-ami- no-1 -thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]amino}-2- oxoethylidene] amino} oxy)propanoic acid
Anti Epimer A
[00877] ¾ NMR (400 MHz, DMSO-rf6): δ = 1.07 (s, 3H), 1.37 (s, 3H), 1.37-
1.42 (m, 2H), 2.90-3.07 (m, 1H), 3.08-3.17 (m, 1H), 4.35-4.42 (m, 1H), 4.42-4.49 (m, 1H), 4.59 (d, / = 7.8 Hz, 1H), 4.96-5.00 (m, 1H), 6.83 (s, 1H), 7.19 (d, / = 8.9 Hz, 2H), 7.73 (d, / = 9.0 Hz, 2H), 8.29 (br. s, 3H), 9.04 (br. s, 1H), 9.45 (d, / = 7.8 Hz, 1H), 9.67 (br. s, 1H), 9.78 (br. s, 1H).
[00878] MS (ES+) m/z: [M+H]+ calcd for C23H27N8OioS2: 639.13. Found: 639.08.
[00879] HPLC: 96.02 %.
Anti Epimer B
[00880] Ή NMR (400 MHz, DMSO-d6): δ = 1.23 (s, 3H), 1.39 (s, 3H), 1.37-
1.43 (m, 2H), 2.90-3.07 (m, 1H), 3.08-3.17 (m, 1H), 4.43-4.48 (m, 2H), 4.58 (d, / = 7.4 Hz, 1H), 4.97-5.02 (m, 1H), 6.84 (s, 1H), 7.19 (d, / = 8.9 Hz, 2H), 7.73 (d, / = 9.0 Hz, 2H), 8.31 (br. s, 3H), 9.05 (br. s, 1H), 9.43 (d, / = 7.8 Hz, 1H), 9.68 (br. s, 1H), 9.79 (br. s, 1H).
[00881] MS (ES+) m/z: [M+H]+ calcd for C23H27N8O10S2: 639.13. Found: 639.01. [00882] HPLC: 93.77 %. Example 101
2S 2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l- sulfoazetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[(3S)-l- methylpyrrolidin-3-yl]carbamimidoyl}phenoxy)propanoic acid [00883] Ή NMR (400 MHz, DMSO-rf6): δ = 1.07 (s, 3H), 1.36 (s, 3H), 2.16 - 2.33 (m, IH), 2.65 (br. s, IH), 2.90 (br. s, 3H), 3.39 (br. s, 6H), 3.75 (br. s, IH), 4.30 - 4.54 (m, 3H), 4.58 (d, / = 7.8 Hz, IH), 4.96 (t, / = 3.7 Hz, IH), 6.78 (s, IH), 7.18 (d, / = 8.6 Hz, 2H), 7.23 (br. s, 2H), 7.75 (d, / = 7.8 Hz, 2H), 9.12 (br. s, IH), 9.38 (d, / = 7.4 Hz, IH), 9.55 (br. s, IH).
[00884] MS (ES ) m/z: [M-H]" calcd
Figure imgf000240_0001
667.17. Found: 666.99.
[00885] HPLC: 97.10 %.
Example 102
(25)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[iV-(l,3-diaminopropan-2- yl)carbamimidoyl]phenoxy}propanoic acid
[00886] Ή NMR (400 MHz, DMSO- ): δ = 1.04 (s, 3H), 1.37 (s, 3H), 2.29 - 2.36 (m, IH), 2.64 - 2.71 (m, IH), 3.08 - 3.29 (m, 4H), 4.22 - 4.35 (m, IH), 4.35 - 4.54 (m, 2H), 4.60 (d, / = 7.8 Hz, IH), 4.93 - 5.02 (m, IH), 6.55 (s, IH), 6.81 (s, IH), 7.24 (d, / = 7.8 Hz, 2H), 7.28 (br. s, IH), 7.90 (d, / = 8.9 Hz, 2H), 8.01 (br. s, 2H), 8.86 - 9.10 (m, IH), 9.32 (d, / = 9.7 Hz, IH), 9.42 (d, / = 7.4 Hz, IH), 9.71 - 9.82 (m, IH).
[00887] MS (ES+) m/z: [M+H]+ calcd for C23H32N9O10S2: 658.17. Found: 657.94.
[00888] HPLC: 81.08 %.
Example 103
(2«)-2^{[(lZ)-l 2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl] amino} -2-oxoethylidene] amino}oxy)-3- {4- [N- ( 1 , 3-diaminopropan-2- yl)carbamimidoyl]phenoxy}propanoic acid [00889] Ή NMR (400 MHz, DMSO-d6): δ = 1.23 (s, 3H), 1.39 (s, 3 H), 2.25 - 2.39 (m, 3Η), 2.64 - 2.73 (m, 2Η), 3.56 - 3.79 (m, 2H), 4.47 (br. s, 3Η), 4.59 (d, / = 7.4 Hz, IH), 4.98 (br. s, IH), 6.58 (br. s, 2H), 6.82 (s, IH), 7.24 (d, / = 8.5 Hz, IH), 7.28 (br. s, IH), 7.80 (d, / = 8.5 Hz, IH), 7.97 (br. s, 2H), 8.20 (br. s, IH), 8.93 - 9.18 (m, IH), 9.42 (br. s, IH), 9.69 (br. s, IH).
[00890] MS (ES ) m/z: [M-H]' calcd for C23H30N9O10S2: 656.16. Found: 656.06.
[00891] HPLC: 83.70 %.
Example 104
(25)-2-({[(lZ -l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(lH-imidazol-2-ylmeth- yl)carbamimidoyl]phenoxy}propanoic acid
[00892] Ή NMR (400 MHz, DMSO-rf6): δ = 1.28 (s, 3H), 1.38 (s, 3H), 4.39 - 4.42 (m, 2H), 4.49 - 4.55 (m, 4H), 6.58 (s, IH), 6.81 (s, IH), 7.05 (s, 2H), 7.18 (s, 2H), 7.22 (d, / = 8.8 Hz, 2H), 7.76 (d, / = 8.8 Hz, 2H), 8.18 (br. s, IH).
[00893] MS (ES ) m/z: [M-H]" calcd for CwHaeNgOioSz: 664.12. Found: 663.95.
[00894] HPLC: 92.00 %.
Example 105
(2^)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[ -(lH-imidazol-2-ylmeth- y l)carbamimidoyl] phenoxy} propanoic acid
[00895] Ή NMR (400 MHz, DMSO-rf6): δ = 1.25 (s, 3H), 1.36 (s, 3H), 4.18 (m, IH), 4.45 - 4.65 (m, 5H), 6.62 (br. s, IH), 6.85 (s, IH), 7.05 (br. s, 2H), 7.18 (s, 2H), 7.22 (d, / = 8.8 Hz, 2H), 7.78 (d, / = 8.8 Hz, 2H), 8.18 (br. s, IH). [00896] MS (ES ) m/z: [M-H]" calcd for C24H26N9O10S2: 664.12. Found: 664.01. [00897] HPLC: 80.60 %. Example 106
(2S)-3-{4-[N-(4-Aminopyrrolidin-3-yl)carbam
l;3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]amino}-2-oxo- ethylidene] amino}oxy)propanoic acid
[00898] ¾ NMR (400 MHz, DMSO-c¾: δ = 1.03 (s, 3H), 1.38 (s, 3H), 3.00 (m, 2H), 3.65 - 3.83 (m, 1H), 4.08 - 4.22 (m, 1H), 4.38 - 4.68 (m, 4H), 5.01 (m, 1H), 6.78 (s, 1H), 7.19 - 7.38 (m, 3H), 7.80 (m, 2H), 8.40 (m, 1H), 9.38 - 9.48 (m, 1H), 9.60 (m, 1H), 9.70 (m, 1H).
[00899] MS (ES-) m/z: [M-H]- calcd for C24H30N9O10S2: 668.16. Found: 668.05. [00900] HPLC: 92.04 %. Example 107
(25)-2-({[(lZ)-l-(2-Amino-l;3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(azetidin-3-yl)carbamimid- oyl]phenoxy}propanoic acid
[00901] Ή NMR (400 MHz, DMSO-i6): δ = 1.06 (s, 3H), 1.35 (s, 3H), 4.14 - 4.33 (m, 4H), 4.35 - 4.51 (m, 2H), 4.57 (d, / = 7.8 Hz, 1H), 4.63 - 4.80 (m, 1H), 4.97 (m, 1H), 6.79 (s, 1H), 7.20 (d, / = 8.9 Hz, 2H), 7.25 (br. s, 2H), 7.76 (d, / = 8.9 Hz, 2H), 8.85 - 9.03 (br. s, 2H), 9.02 (s, 1H), 9.39 (d, / = 7.8 Hz, 1H), 9.61 (br. s, 1H), 10.11 (d, / = 7.8 Hz, 1H).
[00902] MS (ES ) m/z: [M-H]" calcd for C23H27N8O10S2: 639.13. Found: 638.92. [00903] HPLC: 95.07 %.
Example 108
(25)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2 [(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy) azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[ -(piperidin-4-yl)carb- amimidoyl]phenoxy} ropanoic acid
[00904] Ή NMR (400 MHz, DMSO-c/6): δ = 1.27 (s, 3H), 1.44 (s, 3H), 1.71 (br. s, 2H), 1.98 (br. s, 2H), 2.78 (br. s, 2H), 3.23 (br. s, 2H), 3.83 (br. s, 1H), 4.43 (m, 2H), 4.65 - 4.75 (m, 2H), 6.84 (s, 1H), 7.15 (br. s, 2H), 7.20 (d, / = 8.7 Hz, 2H), 7.70 (d, / = 8.7 Hz, 2H) .
[00905] MS (ES ) m/z: [M-H]" calcd for CzsHsiNsOioSz: 667.16. Found: 666.93. [00906] HPLC: 95.80 %. Example 109
(2S 2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(azetidin-3-yl)carb- amimidoyl]phenoxy}propanoic acid
[00907] Ή NMR (400 MHz, DMSO-rf6): δ = 1.04 (s, 3H), 1.36 (s, 4H), 2.68 (t, / = 4.6 Hz, 4H), 3.27 (d, / = 11.7 Hz, 4H), 3.77 - 4.00 (m, 3H), 4.15 (t, / = 11.7 Hz, 3H), 4.31 - 4.81 (m, 8H), 4.99 (br. s, 2H), 6.80 (s, 1H), 7.27 (d, / = 8.6 Hz, 5H), 7.92 (d, / = 8.9 Hz, 3H), 8.63 (br. s, 2H), 9.38 (d, / = 7.8 Hz, 1H), 10.37 (br. s, 1H), 10.62 (br. s, 1H).
[00908] MS (ES ) m/z: [M-H]" calcd forC24H3oN8OioS2: 653.15. Found: 652.96.
[00909] HPLC: 91.44 %. Example 110
(25)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[2-(pyrimidin-2-ylami- no)ethyl]carbamimidoyl}phenoxy)propanoic acid
[00910] ¾ NMR (400 MHz, DMSO-i6): δ = 1.09 (s, 3H), 1.36 (s, 3H), 3.30 - 3.60 (m, 4H), 4.59 - 4.35 (m, 2H), 4.95 (d, / = 11.2 Hz, 1H), 4.96 (br.s, 1H), 6.61 (t, / = 4.8 Hz, 1H), 6.79 (s, 1H), 7.25 (d, / = 9.2 Hz, 2H), ), 7.36 (br. s, 2H), 7.68 (d, / = 9.2 Hz, 2H), 8.28 (d, / = 4.8 Hz, 2H), 8.91 (br. s, 2H), 9.32 (br. s, 1H), 9.42 (d, / = 11.2 Hz, 1H), 9.60 (br. s, 1H).
[00911] MS (ES ) m/z: [M-H]" calcd CzeHsoNioOioSz: 706.72. Found: 705.14.
[00912] HPLC: 96.03 %
Example 111
(2ii)-2 {[(lZ)-l 2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[2-(pyrimidin-2-ylamin ethyl] carbamimidoyl}phenoxy)propanoic acid
[00913] Ή NMR (400 MHz, DMSO-de): δ = 1.39 (s, 3H), 2.50 (s, 3H), 3.57 - 3.51 (m, 4H), 4.45 - 4.43 (m, 2H), 4.60 (d, / = 7.6 Hz, 1H), 5.00 - 4.97 (m, 1H), 6.64 (t, / = 4.4 Hz, 1H), 6.82 (s, 1H), 7.18 (d, / = 8.8 Hz, 2H), 7.40 (br. s, 2H), 7.70 (d, / = 8.8 Hz, 2H), 8.30 (d, / = 4.4 Hz, 2H), 8.95 (br. s, 2H), 9.35 (br. s, 1H), 9.43 (d, / = 7.6 Hz, 1H), 9.62 (br. s, 1H).
[00914] MS (ES ) m/z: [M-H]" calcd C26H30N10O10S2: 706.72. Found: 705.14.
[00915] HPLC: 79.11 %
Example 112 tert-Butyl {[4-({l-[({(lZ)-2-{[(3S)-2i2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]amino}-
2-oxo-l-[2-(tritylamino)-l,3-thiazol-4-yl]ethylidene}amino)oxy]-3-hydroxypropan-2- yl}oxy)phenyl](imino)methyl}carbamate
[00916] ¾ (400 MHz, DMSO-d6): δ = 1.16 (s, 1.5H), 1.17 (s, 1.5H), 1.27 (s, 3H), 1.5 (s, 9H), 3.6 - 3.7 (m, 2H), 4.2 - 4.3 (m, 2H), 4.5 (t, / = 7.6 Hz, 1H), 4.7 (br. s., 1H), 5.0 (br. s., 1H), 6.7 (s, 1H), 7.1 (d, / = 9.0 Hz, 2H), 7.2 - 7.4 (m, 16H), 7.8 (d, / = 9.0 Hz, 2H), 9.35(d, / = 7.6, 0.5H), 9.38(d, / = 7.6, 0.5H).
[00917] MS (ES ) m/z: [M-H]- calcd C38H43N7O11S2: 837.93. Found: 836.44.
[00918] HPLC: 90.05 %
Pharmacological Methods
Abbreviations
MIC: minimum inhibitory concentration
CFU: colony forming units
ED100: 100% protective dose
[00919] The antimicrobial activity of the compounds of this invention against a selection of different bacteria may be evaluated by a number of assays, including the in-vitro determination of the minimum inhibitory concentration (MIC) or the determination of the in-vivo efficacy in mouse infection models.
Minimum Inhibitory Concentration (MIC) Determination
[00920] Compounds of this invention were tested for antimicrobial activity by determining minimum inhibitory concentrations (MICs, in pg/mL) using the broth microdilution method according to the guidelines of the Clinical Laboratories and Standards Institute ("Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically", Approved standard, 7th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A8, Wayne, Pa., USA, 2009.). Test compounds were dissolved in DMSO. The compounds were then diluted in microbial growth medium (Mueller Hinton Broth II, cation adjusted) resulting in a final concentration range of 0.063-32 pg/mL in serial two-fold dilution. In all cases the final DMSO concentration was less than 0.5%. Bacteria were added to 96-well microtitre plates containing the serial two-fold dilutions of the compounds; the final cell density was approximately 5 l05 colony forming units/mL (CFU/mL). Plates were incubated at 37°C for 18-24 hours and read visually. The MIC, i.e. the lowest concentration of the test compound that inhibited visible growth of the bacteria, was recorded. The same assay conditions were used when the compounds of this invention were tested in combination with ^-lactamase inhibitors. While the compounds of this invention were serially diluted as described above, a constant concentration of the ^-lactamase inhibitors of 4 pg/mL was used. [00921] Bacterial strains that were used to evaluate the antimicrobial acitivity using the MIC determination included but were not limited to E. coli ATCC25922, K. pneumoniae 60, E. cloacae 34654, C. freundii K21/3034, M. morganii 126/3048, P. aeruginosa PAOl, P. aeruginosa 2297 (AmpC wt), P. aeruginosa 2297-con (AmpC derepressed), A. haumannii ATCC15308, 5. maltophilia ICB7569, S. aureus 133, M. catarrhalis ICB489, H. influenzae ATCC 49247, S. pneumoniae 113, B. fragilis 6688, C. perfringens DSM756, E. coli J62, and E. coli J62-TEM-3.
Table 4. Biological data comstrain strain strain strain strain strain strain strain strain strain strain pound 1 2 3 4 5 6 7 8 9 10 11 example MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC
No. [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L]
1 0.25 0.25 0.5 0.5 0.125 4 8 4 8 8
2 0.125 0.125 0.25 0.125 ≤0.063 2 4 0.125 0.25
3 0.125 <0.063 0.125 ≤0.063 0.125 2 4 16 1 <0.063
4 0.125 0.25 0.5 0.125 0.25 4 16 8 1 4 <0.063
5 0.25 <0.063 0.125 0.25 0.125 4 4 32 1 0.125
6 0.125 0.25 0.125 <0.125 <0.125 4 8 16 1 32
7 0.5 1 1 0.5 0.5 8 16 8 2 4 <0.063
8 1 0.5 2 0.5 0.25 8 32 32 4 0.25
9 0.125 0.125 0.125 0.125 0.125 2 2 16 0.5 32 <0.063
10 0.5 2 1 1 4 8 8 8
11 0.125 <0.125 <0.063 <0.125 <0.063 1 2 16 0.5 32 0.125
12 0.5 0.25 0.5 0.25 0.25 4 8 4 8 0.125
13 0.5 1 1 0.25 0.5 8 16 8 1 <0.063
14 0.5 1 0.5 0.25 0.5 4 8 32 2 <0.063
15 0.5 1 1 0.5 0.5 8 8 8 2 4 ≤0.063
16 1 1 1 2 0.5 32 32 32 4 8 <0.063
Figure imgf000249_0001
Figure imgf000249_0002
comstrain strain strain strain strain strain strain strain strain strain pound 12 13 14 15 16 17 18 19 20 21 example MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC
No. [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L]
17 2 1 2 4 2 32 1 2 2
18 0.5 0.5 4 4 2 4 2 2 2
19 16 0.5 32 0.5 1 1
20 0.5 0.5 16 16 2 32 2 2 1
21 0.25 1 32 32 2 16 0.5 1 1
22 0.125 <0.063 2 4 2 1 8 0.5 1 1
23 <0.063 <0.063 1 4 2 0.25 1 0.125 0.125 0.25
24 <0.063 <0.063 2 2 2 0.125 2 0.125 0.25 0.5
25 <0.063 <0.063 4 2 2 0.25 4 0.125 0.125 0.125
26A <0.063 2 32 8 0.125 32 ≤0.063 0.125 0.125
26B 2 2 32 1 2 2
27A <0.063 0.5 8 4 0.25 8 0.25 0.25 0.25
27B 0.25 0.5 32 32 2 8 1 2 2
28 0.25 0.5 2 8 0.25 32 0.25 0.25 0.25
29 4 0.5 8 0.5 0.5 0.5
30 0.25 0.5 4 8 0.25 16 0.25 0.25 0.25
comstrain strain strain strain strain strain strain strain strain strain strain pound 1 2 3 4 5 6 7 8 9 10 11 example MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC
No. [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L]
31 0.125 <0.063 0.25 <0.063 0.25 8 8 32 1 <0.063
32 1 0.5 0.5 0.5 16 32 2 ≤0.063
33 0.25 0.5 0.5 0.25 0.25 8 16 8 8 16 <0.063
34A 1 1 0.5 1 0.25 8 8 16 32 8 <0.063
34B 8 8 4 8 4 32 32 32 32 32 0.25
35 2 2 4 2 1 16 16 32 2 0.25
36A 0.125 <0.063 <0.063 0.125 <0.063 4 4 4 4 2 <0.063
36B 2 1 2 0.5 2 16 32 32 16 0.125
37 2 2 2 2 1 8 8 4 1
38 0.125 0.25 0.25 0.125 0.5 4 8 4 0.25 32 <0.063
39 0.25 0.5 0.5 0.25 0.5 2 4 2 0.5 16 ≤0.063
40 0.125 0.25 0.5 0.125 0.5 4 8 4 2 16 <0.063
41 0.25 0.5 0.25 0.125 0.25 4 4 4 1 4 ≤0.063
42 1 1 2 1 2 16 16 16 8 16 <0.063
43 0.5 0.5 1 0.25 1 8 8 8 0.5 32
44A ≤0.063 <0.063 0.125 <0.063 0.125 1 2 1 2 2 <0.063 comstrain strain strain strain strain strain strain strain strain strain pound 12 13 14 15 16 17 18 19 20 21 example MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC
No. [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L]
31 0.25 0.25 8 4 0.25 32 0.125 0.25 0.25
32 0,75 0.5 8 3 2 32 1 2 1
33 0.125 <0.063 32 4 2 0.5 32 0.25 0.25 0.5
34A <0.063 0.5 16 2 1 32 0.5 0.5 0.5
34B 0.5 8 32 16 32 4 4 8
35 1 1 32 16 4 32 2 8 4
36A <0.063 0.5 8 2 0.125 8 0.125 ≤0.063 0.125
36B 0.5 4 32 32 4 32 2 2 2
37 0.5 1 4 16 4 2 2 2
38 <0.063 ≤0.063 2 4 2 0.25 4 0.125 0.25 0.25
39 0.25 0.25 2 16 8 0.25 4 0.125 0.25 0.25
40 <0.063 <0.063 4 2 0.25 8 0.125 0.25 0.25
41 ≤0.063 <0.063 4 2 1 0.25 8 0.25 0.25 0.25
42 0.25 0.125 16 8 4 1 16 1 1 1
43 0.125 <0.063 4 8 2 0.5 8 0.25 0.5 0.5
44A <0.063 0.5 32 8 1 0.125 2 <0.063 ≤0.063 <0.063 comstrain strain strain strain strain strain strain strain strain strain strain pound 1 2 3 4 5 6 7 8 9 10 11 example MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC
No. [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L]
44B 2 1 4 2 4 8 16 8 8 16 ≤0.063
45A 0.5 0.5 1 0.25 0.5 8 16 8 2 8
45B 2 2 4 1 4 16 32 32 4 32 <0.063
46 2 1 2 1 1 8 32 32 16 8
47 0.25 0.5 1 0.5 2 4 2 2 <0.063
48 2 4 4 2 1 8 16 32 8 0.5
49 1 2 2 1 2 8 16 32 4 0.125
50 0.5 0.5 1 1 0.5 8 16 32 2 0.125
51 2 4 2 2 2 16 16 32 4 0.5
52 1 0.5 1 0.25 1 4 4 16 1 2
53 0.5 0.5 0.5 2 16 16 32 4
54 0.5 0.5 0.5 0.25 1 4 8 4
55 0.5 1 0.5 0.25 0.25 16 32 4 0.25
56 2 0.5 4 0.5 0.5 32 32 4 1
57 1 2 2 1 1 32 32 16 2 32 <0.063
58 2 4 4 1 1 16 32 16 16 <0.063 comstrain strain strain strain strain strain strain strain strain strain pound 12 13 14 15 16 17 18 19 20 21 example MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC
No. [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L]
44B 0.5 4 2 4 2 2 4
45A 8 0.5 1 0.5 0.5 0.5
45B 0.5 0.125 16 4 2 4 16 2 4 4
46 0.25 1 32 4 2 16 1 1 1
47 0.125 0.125 1 16 1 0.5 32 0.5 0.5 0.5
48 0.5 1 4 16 2 2 2 2
49 0.5 0.5 16 16 2 2 2 2
50 0.25 1 8 16 1 1 1 1
51 0.5 1 8 16 4 4 4 4
52 8 16 8 32 2 2 2 2
53 32 1 1 1 1
54 2 0.5 16 0.5 0.25 0.5
55 1 0.125 8 8 1 1 0.5 0.5
56 2 4 8 32 2 32 1 4 4
57 0.125 ≤0.063 4 1 2 2 32 1 1 2
58 0.5 <0.063 4 4 4 4 32 2 2 2 comstrain strain strain strain strain strain strain strain strain strain strain pound 1 2 3 4 5 6 7 8 9 10 11 example MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC
No. [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L]
59 1 1 1 0.5 1 16 16 32 1 0.25
60 1 1 2 1 0.5 16 16 32 4 0.25
61 2 2 2 1 0.5 2 2 16 2 16 <0.063
62 1 0.5 1 0.5 0.125 4 8 32 2 0.125
63 0.5 0.25 0.5 0.25 0.5 8 8 16 16 0.5
64 0.5 0.25 0.5 0.5 0.5 8 16 8 32 16
65 0.5 0.25 0.5 0.25 0.125 16 32 8 0.25
66 2 1 4 2 2 32 32 4 1
67 0.5 2 0.5 0.25 0.125 8 32 4 0.25
68 0.125 0.25 0.125 0.125 0.125 2 8 32 2 <0.063
69 0.125 0.25 0.25 0.125 0.125 4 8 2 <0.063
70 0.125 0.25 0.25 0.125 0.125 4 4 2 0.125
71 2 1 4 1 1 16 32 4 4 0.25
72 0.5 0.25 1 0.5 0.25 8 8 4 0.25
73 0.5 0.5 0.5 0.5 0.5 16 32 32 16 32 <0.063
74 1 2 4 1 1 16 32 32 2 16 <0.063
Figure imgf000254_0001
Figure imgf000254_0002
comstrain strain strain strain strain strain strain strain strain strain pound 12 13 14 15 16 17 18 19 20 21 example MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC
No. [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L]
75 16 0.5 1 0.25 0.5 0.5
76 0.25 <0.063 4 4 2 0.5 8 0.5 0.5 0.5
77 0.5 16 1 1 1
78 <0.063 <0.063 1 4 2 0.5 4 0.25 0.5 0.5
79 <0.063 <0.063 2 4 2 0.5 8 0.5 0.5 0.5
80 4 0.5 16 0.5 0.5 0.5
81A 2 0.25 32 16 8 8 32 8 8 8
81 B 2 0.125 32 16 4 4 4 4 4 4
82 <0.063 <0.063 8 4 4 0.25 8 0.25 0.25 0.5
83 <0.063 <0.063 2 4 2 0.25 4 0.125 0.25 0.25
84 <0.063 ≤0.063 2 4 2 0.125 4 <0.063 0.125 0.125
85 <0.063 ≤0.063 8 4 4 0.5 8 0.25 0.25 0.5
86 <0.063 ≤0.063 4 4 2 0.25 16 0.25 0.25 0.5
87A 0.25 0.5 32 8 2 32 1 1 2
87B 0.125 1 16 16 1 32 0.5 1 2
88 <0.063 0.5 32 8 0.5 0.125 2 <0.063 <0.063 ≤0.063
Figure imgf000256_0001
comstrain strain strain strain strain strain strain strain strain strain pound 12 13 14 15 16 17 18 19 20 21 example MIC MIC MIC MIC MIC MIC MIC MIC MIC MIC
No. [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L] [mg/L]
89 <0.063 0.5 32 8 1 0.125 4 <0.063 <0.063 0.125
90 0.5 0.5 4 16 1 0.5 0.5 0.5 1
91 <0.063 <0.063 2 4 2 0.125 4 0.125 0.125 0.125
92 0.125 ≤0.063 8 8 2 1 32 0.5 0.5 0.5
93 32 0.125 4 0.125 0.125 0.125
94 <0.063 0.5 32 8 0.5 0.25 8 0.125 ≤0.063 0.125
95 <0.063 0.5 8 2 0.125 4 0.125 <0.063 0.125
96 <0.063 0.5 32 8 1 0.125 4 <0.063 ≤0.063 <0.063
97 <0.063 0.5 32 4 0.5 0.125 4 ≤0.063 <0.063 <0.063
98 <0.063 0.5 32 8 2 0.125 8 0.125 0.125 0.125
99 ≤0.063 0.5 32 8 0.5 0.25 4 0.125 0.125 0.25
100A <0.063 0.5 8 2 0.25 32 0.125 0.125 0.25
100B 4 16 2 2 2
101 ≤0.063 0.5 8 2 0.125 8 <0.063 <0.063 0.125
102 ≤0.063 0.5 8 2 0.125 4 <0.063 <0.063 0.125
103 0.25 4 32
Figure imgf000257_0001
Figure imgf000257_0002
strain 1 E. coli ATCC25922
strain 2 K. pneumoniae 60
strain 3 £. cloacae 34654
strain 4 C. /ra in K21/3034
strain 5 M. morganii 126/3048
strain 6 P. aeruginosa PAOl
strain 7 P. aeruginosa 2297 (AmpC wt)
strain 8 P. aeruginosa 2297-con (AmpC derepressed) strain 9 A. baumannii ATCC15308
strain 10 5. maltophilia ICB7569 strain 11 M. catarrhalis ICB489
strain 12 H. influenzae ATCC 49247
strain 13 S. pneumoniae 113
strain 14 5. aureus 133
strain 15 5. fragilis 6688
strain 16 C. perfringens DSM756
strain 17 E. coli ]62
strain 18 E. co/i J62-TEM-3
strain 19 £. coli J62-TEM-3 + 4 μg/mL clavulanic acid
strain 20 E. co/i J62-TEM-3 + 4 μg/mL sulbactam
strain 21 £. co// J62-TEM-3 + 4 g/mL tazobactam
Determination of the in-vivo activity in mouse infection models
Formulations
[00922] Commercial 10% aqueous mannitol solution was diluted with Aquadest to a 3% aqueous mannitol solution. Compounds of this invention were dissolved at 20-45 °C to form clear application solutions of a concentration in the range from 0.02 mg/mL to 3 mg/mL.
[00923] Commercial 10% aqueous mannitol solution was diluted with Aquadest to a 3% aqueous mannitol solution. Solid sodium acetate was added to obtain 2-20 mM sodium acetate solutions in 3% aqueous mannitol. Compounds of this invention were dissolved at 20-45 °C to form clear application solutions of a concentration in the range from 0.02 mg/mL to 3 mg/mL.
[00924] Compounds of this invention were dissolved in DMSO at 20-25 °C to form clear stock solutions of a concentration in the range of 60 mg/mL. The stock solutions were diluted with 3% aqueous mannitol solution at 20-25 °C to form clear application solutions of a concentration in the range of 2.1 mg/mL.
[00925] Compounds of this invention were dissolved at 20-45 °C in commercial lactated Ringer's solution to form clear application solutions of a concentration in the range from 0.02 mg/mL to 3 mg/mL.
[00926] Compounds of this invention were dissolved at 20-45 °C in commercial Dulbecco's Phosphate Buffered Saline (DPBS) without calcium and magnesium to form clear application solutions of a concentration in the range from 0.02 mg/mL to 3 mg/mL.
[00927] D(+)-Glucose monohydrate was dissolved in Aquadest to a 5% aqueous glucose solution. Compounds of this invention were dissolved at 20-45 °C to form clear application solutions of a concentration in the range from 0.02 mg/mL to 3 mg/mL.
[00928] Compounds of this invention were dissolved at 20-45 °C in commercial 0.9% saline to form clear application solutions of a concentration in the range from 0.02 mg/mL to 3 mg/mL.
Peritonitis models
[00929] Female CD-I mice were infected intraperitoneally with a bacterial inoculum in 5% mucin that led to the death of the untreated group (n=5) within the first 24 hours of the experiment (~1 x 104 CFU - ~5 x 107 CFU per mouse depending on the virulence of the strain used). Strains that were used included but were not limited to wild-type E. coli Neumann, wild-type P. aeruginosa Walther, wild-type A. baumannii ATCC 15308 and resistant K. pneumoniae CL5761 (KPC-3 producer). Mice were treated via intravenous injection 30, 60 and 120 minutes post infection with compounds of this invention (alone or in combination with a ^-lactamase inhibitor) as well as with control antibiotics including but not limited to meropenem. Lethalities were followed over 5 days and the 100% protective dose (ED 100) was determined.
Lung infection model
[00930] Female BALB/c mice anesthetized with isoflurane and infected in- tranasally with 32 pL of the bacterial inoculum (e.g. -3.5 x 107 CFU per mouse for P. aeruginosa PAOl). Mice were treated via intravenous injection 30, 60 and 120 minutes post infection with compounds of this invention as well as with control antibiotics including but not limited to meropenem. Animals, including an untreated control group were sacrified after 24 hours. Lungs were aseptically removed, homogenized, serially diluted and plated onto sheep-blood agar plates to determine CFU counts.
Urinary tract infection model
[00931] Female CD-I mice were given 5% glucose solution as the sole source of drinking water from 16 hours before the experiment to the end. Anesthetized mice were infected via the urethra with an uropathogenic E. coli strain (e. g. E. coli 70430001) in 0.9% NaCl with 0.25% agar-agar in a 25 pL volume (~5 x 106 CFU per mouse). Mice were treated via intravenous injection 1, 5, 23, and 30 hours post infection with compounds of this invention as well as with control antibiotics including but not limited to meropenem. Mice, including an untreated control group were sacrified at 48 hours post infection. Bladders were aseptically removed, homogenized, serially diluted and plated onto Mueller Hinton agar plates to determine CFU counts.

Claims

Claims
1. Compound of formula
Figure imgf000261_0001
in which
R1 and R2 independently of one another represent hydrogen, aminocar- bonyl or (Ci-C4)-aikyl, or
R1 and R2 together with the carbon atom to which they are bonded form a
(C3-C8)-cycloalkyl,
R3 represents -(CH2)m-(S02)OH or -0-(CH2)0-(S02)OH, wherein m and o independently of one another represent an integer 0, 1, 2 or 3, and wherein any CH2-group contained in the residues which R3 represents may be substituted with one or two (Ci-C4)-alkyl- residues, X represents CR4 or N,
R4 represents hydrogen or halogen, Z represents a bond or an alkyl-chain having one, two, three or four carbon atoms, whereby the alkyl-chain may be substituted with one, two, three or four substituents, selected independently of one another from the group consisting of carboxy, aminocarbonyl and (0-C4)- alkyl, whereby alkyl in turn may be substituted with a substituent selected from the group consisting of hydroxy, car- boxy and aminocarbonyl,
Y represents a bond, O, NH or S, A represents (C6-Ci0)-aryl or 5- to 10-membered heteroaryl, whereby aryl and heteroaryl are substituted with a substituent of the following formula
Figure imgf000262_0001
wherein
Rlb, R2b and R3b independently of one another represent hydrogen, amino, hydroxy, (G-C4)-alkyl, (Ci-C4)-alkoxy, (C3-C6)-cycloalkyl, 4-, 5- 6- or 7-membered heterocyclyl or 5- or 6-membered heteroaryl, whereby amino and hydroxy may be substituted with one or two substituents selected independently of one another from the group consisting of carbonyl, (G-C4)-alkylcarbonyl, mono- or di-(G-C4)-alkylaminocarbonyl, and (G-C4)-alkyl, whereby alkoxy, heterocyclyl and heteroaryl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, (Ci-C4)-alkylcarbonyl, (G-C4)- alkoxy, mono- or di-(Ci-C4)-alkylamino, mono- or di-(Ci-C4)-alkylaminocarbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), -C(=NH)CH3 and (G-C4)-alkyl, and whereby alkyl and cycloalkyl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, car- boxy, carbonyloxy, aminocarbonyl, carbonyla- mino, (Ci-C4)-alkylcarbonyl, (G-C4)-alkoxy, mono- or di-(Ci-C4)-alkylamino, mono- or di-(G-C4)- alkylaminocarbonyl, -NH-CH(=NH), -NH-C(=NH)- (NH2), -CH(=NH)CH3, (C6-C10)-aryl, 5- or 6- membered heteroaryl and 5- or 6-membered heterocyclyl, whereby heteroaryl and heterocyclyl in turn may be substituted with (G-C4)-alkyl, and whereby amino in turn may be substituted with 5- or 6-membered heteroaryl, or
R2b and R3b together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle including one, two or three further heteroatoms selected from the series N, O and S and Rl is as defined above,
R4b represents hydrogen, amino, hydroxy, (Ci-C4)-alkyl or (Ci-C4)-alkoxy, whereby amino and hydroxy may be substituted with one or two substituents selected independently of one another from the group consisting of (G-C4)-alkylcarbonyl, mono- or di-(G-C4)- alkylaminocarbonyl and (G-C4)-alkyl, whereby alkoxy may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, (G-C4)- alkylcarbonyl, (G-C4)-alkoxy, mono- or di-(G-C4)- alkylamino, mono- or di-(G-C4)-alkylamino- carbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), -CH(=NH)CH3 and (G-C4)-alkyl, and whereby alkyl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hy- droxy, amino, carbonyl, carboxy, aminocarbonyl, (Ci-C4)-alkylcarbonyl, (G-C4)-alkoxy, mono- or di- (Ci-C4)-alkylamino, mono- or di-(G-C4)-alkyl- aminocarbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), -CH(=NH)CH3, (Ci-C4)-alkyl, (C6-C10)-aryl and 5- or 6-membered heteroaryl,
R5 represents hydrogen or (G-C4)-alkyl,
Q represents a bond, CH2 or NH, k represents an integer 1 or 2, and
* is the linkage site to the residue represented by A, and whereby aryl and heteroaryl further may be substituted with one or two substituents selected independently of one another from the group consisting of halogen, cyano, amino, hydroxy, (G- C4)-alkyl, (G-C4)-alkoxy, mono- or di-(G-C4)-alkylamino, ami- no-(G-C4)-alkyl, hydroxy-(G-C4)-alkyl or carboxy, whereby alkyl, alkoxy, alkylamino, aminoalkyl, hydroxy- alkyl and carboxy in turn may be substituted with a sub- stituent selected from the group consisting of halogen, (G-C4)-alkyl and carbonyl, and
1 represents an integer 0, 1, 2 or 3, and the salts thereof, the solvates thereof and the solvates of the salts thereof.
2. Compound according to claim 1, characterized in that
R1 and R2 independently of one another represent hydrogen or (0-C4)- alkyl, or
R1 and R2 together with the carbon atom to which they are bonded form a
(C3-C8)-cycloalkyl;
R3 represents -(CH2)m-(S02)OH or -0-(CH2)0-(S02)OH, wherein m and o independently of one another represent an integer 0 or 1 and wherein any CH2-group contained in the residues which R3 represents may be substituted with one or two (G-C4)-alkyl- residues,
X represents CR4 or N,
R4 represents hydrogen or halogen,
Z represents a bond or an alkyl-chain having one, two or three carbon atoms, whereby the alkyl-chain may be substituted with one, two or three substituents, selected independently of one another from the group consisting of carboxy, aminocarbonyl and (Ci-C4)- alkyl, whereby alkyl in turn may be substituted with a substitu- ent selected from the group consisting of hydroxy and carboxy, represents a bond, O, NH or S, represents (C6-Cio)-aryl or 5- to 10-membered heteroaryl, whereby aryl and heteroaryl are substituted with a substituent of the following formula
Figure imgf000267_0001
wherein
Rlb, R2 and R3 independently of one another represent hydrogen, amino, hydroxy, (G-C4)-alkyl, 4-, 5-, 6- or 7- membered heterocyclyl or 5- or 6-membered heteroaryl, whereby heterocyclyl and heteroaryl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, (Ci-C4)-alkylcarbonyl, (Ci-C4)-alkoxy, mono- or di-(Ci-C4)-alkylamino, mono- or di-(0- C4)-alkylaminocarbonyl, -NH-CH(=NH), -NH- C(=NH)(NH2), -C(=NH)CH3 and (G-C4)-alkyl, and whereby alkyl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, carbonyloxy, aminocarbonyl, carbonylamino, (G-C4)- alkylcarbonyl, (G-C4)-alkoxy, mono- or di-(G-C4)- alkylamino, mono- or di-(G-C4)-alkylamino- carbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), -CH(=NH)CH3, (C6-C10)-aryl, 5- or 6-membered heteroaryl and 5- or 6-membered heterocyclyl, whereby heteroaryl and heterocyclyl in turn may be substituted with (G-C4)-alkyl or
R2 and R3b together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocycle including one, two or three further heteroatoms selected from the series N, O and S and Rlb is as defined above,
R4 represents hydrogen, amino, hydroxy, (G-C4)-alkyl or (Ci-C4)-alkoxy, whereby amino and hydroxy may be substituted with one or two substituents selected independently of one another from the group consisting of (Ci-C4)-alkylcarbonyl, mono- or di-(G-C4)- alkylaminocarbonyl and (G-C4)-alkyl, and whereby alkyl may be substituted with one, two or three substituents selected independently of one another from the group consisting of halogen, hydroxy, amino, carbonyl, carboxy, aminocarbonyl, (Ci-C4)-alkylcarbonyl, (G-C4)-alkoxy, mono- or di- (Ci-C4)-alkylamino, mono- or di-(G-C4)-alkyl- aminocarbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), -CH(=NH)CH3, (Ci-C4)-alkyl, (C6-Ci0)-aryl and 5- or 6-membered heteroaryl, RS represents hydrogen or (Ci-C4)-alkyl,
Q represents a bond, CH2 or NH, k represents an integer 1 or 2, and
* is the linkage site to the residue represented by A, and whereby aryl and heteroaryl further may be substituted with one or two substituents selected independently of one another from the group consisting of halogen, cyano, amino, hydroxy, (G- C4)-alkyl, (G-C4)-alkoxy, mono- or di-(G-C4)-alkylamino, ami- no-(Ci-C4)-alkyl, hydroxy-(G-C4)-alkyl or carboxy, whereby alkyl, alkoxy, alkylamino, aminoalkyl, hydroxy- alkyl and carboxy in turn may be substituted with a sub- stituent selected from the group consisting of halogen, (Ci-C4)-alkyl and carbonyl, and
1 represents an integer 0 or 1 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
3. Compound according to claim 1 or 2, characterized in that
R1 and R2 independently of one another represent hydrogen or (G-C4)- alkyl, or
R1 and R2 together with the carbon atom to which they are bonded form a
(C3-C8)-cycloalkyl, represents -(S02)OH or -0-(CH2)o-(S02)OH, wherein o is an integer 0 or 1, and wherein any CH2-group contained in the residues which R3 represents may be substituted with one or two (Ci-C4)-alkyl- residues, represents CH, represents an alkyl-chain having two or three carbon atoms, whereby the alkyl-chain may be substituted with one or two substituents selected independently of one another from the group consisting of carboxy, aminocarbonyl, methyl, hy- droxymethyl, hydroxyethyl, represents O represents phenyl or 5- or 6-membered heteroaryl, whereby phenyl and heteroaryl are substituted with a substitu- ent of the following formula
Figure imgf000270_0001
wherein Rlb, R2b and R3b independently of one another represent hydrogen, amino, hydroxy, (Ci-Gj)-alkyl or 4-, 5-, 6- or 7- membered heterocyclyl, whereby heterocyclyl may be substituted with one or two substituents selected independently of one another from the group consisting of amino, car- boxy, mono- or di-(Ci-C4)-alkylamino, and (Ci-C4)- alkyl, and whereby alkyl may be substituted with one or two substituents selected independently of one another from the group consisting of hydroxy, amino, carboxy, carbonyloxy, aminocarbonyl, carbonyla- mino, mono- or di-(Ci-C4)-alkylamino, mono- or di-(Ci-C4)-alkylaminocarbonyl, -NH-CH(=NH), -NH-C(=NH)(NH2), phenyl, 6-membered heteroaryl and 5- or 6-membered heterocyclyl, or,
R2b and R3b together with the nitrogen atom to which they are bonded form a 6-membered heterocycle including one or two nitrogen atoms and Rl is hydrogen,
R4b represents hydrogen or amino, whereby amino may be substituted with one or two (Ci-C4)-alkyl substituents,
R5b represents hydrogen,
Q represents a bond, k represents an integer 1 or 2, and
* is the linkage site to the residue represented by A, and whereby phenyl und heteroaryl further may be substituted with one or two substituents selected independently of one another from the group consisting of halogen, cyano, amino, hydroxy, (Ci-C4)-alkyl or hydroxy-(G-C4)-alkyl, whereby hydroxyalkyl in turn may be susbstituted with a carbonyl substituent, and
1 represents 0 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
4. Compound according to any one of claims 1 to 3, characterized in that independently of one another represent hydrogen or methyl, represents -(S02)OH or -0-(S02)OH, represents CH, represents an alkyl-chain having two or three carbon atoms, whereby the alkyl-chain may be substituted with one or two substituents, selected independently of one another from the group consisting of carboxy and methyl,
Y represents O, represents phenyl or 6-membered heteroaryl, whereby phenyl and heteroaryl are substituted with a substitu- ent of the following formula
Figure imgf000273_0001
wherein
Rlb and R2 represent hydrogen,
R3b represents hydrogen, amino, hydroxy, (G-C4)-alkyl or 4-, 5- or 6-membered nitrogen-containing heterocyclyl, whereby alkyl may be substituted with a substitu- ent selected from the group consisting of hydroxy, amino, carboxy, carbonyloxy, mono- or di-(G-C4)- alkylamino, -NH-CH(=NH), -NH-C(=NH)(NH2), 5- or 6-membered nitrogen-containing heteroaryl and 5- or 6-membered nitrogen-containing heterocyclyl,
Q represents a bond,
* is the linkage site to the residue represented by A, and whereby aryl and heteroaryl further may be substituted with one substituent selected from the group consisting of halogen, cy- ano, amino, hydroxy, (G-C4)-alkyl or hydroxy-(G-C4)-alkyl, and 1 represents 0 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
5. Compound according to any one of claims 1 to 4, characterized in that
R1 and R2 represent methyl,
R3 represents -0-(S02)OH,
X represents CH,
Z represents an alkyl-chain having two carbon atoms, whereby the alkyl-chain may be substituted with a carboxy substituent,
Y represents O,
A represents phenyl substituted with a substituent of the following formula
Figure imgf000274_0001
wherein
Rlb and R2b represent hydrogen, R3 represents aminoethyl, azetidine, pyrrolidine or piperidine,
Q represents a bond,
* is the linkage site to the residue represented by A, and 1 represents 0 and the salts thereof, the solvates thereof and the solvates of the salts thereof.
6. Compound according to any one of claims 1 to 5 characterized in that
R1 and R2 represent methyl,
R3 represents -0-(S02)OH,
X represents CH,
Z represents a two carbon alkyl-chain, substituted with a carboxy substituent,
Y represents O,
A represents phenyl substituted with a substituent of the following formula
wherein
Figure imgf000275_0001
Rlb and R2 represent hydrogen, R3b represents aminoethyl, azetidine, pyrrolidine or piper- idine,
Q represents a bond,
* is the linkage site to the residue represented by A, and
1 represents 0
and the salts thereof, the solvates thereof and the solvates of the salts thereof.
7. Compound according to claim 1, characterized in that
A represents a group selected from the following formulae
Figure imgf000277_0001
Figure imgf000277_0002
277
Figure imgf000278_0001
and the salts thereof, the solvates thereof and the solvates of the salts thereof.
8. Compound which is
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-3-hydroxyphenoxy)- ethoxy]imino}-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
(2S/3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-3-hydroxy- phenoxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(6-carbamimidoylpyridin-3- yl)oxy] ethoxy} imino) acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(6-carbamimidoylpyridin-3- yl)oxy]ethoxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]ethanamide
(2S;3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(5-carbamimidoylpyridin-2- yl)oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l -sulfonic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(4-carbamimidoylphenyl)sulfanyl]- ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(4- carbamimidoylphenyl)sulfanyl] ethoxy}imino)-N- [(3S)-2,2-dimethyl-4-oxo- 1 - (sulfooxy)azetidin-3-yl]ethanamide
(2S,3S)-3-{[(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-({2-[(4-carbamimidoylphenyl)- amino] ethoxy} imino)acetyl] amino}-2-methy 1-4-oxoazetidine- 1 -sulfonic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)- ethoxy] imino}acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid (2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4 arbamimidoylphenoxy)ethoxy]imino}-N- [(2R,3S)-2-methyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
(2R,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)- ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
{[(2S;3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)- ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidin-l-yl]oxy}methanesulfonic acid
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-3- methylphenoxy)ethoxy]imino}-N-[(3S)-2;2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]ethanamide
(2S;3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-3- methylphenoxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-({2-[(2-carbamimidoylpyridin-4- yl)oxy]ethoxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]ethanamide
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)ethoxy]imino}-N- [2-oxo- l-(sulfooxy)- l-azaspiro[3.4] oct-3-yl] ethanamide
(2S/3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)-2- methylpropoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({[l-(4-carbamimidoylphenoxy)-2- methylpropan-2-yl]oxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-2- fluorophenoxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid (2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoyl-2- chlorophenoxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S;3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[4-(N-hydroxycarbamimidoyl)- phenoxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(4-carbamimidoylpyridin-2- yl)oxy]ethoxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yljethanamide
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]-2-[(2-{4 N-(piperidin-4-yl)carbamimidoyl]phenoxy}ethoxy)imino]ethanamide
(2Z)-2-[(2 4-[N-(2-Aminoethyl)carbamimidoyl]phenoxy}ethoxy)imino]-2-(2-amino- l,3-thiazol-4-yl)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
(2Z)-2-(2-Amino- 1 ,3-thiazol-4-yl)-2-({2- [4-(4,5-dihydro- 1 H-imidazol-2- yl)phenoxy] ethoxy}imino)-N- [(3S)-2,2-dimethyl-4-oxo- 1 -(sulfooxy)azetidin-3- yl]ethanamide
(2S and 2R)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(2S,3S)-2-methyl-4-oxo-l-sulfo- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-carbamidinoyl- phenoxy)propanoic acid
(2S and 2R)-2-({ [(1 Z)- 1 -(2-Amino- 1 ,3-thiazol-4-yl)-2-{ [(3S)-2,2-dimethyl-4-oxo- 1 - (sulfooxy)azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-carbamimidoyl- phenoxy)propanoic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l>3-thiazol-4-yl)-2-({2-[(6-carbamimidoylpyridazin-3- yl) oxy] ethoxyjimino) acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid (2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(6-carbamimidoylpyridazin-3-yl)oxy]- ethoxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
(2S)3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(5-carbamimidoylpyrazin-2- yl) oxy] ethoxyjimino) acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
(2S/3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(4-carbamimidoyl-l 3-thiazol-2- yl)oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2Si3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-(2-[(4-carbamimidoylthiophen-2- yl)methoxy] imino)acetyl] amino}-2-methyl-4-oxoazetidine- 1-sulfonic acid
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(6-carbamimidoyl-5-hydroxypyridin-3- yl)oxy]ethoxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yljethanamide
(2S and 2R)-2-({[(lZ)-l-(2-Amino-l;3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l- (sulfooxy)azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-carbamimidoyl-3- hydroxyphenoxy)propanoic acid
(2S,3S)-3-{[(2Z)-2-{[2-(2-Amino-4-carbamimidoylphenoxy)ethoxy]imino}-2-(2-amino- l,3-thiazol-4-yl)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S and 2R)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l- (sulfooxy)-azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-[(6- carbamimidoylpyridin-3-yl)oxy]propanoic acid
(2S, 3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[{3-(4-carbamimidoylphenoxy)- propoxy]imino}-acetyl] -amino}-2-methyl-4-oxoazetidine- 1 -sulfonic acid (2Z)-2^2-Amino-l)3-thiazol-4-yl)-N-[(3S)-l-hydroxy-2,2-dimethyl-4-oxoazetidin-3-yl]-
2-({2 4-(N-{2-[(iminomethyl)amino]ethyl}carbamimidoyl)phenoxy]ethoxy}imino)- ethanamide
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(3S)-2;2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]-2-{[2-(4-{N-[(3S)-pyrrolidin-3-yl]carbamimidoyl}phenoxy)ethoxy]imino}- ethanamide
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-{N-[2-(dimethylamino)ethyl]carbamimido- yl}phenoxy)ethoxy]imino}-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]- ethanamide
(2Z)-2-(2-Amino-1 -thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)ethoxy]imino}-N- [(3S)-2;2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
(4S)-4-{[{4-[2-({[(lZ)-l-(2-Amino-l 3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-
(sulfooxy)-azet-idin-3-yl]amino}-2-oxo-ethylidene]-amino}-oxy)-ethoxy]-phenyl}-
(imino)methyl]amino}-N,N-dimethyl-L-prolinamide
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(3S)-2/2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]-2-{[2-(4-{N-[(3S)-l-ethanimidoylpyrrolidin-3-yl]carbamimidoyl}phenoxy)ethoxy]- imino} ethanamide
(2R and 2S)-3-{4-[N-(2-Aminoethyl)carbamimidoyl]phenoxy}-2-({[(lZ)-l-(2-amino- l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]amino}-2-oxo- ethylidene] amino} -oxy)-propanoic acid
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({[(2R and 2S)-l-(4-carbamimidoylphenoxy)-3- hydroxypropan-2-yl]oxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl] ethanamide 3-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2;2-dimethyl-4-oxo-l-(sulfooxy)azeti- din-3-yl]amino}-2-oxoethylidene]amino}oxy)-4-(4 arbamimidoylphenoxy)butanoic acid
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)ethoxy]imino}-N- [(2S,3S)-2-methyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
(2R,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[3-(4-carbamimidoylphenoxy)prop- oxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S;3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(2-bromo-4-carbamimidoylphen- oxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidamidophenoxy)- ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[3-(4-carbamimidamidophenoxy)- propoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2Z)-2-(5-Amino-l,2,4-thiadiazol-3-yl)-2-{[2-(4-carbamimidoylphenoxy)ethoxy]- imino}-N-[(2S,3S)-l-hydroxy-2-methyl-4-oxoazetidin-3-yl]ethanamide
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[2-(3-carbamimidoylphenoxy)- ethoxy] iminojacetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
(2S/3S)-3-({(2Z)-2-(2-Amino-l/3-thiazol-4-yl)-2-[(2-{4-[N-(propan-2-yl)carbamimidoyl]- phenoxy}ethoxy)imino]acetyl}amino)-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[(4-carbamimidoylbenzyl)oxy]- iminojacetyl] amino}-2-methyl-4-oxoazetidine- 1 -sulfonic acid (2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(4-carbamimidoylthiophen-2- yl)methoxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[(4-carbamimidoylbenzyl)oxy]imino}-N-[(3S)-2,2- dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[3-(4-carbamimidoylphenoxy)propoxy]imino}-N- [(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[4-carbamimidoyl-2-(hydroxy- methyl)phenoxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-({(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[(2-{4-carbamimidoyl-2-[(formyloxy)- methyl]phenoxy}ethoxy)imino]acetyl}amino)-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S 3S)-3-{[(2Z)-2-(2-Amino-5-chloro-l,3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphen- oxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-{[(2Z)-2 {2-[4-(2-Amino-2-iminoethyl)phenoxy]ethoxy}imino)-2-(2-amino- l,3-thiazol-4-yl)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S;3S)-3-({(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[(2-{4-[(2-formylhydrazinyl)(imino)- methyl]phenoxy}ethoxy)imino]acetyl}amino)-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S;3S)-3-({(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[(2-{4-[hydrazinyl(imino)methyl]- phenoxy}ethoxy)imino]acetyl}amino)-2-methyl-4-oxoazetidine-l -sulfonic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-({2-[(5-carbamimidoyl-l,3,4-thiadiazol- 2-yl)oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid (2S,3S)-3-{[(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-{[2-(4-carbamimidoylphenoxy)ethoxy]- imino}acetyl]amino}-2-carbamoyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-{[(2Z)-2 2-Amino-l,3-thiazol-4-yl)-2-({2-[(3-carbamimidoyl-l,2-oxazol-5- yl) oxy] ethoxy}imino)acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
(2S;3S)-3-{[(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-({2-[4-(N-methylcarbamimidoyl)phen- oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-({(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[(2-{4-[N-(2-hydroxyethyl)carbamimi- doyl]phenoxy}ethoxy)imino]acetyl}amino)-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S;3S)-3-{[(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-{[2-(4-{N-[2-(formyloxy)ethyl]carbam- idoyl}phenoxy)ethoxy]imino}acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
(2S,3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2 {2-[(3-carbamimidoyl-l-methyl-lH- pyrazol-5 -yl) oxy] ethoxy}imino)acetyl] amino} -2-methyl-4-oxoazetidine- 1 -sulfonic acid
(2S)3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(5-carbamimidoyl-l-methyl-lH- pyrazol-3-yl)oxy]ethoxy}imino)acetyl]amino}-2-methyl-4-oxoazetidine-l-sulfonic acid
N-[{4-[2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)ethoxy]phenyl}(imino)methyl]- glycine
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({2-[(2-carbamimidoyl-5-methyl-l,3-thiazol-4- yl)oxy]ethoxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethan- amide 2-({[(lZ) -(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azeti- din-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-carbamimidoylphenoxy)propan- amide
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(3S)-2>2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]-2-[(2-{4-[N-(pyridin-2-ylmethyl)carbamimidoyl]phenoxy}ethoxy)imino]ethan- amide
{[(2S,3S)-3-{[(2Z)-2-[(2-{4-[N-(2-Aminoethyl)carbamimidoyl]phenoxy}ethoxy)imino]- 2-(2-amino- 1 , 3 -thiazol-4-yl)acetyl] amino} -2-methyl-4-oxoazetidin- 1 -yl] oxy} methane- sulfonic acid
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-[(2-{4-[N-(2-carbamimidamidoethyl)carbamimido- yl]phenoxy}ethoxy)imino]-N-[(3S)-2i2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]- ethanamide
1 -(2-{ [{4- [2-({ [(1Z)- 1 -(2-Amino- 1 ;3-thiazol-4-yl)-2-{ [(3S)-2, 2-dimethyl-4-oxo- l-(sulfo- oxy)azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)ethoxy]phenyl}(imino)- methyl]amino}ethyl)-l-methylpyrrolidinium chloride
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yl]-2-[(2-{4-[imino(piperazin-l-yl)methyl]phenoxy}ethoxy)imino]ethanamide
(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-({[l-(4-carbamimidoylphenoxy)- (2R and 2S)-4- hydroxybutan-2-yl]oxy}imino)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3- yljethanamide
(2Z)-2-{[2-({6-[N-(2-Aminoethyl)carbamimidoyl]pyridin-3-yl}oxy)ethoxy]imino}-2-(2- amino-l,3-thiazol-4-yl)-N-[(3S)-2/2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethan- amide (2Z)-2-[(2-{4-[N-(3-Aminopropyl)carbamimidoyl]phenoxy}ethoxy)imino]-2-(2-amino- l,3-thiazol-4-yl)-N (3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]ethanamide
(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-[(2-{4-[N-(l,3-diaminopropan-2-yl)carbamimido- yl]phenoxy}ethoxy)imino]-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]- ethanamide
(2Z)-2-{[2-(4-{N-[(2R)-l-Amino-3-hydroxypropan-2-yl]carbamimidoyl}phenoxy)- ethoxy]imino}-2-(2-amino-l,3-thiazol-4-yl)-N-[(3S)-2i2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl] ethanamide
(2Z)-2-({2-[4-(5-Amino-l;4/5,6-tetrahydropyrimidin-2-yl)phenoxy]ethoxy}imino)-2-
(2-amino-l/3-thiazol-4-yl)-N-[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]- ethanamide
(2R and 2S) 3-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l- (sulfooxy)azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-2-(4-carbamimidoyl- phenoxy)propanoic acid
(2S)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2;2-diraethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[(3ii)-piperidin-3-yl]carb- amimidoyl}phenoxy)propanoic acid
(2^)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(35)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[(3^)-piperidin-3-yl]- carbamimidoyl}phenoxy)propanoic acid
{[(3S)-3-{[(2Z)-2-(2-Amino-l,3-thiazol-4-yl)-2-{[(4-carbamimidoylbenzyl)oxy]imino}- acetyl] amino}-2,2-dimethyl-4-oxoazetidin- 1 -yl] oxyjmethanesulf onic acid (2Z)-2-[(2-{4-[5-(Aminomethyl)-4,5-dihydro-lH-imidazol-2-yl]phenoxy}ethoxy)- imino]-2-(2-amino- 1 , 3-thiazol-4-yl)-N- [(3S)-2,2-dimethyl-4-oxo- 1 -(sulfooxy)azetidin- 3-yl]ethanamide
(3S)-3-({(2Z)-2-(2-Amino-l;3-thiazol-4-yl)-2-[(2-{4-[N-(pyrazolidin-4-yl)carbamimido- yl]phenoxy}ethoxy)imino]acetyl}amino)-2)2-dimethyl-4-oxoazetidine-l-sulfonic acid
(2S)-2-({[(lZ)-1^2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-sulfoazeti- din-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[(3S)-pyrrolidin-3-yl]carbam- imidoyl}phenoxy)propanoic acid
(2S)-3-{4-[N-(2-Amino-2-methylpropyl)carbamimidoyl]phenoxy}-2-({[(lZ)-l-(2- amino-l,3-thiazol-4-yl)-2-{[(3S)-2;2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]amino}- 2-oxoethylidene]amino}oxy)propanoic acid
(2S)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[2-(methylamino)ethyl]- carbamimidoyl}phenoxy)propanoic acid
(2S)-2-({ [(1Z)- l-(2-Amino- 1 ,3-thiazol-4-yl)-2-{ [(3S)-2,2-dimethyl-4-oxo- 1 -sulfo- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[(3R)-pyrrolidin-3-yl]carb- amimidoyl}phenoxy)propanoic acid
(2S)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(piperidin-3-yl)carbam- imidoyl]phenoxy}propanoic acid
(2S)-2-({[(lZ)-l-(2-Amino-l/3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(pyrrolidin-2-ylmethyl)- carbamimidoyl]phenoxy}propanoic acid (2S)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(piperidin-2-ylmethyl)- carbamimidoyl]phenoxy}propanoic acid
(2S)-3-{4-[N-(trans-(R,R and S,S)-2-Aminocyclopropyl)carbamimidoyl]phenoxy}-2- ({[(lZ)-l-(2-amino-l,3-thiazol-4-yl)-2-{[(3S)-2/2-dimethyl-4-oxo-l-(sulfooxy)azetidin- 3-yl]amino}-2-oxoethylidene]amino}oxy)propanoic acid
(2S)-2-({ [(1Z)- 1 -(2-Amino- 1 ,3-thiazol-4-yl)-2-{ [(3S)-2,2-dimethyl-4-oxo- 1 -sulf oazeti- din-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[(3S)-l-methylpyrrolidin-3-yl]- carbamimidoyl}-phenoxy)-propanoic acid
(2S)-2-({[(lZ)-l-(2-Amino-l/3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(l,3-diaminopropan-2-yl)- carbamimidoyl]phenoxy}propanoic acid
(2R)-2-({[(lZ)-l-(2-Amino-l;3-thiazol-4-yl)-2 [(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(l;3-diaminopropan-2-yl)- carbamimidoyl]phenoxy}propanoic acid
(2S)-2-({[(lZ)-l-(2-Amino-l/3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(lH midazol-2-ylmethyl)- carbamimidoyl]phenoxy}propanoic acid
(2R)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(lH-imidazol-2-ylmethyl)- carbamimidoyl] phenoxy} propanoic acid
(2S)-3-{4-[N-(4-Aminopyrrolidin-3-yl)carbamimidoyl]phenoxy}-2-({[(lZ)-l-(2-amino- li3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)azetidin-3-yl]amino}-2- oxoethylidene]amino}oxy)propanoic acid (2S)-2-({[(lZ)-l-(2-Amino-l/3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(azetidin-3-yl)carbam- imidoyl]phenoxy}propanoic acid
(2S)-2-({ [(1Z)- 1 -(2-Amino- 1 ,3-thiazol-4-yl)-2-{ [(3S)-2,2-dimethyl-4-oxo- 1 -(sulf ooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(piperidin-4-yl)carbam- imidoyl]phenoxy}propanoic acid
(2S)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l-(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-{4-[N-(azetidin-3-yl)carbam- imidoyl]phenoxy}propanoic acid
(2S)-2-({[(lZ)- 1 -(2-Amino- 1 ,3-thiazol-4-yl)-2-{ [(35)-2,2-dimethyl-4-oxo- 1 -(sulfooxy)- azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[2-(pyrimidin-2-ylamino)- ethyl]carbamimidoyl}phenoxy)propanoic acid
(2^)-2-({[(lZ)-l-(2-Amino-l,3-thiazol-4-yl)-2-{[(3S)-2,2-dimethyl-4-oxo-l- (sulfooxy)azetidin-3-yl]amino}-2-oxoethylidene]amino}oxy)-3-(4-{N-[2-(pyrimidin-2- ylamino)ethyl]carbamimidoyl}phenoxy)propanoic acid and the salts thereof, the solvates thereof and the solvates of the salts thereof.
9. Compound according to any one of claims 1 to 8 for use in a method of treating and/or preventing diseases, in particular bacterial infections, especially with Gram- negative bacteria.
Method for the preparation of a compound of formula (I) according to claim 1 comprising removing the protecting group from a compound of formula
Figure imgf000292_0001
in which Pg represents a protecting group and R^R3, A, 1, X, Y and Z are as defined in claim 1.
11. Method according to claim 10, characterized in that compound (II) is prepared by reacting a compound of formula
Figure imgf000292_0002
in which Pg represents a protecting group and A, 1, X, Y and Z are as defined in claim 1, with a compound of formula
Figure imgf000292_0003
in which R1, R2and R3 are as defined in claim 1.
12. Use of a compound according to any one of claims 1 to 9 for the treatment and/or prophylaxis of diseases.
13. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment and/or prophylaxis of diseases.
14. Use of a compound according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment and/or prophylaxis of bacterial infections.
15. Medicament comprising at least one compound according to any one of claims 1 to 9 in combination with at least one further active compound.
16 Medicament according to claim 15, characterized in that the further active compound is a /3-lactamase inhibitor.
17. Medicament comprising at least one compound according to any one of claims 1 to 9 in combination with at least one inert, non-toxic, pharmaceutically acceptable excipient.
18. Medicament according to any one of claims 15 to 17 for use in a method of treating and/or preventing bacterial infections.
19. Method for controlling bacterial infections in humans and animals by administering an antibacterially effective amount of at least one compound according to any one of claims 1 to 9 or a medicament according to any one of claims 15 to 18.
PCT/EP2013/051217 2012-01-24 2013-01-23 Amidine substituted beta - lactam compounds, their preparation and use as antibacterial agents WO2013110643A1 (en)

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MX2014008915A MX346602B (en) 2012-01-24 2013-01-23 Amidine substituted beta - lactam compounds, their preparation and use as antibacterial agents.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015103583A1 (en) * 2014-01-06 2015-07-09 President And Fellows Of Harvard College Monobactams and methods of their synthesis and use
WO2015148379A1 (en) 2014-03-24 2015-10-01 Novartis Ag Monobactam organic compounds for the treatment of bacterial infections
WO2017050218A1 (en) * 2015-09-23 2017-03-30 Novartis Ag Salts and solid forms of monobactam antibiotic
WO2017106064A1 (en) 2015-12-15 2017-06-22 Merck Sharp & Dohme Corp. Biaryl monobactam compounds and methods of use thereof for the treatment of bacterial infections
WO2017155765A1 (en) 2016-03-07 2017-09-14 Merck Sharp & Dohme Corp. Bicyclic aryl monobactam compounds and methods of use thereof for the treatment of bacterial infections
WO2018014823A1 (en) 2016-07-21 2018-01-25 中国科学院上海药物研究所 Monocyclic β-lactam-iron carrier conjugate, and manufacturing method and application thereof
WO2018038906A1 (en) * 2016-08-26 2018-03-01 Codexis, Inc. Engineered imine reductases and methods for the reductive amination of ketone and amine compounds
WO2018065636A1 (en) 2016-12-21 2018-04-12 Aicuris Anti-Infective Cures Gmbh COMBINATION THERAPY WITH AMIDINE SUBSTITUTED ß-LACTAM COMPOUNDS AND ß-LACTAMASE INHIBITORS FOR INFECTIONS WITH ANTIBIOTIC RESISTANT BACTERIAL STRAINS
WO2018091671A1 (en) 2016-11-18 2018-05-24 Aicuris Anti-Infective Cures Gmbh Liposomal formulations of amidine substituted beta-lactam compounds for use in the treatment of bacterial infections
WO2018091668A1 (en) 2016-11-18 2018-05-24 Aicuris Anti-Infective Cures Gmbh Novel formulations of amidine substituted beta-lactam compounds on the basis of modified cyclodextrins and acidifying agents, their preparation and use as antimicrobial pharmaceutical compositions
WO2019016066A1 (en) 2017-07-18 2019-01-24 Bayer Cropscience Aktiengesellschaft Substituted 3-heteroaryloxy-1h-pyrazoles and salts thereof and their use as herbicidal active substances
WO2019020810A1 (en) 2017-07-28 2019-01-31 Aicuris Anti-Infective Cures Gmbh Crystalline form of (2s)-2-[[(z)-[-1-(2-amino-4-thiazolyl)-2-[[(3s)-2,2-dimethyl-4-oxo-1-(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-3-[4-[imino[(3r)-3- piperidinylamino]methyl]phenoxy]-propanoic acid
WO2019070492A1 (en) 2017-10-02 2019-04-11 Merck Sharp & Dohme Corp. Chromane monobactam compounds for the treatment of bacterial infections
WO2019144969A1 (en) 2018-01-29 2019-08-01 南京明德新药研发股份有限公司 Monocyclic β-lactam compound for treating bacterial infection
WO2020125670A1 (en) 2018-12-18 2020-06-25 南京明德新药研发有限公司 APPLICATION OF MONOCYCLIC β-LACTAM COMPOUND IN PHARMACY
WO2021121387A1 (en) 2019-12-19 2021-06-24 南京明德新药研发有限公司 Application of compound in drug preparation
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US11414411B2 (en) 2017-08-02 2022-08-16 Novartis Ag Chemical process for manufacturing monobactam antibiotic and intermediates thereof
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WO2023091438A1 (en) 2021-11-18 2023-05-25 Merck Sharp & Dohme Llc Chromane amidine monobactam antibiotics

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Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002008A1 (en) 1977-11-03 1979-05-30 Linde Aktiengesellschaft Process for the biological purification of waste water
EP0073061A2 (en) 1981-08-27 1983-03-02 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Optically uniform beta-lactams, their preparation and use in the preparation of antimicrobial beta-lactams, and starting compounds for use in their preparation
DE3336262A1 (en) 1982-10-06 1984-04-12 E.R. Squibb & Sons, Inc., 08540 Princeton, N.J. NEW SS LACTAME
BE904699A (en) 1985-04-29 1986-08-18 Squibb & Sons Inc HYDROXAMIC ACIDS OF BETA-LACTAMES O-SULPHATES, THEIR ACID ADDED SALTS, AS WELL AS THEIR PREPARATION AND THEIR USE.
EP0336667A2 (en) 1988-04-04 1989-10-11 E.R. Squibb &amp; Sons, Inc. [3S(Z)]-3-[[(2-amino-4-thiazolyl)[[2-(hydroxyamino)-2-oxoethoxy]imino]acetyl]-amino]-2,2-dimethyl-4-oxo-1-azetidinyl sulfate
US5112968A (en) 1989-07-28 1992-05-12 E. R. Squibb & Sons, Inc. Monobactam hydrazide derivatives
EP0484881A2 (en) 1990-11-05 1992-05-13 E.R. SQUIBB &amp; SONS, INC. Heteroaroyl derivatives of monocyclic beta-lactam antibiotics
EP0531976A1 (en) 1991-09-09 1993-03-17 E.R. SQUIBB &amp; SONS, INC. Heteroaryl derivatives of monocyclic beta-lactam antibiotics
US5318963A (en) 1989-09-21 1994-06-07 E. R. Squibb & Sons, Inc. Heterocyclic hydrazide derivatives of monocyclic β-lactam antibiotics
WO1999010324A1 (en) * 1997-08-29 1999-03-04 Naeja Pharmaceutical Inc. AZETIDINONE DERIVATIVES AS β-LACTAMASE INHIBITORS
WO2002022613A1 (en) 2000-09-14 2002-03-21 Pantherix Limited 3-(heteroaryl acetamido)-2-oxo-azetidine-1-sulfonic acids derivatives as antibacterial agents
WO2005070874A1 (en) 2004-01-27 2005-08-04 Merck Frosst Company Nitric oxide releasing prodrugs of diaryl-2-(5h)-furanones as cyclooxygenase-2 inhibitors
WO2007065288A2 (en) 2005-12-07 2007-06-14 Basilea Pharmaceutica Ag Useful combinations of monobactam antibiotics with beta-lactamase inhibitors
WO2008096189A2 (en) 2005-09-23 2008-08-14 M's Science Corporation Piperidine and piperazine derivatives
WO2008116813A2 (en) 2007-03-23 2008-10-02 Basilea Pharmaceutica Ag Combination medicaments for treating bacterial infections
EP1990336A1 (en) 2006-02-14 2008-11-12 Ihara Chemical Industry Co., Ltd. Process for production of 5-alkoxy-4-hydroxymethylpyrazole compound
US20090012054A1 (en) 2006-03-16 2009-01-08 Astellas Pharma Inc. Cephem Compounds and Use as Antimicrobial Agents
WO2009049028A1 (en) 2007-10-09 2009-04-16 Targegen Inc. Pyrrolopyrimidine compounds and their use as janus kinase modulators
WO2010070523A1 (en) 2008-12-19 2010-06-24 Pfizer Inc. Monocarbams

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE794886A (en) * 1972-02-22 1973-08-02 Pfizer 6- (ALPHA- (OMEGA-GUANIDINOALCANOYLAMINO) ACYLAMINO) -PENICILLANIC ACIDS
DE2458973A1 (en) * 1974-12-13 1976-06-16 Hoechst Ag ACYLAMINOPENICILLANIC ACIDS AND THE METHOD FOR THEIR PRODUCTION
ZA806977B (en) * 1979-11-19 1981-10-28 Fujisawa Pharmaceutical Co 7-acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof
JPS58210061A (en) * 1982-05-31 1983-12-07 Takeda Chem Ind Ltd 1-sulfo-2-oxoazetidine derivative, its preparation and use

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002008A1 (en) 1977-11-03 1979-05-30 Linde Aktiengesellschaft Process for the biological purification of waste water
EP0073061A2 (en) 1981-08-27 1983-03-02 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Optically uniform beta-lactams, their preparation and use in the preparation of antimicrobial beta-lactams, and starting compounds for use in their preparation
DE3336262A1 (en) 1982-10-06 1984-04-12 E.R. Squibb & Sons, Inc., 08540 Princeton, N.J. NEW SS LACTAME
BE904699A (en) 1985-04-29 1986-08-18 Squibb & Sons Inc HYDROXAMIC ACIDS OF BETA-LACTAMES O-SULPHATES, THEIR ACID ADDED SALTS, AS WELL AS THEIR PREPARATION AND THEIR USE.
EP0336667A2 (en) 1988-04-04 1989-10-11 E.R. Squibb &amp; Sons, Inc. [3S(Z)]-3-[[(2-amino-4-thiazolyl)[[2-(hydroxyamino)-2-oxoethoxy]imino]acetyl]-amino]-2,2-dimethyl-4-oxo-1-azetidinyl sulfate
US5112968A (en) 1989-07-28 1992-05-12 E. R. Squibb & Sons, Inc. Monobactam hydrazide derivatives
US5318963A (en) 1989-09-21 1994-06-07 E. R. Squibb & Sons, Inc. Heterocyclic hydrazide derivatives of monocyclic β-lactam antibiotics
EP0484881A2 (en) 1990-11-05 1992-05-13 E.R. SQUIBB &amp; SONS, INC. Heteroaroyl derivatives of monocyclic beta-lactam antibiotics
US5290929A (en) 1990-11-05 1994-03-01 E. R. Squibb & Sons, Inc. Heteroaryl derivatives of monocyclic beta-lactam antibiotics
EP0531976A1 (en) 1991-09-09 1993-03-17 E.R. SQUIBB &amp; SONS, INC. Heteroaryl derivatives of monocyclic beta-lactam antibiotics
WO1999010324A1 (en) * 1997-08-29 1999-03-04 Naeja Pharmaceutical Inc. AZETIDINONE DERIVATIVES AS β-LACTAMASE INHIBITORS
WO2002022613A1 (en) 2000-09-14 2002-03-21 Pantherix Limited 3-(heteroaryl acetamido)-2-oxo-azetidine-1-sulfonic acids derivatives as antibacterial agents
WO2005070874A1 (en) 2004-01-27 2005-08-04 Merck Frosst Company Nitric oxide releasing prodrugs of diaryl-2-(5h)-furanones as cyclooxygenase-2 inhibitors
WO2008096189A2 (en) 2005-09-23 2008-08-14 M's Science Corporation Piperidine and piperazine derivatives
WO2007065288A2 (en) 2005-12-07 2007-06-14 Basilea Pharmaceutica Ag Useful combinations of monobactam antibiotics with beta-lactamase inhibitors
EP1990336A1 (en) 2006-02-14 2008-11-12 Ihara Chemical Industry Co., Ltd. Process for production of 5-alkoxy-4-hydroxymethylpyrazole compound
US20090012054A1 (en) 2006-03-16 2009-01-08 Astellas Pharma Inc. Cephem Compounds and Use as Antimicrobial Agents
WO2008116813A2 (en) 2007-03-23 2008-10-02 Basilea Pharmaceutica Ag Combination medicaments for treating bacterial infections
WO2009049028A1 (en) 2007-10-09 2009-04-16 Targegen Inc. Pyrrolopyrimidine compounds and their use as janus kinase modulators
WO2010070523A1 (en) 2008-12-19 2010-06-24 Pfizer Inc. Monocarbams

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
BIOORG. MED. CHEM., vol. 38, no. 21, 2007, pages 6716 - 6732
CHEM. & PHARM. BULL., vol. 38, no. 12, 1990, pages 3476 - 3479
CHEM. COMMUN., 2007, pages 2977 - 2979
CHEMMEDCHEM., vol. 2, no. 5, 2007, pages 641 - 654
DAVID M. FLOYD; ALAN W. FRITZ; JOSIP PLUSCEC; EUGENE R. WEAVER; CHRISTOPHER M. CIMARUSTI, J. ORG. CHEM., vol. 47, no. 26, 1982, pages 5160 - 5167
H.W. BOUCHER ET AL.: "Bad bugs, no drugs: No ESKAPE! An update from the Infectious Diseases Society of America", CLIN INF DIS, vol. 48, 2009, pages 1 - 12
HETEROCYCLES, vol. 65, no. 11, 2005, pages 2667 - 2674
J. AM . CHEM. SOC., vol. 131, no. 10, 2009, pages 3762 - 3771
J. AM. CHEM. SOC., vol. 121, 1999, pages 6086 - 6087
J. ANTIBIOTICS, vol. 38, no. 11, 1985, pages 1536 - 1549
J. MED. CHEM., 1989, pages 2104 - 2110
J. ORG. CHEM., vol. 47, no. 26, 1982, pages 5160 - 5167
KENNETH BOWDEN; I. M. HEILBRON; E. R. H. JONES; B. C. L. WEEDON, J. CHEM. SOC., 1946, pages 39 - 45
M. SENDAI; S. HASHIGUCHI; M. TOMIMOTO; S. KISHIMOTO; T. MATSUO; M. OCHIAI, CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 33, no. 9, 1985, pages 3798 - 3810
ORG. PROC. RES. DEV., vol. 6, no. 6, 2002, pages 863 - 868
R.B. SYKES; D.P. BONNER: "Discovery and Development of the monobactams", REV. INFECT. DIS., vol. 7, no. 4, 1985, pages 579 - 593
SAKAGAMI, KENJI; IWAMATSU, KATSUYOSHI; ATSUMI, KUNIO; HATANAKA, MINORU, CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 38, no. 12, 1990, pages 3476 - 3479
TETRAHEDRON LETT., vol. 42, no. 50, 2001, pages 8743 - 8745
W.C. HELLINGER; N.S. BREWER; CARBAPENEMS; MONOBACTAMS: "Imipenem, Meropenem and Aztreonam", MAYO CLIN. PROC., vol. 74, 1999, pages 420 - 434
YAMAWAKI, KENJI; NOMURA, TAKASHI; YASUKATA, TATSURO; UOTANI, KOICHI; MIWA, HIDEAKI; TAKEDA, KEI; NISHITANI, YASUHIRO, BIOORGANIC & MEDICINAL CHEMISTRY, vol. 38, no. 21, 2007, pages 6716 - 6732

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EP3426248A4 (en) * 2016-03-07 2019-07-10 Merck Sharp & Dohme Corp. Bicyclic aryl monobactam compounds and methods of use thereof for the treatment of bacterial infections
US10407421B2 (en) 2016-03-07 2019-09-10 Merck Sharp & Dohme Corp Bicyclic aryl monobactam compounds and methods of use thereof for the treatment of bacterial infections
WO2017155765A1 (en) 2016-03-07 2017-09-14 Merck Sharp & Dohme Corp. Bicyclic aryl monobactam compounds and methods of use thereof for the treatment of bacterial infections
CN108778273A (en) * 2016-03-07 2018-11-09 默沙东公司 The method of aryl bicyclic monocycle beta-lactam compound and its purposes for treating bacterium infection
US10501454B2 (en) 2016-07-21 2019-12-10 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Monocyclic β-lactam-siderophore conjugate, and preparation method and use thereof
WO2018014823A1 (en) 2016-07-21 2018-01-25 中国科学院上海药物研究所 Monocyclic β-lactam-iron carrier conjugate, and manufacturing method and application thereof
WO2018038906A1 (en) * 2016-08-26 2018-03-01 Codexis, Inc. Engineered imine reductases and methods for the reductive amination of ketone and amine compounds
US11987818B2 (en) 2016-08-26 2024-05-21 Codexis, Inc. Engineered imine reductases and methods for the reductive amination of ketone and amine compounds
US11046936B2 (en) 2016-08-26 2021-06-29 Codexis, Inc. Engineered imine reductases and methods for the reductive amination of ketone and amine compounds
WO2018091668A1 (en) 2016-11-18 2018-05-24 Aicuris Anti-Infective Cures Gmbh Novel formulations of amidine substituted beta-lactam compounds on the basis of modified cyclodextrins and acidifying agents, their preparation and use as antimicrobial pharmaceutical compositions
WO2018091671A1 (en) 2016-11-18 2018-05-24 Aicuris Anti-Infective Cures Gmbh Liposomal formulations of amidine substituted beta-lactam compounds for use in the treatment of bacterial infections
CN110312715A (en) * 2016-12-21 2019-10-08 艾库里斯有限及两合公司 For the 'beta '-lactam compounds of antibiotic resistant bacteria strain infection replaced using amidine and the combination treatment of beta-lactamase inhibitor
WO2018065636A1 (en) 2016-12-21 2018-04-12 Aicuris Anti-Infective Cures Gmbh COMBINATION THERAPY WITH AMIDINE SUBSTITUTED ß-LACTAM COMPOUNDS AND ß-LACTAMASE INHIBITORS FOR INFECTIONS WITH ANTIBIOTIC RESISTANT BACTERIAL STRAINS
WO2019016066A1 (en) 2017-07-18 2019-01-24 Bayer Cropscience Aktiengesellschaft Substituted 3-heteroaryloxy-1h-pyrazoles and salts thereof and their use as herbicidal active substances
WO2019020810A1 (en) 2017-07-28 2019-01-31 Aicuris Anti-Infective Cures Gmbh Crystalline form of (2s)-2-[[(z)-[-1-(2-amino-4-thiazolyl)-2-[[(3s)-2,2-dimethyl-4-oxo-1-(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-3-[4-[imino[(3r)-3- piperidinylamino]methyl]phenoxy]-propanoic acid
US11414411B2 (en) 2017-08-02 2022-08-16 Novartis Ag Chemical process for manufacturing monobactam antibiotic and intermediates thereof
US11433055B2 (en) 2017-10-02 2022-09-06 Merck Sharp & Dohme Llc Chromane monobactam compounds for the treatment of bacterial infections
WO2019070492A1 (en) 2017-10-02 2019-04-11 Merck Sharp & Dohme Corp. Chromane monobactam compounds for the treatment of bacterial infections
EP3691639A4 (en) * 2017-10-02 2021-03-31 Merck Sharp & Dohme Corp. Chromane monobactam compounds for the treatment of bacterial infections
CN111201021A (en) * 2017-10-02 2020-05-26 默沙东公司 Chroman monocyclic β -lactams for use in the treatment of bacterial infections
US11459323B2 (en) 2018-01-29 2022-10-04 Medshine Discovery Inc. Monocyclic β-lactam compound for treating bacterial infection
CN111511737B (en) * 2018-01-29 2022-10-18 南京明德新药研发有限公司 Monocyclic beta-lactam compounds for the treatment of bacterial infections
WO2019144969A1 (en) 2018-01-29 2019-08-01 南京明德新药研发股份有限公司 Monocyclic β-lactam compound for treating bacterial infection
CN111511737A (en) * 2018-01-29 2020-08-07 南京明德新药研发有限公司 Monocyclic β -lactam compounds for the treatment of bacterial infections
EP3747883A4 (en) * 2018-01-29 2020-12-16 Medshine Discovery Inc. Monocyclic b-lactam compound for treating bacterial infection
WO2020125670A1 (en) 2018-12-18 2020-06-25 南京明德新药研发有限公司 APPLICATION OF MONOCYCLIC β-LACTAM COMPOUND IN PHARMACY
WO2021121387A1 (en) 2019-12-19 2021-06-24 南京明德新药研发有限公司 Application of compound in drug preparation
EP4165039A1 (en) * 2020-07-16 2023-04-19 Ningxia Academy of Agriculture and Forestry Sciences Novel monobactam compounds, their preparation and use as antibacterial agents
EP4165039A4 (en) * 2020-07-16 2023-06-21 Ningxia Academy of Agriculture and Forestry Sciences Novel monobactam compounds, their preparation and use as antibacterial agents
CN114728953A (en) * 2020-08-06 2022-07-08 宁夏农林科学院 Beta-lactam compounds, process for their preparation and their use as antibiotics
WO2022027439A1 (en) * 2020-08-06 2022-02-10 Ningxia Academy Of Agriculture And Forestry Sciences β-LACTAM COMPOUNDS, THEIR PREPARATION AND USE AS ANTIBACTERIAL AGENTS
CN114728953B (en) * 2020-08-06 2024-04-09 宁夏农林科学院 Beta-lactams, process for their preparation and their use as antibiotics
EP4007759A4 (en) * 2020-08-06 2024-04-10 Ningxia Academy Agriculture & Forestry Sciences Beta-lactam compounds, their preparation and use as antibacterial agents
WO2023091438A1 (en) 2021-11-18 2023-05-25 Merck Sharp & Dohme Llc Chromane amidine monobactam antibiotics
US11932637B2 (en) 2021-11-18 2024-03-19 Merck Sharp & Dohme Llc Chromane amidine monobactam compounds for the treatment of bacterial infections

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