GB2602096A - Compounds - Google Patents

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GB2602096A
GB2602096A GB2020047.3A GB202020047A GB2602096A GB 2602096 A GB2602096 A GB 2602096A GB 202020047 A GB202020047 A GB 202020047A GB 2602096 A GB2602096 A GB 2602096A
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United Kingdom
Prior art keywords
compound
phenyl
group
alkyl
tested
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GB2020047.3A
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GB202020047D0 (en
Inventor
Cooper Ian
Orr David
Wilkinson Andrew
Kirkham James
Bunt Adam
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Infex Therapeutics Ltd
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Infex Therapeutics Ltd
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Priority to GB2020047.3A priority Critical patent/GB2602096A/en
Publication of GB202020047D0 publication Critical patent/GB202020047D0/en
Publication of GB2602096A publication Critical patent/GB2602096A/en
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein ring A is a pyrrole or pyrazole ring and when ring A is a pyrrole X is C(R4) and when ring A is a pyrazole X is N(R5) and one of R1 and R5 is absent; L1 is absent or a linker selected from alkylene, O, NR6 and S; R2 is phenyl, naphthyl, heteroaryl, heterocycloalkyl or cycloalkyl; R3 is C(O)OH, or C(O)OM wherein M is a group 1 cation; and R1, R4, R5 and R6 are as defined herein. Exemplified compounds include 1-methyl-2-phenyl-4-sulfamoyl-pyrrole-3-carboxylic acid; 2-(6-amino-3-pyridyl)-1-methyl-4-sulfamoyl-pyrrole-3-carboxylic acid; and 1-methyl-3-phenyl-5-sulfamoyl-pyrazole-4-carboxylic acid. A pharmaceutical composition comprising a compound of formula (I) is also disclosed. The compounds of the invention are enzyme inhibitors, particularly metallo-β-lactamase inhibitors, for use in treating a disease or disorder caused by aerobic or anaerobic Gram-positive, or aerobic or anaerobic Gram-negative bacteria. The compounds of the invention may be used to treat bacterial infection. The compounds of formula (I) may be used in combination with an antibacterial agent, preferably a carbapenem, to treat a bacterial infection.

Description

COMPOUNDS
[0001] This invention relates to compounds that can be used to treat bacterial infections in combination with other antibacterial agents, and more specifically in combination with a class of antibacterial agents known as carbapenems. The novel compounds of the present invention are enzyme inhibitors and more particularly are metallo-p-lactamase inhibitors.
[0002] Each year, throughout Europe, over 4 million people contract a healthcare associated bacterial infection, resulting in -37,000 deaths (Public Health England). The increasing prevalence of multi-drug resistant bacteria has worsened patient outcomes, prolonged hospital stays and necessitated use of 'last resort' and potentially toxic antimicrobials, such as colistin and polymyxin B. It has been estimated that by 2050, without intervention, antibiotic-resistant bacteria will cause the death of over 10 million people each year, and this will equate to an economic burden of 100 trillion US dollars.
[0003] In the clinic, antibiotic-resistant Gram-negative pathogens cause diverse infections, including pneumonia, blood stream infections, surgical site infections, skin and soft tissue infections, and urinary tract infections. There are limited effective treatment options for these organisms and empirical antibiotic therapy often fails in patients infected with Gram-negative organisms of the ESKAPE pathogen group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).
[0004] In February 2017, the World Health Organisation (WHO) issued a prioritised list of bacterial pathogens to assist member states in focusing research and development to the areas of greatest need. Of these bacteria, the WHO classed the following Gram-negative organisms as a critical priority: carbapenem resistant A. baumannii; carbapenem resistant P. aeruginosa; carbapenem resistant and ES BL-producing Enterobacteriaceae (including K. pneumoniae and E. cob). Consequently, carbapenem-resistant Gram-negative bacteria have been defined as a critical unmet medical need. The mode of action of p-lactams, such as carbapenems, involves covalently binding to the active site of transpeptidases that link peptidoglycan chains of the bacterial cell wall. This results in inhibition of cell wall synthesis and ultimately cell death. The advantage of carbapenems is a broader spectrum of activity compared with most other p-lactams and until recently their use had not been significantly impacted by resistance development.
[0005] The use of carbapenems as a last line of defence against multi-drug resistant Gram-negatives has been compromised by the emergence of carbapenemases from the metallo-6-lactamase (MBL) class. These enzymes bind to carbapenems and cleave the p-lactam ring, resulting in antibiotic deactivation. The Ambler classification system divides known 13-lactamase enzymes into four classes according to amino acid sequence. Classes A, C and D [3-lactamases cleave [3-lactams through transient binding of a serine group within the enzyme's active site to the carbonyl of the 6-lactam ring. This results in formation of an acyl-enzyme and cleavage of the p-lactam ring. Subsequently, an activated water molecule deacylates the acyl-enzyme intermediate, hydrolysing the bond between serine and carbonyl, releasing the deactivated 13-lactam. MBLs are mechanistically and structurally discrete from class A, C and D serine-6-lactamases. In this case, cleavage of p-lactams occurs in a single step, without formation of a covalent intermediate. MBLs coordinate water molecules and zinc ions to His, Cys and Asp residues in their active site, where water molecules facilitate nucleophilic attack and bond cleavage within the p-lactam ring. The subclasses of MBLs are structurally divergent, with B1 and B3 enzymes containing two zinc ions in the active site and displaying a broad substrate profile. Group B2 enzymes rely upon a single zinc ion and hydrolyse only carbapenems. Clinically, MBLs of the B1 class, including N DM, VIM and IMP, are most prevalent and are frequently identified within mobile genetic elements.
[0006] Pre-existing serine-p-lactamase inhibitors (effective against Ambler Class A, C and some Class D p-lactamases) have successfully restored activity of numerous 1-lactams. Inhibitors bind to the active site of the enzyme transiently or permanently with high affinity, effectively outcompeting binding of p-lactams. Marketed 13-lactam/[3-lactamase inhibitor combinations include amoxicillin and clavulanic acid (Co-amoxiclav) and ceftazidime and avibactam (Avycaz). Currently, there are no metallo-6-lactamase inhibitors (MBLIs) in clinical development or clinically available, indicating commercial potential for a broad spectrum MBLI that restores the activity of carbapenems.
[0007] The first carbapenem used clinically was imipenem, for the treatment of complex microbial infections. A disadvantage of imipenem is its hydrolysis in the mammalian kidney by dehydropeptidase I (DHPI) necessitating co-formulation with the dehydropeptidase inhibitor cilastatin. Subsequent carbapenem iterations, including meropenem, are insusceptible to DHPI hydrolysis due to the presence of a methyl group at the 113 position of the carbapenem moiety. Meropenem is less potent than imipenem against Gram-positive pathogens but has enhanced potency against Gram-negative organisms and is employed widely in the clinic. To combat resistance to carbapenems, we have discovered a series of compounds that inhibit metallo-13-lactamase enzymes.
The compounds significantly improve the efficacy of meropenem against drug resistant bacteria when co-administered with meropenem. The invention relates specifically to these compounds and to combinations of these compounds with a carbapenem such as meropenem. The invention also relates to methods of using said compounds and to pharmaceutical formulations comprising said compounds.
[0008] It is contemplated that other approved carbapenems might also benefit from co-formulation with the compounds of the invention. Other currently approved carbapenems include: ertapenem, doripenem, panipenem, biapenem and tebipenem.
[0009] Until comparatively recently, bacterial infections were one of the most common causes of death, disfigurement and disablement. During the 19th century a series of antibiotic drug classes were developed, meaning that the successful treatment of bacterial infections has become routine. However, microbial resistance to antibiotics is becoming a significant problem and many consider that this will become one of the most significant challenges to human health. Indeed, in some bacterial pathogens, mulfidrug resistance has already become common.
[0010] The greatest unmet medical need is the dearth of effective treatments for multidrug resistant Gram-negative bacteria. Therefore discovery of novel antibiotics that are active against WHO listed pathogens of critical concern, or drugs that circumvent existing bacterial resistance mechanisms is essential.
[0011] W02015/112441 discloses a series of novel metallo-p-lactamase inhibitors and their uses which are intended for reducing bacterial p-lactam antibiotic resistance. The compounds are a series of substituted 11-1 and 2H-tetrazol-5-ylphenylsulphonamides.
[0012] US2016/0272601 also discloses a series of novel compounds and their use as metallo-p-lactamase inhibitors for use in combination with p-lactam antibiotics. The compounds of this disclosure are thiazole-4-carboxylic acid derivatives.
[0013] W02017/093727 discloses another series of compounds which are inhibitors of metallo-P-lactamases and may be used in the treatment of bacterial infections. The exemplified compounds of this disclosure are a series of substituted 1I-I-indoles.
[0014] W02019/220125 and PCT/GB2020/052961 (unpublished) disclose a series of compounds which are inhibitors of metallo-p-lactamases used in combination with antibacterial agents to treat bacterial infections.
[0015] It is an aim of certain embodiments of this invention to provide compounds which can prevent or slow unwanted metabolism of p-lactams such as carbapenems, and in particular meropenem. A further aim is to provide formulations of a carbapenem, for example meropenem, with a compound of the invention which is active against Gram-negative bacteria including antibiotic-resistant organisms. It is an aim of certain embodiments of this invention to provide compounds that can be included in the formulations which are active against bacterial strains that are resistant to one or more other antibiotics. In spite of the numerous different antibiotics known in the art for a variety of different infections, there continues to be a need to develop antibiotics that can provide effective treatment in a reliable manner. In addition, there remains a need for drugs which can avoid or reduce the side-effects associated with known antibiotics. A further aim of certain embodiments is to provide treatment which is effective in a selective manner at a chosen site of interest. Another aim of certain embodiments is to develop drugs with a suitable pharmacokinefic profile and duration of action following dosing.
[0016] The present invention seeks to overcome the disadvantages of known carbapenems. The present invention also aims to improve the efficacy of existing carbapenems such as meropenem. In certain embodiments, the present invention aims to provide a compound that can restore or prolong the activity of antibiotics (particularly carbapenems) against antibiotic resistant bacterial strains. It is also an aim of certain embodiments of the present invention to increase the antibiotic efficacy of an antibiotic against bacterial strains having a wide spectrum of metallo-3-lactamase enzymes, for example some or all of VIM, NDM, and IMP.
[0017] It is an aim of certain embodiments of this invention to provide new antibiotic formulations which are active against resistant strains of Gram-negative bacteria. A further aim of certain embodiments of the present invention is to provide antibiotic formulations in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe). A further aim of the invention is to provide prodrugs which are not species dependent and/or which reduce inter-patient variability due to differences in metabolism. Another aim of the invention is to provide prodrugs which are able to overcome the food effect in the sense that they can be administered to fed or fasted patients without the need to control carefully the dosing schedule relative to meal times.
[0018] The novel compounds of the present invention satisfy some or all of the above aims.
BRIEF SUMMARY OF THE INVENTION
In a first aspect of the invention is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof: 0=S=0 NH2 wherein Ring A is a heteroaromatic ring selected from pyrrole or pyrazole; where Ring A is a pyrrole, X is 0(R4); where Ring A is a pyrazole, X is -N(R5)-and a single one of 51 and 55 is absent; -1_1-is absent or is a linker selected from Ci-C3-alkylene, -0-, -N56-and -S-; R1 and 55, where present, are selected from the group comprising: H, C1-6 alkyl, Ci_s haloalkyl, or Co_salkylene-57; 52 is selected from phenyl, naphthyl, 5-, 6-, 9-or 10-membered heteroaryl, 4-, 5-, 6-, 7-or 8-membered heterocycloalkyl and C3-08-cycloalkyl; wherein 52 is substituted with a single 58 group; and wherein, where R2 is heteroaryl, phenyl or naphthyl, said heteroaryl, phenyl or naphthyl group is optionally further substituted with from 1 to 5 R9 groups; or where R2 is heterocycloalkyl or cycloalkyl, said heterocycloalkyl or cycloalkyl group is optionally further substituted with from 1 to 5 516 groups; 53is -C(0)0H or-C(0)OM; wherein M is a group 1 cation; R4 is selected from H, halo or 01.4 haloalkyl; R6 and R11 are each independently at each occurrence selected from: H, 03-Cs-cycloalkyl and Ci-C6-alkyl; or where two R11 groups are attached to the same nitrogen atom, said R11 groups, together with said nitrogen atom, form a 4-, 5-, 6-or 7-membered heterocycloalkyl ring; 57 is selected from -N511512, -0513, S511, C(0)0511, -N(511)0(0)514, -N(511)S(0)2514, -S(0)2NR11R15 and -C(0)NR11515, phenyl, 5-or 6-membered heteroaryl, 5-, 6-, 7-or 8-membered heterocycloalkyl and C3-C8-cycloalkyl; said heteroaryl or phenyl group being optionally substituted with from 1 to 5 R2 groups; or said heterocycloalkyl or cycloalkyl group being optionally substituted with from 1 to 5 R16 groups 58 is selected from H, -N(R11)C(0)514, -N(R11)S(0)2514, -S(0)2NR11R15 and -C(0)NR11515 and Coe alkylene-58a, wherein 58a is selected from phenyl, 5-or 6-membered heteroaryl, 5-, 6-, 7-or 8-membered heterocycloalkyl and C5-08-cycloalkyl; said heteroaryl or phenyl (I) group being optionally substituted with from 1 to 5 R9 groups or said heterocycloalkyl or cycloalkyl group being optionally substituted with from 1 to 5 R10 groups; R9 is independently at each occurrence selected from: Ci-C6-alkyl, C3-C6-cycloalkyl, halogen, nitro, OR', SR11, S(0)2R11, C(0)R11, C(0)0R11, C(0)NR11R11, S(0)2NR11Rii, s(0)R11, cyano, C2-C6-alkenyl, C2-C6-alkynyl, and NIR" R12; R" is independently at each occurrence selected from: =0, =S, C1C6-haloalkyl, C3-C6-cycloalkyl, halogen, nitro, OR", SR11, S(0)2R11, C(0)R11, C(0)0R11, C(0)NR11R11, S(0)2NR" S(0)R11, cyano, C2-C6-alkenyl, C2-C6-alkynyl, and NR11R12; 512 is independently at each occurrence selected from; H, C(0)-R12a and S(0)2-R18, R128 being independently at each occurrence selected from Ci-Cs-alkyl, C3-C8-cycloalkyl, phenyl, or benzyl; or where an R" group and an R12 group are attached to the same nitrogen atom, said R" and R12 groups, together with said nitrogen atom, form a 4-, 5-, 6-or 7-membered heterocycloalkyl ring; IR13 is independently at each occurrence selected from: H, Cs-C6-cycloalkyl, C1-Cs-alkyl and Ci-C6-haloalkyl; R14 is independently at each occurrence selected from: Ci-C4-alkylene-R14a; wherein R148 is independently at each occurrence selected from -NR11 iR 2, _0-13, CN, -0S(0)20R11, SR11, C(=0)0R11, C(=0)NR" R11; R15 is independently at each occurrence selected from: H, C3-C6-cycloalkyl and Cl-C4-alkylene-Rlsa and C2-C4-alkylene-R15b; wherein R15 is independently at each occurrence selected from CN, C(=0)0R11, C(=0)NR11n11; and Rlsb is independently at each occurrence selected from -NR11R12, -OS(0)20R11 and SR"; wherein any aforementioned alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl (including where two R11 groups or an R11 group and an R12 group together with a nitrogen to which they are attached form a heterocycloalkyl ring), alkynyl, C(0)-alkyl, S(0)2-alkyl and benzyl is optionally substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: =0; =NRa, =NORa, C1-C4-alkyl, halo, nitro, cyano, C2-C4-alkenyl, C2-C4-alkynyl, NRaRb, S(0)2R3, S(0)R2, S(0)(NR3)Ra, S(0)2NR3R2, CO2Ra, C(0)Ra, CONRaRa, ORa and SRa; wherein R2 is independently at each occurrence selected from H and Ci-C4-alkyl; and Rh is independently at each occurrence selected from H, C(0)-Ci-C4-alkyl and S(0)2-Ci-C4-alkyl.
[0019] In certain embodiments, the compound of formula (I) is a compound of formula (II) or a pharmaceutically acceptable salt thereof: 0=S=0 NH2 wherein Ring A, X, R1, R2 and R3 are as described above for formula (I) [0020] In certain embodiments, the compound of formula (I) is a compound of formula (III) or a pharmaceutically acceptable salt thereof: 0=S=0 NH2 (III) wherein R1, R2, R3 and R4 are as described above for formula (I).
[0021] In certain embodiments, the compound of formula (I) is a compound of formula (IV) or a pharmaceutically acceptable salt thereof: 0=S=0 NH2 (IV) wherein R1, R2, and R3 are as described above for formula (I).
[0022] In certain embodiments, the compound of formula (I) is a compound of formula (V), or a pharmaceutically acceptable salt thereof 0=S=0 NH2 wherein R2, R3 and R5 are as described above for formula (I).
[0023] In certain embodiments, the compound of formula (I) is a compound of formula (Via), (Vlb), (Vic) or (VId) or a pharmaceutically acceptable salt thereof: (V) N N 8 R8 R1 R
A IR1 (Via)
N-N 8 RI jR
X A 0=S=0 NH2 0=S=0 NH2 0=S=0 NH2 (Vlb) (Vic) 0=8=0
NH2 (VI d) wherein R8 is independently selected from -N(R11)C(0)R14, -N(R11)S(0)2R14, -S(0)2NR11R18 and -C(0)NR11R18 and Co_6 alkylene-R88, and wherein Ring A, X, IR1, R8, R8a, R", R14 and R18 are as described above for formula (I).
[0024] In certain embodiments, the compound of formula (I) is a compound of formula (Vila), (VIlb), (VIlc) or (VIld) or a pharmaceutically acceptable salt thereof 0=S=0 NH2 (VII d) (VIlb) 0=S=0 NH2 0=S=0 NH2 0=S=0 NH2 (Vlic) wherein R8 is independently selected from -N(R11)C(0)R14, -N(R11)S(0)2R14, -S(0)2NR11IR1 5 and -C(0)NR11R18 and Co_s alkylene-Rea, and wherein Ring A, X, R1, IR8, IR8a, IR", R14 and IR15 are as described above for formula (I).
[0025] In certain embodiments, the compound of formula (I) is a compound of formula (Villa), (VIlib), (VIlic), (VIlid) or (Ville) or a pharmaceutically acceptable salt thereof: R8 R8 0=S=0 NH2 0=S=0 NH2 (VIlib) (Villa) R8 0=S=0 NH2 0=S=0 NH2 (VIlid) R4 R3 0=s=0 NH2 (Vilic) (Ville) 8* N R RI -/ wherein R8 is independently selected from -N(R11)C(0)R14, -N(R11)S(0)2R14, -S(0)2NR11R15 and -C(0)NR11R15 and Co-s alkylene-R84, and wherein R1, R3, R4, R8a, R11, IR14 and R15 are as described above for formula (I).
[0026] In certain embodiments, the compound of formula (I) is a compound of formula (IXa), (IXb), (IXc), (IXd) or (IXe) or a pharmaceutically acceptable salt thereof: wherein R8 is independently selected from -N(R11)C(0)R14, -N(R11)S(0)2514, -S(0)2NR11R15 and -C(0)NR11515 and Coe alkylene-R84, and wherein R1, R3, 584, R11, R14 and R15 are as described above for formula (I).
[0027] In certain embodiments, the compound of formula (I) is a compound of formula (Xa), (Xb), (Xc), (Xd) or (Xe) or a pharmaceutically acceptable salt thereof: 0=S=0 NH2 0=S=0 NH2 (IXb) (IXc) 0=S=0 NH2 0=S=0 NH2 (IXd) (IXe) R5 0=S=0 0=S=0 NH2 (Xa) NH2 (Xb) R5 R5 N_ R5--N V R3 0=5=0 NH2 0=S=0 (Xc) (Xd) NH2 R5 0=s=0 NH2 (Xe) wherein R5 is independently selected from -N(R11)C(0)R14, -N(R11)S(0)2R14, -S(0)2NR11R15 and -C(0)NR11R15 and C0_6 alkylene-Rea, and wherein R3, R5, IR', R11, R14 and R15 are as described above for formula (I).
[0028] In certain embodiments, the compound of formula (I) is a compound of formula (Xla), (Xlb), (Xlc) or (Xld), or a pharmaceutically acceptable salt thereof N-, / \\N IR1 IR9 0=S=0 NH2 (Xlc) (R9)n 0=S=0 NH2 (Xlb) 0=S=0 NH2 (Xld) wherein n is 1, 2, 3, 4 or 5, and R1, IR4 and R9 are as described above for formula (I).
[0029] In certain embodiments, the compound of formula (I) is a compound of formula (XIla), (X11b), (X11c) or (X11d), or a pharmaceutically acceptable salt thereof: N-Th / \\N IR1 R1 R9
N N (R9)n
(X11c) (X11b) 0=S=0 NH2 0=S=0 NH2 0=S=0 NH2 0=S=0 NH2 (X11d) wherein n is 1, 2, 3, 4 or 5, and R1 andR9 are as described above for formula (I).
[0030] In certain embodiments, the compound of formula (I) is a compound of formula (XIII), or a pharmaceutically acceptable salt thereof 0=S=0 NH2 0=S=0 NH2 N-, /N R9
N_ 7 R3 0=S=0
(X111 b) NH2 (XII1c) R5 R5 N_ N R3 0=S=0 (X111d) NH2 wherein n is 1, 2, 3, 4 or 5, and R5 and R9 are as described above for formula (I).
[0031] In certain embodiments, the compound of formula (I) is a compound of formula (XIV), or a pharmaceutically acceptable salt thereof: 0=S=0 NH2 (XIV) wherein R1, R3 andR4 are as described above for formula (I).
[0032] In certain embodiments, the compound of formula (I) is a compound of formula (XV), or a pharmaceutically acceptable salt thereof: 0=S=0 NH2 (XV) wherein R1 and R3 areas described above for formula (I).
[0033] In certain embodiments, the compound of formula (I) is a compound of formula (XVI), or a pharmaceutically acceptable salt thereof 0=S=0 NH2 (XVI) wherein IP3 and IP5 are as described above for formula (I).
[0034] The following embodiments apply to compounds of any of formulae (I) to (XVI).
These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically allowed. In other words, any of the features described in the following embodiments may (where chemically allowable) be combined with the features described in one or more other embodiments. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the embodiments listed below, expressed at any level of generality, which encompass that compound may be combined to provide a further embodiment which forms part of the present disclosure.
[0035] It may be that Ring A is a pyrrole. Thus, it may be that X is CR4.
[0036] It may be that Ring A is a pyrazole. Thus, it may be that X is -N(R5)-and R1 is absent. Alternatively, where Ring A is a pyrazole, it may be that R5 is absent and R1 is selected from H, C1.6 alkyl, Ci_6 haloalkyl, or Com alkylene-R7.
[0037] -L1-may be absent, -CH2-, -CH2CH2-, -0-, -N(H)-, -N(Me)-or -S-. -L1-may be absent or -CH2-. -L1-may be -0-, -N(H)-, -N(Me)-or -S-. Preferably, -L1-is absent.
[0038] It may be that Ring A is a pyrrole and -L1-is absent. It may be that Ring A is a pyrazole and -L1-is absent.
[0039] R1 may be selected from H, Cl_6alkyl or Cmalkylene-R7 R1 may be H. It may be that R1 is selected from Ci_s alkyl or Comalkylene-R7. R1 may be Ci_s alkyl, e.g. methyl, ethyl or propyl. R1 may be methyl. R1 may be Com alkylene-R7, optionally C1.4 alkylene-R7, e.g. -CH2R7, -CH2CH2R7 or -CH2CH2CH2R7.
[0040] It may be that -1_1-is absent, X is CR4 and R1 is H. It may be that -L1-is absent, Xis CR4 and R1 is C1.8 alkyl, e.g. methyl. It may be that -L1-is absent, Xis CR4 and R1 is alkylene-R7. It may be that -12-is absent, Xis -N(R5)-, R5 is absent and R1 is H. It may be that -L1-is absent, Xis -N(R5)-, R5 is absent and R1 is Ci.6 alkyl, e.g. methyl. It may be that -1_1-is absent, Xis -N(R5)-, R5 is absent and 51 is 00.6 alkylene-R7, e.g. -CH257, -CH2CH2R7 or -CH2CH2CH2R7.
[0041] R5 may be selected from H, 01.6 alkyl or Cm alkylene-R7. R5 may be H. It may be that R5is selected from Cl_s alkyl or Com alkylene-57. R5 may be Ci_s alkyl, e.g. methyl, ethyl or propyl. R5 may be methyl. R5 may be Co_6alkylene-R7, e.g. -CH2R7, -CH2CH2R7 or -CH2CH2CH2R7 [0042] It may be that -1_1-is absent, X is -N(155)-, R1 is absent and 55 is H. It may be that -1_1-is absent, X is -N(55)-, R1 is absent and R5 is Ci.6 alkyl, e.g. methyl. It may be that -1_1-is absent, Xis -N(R5)-, R1 is absent and R5 is Com alkylene-R7, e.g. -0H2R7, -CH2CH2R7 or -CH2CH2CH2R7.
[0043] 52 may be selected from phenyl, napthyl, and 5-, 6-, 9-or 10-membered heteroaryl; wherein R2 is substituted with a single 58 group. The 58 group is substituted on a ring atom in the phenyl, napthyl 01 5-, 6-, 9-or 10-membered heteroaryl ring system where valence considerations allow.
[0044] Where R2 is phenyl, napthyl 01 5-, 6-, 9-or 10-membered heteroaryl, R2 may be optionally further substituted with 1, 2, 3, 4 or 5 R8 groups. It may be that R2 is optionally further substituted with 1 or 2 58 groups. It may be that R2 is optionally substituted with 1 59 group. When present, each 58 group is substituted on a ring atom in the phenyl, napthyl or 5-, 6-, 9-or 10-membered heteroaryl ring system where valence considerations allow.
[0045] R2 may be selected from 5-, 6-, 9-or 10-membered heteroaryl, and 5-, 6-, 7-or 8-membered heterocycloalkyl, said heterocycloalkyl group being optionally further substituted with from 1 to 5 51° groups.
[0046] R2 may be selected from phenyl and 5-or 6-membered heteroaryl; wherein 52 is substituted with a single R° group. The R° group may be substituted on a ring atom in the phenyl, or 5-01 6-membered heteroaryl ring system where valence considerations allow.
[0047] Where R2 is phenyl, or 5-or 6-membered heteroaryl, R2 may be optionally further substituted with 1 or 2 58 groups. It may be that R2 is optionally substituted with 1 IR8 group. When present, each R8 group is substituted on a ring atom in the phenyl or 5-or 6-membered heteroaryl ring system where valence considerations allow.
[0048] Where R2 is phenyl or 6-membered heteroaryl, the R8 substituent may be substituted in the meta or para position of the phenyl or 6-membered heteroaryl with respect to the point of attachment of R2 to the remainder of the molecule in the compound of Formula (I). The R8 substituent is preferably substituted in the para position of the phenyl or 6-membered heteroaryl with respect to the point of attachment of R2 to the remainder of the molecule in the compound of Formula (0.
[0049] 52 may be phenyl, pyridyl, pyrimidyl, pyrrole, pyrazole, or imidazole 52 may be phenyl, pyridyl, pyrimidyl or pyrazole. R2 is preferably phenyl.
[0050] R2 may be selected from: N----"-c--- R9
II (R9)n
where n is 1, 2, 3, 4 or 5. Preferably, n is 1 or 2. [0051] R2 may be selected from: R8 [0052] 52 may be selected from: [0053] R2 may be selected from: where n is 1, 2, 3, 4 or 5. Preferably, n is 1 or 2.
[0054] R2 may be selected from: where n is 1, 2, 3, 4 or 5. Preferably, n is 1 or 2. [0055] n may be 1.
[0056] R2 may be selected from: VJII/N -R 8 [0057] R3 maybe -C(0)0H. Alternatively, R3 may be -C(0)0M. M may be Na or K. Preferably, M is Na.
[0058] R4 may be selected from H or halo. R4 may be selected from H or 01.4 haloalkyl.
R4 may be selected from halo or 01.4 haloalkyl. R4 may be H. R4 may be halo, e.g. F, Cl, Br. R4 may be 01.4 haloalkyl, e.g. CF3, CH2CF3, CH(CF3)CH3.
[0059] R6 may be H or Ci-C6-alkyl. R6 may be H. R6may be Ci-C6-alkyl, e.g. methyl, ethyl, propyl. Re may be C3-05-cycloalkyl; e.g. cyclopropyl, cyclopentyl, cyclohexyl.
[0060] R7 may be selected from -NR11R12, -0R13, C(0)0R11, -N(R11)C(0)R14, - S(0)2NR11R16 and -C(0)NR11R15, phenyl, 5-or 6-membered heteroaryl, 5-or 6- membered heterocycloalkyl and Ca-C8-cycloalkyl; said heteroaryl or phenyl group being optionally substituted with from 1 or 2 R9 groups; or said heterocycloalkyl or cycloalkyl group being optionally substituted with from 1 or 2 R16 groups. 57 may be selected from -NR11R12, C(0)0R11, phenyl and C3-C8-cycloalkyl. 57 may be -NR11R12, e.g. NH2, NHMe or NMe2. R7 may be -0R13, e.g. OH or OMe. R7 may be C(0)0R11, e.g. C(0)0H, C(0)0Me or C(0)0Et. R7 may be phenyl. R7 may be C3-03-cycloalkyl, e.g. cyclopropyl.
[0061] R8 may be selected from H, -N(R11)C(0)R14, -N(R11)S(0)2R14, -S(0)2NR11R1 5 and -C(0)NR11R16 and 00.6 alkylene-R". R8 may be selected from H, -N(R11)S(0)2R14, -C(0)NR"R15 and 00.6 alkylene-R88. 58 may be selected from -N(R11)S(0)2R14, -C(0)NR11R15 and 00.6 alkylene-R8a. R8 may be H. R8 may be 00.6alkylene-R8a, e.g. R8a, CH2R8, CH2CH2R8a, or CH2CH2CH2R". R8 may be -N(R11)S(0)2R14, e.g. NHS(0)2Me, NHS(0)2-(C3_6 cycloalkyl). Ra may be -C(0)NR11R18, e.g. -C(0)NH(Ci-C4-alkylene-R1") and -C(0)NH(C2-C4-alkylene-R189).
[0062] Rae may be selected from phenyl, 5-01 6-membered heteroaryl, 5-or 6-membered heterocycloalkyl and Cs-Cs-cycloalkyl; said heteroaryl or phenyl group being optionally substituted with from 1 or 2 R9 groups; or said heterocycloalkyl or cycloalkyl group being optionally substituted with from 1 or 2 R1° groups. Rae may be phenyl or 5-or 6-membered heteroaryl, e.g. pyrrole, pyrazole, pyridine, pyrimidine or imidazole. Rae may be a 5-or 6-membered heterocycloalkyl, e.g. pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl. Rae may be Cs-Cs-cycloalkyl, e.g. cyclopentyl or cyclohexyl.
[0063] R9 may be independently at each occurrence selected from: Ci-Cs-alkyl, 03-Cacycloalkyl, OR13, S(0)2R11, C(0)R11, C(0)0R11, C(0)NR11R11, S(0)2NR11R11, and NR11R12. R9 may be independently at each occurrence selected from: Ci-Cs-alkyl, OR's, C(0)R11, C(0)0R11, C(0)NR11R11, and NR11R12. R9 may be independently at each occurrence selected from: C1-06-alkyl, C(0)NR11R11, and NR11R12. R9 may be at any given occurrence methyl, ethyl or propyl. R9 may be at any given occurrence C(0)NH2, C(0)NHMe or C(0)NMe2. Rg may be at any given occurrence NH2, NHMe, NMe2, NHS(0)2Me, NHS(0)2Et, NHS(0)2-cyclopropyl, NHS(0)2-phenyl, or NHS(0)2-benzyl [0064] R1° may be independently at each occurrence selected from: =0, Ci-Cs-alkyl, halogen, OR13, S(0)2R11, C(0)R11, C(0)0R11, C(0)NR11n11, S(0)2NRn1111, cyano, and NR11 iR 2 1-9 -19 may be independently at each occurrence selected from: =0, Ci-Cs-alkyl, halogen, OR13, and NIR11R12 [0065] R11 may be independently selected at each occurrence from H or Ci-Cs-alkyl. R" may at any given occurrence be H. R11 may at any given occurrence be C1-Cs-alkyl, e.g. methyl, ethyl, propyl. R11 may at any given occurrence be C3-06-cycloalkyl, e.g. cyclopropyl, cyclopentyl, cyclohexyl.
[0066] R12 is independently at each occurrence selected from; H, C1-05-alkyl, and S(0)2-R12e. R12 may be H. R12 may be 01-08-alkyl, e.g. methyl, ethyl, propyl. R12 may be S(0)2-R12a, e.g. S(0)2Me, S(0)2Et, S(0)2-cyclopropyl, S(0)2-phenyl, or S(0)2-benzyl.
[0067] R128 may at any given occurrence be 03-Cs-cycloalkyl, e.g. cyclopropyl. R1' may at any given occurrence be Ci-Cs-alkyl, e.g. methyl, ethyl, propyl. R12a may at any given occurrence be phenyl, or benzyl.
[0068] R13 is independently at each occurrence selected from: H, Ca-C6-cycloalkyl and Ci-C6-alkyl. R13 may at any given occurrence be H. R13 may at any given occurrence be C3-C6-cycloalkyl, e.g. cyclopropyl, cyclopentyl or cyclohexyl. R13 mayat any given occurrence be C1-C6-alkyl, e.g. methyl, ethyl, propyl.
[0069] R14 may be independently at each occurrence selected from CH2R14a, -CH2CH2R14a, and -CH2CH2CH2R148.
[0070] R14 may be independently selected at each occurrence from -NR11R125_0R13, _ OS(0)20R11, C(=0)0R11, c(=o)NRiiRii. r< n14a may be independently selected at each occurrence from _NR, i Ri2 or -0R13.
[0071] R15 is independently at each occurrence selected from: H, Ci-C6-alkyl, Ci-C4-alkylene-R1" and C2-C4-alkylene-R15b. R15 may at any given occurrence be H. R15 maybe independently at each occurrence selected from Ci-C4-alkylene-R' and C2-C4-alkylene-Ri3b. R15 mayat any given occurrence be Ci-C4-alkylene-R15a, e.g. CH2R1", CH2CH2R1", CH2CH2CH2R15a.R15may at any given occurrence be C2-C4alkylene-R1bb, e.g. CH2CH2R15b, 0rCH2CH2CH2R15b.
[0072] Rl'a may at any given occurrence be CN. R1' may at any given occurrence be C(=0)0R", e.g. C(=0)0H, C(=0)0Me or C(=0)0Et. R1' may at any given occurrence be C(=0)NR11 R", e.g. C(=0)NH2, C(=0)NHMe, C(=0)NHEt, or C(=0)NMe2.
[0073] INril5b may at any given occurrence be.--*12, -NRrc 11 e.g. NH2, NHMe or NMe2. R15b may at any given occurrence be -OR', e.g. OH or OMe. R1" may at any given occurrence be -0S(0)20R", e.g. -0(0)20H or -0(0)20Me.
[0074] Ra may at any given occurrence be H. Ra may at any given occurrence be methyl, ethyl, or propyl.
[0075] Rb may be independently selected at each occurrence from H or C1-C4-alkyl, e.g. methyl, ethyl, or propyl. Rb may at any given occurrence be H. Rb may at any given occurrence be methyl, ethyl, or propyl. Rb may at any given occurrence be C(0)-C1-C4alkyl, e.g. C(0)Me or C(0)Et. Rb may at any given occurrence be S(0)2-Ci-C4-alkyl, e.g. S(0)2Me or S(0)2Et.
[0076] R1 may be selected from H, -CH3, V-Nsv 0 0 [0077] R5 may be selected from H, -CH3, tc----....".""NH 2 N1-12 y-,y0H 0 0 [0078] R2 may be selected from: H a NH N, N N H2 N N N H2
N -N H2
[0079] The compound of formula (I) may be selected from the following compounds or pharmaceutically acceptable compounds thereof: NH2 0=S=0 0=S=0 0=S=0 0=S=0 I i i I NH2 NH2 NH2 NH2 \ NH
S N H2N
0=S=0 0=S=0 0=3=0
I I I
NH2 NH2 NH2 0=S=0 0=S=0 0=S=0 i I I NH2 NH2 NH2
DETAILED DESCRIPTION
[0080] The chemical terms used in the specification have their generally accepted meanings in the art.
[0081] The term "halo" refers to fluoro, chloro, bromo and iodo.
[0082] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon chain. For example, Cita-alkyl may refer to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The alkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each alkyl group independently may be halo, OR or NNW'.
[0083] The term "alkylene" refers to a linear saturated divalent hydrocarbon chain. The alkylene groups may be unsubstituted or substituted by one or more substituents.
Specific substituents for each alkylene group independently may be C1-C4-alkyl, halo, OR" or NHR11.
OH
0=3=0 0=3=0 NH2 NH2 H2N H,N N_
OH -
N
[0084] The term "haloalkyl" refers to a hydrocarbon group substituted with at least one halogen atom independently chosen at each occurrence from: fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, Ci-C6-haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloroethyl and 2-chloroethyl, trichloroethyl e.g. 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1-fluoroethyl and 2-fluoroethyl, trifluoroethyl e.g. 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. A haloalkyl group may be a fluoroalkyl group, i.e. a hydrocarbon chain substituted with at least one fluorine atom. Thus, a haloalkyl group may have any amount of halogen substituents. The group may contain a single halogen subsfituent, it may have two or three halogen substituents, or it may be saturated with halogen substituents.
[0085] The term "alkenyl" refers to a branched or linear hydrocarbon group containing at least one double bond. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain; for example, "C2-C6-alkenyl" may refer to ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. The alkenyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkenyl group independently may be Ci_4 alkyl, halo, OR11 or NHR11.
[0086] The term "alkynyl" refers to a branched or linear hydrocarbon chain containing at least one triple bond. The triple bond may be at any possible position of the hydrocarbon chain. For example, "C2-C6-alkynyl" may refer to ethynyl, propynyl, butynyl, pentynyl and hexynyl. The alkynyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for any saturated carbon atom in each alkynyl group independently may be Ci_4 alkyl, halo, OR11 or NHR11.
[0087] The term "cycloalkyl" refers to a saturated hydrocarbon ring system containing, for example, 3, 4, 5 or 6 carbon atoms. For example, "C3-C6-cycloalkyl" may refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The cycloalkyl groups may be unsubstituted or substituted by one or more substituents. Specific substituents for each cycloalkyl group independently may be C1.4 alkyl, halo, 01R11 or NHR11.
[0088] The term "heterocycloalkyl" may refer to a monocyclic or bicyclic saturated or partially saturated group having the indicated number of atoms in the ring system and comprising 1 or 2 heteroatoms independently selected from 0, S and N in the ring system On other words 1 or 2 of the atoms forming the ring system are selected from 0, S and N). By partially saturated it is meant that the ring may comprise one or two double bonds. This applies particularly to monocyclic rings with from 5 to 6 members. The double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom. Examples of heterocycloalkyl groups include; piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydrofuran, tetrahydropyran, dihydropyran, dioxane, azepine. A heterocycloalkyl group may be unsubsfituted or substituted by one or more substituents. Specific subsfituents for any saturated carbon atom in each heterocycloalkyl group may independently be C1.4 alkyl, halo, OR" or NHR".
[0089] The term "aryl" may refer to any aromatic carbocyclic ring system (i.e. a ring system containing 2(2n + 1)-rr electrons). Aryl groups may have from 6 to 12 carbon atoms in the ring system. Aryl groups will typically be phenyl groups. Aryl groups may be naphthyl groups or biphenyl groups.
[0090] The term "heteroaryl" or "heteroaromatic" means any aromatic (i.e. a ring system containing 2(2n + 1)rr electrons) 5-10 membered ring system comprising from 1 to 4 heteroatoms independently selected from 0, S and N On other words from 1 to 4 of the atoms forming the ring system are selected from 0, S and N). Thus, any heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 14 heteroatoms independently selected from 0, S and N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 (e.g.1-2) nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms independently selected from 0, S and N; 10-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms. Specifically, heteroaryl groups may be independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, thiazole, isothiazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzothiazole, benzisoxazole, benzofurazine, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine, carbazole, phenazine, benzoisoquinoline, pyridopyrazine, thiophenofuran, 2H-furopyrazine, 5H-pyridooxazine, 1H-pyrazoloxazole, 4H-imidazothiazole, pyrazinopyridazine, imidazothiazole, imidazotriazine.
[0091] It may be that, in any group which is an aryl or heteroaryl group, that aryl or heteroaryl group is unsubstituted or is optionally substituted, where chemically possible, by 1 to 5 subsfituents which are each independently selected at each occurrence from: halo, nitro, cyano, NR"R", NR11S(0)2R11, NR11C(0)R11, NR"CONR"R", NR11CO2R11, ORfl, SR11, S(0)R11, S(0)20R11, S(0)2R11, S(0)2NR11R", CO2R11, C(0)R11, CONR"R", CR111R11NR11R11, CR"R110R11, C2-C4-alkenyl, C2-a4-alkynyl and C1-C4-haloalkyl; wherein R11 is as described above for formula (I).
[0092] Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains a double bond such as a C=C or C=N group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
[0093] Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
[0094] The compounds of the invention may be obtained, stored and/or used in the form of a pharmaceutically acceptable salt. Suitable salts include, but are not limited to, salts of acceptable inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of agronomically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, sulfanilic, aspartic, glutamic, edefic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Suitable salts also include salts of inorganic and organic bases, e.g. counterions such as Na, Ca, K, Li, Mg, ammonium, trimethylsulfonium. The compounds may also be obtained, stored and/or used in the form of an N-oxide. Also included are acid addition salts or base salts wherein the counter ion is optically active; for example, d-lactate or 1-lysine, or racemic; for example, dl-tartrate or dl-arginine.
[0095] Pharmaceutically acceptable salts of compounds of the invention may be prepared by for example, one or more of the following methods: (i) by reacting the compound of the invention with the desired acid or base; (ii) by removing an acid-or base-labile protecting group from a suitable precursor of the compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of the invention to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
These methods are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised [0096] Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
[0097] Conventional techniques for the preparation/isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (H PLC). Thus, chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and for specific examples, 0 to 5% by volume of an alkylamine e.g. 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
[0098] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallisation and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
[0099] Wien any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enanfiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
[00100] While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art -see for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. VVilen (Wiley, 1994).
[00101] It is to be understood that the present invention encompasses all isomeric forms and mixtures thereof that possess metallo-13-lactamase inhibitory activity.
[00102] Methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in "Advanced Organic Chemistry, 7th edition J. March, John Wiley and Sons, New York, 2013).
[00103] Compounds of the Formula (I) containing an amine function may also form N-oxides. A reference herein to a compound of the Formula (I) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid); this is described in general textbooks such as Advanced Organic Chemistry, by J. March referred to above. N-oxides can be made in a variety of ways which are known to the skilled person; for example, by reacting the amine compound with m-chloroperoxybenzoic acid (mCPBA) in a solvent such as dichloromethane.
[00104] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H(D), and 21-1 (T); C may be in any isotopic form, including 120, 130, and 140; and 0 may be in any isotopic form, including 160 and180; and the like. Similarly, isotopic variants of N, S and P may be utilised.
[00105] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps.
Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
[00106] Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
[00107] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.
[00108] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable excipients.
[00109] Compounds of the invention have been described throughout the present application as a compound or a salt of a compound. It would be understood by the skilled person that a compound can be converted into a salt and a salt can be converted into a compound, in other words the free acid or free base corresponding to the salt. Accordingly, where a compound is disclosed or where a salt is disclosed, the present invention also includes the corresponding salt form, free acid form or free base form, as appropriate. For example, the disclosure of the below salt also covers the disclosure of the corresponding free acid, also shown below. This applies to all compounds or salts disclosed herein.
0=S=0 0=S=0 NH2 NH2 [00110] The compounds of the present invention are inhibitors of metallo-p-lactamases (MBLs). As discussed above, many bacteria have developed resistance to P-Iactam antibacterials (BLAs) and one of the main resistance mechanisms is the hydrolysis of BLAs by MBLs. The compounds of the invention address this issue. In particular, the
OH
inhibition of bacterial M BLs by the compounds of Formula (I) can significantly enhance the activity of BLAs when one or more of these compounds is administered with a compound of the present invention.
[00111] Bacterial infections which can be treated using compounds of Formula (I) and compositions containing compounds of Formula (I) include those caused by Gram-negative or Gram-positive bacteria. For example, the bacterial infection may be caused by bacteria from one or more of the following families; Streptococcus, Acinetobacter. Staphylococcus, Clostridloides, Pseudomonas, Escherichia, Salmonella, Klebsiella, Leg/one//a, Neisseria, Enterococcus, Enterobacter, Serratia, Stenotrophomonas, Aeromonas, Mycobacterium, Morganella, Yersinia, Pasteurella, Haemophilus, Citrobacter, Burkholderia, BruceIla, or Moraxella.
[00112] Particular examples of bacteria which are targeted by this invention include bacterial strains in the following families of bacteria: Escherichia, Acinetobacte,r, Pseudomonas, and Klebsiella. The bacterial infection may, for example, be caused by one or more bacteria selected from Escherichia coil, Acinetobacter be,umannii, Pseudomonas aeruginosa or Klebsiella pneumoniae.
[00113] In one aspect, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I) or pharmaceutically acceptable salt thereof for use in the inhibition of metallo-p-lactamase activity.
[00114] In another aspect, the compounds or compositions of the present invention may be for use in the treatment of a disease or disorder in which metallo-P-Iactamase activity is implicated [00115] In a further aspect, the compounds or compositions of the present invention may be for use in a method of treating a disease or disorder caused by aerobic or anaerobic Gram-positive, or aerobic or anaerobic Gram-negative bacteria. It may be that the disease or disorder is caused by metallo-p-lactamase producing Gram-positive bacteria.
[00116] It may be that the disease or disorder is selected from: pneumonia, respiratory tract infections, urinary tract infections, intra-abdominal infections, skin and soft tissue infections, bloodstream infections, septicaemia, intra-and post-partum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis and febrile neutropenia.
[00117] It may be that the disease or disorder is selected from: community acquired pneumonia, nosocomial pneumonia (hospital-acquired/ventilator-acquired), respiratory tract infections associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infection, intra-abdominal infections, skin and soft tissue infection, bacteraemia, septicaemia, intra-and post-partum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis and febrile neutropenia.
[00118] It may be that the disease or disorder is selected from: community acquired pneumonia, nosocomial pneumonia (hospital-acquired/ventilator-acquired), respiratory tract infections associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infection, intra-abdominal infections, skin and soft tissue infection, bacteraemia and septicaemia.
[00119] It may be that the compounds or compositions of the present invention are for use in a method of treatment, wherein the compound or composition is administered in combination with one or more BLAs.
[00120] Administration of the compounds of Formula (I) may be together with one or more BLAs which are all present in the same dosage form or it may be the case that the one or more BLAs are presented in separate dosage forms and the one or more compounds of Formula (I) are presented in separate dosage forms. In a preferred embodiment, an effective antibacterial treatment will consist of a compound of Formula (I) and a BLA. The BLA will preferably be meropenem. In another preferred embodiment, the compound of Formula (I) is co-administered with the BLA, which can preferably be meropenem, in a single formulation i.e. a single dosage form.
[00121] The compounds of Formula (I) may be presented in dosage forms which are suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), or they may be suitable for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions). Other suitable dosage forms also include those intended for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing). In a preferred embodiment oral or intravenous administration is preferred, with intravenous administration being most preferred [00122] Oral dosage formulations may contain, together with the active compound, one or more of the following excipients: diluents, lubricants, binding agents, desiccants, sweeteners, flavourings, colouring agents, wetting agents, and effervescing agents.
[00123] If the MBLI and BLA are presented in separate dosage forms, these may be administered simultaneously or sequentially. Usually, it is preferred to administer the MBLI i.e. the compound of Formula (I) of the invention and the BLA i.e. the antibacterial compound in a single dosage form. Preferably this is an intravenous dosage form, and more preferably it is a solid dosage form. Tablets, capsules and caplets are particularly preferred.
[00124] The process of contacting a cell, or indeed other biological material or samples, which contain bacteria with compounds of the invention effectively means exposing bacteria to compounds of the invention.
[00125] Compounds of Formula (I) are inhibitors of metallo-p-lactamases and the present invention therefore provides a method of inhibiting bacterial metallo-p-lactamase activity in vitro or in vivo. This method comprises contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or contacting a cell with a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
[00126] Accordingly, in one aspect of the invention, there is provided a method of inhibiting bacterial metallo-p-lactamase activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof; or contacting a cell with a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
[00127] In another aspect, the present invention provides a method for the prevention or treatment of bacterial infection in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a combination of an antibacterial agent with a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or administering to said patient a therapeutically effective amount of an antibacterial agent in combination with a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
[00128] In another aspect, the present invention provides a method for the prevention or treatment of a disease or disorder, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a combination of an antibacterial agent with a compound of Formula (I) or a pharmaceutically acceptable salt thereof; or administering to said patient a therapeutically effective amount of an antibacterial agent in combination with a pharmaceutical composition comprising compound of Formula (I) or a pharmaceutically acceptable salt thereof.
[00129] It may be that the disease or disorder is caused by aerobic or anaerobic Gram-positive or aerobic or anaerobic Gram-negative bacteria. It may be that the disease or disorder is caused by metallo-13-lactamase producing Gram-positive bacteria.
[00130] It may be that the disease or disorder is selected from: pneumonia, respiratory tract infections, urinary tract infections, intra-abdominal infections, skin and soft tissue infections, bloodstream infections, septicaemia, intra-and post-partum infections, prosthetic joint infections, endocardifis, acute bacterial meningitis and febrile neutropenia.
[00131] It may be that the disease or disorder is selected from: community acquired pneumonia, nosocomial pneumonia (hospital-acquired/ventilator-acquired), respiratory tract infections associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infection, intra-abdominal infections, skin and soft tissue infection, bacteraemia, septicaemia, intra-and post-partum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis and febrile neutropenia.
[00132] It may be that the disease or disorder is selected from: community acquired pneumonia, nosocomial pneumonia (hospital-acquired/ventilator-acquired), respiratory tract infections associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infection, intra-abdominal infections, skin and soft tissue infection, bacteraemia and septicaemia.
[00133] The antibacterial agent may be a carbapenem. Non limiting examples of carbapenems include: meropenem, faropenem, imipenem, ertapenem, doripenem, panipenem/betamipron and biapenem as well as razupenem, tebipenem, lenapenem and tomopenem.
[00134] In another aspect, the present invention provides a method of inhibiting bacterial infection, said method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a suitable antibacterial agent. The contacting of the cell may occur in vitro or in vivo, with in vivo contact being preferred.
[00135] In another aspect, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in therapy.
[00136] In another aspect, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection. The treatment may be curative or preventative i.e. prophylactic. Preferably, the treatment is curative; this means that the treatment reduces the overall level of bacterial infection.
[00137] In another aspect, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in combination with an antibacterial agent, for use in the treatment of a bacterial infection. The compound and the antibacterial agent may be present in the same dosage forms.
[00138] In a further aspect, the present invention provides a kit of parts comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a BLA. The kit may be provided together with instructions for use in treating bacterial infections and / or packaging which provides the combined dose of the compound of Formula (I) and the BLA.
General Synthetic Schemes Compounds of formula I can be made according to schemes A to D. Compounds of the invention can be accessed via pyrrole-containing compounds of formula A. VVhere IR1 is not H, Rl is introduced into a compound of formula A to provide a compound of formula B, e.g. by treating A with an R1-halide in the presence of a base. Removal of the tert-butyl group, e.g. using trifluoroacetic acid, then provides a compound of formula C Deprotection of the ethyl ester of the compounds of formula C (e.g. using UCH) then forms compounds of formula D, a subset of compounds of the invention.
R2 R1NN 0-Ci_3 alkyl R2 R4 0
H
R4R4 -o 0 R40 s::: NH2 NH2
D C
Scheme A Alternatively, compound of the invention can be accessed via the iodo-pyrrole compound of formula E. A palladium coupling reaction (e.g. Suzuki) with a boronic ester of formula F(i) or boronic acid of formula F(ii) can provide a compound of formula G. Deprotection of the methyl ester of the compound of formula G (e.g. using Li0H) then forms a compound of formula H. Removal of the tert-butyl group, e.g. using trifluoroacefic acid, then provides a compound of formula J, a subset of compounds of the invention.
A R2
R1NN OH R1'N R2 0-C1_3 alkyl 0-C1_3 alkyl 0 OttS,
HN R2 1 0 I B,
or HO OH F(i) Scheme B In a further alternative, compounds of the invention can be accessed via pyrazole K(i) or K(ii). VVhere R1/R5 is not H, R1/R5 is introduced into a compound of formula K(i)/K(ii) to provide a compound of formula LoyLoo, e.g. by treating K(i)/K(ii) with an R1/R5-halide in the presence of a base. Treating the compound of formula L(i)/L(ii) with a chlorinating agent, e.g. 1,3-Dichloro-5,5-dimethylhydantoin (DCDMH), followed by tert-butyl amine provides a compound of formula M(i)/M(ii). Removal of the tert-butyl groups, e.g. using trifluoroacetic acid, then provides compounds of formula N(i)/N(ii), a subset of compounds of the invention. R2 R1 R1
\N OH NN R2 R2 Or R5 L(i) or R2 R2 R2 N OH OH0 ( R1 R1 N 0 Or,Nrl \ i 0 N-- 0 %5N \ t K 1 N1/4 R5 or -,--0 -:-Sr--° -°St--NH2 NH2 NH N(I) N(ii) -7( MO) Scheme C In a further alternative, compounds of the invention can be accessed via compounds of formula 0. A cyclisation reaction involving a compound of formula 0 and H2N-NHR5 forms a pyrrole compound of formula P. Treating the compound of formula P with a chlorinating agent, e.g. 1,3-Dichloro-5,5-dimethylhydantoin (DCDMH), followed by tert-butyl amine provides a compound of formula Q. Removal of the tert-butyl group, e.g. using trifluoroacetic acid, then provides compounds of formula R, a subset of compounds of the invention.
H2NN R-
R R5
Scheme D
EXAMPLES
The following compounds represent examples of compounds which can be synthesised in accordance with the invention. Some of the compounds were also tested in a biological assay and the results are presented below. The compounds show activity as inhibitors of metallo-p-lactamases and thus have utility in the treatment of infections, particularly antibiotic resistant infections General Experimental Microwave assisted reactions were performed using a Biotage lnitiator+TM microwave synthesizer in sealed vials.
Throughout this document the following abbreviations have been used: Boc -tert-butyloxycarbonyl DCM -dichloromethane DMF -N,N-dimethylformamide DMSO -dimethyl sulfoxide HBTU -N,N,N',N'-tetramethy1-0-(1H-benzotriazol-1-yl)uronium hexafluorophosphate TFA -trifluoroacetic acid THF -tetrahydrofuran; XPhos Pd G2 -chloro(2-dicyclohexylphosphino-2',4',6'-triisopropy1-1,1r-biphenyl)[2- (2'-amino-1,11-biphenyWpalladium(10 Analytical Methods All 1H and 19F NMR spectra were obtained on a Bruker AVI 500 with 5 mm QNP. Chemical shifts (5) are expressed in parts per million (ppm) and are referenced to the solvent. Coupling constants (J) are expressed in Hertz (Hz).
LC-MS were obtained on a Waters Alliance ZQ (Methods A, B, C and E) or Waters Acquity H-class UPLC (Method D) using the methods detailed below. Wavelengths were 254 and 210 nm.
Method A Column: YMC-Triart 018, 2.0 x 50 mm, 5 pm Flow rate: 0.8 mlimin. Injection volume: 6 pL Mobile Phase: A = water, B = acetonitrile, C = 1:1 water:acetonitrile + 1.0% formic acid Time %A %B %C Initial 90 5 5 4.0 0 95 5 6.0 0 95 5 Method B Column: YMC-Triart 018, 2.0 x 50 mm, 5 pm. Flow rate: 0.8 mi./min. Injection volume: 6 pL Mobile Phase: A = water, B = acetonitrile, C = 1:1 water:acetonitrile + 1.0% ammonia (aq.) Time %A %B %C Initial 90 5 5 4.0 0 95 5 6.0 0 95 5 Method C Column: YMC-Triart C18, 2.0 x 50 mm, 5 pm. Flow rate: 0.8 mLimin. Injection volume: 6 pL Mobile Phase: A = water, B = acetonitrile, C = 1:1 water:acetonitrile + 1.0% formic acid Time %A %B %C Initial 95 0 5 2.0 95 0 5 12.0 0 95 5 14.0 0 95 5 14.1 95 5 0 15.0 95 5 0 Method D Column: YMC-Triart C18, 2.0 x 50 mm, 5 pm. Flow rate: 0.8 mlimin. Injection volume: 6 pL Mobile Phase: A = water, B = acetonitrile, C = 1:1 water:acetonitrile + 1.0% ammonia (aq.) Time %A %B %C Initial 97.5 0 2.5 3.0 97.5 0 2.5 3.0 0 95 5 5.0 0 95 5 Method E Column: CSH C18, 2.1 x 50 mm, 1.7 pm. Flow rate: 1.0 mdmin. Injection volume: 5 pL Mobile Phase: A = water + 0.1% formic acid, B = acetonitrile + 0.1% formic acid Time %A %B Initial 98 2 0.2 98 2 2.5 2 98 3.0 2 98 3.1 98 2 3.5 98 2 Method F Column: BEH C18, 2.1 x 50 mm, 1.7 pm. Flow rate: 1.0 mUmin. Injection volume: 5 pL Mobile Phase: A = water + 0.1% ammonia (aq.), B = acetonitrile + 0.1% ammonia (aq.) Time %A %B Initial 98 2 0.2 98 2 2.5 2 98 3.0 2 98 3A 98 2 3.5 98 2 Method G Column: CSH C18, 2.1 x 100 mm, 1.7 pm. Flow rate: 0.6 mL/min. Injection volume: 5 pL Mobile Phase: A = water + 0.1% formic acid, B = acetonitrile + 0.1% formic acid Time %A %B Initial 98 2 0.5 98 2 6.5 2 98 7.5 2 98 7.6 98 2 8.0 98 2 Intermediate 1: Ethyl 4-(tert-butylsulfamoyI)-2-phenyl-1H-pyrrole-3-carboxylate o 0 "
S-NH
Step A: Ethyl 1-(benzenesulfony0-2-phenyl-pyrrole-3-carboxylate Sodium hydride (60% in mineral oil, 966 mg, 24.2 mmol) was added portionwise to a solution of ethyl 2-phenyl-1H-pyrrole-3-carboxylate (5.17 mL, 22.0 mmol) in THE (30 mL) at 0 °C and stirred for 15 minutes under nitrogen. Benzenesulfonyl chloride (3.1 mL, 24.2 mmol) was added dropwise to the reaction mixture, before stirring for 5 minutes at 0 °C, allowing to warm to room temperature and stirring for a further 2 hours. The reaction mixture was cooled to 0 °C, diluted slowly with saturated aqueous NH4C1 (100 mL) and extracted into ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 x 20 mL), brine (2 x 20 mL), dried over Mg504, filtered, concentrated under reduced pressure and purified by column chromatography (0-20% ethyl acetate in petroleum ether) to afford the desired product as a pale orange oil (5.96 g, 76%).
LC-MS (Method A): RT = 3.92 min, m/z = 354.3 [M-H]. 1H NMR (500 MHz, DMSO-d6) 7.76-7.72 (m, 1H), 7.64 (d, J= 3.5 Hz, 1H), 7.53 (br t, J= 7.9 Hz, 2H), 7.44-7.38 (m, 3H), 7.29 (br t, J = 7.7 Hz, 2H), 6.95 (br d, J= 7.2 Hz, 2H), 6.76 (d, J= 3.5 Hz, 1H), 3.92 (q, J = 7.0 Hz, 2H), 0.91 (t, J= 7.1 Hz, 3H).
Step B: Ethyl 1-(benzenesulfony0-4-(tett-butylsulfamoy0-2-phenyl-pyrrole-3-carboxylate Chlorosulfonic acid (13.0 mL, 195 mmol,) was added portionwise to a solution of ethyl 1- (benzenesulfony1)-2-phenyl-pyrrole-3-carboxylate (5.73 g, 16.1 mmol) in anhydrous acetonitrile (100 mL) at 0 °C, allowed to warm to room temperature and stirred for three days. The reaction mixture was cooled to 0 °C, additional chlorosulfonic acid (16.1 mL, 242 mmol,) added dropwise, allowed to warm to room temperature and stirred for a further 18 hours. The reaction mixture was quenched by dropwise addition into ice cold water (500 mL), allowed to warm to room temperature and stirred for 10 minutes. The resulting white precipitate was isolated by filtration and dried under reduced pressure. This solid was redissolved in THE (50 mL) followed by the addition of tert-butylamine (3.48 g, 47.6 mmol, 5 mL) and stirred at room temperature under nitrogen for 2 hours.
The reaction mixture was concentrated under reduced pressure and the resulting residue purified by column chromatography (dry loaded onto celite, 10-70% ethyl acetate in petroleum ether) to afford the desired product as a yellow oil (5.55 g, 70%).
LC-MS (Method B): RT = 4.10 min, m/z = 489.4 [M-H]. 1H NMR (500 MHz, DMSO-d6) 7.98 (s, 1H), 7.79 (bit, J= 7.3 Hz, 1H), 7.56 (bit, 1= 7.8 Hz, 2H), 7.50-7.44 (m, 3H), 7.34 (bit, J = 7.8 Hz, 2H), 7.00 (bid, J = 7.3 Hz, 2H), 6.71 (s, 1H), 3.91 (q, J = 7.0 Hz, 2H), 1.19 (s, 9H), 0.77 (t, 1= 7.0 Hz, 3H).
Step C: Ethyl 4-(tert-butylsulfamoy1)-2-phenyl-1H-pyrrole-3-carboxylate A solution of tetrabutylammonium fluoride (1 M in THF, 13.6 mL) was added to a solution of ethyl 1-(benzenesulfony1)-4-(tert-butylsulfamoy1)-2-phenyl-pyrrole-3-carboxylate (5.55 g, 11.3 mmol) in anhydrous THE (30 mL) and stirred for 2 hours at room temperature. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered, concentrated under reduced pressure and purified by column chromatography (5-60% ethyl acetate in petroleum ether) to afford the desired product as a white solid (3.27 g, 83%).
LC-MS (Method B): RT = 3.38 min, m/z = 349.4 [M-H]. 1H NMR (500 MHz, DMSO-d6) 12.25 (br s, 1H), 7.48-7.42(m, 5H), 7.40(d, J= 2.3 Hz, 1H), 6.27(s, 1H), 4.12(q, 1=7.0 Hz, 2H), 1.19 (s, 9H), 1.06 (t, J = 7.0 Hz, 3H).
Intermediate 2: Methyl 4-(tert-butylsulfamoyI)-2-iodo-1-methyl-pyrrole-3-carboxylate Step A: Methyl 1-(benzenesulfonyOpyrrole-3-carboxylate Sodium hydride (60% purity in mineral oil, 1.05 g, 26.3 mmol) was added to a solution of methyl 1H-pyrrole-3-carboxylate (2.99 g, 23.9 mmol) in anhydrous THF (10 mL) at 0 °C under nitrogen, stirred for 10 minutes then allowed to warm to room temperature and stirred for a further 20 minutes. Benzenesulfonyl chloride (3.4 mL, 26.6 mmol) was added dropwise and the reaction mixture stirred for 2.5 hours, then cooled to 0 °C, quenched slowly with water (20 mL) and extracted into ethyl acetate (3 x 10 mL). The combined extracts were washed with brine (10 mL), dried over MgSO4, filtered, concentrated to dryness and purified by column chromatography (0-25% ethyl acetate in petroleum ether) to afford the desired product as a white solid (5.54 g, 88%).
LC-MS (Method A): RT = 3.33 min, m/z = 264.3 [M-H]. 'H NMR (500 MHz, DMSO-d6) 6 8.11 (d, J = 7.6 Hz, 2H), 7.97(t, J= 1.8 Hz, 1H), 7.81 (bit, J= 7.5 Hz, 1H), 7.69 (br t, J= 7.8 Hz, 2H), 7.49-7.48 (m, 1H), 6.67 (dd, 1= 3.4, 1.5 Hz, 1H), 3.74 (s, 3H).
Step B: Methyl 1-(benzenesulfony0-2-iodo-pyrrole-3-carboxylate Diisopropylamine (2.82 mL, 20.0 mmol) was added dropwise to a solution of 2M nbutylithium in hexane (9.7 mL, 19.4 mmol) in anhydrous THF (20 mL) at -78 °C under nitrogen and, on complete addition, the reaction mixture was allowed to warm to 0 °C then immediately cooled back to -78 °C. A solution of methyl 1-(benzenesultonyhpyrrole- 3-carboxylate (3.43 g, 12.9 mmol) in anhydrous THE (20 mL) was added dropwise to the reaction mixture and stirred at -78 °C for 4 hours. The reaction mixture was diluted with anhydrous THF (20 mL) followed by the dropwise addition of a solution of iodine (4.26 g, 16.8 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred for 10 minutes at -78 °C, quenched with saturated aqueous NH4CI (20 mL) and allowed to warm to room temperature. The solution was extracted with ethyl acetate (3 x 30 mL) and the combined extracts were washed with saturated aqueous sodium thiosulfite (2 x 20 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (5-50% diethyl ether in petroleum ether) to afford the desired product as a yellow solid (4.41 g, 70%, 80% purity).
Used in subsequent steps without further purification.
LC-MS (Method A): RT = 3.58 min, tit& = 390.1 [M-H]. 1H NMR (500 MHz, DMSO-d6) 7.98-7.95 (m, 2H), 7.90(d, J= 3.7 Hz, 1H), 7.85-7.82 (m, 1H), 7.74-7.70 (m, 2H), 6.80 (d, J = 3.7 Hz, 1H), 3.72 (s, 3H).
Step C: Methyl 1-(benzenesulfony1)-4-(tert-butylsulfamoy1)-2-iodo-pyrrole-3-carboxylate Chlorosulfonic acid (13.0 mL, 195 mmol) was added dropwise to a cooled solution of methyl 1-(benzenesulfonyI)-2-iodo-pyrrole-3-carboxylate (4.41 g, 11.3 mmol) in anhydrous acetonitrile (100 mL) at 0 °C and, on complete addition, allowed to warm to room temperature and stirred for 17 hours. The reaction mixture was recharged with chlorosulfonic acid (13.0 mL, 195 mmol), stirred for a further 24 hours, recharged with chlorosulfonic acid (22.0 mL, 330 mmol) and stirred for 48 hours. The reaction mixture was quenched slowly into ice-water (600 mL), allowed to warm to room temperature and stirred vigorously for 30 minutes. The resulting solid was isolated by filtration and dried under vacuum filtration to afford the desired product as an orange solid (3.169, 37%, 65% purity). Additional product was isolated by concentration of the filtrates under reduced pressure to remove acetonitrile and the resulting solid filtered and dried under vacuum filtration to afford the desired product as a beige solid (285 mg, 5%, 76% purity). Combined solids were redissolved in THF (15 mL) followed by the addition of tettbutylamine (2.40 mL, 22.9 mmol) and stirred at room temperature under nitrogen for 20 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (10-60% ethyl acetate in petroleum ether) to afford the desired product as a white solid (2.50 g, 42% yield over two steps).
LC-MS (Method B): RT = 3.63 min, m/z = 525.2 [M-H].
Step D: Methyl 4-(tert-butylsulfamoyI)-2-iodo-1H-pyrrole-3-carboxylate 1M Tetrabutylammonium fluoride in THF (5.70 mL, 5.70 mmol) was added to a solution of methyl 1-(benzenesulfonyI)-4-(tert-butylsulfamoy1)-2-iodo-pyrrole-3-carboxylate (2.50 g, 4.75 mmol) in THF (30 mL) and the resulting solution stirred at room temperature for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (10 mL), dried over MgSO4, filtered, concentrated under reduced pressure and purified by column chromatography (0-50% ethyl acetate in petroleum ether) to afford the desired product as colourless oil (1.35 g, 74%).
LC-MS (Method A):IRT = 2.91 min, m/z = 385.2 Em-Hr. 1H NMR (500 MHz, DMSO-d6) 12.06 (br s, 1H), 7.44 (d, J= 2.0 Hz, 1H), 6.29 (s, 1H), 3.80 (s, 3H), 1.14 (s, 9H).
Step E: Methyl 4-(tert-butylsulfamoyI)-2-iodo-l-methyl-pyrrole-3-carboxylate lodomethane (283.0 pL, 4.54 mmol) was added to a suspension of methyl 4-(tertbutylsulfamoy1)-2-iodo-1fH-pyrrole-3-carboxylate (1.35 g, 3.50 mmol) and potassium carbonate (966 mg, 6.99 mmol) in DMF (10 mL) and stirred at room temperature for 4 hours. The reaction mixture was quenched with water (20 mL) and extracted into ethyl acetate (3 x 30 mL). The combined extracts were washed with saturated aqueous sodium thiosulfite (2 X 10 mL), 1:1 brine/water (2 X 10 mL), dried over MgSO4, filtered and purified by column chromatography (10-50% ethyl acetate in petroleum ether) to afford the desired product as a white solid (1.069, 76%).
LC-MS (Method B): RT = 3.23 min, m/z = 399.2 EM-Hy. 1H NMR (500 MHz, DMSO-d6) 7.78 (s, 1H), 6.33 (s, 1H), 3.80 (s, 3H), 3.67 (s, 3H), 1.15 (s, 9H).
Intermediate 3: tert-Butyl N-methyl-N-[24methy1[4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yObenzoyliaminoiethylicarbamate Boc N,N-Diisopropylethylamine (4.91 mL, 28.22 mmol) followed by HBTU (3.67 g, 9.67 mmol) was added to a solution of 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)benzoic acid (2.0 g, 8.06 mmol) in DCM (50 mL) and stirred for 5 minutes at room temperature. tettButyl N-methyl-N-[2-(methylamino)ethyl]carbamate (1.67 g, 8.87 mmol) was added to the reaction mixture and stirred overnight at room temperature. The reaction was quenched by addition of water (30 mL) and saturated aqueous NaHCO3 (20 mL) and the resulting layers separated. The aqueous phase was further extracted with DCM (2 x 30 mL). The combined organic extracts were washed with 2 M aqueous HCI (2 x 30 mL), brine (10 mL), dried over Mg304, filtered, concentrated under reduced pressure and purified by column chromatography (10-60% ethyl acetate in petroleum ether). The resulting oil was azetroped with 1:1 petroleum ether/diethyl ether (2 x 10 mL) to afford the desired product as a white solid (2.74 g, 81%).
LC-MS (Method A): RT = 2.04 min, m/z = 319.2 [M+H-Boc].1H NMR (500 MHz, DMS0-de) 6 7.73-7.69 (m, 2H), 7.35-7.29 (m, 2H), 3.60 (br s, 1H), 3.44 (br s, 1H), 3.36 (br s, 1H), 3.23 (br s, 1H), 3.00 (br s, 1H), 2.89-2.83 (m, 3H), 2.70 (s, 1H), 2.42 (br s, 1H), 1.43-1.26 (m, 21H).
Intermediate 4: tert-butyl 5-benzylsulfany1-3-pheny1-1H-pyrazole-4-carboxylate Ph Step A: tett-Butyl 2-benzoy1-3,3-bis(benzylsulfanyl)prop-2-enoete A suspension of potassium carbonate (5.65 g, 40.9 mmol) in DMF (20 mL) was cooled to 0 °C followed by the addition of tert-butyl 3-oxo-3-phenyl-propanoate (1.80 mL, 16.34 mmol) then the dropwise addition of 5 M carbon disulfide in THE (3.92 mL, 19.6 mml). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was recooled to 0 °C before the dropwise addition of bromomethylbenzene (6.15 g, 35.96 mmol, 4.27 mL) then allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted into ethyl acetate (3 x 50 mL). The combined organic extracts were washed with 1:1 water/brine (3 x 50 mL), dried over MgSO4, filtered, concentrated to dryness under reduced pressure and purified by column chromatography (0-20% ethyl acetate in petroleum ether) to afford the desired product as an off white solid (4.52 g, 58%).
LC-MS (Method A): RT = 4.67 min, m/z = 499.1 [M+Na].1H NMR (500 MHz, DMSO-d6) 6 7.71-7.66 (m, 2H), 7.55-7.49 (m, 1H), 7.40-7.27 (m, 7H), 7.23-7.18(m, 3H), 7.12-7.07(m, 2H), 4.17 (s, 2H), 3.96 (s, 2H), 1.29 (s, 9H).
Step B: tert-Butyl 5-benzylsulfany1-3-pheny1-1H-pyrazole-4-carboxylate To a solution of tert-butyl 2-benzoy1-3,3-bis(benzylsulfanyl)prop-2-enoate (1.00 g, 2.10 mmol) in acetonitrile (10 mL) was added hydrazine hydrate (122 pL, 2.52 mmol) before heating to reflux under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, concentrated to dryness under reduced pressure and purified by column chromatography (0-40% ethyl acetate in petroleum ether) to afford the desired product as a white solid (745 mg, 97%). LC-MS (Method A): RI-= 4.04 min, m/z = 365.4 [M-H]. 1H NMR (500 MHz, CDC13) 6 9.97 (br s, 1H), 7.54-7.48 (m, 2H), 7.477.39 (m, 5H), 7.34-7.28 (m, 2H), 7.27-7.22 (m, 1H), 4.34 (s, 2H), 1.41 (s, 9H).
Example 1: 1-Methyl-2-phenyl-4-sulfamoyl-pyrrole-3-carboxylic acid Step A: Ethyl 4-(ten'-butylsulfamoy1)-1-methy1-2-phenyl-pyrrole-3-carboxylate Potassium carbonate (316 mg, 2.28 mmol) was added to a solution of ethyl 4-(tertbutylsulfamoy1)-2-pheny1-11-1-pyrrole-3-carboxylate (400 mg, 1.14 mmol) in anhydrous DMF (2 mL) and stirred for 5 minutes at room temperature under nitrogen. lodomethane (85 pL, 1.37 mmol) was added to the reaction mixture and stirred for 1.5 hours at room temperature before quenching with water (10 mL) and extracting into ethyl acetate (3 x mL). The combined extracts were washed with 1:1 brine/water (2 x 10 mL), dried over MgSO4, filtered, concentrated under reduced pressure and purified by column chromatography (10-50% ethyl acetate in petroleum ether) to afford the desired product as a white solid (350 mg, 84%).
LC-MS (Method B): RT = 3.74 min, m/z = 363.3 [M-H]. 1H NMR (500 MHz, DMSO-d6) 6 7.57(s, 1H), 7.49-7.47 (m, 3H), 7.38-7.35(m, 2H), 6.24 (s, 1H), 3.95(q, J= 7.0 Hz, 2H), 3.44 (s, 3H), 1.21 (s, 9H), 0.84 (t, J= 7.0 Hz, 3H).
Step B: Ethyl 1-methy1-2-pheny1-4-sulfamoyl-pyrrole-3-carboxylate Trifluoroacetic acid (1.0 mL, 13.5 mmol) was added to a solution of ethyl 4-(tert-butylsulfamoy1)-1-methyl-2-phenyl-pyrrole-3-carboxylate (38 mg, 104 pmol) in DCM (1.0 mL) and stirred under nitrogen at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with DCM (2 X 5 mL) then 1:1 DCM/diethyl ether (5 mL). The resulting solid was slurried in diethyl ether (3 x 5 mL), the solvent decanted and the remaining solid dried under reduced pressure to afford the desired product as a white solid (22 mg, 69%).
LC-MS (Method B): RT = 3.01 min, m/z = 307.3 [M-H]. 1H NMR (500 MHz, CD30D) 7.40-7.37(m, 3H), 7.32 (s, 1H), 7.24-7.22(m, 2H), 3.90(q, J= 7.2 Hz, 2H), 3.35(s, 3H), 0.78 (t, J = 7.2 Hz, 3H).
Step C: 1-Methy1-2-pheny1-4-sulfamoyl-pyrrole-3-carboxylic acid Lithium hydroxide monohydrate (12 mg, 285 pmol) was added to a solution of ethyl 1-methy1-2-pheny1-4-sulfamoyl-pyrrole-3-carboxylate (22 mg, 71 pmol) in a mixture of water (0.25 mL) and THF (0.5 mL) and stirred for 2 hours at room temperature then heated to 70 °C for 23 hours. The reaction mixture was allowed to cool to room temperature and washed with diethyl ether (4 x 5 mL). The aqueous layer was acidified with 2M aqueous HC1 (until pH 1) and extracted with ethyl acetate (5 X 5 mL). The combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as a white solid (16 mg, 76%).
LC-MS (Method A): RT = 2.27 min, m/z = 279.3 [M-H]. 1H NMR (500 MHz, DM50-cl6) 12.28 (br s, 1H), 7.52(s, 1H), 7.48-7.45 (m, 3H), 7.39-7.36(m, 2H), 6.83 (br s, 2H), 3.39 (s, 3H).
The following examples were prepared in a similar manner to 1-methy1-2-pheny1-4-sulfamoyl-pyrrole-3-carboxylic acid (Example 1). The alkylating reagents used in Step A are highlighted in the table.
Example Alkylating Reagent Structure Name and Analytical Data 2 H Ph 1-(3-Aminopropy1)-2-pheny1-4-sulfamoylpyrrole-3-carboxylic acid -.1(0,N...,....",--..".""Br 11 Hpr\---"NN \ 0 LC-MS (Method A): RT = 0.76 min, m/z = 322.3 EM-Hr. 1H NMR (500 MHz, DM80d6) 57.63 (br s, 2H), 7.39-7.35 (m, 3H), 7.32 (s, 1H), 7.29-7.27 (m, 2H), 3.74 (t, J = 7.2 Hz, 2H), 2.48-2.44 (m, 2H), 1.61 (quin, J= 7.2 Hz, 2H). The multiplet at 2.48-2.44 is obscured by residual solvent peak.
OH -sFo
H2h1 *0 3**, t N/A Ph 2-Pheny1-4-sulfamoy1-1H-pyrrole-3-carboxylic acid HN \ 0 LC-MS (Method A): RT = 1.65 min, m/z = 265.3 [M-Hr. 'H NMR (500 MHz, DMSOds) 612.57 (br s, 1H), 12.14 (br s, 1H), 7.51-7.48 (m, 2H), 7.46-7.40 (m, 3H), 7.35 (d, J= 2.9 Hz, 1H), 6.81 (s, 2H). --...
OH
H2N-SS:00 4"", tt HO HO"....."...N Ph 1-(2-Hydroxyethyl)-2-pheny1-4-sulfamoylpyrrole-3-carboxylic acid N 0 LC-MS (Method A): RT = 1.82 min, m/z = 309.3 EM-Hr. ,H NMR (500 MHz, DMS0-de) 612.30 (br s, 1H), 7.52 (s, 1H), 7.497.44 (m, 3H), 7.37-7.35 (m, 2H), 6.83 (s, 2H), 4.93 (br s, 1H), 3.74 (bit, J = 5.2 Hz, 2H), 3.48 (bit, J = 5.2 Hz, 2H).
OH
H2N *0 ),.....-I 0,......." H2N -N:h 0 1-(2-aminoethyl)-2-pheny1-4-sulfamoylpyrrole-3-carboxylic acid (21,w"......,ci H2N LC-MS (Method A): RT = 0.57 min, m/z = 308.4 [M-Hr. 1H NMR (500 MHz, DMSOds) 67.80 (br s, 2H), 7.39-7.28 (m, 3H), 7.31-7.28 (m, 2H), 7.23 (s, 1H), 3.64 (t, J= 6.7 Hz, 2H), 2.58 (t, J = 6.7 Hz, 2H).
6 A.,..." Br Ph 1-(Cyclopropylmethyl)-2-pheny1-4-sulfamoyl-pyrrole-3-carboxylic acid LC-MS (Method A): RT = 2.77 min, m/z = 319.4 [M-Hr.11-INMR (500 MHz, DMSOd6) 612.31 (br s, 1H), 7.59 (s, 1H), 7.487.44 (m, 3H), 7.35-7.32 (m, 2H), 6.84 (s, 2H), 3.57 (d, J = 7.2 Hz, 2H), 0.92-0.85 (m, 1H), 0.42-0.38 (m, 2H), 0.16-0.15 (m, 2H).
\r. N 0
OH
-SF
H2N '0° 7 IS Br Ph 1-Benzy1-2-pheny1-4-sulfamoyl-pyrrole-3-carboxylic acid Ph 0 LC-MS (Method A): RT = 3.00 min, m/z = 355.4 [M-Hr.IIHNMR (500 MHz, DMSOds) 612.36 (br s, 1H), 7.59 (s, 1H), 7.457.39 (m, 3H), 7.29-7.24 (m, 5H), 6.88 (dd, J = 7.8, 1.8 Hz, 2H), 6.86 (br s, 2H), 4.99 (s,
OH
-SFO H2N.0 2H).
8ttt.."'NH N Ph 142-(Methylamino)-2-oxo-ethy1]-2-phenyl4-sulfamoyl-pyrrole-3-carboxylic acid LC-MS (Method A): RT = 1.47 min, m/z = 336.4 [M-Hr. 'H NMR (500 MHz, DMS0-cis) 67.76-7.74 (br m, 2H), 7.35-7.32 (m, 3H), 7.25-7.22 (m, 2H), 7.18 (br s, 1H), 4.28 (s, 2H), 2.55-2.53 (m, 3H). Multiplet at 2.55-2.53 is obscured by DMSO-d0 solvent peak.
"Br.....H o o... sFo H24.0 9ttt.--NH o..........a HO Ph 1-(Carboxymethyl)-2-phenyl-4-sulfamoylpyrrole-3-carboxylic acid N o LC-MS (Method A): RT = 1.75 min, m/z = 323.4 EM-Hr. 1H NMR (500 MHz, DMS0-de) 67.36-7.34 (m, 3H), 7.33-7.31 (m, 2H), 7.18 (s, 1H), 7.16 (br s, 2H), 3.91 (br s, 2H). s,=0
H2N. .0 *Step C required the aqueous to be acidified to pH 4-5 for extraction. **Step C required heating to 50 °C.
*"* Step C required recharging once with the same quantity of LOH.
**** Step A required heating at 60 °C overnight. Step B required crude material to be dissolved in Me0H and loaded on to a 5 g strong cation exchange (SCX) cartridge, flushed with Me0H (20 mL) and product eluted from the cartridge using 1M NH3 in Me0H (20 mL). Step C required the aqueous to be acidified to pH 2 for extraction followed by purification by column chromatography (5-100% methanol in ethyl acetate).
t Step A was not required, with ethyl 4-(tert-butylsulfamoyI)-2-phenyl-1H-pyrrole-3-carboxylate used directly in Step B. tt Step A required heating to 50 °C then 80 °C.
ttt Step C required two days at room temperature to achieve full consumption of starting material but gave Example 9 as a side product. Example 8 and Example 9 were purified by column chromatography (5-50% methanol in DCM) to afford clean products.
Step A: Methyl 4-(tert-butylsulfamoy0-1-methyl-2- (1-methylpyrazol-4-yOpyrrole-3-carboxylate A solution of K3PO4 (149 mg, 700 pmol) in water (0.5 mL) was added to a nitrogen degassed solution of methyl 4-(tert-butylsulfamoyI)-2-iodo-1-methyl-pyrrole-3-carboxylate (80 mg, 200 pmol), 1-methy1-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1) pyrazole (46 mg, 220 pmol) and XPhos Pd G2 (15.7 mg, 20.0 pmol) in 1,4-dioxane (3 mL), then heated to 50 °C under microwave irradiation for 2 hours. The reaction mixture was diluted with water (10 mL) and ethyl acetete (10 mL) and the resulting layers separated. The aqueous was further extracted with ethyl acetate (2 x 10 mL) and the combined extracts were washed with brine (10 mL), dried over MgSO4, filtered, concentrated under reduced pressure and purified by column chromatography (10-100% ethyl acetate in petroleum ether and then 0-20% methanol in ethyl acetate) to afford the desired product as a yellow solid (51 mg, 72% yield).
LC-MS (Method F): RT = 1.44 min, miz = 377.2 [M+Na]t.1H NMR (500 MHz, DMSO-c15) 7.98 (s, 1H), 7.61 (s, 1H), 7.52 (s, 1H), 6.28 (s, 1H), 3.89 (s, 3H), 3.64 (s, 3H), 3.54 (s, 3H), 1.18 (s, 9H).
Step B: 4-(tert-Butylsulfamoy0-1-methyl-2- (1-methylpyrazol-4-yOpyrrole-3-carboxylic acid A solution of lithium hydroxide monohydrate (60.4 mg, 1.44 mmol) in water (0.5 mL) was added to a solution of methyl 4-(tert-butylsulfamoy1)-1-methyl-2- (1-methylpyrazol-4-yhpyrrole-3-carboxylate (51 mg, 144 pmol) in a mixture of methanol (0.5 mL) and THF (0.5 mL) and stirred for 65 hours at room temperature. The reaction mixture was diluted with water (10 mL) and organics removed under reduced pressure. The resulting aqueous was washed with ethyl acetate (2 x 10 mL), then acidified with 2M aqueous HCI (until pH 1) and extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product as a white solid (40 mg, 82%).
Example 10: 1-Methy1-2-pheny1-4-sulfamoyl-pyrrole-3-carboxylic acid N,N
OH
LC-MS (Method E): RT = 1.31 min, m/z = 339.1 [M-H]. 1H NMR (500 MHz, DMSO-d6) 12.46 (br s, 1H), 7.95 (s, 1H), 7.58 (s, 1H), 7.51 (s, 1H), 6.39 (br s, 1H), 3.88 (s, 3H), 3.50 (s, 3H), 1.18 (s, 9H).
Step C: 1-Methyl-2-(1-methylpyrazol-4-y0-4-sulfamoyl-pyrrole-3-carboxylic acid Trifluoroacetic acid (0.5 mL, 6.75 mmol) was added to a solution of 4-(tert-butylsulfamoy1)-1-methy1-2-(1-methylpyrazol-4-y1) pyrrole-3-carboxylic acid (40 mg, 118 pmol) in DCM (2 mL) and stirred for 20 hours. The reaction mixture was concentrated under reduced pressure, azetroped with DCM (2 x 5 mL) and slurried in 1:1 DCM/diethyl ether (5 mL) then diethyl ether (2 x 5 mL), the solvent decanted and the solid dried under reduced pressure to afford the desired product as a white solid (22.7 mg, 68%).
LC-MS (Method E): RT = 0.80 min, m/z = 285.1 [m+H]t 1H NMR (500 MHz, DMSO-d6) 5 12.38 (br s, 1H), 7.94(s, 1H), 7.58(s, 1H), 7.48 (s, 1H), 6.76(s, 2H), 3.89(s, 3H), 3.50 (s, 3H) The following examples were prepared in a similar manner to 1-methyl-2-(1-methylpyrazol-4-y1)-4-sulfamoyl-pyrrole-3-carboxylic acid (Example 10).
Example Structure Name and Analytical Data 114' NH2 246-Amino-3-pyridy1)-1-methyl-4-sulfamoyl-pyrrole-3-carboxylic acid N LC-MS (Method G): RT = 0.43 min, m/z = 297.0 [M-H]-.1H NMR (500 MHz, DMSO-de) 6 12.69 (br s, 1H), 8.07 (br s, 1 H), 8.01-7.83 (m, 3H), 7.56 (s, 1H), 6.98-6.93 (m, 1H), 6.83 (s, 2H), 3.49 (s, 3H). \ i ^ 0 \
--- OH H2N 0
12" H2N 2-(5-Amino-3-pyridy1)-1-methyl-4-sulfamoyl-pyrrole-3-carboxylic acid -- LC-MS (Method G): RT = 0.43 min, m/z = 297.1 [M-H]. 1H NMR (500 MHz, DMSO-cfs) 6 12.69 (br s, 1H), 8.04 (d, J= 2.1 Hz, 1H), 8.02 (s, 1H), 7.59 (s, 1H), 7.37 (br s, 1H), 6.85 (br s, 2H), 3.48 (s, 3H). \ 1
-- OH H2N 0
13** NH2 2-(2-Aminopyrimidin-5-yI)-1-methyl-4-sulfamoyl-pyrrole-3-carboxylic acid NAN N / LC-MS (Method G): RT = 0.43 min, m/z = 298.1 [M+H].1H NMR (500 MHz, DMSO-ds) 612.53 (br s, 1H), 8.24 (s, 2H), 7.54 (s, 1H), 6.98 (br s, 2H), 6.80 (s, 2H), 3.49 (s, 3H). \
-- OH S,F0 H2N 0
14::2:0 2-[4-(Cyclopropylsulfonylamino)phenyI] -1-methyl-4-sulfamoylpyrrole-3-carboxylic acid HN-S LC-MS (Method A): RT = 2.20 min, m/z = 398.5 EM-Hr. 1H NMR (500 MHz, DMSO-de) 6 12.35 (br s, 1H), 9.97 (s, 1H), 7.50 (s, 1H), 7.33-7.31 (m, 2H), 7.30-7.28 (m, 2H), 6.80 (br s, 2H), 3.40 (s, 3H), 2.71 (quintet, J = 6.2 Hz, 1H), 0.99-0.96 (m, 4H). * \
---- OH AF-0 H2N o
15*** 1141 o 1-Methyl-244-(4-piperidyhpheny1]-4-sulfamoyl-pyrrole-3-carboxylic acid trifluoroacetate salt CFACF3 LC-MS (Method E): RT = 0.16 min, m/z = 362.2 EM-Hr. 1H NMR (500 MHz, DMSO-ds) 6 12.61-12.31 (br m, 1H), 8.598.22 (br m, 1H), 7.54-7.51 (m, 1H), 7.37-7.31 (m, 3H), 6.81-6.78 (m, 2H), 3.40-3.35 (m, 5H), 3.08-2.99 (m, 2H), 2.96-2.89 (71, 1H), 2.03-1.99 (m, 2H), 1.85-1.76 (m, 2H). Multiplet at 3.40-3.35 is obscured by water signals. 19F NMR (470 MHz, DMSO-do) 6 -73.68 (s, 3F). le I o \
- OH 8,F 0
H2N. o 16*** 0 / 1-Methyl-2-[4-[methyl-[2-N11141 (methylamino)ethyl]carbamoyl]pheny1]-4-sulfamoyl-pyrrole-3-carboxylic acid trifluoroacetate salt 0, l'H0 LC-MS (Method A): RT = 1.27 min, m/z = 393.7 EM-Hr. 1H NMR (500 MHz, DMSO-ds) 612.46 (br s, 1H), 8.37 (bra, 2H), 7.58 (bid, J = 7.8 Hz, 2H), 7.56 (s, 1H), 7.47 (d, J = 7.8 Hz, 2H), 6.84 (bra, 2H), 3.76 (bra, 2H), 3.22 (br s, 2H), 2.99 (br s, 3H), 2.65 (br s, 3H). 19F NMR (470 MHz, DMSO-d6) 6 -73.70 (s, 3F).
N 0 crk CF,
-- OH
AFO H2N 0
* In Step B the aqueous was acidified to pH 4. ** In Step B the aqueous was acidified to pH 3.
**" Amines were protected with a Boc group through Steps A and B. Example 17: 5-Bromo-1-methy1-2-pheny1-4-sulfamoyl-pyrrole-3-carboxylic acid Ph Step A: Ethyl 5-bromo-4-(tert-butylsulfamoy0-1-methy1-2-phenyl-pyrrole-3-carboxylate N-Bromosuccinimide (53 mg, 296 pmol) was added to a solution of ethyl 4-(tert-butylsulfamoy1)-1-methyl-2-phenyl-pyrrole-3-carboxylate (90 mg, 247 pmol) in DMF (1.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted into ethyl acetate (3 x 10 mL). The combined organic extracts were washed with 1:1 brine/water (20 mL), dried over MgSO4, filtered, concentrated under reduced pressure and purified by column chromatography (10-50% ethyl acetate in petroleum ether) to afford the desired product as a white solid/gum (71 mg, 65%).
LC-MS (Method A): RT = 3.91 min, m/z = 1:1 ratio of 443.1/455.1 [M+H]t1H NMR (500 MHz, DMSO-d6) 57.51-7.48 (m, 3H), 7.39-7.37 (m, 2H), 6.74 (s, 1H), 3.96 (q, J= 7.0 Hz, 2H), 3.43 (s, 3H), 1.22 (s, 9H), 0.85 (t, J = 7.0 Hz, 3H).
Steps B and C: 5-Bromo-1-methy1-2-pheny1-4-sulfamoyl-pyrrole-3-carboxylic acid Example 17 was made in a similar manner to Example 1 using steps B and C from ethyl 5-bromo-4-(fert-butylsulfamoy1)-1-methy1-2-phenyl-pyrrole-3-carboxylate to afford the desired product as a white solid (52 mg, 51% yield over two steps).
LC-MS (Method A): RT = 2.59 min, ink = 1:1 ratio of 357.3/359.3 [M-H]. 1H NM R (500 MHz, DMSO-d6) 6 12.62 (br s, 1H), 7.50-7.48 (m, 3H), 7.40-7.37 (m, 2H), 7.13 (s, 2H), 3.38 (s, 3H).
Example 18: 5-Pheny1-3-sulfamoy1-1H-pyrazole-4-carboxylic acid Ph H2N 0 Step A: tert-Butyl 3-(tert-butylsulfamoy0-5-phenyl-1H-pyrazole-4-carboxylate To a solution of terf-butyl 3-benzylsulfany1-5-phenyl-1H-pyrazole-4-carboxylate (100 mg, 273 pmol) in DCM (1.0 mL) was added acetic acid (0.1 mL) and water (0.2 mL). After cooling to 0°C a solution of 1,3-dichloro-5,5-dimethylhydantoin (108 pL, 819 pmol) in DCM (1.0 mL) was added dropwise before vigorous stirring at 0 °C for 1 hour, allowing to H2N 0 warm to room temperature and stirring for 2 hours. The reaction mixture was washed with water (3 x 5 mL) and the organic phase added dropwise to a solution of tert-butylamine (72 pL, 682 pmol) in DCM (1.0 mL) at 0 °C, allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was filtered, washed with DCM (5 mL) and the combined filtrate concentrated under reduced pressure and purified by column chromatography (0-60% ethyl acetate in petroleum ether) to afford the desired product as a white solid (57 mg, 55%).
LC-MS (Method A): RT = 3.58 min, m/z = 378.4 [M-H]. 1H NMR (500 MHz, CDCI3) 6 10.51 (br s, 1H), 7.53-7.44 (m, 5H), 6.20 (s, 1H), 1.34 (s, 9H), 1.30 (s, 9H).
Step B: 5-Phenyl-3-sulfamoy1-1H-pyrazole-4-carboxylic acid A solution of tert-butyl 3-(tert-butylsulfamoy1)-5-phenyl-1H-pyrazole-4-carboxylate (57 mg, 150 pmol) in trifluoroacetic acid (2 mL) was stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness under reduced pressure, azeotroped with diethyl ether (3 x 5 mL), slurried in diethyl ether (2 mL) and dried under reduced pressure to afford the desired product as a white solid (32 mg, 76%).
LC-MS (Method C): IRT = 3.62 min, m/z = 266.3 [M-H]. 1H NMR (500 MHz, DMSO-d6) 6 14.03 (br s, 1H), 12.99 (br s, 1H), 7.63-7.57 (m, 2H), 7.55-7.48 (m, 3H), 7.35 (br s, 2H).
Example 19: 1-Methy1-5-pheny1-3-sulfamoyl-pyrazole-4-carboxylic acid Ph H2N Step A: tert-Butyl 3-benzylsulfany1-1-methy1-5-phenyl-pyrazole-4-carboxylate To a suspension of tert-butyl 5-benzylsulfany1-3-phenyl-1H-pyrazole-4-carboxylate (100 mg, 273 pmol) and potassium carbonate (45 mg, 327 pmol) in DMF (0.5 mL) was added iodomethane (19 pL, 300 pmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (3 mL) and extracted into ethyl acetate (3 x 3 mL).
The combined extracts were washed with 1:1 water: brine (3 x 5 mL), dried over MgSO4, filtered and concentrated to dryness under reduced pressure to afford the desired product as an 80:20 mixture of regioisomers as a yellow oil (90.0 mg, 87%). Used in subsequent step without further purification.
LC-MS (Method A): RT = 4.39 min, m/z = 381.3 [M+H]t 1H NMR (500 MHz, CDCI3) 6 7.50-7.43 (m, 5H), 7.34-7.27 (m, 4H), 7.25-7.22 (m, 1H), 4.37 (s, 2H), 3.64 (s, 3H), 1.25 (s, 9H).
Step B: tert-Butyl 3-(tert-butylsulfamoy0-1-methy1-5-phenyl-pyrazole-4-carboxylate To a solution of tert-butyl 3-benzylsulfany1-1-methyl-5-phenyl-pyrazole-4-carboxylate (193 mg, 507 pmol) in DCM (1.0 mL) was added acetic acid (0.1 mL) and water (0.2 mL). After cooling to 0°C a solution of 1,3-dichloro-5,5-dimethylhydantoin (200 pL, 1.52 mmol) in DCM (0.8 mL) was added dropwise before vigorous stirring at 0 °C for 1 hour, allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was washed with water (3 X 5 mL) and the organic phase added dropwise to a solution of tert-butylamine (133 pL, 1.27 mmol) in DCM (1.0 mL) at 0 °C, allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was filtered, washed with DCM (5 mL) and the combined filtrates concentrated under reduced pressure and purified by column chromatography (0-60% ethyl acetate in petroleum ether) to afford the desired product (41 mg, 21%).
LC-MS (Method A): RT = 3.84 min, m/z = 394.3 [m+H]t 1H NMR (500 MHz, CDCI3) 6 7.53-7.48 (m, 3H), 7.32-7.27 (m, 2H), 6.37(s, 1H), 3.71 (s, 3H), 1.31 (s, 9H), 1.18 (s, 9H).
Step C: 1-Methyl-5-phenyl-3-sulfamoyl-pyrazole-4-carboxylic acid A solution of tert-butyl 3-(tert-butylsulfamoyI)-1-methyl-5-phenyl-pyrazole-4-carboxylate (41 mg, 104 pmol) in trifluoroacetic acid (2.0 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure, azeotroped with diethyl ether (3 X 5 mL), slurried in diethyl ether (2 mL) and dried under reduced pressure to afford the desired product as a white solid (27 mg, 88%).
LC-MS (Method C): RT = 4.95 min, m/z = 280.3 [M-Hr 1H NMR (500 MHz, DMSO-d6) 6 12.89 (br s, 1H), 7.62-7.57(m, 3H), 7.57-7.51 (m, 2H), 7.39 (s, 2H), 3.75 (s, 3H).
The following examples were prepared in a similar manner to 1-methyl-2-(1-methylpyrazol-4-y1)-4-sulfamoyl-pyrrole-3-carboxylic acid (Example 19). The alkylafing reagents used in Step A are highlighted in the table.
Example Alkylating Reagent Structure Name and Analytical Data 20* H " 0 1-(2-Aminoethyl)-5-phenyl-3-sulfamoylpyrazole-4-carboxylic acid trifluoroacetate salt.
Nf CI H315--r-. OH LC-MS (Method D). RT = 0.33 min, m/z = 311.1 [M+Hr.1H NMR (500 MHz, DM50-d6) 6 12.81 (br s, 1H), 7.81 (br s, ->ri CP NI- -0 TcF. "6" 3H), 7.49-7.44 (m, 3H), 7.43-7.38 (m, 2H), 7.29 (s, 2H), 4.08 (t, J = 6.6 Hz, 2H), 3.13 (bit, J = 5.6 Hz, 2H).
21* L.,---01 0 Ph ° 1-(2-Aminoethyl)-3-phenyl-5-sulfamoylpyrazole-4-carboxylic acid trifluoroacetate salt.
>CI -1:CF5 LC-MS (Method D): ST = 0.37 min, m/z = 309.3 [M-H]. 1H NMR (500 MHz, DM50-de) 6 8.17 (br s, 4H), 7.71 (d, J = 7.0 Hz, 2H), 7.46-7.36 (m, 3H), 4.70 (t, J = 6.0 Hz, 2H), 3.34 (br t, J = 6.0 Hz, 2H)
OH s_o
22** H Ph 0 0,; 1 0H 1-(3-Aminopropy1)-3-phenyl-5-sulfamoyl-n o o6 yo P razole-4-carboxylic acid trifluoroacetate salt HI '0 LC-MS (Method D): ST = 0.39 min, m/z = 323.4 [M-H]-.1H NMR (500 MHz, DM50d6) 6 7.95 (br s, 4H), 7.67 (d, J = 7.0 Hz, 2H), 7.46-7.36 (m, 3H), 4.53 (t, J = 7.0 Hz, 2H), 2.92-2.86 (m, 2H), 2.14 (quintet, J = 7.0 Hz, 2H).
23** H h 0 1-(3-Aminopropy1)-5-phenyl-3-sulfamoylpyrazole-4-carboxylic acid trifluoroacetate salt 1<? Hy--r- 06 LC-MS (Method D): ST = 0.40 min, m/z = 325.3 [M+H]t.1H NMR (500 MHz, DMSO-d6) 6 12.93 (br s, 1H), 7.71 (br s, 3H), 7.57-7.52 (m, 3H), 7.48-7.44 (m, 2H), 7.39 (br s, 2H), 4.02 (t, J = 7.4 Hz, 2H), 2.78 (br t, J= 7.4 Hz, 2H), 1.96 (quintet, J = 7.4 Hz, 2H).
11N oyFa s?.. ivi
*Step A gave a mixture of regioisomers which were separated by column chromatography (0-40% ethyl acetate in petroleum ether). These were taken separately through Steps B and C to afford tabulated examples 20 and 21.
**Step A gave a mixture of regioisomers which were separated by column chromatography (0-40% ethyl acetate in petroleum ether). These were taken separately through Steps B and C to afford tabulated examples 22 and 23.
Example 24: 1-Methy1-3-pheny1-5-sulfamoyl-pyrazole-4-carboxylic acid Step A: tert-Butyl 5-benzylsulfany1-1-methyl-3-phenyl-pyrazole-4-carboxylate To a solution of tert-butyl 2-benzoy1-3,3-bis(benzylsulfanyl)prop-2-enoate (700 mg, 1.47 mmol) in acetonitrile (7.0 mL) was added methylhydrazine (93 pL, 1.76 mmol) before heating to reflux under a nitrogen atmosphere for 5 hours. The reaction mixture was allowed to cool to room temperature, concentrated to dryness under reduced pressure and purified by column chromatography (0-30% ethyl acetate in petroleum ether) to afford the desired product as a colourless oil which solidified on standing (510 mg, 91%).
LC-MS (Method A): RT = 4.36 min, m/z = 381.2 [m+H]t 1H NMR (500 MHz, CDC13) 6 7.58-7.52 (m, 2H), 7.43-7.33 (m, 3H), 7.25-7.20 (m, 3H), 7.11-7.05 (m, 2H), 4.13 (s, 2H), 3.41 (s, 3H), 1.44 (s, 9H).
Step B: tert-Butyl 5-(tert-butylsulfamoyI)-1-methyl-3-phenyl-pyrazole-4-carboxylate To a solution of tert-butyl 5-benzylsulfany1-1-methy1-3-phenyl-pyrazole-4-carboxylate (500 mg, 1.31 mmol) in DCM (2.0 mL) was added acetic acid (0.2 mL) and water (0.4 mL). After cooling to 0°C a solution of 1,3-dichloro-5,5-dimethylhydantoin (518 pL, 3.94 mmol) in DCM (1.5 mL) was added dropwise before vigorous stirring at 0 °C for 1 hour, allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was washed with water (3 x 10 mL) and the organic phase added dropwise to a solution of tert-butylamine (345 pL, 3.29 mmol) in DCM (2.0 mL) at 0°C, allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was filtered, washed with DCM (10 mL) and the combined filtrates concentrated under reduced pressure and purified by column chromatography (0-40% ethyl acetate in petroleum ether) to afford the desired product as a white solid (305 mg, 59%).
LC-MS (Method A): RT = 3.98 min, m/z = 392.4 EM-H]-.1H NMR (500 MHz, CDC13) 6 7.48- 7.44(m, 2H), 7.43-7.37 (m, 3H), 6.75 (s, 1H), 4.22 (s, 3H), 1.31 (s, 18H).
Step C: 1-Methyl-3-phenyl-5-sulfamoyl-pyrazole-4-carboxylic acid A solution of tert-butyl 5-(tert-butylsulfamoyI)-1-methyl-3-phenyl-pyrazole-4-carboxylate (305 mg, 775 pmol) in a mixture of DCM (2.0 mL) and trifluoroacefic acid (2.0 mL) was stirred at room temperature for 3 days. Additional trifluoroacetic acid (5.0 mL) was added before stirring at room temperature for 4 days. The reaction mixture was concentrated to dryness under reduced pressure, azeotroped with diethyl ether (3 x 5 mL), slurried in diethyl ether (3 mL), filtered and dried under reduced pressure to afford the desired product as a white solid (114 mg, 50%).
LC-MS (Method C): RT = 5.44 min, m/z = 280.3 [M-H]-.1H NMR (500 MHz, DMSO-d6) 6 13.40 (br s, 1H), 8.11 (s, 2H), 7.71-7.65 (m, 2H), 7.54-7.49 (m, 2H), 7.49-7.43 (m, 1H), 4.14 (s, 3H).
Biological Example 1
Compounds of the invention were tested in a metallo-p-lactamase inhibition assay to investigate mechanism of action of the compounds. Results are reported as the concentration of test article required to inhibit enzyme activity by 50% (IC60). Compounds exhibited IC60 values consistent with potent, specific inhibition of the tested metallo-p-lactamase.
Inhibition of metallo-p-lactamase enzyme function was performed at 37°C in buffer at pH 7.5 (50 mM HEPES, 150 mM NaCI, 0.1 mM ZnSO4, 20 pg/mL PEG4000), containing 1.5 nM NDM-1, 100 pM nitrocefin, and a range of concentrations of compound. Absorbance at 490 nm was measured using a BMG LABTECH FLUOstar Omega microplate reader every minute for 30 minutes. ICsos were determined from the average increase in OD per minute versus the Logi 0 concentration of compound using GraphPad Prism. The data is provided in Table 1 below.
Table 1: Enzyme Data
Example NDWI-1 IC50 (nIVI) 1 Not tested 2 Not tested 3 Not tested 4 Not tested Not tested 6 Not tested 7 Not tested 8 Not tested 9 Not tested Not tested 11 5253 12 Not tested 13 Not tested 14 Not tested 695.8 16 2837.8 17 1764.5 18 Not tested 19 Not tested Not tested 21 Not tested 22 Not tested 23 Not tested 24 Not tested MICs were determined by exposing bacteria to serial dilutions of antibacterial agents in MHB-II (cation-adjusted Mueller-Hinton Broth pH 7.4) according to Clinical and Laboratory Standards Institute broth microdilution guidelines (CLSI, 2018).
Combination MICs were performed as described for MIC determinations with the addition of 4 mg/L test article to MHB-II.
Cytotoxicity was evaluated in human Hep G2 cells (ATCC HB-8065) seeded at a density of 2 x 104 cells per well and incubated for 24 hours at 37°C, 5% CO2. Cells were exposed to a doubling dilution series of test article. After 24 hours exposure, the viability of the cells was determined using CellTiter-Glo® (Promega, WI, USA) according to the manufacturer's instructions. Results are reported as the concentration of test article required to reduce cell viability by 50% (CC50).
The following literature references provide additional information on the assay methods used in the assessment of compounds of the invention and the disclosures of these documents in relation to such methods is specifically incorporated herein. For the avoidance of doubt, it is intended that the disclosures of the methods in each of those documents specifically forms part of the teaching and disclosure of this invention. The last two references below provide methodology to establish and demonstrate the existence of synergy and thus the procedures described therein can be used to demonstrate synergistic activity between the compounds of the invention and carbapenems such as meropenem.
CLSI. 2018. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Eleventh Edition: M07.
PILLAI, S.K., MOELLERING, R.C., & ELIOPOULOS, G.M. 2005. Antimicrobial Combinations. In: Antibiotics in Laboratory Medicine. Philadelphia: Lippincott Williams and Wilkins, pp. 365-440.
BURKHART, C.G., BURKHART, C.N., & !SHAM, N. 2006. Synergistic Antimicrobial Activity by Combining an Ally!amine with Benzoyl Peroxide with Expanded Coverage against Yeast and Bacterial Species. British Journal of Dermatology 154(2): 341-344.
Biological Example 2
Compounds of the invention were tested and shown to result in a significant improvement in meropenem activity as presented in Table 2 below. MICs were determined in a range of bacterial species carrying either NDM-, IMP-or VIM-type MBLs. Relative to the baseline study using meropenem alone, all compounds resulted in significant improvement in meropenem activity against the organism in which the compound was tested. Some of the compounds tested improved meropenem MICs by more than 10 or 20 times in comparison with meropenem alone. The compounds are effective against a wide range of different bacteria when used in conjunction with meropenem.
The compounds of the invention were tested against a primary bacterial strain, column I of Table 2. As appropriate, compounds considered suitable for further investigation were tested against a secondary panel of bacterial strains, columns III and V of Table 2. As appropriate, compounds considered suitable for further investigation were tested against a third panel of bacterial strains, columns VI and VII of Table 2.
Table 2: Meropenem combination MICs (pg/mL) Example I II III IV V VI VII E. coli E. coil No K. A. ATCC K. K. ATCCBAA- NCTC13476 pneumoniae baumannii SG698 K. pneumoni ae pneumoniae NCTC13439 2452 BAA2146 pneumoniae NCTC13440 NCTC13443 NDM-1 IMP NDM-1 NDM-1 VIM-1 NDM-1 VIM-1 Mero- 1 4 16 8 1 128 0.5 penem 1 A A B C A Not tested Not tested 2 B Not tested Not tested D B Not tested Not tested 3 A B C C B Not tested Not tested 4 A B C Not tested Not tested Not tested Not tested B Not tested Not tested Not tested Not tested Not tested Not tested 6 B Not tested Not tested Not tested Not tested Not tested Not tested 7 B Not tested Not tested Not tested Not tested Not tested Not tested 8 B Not tested Not tested Not tested Not tested Not tested Not tested 9 B Not tested Not tested Not tested Not tested Not tested Not tested A Not tested Not tested Not tested Not tested Not tested Not tested 11 A B B C A D A 12 A B C Not tested B Not tested Not tested 13 A A B Not tested A Not tested Not tested 14 A Not tested Not tested Not tested Not tested Not tested Not tested
A A B C A D A
16 A A B C A D B 17 A A C Not tested A Not tested Not tested 18 B Not tested Not tested D B Not tested Not tested 19 A A D D B Not tested Not tested B Not tested Not tested Not tested Not tested Not tested Not tested 21 B Not tested Not tested Not tested Not tested Not tested Not tested 22 B Not tested Not tested Not tested Not tested Not tested Not tested 23 B Not tested Not tested Not tested Not tested Not tested Not tested 24 B Not tested Not tested Not tested Not tested Not tested Not tested Key to Table: The following letters in Table 2 above represent the MIC (minimum inhibitory concentration) values in pg/mL: A 5 0.2, B 5 2, C 5 10, D 5 40.
Biological Example 3
Compounds were also tested for cytotoxicity. The data below in Table 3 shows that the tested compounds did not exhibit any significant cytotoxic activity.
Table 3: Cytotoxicity Data Example HEPG2 CC50 (pg/mL) 1 >256 2 Not tested 3 Not tested 4 Not tested Not tested 6 Not tested 7 Not tested 8 Not tested 9 Not tested Not tested 11 127.8 12 Not tested 13 Not tested 14 Not tested >256 16 >256 17 >256 18 Not tested 19 Not tested Not tested 21 Not tested 22 Not tested 23 Not tested 24 >256

Claims (25)

  1. CLAIMS1. A compound of formula (I) or pharmaceutically acceptable salt thereof: 0=S=0 NH2 wherein Ring A is a heteroaromatic ring selected from pyrrole or pyrazole; where Ring A is a pyrrole, Xis C(R4); where Ring A is a pyrazole, X is -N(R5)-and a single one of R1 and R5 is absent; -1_1-is absent or is a linker selected from Ci-C3-alkylene, -0-, -NR6-and -S-; R1 and R5, where present, are selected from the group comprising: H, Ci_s alkyl, C1_6 haloalkyl, or Cm alkylene-R7; R2 is selected from phenyl, naphthyl, 5-, 6-, 9-or 10-membered heteroaryl, 4-, 5-, 6-, 7-or 8-membered heterocycloalkyl and C3-Cs-cycloalkyl; wherein R2 is substituted with a single R8 group; and wherein, where R2 is heteroaryl, phenyl or naphthyl, said heteroaryl, phenyl or naphthyl group is optionally further substituted with from 1 to 5 R° groups; or where R2 is heterocycloalkyl or cycloalkyl, said heterocycloalkyl or cycloalkyl group is optionally further substituted with from 1 to 5 R1° groups; R3is -C(0)0H or-C(0)OM; wherein M is a group 1 cation; R4 is selected from H, halo or C1.4 haloalkyl; R6 and R11 are each independently at each occurrence selected from: H, Cs-C6-cycloalkyl and C1-C6-alkyl; or where two R11 groups are attached to the same nitrogen atom, said R11 groups, together with said nitrogen atom, form a 4-, 5-, 6-or 7-membered heterocycloalkyl ring; R7 is selected from -NR11R12, SR11, C(0)0R11, -N(R11)C(0)R14, -N(R11)S(0)2R14, - S(0)2NR11R15 and -C(0)NR11R15, phenyl, 5-or 6-membered heteroaryl, 5-, 6-, 7-or 8-membered heterocycloalkyl and Ca-C8-cycloalkyl; said heteroaryl or phenyl group being optionally substituted with from 1 to 5 R9 groups; or said heterocycloalkyl or cycloalkyl group being optionally substituted with from 1 to 5 R1° groups R3 is selected from H, -N(R11)C(0)R14, -N(R11)S(0)2R14, -S(0)2NR11R18 and -C(0)NR11R18 and Co-s alkylene-R8a, wherein IR" is selected from phenyl, 5-or 6-membered heteroaryl, 5-, 6-, 7-or 8-membered heterocycloalkyl and Cs-Cs-cycloalkyl; said heteroaryl or phenyl group being optionally substituted with from 1 to 5 R9 groups; or said heterocycloalkyl or cycloalkyl group being optionally substituted with from 1 to 5 R19 groups; R9 is independently at each occurrence selected from: C1-C6-alkyl, CiCs-haloalkyl, 03-06cycloalkyl, halogen, nitro, OR13, 3IR11, S(0)2R11, C(0)R11, C(0)0R11, C(0)NR11R11, S(0)2NR11R11, S(0)R11, cyano, C2-C6-alkenyl, C2-C6-alkynyl, and NIR111R12; R13 is independently at each occurrence selected from: =0, =S, 0105-haloalkyl, C3-C6-cycloalkyl, halogen, nitro, OR13, SR11, S(0)2R11, C(0)R11, C(0)0R11, C(0)NR11R11, S(0)2N1R111R11, S(0)R11, cyano, C2-06-alkenyl, C2-06-alkynyl, and NR111R12; R12 is independently at each occurrence selected from; H, C(0)-R123 and S(0)2-R, R128 being independently at each occurrence selected from Ci-Cs-alkyl, 03-08-cycloalkyl, phenyl, or benzyl; or where an Ril group and an R12 group are attached to the same nitrogen atom, said Ril and R12 groups, together with said nitrogen atom, form a 4-, 5-, 6-or 7-membered heterocycloalkyl ring; R13 is independently at each occurrence selected from: H, C3-C6-cycloalkyl, C1-C6-alkyl and Ci-Cs-haloalkyl; 514 is independently at each occurrence selected from: Cl-C4-alkylene-R14a; wherein 514a is independently at each occurrence selected from -NR11R12, CN, -0S(0)20R11, SR, C(=0)0R11, C(=0)NR11Rn; R18 is independently at each occurrence selected from: H, Cs-Cs-cycloalkyl and Cl-C4-alkylene-R15a and C2-C4-alkylene-R1"; wherein R1' is independently at each occurrence selected from ON, C(=0)0R11, C(=0)NR11R11; and R1' is independently at each occurrence selected from -NR11R12, -0R13, -0S(0)20R11 and SR; wherein any aforementioned alkyl, alkylene, alkenyl, cycloalkyl, heterocycloalkyl (including where two R11 groups or an R11 group and an R12 group together with a nitrogen to which they are attached form a heterocycloalkyl ring), alkynyl, C(0)-alkyl, S(0)2-alkyl and benzyl is optionally substituted, where chemically possible, by 1 to 4 substituents which are each independently selected at each occurrence from the group consisting of: =0; =NRa, =NOR', Ci-C4-alkyl, halo, nitro, cyano, CrC4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, NIRaRb, S(0)2R3, S(0)Ra, S(0)(NRa)Ra, S(0)2NR'R8, CO2Ra, C(0)R8, CONRaRa, OR' and SRa; wherein R8 is independently at each occurrence selected from H and Ci-C4-alkyl; and Rb is independently at each occurrence selected from H, C(0)-C1-C4-alkyl and S(0)2-0-C4-alkyl.
  2. 2. The compound of claim 1, wherein R2 is phenyl, or 5-or 6-membered heteroaryl, wherein R2 is substituted with a single R8 group, and wherein R2 is optionally further substituted with 1 or 2 R9 groups.
  3. 3. The compound of claim 1 or claim 2, wherein R2 is phenyl, pyridyl, pyrimidyl or pyrazole.
  4. 4. The compound of any of claims 1 to 3, wherein R2 is phenyl.
  5. 5. The compound of any of claims 1 to 4, wherein R8 is selected from -N(1511)S(0)2R14, and -C(0)NR11R15 and C0.6 alkylene-Rea, and R9 is absent; or wherein 155 is H and R2 is substituted with 1 R9 group, wherein R9 is independently selected at each occurrence from Ci-C6-alkyl, C(0)N511n11, and N511 512.
  6. 6. The compound of claim 5, wherein R1 is C1-6 alkyl.
  7. 7. The compound of claim 4, wherein 155 is H and R9 is absent.
  8. 8. The compound of claim 7, wherein 51 is selected from methyl, -CH257, -20 CH2CH2R7 or -CH2CH2CH2R7.
  9. 9. The compound of any preceding claim, wherein -1_1-is absent and X is CR4.
  10. 10. The compound of any preceding claim, wherein R4 is selected from H, F, Cl, and Br.
  11. 11. The compound of claim 4 or claim 7, wherein -1_1-is absent and X is -N(R5)-.
  12. 12. The compound of claim 11, wherein 51 is absent and Rs is selected from H, methyl, -CH2R7, -CH2CH2R7 or -CH2CH2CH2R7; or R5 is absent and 51 is selected from H, methyl, -CH2R7, -CH2CH2R7 or -CH2CH2CH2R7.
  13. 13. The compound of any preceding claim, wherein R5 is -C(0)0H.
  14. 14. The compound of claim 1, wherein R2 is selected from 5-, 6-, 9-or 10-membered heteroaryl, and 5-, 6-, 7-or 8-membered heterocycloalkyl.
  15. 15. The compound of any of claims 1 to 13, wherein the compound is selected from the following compounds or pharmaceutically acceptable compounds thereof: 0=S=0 0=S=0 0=S=0 NH2 NH2 NH2 NH2NH NH20=S=0 0=S=0 NH2 C? -0 NHNH H2NOH0=S=0 0=8=0 NH2 NH2
  16. 16. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable excipients.
  17. 17. The compound of any of claims 1 to 15, or the composition of claim 16 for use in the inhibition of metallo-p-lactamase activity.
  18. 18. The compound of any of claims 1 to 15, or the composition of claim 16 for use in the treatment of a disease or disorder in which metallo-p-lactamase activity is implicated.
  19. 19. The compound of any of claims 1 to 15, or the composition of claim 16 for use in a method of treating a disease or disorder caused by aerobic or anaerobic Gram-positive, or aerobic or anaerobic Gram-negative bacteria.OH0=3=0 0=3=0 NH2 NH2 H2N-\\__\ H,N1 N_OH -N0=S=0 0=3=0 NH2 NH2 H2N
  20. 20. The compound or composition for use of any of claims 17 to 19, wherein the disease or disorder is caused by metallo-p-lactamase producing Gram-positive bacteria.
  21. 21. The compound or composition for use of any claims 17 to 20, wherein the disease or disorder is selected from: pneumonia, respiratory tract infections, urinary tract infections, intra-abdominal infections, skin and soft tissue infections, bloodstream infections, septicaemia, intra-and post-partum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis and febrile neutropenia, optionally wherein the disease or disorder is selected from: community acquired pneumonia, nosocomial pneumonia (hospital-acquired/ventilator-acquired), respiratory tract infections associated with cystic fibrosis, non-cystic fibrosis bronchiectasis, COPD, urinary tract infection, intraabdominal infections, skin and soft tissue infection, bacteraemia, septicaemia, intra-and post-partum infections, prosthetic joint infections, endocarditis, acute bacterial meningitis and febrile neutropenia.
  22. 22. A compound of any of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a composition of claim 16, for use in the treatment of a bacterial infection.
  23. 23. A compound of any of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a composition of claim 16, in combination with an antibacterial agent, for use in the treatment of a bacterial infection, optionally wherein the compound and the antibacterial agent are present in the same dosage forms
  24. 24. The compound or composition for use of claims 23, wherein the antibacterial agent is a carbapenem, and preferably the carbapenems is selected from the group comprising: meropenem, faropenem, imipenem, ertapenem, doripenem, panipenem/betamipron and biapenem, razupenem, tebipenem, lenapenem and tomopenem, optionally wherein the antibacterial agent is meropenem.
  25. 25. The compound or composition for use of any of claims 22 to 24, wherein the bacterial infection is caused by bacteria from one or more of the following families; Streptococcus, Acinetobacten Staphylococcus, Clostridioides, Pseudomonas, Escherichia, Salmonella, Klebsiella, Legionella, Neisseria, Enterococcus, Enterobacter, Serratia, Stenotrophomonas, Aeromonas, Mycobacterium, Morganella, Yersinia, Pasteurella, Haemophilus, Citrobacter, Burkholderia, Brucella, or Moraxella.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3793990A1 (en) * 2018-05-16 2021-03-24 Infex Therapeutics Limited Antibacterial compounds
EP3795149A1 (en) * 2018-05-14 2021-03-24 National University Corporation Tokai National Higher Education and Research System Inhibitor & x3b2;-lactamase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3795149A1 (en) * 2018-05-14 2021-03-24 National University Corporation Tokai National Higher Education and Research System Inhibitor & x3b2;-lactamase
EP3793990A1 (en) * 2018-05-16 2021-03-24 Infex Therapeutics Limited Antibacterial compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
mBio, Vol. 11, 2020, Wachino et al., "Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-Beta-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance", e03144-19. *

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