Classifications

• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • 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
  • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
• • 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
  • A61P31/04—Antibacterial agents
• • 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
  • C07D471/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • 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

• the invention relates to compounds which are inhibitors of serine beta lactamase enzymes, and compositions containing the compounds.
• the compounds are useful in the treatment of bacterial infection.
• the invention also relates to combinations of the compounds with other active agents useful in the treatment of bacterial infection.
• Antibiotic resistance in pathogenic bacteria is a major public health threat worldwide.
• Resistance of bacteria to b-lactam antibiotics caused by the hydrolysis of b-lactam antibiotics by b-lactamase enzymes is of particular concern.
• the enzymes effect the hydrolytic cleavage of the b-lactam ring, rendering the b-lactam antibiotic inactive.
• Beta- lactamases belong to two structurally and mechanistically unrelated families of enzymes: the serine b-lactamases (SBLs; classes A, C and D) which use an active serine to cleave the b-lactam in a covalent mechanism, and the metallo b-lactamases (MBLs; class B) which use metal ion catalysis to directly hydrolyze the b-lactam without the formation of a covalent intermediate.
• SBLs serine b-lactamases
• MBLs metallo b-lactamases
• carbapenems such as meropenem and imipenem are widely regarded as the drugs of choice for the treatment of severe infections caused by ESBL-producing Enterobacteriaceae and Acinetobacter baumannii. While avibactam is a good nanomolar inhibitor of many of the clinically-relevant SBLs that hydrolyse carbapenems, it is poor against (i) variants of the OXA family which are among the most prevalent
• SBL inhibitors in particular inhibitors capable of inhibiting the OXA family of b-lactamases.
• broad spectrum inhibitors capable of inhibiting a range of SBLs, including the extended spectrum b- lactamases (ESBLs) and carbapenemases.
• ESBLs extended spectrum b- lactamases
• carbapenemases There is further a need to provide inhibitors capable of inhibiting SBLis produced by Acinetobacter baumannii.
• the present invention aims to address some or all of these issues.
• novel analogues in the DBO field have unexpected activity against SBL enzymes including the OXA variants. As such, these compounds are expected to be of use as an adjunct to carbapenems in treating infectious disease.
• the invention provides a compound as set out in aspect [1].
• the compounds are useful in the treatment of bacterial infection, in particular they are useful in removing or reducing SBL-derived bacterial resistance to antibiotics. They are therefore useful in the treatment of infection caused by SBL-producing bacteria, e.g. in combination with antibiotics.
• the treatment or prevention of bacteria is typically carried out by administering the compound of the invention in combination with an antibiotic agent.
• the compounds are also useful in combination with metallo ⁇ -lactamase (MBL) inhibitors, in particular where the bacterial infection is caused by both SBL and MBL-producing bacteria.
• MBL metallo ⁇ -lactamase
• R is selected from halogen, C(0)R 1 , Ci -4 alkyl and L-X-R 1 , wherein the Ci -4 alkyl group is substituted with at least one halogen atom and is optionally further substituted with one or two substituents R 2 ;
• R 1 is Ci- 4 alkyl which is substituted with at least one halogen atom and is optionally further substituted with one or two substituents R 2 ;
• each R 2 is independently selected from OFI; Ci -4 alkoxy which is unsubstituted or substituted with one or more halogen atoms; C(0)R 3 ; C(0)OFI; C(0)OR 3 ; 6- to 10- membered aryl; 5- to 6-membered heteroaryl; and 4- to 6-membered heterocyclyl; wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted with one, two or three substituents selected from halogen, OFI, C(0)R 3 , C(0)OFI, C(0)OR 3 and Ci -4 alkyl and Ci -4 alkoxy groups which are themselves unsubstituted or substituted with one or more halogen atoms;
• o R 3 is Ci- 4 alkyl which is unsubstituted or substituted with one or more halogen
• o L is a bond or is a Ci -2 alkylene group which is unsubstituted or is substituted with at least one halogen atom;
• o X is O or S(0) z wherein z is 0, 1 or 2.
• a compound according to aspect 1 which is a diazabicyclooctanone of Formula (II) or a pharmaceutically acceptable salt thereof:
• a compound according to aspect 1 which is a diazabicyclooctanone of Formula (II) or a pharmaceutically acceptable salt thereof:
• o R is selected from C(0)R' and Ci -4 alkyl, wherein the Ci -4 alkyl group is
• R 1 is Ci- 4 alkyl which is substituted with at least one halogen atom and is optionally further substituted with one or two substituents R 2 ;
• each R 2 is independently selected from OFI; Ci -4 alkoxy which is unsubstituted or substituted with one or more halogen atoms; C(0)R 3 ; C(0)OFI; C(0)OR 3 ; 6- to 10- membered aryl; 5- to 6-membered heteroaryl; and 4- to 6-membered heterocyclyl; wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted with one, two or three substituents selected from halogen, OFI, C(0)R 3 , C(0)OFI, C(0)OR 3 and Ci -4 alkyl and Ci -4 alkoxy groups which are themselves unsubstituted or substituted with one or more halogen atoms;
• o R 3 is Ci- 4 alkyl which is unsubstituted or substituted with one or more halogen
• R is selected from C(0)R 1 and Ci -4 alkyl, wherein the Ci -4 alkyl group is substituted with at least one halogen atom and is optionally further substituted with one substituent R 2 .
• R 1 is Ci -4 alkyl which is substituted with at least one halogen atom and is optionally further substituted with one substituent selected from OH and Ci -4 alkoxy which is itself unsubstituted or substituted with one or more halogen atoms.
• each R 2 is independently selected from OH; Ci -2 alkoxy which is itself unsubstituted or substituted with one or more halogen atoms; C(0)0R 3 , wherein R 3 is unsubstituted Ci -2 alkyl; and unsubstituted 5- to 6-membered heteroaryl.
• each R 2 is independently selected from OH; OMe; C(0)OMe; and unsubstituted thiazolyl.
• R is selected from C(0)R 1 and Ci -4 alkyl, wherein the Ci -4 alkyl group is substituted with at least one halogen atom and is optionally further substituted with one substituent R 2 ;
• R 1 is Ci- 4 alkyl which is substituted with at least one halogen atom and is optionally further substituted with one substituent selected from OH and Ci -4 alkoxy, the Ci -4 alkyl group being unsubstituted or substituted with one or more halogen atoms; and R 2 is selected from OH; Ci -2 alkoxy which is itself unsubstituted or substituted with one or more halogen atoms; C(0)OR 3 , wherein R 3 is unsubstituted Ci -2 alkyl; and unsubstituted 5- to 6-membered heteroaryl. 15.
• R is selected from C(0)R 1 and Ci -4 alkyl, preferably Ci -2 alkyl, wherein the alkyl group is substituted with at least one halogen atom and is optionally further substituted with one substituent R 2 ;
• R 1 is Ci-2 alkyl, wherein the Ci -2 alkyl group is substituted with at least two halogen atoms selected from fluorine or chlorine;
• R 2 is selected from OH; OMe; C(0)OMe; and unsubstituted thiazolyl.
• R is Ci -2 alkyl, wherein the Ci -2 alkyl group is substituted with at least one halogen atom and is optionally further substituted with one substituent R 2 .
• R is selected from CF 3 , CHF 2 , CHCb, CCb, CH 2 F, CF 2 CH 3 , CF 2 CH 2 C0 2 Me, COCF 3 , CF 2 -thiazolyl, CF 2 CH 2 OCH 3 ,
• R is selected from CF 3 , CHF 2 and CHCb. 19.
• R is -L-X-R 1 , wherein:
• L is a bond or is an unsubstituted Ci alkylene group
• R 1 is a Ci alkyl group substituted by 1, 2 or 3 halogen groups
• R is selected from -CH 2 -0-CF 3 and -S-CF 3 .
• a pharmaceutical composition comprising a compound according to any one of the preceding aspects and a pharmaceutically acceptable carrier or diluent and optionally further comprising (i) an antibiotic agent and/or (ii) a metal Io-b-lactamasc inhibitor.
• a metallo ⁇ -lactamase inhibitor for use in the treatment or prevention of bacterial infection by co-administration with a compound according to any one of aspects 1 to 21, and optionally an antibiotic agent.
• the antibiotic agent is a b-lactam antibiotic, preferably a b- lactam antibiotic selected from carbapenems, penicillins, cephalosporins and penems.
• Enterobacteriaceae, Pseudomonadaceae and Moraxellaceae are selected from Klebsiella pneumoniae, Escherichia coli, Enterobacter Cloacae, Pseudomonas aeruginosa,
• Burkholderia cepacia and Acinetobacter baumannii Burkholderia cepacia and Acinetobacter baumannii.
• the metallo ⁇ -lactamase inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof.
• 35 A composition, combination or compound, antibiotic agent or metal Io-b-lactamasc inhibitor for use according to aspect 34, wherein the metal Io-b-lactamasc inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein
• R 1A is selected from H, R lb and -CFt 2 OC(0)R lb , wherein R lb is selected from an unsubstituted Ci to C 4 alkyl group and phenyl;
• o (A) is a cyclic group selected from C 6 to Cio aryl, 5- to lO-membered heteroaryl, and
• each R 2A is independently selected from:
• halo or R 8 (i) Ci- 3 alkyl, 0(Ci -3 alkyl), S(Ci -3 alkyl), SO(Ci -3 alkyl) or S0 2 (Ci -3 alkyl), any of which may optionally be substituted with 1, 2 or 3 halo substituents and/or one R 8 substituent; and
• each R a and R b is independently selected from hydrogen and unsubstituted Ci -2 alkyl and each R c is
• each R 8 is independently selected from CN, OH, -C(0)NR f R g , -NR f R g ,
• each of R f and R g is independently H or unsubstituted Ci -2 alkyl;
• o m 0, 1, 2 or 3
• R 3A is selected from hydrogen and a Ci to C 3 alkyl group which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, -OR 10 , and - NR 10 R n ;
• o n 0 or 1
• o Z A is a bond or is selected from -NR 10 C(O)-, -C(0)NR 10 -, -NR 10 C(O)NR u -,
• o L A is a bond or is selected from Ci -4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene,
• Ci -3 alkylene-(C 3-6 cycloalkylene)-Ci -3 alkylene, Ci -4 alkylene-(C 3-6 cycloalkylene) and (C 3-6 cycloalkylene)-Ci -4 alkylene, wherein L is unsubstituted or is substituted with 1 or 2 substituents selected from halogen, -OR 10 , and -NR 10 R n ; or L is -C(R 10 ) N-;
• o p is 0 or 1 ;
• R 4A is selected from H, -CN and Ci to C 3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, -OR 10 ,
• R 4A is joined together with R 5A to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R n , and -CN;
• R 5A is selected from H, -CN and Ci to C 3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, -OR 10 ,
• R 5A is joined together with R 4A to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R n , and -CN;
• R 5A is joined together with R 6 to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R n , and -CN;
• R 6A is selected from H, -CN and Ci to C 3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, -OR 10 ,
• R 6A is joined together with R 5A to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R n , and -CN;
• R 6A is joined together with R 7A if present to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from
• Ci unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R U , and -CN;
• R 7A if present is selected from H, -CN and Ci to C 3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, -OR 10 ,
• R 7A is joined together with R 6A to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R n , and -CN;
• each R 10 , R 11 , R 12 , R 13 and R 14 is independently H or methyl
• each R 15 is independently substituted Ci to C 4 alkyl or unsubstituted C 2 to C 4 alkyl, wherein when R 15 is a substituted alkyl group the alkyl group is substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR 10 and -NR 10 R n .
• composition, combination or compound, antibiotic agent or metal Io-b-lactamase inhibitor for use according to aspect 35 wherein the metal Io-b-lactamase inhibitor is a compound of Formula (A) or a pharmaceutically acceptable salt thereof, wherein
• R 1A is H
• (A) is selected from phenyl, cyclohexane, piperidine, pyridazine, pyridine and
• each R 2A is independently selected from:
• Ci -2 alkyl 0(Ci -2 alkyl), S(Ci -2 alkyl), SO(Ci -2 alkyl) any of which may optionally be substituted with 1, 2 or 3 substituents selected from halo, CN, OH;
• Z A is selected from -NR 10 C(O)-, -C(0)NR 10 -, and -NR 10 C(O)NR u -;
• L A is a bond or is selected from Ci -3 alkylene and C 2-3 alkenylene.
• R 4A is H
• R 5A is selected from H, -CN and Ci to C 2 alkyl which is unsubstituted or is
• Figure 1 shows MIC data (described in the Examples) showing the activity of various inhibitors against two panels ( Figures 1A and 1B) of clinical strains of OXA positive enterobacteriaceae that are resistant to betalactam antibiotics such as meropenem, cefepime and ceftazidime. Data are shown for (i) meropenem alone (“MEM”), (ii) the clinical combination of inhibitor VNRX-5133 and antibiotic cefepime (“CEF/VNRX”); (iii) the clinical combination of inhibitor avibactam and antibiotic ceftazidime(“CAZ/AVI”); and (iv) the compound of Example 10 and the antibiotic meropenem (“MEM+Example 10”).
• Figure 2 shows MIC data (described in the Examples) showing the activity of various inhibitors against a panel of clinical strains of KPC positive enterobacteriaceae that are resistant to betalactam antibiotics such as meropenem, cefepime and ceftazidime. Data are shown for (i) meropenem alone (“MEM”), (ii) the clinical combination of inhibitor VNRX-5133 and antibiotic cefepime (“CEF/VNRX”); (iii) the clinical combination of inhibitor avibactam and antibiotic ceftazidime (“CAZ/AVI”); and (iv) the compound of Example 10 and the antibiotic meropenem (“MEM+Example 10”).
• FIG 3 shows MIC data (described in the Examples) showing the activity of various inhibitors against Acinetobacter baumannii. Data are shown for (i) meropenem alone (“MEM”), (ii) the clinical combination of inhibitor VNRX-5133 and antibiotic cefepime (“CEF/VNRX”); (iii) the clinical combination of inhibitor avibactam and antibiotic ceftazidime (“CAZ/AVI”); and (iv) the compound of Example 10 and the antibiotic meropenem (“MEM+Example 10”).
• Figure 4 shows scattergrams showing mouse thigh burdens (cfu/g) following infection with (A) KPC-positive K. pneumoniae NR-48977; (B) OXA-positive K.
• Ci to C 6 alkyl group is a linear or branched alkyl group containing from
• a Ci to C 4 alkyl group is a linear or branched alkyl group containing from 1 to 4 carbon atoms.
• a Ci to C 4 alkyl group is often a Ci to C 3 alkyl group or a Ci to C 2 alkyl group.
• Examples of Ci to C 4 alkyl groups include methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.
• a Ci to C 2 alkyl group is methyl or ethyl, typically methyl. For the avoidance of doubt, where two alkyl groups are present, the alkyl groups may be the same or different.
• a Ci to C 2 alkylene group is an unsubstituted or substituted bidentate moiety obtained by removing two hydrogen atoms from a Ci to C 2 alkane. The hydrogen atoms may be removed from the same carbon atom or from different carbon atoms.
• a Ci to C 2 alkylene group is methylene or ethylene, typically methylene.
• Ci -4 alkoxy is a Ci -4 alkyl group as defined above joined to an oxygen atom.
• a C 2-4 alkenyl group is a linear or branched alkenyl group containing from
• a C 2-4 alkenyl group is a C 2-3 alkenyl group.
• Examples of C 2-4 alkenyl groups include ethenyl, propenyl and butenyl.
• a C 2-4 alkenylene group is an unsubstituted or substituted bidentate moiety obtained by removing two hydrogen atoms from a C 2-4 alkene.
• a C 2-4 alkenylene group is a C 2-3 alkenylene group, for example ethenylene, propenylene or butenylene.
• a C 2-4 alkynyl group is a linear or branched alkynyl group containing from 2 to 4 carbon atoms and having one or more, e.g. one or two, typically one triple bonds.
• a C 2-4 alkenyl group is a C 2-3 alkenyl group, for example ethynyl, propynyl or butynyl.
• a C 2-4 alkynylene group is an unsubstituted or substituted bidentate moiety obtained by removing two hydrogen atoms from a C 2-4 alkyne.
• a C 2-4 alkynylene group is a C 2-3 alkynylene group, for example ethynylene, propynylene or butynylene.
• alkyl, alkyl ene, alkoxy, alkenyl, alkynyl or alkynylene group as used herein may be unsubstituted or substituted.
• substituted alkyl, alkylene, alkoxy, alkenyl, alkenylene, alkynyl or alkynylene groups typically carry one or more, e.g. 1, 2, 3 or 4, such as one, two or three e.g. two, or three substituents.
• Preferred substituents are halogen atoms.
• an alkyl group may also be substituted with one or two groups R 2 as defined herein.
• the substituents on a substituted alkyl or alkoxy group are typically themselves unsubstituted unless otherwise stated. Where more than one substituent is present, these may be the same or different.
• a halogen is typically chlorine, fluorine, bromine or iodine and is preferably chlorine, bromine or fluorine, especially chorine or fluorine, and most especially fluorine.
• a group or moiety is substituted with one or more halogen atoms, preferably it carries one, two, three or four halogen atoms, preferably two or three halogen atoms.
• the halogen atoms may be the same or different. Typically, the halogen atoms are the same.
• a 6- to lO-membered aryl group is a substituted or unsubstituted, monocyclic or fused polycyclic aromatic group containing from 6 to 10 carbon atoms in the ring portion.
• Examples include monocyclic groups such as phenyl and fused bicyclic groups such as naphthyl and indenyl. Phenyl (benzene) is preferred.
• a 5- to lO-membered heteroaryl group is a substituted or unsubstituted, monocyclic aromatic group containing from 5 to 10 atoms in the ring portion, including at least one heteroatom, for example 1, 2 or 3 heteroatoms, typically selected from O, S and N; and is typically a 5- to 6- membered heteroaryl group which is a substituted or unsubstituted, monocyclic aromatic group containing 5 or 6 atoms in the ring portion, including at least one heteroatom, for example 1, 2 or 3 heteroatoms, typically selected from O, S and N.
• Examples of 5- and 6- membered heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyridine, pyridazine, pyrimidine, and pyrazine.
• a 3- to 10- membered heterocyclyl group is a cyclic group containing from 3 to 10 atoms selected from C, O, N and S in the ring, including at least one heteroatom, and typically one or two heteroatoms; and is typically a 3- to 8- membered heterocyclyl group, typically a 4- to 6- membered heterocyclyl group which is a cyclic group containing from 4 to 6 atoms selected from C, O, N and S in the ring, including at least one heteroatom, and typically one or two heteroatoms.
• the heteroatom or heteroatoms are typically selected from O, N, and S.
• a heterocyclic group may be saturated or partially unsaturated.
• a 4- to 6- membered partially unsaturated heterocyclic group is a cyclic group containing from 4 to 6 atoms selected from C, O, N and S in the ring and containing 1 or 2, e.g. 1 double bond.
• a 3- to 10- membered carbocyclyl group is a cyclic hydrocarbon containing from 3 to 10 carbon atoms.
• a carbocyclyl group may be saturated or partially unsaturated, but is typically saturated.
• a 3- to 10- membered partially unsaturated carbocyclyl group is a cyclic hydrocarbon containing from 3 to 10 carbon atoms and containing 1 or 2, e.g. 1 double bond.
• a 3- to 10- membered carbocyclyl group is typically a 4- to 10- membered carbocyclyl group e.g. 3- to 8- membered carbocyclyl group such as a 3- to 6-, 4- to 6- membered or 5- to 6- membered carbocyclic group. Examples of 3- to 6- membered saturated carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
• Examples of 4- to 6- membered saturated heterocyclic groups include oxetane, azetidine, piperazine, piperidine, morpholine, pyrrolidine, imidazolidine, and oxazolidine.
• Examples of 4- to 6- membered partially unsaturated heterocyclic groups include tetrahydropyrazine, tetrahydropyridine, dihydro- l,4-oxazine, tetrahydropyrimidine, dihydro-l,3-oxazine, dihydropyrrole, dihydro imidazole and dihydrooxazole.
• An aryl, heterocyclyl or heteroaryl group may be unsubstituted or substituted as described herein.
• an aryl, heterocyclyl or heteroaryl group may be unsubstituted or substituted with 1, 2 or 3, typically 1 or 2 such as e.g. 1 substituent.
• Suitable substituents include halogen, OFI, C(0)Ci -4 alkyl, C(0)0FI, C(0)0Ci -4 alkyl, Ci -4 alkyl and Ci -4 alkoxy, wherein the Ci -4 alkyl and Ci -4 alkoxy groups and moieties are themselves unsubstituted or substituted with one or more halogen atoms.
• a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
• Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as oxalic, citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p- toluenesulphonic acid.
• Pharmaceutically acceptable bases include alkali metal (e.g.
• alkaline earth metal e.g. calcium or magnesium
• organic bases such as alkyl amines, aralkyl amines and heterocyclic amines.
• Preferred pharmaceutically acceptable salts are salts formed at the SO 3 FI group with
• tetrabutylammonium salts or alkali metal salts, e.g. sodium or potassium salts, most preferably sodium salts.
• the bicyclic ring adopts the stereochemistry depicted.
• the R group is in the axial“up” position or the equatorial“down” position, whilst the second ring carrying the OSO 3 FI substituent is in the axial“down” position.
• the bicyclic ring adopts the stereochemistry depicted.
• the R group is in the axial“up” position, whilst the second ring carrying the OSO3FI substituent is in the axial“down” position.
• the bicyclic ring adopts the stereochemistry depicted.
• the R group is in the equatorial “down” position, whilst the second ring carrying the OSO3FI substituent is in the axial “down” position.
• a compound or composition described herein contains at least 50%, preferably at least 60%, 75%, 90% or 95% of a compound of Formula (I) having the stereochemistry in the bicyclic ring (i.e. at the two chiral centres on the bicyclic ring) as depicted above.
• the compound is substantially diastereomerically pure at the two chiral centres depicted above.
• a compound or composition described herein comprises a compound of Formula (II)
• at least 50%, preferably at least 60%, 75%, 90% or 95% of said compound has the stereochemistry in the bicyclic ring (i.e. at the two chiral centres on the bicyclic ring) as depicted above.
• the compound is substantially diastereomerically pure at the two chiral centres depicted above.
• a compound or composition described herein comprises a compound of Formula (III)
• at least 50%, preferably at least 60%, 75%, 90% or 95% of said compound has the stereochemistry in the bicyclic ring (i.e. at the two chiral centres on the bicyclic ring) as depicted above.
• the compound is substantially diastereomerically pure at the two chiral centres depicted above.
• a compound or composition described herein contains at least 50%, preferably at least 60, 75%, 90% or 95% of a compound according to Formula (I), (II) or (III) which is diasteriomerically pure with regard to a chiral centre in the R group.
• a compound or composition of the invention comprises by weight at least 60%, such as at least 75%, 90%, or 95% of a single diastereomer.
• the compound is substantially optically pure.
• a compound of Formula (I) is a compound of Formula (II).
• the compounds of the invention may be used in any tautomeric form.
• “removing or reducing resistance” to antibiotics, or“removing or reducing resistance” in bacteria means that the bacterial resistance mechanism, e.g. the breakdown of an antibiotic compound by SBL, is prevented or inhibited. Therefore the effects of bacterial resistance (i.e. inefficacy of antibiotics) is removed or reduced.
• the compounds of the invention are useful in inhibiting or preventing hydrolysis of a b- lactam ring, i.e. in inhibiting or preventing hydrolysis of an antibiotic compound. They therefore improve the efficacy of antibiotics when used to treat infection caused by SBL- producing bacteria.
• R is halogen.
• R is fluorine or chlorine.
• R is fluorine.
• the compound of Formula (I) may be a compound of Formula (II) or a pharmaceutically acceptable salt thereof or a compound of Formula (III) or a
• the compound of Formula (I) is a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
• the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof or a compound of Formula (III) or a pharmaceutically acceptable salt thereof and R is fluorine or chlorine. More preferably, the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof and R is fluorine or chlorine. Most preferably, the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof and R is fluorine.
• the compound of Formula (I) is a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) is a compound of Formula (II) or a pharmaceutically acceptable salt thereof; wherein
• R is selected from C(0)R 1 , Ci -4 alkyl and L-X-R 1 , wherein the Ci -4 alkyl group is substituted with at least one halogen atom and is optionally further substituted with one or two substituents R 2 ;
• R 1 is Ci- 4 alkyl which is substituted with at least one halogen atom and is optionally further substituted with one or two substituents R 2 ;
• each R 2 is independently selected from OFI; Ci -4 alkoxy which is unsubstituted or substituted with one or more halogen atoms; C(0)R 3 ; C(0)0FI; C(0)0R 3 ; 6- to 10- membered aryl; 5- to 6-membered heteroaryl; and 4- to 6-membered heterocyclyl; wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted with one, two or three substituents selected from halogen, OFI, C(0)R 3 , C(0)OFI, C(0)OR 3 and Ci -4 alkyl and Ci -4 alkoxy groups which are themselves unsubstituted or substituted with one or more halogen atoms;
• R 3 is Ci- 4 alkyl which is unsubstituted or substituted with one or more halogen atoms;
• o L is a bond or is a Ci -2 alkylene group which is unsubstituted or is substituted with at least one halogen atom;
• o X is O or S(0) z wherein z is 0, 1 or 2.
• L is preferably a bond or an unsubstituted Ci-2 alkylene group. More preferably, L is a bond or is an unsubstituted Ci alkylene (methylene) group.
• X is selected from O and S(0) z wherein z is 0, 1 or 2; i.e. X is selected from O, S, S(O), and S(0) 2 .
• Preferably X is selected from O and S.
• Preferred L-X-R 1 groups include -CFb-O-R 1 , -S-R 1 , and -SO2-R 1 wherein R 1 is as defined herein.
• L-X-R 1 groups include -CFI2-O-R 1 and -S-R 1 , wherein R 1 is as defined herein.
• R 1 is preferably a Ci or C2 alkyl group, preferably a Ci alkyl group.
• the R 1 group is preferably substituted by 1, 2 or 3 halogen groups, e.g. by three halogen groups; for example the R 1 group is preferably CF 3 .
• Most preferred L-C-R 1 groups thus include -L-X-CF3 groups such as -CFI2-O-CF3 and -S-CF3.
• the compound of Formula (I) is a compound of Formula (II) or a pharmaceutically acceptable salt thereof; wherein
• R is selected from C(0)R 1 and Ci -4 alkyl, wherein the Ci -4 alkyl group is
• R 1 is Ci- 4 alkyl which is substituted with at least one halogen atom and is optionally further substituted with one or two substituents R 2 ;
• each R 2 is independently selected from OFI; Ci -4 alkoxy which is unsubstituted or substituted with one or more halogen atoms; C(0)R 3 ; C(0)0FI; C(0)0R 3 ; 6- to 10- membered aryl; 5- to 6-membered heteroaryl; and 4- to 6-membered heterocyclyl; wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted with one, two or three substituents selected from halogen, OFI, C(0)R 3 , C(0)OFI, C(0)OR 3 and Ci -4 alkyl and Ci -4 alkoxy groups which are themselves unsubstituted or substituted with one or more halogen atoms;
• R 3 is Ci- 4 alkyl which is unsubstituted or substituted with one or more halogen atoms.
• R is Ci-4 alkyl, wherein the Ci-4 alkyl group R is as defined herein.
• R is selected from C(0)R' and Ci-4 alkyl, wherein the Ci-4 alkyl group is substituted with at least one halogen atom (e.g. fluorine or chlorine) and is optionally further substituted with one substituent R 2 .
• R is selected from
• the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof and R is Ci-4 alkyl, wherein the Ci-4 alkyl group is substituted with at least one halogen atom (e.g. fluorine or chlorine) and is optionally further substituted with one or two, e.g. one, substituent R 2 .
• R is Ci-4 alkyl, wherein the Ci-4 alkyl group is substituted with at least one halogen atom (e.g. fluorine or chlorine) and is optionally further substituted with one or two, e.g. one, substituent R 2 .
• the alkyl group is substituted with at least two, e.g. two or three, halogen atoms.
• the halogen atoms are preferably selected from fluorine and chlorine.
• R is Ci -2 alkyl, wherein the Ci -2 alkyl group is substituted with at least one halogen atom (e.g. fluorine or chlorine) and is optionally further substituted with one substituent R 2 .
• R is Ci -2 alkyl, wherein the Ci -2 alkyl group is substituted with at least two halogen atoms selected from fluorine and chlorine.
• R is a methyl group which is substituted with two or three halogen atoms selected from fluorine and chlorine, e.g. CF 3 , CCh, CHF 2 and CHCb.
• R 1 is Ci -4 alkyl which is substituted with at least one halogen atom (e.g. fluorine or chlorine) and is optionally further substituted with one substituent selected from OFI and Ci -4 alkoxy which is itself unsubstituted or substituted with one or more halogen atoms (e.g. fluorine or chlorine).
• R 1 is Ci -4 alkyl which is substituted with at least one, more preferably at least two (e.g. two or three), halogen atoms.
• the halogen atoms are preferably selected from fluorine and chlorine.
• R 1 is Ci -2 alkyl, wherein the Ci -2 alkyl group is substituted with at least two halogen atoms selected from fluorine and chlorine. Most preferably R 1 is a methyl group which is substituted with two or three halogen atoms selected from fluorine and chlorine, e.g. CF3.
• R 2 When R 2 represents 6- to lO-membered aryl, it is typically phenyl.
• R 2 represents 5- to 6-membered heteroaryl it is typically a 5-membered heteroaryl selected from thiazolyl, pyrrolyl, furanyl, thiophenyl, imidazolyl and oxazolyl, preferably thiazolyl.
• R 2 represents 4- to 6-membered heterocyclyl it is typically a 4- or 5-membered heterocyclyl group selected from oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl and
• tetrahydrothiophenyl Preferably it is a 4-membered heterocyclyl group selected from oxetanyl and azetidinyl, most preferably oxetanyl.
• R 2 represents an aryl, heteroaryl or heterocyclyl group, it is unsubstituted or substituted with one, two or three (e.g. one or two) substituents selected from halogen, OFI, C(0)R 3 , C(0)OFI, C(0)OR 3 and Ci -4 alkyl and Ci -4 alkoxy groups which are themselves unsubstituted or substituted with one or more halogen atoms.
• Preferred substituents are halogen; OFI; and Ci -2 alkyl and Ci -2 alkoxy groups which are themselves unsubstituted or substituted with one or more halogen atoms. More preferred substituents are halogen, OH, Me and OMe. Most preferably when R 2 represents an aryl, heteroaryl or heterocyclyl group, it is unsubstituted.
• Each R 2 is typically independently selected from OH; Ci -2 alkoxy which is itself unsubstituted or substituted with one or more halogen atoms; C(0)OR 3 , wherein R 3 is unsubstituted Ci -2 alkyl; and unsubstituted 5- to 6-membered heteroaryl.
• each R 2 is independently selected from OH; OMe; C(0)OMe; and unsubstituted thiazolyl.
• R 3 is typically unsubstituted Ci -2 alkyl, preferably methyl.
• the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof, and
• R is Ci- 4 alkyl, wherein the Ci -4 alkyl group is substituted with at least one halogen atom and is optionally further substituted with one or two substituents R 2 ; wherein preferably R is Ci -2 alkyl, wherein the Ci -2 alkyl group is substituted with at least one halogen atom (e.g. fluorine or chlorine) and is optionally further substituted with one substituent R 2 ;
• halogen atom e.g. fluorine or chlorine
• each R 2 is independently selected from OH; Ci -4 alkoxy which is unsubstituted or substituted with one or more halogen atoms; C(0)R 3 ; C(0)OH; C(0)OR 3 ; 6- to 10- membered aryl; 5- to 6-membered heteroaryl; and 4- to 6-membered heterocyclyl; wherein the aryl, heteroaryl and heterocyclyl groups are unsubstituted or substituted with one, two or three substituents selected from halogen, OH, C(0)R 3 , C(0)OH, C(0)OR 3 and Ci -4 alkyl and Ci -4 alkoxy groups which are themselves unsubstituted or substituted with one or more halogen atoms; wherein preferably each R 2 is selected from OH; Ci -2 alkoxy which is itself unsubstituted or substituted with one or more halogen atoms; C(0)OR 3 and unsubstituted 5- to 6-membered heteroaryl; and
• R 3 is Ci- 4 alkyl which is unsubstituted or substituted with one or more halogen atoms; preferably R 3 is unsubstituted Ci -2 alkyl.
• R is selected from C(0)R 1 and Ci -4 alkyl, wherein the Ci -4 alkyl group is substituted with at least one halogen atom (e.g. fluorine or chlorine) and is optionally further substituted with one substituent R 2 ;
• R 1 is Ci- 4 alkyl which is substituted with at least one halogen atom (e.g. fluorine or chlorine) and is optionally further substituted with one substituent selected from OH and Ci -4 alkoxy which is itself unsubstituted or substituted with one or more halogen atoms (e.g. fluorine or chlorine); and
• R 2 is selected from OH; Ci -2 alkoxy which is itself unsubstituted or substituted with one or more halogen atoms; C(0)OR 3 , wherein R 3 is unsubstituted Ci -2 alkyl; and unsubstituted 5- to 6-membered heteroaryl.
• More preferred compounds of the invention are those wherein the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof, and wherein:
• R is selected from C(0)R' and Ci -4 alkyl, in particular Ci -2 alkyl, wherein the alkyl group is substituted with at least one halogen atom (e.g. fluorine or chlorine) and is optionally further substituted with one substituent R 2 ;
• halogen atom e.g. fluorine or chlorine
• R 1 is Ci-2 alkyl, wherein the Ci -2 alkyl group is substituted with at least two halogen atoms selected from fluorine and chlorine;
• R 2 is selected from OH; OMe; C(0)OMe; and unsubstituted thiazolyl.
• Still more preferred compounds of the invention are those wherein the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof, and wherein R is COCF3 or Ci-2 alkyl, wherein the Ci-2 alkyl group is substituted with at least one halogen atom (e.g. fluorine or chlorine) and is optionally further substituted with one substituent R 2 , wherein R 2 is selected from OH; OMe; C(0)OMe; and unsubstituted thiazolyl. More preferably, R is Ci-2 alkyl, wherein the Ci-2 alkyl group is substituted with at least two halogen atoms selected from fluorine or chlorine. Most preferably R is a methyl group which is substituted with two or three halogen atoms selected from fluorine and chlorine, e.g. CF 3 , CCb, CHF 2 and CHCb.
• R is COCF3 or Ci-2 alkyl, wherein the Ci-2 alkyl group is substituted with at least one hal
• R groups include CF 3 , CHF 2 , CHCb, CCb, C3 ⁇ 4F, CF 2 CH 3 , CF 2 CH 2 C0 2 Me, COCF 3 , CF 2 -thiazolyl, CF 2 CH 2 OCH 3 , CF 2 CH 2 CH 2 OH, CH(OH)CF 3 ,
• Preferred compounds of the invention include:
• Preferred pharmaceutically acceptable salts of these compounds are salts at the SO 3 H group, in particular quaternary ammonium salts, e.g. tetrabutylammonium salts, and alkali metal salts, e.g. sodium and potassium salts.
• quaternary ammonium salts e.g. tetrabutylammonium salts
• alkali metal salts e.g. sodium and potassium salts.
• More preferred compounds are:
• Preferred pharmaceutically acceptable salts of these compounds are salts at the SO 3 H group, in particular quaternary ammonium salts, e.g. tetrabutylammonium salts, and alkali metal salts, e.g. sodium and potassium salts.
• quaternary ammonium salts e.g. tetrabutylammonium salts
• alkali metal salts e.g. sodium and potassium salts.
• Preferred pharmaceutically acceptable salts of these compounds are salts at the SO 3 H group, in particular quaternary ammonium salts, e.g. tetrabutylammonium salts, and alkali metal salts, e.g. sodium and potassium salts.
• quaternary ammonium salts e.g. tetrabutylammonium salts
• alkali metal salts e.g. sodium and potassium salts.
• Preferred pharmaceutically acceptable salts of these compounds are salts at the SO 3 H group, in particular quaternary ammonium salts, e.g. tetrabutylammonium salts, and alkali metal salts, e.g. sodium and potassium salts.
• quaternary ammonium salts e.g. tetrabutylammonium salts
• alkali metal salts e.g. sodium and potassium salts.
• the BOC-pyrrolidinone (2) may be reacted with a sulfoxonium ylid reagent to give in situ the new ring-opened ylid (6).
• Protonation generates a positively charged sulfoxonium species which is nucleophilically attacked by chloride anion, resulting in loss of DMSO and generating the chloromethyl ketone which condenses with O-benzyl hydroxylamine to give oxime (7).
• Scheme A shows synthetic routes to compounds of the invention of Formula (II).
• the starting material in Scheme B corresponds to compound (9) in Scheme A and can be synthesized in accordance with Scheme A, starting from a carboxyl-functionalised compound (2).
• the halo-compounds shown in Scheme B can be converted from the -OBn form to the -OSO3 form via debenzylation and sulfonation as described above and in the Examples.
• Corresponding compounds of Formula (III) can be prepared starting from the stereoisomer of the starting material.
• Li includes one example of the very rare F-CFI2-N-CO functionality, but this is in a special situation where there are two carbonyl groups on the single nitrogen, effectively removing the nitrogen lone pair through extensive delocalisation to the oxygens of the carbonyl groups. There are very few examples of this functionality with only one carbonyl group on the nitrogen, and even they are restricted to reactive intermediates for glycosylation-type reactions, proceeding via iminium formation followed by quenching of the iminium ion with alcohol (2016, Organic Letters, 18, 9890). The inventors have found that the propensity of a molecule to fragment and decompose can be overcome by organising the functionality such that stereochemical control can overcome the natural tendency for reactivity.
• stabilisation can be introduced by the decomposition pathway via the iminium species going via a“bridgehead double bond”.
• the impossibility of forming a bridgehead double bond was first observed by Bredt (1902,“Ueber isomere Dehydrocamphersauren,
• the compounds of the invention may be provided in a pharmaceutical composition, the pharmaceutical composition comprising a compound of the invention together with a pharmaceutically acceptable carrier or diluent.
• the composition contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention.
• Preferred pharmaceutical compositions are sterile and pyrogen free.
• the pharmaceutical compositions provided by the invention contain a compound of the invention which is optically active, the compound of the invention is typically a substantially pure optical isomer.
• the compounds of the invention are useful in treating or preventing bacterial infection.
• they are inhibitors of SBL enzymes and are therefore useful for removing or reducing resistance of Gram-negative bacteria to antibiotics.
• the compounds may be used alone or they may be used in combination therapies with antibiotic agents, to enhance the action of the antibiotic agent.
• the compounds may also be used in combination with MBL inhibitors, in particular where the bacteria causing the infection are resistant to treatment by an antibiotic agent alone and the resistance is, or is suspected of being, caused at least in part by metal Io-b-lactamase enzymes.
• the present invention therefore also provides a combination of (i) a compound of the invention; and one or more of (ii) a m c ta 11 o - b - 1 a c tarn a sc (MBL) inhibitor; and (iii) an antibiotic agent.
• the combinations may also comprise further active agents if desired.
• the active agents may each be provided in a single formulation or one or more of them may be separately formulated. Where separately formulated, the two or more agents may be administered simultaneously or separately. Active agents which are separately formulated may be provided in the form of a kit, optionally together with instructions for their administration.
• the kit may comprise (i) a composition comprising a compound of the invention; and one or both of (ii) a composition comprising an antibiotic agent and (iii) a composition comprising an MBL inhibitor, optionally together with instructions for their use.
• the two or more active agents may be provided as a pharmaceutical composition.
• the pharmaceutical composition may therefore comprise (i) a compound of the invention as described herein; (ii) a pharmaceutically acceptable carrier or diluent; and optionally one or both of (iii) an antibiotic agent; and (iv) a metallo-b- lactamase (MBL) inhibitor.
• the compound of the invention and the antibiotic agent may be formulated together or separately. Further, the compound of the invention and the MBL inhibitor may be formulated together or separately. Where all three active agents are present, the compound of the invention, the MBL inhibitor and the antibiotic agent may each be provided in a single formulation, or they may be separately formulated. Alternatively, two of the components may be provided in a single formulation and the remaining component may be provided separately.
• the compound of the invention may be formulated with the MBL inhibitor and the antibiotic agent; or the compound of the invention may be formulated with the MBL inhibitor whilst the antibiotic agent is provided separately; or the compound of the invention may be formulated with the antibiotic agent whilst the MBL inhibitor is provided separately; or the MBL inhibitor may be formulated with the antibiotic agent whilst the compound of the invention is provided separately; or the compound of the invention, the MBL inhibitor and the antibiotic agent may each be formulated separately.
• the antibiotic agent which is administered with the compound of the invention, or used in the combinations or compositions of the invention is a b-lactam antibiotic.
• the antibiotic agent is a b-lactam antibiotic selected from carbapenems, penicillins, cephalosporins and penems; or the antibiotic agent is aztreonam.
• carbapenem antibiotics include Benapenem, Imipenem, Meropenem, Ertapenem,
• Doripenem and Biapenem examples include penicillins include Amoxicillin, Ampicillin, Ticarcillin, Piperacillin and Cloxacillin.
• cephalosporins examples include Cefepime, Cefazolin, Ceftriaxone, Ceftazidine and Ceftobiprole.
• penems include Faropenem.
• Other antibiotic agents include tobramycin, neomycin, streptomycin, gentamycin, tazobactam, rifampicin, ciprofloxacin, amikacin, cobstin, aztreonam and levofloxacin.
• the b-lactam antibiotic is aztreonam or a carbapenem antibiotic, more preferably biapenem, imipenem or meropenem.
• biapenem is a preferred carbapenem antibiotic.
• meropenem is a preferred carbapenem antibiotic.
• the b-lactam antibiotic is a carbapenem antibiotic, more preferably imipenem or meropenem, most preferably meropenem.
• the MBL inhibitor is preferably a compound as described in WO 2014/198849, GB2533136, PCT/EP2018/069827
• the MBL inhibitor is a compound of Formula (A), or a pharmaceutically acceptable salt thereof,
• R 1A is selected from H, R lb and -CH 2 0C(0)R lb , wherein R lb is selected from an unsubstituted Ci to C 4 alkyl group and phenyl;
• o (A) is a cyclic group selected from C 6 to Cio aryl, 5- to lO-membered heteroaryl, and 4- to 10- membered carbocyclic and heterocyclic groups;
• each R 2A is independently selected from:
• Ci- 3 alkyl 0(Ci -3 alkyl), S(Ci -3 alkyl), SO(Ci -3 alkyl) or S0 2 (Ci -3 alkyl), any of which may optionally be substituted with 1, 2 or 3 halo substituents and/or one R 8 substituent; and
• each R a and R b is independently selected from hydrogen and unsubstituted Ci -2 alkyl and each R c is
• each R 8 is independently selected from CN, OH, -C(0)NR f R g , -NR f R g ,
• each of R f and R g is independently H or unsubstituted Ci -2 alkyl;
• o m 0, 1, 2 or 3
• R 3A is selected from hydrogen and a Ci to C 3 alkyl group which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, -OR 10 , and - NR 10 R n ;
• o n 0 or 1
• o Z A is a bond or is selected from -NR 10 C(O)-, -C(0)NR 10 -, -NR 10 C(O)NR u -,
• o L A is a bond or is selected from Ci -4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene,
• Ci -3 alkylene-(C 3-6 cycloalkylene)-Ci -3 alkylene, Ci -4 alkylene-(C 3-6 cycloalkylene) and (C 3-6 cycloalkylene)-Ci- 4 alkylene, wherein L is unsubstituted or is substituted with 1 or 2 substituents selected from halogen, -OR 10 , and -NR 10 R n ; or L is -C(R 10 ) N-;
• R 4A is selected from H, -CN and Ci to C 3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, -OR 10 ,
• R 4A is joined together with R 5A to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R n , and -CN;
• R 5A is selected from H, -CN and Ci to C 3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, -OR 10 ,
• R 5A is joined together with R 4A to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R n , and -CN;
• R 5A is joined together with R 6 to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R n , and -CN;
• R 6A is selected from H, -CN and Ci to C 3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, -OR 10 ,
• R 6A is joined together with R 5A to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R n , and -CN;
• R 6A is joined together with R 7A if present to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from
• Ci unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R U , and -CN;
• R 7A if present is selected from H, -CN and Ci to C 3 alkyl which is unsubstituted or is substituted with 1, 2 or 3 substituents selected from halogen, -OR 10 ,
• R 7A is joined together with R 6A to form, together with the atoms to which they are attached, a 5- to 6- membered heterocyclic group comprising at least one saturated carbon atom in the ring, said heterocyclic group being unsubstituted or substituted with 1 or 2 substituents selected from unsubstituted Ci to C 2 alkyl, halogen, -OR 10 , -NR 10 R n , and -CN;
• each R 10 , R 11 , R 12 , R 13 and R 14 is independently H or methyl
• each R 15 is independently substituted Ci to C 4 alkyl or unsubstituted C 2 to C 4 alkyl, wherein when R 15 is a substituted alkyl group the alkyl group is substituted with 1, 2 or 3 substituents independently selected from halogen, CN, OR 10 and -NR 10 R n .
• the MBL inhibitor is a compound of Formula (A), or a pharmaceutically acceptable salt thereof, wherein:
• R 1A is H
• (A) is selected from phenyl, cyclohexane, piperidine, pyridazine, pyridine and
• each R 2A is independently selected from:
• Ci -2 alkyl 0(Ci -2 alkyl), S(Ci -2 alkyl), SO(Ci -2 alkyl) any of which may optionally be substituted with 1, 2 or 3 substituents selected from halo, CN, OH; • /? is 0;
• Z A is selected from -NR 10 C(O)-, -C(0)NR 10 -, and -NR 10 C(O)NR u -;
• L A is a bond or is selected from Ci -3 alkylene and C 2- 3 alkenylene.
• R 4A is H
• R 5A is selected from H, -CN and Ci to C 2 alkyl which is unsubstituted or is
• the MBL inhibitor is a compound of Formula (A) selected from:
• the MBL inhibitor may preferably be a compound of Formula (B), or a pharmaceutically acceptable salt thereof,
• R 1B is hydrogen, halo, CN, R 12B , OR 12B , SR 12B or NR 12B R 13B ;
• R 12B is Ci -6 alkyl optionally substituted with one or more substituent R aB ; phenyl or 5- to 6-membered heteroaryl, either of which may optionally be substituted with one or more substituent R bB ; or 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl, either of which is optionally substituted with one or more substituent R cB ;
• each R aB is independently halo, CN, OFI or OCi -4 alkyl optionally
• each R bB is independently halo, CN, OFI or Ci -4 alkyl or OCi -4 alkyl either of which may optionally substituted by one or more substituent selected from halo and OFI;
• each R cB is independently halo, CN, OFI, oxo or Ci -4 alkyl or OCi -4 alkyl optionally substituted by one or more substituent selected from halo and OH;
• o R 13B is hydrogen or Ci -6 alkyl optionally substituted with one or more substituent R a as defined above;
• Y B is a single bond, -Ci -4 alkylene- or -C 2-4 alkenylene-, either of which may be substituted with a group R 17B or
• R 17B is OR 1B , NR 1B R mB , NR 1B C(0)R mB , C(0)NR 1B R mB , C(0)OR mB ;
• each R 1B and R mB is independently H or C M alkyl
• R 8B is hydrogen or Ci -6 alkyl or -C(0)Ci- 6 alkyl either of which is optionally substituted by one or more substituent R dB ;
• Ci- 4 alkylene chains may optionally be substituted with one or more
• each R dB and R eB is independently halo, CN, OH or OC M alkyl optionally substituted by one or more substituent selected from halo and OH;
• a B represents a cyclic group selected from a 6- to lO-membered aryl, 5- to 10- membered heteroaryl or a 3- to 10- membered carbocyclyl or heterocyclyl group;
• nB is 0 to 4.
• each R 2B is independently selected from R 3B ;
• CM alkyl C 2 -4 alkenyl, 0(CM alkyl), S(CM alkyl), SO(Ci -4 alkyl) or S0 2 (Ci -4 alkyl), any of which may optionally be substituted with one or more substituent R 3b ; or
• R 2B may also be oxo
• each R 3B is independently halo, nitro, CN, OH; or
• each of R 14B and R 15B is independently H, or Ci -6 alkyl optionally
• each R 7B is independently halo, CN, OH; or Ci -4 alkyl or OCi -4 alkyl either of which may optionally substituted by one or more substituent selected from halo and OH; or NR jB R kB , wherein each R jB and R kB is independently H or Ci -4 alkyl;
• each of R 21B and R 22B is hydrogen or Ci -4 alkyl or R 21B and R 22B together with the nitrogen atom to which they are attached may form a 5- or 6- membered heterocyclic ring, optionally containing one further heteroatom selected from N, O and S and optionally substituted with Ci -4 alkyl or halo;
• R 4B is hydrogen or Ci -6 alkyl optionally substituted with halo, CN, OH, NR jB R kB ; or OCi -4 alkyl which may optionally substituted by one or more substituent selected from halo and OH; wherein each R jB and R kB is independently H or Ci -4 alkyl
• R 5B is hydrogen, phenyl, 5- to 6-membered heteroaryl, 3- to 8-membered
• Ci- 6 alkyl optionally substituted with phenyl, 5- to 6-membered heteroaryl, 3- to 8- membered carbocyclyl or 3- to 8-membered heterocyclyl;
• phenyl and heteroaryl groups are optionally substituted by one or more substituent R ffl and carbocyclyl and heterocyclyl groups are optionally substituted by one or more substituent R gB and wherein:
• each R ffl is independently halo, CN, OH or Ci -4 alkyl or OCi -4 alkyl either of which may optionally be substituted by one or more substituent selected from halo and OH;
• each R gB is independently halo, CN, OH, oxo or Ci -4 alkyl or OCi -4 alkyl optionally substituted by one or more substituent selected from halo and OH;
• R 6B is Ci- 6 alkyl optionally substituted with one or more R hB , or phenyl or 5- to 6- membered heteroaryl either of which is optionally substituted with one or more substituent R lB ; o each R hB is independently halo, CN, OH, NH 2 , phenyl, pyridyl, COOH or OCi- 4 alkyl optionally substituted by one or more substituent selected from halo and OH;
• each R lB is independently halo, CN, OH, NH 2 or Ci -4 alkyl or OCi -4 alkyl either of which may optionally be substituted by one or more substituent selected from halo and OH;
• R 11B is hydrogen, Ci -4 alkyl optionally substituted by halo or benzyl optionally substituted by halo.
• the MBL inhibitor is a compound of Formula (B), or a
• R 1B is hydrogen
• Y B is a single bond or -Ci -4 alkylene-
• a B represents a cyclic group selected from phenyl, pyridyl, pyrazolyl, thiophenyl or benzothiophenyl;
• nB is 0 to 3;
• each R 2B is independently selected from
• NR 4B R 5B wherein R 4B is hydrogen or Ci -4 alkyl and R 5B is hydrogen; or o NR 4B C(0)R 6B wherein R 4B is hydrogen or methyl, and R 6B is Ci -4 alkyl optionally substituted with one or more substituent independently selected from OH, NH 2 , and OCi -4 alkyl; and
• the MBL inhibitor is a compound of Formula (B)
• the MBL inhibitor is preferably selected from
• the invention therefore provides a combination of a compound of the invention as described herein, e.g. a compound of Formula (I), (II) or (III) wherein R is as defined herein, preferably wherein R is halogen, and an MBL inhibitor of Formula (A) or Formula (B) as defined herein, wherein the MBL inhibitor is preferably of Formula (A).
• the combination may further comprise an antibiotic agent as described herein.
• combination may be in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or diluent.
• the compounds, compositions or combinations described herein may be administered in a variety of dosage forms.
• they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. They may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrastemally, transdermally or by infusion techniques.
• the compound, composition or combination may also be administered as a suppository.
• the compound, composition or combination is administered via parenteral administration, in particular via intravenous administration.
• solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, com starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
• Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
• Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
• the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
• Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
• Suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
• Solutions for injection may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
• Compositions for injection e.g. i.v. administration
• Pharmaceutical compositions suitable for delivery by needleless injection, for example, transdermally, may also be used.
• the compounds of the present invention are therapeutically useful.
• the present invention therefore provides compounds, compositions and combinations as described herein, for use in medicine.
• the present invention provides compounds as described herein, for use in treating the human or animal body.
• the compound of the invention may be administered in the form of a solvate.
• the compounds, compositions and combinations of the invention are useful in treating or preventing bacterial infection.
• the present invention therefore provides a compound, composition or combination of the invention for use in treating or preventing bacterial infection.
• the invention also provides the use of a compound, composition or combination of the invention in the manufacture of a medicament for use in the prevention or treatment of bacterial infection.
• the invention also provides a method of treating or preventing bacterial infection in a subject in need thereof, which method comprises administering to said subject an effective amount of a compound, composition or combination as described herein.
• the compounds of the invention may be used as standalone therapeutic agents.
• the compounds of the invention may be used as standalone adjuncts in antibacterial therapy, for example in chemotherapy regimes.
• they may be used in combination with antibiotic agents, and optionally with MBL inhibitors, to enhance the action of the antibiotic agent.
• the compounds of the invention may find particular use in treating or preventing bacterial infection caused by bacteria which are resistant to treatment with antibiotic agents when administered alone, particularly where the resistance is caused by presence of SBL enzymes. Treatment or prevention of such infection with b- lactam antibiotics alone may be unsuccessful.
• the compounds are therefore useful in the removal or reduction of antibiotic resistance, in particular in Gram-negative bacteria.
• the compounds are useful in removing or reducing resistance caused by SBL enzymes.
• the invention also provides a compound of the invention for use in treating or preventing bacterial infection by co-administration with (i) an antibiotic agent and/or (ii) an MBL inhibitor. Also provided is an antibiotic agent for use in treating or preventing bacterial infection by co-administration with (i) a compound of the invention and optionally (ii) an MBL inhibitor. Also provided is an MBL inhibitor for use in treating or preventing bacterial infection by co-administration with (i) a compound of the invention and optionally (ii) an antibiotic agent.
• a compound of the invention in the manufacture of a medicament for use in treating or preventing bacterial infection by co-administration with (i) an antibiotic agent and/or (ii) an MBL inhibitor.
• an antibiotic agent in the manufacture of a medicament for use in treating or preventing bacterial infection by co-administration with (i) a compound of the invention and optionally (ii) an MBL inhibitor.
• an MBL inhibitor in the manufacture of a medicament for use in treating or preventing bacterial infection by co- administration with (i) a compound of the invention and optionally (ii) an antibiotic agent.
• the subject to be treated is a mammal, in particular a human.
• it may be non-human.
• Preferred non-human animals include, but are not limited to, primates, such as marmosets or monkeys, commercially farmed animals, such as horses, cows, sheep or pigs, and pets, such as dogs, cats, mice, rats, guinea pigs, ferrets, gerbils or hamsters.
• the subject can be any animal that is capable of being infected by a bacterium.
• the compounds, compositions and combinations described herein are useful in the treatment of bacterial infection which occurs after a relapse following an antibiotic treatment.
• the compounds, compositions and combinations can therefore be used in the treatment of a patient who has previously received antibiotic treatment for the (same episode of) bacterial infection.
• the bacterium causing the infection may be any bacterium expressing an SBL enzyme or an analogue thereof. Typically the bacterium causing the infection expresses an SBL enzyme.
• the bacterium is typically Gram-negative.
• the bacterium may in particular be a pathogenic bacterium.
• the bacterial infection to be treated using the compounds of the invention is resistant to treatment with a conventional antibiotic when the conventional antibiotic is used alone or in a combination with another partner.
• the bacterial infection to be treated using the compounds of the invention may be resistant to treatment when the conventional antibiotic is used solely in combination with an MBL inhibitor.
• the Gram-negative bacteria of which antibiotic resistance can be removed using the compounds of general formula (I) are bacteria which produce serine-P-lactamases, which may be serine-P-lactamases of subclasses A, C or D.
• the bacteria may be those which produce extended spectrum P-lactamases (ESBLs) and/or carbapenemases, in particular the OXA and/or KPC classes of carbapenemases, preferably the OXA class of carbapenamases .
• the bacterial infection may be caused by bacteria from the families Enterobacteriaceae, Pseudomonadaceae and/or Moraxellaceae, more typically the bacterial infection is caused by bacteria from the families Enterobacteriaceae and/or Pseudomonadaceae, and most typically the bacterial infection is caused by bacteria from the family Enterobacteriaceae.
• the bacterial infection may be caused by Pseudomonas (e.g. Pseudomonas aeruginosa, Pseudomonas oryzihabitans, or Pseudomonas plecoglossicidd), Klebsiella, Escherichia, Enterobacter, Acinetobacter or Burkholderia.
• the bacterial infection may be caused by Pseudomonas (e.g. Pseudomonas aeruginosa, Pseudomonas oryzihabitans, or Pseudomonas plecoglossicidd), Klebsiella, Escherichia, Enterobacter, or Acinetobacter More preferably, the bacterial infection is caused by Acinetobacter or Klebsiella, most preferably Acinetobacter. For example, the bacterial infection may be caused by Pseudomonas (e.g. Pseudomonas aeruginosa, Pseudomonas oryzihabitans, or Pseudomonas plecoglossicidd), Klebsiella, Escherichia, Enterobacter, or Acinetobacter More preferably, the bacterial infection is caused by Acinetobacter or Klebsiella, most preferably Acinetobacter. For example, the bacterial infection may be caused by
• the bacterial infection may be caused by Klebsiella pneumoniae, Escherichia coli, Enterobacter Cloacae, Pseudomonas aeruginosa, Burkholderia cepacia or Acinetobacter baumannii.
• the bacterial infection may be caused by Klebsiella pneumoniae, Escherichia coli, Enterobacter Cloacae, Pseudomonas aeruginosa, or Acinetobacter baumannii. More preferably, the bacterial infection is caused by Acinetobacter baumannii or Klebsiella pneumoniae, most preferably Acinetobacter baumannii.
• the bacterium may be an opportunistic pathogen.
• the compound, composition or combination of the invention may be used to treat or prevent infections and conditions caused by any one or a combination of the above- mentioned bacteria.
• the compound, composition or combination of the invention may be used in the treatment or prevention of pneumonia.
• the compound, composition or combination may also be used in the treatment of septic shock, urinary tract infection, and infections of the gastrointestinal tract, skin or soft tissue.
• the compound, composition or combination of the invention may be used to treat patients with Carbapenem Resistant Enterobacteriaceae (CRE).
• CRE can be found in the community or in hospitals and other institutions which are commonly associated with long term patients and those that are undergoing significant medical interventions such as are commonly cared for in Intensive Care Units (ICUs).
• ICUs Intensive Care Units
• a compound, composition or combination of the invention can be administered to the subject in order to prevent the onset or reoccurrence of one or more symptoms of the bacterial infection. This is prophylaxis.
• the subject can be
• a prophylactically effective amount of the agent or formulation is administered to such a subject.
• a prophylactically effective amount is an amount which prevents the onset of one or more symptoms of the bacterial infection.
• a compound, composition or combination of the invention can be administered to the subject in order to treat one or more symptoms of the bacterial infection.
• the subject is typically symptomatic.
• a therapeutically effective amount of the agent or formulation is administered to such a subject.
• a therapeutically effective amount is an amount effective to ameliorate one or more symptoms of the disorder.
• a therapeutically or prophylactically effective amount of the compound of the invention is administered to a subject.
• the dose may be determined according to various parameters, especially according to the compound used; the age, weight and condition of the subject to be treated; the route of administration; and the required regimen.
• a physician will be able to determine the required route of administration and dosage for any particular subject.
• a typical daily dose is from about 0.01 to 100 mg per kg, preferably from about 0.1 mg/kg to 50 mg/kg, e.g. from about 1 to 10 mg/kg of body weight, according to the activity of the specific inhibitor, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
• daily dosage levels are from 70 mg to 3.5 g.
• higher dosages are required, such as from about 0.01 to about 250 mg per kg, e.g. from about 0.1 mg/kg to about 200 mg/kg, e.g. from about 1 to about 150 mg/kg of body weight, according to the activity of the specific inhibitor, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
• Such preferred daily dosage levels may be e.g. from 70 mg to 8 g.
• Higher dosages may be particularly suitable if the compound of the invention is administered to the subject multiple times per day, such as 2, 3 or 4 times per day, e.g. 4 times daily.
• a suitable daily dosage may be from 70 mg to 8 g per day administered in 2, 3 or 4 separate dosages.
• the dose of the other active agent can be determined as described above.
• the dose may be determined according to various parameters, especially according to the agent used; the age, weight and condition of the subject to be treated; the route of administration; and the required regimen. Again, a physician will be able to determine the required route of administration and dosage for any particular subject.
• a typical daily dose is from about 0.01 to 100 mg per kg, preferably from about 0.1 mg/kg to 50 mg/kg, e.g.
• daily dosage levels are from about 1 to 10 mg/kg of body weight, according to the activity of the specific inhibitor, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
• daily dosage levels are from 70 mg to 3.5 g.
• higher dosages are required, such as from about 0.01 to about 250 mg per kg, e.g. from about 0.1 mg/kg to about 200 mg/kg, e.g. from about 1 to about 150 mg/kg of body weight, according to the activity of the specific inhibitor, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration.
• Such preferred daily dosage levels may be e.g. from 70 mg to 8 g.
• Higher dosages may be particularly suitable if the combination or composition of the invention is administered to the subject multiple times per day, such as 2, 3 or 4 times per day, e.g. 4 times daily.
• a suitable daily dosage may be from 70 mg to 8 g per day administered in 2, 3 or 4 separate dosages.
• Z represents a suitable ester substituent such as the benzyl group in (9) of Scheme 1.
• the ester functionality such as (9) in Scheme 1 can be reduced to an alcohol (11) which can be oxidised to an aldehyde (12).
• the aldehyde can be transformed into a difluoromethyl substituent (13) or a dichloromethyl substituent (14) using DAST (diethylaminosulfur trifluoride, see Xu, Y., Prestwich, G. D., Journal of Organic Chemistry, 2002, 67, 20, 7158 - 7161) or PC15 (Gauthier, J. et al, Bioorganic and Medicinal Chemistry Letters, 2008, 18, 923 - 928) or similar reagents, chemistry that is well known to those skilled in the art.
• the alcohol can be transformed into fluoromethyl (15) with DAST (Liu, Y.
• 2- trimethylthiazole can react with aldehydes followed by TMS ether cleavage and oxidation of the alcohol to generate the 2-thiazolyl ketone (21) (for an example of this chemistry, see Dondoni, A. et al, JOC2004, 69, 5023) which can be transformed into the
• difluoromethylene using DAST reagent.
• Related silicon chemistry can be used to generate for example the trifluoromethyl ketone substituent, as (trifluoromethyl)trimethylsilane can react with aldehydes to give the corresponding carbinol (Cheng, FL, et al Tet. Lett., 2013, 54, 4483). Standard oxidation then accesses the trifluoromethyl ketone (22).
• Fractions 1 and 3 did not contain the desired compound but Fraction 2 (TLC; Rf 0.4 in 20% ethyl acetate/hexane), a white solid (130 mg, 5%), showed spectroscopic data consistent with the desired compound.
• FIMBC NMR studies showed a close spatial proximity between the carbonyl carbon and the C2-FI proton, thereby defining the -CC12FI substituent as axial and the C2- chirality as S, as in the diagram.
• Example 4 was prepared from the key intermediate alcohol by conversion to the fluoromethyl substituent using standard DAST treatment (see for example Collet, C. et al, Bioorg. Med. Chem. Lett. 2017, 25, 5603).
• Example 5 was prepared by conversion of the acid to the Weinreb amide, methyl ketone formation using methyl magnesium bromide then conversion of the methyl ketone to the difluoroethyl substituent using DAST (Wityak, J., et al, J. Medicinal Chemistry, 2015, 58, 2967).
• Example 6 was prepared by reaction of the alcohol with methane sulfonyl chloride in the presence of triethylamine to give the corresponding mesylate then displacement using tetra-n-butyl ammonium chloride to afford the choromethyl intermediate.
• Example 7 was prepared by a decarboxylative approach, using related methodology to that for introducing halogens but using silver(I) trifluoromethanethiolate following the conditions described by Liu, C. et al (RSC Advances, 2017, 7, 880).
• Example 8 was prepared by trifluoromethylation of the alcohol using
• TMSCF3 trifluoromethyltrimethylsilane
• Example 9 was prepared from the aldehyde which was transformed into the thiazolyl ketone following the methodology as described by Dondoni, A., et al, (2004, Journal of Organic Chemistry, 69, 5023), namely in situ generation of the thiazole anion and reaction with the aldehyde; trapping with acetic anhydride to give the acetate; hydrolysis of the acetate followed by a Swem-like oxidation to generate the ketone. This was reacted with DAST in the usual way to generate the geminal difluoride.
• reaction mixture was diluted with water (50 mL) and washed with EtOAc (2x100 mL).
• the aqueous layer was acidified with 1N FIC1 (to pFI ⁇ 3) and then extracted with EtOAc (2x100 mL).
• the combined organic phases were washed with water, brine, dried over anhydrous Na 2 S0 4 , filtered and concentrated to obtain (2S,5R)-6- (benzyloxy)-7-oxo- 1, 6-diazabicyclo [3.2. l]octane-2-carboxylic acid (5g, 79%) as a white solid which was used in the next step without purification.
• the combined filtrate was again treated with DowexTM Na resin (1 g) for 1 h, filtered through a bed of DowexTM Na resin, washing with H 2 0 (5 mL). This process was repeated for another 3 times.
• the combined filtrates were freeze- dried to obtain the title compound (90 mg, 75%) as an off-white solid.

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