WO2020178316A1 - Azaindazoles en 5 ou 7 utilisés comme inhibiteurs de bêta-lactamase - Google Patents

Azaindazoles en 5 ou 7 utilisés comme inhibiteurs de bêta-lactamase Download PDF

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WO2020178316A1
WO2020178316A1 PCT/EP2020/055658 EP2020055658W WO2020178316A1 WO 2020178316 A1 WO2020178316 A1 WO 2020178316A1 EP 2020055658 W EP2020055658 W EP 2020055658W WO 2020178316 A1 WO2020178316 A1 WO 2020178316A1
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alkyl
mmol
group
pyridine
ethylphenyl
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PCT/EP2020/055658
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Rosella Ombrato
Barbara Garofalo
Federica PRATI
Gabriele Magaro'
Rosa BUONFIGLIO
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Aziende Chimiche Riunite Angelini Francesco - A.C.R.A.F. S.P.A.
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Publication of WO2020178316A1 publication Critical patent/WO2020178316A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to b-lactamase inhibitors and pharmaceutical compositions thereof. More in particular, the present invention relates to 5- and 7- azaindazole derivatives able to inhibit b-lactamases and pharmaceutical compositions comprising a combination of the b-lactamase inhibitors of the present invention and b- lactam antibiotics.
  • b-lactam antibiotics are a class of broad-spectrum antibiotics containing a beta-lactam ring in their molecular structures. This class generally includes penicillin derivatives, cephalosporins, monobactams, and carbapenems. Most b-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics b-lactam antibiotics are widely employed, and it has been estimated that, when measured by sales, more than half of all commercially available antibiotics in use were b-lactam compounds.
  • b-lactamases The most widely used classification of b-lactamases is the Ambler classification (Ambler R.P. The structure of beta-lactamases. Philos Trans R Soc B Biol Sci. 1980 May; 289 (1036):321— 31 ) that divides b-lactamases into four classes (A, B, C and D) based upon their amino acid sequences.
  • Classes A, C and D include enzymes that hydrolyze their substrates by forming an acyl enzyme through an active site serine, for this reason they are also named as serine ⁇ -lactamases, whereas class B b-lactamases are metalloenzymes that utilize at least one active-site zinc ion to facilitate b-lactam hydrolysis.
  • antibiotic resistance such as reducing antibiotic prescriptions, using antibiotic alternatives or developing new antibiotic inhibitors, particularly small organic molecules, that target directly the biochemical mechanisms of antibiotic resistance.
  • the combination of the penicillin analogue amoxicillin, and the b-lactamase inhibitor, clavulanic acid provides a remarkable example of a combination therapy that permits extension of the pharmacodynamic spectrum of amoxicillin to bacteria that produce conventional or extended-spectrum b-lactamase.
  • KPC K. pneumoniae carbapenemase
  • inhibitors which do not bear the b-lactam nucleus, like diazabicyclooctane derivatives (Avibactam, Relebactam, zidebactam, nacubactam, CB-618) and boronic acid derivatives (4,7-Dichloro-1 -benzothien-2-yl sulfonylaminomethyl boronic acid (aka DSABA), Vaborbactam, VNRX-5133).
  • Diazabicyclooctane derivatives are also described in US2014288051 A1 , US2014315876A1 , W02017109025A1 , and WO2017136254A1 , and boronic acid derivatives in W02017100537A1 , US2017065626A1 , US2017226135A1 and US2017107239A1.
  • beta-lactamase inhibitors clavulanic acid, sulbactam, tazobactam
  • sulbactam sulbactam
  • tazobactam tazobactam
  • These enzyme inhibitors are available only as fixed combinations with penicillin derivatives.
  • No combinations with cephalosporins (or carbapenems) are clinically available. This fact, combined with the increased use of newer generation cephalosporins and carbapenems, is driving the selection and spread of the new beta-lactamase variants (ESBLs, carbapenemases, chromosomal and plasmid-mediated Class C, Class D oxacillinases, etc.).
  • the legacy beta-lactamase inhibitors are largely ineffective against the new Class A and Class B carbapenemases, against the chromosomal and plasmid-mediated Class C cephalosporinases and against many of the Class D oxacillinases.
  • the Applicant has faced the problem of developing new b-lactamase inhibitors.
  • the Applicant has surprisingly found that a group of azaindazole derivatives are able to inhibit clinically important carbapenem-hydrolyzing b- lactamases.
  • the Applicant has surprisingly found that 5- and 7-azaindazole derivatives were able to inhibit OXA-48 b-lactamases.
  • the present invention relates to b-lactamase inhibitors having the following general formula (I):
  • Xi and X 2 are CH or N, at least one thereof being N and at least one thereof being CH
  • R 1 is selected from the group consisting of halogen, O-Ci-Ce alkyl, C 1 -C6 alkyl-OH, COOH, Ci-Ce alkyl-COOH, COO-Ci-C 6 alkyl, Ci-Ce alkyl-COO- Ci-Ce alkyl, CONH 2 , CONHOH, SO 2 NH 2 , NHSO 2 -C 1 -C6 alkyl, and Ci-Ce alkyl,
  • R 2 is selected from the group consisting of halogen, OH, C 2 -C6 alkyl, C 1 -C6 alkyl- phenyl, aliphatic carbocyclic ring having from 3 to 12 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, O-i-Ob haloalkyl, O-i-Ob haloalkoxy, O-i-Ob alkyl-OH, and O-i-Ob alkyl, aromatic carbocyclic ring having from 3 to 12 members substituted by one or more substituents selected from the group consisting of halogen, OH, O-i-Ob haloalkyl, O-i-Ob haloalkoxy, O-i-Ob alkyl-OH, and C 1 -C 6 alkyl, and heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, other than pyridyl and thienyl, optional
  • R 3 is selected from the group consisting of COOH, C 1 -C6 alkyl-COOH, COO-C 1 -C6 alkyl, C 1 -C6 alkyl-COO-alkyl, CONH 2 , CONHOH, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, substituted by one or more substituents S a selected from the group consisting of halogen, NO 2 , COOH, C 1 -C6 alkyl- COOH, COO-C1-C6 alkyl, S0 2 N(R ll R l11 ), NHS0 2 -R IV , S0 2 CH 2 -R IV , CH 2 S0 2 -R IV , S-R v , S0 2 -R v , with the proviso that when the substituent S a of said carbocyclic or heterocyclic ring is halogen, said carbocyclic or heterocyclic ring comprises a second substitu
  • R" R 111 , R IV , and R v are independently hydrogen, Ci-Ce alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, CN, C 1 -C6 haloalkyl, C 1 -C6 haloalkoxy, C 1 -C6 alkyl, C3-C6 cycloalkyl, 0-Ci-Ce alkyl, Ci-Ce alkyl-OH, COOH, COO-Ci-C 6 alkyl, CONH 2 , NHCOCHs, and
  • R 4 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, O-Ci-Ce alkyl, C-I-C6 alkyl-OH, and O-i-Ob alkyl.
  • the dotted line of formula (I) represents any one of the sequence of single and double bonds able to form for each meaning of Xi and X 2 an aromatic bicycle ring and allowing R 4 to be linked either to the 1 -position or the 2-position of the bicycle ring, as illustrated in the formulae of the examples.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one b-lactamase inhibitor of formula (I) as described above, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and at least one inert pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the invention further comprises a beta-lactam antibiotic.
  • the pharmaceutical composition further comprises a beta-lactam antibiotic, wherein the beta-lactam antibiotic is a penicillin, cephalosporin, penem, carbapenem, clavam, monobactam, bridged monobactam, any other compound susceptible to serine beta-lactamases, or a combination thereof.
  • the beta-lactam antibiotic is a penicillin, cephalosporin, penem, carbapenem, clavam, monobactam, bridged monobactam, any other compound susceptible to serine beta-lactamases, or a combination thereof.
  • the present invention relates to the combination of (i) at least one b- lactamase inhibitor of formula (I) as described above, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and (ii) a beta-lactam antibiotic, for use in the treatment of a bacterial infection.
  • a fourth aspect provides a method of treating a bacterial infection in a subject, comprising administering to the subject a b-lactamase inhibitor of formula (I) in combination with a therapeutically effective amount of beta-lactam antibiotic.
  • the invention is a b-lactamase inhibitor according to formula (I) as described above.
  • Xi is N
  • X 2 is CH
  • Xi is CH, and X 2 is N.
  • one aspect of the invention is a b-lactamase inhibitor according to any of the formulae (lc) to (1 f) described below:
  • R 1 is selected from the group consisting of halogen, 0-Ci-Ce alkyl, Ci-C 6 alkyl-OH, COOH, Ci-C 6 alkyl-COOH, COO-Ci-Ce alkyl, Ci-C 6 alkyl-COO-Ci- Ce alkyl, CONH2, CONHOH, SO2NH2, NHS0 2 -Ci-Ce alkyl, and Ci-Ce alkyl.
  • R 1 is selected from the group consisting of halogen, O-C 1 -C 4 alkyl, Ci-C 4 alkyl-OH, COOH, Ci-C 4 alkyl-COOH, COO-C 1 -C 4 alkyl, Ci- C 4 alkyl-COO-Ci-C 4 alkyl, CONH 2 , CONHOH, SO2NH2, NHSO2-C1-C4 alkyl, and C1-C4 alkyl.
  • R 1 is selected from the group consisting of halogen, O-C 1 -C 2 alkyl, Ci-C 2 alkyl-OH, COOH, Ci-C 2 alkyl-COOH, COO-C 1 -C 2 alkyl, Ci- C 2 alkyl-COO-Ci-C 2 alkyl, CONH 2 , CONHOH, SO2NH2, NHSO2-C1-C2 alkyl, and C1-C2 alkyl.
  • R 1 is selected from the group consisting of halogen, O-C 1 -C 2 alkyl, C 1 -C 2 alkyl-OH, COOH, COO-C 1 -C 2 alkyl, CONH 2 , CONHOH, C 1 -C 2 alkyl.
  • R 2 is selected from the group consisting of halogen, OH, C 2 -C 6 alkyl, C 1 -C 6 alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 12 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, Ci-Ce haloalkyl, Ci-C6haloalkoxy, Ci-C6alkyl-OH, and Ci-Ce alkyl, aromatic carbocyclic ring having from 3 to 12 members substituted by one or more substituents selected from the group consisting of halogen, OH, Ci-Ce haloalkyl, Ci-C 6 haloalkoxy, Ci- Ce alkyl-OH, and Ci-Ce alkyl, and heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, other than pyridyl and thienyl, optionally substituted by one or more substituents selected from the group consisting
  • R 2 is selected from the group consisting ofhalogen, OH, C 2 -C 4 alkyl, C 1 -C 4 alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 10 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkyl-OH, and C 1 -C 4 alkyl, aromatic carbocyclic ring having from 4 to 10 members substituted by one or more substituents selected from the group consisting of halogen, OH, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkyl-OH, and C 1 -C 4 alkyl, and heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, other than pyridyl and
  • R 2 is selected from the group consisting ofhalogen, OH, C 2 -C 4 alkyl, C 1 -C 2 alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 6 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, Ci-C 2 alkyl-OH, and C 1 -C 2 alkyl, aromatic carbocyclic ring having from 4 to 10 members substituted by one or more substituents selected from the group consisting of halogen, OH, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 2 alkyl-OH, and C 1 -C 2 alkyl, and heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, other than pyridyl and thien
  • R 2 is selected from the group consisting of halogen, OH, C3 alkyl, C1 -C2 alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 6 members optionally substituted by one or more substituents selected from the group consisting of halogen, OH, C1 -C2 haloalkyl, C1 -C2 haloalkoxy, C1 -C2 alkyl-OH, and C1 -C2 alkyl, aromatic carbocyclic ring having from 3 to 6 members substituted by one or more substituents selected from the group consisting of halogen, OH, C1 -C2 haloalkyl, C1 -C2 haloalkoxy, C1 -C2 alkyl-OH, and C1 -C2 alkyl, and heterocyclic ring, aliphatic or aromatic, having from 3 to 6 members, other than pyridyl and thienyl, substituted by
  • R 3 is selected from the group consisting of COOH, Ci-C 6 alkyl- COOH, COO-Ci-C 6 alkyl, Ci-C 6 alkyl-COO-alkyl, CONH 2 , CONHOH, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, substituted by one or more substituents S a selected from the group consisting of halogen, NO 2 , COOH, Ci- Cealkyl-COOH, COO-Ci-C 6 alkyl, S0 2 N(R ll R l11 ), NHS0 2 -R IV , S0 2 CH 2 -R IV , CH 2 S0 2 -R IV , S- R v , S0 2 -R v , with the proviso that when the substituent S a of said carbocyclic or heterocyclic ring is halogen, said carbocyclic or heterocyclic ring comprises a second substituent S a
  • R" R 111 , R IV , and R v are independently hydrogen, Ci-Ce alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, CN, C 1 -C6 haloalkyl, C 1 -C6 haloalkoxy, C 1 -C6 alkyl, C3-C6 cycloalkyl, 0-Ci-Ce alkyl, Ci-Ce alkyl-OH, COOH, COO-Ci-C 6 alkyl, CONH 2 ,
  • R 3 is selected from the group consisting of COOH, Ci-C 4 alkyl-COOH, COO-C 1 -C 4 alkyl, Ci-C 4 alkyl-COO-alkyl, CONH 2 , CONHOH, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, substituted by one or more substituents S a selected from the group consisting of halogen, NO2, COOH, Ci-C 4 alkyl-COOH, COO-Ci-C 4 alkyl, S0 2 N(R ll R l11 ), NHS0 2 -R IV , SO2CH2- R IV , CH 2 S0 2 -R iv , S-R v , S0 2 -R v , with the proviso that when the substituent S a of said carbocyclic or heterocyclic ring is halogen, said carbocyclic or heterocyclic ring comprises a second substituent
  • R" R IN , R IV , and R v are independently hydrogen, Ci-C 4 alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, CN, Ci-C 4 haloalkyl, Ci-C 4 haloalkoxy, Ci-C 4 alkyl, C 3 -C 6 cycloalkyl, 0-Ci-C 4 alkyl, Ci-C 4 alkyl-OH, COOH, COO-Ci-C 4 alkyl, CONH 2 , NHCOCH3.
  • R 3 is selected from the group consisting of COOH, C1-C2 alkyl-COOH, COO-C1-C2 alkyl, Ci-C 2 alkyl-COO-alkyl, CONH 2 , CONHOH, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members, substituted by one or more substituents S a selected from the group consisting of halogen, NO2, COOH, C1-C2 alkyl-COOH, COO-C1-C2 alkyl, S0 2 N(R ll R l11 ), NHS0 2 -R IV , SO2CH2- R IV , CH 2 S0 2 -R iv , S-R v , S0 2 -R v , with the proviso that when the substituent S a of said carbocyclic or heterocyclic ring is halogen, said carbocyclic or heterocyclic ring comprises a second substituent S a selected from the group
  • R" R 111 , R IV , and R v are independently hydrogen, C 1 -C 2 alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, CN, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 2 alkyl, C3-C6 cycloalkyl, O-C 1 -C 2 alkyl, C 1 -C 2 alkyl-OH, COOH, COO-C 1 -C 2 alkyl, CONH 2 , NHCOCH3.
  • R 3 is selected from the group consisting of COOH, C 1 -C 2 alkyl-COOH, COO-C 1 -C 2 alkyl, C 1 -C 2 alkyl-COO-alkyl, CONH 2 , CONHOH, and carbocyclic or heterocyclic ring, aromatic, having from 5 to 6 members substituted by one or more substituents S a selected from the group consisting of halogen, NO 2 , COOH, C 1 -C 2 alkyl- COOH, COO-C1-C2 alkyl, S0 2 N(R ll R l11 ), NHS0 2 -R IV , S0 2 CH 2 -R IV , CH 2 S0 2 -R IV , S-R v , S0 2 -R v , with the proviso that when the substituent S a of said carbocyclic or heterocyclic ring is halogen, said carbocyclic or heterocyclic ring comprises a second substituent S a second substitu
  • R" are independently hydrogen, C 1 -C 2 alkyl, carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members substituted by one or more substituents selected from the group consisting of halogen, OH, CN, C-i- C 2 haloalkyl, C 1 -C 2 alkyl, C3-C6 cycloalkyl, O-C 1 -C 2 alkyl, Ci-C 2 alkyl-OH, and CONH 2 .
  • the carbocyclic or heterocyclic ring of R 3 is selected from phenyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, isoxazolyl, triazolyl, thiazolyl, pyrazolyl, and thiophenyl.
  • R 4 is selected from the group consisting of hydrogen, Ci-Ce alkyl, C 1 -C6 alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C 1 -C6 haloalkyl, C 1 -C6 haloalkoxy, OH, 0-Ci-Ce alkyl, Ci-Ce alkyl-OH, and C 1 -C 6 alkyl.
  • R 4 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, OH, O-C 1 -C 4 alkyl, Ci-C 4 alkyl-OH, and C 1 -C 4 alkyl.
  • R 4 is selected from the group consisting of hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkyl-C3-C6 cycloalkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, OH, O-C 1 -C 2 alkyl, Ci-C 2 alkyl-OH, and C 1 -C 2 alkyl.
  • R 4 is selected from the group consisting of hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkyl-C3-C6 cycloalkyl, and aromatic carbocyclic or heterocyclic ring having 6 members substituted by one or more substituents selected from the group consisting of halogen, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, OH, O-C 1 -C 2 alkyl, Ci-C 2 alkyl-OH, and C 1 -C 2 alkyl.
  • the carbocyclic or heterocyclic ring of R 4 is selected from phenyl and pyridinyl.
  • At least one of Ri and R 3 as described above comprises at least one acidic hydrogen containing group or substituent.
  • both Ri and R 3 as described above comprise at least one acidic hydrogen containing group or substituent.
  • acidic hydrogen containing group or substituent herein means a group or substituent having an acid dissociation constant (pKa) of not more than 7, preferably not more than 6.5, more preferably not more than 6, and advantageously not more than 5.
  • acidic hydrogen containing groups or substituents are -COOH, - OH (especially when linked to an aromatic or heteroaromatic ring), -SO3H, -SO2NH-, - NHSO2-, -CONH2, -CONH-, -NHCO-, -CONHOH, -SO2NH2, and -NHS0 2 -Ci-Ce alkyl.
  • halogen atom includes iodide, bromide, chloride and fluoride, preferably bromide, chloride and fluoride, more preferably chloride and fluoride.
  • C1-C6 alkyl means a linear or branched alkyl chain comprising from 1 to 6 carbon atoms, such as for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, sec-pentyl, 3- pentyl, n-hexyl, isohexyl, neo-hexyl, 3-methyl-pentyl, 2,3-dimethylbutyl.
  • C1-C4 alkyl means a linear or branched alkyl chain comprising from 1 to 4 carbon atoms, such as for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • C1-C2 alkyl means a linear alkyl chain comprising from 1 to 2 carbon atoms, such as methyl and ethyl.
  • C3-C6 cycloalkyl means a saturated or unsaturated ring comprising from 3 to 6 carbon atoms, such as for example cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl.
  • Ci-Ce alkyl-OH has the meaning of a“C1-C6 alkyl”, “C1-C4 alkyl” and “C1-C2 alkyl” group, respectively, wherein one or more hydrogen atom of the alkyl chain is substituted by a hydroxyl group (OH), such as for example, -CH2OH, -(CH 2 ) 2 0H, - (CH 2 ) 3 OH, and (CH 3 )2CHOHCH 2 -.
  • OH hydroxyl group
  • O-C1-C6 alkyl has the meaning of a“C1-C6 alkyl”, “C1-C4 alkyl” and “Ci- C2 alkyl” group, respectively, wherein the alkyl chain is linked by a oxy group (O), such as for example, CH3O-, CH3CH2O-, CH 3 (CH 2 )20-, and (0H 3 ) 3 00-.
  • a oxy group such as for example, CH3O-, CH3CH2O-, CH 3 (CH 2 )20-, and (0H 3 ) 3 00-.
  • C1-C6 haloalkyl has the meaning of a“C1-C6 alkyl”, “C1-C4 alkyl” and “C1-C2 alkyl” group, respectively, wherein one or more hydrogen atom of the alkyl chain is substituted by a halogen atom (F, Cl, Br, I), such as for example, halomethyl, haloethyl, halopropyl, haloisopropyl, n-halobutyl, haloisobutyl, sec-halobutyl, tert-halobutyl, n- halopentyl, haloisopentyl, haloneopentyl, tert-halopentyl, sec-halopentyl, 3-halopentyl, n- halohexyl, ha
  • haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2- difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 1 , 1 -difluoroethyl, pentafluoroethyl, 1 -fluoro-1-methylethyl, 2-fluoro-1 ,1-dimethylethyl, 2-fluoro-1 - fluoromethyl-1-methylethyl, 2-fluoroo
  • haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl.
  • C1-C6 haloalkoxy has the meaning of a "C1-C6 haloalkyl”, “Ci- C4 haloalkyl”, and “C1-C2 haloalkyl” group, respectively, wherein the haloalkyl chain is linked by a oxy group (O), such as for example, halomethoxy, haloethoxy, halopropoxy, haloisopropoxy, n-halobutoxy, haloisobutoxy, sec-halobutoxy, tert-halobutoxy, n- halopentoxy, haloisopentoxy, haloneopentoxy, tert-halopentoxy, sec-halopentoxy, 3- halopentoxy, n-halohexoxy, haloisohexoxy, neo-halo hexoxy
  • haloalkoxy refers to an alkoxy group substituted with 1 to 3 halogens, preferably chloride, bromide, and fluoride, more preferably fluoride.
  • haloalkyl include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and 2-chloro-3-fluoropentoxy.
  • C1-C6 alkyl-COOH has the meaning of a“Ci-C 6 alkyl”, “C1-C4 alkyl” and “C1-C2 alkyl” group, respectively, wherein one or more hydrogen atom of the alkyl chain is substituted by a carboxyl group (COOH), such as for example, -CH2COOH, -(CH 2 ) 2 COOH, -(CH 2 ) 3 COOH, and (CH 3 ) 2 CCOOH.
  • COOH carboxyl group
  • COO-C1-C6 alkyl has the meaning of a“C1-C6 alkyl”, “C1-C4 alkyl” and “C1-C2 alkyl” group, respectively, substituting the hydrogen atom of the carboxyl group (COOH), such as for example, -COOCH3, -COOCH2CH3, -COO(CH 2 ) 2 CH3, and - C00C(CH 2 ) 3 .
  • Ci-C 6 alkyl- COO-Ci-C 6 alkyl has the meaning of a “Ci-Ce alkyl-COOH”, “C1-C4 alkyl-COOH”, and "C1-C2 alkyl-COOH” group, respectively, wherein the hydrogen atom of the carboxyl group (COOH) is substituted by a“C 1 -C6 alkyl”, “C 1 -C 4 alkyl” and "C 1 -C 2 alkyl” group, respectively, such as for example, - CH2COOCH2CH3,
  • the aliphatic or aromatic carbocyclic ring as defined in the above described formula (I) can be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, cyclobutenyl, cyclopentenyl cyclohexenyl, decalinyl, phenyl, and naphthalenyl.
  • the aliphatic or aromatic heterocyclic ring as defined in the above described formula (I) can be selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, imidazolyl, morpholinyl, thiazolyl, thiazolidinyl, thiadiazolyl, thiadiazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, triazolyl, and pyrazolyl.
  • the aliphatic or aromatic carbocyclic ring as defined in the above described formula (I) can be selected from the group consisting of phenyl, cyclopropyl, cyclohexenyl, and cyclohexyl.
  • the aliphatic or aromatic heterocyclic ring as defined in the above described formula (I) can be selected from the group consisting of pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, furanyl, thiophenyl, pyrrolyl, isoxazolyl, triazolyl, thiazolyl, and pyrazolyl.
  • the wording "optionally substituted” indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted.
  • the appropriate number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valence of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound.
  • the particular group when a particular group is designated as being optionally substituted with one or more substituents, the particular group may be unsubstituted.
  • the particular group may bear one substituent.
  • the particular substituent may bear two substituents.
  • the particular group may bear three substituents.
  • the particular group may bear four substituents. In a further aspect, the particular group may bear one or two substituents. In still a further aspect, the particular group may be unsubstituted, or may bear one or two substituents.
  • pharmaceutically acceptable and “physiologically acceptable” are intended to define, without any particular limitation, any material suitable for preparing a pharmaceutical composition to be administered to a living being.
  • R 1 is selected from halogen, O-Ci-Ce alkyl, Ci-C 6 alkyl-OH, COOH, COO-Ci-Ce alkyl, CONH 2 , CONHOH, Ci-Ce alkyl.
  • R 2 is selected fromhalogen, OH, C 2 -C 6 alkyl, C 1 -C 6 alkyl-phenyl, aliphatic carbocyclic ring having from 3 to 6 members optionally substituted by one or more substituents selected from the group consisting of halogen, and Ci-Ce alkyl, aromatic carbocyclic ring having from 3 to 6 members substituted by one or more substituents selected from the group consisting of halogen, and Ci-Ce alkyl, and heterocyclic ring, aliphatic or aromatic, having from 3 to 6 members, other than pyridyl and thienyl, substituted by one or more substituents selected from the group consisting of O-C 1 -C 2 alkyl, Ci-C 2 alkyl-OH, and C 1 -C 2 alkyl.
  • R 3 is represented by the following general formula (a):
  • Rng1 is selected from the group consisting of carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members,
  • L is a divalent linking group selected from the group consisting of -SO 2 NH-, -NHSO 2 -, -SO2CH2-, -CH2SO2-, -S-, and -SO2-,
  • Rng2 is selected from the group consisting of carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members,
  • S1 is one or more substituents selected from the group consisting of halogen, OH, CN, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, Ci-Ce alkyl, C3-C6 cycloalkyl, O-Ci-Ce alkyl, C-i-Cealkyl- OH, COOH, COO-Ci-Ce alkyl, CONH 2 , and NHCOCH3.
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 haloalkyl, O-C 1 - Ce alkyl, C1-C6 alkyl-OH, COOH, Ci-Ce alkyl-COOH, COO-Ci-Ce alkyl, Ci-Ce alkyl-COO- Ci-Ce alkyl, CONH 2 , CONHOH, SO2NH2, NHS0 2 -Ci-Ce alkyl, Ci-Ce alkyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, C 1 -C6 haloalkyl, C 1 -C6 haloalkoxy, OH, O-Ci-Ce alkyl, C 1 -C6 alkyl-OH, COOH, and COO-C 1 -C 6 alkyl, and
  • R 2 is selected from the group consisting of hydrogen, halogen, OH, Ci-Ce alkyl, C 1 -C6 alkyl-phenyl, C 1 -C6 alkyl-OH, C-i-Ce haloalkyl, O-C-i-Ce alkyl, O-phenyl, and carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, OH, C-i-Ce haloalkyl, Ci-C 6 haloalkoxy, O-Ci-Ce alkyl, Ci-Ce alkyl-OH, and Oi-Ob alkyl.
  • R 3 is represented by the following general formula (b):
  • Rng1 is selected from the group consisting of carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 3 to 12 members, and
  • S2 is one or more substituents selected from the group consisting of halogen, NO2, COOH, C1-C6 alkyl-COOH, COO-Ci-Ce alkyl, SO2NH2, S0 2 NHCi-Ce alkyl, NHS0 2 Ci-C 6 alkyl, S-C1-C6 alkyl, and SO2-C1-C6 alkyl, with the proviso that when S2 is halogen, Rng1 comprises a second S2 substituent, preferably selected from the group consisting of COOH and S0 2 N(R ll R l11 ).
  • Rng1 is a carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, preferably a carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members.
  • Rng1 is selected from phenyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, isoxazolyl, triazolyl, pyrazolyl, thiazolyl, and thiophenyl.
  • Rng2 is a carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 4 to 10 members, preferably a carbocyclic or heterocyclic ring, aliphatic or aromatic, having from 5 to 6 members.
  • Rng2 is selected from phenyl, pyridinyl, pyrazolyl, and thiophenyl.
  • S1 is selected from halogen, CN, C1-C6 haloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, O-Ci-Ce alkyl, COOH, and CONH2.
  • S2 is selected from halogen, NO2, COOH, Ci-Ce alkyl-COOH, SO2NH2, S0 2 NHCi-C e alkyl, and NHS0 2 Ci-C 6 alkyl, with the proviso that when S2 is halogen, Rng1 comprises a second S2 substituent, preferably selected from the group consisting of COOH and S0 2 N(R M R IM ).
  • R 4 is selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkyl-C3-C6 cycloalkyl, and phenyl-C-i-Ce alkyl.
  • the compounds of formula (I) according to the present invention may form stable pharmaceutically acceptable acid or base salts with a pharmaceutically acceptable organic or inorganic acid or base, and in such cases administration of a compound as a salt may be appropriate.
  • acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nit
  • base addition salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N- methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and so forth.
  • basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others.
  • Non toxic physiologically-acceptable salts are preferred, although other salts may be useful, such as in isolating or purifying the product.
  • the salts may be formed by conventional means, such as by reacting the free form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble, such as for example water or ethanol, which is removed under vacuum or by freeze drying.
  • the present invention also includes the prodrugs, stereoisomers, and enantiomers of the compounds of formula (I) described above.
  • prodrug refers to an agent, which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • prodrug a compound of the present invention wherein it is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolysed once inside the cell where water solubility is beneficial.
  • Prodrugs have many useful properties. For example, a prodrug may be more water- soluble than the ultimate drug, thereby facilitating intravenous administration of the drug. A prodrug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue. In the present invention, prodrugs are particularly useful to make active beta-lactamase inhibitor compounds orally bioavailable following absorption from the gastrointestinal tract.
  • Ester prodrugs of the compounds disclosed herein are specifically contemplated.
  • An ester may be formed from a hydroxyl functional group linked to a compound of formula (I) above by reaction with a carboxylic acid or an aminoacid. While not intending to be limiting, an ester may be an alkyl ester, an aryl ester, or a heteroaryl ester.
  • alkyl has the meaning generally understood by those skilled in the art and refers to linear, branched, or cyclic alkyl moieties.
  • Ci-e alkyl esters are particularly useful, where alkyl part of the ester has from 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and combinations thereof having from 1 to 6 carbon atoms.
  • Certain compounds of this invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of those compounds unless otherwise specified.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e. , the R and S configurations for each asymmetric centre.
  • single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.
  • this invention encompasses each diastereomer or enantiomer substantially free of other isomers (>90%, and preferably >95%, free from other stereoisomers on a molar basis) as well as a mixture of such isomers.
  • optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereomeric salts, by treatment with an optically active acid or base.
  • appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereomers by crystallization followed by liberation of the optically active bases from these salts.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers.
  • Still another method involves synthesis of covalent diastereomers by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate.
  • the synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolysed to deliver the enantiomerically pure compound.
  • Optically active compounds of the invention can be obtained by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
  • the compounds of this invention can exist in radiolabeled form, i.e. , said compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number ordinarily found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine and chlorine include 3 H, 14 C, 32 P, 35 S, 18 F and 36 CI, respectively.
  • Compounds of this invention which contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. , 3 H, and carbon-14, i.e., 14 C, radioisotopes are particularly preferred for their ease of preparation and detectability.
  • Radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed herein except substituting a readily available radiolabeled reagent for a non-radiolabelled reagent.
  • the b-lactamase inhibitors according to formula (I) useful in this invention are administered in the form of a pharmaceutical composition.
  • a further aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula (I) as described above and at least one inert pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention is prepared in suitable dosage forms comprising an effective amount of at least one compound of formula (I) as described above, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and at least one inert pharmaceutically acceptable excipient.
  • suitable dosage forms are tablets, capsules, coated tablets, granules, solutions and syrups for oral administration; solutions, pomade and ointment for topical administration; medicated patches for transdermal administration; suppositories for rectal administration and injectable sterile solutions.
  • Suitable dosage forms are those with sustained release and those based on liposomes for oral, injectable or transdermal administration.
  • the wording "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically- acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • the pharmaceutical composition of the present invention comprises a compound of the invention together with a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable excipient includes any and all solvents, diluents, or other vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • materials which can serve as pharmaceutically acceptable excipient include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, other non-toxic compatible lubricants such as
  • pharmaceutically acceptable and “physiologically acceptable” are intended to define, without any particular limitation, any material suitable for preparing a pharmaceutical composition to be administered to a living being.
  • the dosage forms can also contain other traditional ingredients such as: preservatives, stabilizers, surfactants, buffers, salts for regulating osmotic pressure, emulsifiers, sweeteners, colorants, flavourings and the like.
  • the amount of the b-lactamase inhibitors according to formula (I) or of the pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention can vary over a wide range depending on known factors, for example, the type of pathology, the severity of the disease, the patient's body weight, the dosage form, the chosen route of administration, the number of administrations per day and the efficacy of the selected b-lactamase inhibitors according to formula (I).
  • a person skilled in the art can determine the optimum amount in easily and routinely manner.
  • the amount of compound of formula (I) or of the pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention will be such as to ensure a level of administration from 0.0001 to 100 mg/kg/day.
  • the level of administration is from 0.001 to 50 mg/kg/day, and even more preferably from 0.01 to 10 mg/kg/day.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • compositions of this invention may also be administered by nasal aerosol or inhalation or delivered by implantation (e.g., surgically), such as with an implantable or indwelling device like a stent.
  • the dosage forms of the pharmaceutical composition of the present invention can be prepared by techniques that are familiar to a pharmaceutical chemist, and comprise mixing, granulation, compression, dissolution, sterilization and the like.
  • the pharmaceutical composition of the invention further comprises a beta-lactam antibiotic.
  • the pharmaceutical composition further comprises a beta-lactam antibiotic, wherein the beta-lactam antibiotic is a penicillin, cephalosporin, penem, carbapenem, clavam, monobactam, bridged monobactam, or any other compound susceptible to serine beta-lactamases, or a combination thereof.
  • the beta-lactam antibiotic is a penicillin, cephalosporin, penem, carbapenem, clavam, monobactam, bridged monobactam, or any other compound susceptible to serine beta-lactamases, or a combination thereof.
  • the beta-lactam antibiotic is a penicillin selected from benzylpenicillin, benzathine benzylpenicillin, procaine benzylpenicillin, phenoxymethylpenicillin (V), propicillin, pheneticillin, azidocillin, clometocillin, penamecillin, cloxacillin, dicloxacillin, flucloxacillin, oxacillin, nafcillin, methicillin, amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, epicillin, ticarcillin, carbenicillin, carindacillin, temocillin, piperacillin, azlocillin, mezlocillin, mecillinam, pivmecillinam, and sulbenicillin, or a prodrug thereof.
  • a penicillin selected from benzylpenicillin, benzathine benzylpenicillin
  • the beta-lactam antibiotic is a cephalosporin selected from cefazolin, cefalexin, cefadroxil, cefapirin, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaloglycin, cefacetrile, cefalonium, cefaloridine, cefalotin, cefatrizine, cefaclor, cefotetan, cephamycins (cefoxitin, cefprozil, cefuroxime, cefuroxime axetil, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefbuperazone, cefuzonam, cefmetazole,) carbacephems (loracarbef), cefixime, ceftriaxone, antipseudomonals (ceftazidime, cefoperazone
  • the beta-lactam antibiotic is a penem selected from faropenem, and ritipenem, or a prodrug thereof.
  • the beta-lactam antibiotic is a carbapenem selected from ertapenem, antipseudomonals (doripenem, imipenem, meropenem), biapenem, and panipenem, or a prodrug thereof.
  • the beta-lactam antibiotic is a monobactam selected from aztreonam, tigemonam, carumonam, and nocardicin A, or a prodrug thereof.
  • the b-lactamase inhibitor of formula (I) is administered in combination with a beta-lactam antibiotic and an additional antibiotic and/or an additional beta-lactamase inhibitor.
  • the additional antibiotic agent is selected from one of the classes of aminoglycosides, spectinomycins, macrolides, ketolides, streptogramins, oxazolidinones, tetracyclines, fluoroquinolones, quinolones, coumarin antibiotics, glycopeptides, lipoglycopeptides, nitroimidazoles, ansamycins, phenicols, mupirocyn, fosfomycin, tobramycin, linezolid, daptomycin, and vancomycin.
  • the b-lactamase inhibitor of formula (I) is administered in combination with a b-lactam antibiotic and a second agent which is designed to address b-lactam resistance, such as, for example, a metallo ⁇ -lactamase (MBL) inhibitor, also known as a Class B inhibitor.
  • a metallo ⁇ -lactamase (MBL) inhibitor also known as a Class B inhibitor.
  • the present invention relates to the combination of (i) at least one b- lactamase inhibitor of formula (I) as described above, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, or a prodrug thereof, and (ii) a beta-lactam antibiotic, for use in the treatment of a bacterial infection.
  • a fourth aspect provides a method of treating a bacterial infection in a subject, comprising administering to the subject a b-lactamase inhibitor of formula (I) in combination with a therapeutically effective amount of beta-lactam antibiotic.
  • infection and "bacterial infection” may refer to any one of the following infections: gynecological infection, a respiratory tract infection (RTI), a lower respiratory tract infection, an upper respiratory tract infection, a sexually transmitted disease, an uncomplicated urinary tract infection (UTI), a complicated urinary tract infection (CUTI), an acute exacerbation of chronic bronchitis (ACEB), an acute otitis media, an acute sinusitis, an infection caused by drug resistant bacteria, a catheter- related sepsis, a chancroid, chlamydia, an acute bacterial prostatitis, a community- acquired pneumonia (CAP), a complicated skin and skin structure infection, an uncomplicated skin and skin structure infection (SSSI), an acute bacterial skin and soft tissue infection, endocarditis, a febrile neutropenia, a gonococcal cervicitis, a gonococcal urethritis, a hospital-acquired pneumonia (H
  • infections can be caused by a variety of bacteria that potentially could be treatable with a b-lactamase inhibitor of formula (I) in combination with a beta-lactam antibiotic.
  • the terms "infection” and "bacterial infection” refer to an infection caused by Gram-negative bacteria, also referred to as a "Gram-negative infection".
  • the Gram-negative infection is an infection resistant to one or more antibiotics.
  • the Gram-negative infection is a multi-drug resistant infection.
  • the Gram negative infection is caused by one or more Enterobacteriaceae spp. pathogens.
  • pathogens includes one or more E. coli, K. pneumoniae, K. oxytoca, C. freundii, C. koseri, E. cloacae, P. mirabilis, M. morganii and/or S. marcescens.
  • the one or more Enterobacteriaceae spp. pathogens includes one or more E. coli or K. pneumoniae pathogen.
  • the Gram-negative infection is caused by one or more biothreat pathogens.
  • the one or more biothreat pathogens is Burkholderia spp., Y. pestis, and/or F. tularensis.
  • the one or more Gram-negative pathogens may express one or more serine beta-lactamase enzymes.
  • the one or more serine beta-lactamase enzymes includes one or more Class A, Class C and/or Class D beta-lactamase.
  • protecting groups are moieties that are used to temporarily block chemical reaction at a potentially reactive site (e.g., an amine, hydroxyl, thiol, aldehyde, etc.) so that a reaction can be carried out selectively at another site in a multifunctional compound.
  • a protecting group reacts selectively in good yield to give a protected substrate that is suitable for the planned reactions; the protecting group should be selectively removable in good yield by readily available, preferably nontoxic reagents that do not unduly attack the other functional groups present; the protecting group preferably forms an readily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group preferably has a minimum of additional functionality to avoid the complication of further sites of reaction.
  • a wide variety of protecting groups and strategies, reagents and conditions for deploying and removing them are known in the art. Also, one may choose reagents enriched for a desired isotope, e.g.
  • tritium in place of hydrogen to create compounds of this invention containing such isotope(s).
  • Compounds containing tritium in place of hydrogen in one or more locations, or containing various isotopes of C, N, P and O, are encompassed by this invention and may be used, for instance, for studying metabolism and/or tissue distribution of the compounds or to alter the rate or path of metabolism or other aspects of biological functioning.
  • the compounds of this invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by a variation thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to those described below.
  • the reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected.
  • step 1 (A) AcN, nBuLi, THF, or (B) AcN, NaH, toluene; step 2: R 4 NH- NH 2 (IV), EtOH; b) step 1 : EtOH, HCI; step 2: 1 M HCI.
  • step 1 NH(R N R in ) (X), pyridine, DCM; b) step 1 : (A) i) Benzyl mercaptan, NaH, ii) SO 2 CI 2 , DCM, or (B) i) SOCI 2 , cud, ii) NaN0 2 ; step 2: NH(R N R in ) (X), pyridine, DCM; step 3: CS 2 CO3, KBFs(vinyl), Pd(dppf)Cl 2 - DCM, DME/H 2 O; step 4: OsC , Nal0 4 , THF/ H 2 O; c) step 1 : DMF, oxalyl chloride; step 2: i) CI 3 CC(0)CI, Aids, ii) NaOMe, MeOH, iii) aq. HCI
  • Step 1 (A) pyruvic acid, AcOFI, or (B) ethyl pyruvate, EtOH, HCI, or (c) methyl pyruvate, MeOH, HCI, or (D) pyruvic acid, EtOH, HCI; step 2: R 2 B(OH)2 or R 2 Bpin (XXI), Pd(dppf)CI 2 DCM, K2CO3, dioxane/ H 2 0; step 3: 3,4-dihydro-2H-pyran, p-TSA, CHC ; step 4: R IV -S0 2 NH 2 (XXIII), /V,/V’-dimethylethane-1 ,2-diamine, Cul, K2CO3; step 5: HCI(4 M in dioxane); step 6: (A) R 4 B(OH) 2 (XXIV), Cu(OAc) 2 , pyridine, DCM/DMF, or (B) R 4 B(0
  • step 1 R 2 CHO (XXVII), LDA, THF; step 2: TBDMScl, imidazole, DMAP; step 3: Dess-Martin periodinane, DCM; step 4: R 4 NH-NH 2 (IV), DIPEA, EtOH/THF; step 5: R 3 B(OH) 2 (XXXIV), Pd(dppf)CI 2 DCM, K 2 C0 3 , dioxane/ H 2 0; step 6: TBAF, THF; step 7: Mn0 2 , DCM; step 8: Y -PPh 3 Br (XXXVII), KOtBu; step 9: H 2 , Pd/C, EtOH, AcOH. ii) Synthesis of compounds with general formula l (IX)
  • step 1 (A) TFA/DCM (1 : 1 ), or (B) HCI, dioxane.
  • step 1 B 2 pin 2 , KOAc, Pd(dppf)CI 2 DCM, dioxane.
  • step 1 R 4 NH-NH 2 (IV), DIPEA, EtOH/THF; step 2: MeONa (30%), MeOH; step 3: R 3 Bpin (XXXIX), Pd(dppf)CI 2 DCM, K2CO3, THF/H 2 0; step 4: BBr 3 (1 M DCM), THF; step 5: POCI 3 , Neat; step 6: Pd(dppf)CI 2 DCM, CO, Et 3 N, MeOH; step 7: LiOH, THF/MeOH/ H 2 0.
  • step 1 NH(R N R in ) (X), pyridine; step 2: HCI(4M in dioxane).
  • step 1 R lv S0 2 CI(XI_V), pyridine
  • step 1 R lv S0 2 CI(XLV), NMM, DCM; b) step 1: pinacol, MgS0 4, Et 2 0; step 2: BrR v (LI), K 2 CO3, DMF.
  • step 1 AcOH/hhO; step 2: neat POC ; step 3: NIS, HBF4, AcN; step 4: 3,4-dihydro-2H-pyran, p-TSA, CHC ; step 5: R 2 B(OH) 2 (XXI), Pd(dppf)CI 2 DCM, Na 2 C0 3 , dioxane; step 6: (A) R 3 NH (XLIV), DIPEA, DMSO, or (B) R 3 B(OH) 2 (XLVIII), Pd(dppf)CI 2 , Na 2 C0 3 , dioxane, or (c) R 3 B(OH) 2 (Lll), Pd(dppf)CI 2 , CsF, dioxane; step 7: mcPBA, DCM; step 8: HCI(4M in dioxane); step 9: LiOH, THF/MeOH/H 2 0; step 10: R 4 B(OH) 2 (XXX
  • step 1 R 4 NH-NH 2 HCI(IV), NaOAc, EtOH.
  • step 1 MeOTf, AcN
  • step 2 N-Soc piperazine, AcN
  • step 3 MeOTf, AcN
  • step 1 NH(R" R m ) (X), pyridine; step 2: Me 3 Sn-Me 3 Sn, Pd(PPh 3 )4, dioxane.
  • step 1 i) toluene, ii) AcOH; step 2: Tf 2 0, pyridine; step 3: (A) R 3 ZnBr (LXXXV), Pd(dppf)CI 2 DCM, dioxane, or (B) R 3 Bpin (XXXIX), K2CO3, THF/H 2 0, or (c) R 3 NH (LXXIII), DIPEA, MeCN, or (D) R 3 SnMe 3 (LXXVIII), Pd(PPh 3 ) , dioxane; step 4: TfOH, DCM; Step 5: LiOH, THF/MeOH/H 2 0.
  • R 3 can be COOMe-/COOEt-Aryl
  • R 3 can be COOH-Aryl Scheme 18.
  • step 1 R 4 Hal (XXV), CuBr, Cs 2 C0 3 , DMF;
  • step 2 R 3 CHO (XX), Ethyl pyruvate, EtOH, HCI; step 3: LiOH, THF/MeOH/H 2 0.
  • Non-limiting examples of compounds of formula (I) are those of the following Table A.
  • the R 4 groups of the following Table 4 are always linked to the 1 -position of the nitrogen containing bicycle ring, but the R 4 group of compound 106, which is linked to the 2-position of the nitrogen containing bicycle ring.
  • R 1 -R 4 and X1-X2 have the meaning of the above described formula (I).
  • aryl and“alkyl”, as used in synthetic schemes below, mean the properly substituted “carbocyclic or heterocyclic aromatic rings having from 3 to 12 members” and“carbocyclic or heterocyclic aliphatic rings having from 3 to 12 members”, respectively.
  • General procedures A1-F1 and H1-J1 relate to the preparation of intermediates and compounds of the Table B.
  • the preparation of compounds 1 -20 of Table A and compounds of Table B is described in general procedure Gi.
  • the preparation of compounds 21 -87 and 108 of Table A is described in general procedure Ki.
  • N-(2-fluorophenyl)-4-formylbenzenesulfonamide (Xlb).
  • the title compound was obtained according to general procedure Ci, step 1 using 2-fluoroaniline (Xb, 0.597 g, 5.38 mmol), pyridine (0.43 ml_, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1.00 g, 4.89 mmol).
  • the crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 0.906 g (66% yield) of the title product.
  • N-(2,4-difluorophenyl)-4-formylbenzenesulfonamide (Xld).
  • the title compound was obtained according to general procedure Ci, step 1 using 2,4-difluoroaniline (Xd, 0.547 mL, 5.38 mmol), pyridine (0.43 mL, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1.00 g, 4.89 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.646 g (44% yield) of the title product.
  • N-(3-cyanophenyl)-4-formylbenzenesulfonamide (Xle).
  • the title compound was obtained according to general procedure Ci, step 1 using 3-aminobenzonitrile (Xe, 0.635 g, 5.38 mmol), pyridine (0.43 mL, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1.00 g, 4.89 mmol).
  • the crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 1.22 g (87% yield) of the title product.
  • the title compound was obtained according to general procedure Ci, step 1 using 5-fluoropyridin-3-amine (Xh, 0.603 g, 5.38 mmol), pyridine (0.43 mL, 5.38 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1 .00 g, 4.89 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 1 g (69% yield) of the title product.
  • the title compound was obtained according to general procedure Ci, step 1 using 3-amino-4- fluorobenzonitrile (Xo, 0.732 g, 5.38 mmol), pyridine (0.43 mL, 5.38 mmol) and 4- formylbenzene-1 -sulfonyl chloride (IXa, 1 .00 g, 4.89 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.462 g (31 % yield) of the title product.
  • N-(4-fluorophenyl)-4-formylbenzenesulfonamide (Xlr).
  • the title compound was obtained according to general procedure Ci, step 1 using 4-fluoroaniline (Xr, 0.21 mL, 2.2 mmol), pyridine (0.18 mL, 2.2 mmol) and 4-formylbenzene-1 -sulfonyl chloride (IXa, 409 mg, 2.00 mmol).
  • the crude was purified by flash chromatography (0-5% MeOH/DCM) to give 431 mg (69% yield) of the title product.
  • N-(4-cyano-1 -cyclopentyl-1 H-pyrazol-3-yl)-4-formylbenzenesulfonamide (Xlu).
  • the title compound was obtained according to general procedure Ci, step 1 using 3-amino-1 - cyclopentyl-1 /-/-pyrazole-4-carbonitrile (Xu, 0.995 g, 5.64 mmol), pyridine (0.46 mL, 5.64 mmol), and 4-formylbenzene-1 -sulfonyl chloride (IXa, 1 .05 g, 5.13 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 1 .04 g (59% yield) of the title product.
  • 6-chloropyridine-3-sul ⁇ onyl chloride (Xlllb).
  • the title compound was obtained according to general procedure Di, step 1 , method (B) using thionyl chloride (4.2 ml_, 57.6 mmol), CuCI (0.015 g, 0.148 mmol), HCI (13.5 ml_, 160 mmol), 6-chloropyridin-3- amine (Xllb, 1 .73 g, 13.46 mmol) and NaNCte (1 .021 g, 14.80 mmol).
  • the crude (1 .75 g, 61 % yield) was used for the next step without further purification.
  • HPLC-MS (ESI) m/z: 193.0 [M-H] + .
  • step 2 follows the same conditions described for general procedure Ci, step 1 .
  • 6-chloro-N-(2-fluorophenyl)pyridine-3-sulfonamide (XlVb).
  • the title compound was obtained according to general procedure Di, step 2 using 6-chloropyridine-3-sulfonyl chloride (Xlllb, 1 .40 g, 6.60 mmol), 2-fluoroaniline (Xb, 0.807 g, 7.26 mmol) and pyridine (0.59 mL, 7.26 mmol).
  • the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 1 .50 g (79% yield) of the title product.
  • HPLC-MS (ESI) m/z: 287 [M-H] + .
  • 6-chloro-N-(pyridin-3-yl)pyridine-3-sulfonamide (XlVd).
  • the title compound was obtained according to general procedure Di, step 2 using 6-chloropyridine-3-sulfonyl chloride (Xlllb, 1 .75 g, 8.25 mmol), pyridin-3-amine (Xn, 0.855 g, 9.09 mmol) and pyridine (0.75 mL, 9.09 mmol).
  • the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 1 .75 g (61 % yield) of the title product.
  • N-(2-fluorophenyl)-5-vinylpyridine-2-sulfonamide (XVa).
  • the title compound was obtained according to general procedure Ei, step 1 using 5-bromo-/V-(2- fluorophenyl)pyridine-2-sulfonamide (XlVa, 0.804 g, 2.428 mmol), potassium trifluoro(vinyl)borate (0.488 g, 3.64 mmol), CS2CO3 (3.16 g, 9.71 mmol) and PdCl2(dppf)- DCM adduct (0.198 g, 0.243 mmol).
  • N-(2-fluorophenyl)-6-vinylpyridine-3-sulfonamide (XVb).
  • the title compound was obtained according to general procedure Ei, step 1 using 6-chloro-N-(2- fluorophenyl)pyridine-3-sulfonamide (XlVb, 1 .498 g, 5.22 mmol), potassium trifluoro(vinyl)borate (1 .050 g, 7.84 mmol), CS2CO3 (6.81 g, 20.90 mmol) and PdCl2(dppf)- CH2CI2 adduct (0.427 g, 0.522 mmol).
  • N-(pyridin-3-yl)-5-vinylpyridine-2-sulfonamide (XVc).
  • the title compound was obtained according to general procedure Ei, step 1 using 5-bromo-/V-(pyridin-3-yl)pyridine-2- sulfonamide (XIVc, 0.45 g, 432 mmol), potassium trifluoro(vinyl)borate (0.288 g, 2.149 mmol), CS2CO3 (1 .86 g, 5.73 mmol) and PdCl2(dppf)-DCM adduct (0.1 17 g, 0.143 mmol).
  • the title compound was obtained according to general procedure Ei, step 1 using 6-chloro-/V-(pyridin-3-yl)pyridine-3- sulfonamide (XlVd, 1 .246 g, 4.62 mmol), potassium trifluoro(vinyl)borate (0.928 g, 6.93 mmol), CS 2 CO3 (6.02 g, 18.48 mmol) and PdCl2(dppf)-cH2Cl2 adduct (0.377 g, 0.462 mmol).
  • N-(2-fluorophenyl)-5-formylpyridine-2-sulfonamide (XVIa).
  • the title compound was obtained according to general procedure Ei, step 2 using A/-(2-fluorophenyl)-5- vinylpyridine-2-sulfonamide (XVa, 0.392 g, 1 .409 mmol), OsC (0.86 mL, 0.141 mmol) and NalC (0.452 g, 2.1 13 mmol).
  • the crude was purified by flash chromatography (S1O2, Hex/EtOAc and DCM/MeOH) to give 0.345 g (87% yield) of the title product.
  • N-(2-fluorophenyl)-6-formylpyridine-3-sulfonamide (XVIb).
  • the title compound was obtained according to general procedure Ei, step 2 using N-(2-fluorophenyl)-6- vinylpyridine-3-sulfonamide (XVb, 1 .046 g, 3.76 mmol), OSO4 (0.46 mL, 0.075 mmol) and Nal0 4 (3.22 g, 15.03 mmol).
  • the crude (1 .131 g, quant yield) was used for the next step without further purification.
  • HPLC-MS (ESI) m/z: 281.0 [M-H] + .
  • the title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H- pyrazol-5-amine (Va, 0.209 g, 1 .1 17 mmol), 4-((4-formylphenyl)sulfonamido)benzamide (Xla, 0.340 g, 1 .1 17 mmol) and ethyl-pyruvate (0.124 ml_, 1 .1 17 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.159 g (25% yield) of the title product.
  • the title compound was obtained according to general procedure Gi, step 1 , method (c) using 3-(4-ethylphenyl)-1 H- pyrazol-5-amine (Va, 0.209 g, 1 .1 17 mmol), 4-((4-formylphenyl)sulfonamido)benzamide (Xla, 0.340 g, 1 .1 17 mmol) and methyl-pyruvate (1 14 mg, 1 .1 17 mmol).
  • the crude was purified by flash chromatography (S1O2, cHex/EtOAc) to give 0.125 g (27% yield) of the title product.
  • the title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.407 g, 2.173 mmo), A/-(2,4-difluorophenyl)-4-formylbenzenesulfonamide (Xld, 0.646 g, 2.173 mmol) and pyruvic acid (0.153 ml_, 2.173 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.677 g (58% yield) of the title product.
  • the title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.091 g, 0.486 mmol), A/-(4-cyano-2-fluorophenyl)-4-formylbenzenesulfonamide (Xlf, 0.148 g, 0.486 mmol), and pyruvic acid (27 pL, 0.378 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.1 14 g (43% yield) of the title product.
  • the title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)- 1 H-pyrazol-5-amine (Va, 0.154 g, 0.825 mmol), 3-((4- formylphenyl)sulfonamido)thiophene-2-carboxamide (XII, 0.256 g, 0.825 mmol) and pyruvic acid (0.073 g, 0.825 mmol).
  • the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 0.038 g (8% yield) of the title product.
  • the title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)- 1 H-pyrazol-5-amine (Va, 0.153 g, 0.819 mmol), 5-(fe/f-butyl)-3-((4- formylphenyl)sulfonamido)thiophene-2-carboxamide (Xlm, 0.300 g, 0.819 mmol) and pyruvic acid (0.072 g, 0.819 mmol).
  • the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 26 mg (5% yield) of the title product.
  • the title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.230 g, 1 .231 mmol), A/-(2-fluorophenyl)-5-formylpyridine-2-sulfonamide (XVIa, 0.345 g, 1.231 mmol) and pyruvic acid (0.67 mL g, 1 .231 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 37 mg (17% yield) of the title product.
  • the title compound was obtained according to general procedure G-i, step 1 , method (A) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.1 10 g, 0.585 mmol), 5-formyl-/V-(pyridin-3-yl)pyridine-2-sulfonamide (XVIc, 0.154 g, 0.585 mmol) and pyruvic acid (0.052 g, 0.585 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 18 mg (32% yield) of the title product.
  • the crude was purified by reverse phase chromatography (Cis, 25-100% AcN/0.1 % formic acid in water) to give 58 mg (7% yield) of l (l) gi A and 142 mg (16% yield) of l (l) gi B.
  • the title compound was obtained according to general procedure Gi, step 1 , method (A) using 3-(4-ethylphenyl)-1 H- pyrazol-5-amine (Va, 0.460 g, 2.46 mmol), A/-(4-cyano-1 -cyclopentyl-1 /-/-pyrazol-3-yl)-4- formylbenzenesulfonamide (Xlu, 0.846 g, 2.46 mmol), and pyruvic acid (173 pL, 2.457 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 0.201 g (14% yield) of the title product.
  • the title compound was obtained according to general procedure Gi, step 1 , method (B) using 3-(4-ethylphenyl)-1 H-pyrazol-5-amine (Va, 0.21 g, 1 .1 mmol), ethyl-5-formylisoxazole-3-carboxylate (XXg, 0.186 g, 1 .10 mmol) and ethyl- pyruvate (0.122 mL, 1 .10 mmol).
  • the crude was purified by preparative HPLC (50-20%, 0.1 % formic acid in water/AcN) to give 34 mg (6% yield) of the title product.
  • the crude was purified by reverse phase chromatography (Cis, 25-100%, 0.1 % formic acid in AcN /0.1 % formic acid in water) to give 57 mg (8% yield) of l (l) t 2A and 61 mg (8% yield) of l (l) t 2B .
  • R 3 R lv -S0 2 NH-Aryl
  • Example 21 The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-bromo-6-(4-(methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4- b]pyridine-4-carboxylate (I3 ⁇ 4i, 35 mg, 0.087 mmol) and LiOH (29.8 mg, 1 .24 mmol). The reaction mixture was evaporated under reduced pressure, the resulting residue was triturated with water, filtered, and dried to give 22 mg (68% yield) of the title product. HPLC-MS (ESI) m/z: 362/364 [M-H] + .
  • Example 23 The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-cyclohexyl-6-(4-(methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4- b]pyridine-4-carboxylate (l (l) fi, 200 mg, 0.491 mmol) and LiOH (58.8 mg, 2.45 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 152 mg (82% yield) of the title product. HPLC-MS (ESI) m/z: 366 [M-H] + .
  • the title compound was obtained according to general procedure Ki, step 1 , method (B) using ethyl-6-(4-(/V-(4- cyano-2-fluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate (l (l) hi , 0.240 g, 0.421 mmol) and a 4 M solution of NaOH in MeOH (0.527 ml_, 2.107 mmol).
  • the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 50 mg (21 % yield) of the title product.
  • the title compound was obtained according to general procedure Ki, step 1 , method (B) using ethyl-6-(4-(/V-(5-cyano-2- fluorophenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate (l (l) i 1 , 0.190 g, 0.334 mmol) and a 4 M solution of NaOH in MeOH (0.42 mL, 1 .668 mmol).
  • the crude was purified by preparative HPLC (0.1 % (NH ⁇ COs in water/AcN) to give 27 mg (15% yield) of the title product.
  • Example 58 The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(4-(methoxycarbonyl)phenyl)-3-(pyridin-4-yl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l (l) n 2 , 259 mg, 0.644 mmol) and LiOH (29.8 mg, 1 .24 mmol). The reaction mixture was evaporated under reduced pressure, the resulting residue was triturated with water, filtered, and dried to give 206 mg (86% yield) of the title product. HPLC-MS (ESI) m/z: 361 [M-H] + .
  • Example 59 The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-6-(4-(methoxycarbonyl)phenyl)-3-(pyridin-2-yl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l (l) o 2 , 185 mg, 0.460 mmol) and LiOH (55.0 mg, 2.30 mmol). The resulting solid was collected by filtration, washed with water/EtOH (1 : 1 ) and dried under vacuum.
  • Example 62 The title compound was obtained according to general procedure Ki, step 1 , method (A) using 3-isopropyl-6-(4-(methoxycarbonyl)phenyl)-1 H-pyrazolo[3,4- b]pyridine-4-carboxylate (l (l) r 2 , 100 mg, 0.295 mmol) and LiOH (28 mg, 1 .2 mmol). The resulting solid was collected by filtration, washed with water and dried under vacuum to give 84 mg (83% yield) of the title product. HPLC-MS (ESI) m/z: 326 [M-H] + .
  • Example 65 6-( 4-carboxyphenyl)-3-( 4-isopropylphenyl)- 1 H-pyrazolo[3, 4-b ]pyridine-4-carboxylic acid (Example 65).
  • the title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-isopropylphenyl)-6-(4-(methoxycarbonyl)phenyl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (l (ll) a, 46 mg, 0.10 mmol) and LiOH (12.4 mg, 0.519 mmol).
  • Example 67 The title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(furan-3-yl)-6-(4-(methoxycarbonyl)phenyl)-1 /-/-pyrazolo[3,4- b]pyridine-4-carboxylate (l (ll) c, 89 mg, 0.23 mmol) and LiOH (54.4 mg, 2.27 mmol). The resulting solid was collected by filtration and dried under vacuum to give 58 mg (72% yield) of the title product. HPLC-MS (ESI) m/z: 350 [M-H] + .
  • the title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-1 - (cyclopropylmethyl)-3-(4-ethylphenyl)-6-(4-(/V-(pyridin-3-yl)sulfamoyl)phenyl)-1 /-/- pyrazolo[3,4-b]pyridine-4-carboxylate (l (IV) d, 0.134 g, 0.230 mmol) and LiOH (4 mL, 4.0 mmol).
  • the reaction mixture was evaporated under reduced pressure, and the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 18 mg (14% yield) of the title product.
  • the title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-1 -isopropyl-6- (4-(N-(pyridin-3-yl)sulfamoyl)phenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l (IV) e, 0.065 g, 0.1 14 mmol) and LiOH (2.3 mL, 2.30 mmol).
  • the reaction mixture was evaporated under reduced pressure, and the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 21 mg (34% yield) of the title product.
  • the title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-3-(4-ethylphenyl)-1 -methyl-6-(4- (N-(pyridin-3-yl)sulfamoyl)phenyl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (l (IV) f, 0.097 g, 0.705 mmol) and LiOH (5 ml_, 5 mmol).
  • the reaction mixture was evaporated under reduced pressure, and the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 1 1 mg (7% yield) of the title product.
  • 1,3-Bis(4-ethylphenyl)-6-(5-(methylsulfonamido)pyridin-2-yl)-1H-pyrazolo[3,4- b]pyridine-4-carboxylic acid (Example 80).
  • the title compound was obtained according to general procedure Ki, step 1 , method (A) using ethyl-1 , 3-bis(4-ethylphenyl)-6-(5- (methylsulfonamido)pyridin-2-yl)-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (l (IV) i, 0.258 g, 0.453 mmol) and LiOH (9 mL, 9.06 mmol).
  • the title compound was obtained according to general procedure Ki, step 1 , method (c) using ethyl-6-(4-(/V-(4- carbamoylphenyl)sulfamoyl)phenyl)-3-(4-ethylphenyl)-1 /-/-pyrazolo[3,4-b]pyridine-4- carboxylate (example 2, 0.250 g, 0.439 mmol) and 30% NH3 solution in water (4 ml_, 63.4 mmol).
  • the crude was purified by preparative HPLC (0.1 % formic acid in water/AcN) to give 8 mg (3% yield) of the title product.
  • the title compound was obtained according to general procedure Ki, step 1 , method (A) using methyl-3-(4-ethylphenyl)-6-(5-(N-(2- fluorophenyl)sulfamoyl)pyridin-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (example 17, 0.067 g, 0.126 mmol) and LiOH (1 M solution in water, 1 .3 ml_, 1 .3 mmol). The resulting solid was collected by filtration washed with water and dried under vacuum to give 42 mg (64% yield) of the title product.
  • Step 1 In a vial, the proper intermediate XL (1 eq.) and MeONa (30% in MeOH) (15 eq.) were added sequentially and the resultant solution was heated in the microwave at 1 10 °C for 5 h. The reaction was quenched with a saturated aqueous solution of NaHCC and extracted with EtOAc. The organic layers were combined, washed with brine and concentrated under reduced pressure. The resulting crude was purified by flash chromatography to give the intermediate compound having general formula XLI.
  • the title compound was obtained according to general procedure Wi, step 1 using 6-chloro-3-(4-ethylphenyl)-4-methoxy-1 H- pyrazolo[4,3-c]pyridine (XLIa, 268 mg, 0.9 mmol), the total mixture containing the boronate N-(pyridin-3-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzene-1 - sulfonamide XXXIXa, and K 2 CO 3 (534 mg, 3.9 mmol). The crude was purified by flash chromatography (0-100% EtOAc/isohexane) to give 90 mg (20% yield) of the title product.
  • a sealed microwave vial containing PdCl2(dppf)-cH2d2 adduct (0.1 eq.) and intermediate l (XXIII) (1 eq.) was evacuated and backfilled with N2 (x3). MeOH (0.1 M) and triethylamine (3 eq.) were added and carbon monoxide was bubbled through the reaction for around 5 minutes using a balloon. The balloon was removed and the reaction stirred at 80 °C overnight. At rt, the vial was purged with N2 and the solvent removed. The residue was dissolved in EtOAc and washed with a saturated solution of NaHCOs and brine. The solvent was evaporated and the crude product was purified by the opportune technique to give a mixture of compounds having general formula l (XXIV) which was used in the next step without further purification.
  • N-(pyridin-3-yl)piperidine-4-sulfonamide hydrochloride (XLIVa).
  • the title compound was obtained according to general procedure Z ⁇ , step 2 using fe/f-butyl 4-(/V-(pyridin-3- yl)sulfamoyl)piperidine-1 -carboxylate (XLIIIa, 0.613 g, 1 .795 mmol) and HCI solution (14 mL, 57.5 mmol).
  • the crude (0.431 g, 86% yield) was used for the next step without further purification.
  • HPLC-MS (ESI) m/z: 242.1 [M-H] + .
  • N-(6-bromopyridin-3-yl)methanesulfonamide (XLVIa).
  • the title compound was obtained according to general procedure A 2 , step 1 , using 6-bromopyridin-3-amine (Xllc, 0.200 g, 1 .156 mmol) and methanesulfonyl chloride (XLVa, 0.100 ml_, 1.272 mmol).
  • the crude was purified by flash chromatography (S1O2, DCM/MeOH) to give 91 mg (31 % yield) of the title product.
  • Step 1 4-Mercaptophenylboronic acid (XLIX, 1 .0 g, 6.49 mmol), pinacol (0.767 g, 6.49 mmol) and MgSC (4.69 g, 39.0 mmol) were mixed in Et 2 0 (0.26 M) and the mixture was stirred at r.t. overnight. The reaction was filtered, the solid was washed with Et 2 0 and discarded. The filtrate was concentrated under vacuum to give 1 .53 g (99% yield) of 4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenethiol (L) which was used for the next step without further purification. HPLC-MS (ESI) m/z: no ionisation.
  • Ethyl-6-chloro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVa).
  • the title compound was obtained according to general procedure D2, step 2 using ethyl-6-hydroxy-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (LIVa, 14.4 g, 69.5 mmol) and POCI 3 (65 mL, 695 mmol).
  • the crude (12.16 g, 78% yield) was used for the next step without further purification.
  • Ethyl-6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVIa).
  • the title compound was obtained according to general procedure E2, step 1 using ethyl-6-chloro- 1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVa, 12.16 g, 53.9 mmol), aqueous 48% HBF4Solution (42 ml_, 270 mmol) and NIS (12.13 g, 53.9 mmol).
  • the crude (17.02 g, 90% yield) was used for the next step without further purification.
  • FIPLC-MS (ESI) m/z: 351 .7 [M-H] + .
  • Ethyl-6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3, 4-b]pyridine-4- carboxylate (LVIla).
  • the title compound was obtained according to general procedure F2, step 1 using ethyl-6-chloro-3-iodo-1 /-/-pyrazolo[3,4-b]pyridine-4-carboxylate (LVIa, 17.02 g, 48.4 mmol), 3,4-dihydro- 2/-/-pyran (6.63 mL, 72.6 mmol) and p-toluenesulfonic acid (0.921 g, 4.84 mmol).
  • step 1 using ethyl-6-chloro-3-iodo-1 -(tetrahydro-2/-/-pyran-2-yl)-1 H- pyrazolo[3,4-b]pyridine-4-carboxylate (LVIla, 6.17 g, 14.16 mmol), (4-ethylphenyl)boronic acid (XXIf, 4.25 g, 28.3 mmol), aqueous 2 M Na 2 C0 3 solution (18.4 ml_, 36.8 mmol), PdCl2(dppf) DCM adduct (1.15 g, 1 .14 mmol).
  • R 3 SR v -aryl
  • R 3 S0 2 R v -aryl
  • R Aryl, alkyl
  • R Aryl, alkyl
  • General procedure K2 step 1 follows the same conditions described for general procedure Ki, step 1 , method (A).
  • Ethyl-6-chloro-1-(4-ethylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (LIXa).
  • the title compound was obtained according to general procedure l_2, step 1 , using ethyl-6- chloro-1 H-pyrazolo[3,4-b]pyridine-4-carboxylate (LVa, 0.8 g, 3.55 mmol), (4- ethylphenyl)boronic acid (XXIVa, 0.798 g, 5.32 mmol), Cu(OAc)2 (0.193 g, 1 .064 mmol) and pyridine (0.86 ml_, 10.64 mmol).

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des inhibiteurs de bêta-lactamase représentés par la formule générale suivante (I) : R1-R4 et X 1-X 2 sont tels que définis dans la description, des compositions pharmaceutiques et leur utilisation pour le traitement d'une infection bactérienne, seuls ou en association avec des antibiotiques bêta-lactame et/ou d'autres antibiotiques et/ou d'autres inhibiteurs de bêta-lactamase.
PCT/EP2020/055658 2019-03-05 2020-03-04 Azaindazoles en 5 ou 7 utilisés comme inhibiteurs de bêta-lactamase WO2020178316A1 (fr)

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