WO2022214519A1 - Composés antibactériens - Google Patents

Composés antibactériens Download PDF

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Publication number
WO2022214519A1
WO2022214519A1 PCT/EP2022/059062 EP2022059062W WO2022214519A1 WO 2022214519 A1 WO2022214519 A1 WO 2022214519A1 EP 2022059062 W EP2022059062 W EP 2022059062W WO 2022214519 A1 WO2022214519 A1 WO 2022214519A1
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compound
ring
mmol
alkyl
inhibitor
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PCT/EP2022/059062
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English (en)
Inventor
Jérôme Émile Georges GUILLEMONT
Magali Madeleine Simone Motte
Dirk Antonie LAMPRECHT
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Janssen Sciences Ireland Unlimited Company
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Publication of WO2022214519A1 publication Critical patent/WO2022214519A1/fr

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    • 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
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds.
  • the invention also relates to such compounds for use as a pharmaceutical and further for the use in the treatment of bacterial diseases, including diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis.
  • Such compounds may work by targeting the respiratory chain, and thereby blocking all energy production of mycobacteria.
  • There are several ways of targeting the electron transport chain of mycobacteria for instance by interfering with ATP synthase in M. tuberculosis.
  • This particular invention focuses on the cytochrome bd target of the respiratory chain, which may be the primary mode of action.
  • such compounds are antitubercular agents, and in particular may act as such when combined with another tuberculosis drug (e.g. another inhibitor of a different target of the electron transport chain).
  • Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infection with a world-wide distribution.
  • TB tuberculosis
  • Estimates from the World Health Organization indicate that more than 8 million people contract TB each year, and 2 million people die from tuberculosis yearly. In the last decade, TB cases have grown 20% worldwide with the highest burden in the most impoverished communities. If these trends continue, TB incidence will increase by 41% in the next twenty years. Fifty years since the introduction of an effective chemotherapy, TB remains after AIDS, the leading infectious cause of adult mortality in the world. Complicating the TB epidemic is the rising tide of multi-drug-resistant strains, and the deadly symbiosis with HIV. People who are HIV-positive and infected with TB are 30 times more likely to develop active TB than people who are HIV-negative and TB is responsible for the death of one out of every three people with HIV/AIDS worldwide.
  • MDR-TB multi-drug-resistant strains
  • MDR-TB multi-drug-resistant strains
  • MDR-TB multi-drug-resistant strains
  • isoniazid and rifampin the most effective drugs of the four-drug standard, isoniazid and rifampin.
  • MDR-TB is lethal when untreated and cannot be adequately treated through the standard therapy, so treatment requires up to 2 years of "second-line" drags. These drugs are often toxic, expensive and marginally effective.
  • infectious MDR-TB patients continue to spread the disease, producing new infections with MDR-TB strains.
  • There is a high medical need for a new drag with a new mechanism of action which is likely to demonstrate activity against drag resistant, in particular MDR strains.
  • a drag resistant Mycobacterium is a Mycobacterium which is no longer susceptible to at least one previously effective drag; which has developed the ability to withstand antibiotic attack by at least one previously effective drug.
  • a drug resistant strain may relay that ability to withstand to its progeny. Said resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs.
  • MDR tuberculosis is a specific form of drug resistant tuberculosis due to a bacterium resistant to at least isoniazid and rifampicin (with or without resistance to other drugs), which are at present the two most powerful anti-TB drugs.
  • drag resistant includes multi drug resistant.
  • Another factor in the control of the TB epidemic is the problem of latent TB.
  • tuberculosis (TB) control programs about 2 billion people are infected by M. tuberculosis, though asymptomatically. About 10% of these individuals are at risk of developing active TB during their lifespan.
  • the global epidemic of TB is fuelled by infection of HIV patients with TB and rise of multi-drug resistant TB strains (MDR-TB).
  • MDR-TB multi-drug resistant TB strains
  • the reactivation of latent TB is a high risk factor for disease development and accounts for 32% deaths in HIV infected individuals.
  • To control TB epidemic the need is to discover new drugs that can kill dormant or latent bacilli.
  • the dormant TB can get reactivated to cause disease by several factors like suppression of host immunity by use of immunosuppressive agents like antibodies against tumor necrosis factor a or interferon-g.
  • immunosuppressive agents like antibodies against tumor necrosis factor a or interferon-g.
  • the only prophylactic treatment available for latent TB is two- three months regimens of rifampicin, pyrazinamide.
  • the tubercle bacilli enter healthy individuals by inhalation; they are phagocytosed by the alveolar macrophages of the lungs. This leads to potent immune response and formation of granulomas, which consist of macrophages infected with M. tuberculosis surrounded by T cells. After a period of 6-8 weeks the host immune response cause death of infected cells by necrosis and accumulation of caseous material with certain extracellular bacilli, surrounded by macrophages, epitheloid cells and layers of lymphoid tissue at the periphery.
  • Self-medication with antimicrobials is another major factor contributing to resistance.
  • Self-medicated antimicrobials may be unnecessary, are often inadequately dosed, or may not contain adequate amounts of active drug.
  • Patient compliance with recommended treatment is another major problem. Patients forget to take medication, interrupt their treatment when they begin to feel better, or may be unable to afford a full course, thereby creating an ideal environment for microbes to adapt rather than be killed.
  • M. tuberculosis is dependent on respiration to synthesise adequate amounts of ATP.
  • targeting the electron transport chain of the mycobacteria and thereby blocking energy production of mycobacteria is thought to be a potentially effective way of providing an efficient regimen against mycobacteria.
  • ATP synthase inhibitors as example of which is bedaquiline (marketed as Sirturo®)
  • cytochrome be inhibitors examples of which include the compound Q203 described in Journal article Nature Medicine, 19, 1157-1160 (2013) by Pethe et al “Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis”, as well as patent applications such as internataional patent applcations WO 2017/001660, WO 2017/001661, WO 2017/216281 and WO 2017/216283.
  • journal article Antimicrob. Agents Chemother, 2014, 6962-6965 by Arora et al describes compounds that target the respiratory bci complex in M. tuberculosis, and where deletion of the cytochrome bd oxidase generated a hypersusceptible mutant.
  • Journal article PANS (Early Edition), 2017, “Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection” by Kalia et al discloses various data around various tuberculosis compounds that target the respiratory chain.
  • Cytochrome bd itself is not essential for aerobic growth, but is upregulated and protects against a variety of stresses in various bacterial strains, for example as described in journal article Biochimica et Biophysica Acta 1837 (2014)
  • the compound CK-2-63 is described as a cytochrome bd inhibitor showing various inhibitor activity data, and combination data is also disclosed including combination of CK-2-63 with a mycobacterium cytochrome bcc inhibitor (e.g. AWE-402, where it is indicated therein that it is structurally related to the cytochrome bcc inhibitor Q203). It is indicated that such dual combination led to in increase in mycobacteria kill. It also described a combination of bedaquiline (a known ATP synthase inhibitor) with CK-2-63, and it is indicated that CK-2-63 showed an enhancement of bedaquiline activity at low concentrations. Data around a triple combination of bedaquiline, AWE-402 (a be inhibitor; see above) and CK-2-63 is also shown.
  • a mycobacterium cytochrome bcc inhibitor e.g. AWE-402
  • This particular invention focuses on novel compounds of the cytochrome bd target of the respiratory chain. New alternative/improved compounds are required, which may be tested/employed for use in combination.
  • R 1 represents C 1 - 6 alkyl, -Br, hydrogen or -C(0)N(R ql )R q2 ;
  • R ql and R q2 independently represent hydrogen or C 1 - 6 alkyl, or may be linked together to form a 3-6 membered carbocylic ring optionally substituted by one or more C1-3 alkyl substituents;
  • Sub represents one or more optional substituents selected from halo (e.g. fluoro), -CN, C 1 - 6 alkyl and -O-Ci alkyl (wherein the latter two alkyl moieties are optionally substituted by one or more fluoro atoms);
  • the “A” ring represents a 6-membered ring which may be aromatic or non-aromatic, or it represents a 5-membered aromatic ring containing one heteroatom (e.g. a sulfur heteroatom);
  • the “B” ring represents a 5-membered heteroaryl ring, which contains between one and four heteroatoms (e.g. selected from nitrogen, oxygen and sulfur), and which “B” ring is optionally substituted by one or more substituents selected from halo and C 1 - 6 alkyl (itself optionally substituted by one or more fluoro atoms);
  • L 1 represents an optional linker group, and hence may be a direct bond, -O- or -C(R xl )(R x2 )-;
  • R xl and R x2 independently represent hydrogen or C1-3 alkyl
  • Z 1 represents any one of the following moieties: (i) ring C represents a 5-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom), and which ring is optionally substituted by one or more substituents independently selected from R f ; ring D represents a 6-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom), and which ring is optionally substituted by one or more substituents independently selected from R g ; Y b represents -[(CH 2 ) I -4 ]- (so forming a 3- to 6-membered N-containing ring), and R h represents one or more optional substituents on such ring;
  • R a , R b , R c , R d and R e independently represent hydrogen or a substituent selected from B 1 ; each R f , each R g and each R h (which are optional substituents), when present, independently represent a substituent selected from B 1 ; each B 1 independently represents a substituent selected from:
  • R el , R e2 , R e3 , R e4 and R e5 each independently represent hydrogen or C 1 - 6 alkyl optionally substituted by one or more fluoro atoms; or a pharmaceutic ally-acceptable salt thereof, which compounds may be referred to herein as “compounds of the invention”.
  • Pharmaceutically-aceeptable salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form.
  • These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxy acetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
  • prodrug of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).
  • parenteral administration includes all forms of administration other than oral administration.
  • Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrag is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent.
  • Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases.
  • General information on prodrugs may be found e.g. in Bundegaard, H. “Design of Prodrugs” p. 1-92, Elesevier, New York-Oxford (1985).
  • Compounds of the invention may contain double bonds and may thus exist as E (ent ought) and Z ( Milton ) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g.
  • a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).
  • Compounds of the invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention.
  • the term "tautomer” or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations.
  • Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e.
  • a resolution for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
  • stereoisomers including but not limited to diastereoisomers, enantiomers and atropisomers
  • mixtures thereof e.g. racemic mixtures
  • stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, ⁇ , n C, 13 C, 14 C , 13 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 1S F, 36 C1, l23 I, and 125 I.
  • Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 14 C
  • Tritiated (3 ⁇ 4) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability.
  • isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the description/Examples hereinbelow, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Ci- q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C3- q -cycloalkyl group).
  • Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic.
  • Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a Ci- q alkenyl or a C2- q alkynyl group).
  • C_3- q cycloalkyl groups may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups).
  • Such cycloalkyl groups may be saturated or unsaturated containing one or more double bonds (forming for example a cycloalkenyl group).
  • Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic.
  • halo when used herein, preferably includes fluoro, chloro, bromo and iodo.
  • Heterocyclic groups when referred to herein may include aromatic or non-aromatic heterocyclic groups, and hence encompass heterocycloalkyl and hetereoaryl.
  • aromatic or non-aromatic 5- or 6-membered rings may be heterocyclic groups (as well as carbocyclic groups) that have 5- or 6-members in the ring.
  • Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between 3 and 20 (e.g. between three and ten, e.g between 3 and 8, such as 5- to 8-). Such heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a Ci- q heterocycloalkenyl (where q is the upper limit of the range) group.
  • a Ci- q heterocycloalkenyl where q is the upper limit of the range
  • Ci- q heterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2. ljheptanyl, 6-azabicyclo[3.1.1]heptanyl, 6- azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.
  • heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heterocycloalkyl groups may also be in the N- or S- oxidised form.
  • Heterocycloalkyl mentioned herein may be stated to be specifically monocyclic or bicyclic.
  • Aromatic groups may be aryl or heteroaryl.
  • Aryl groups that may be mentioned include C6 ⁇ 20, such as Ce-ii (e.g. C6-10) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 12 (e.g. 6 and 10) ring carbon atoms, in which at least one ring is aromatic.
  • C6-10 aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl.
  • the point of attachment of aryl groups may be via any atom of the ring system. For example, when the aryl group is polycyclic the point of attachment may be via atom including an atom of a non-aromatic ring.
  • aryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring. Most preferred aryl groups that may be mentioned herein are “phenyl”. Unless otherwise specified, the term “heteroaryl” when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which have between 5 and 20 members (e.g.
  • heteroaryl group may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group).
  • the heteroaryl group is polycyclic the point of attachment may be via any atom including an atom of a non-aromatic ring.
  • heteroaryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molecule via an aromatic ring.
  • Heteroaryl groups that may be mentioned include 3,4-dihydro- 1/f-isoquinolinyl, 1 ,3-dihydroisoindolyl, 1 ,3-dihydroisoindolyl (e.g. 3,4-dihydro-l//-isoquinolin-2-yl, l,3-dihydroisoindol-2-yl,
  • oxadiazolyl including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl
  • oxazolyl phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1 ,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetra- hydroisoquinolinyl), tetrahydroquinolinyl
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heteroaryl groups may also be in the N- or S- oxidised form.
  • Most preferred heteroaryl groups that may be mentioned herein are 5- or 6- membered aromatic groups containing 1 , 2 or 3 heteroatoms (e.g. preferably selected from nitrogen, oxygen and sulfur).
  • the heteroaryl group is monocyclic or bicyclic.
  • the heteroaryl may consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).
  • Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.
  • aromatic groups When “aromatic” groups are referred to herein, they may be aryl or heteroaryl.
  • aromatic linker groups When “aromatic linker groups” are referred to herein, they may be aryl or heteroaryl, as defined herein, are preferably monocyclic (but may be polycyclic) and attached to the remainder of the molecule via any possible atoms of that linker group. However, when, specifically carbocyclic aromatic linker groups are referred to, then such aromatic groups may not contain a heteroatom, i.e. they may be aryl (but not heteroaryl). For the avoidance of doubt, where it is stated herein that a group may be substituted by one or more substituents (e.g.
  • substituents are independent of one another. That is, such groups may be substituted with the same substituent (e.g. same alkyl substituent) or different (e.g. alkyl) substituents.
  • compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.
  • R 1 represents hydrogen or C 1.3 alkyl.
  • Preferred compounds of the invention include those in which R 1 represents C1-3 alkyl such as methyl or ethyl.
  • R 1 represents methyl.
  • Sub is either not present or represents a halo (e.g. fluoro) atom.
  • Compounds of the invention may have a non-aromatic 6-membered A ring such as in formula la:
  • compounds of the invention may have an aromatic 6-membered A ring such as in formula lb:
  • Compounds of the invention may have an aromatic 5-membered ring in which X x represents a heteroatom such as nitrogen, oxygen or sulfur (and in an embodiment represents sulfur), such as in formula Ic.
  • the “A” ring is unsubstituted or substituted with one fluoro atom. In an embodiment, the “A” ring is a 6-membered aromatic or non-aromatic ring.
  • Preferred compounds of the invention include those in which the “B” ring contain at least one nitrogen atom (in an embodiment, at the ring junction); and/or contains one, two, three or four heteroatoms in total.
  • compounds of the invention are those in which the “B” ring and adjacent 6 membered non-aromatic ring are represented by a sub-formula (II) as defined hereinbelow (where it will be appreciated that the rules of valency will be adhered to, e.g. where C is mentioned then it may need to have a H attached to it), in which: one of X 1 and X 2 represents N (i.e. there is an essential nitrogen at the ring junction) and the other represents C; the other integers X 3 , X 4 and X 5 may represent C (or CH) or a heteroatom (such as N,
  • any one or two of X 3 , X 4 and X 3 represents a heteroatom (e.g. N, O and/or S; and, in an embodiment, N) and the other(s) represents C (or CH).
  • preferred compounds of the invention include those in which: one of X 1 and X 2 represents N; and none, one or two of X 3 , X 4 and X 5 represents N.
  • the “B” ring and adjacent 6 membered non-aromatic ring in compounds of the invention may be depicted as follows in sub formula (II) (in which the left hand side would be further bound to the requisite quinolinone, or tetrahydro-quinolinone, of formula (I) and the right hand side would be further bound to the L 1 group of formula wherein: one of X 1 and X 2 represents N (i.e. there is an essential nitrogen at the ring junction) and the other represents C; the other integers X 3 , X 4 and X 3 may represent C (or CH) or a heteroatom (such as N,
  • any one or two of X 3 , X 4 and X 5 represents a heteroatom (e.g. N, O and/or S) and the other represents C (or CH), and in which in all of the cases above, it will be understood that the rules of valency will need to be adhered to.
  • preferred compounds of the invention include those in which in the sub-formula (II) depicted above:
  • X 1 , X 3 and X 5 represent a heteroatom (e.g. nitrogen) and X 2 and X 4 represent C (or CH).
  • preferred compounds of the invention include those in which in the sub-formula (II) depicted above:
  • X 2 , X 3 and X 5 represent a heteroatom (e.g. nitrogen) and X 1 and X 4 represent C (or CH).
  • sub-formula (II) represents:
  • the “B” ring and adjacent 6 membered non-aromatic ring in compounds of the invention may be depicted as follows, (in which the left hand side would be further bound to the requisite quinolinone, or tetrahydro-quinolinone, of formula (I) and the right hand side would be further bound to the L 1 group of formula (I)):
  • preferred compounds of the invention include those in which in the sub-formula (II) depicted above: X 2 and X 3 represent a heteroatom (e.g. nitrogen) and X 1 , X 4 and X 5 represent C (or CH).
  • X 2 and X 3 represent a heteroatom (e.g. nitrogen) and X 1 , X 4 and X 5 represent C (or CH).
  • the “B” ring and adjacent 6 membered non-aromatic ring in compounds of the invention may be depicted as follows, (in which the left hand side would be further bound to the requisite quinolinone, or tetrahydro-quinolinone, of formula (I) and the right hand side would be further bound to the L 1 group of formula
  • L 1 represents a direct bond or -C(R xl )(R x2 )-;
  • R xl and R x2 independently represent hydrogen for example:
  • L 1 may specifically represent a direct bond, -O- or -CH2- (or, in a more specific embodiment, a direct bond or -CH 2 -; especially a direct bond).
  • L 1 represents a direct bond
  • Z 1 represents:
  • Z 1 represents (i), (ii), (iii) or (iv) (e.g. Z 1 represents (i) or (ii)).
  • Z 1 represents an aromatic ring (i.e. (i), (ii), (iii) or (iv) above), for instance (i) or (ii).
  • Z 1 represents (iv), i.e. a cyclic amino group, then L 1 represenst a direct bond or -CH 2 - (but cannot represent -O-).
  • Z 1 in a specific embodiment represents a 5- or 6-membered ring (pyrrolinyl or piperidinyl; i.e. Y b represents — [(CH 2 )3-4]-), which is optionally substituted by one or more (e.g. one) R h substituent (and R h represents a B 1 susbtituent, and is, in an embodiment, C1-3 alkyl optionally substituted by one or more fluoro atoms).
  • compounds of the invention include those in which when ring C is present, it represents a 5-membered aromatic ring, it contains one, two or three heteroatoms preferably selected from nitrogen, oxygen and sulfur; in a further embodiment, such ring is optionally substituted by one or two substituents independently selected from R f ; when ring D is present, it represents a 6-membered aromatic ring containing one nitrogen atom; and, in a further embodiment, such ring is optionally substituted by one or two substituents independently selected from R g ;
  • R a , R b , R c , R d and R e independently represent hydrogen or a substituent selected from B 1 ;
  • R f and R g each independently represent a substituent selected from B 1 .
  • such aromatic 5-membered (optionally substituted) ring may: (i) contain one sulfur atom (so forming a thienyl); (ii) contain one nitrogen and one sulfur atom (so forming e.g. thiazolyl); (iii) contain two nitrogen atoms (so forming e.g. a pyrazolyl); (iv) contains two nitrogen atoms and one sulfur atom; (v) contains two nitrogen atoms and one oxygen atom; (vi) contains three nitrogen atoms.
  • Ring D is present (i.e. Z 1 represents (iii)
  • such aromatic 6-membered ring may contain one nitrogen atom, so forming a pyridyl group (e.g. a 3- pyridyl group).
  • further preferred compounds of the inventions include those in which: none, but preferably, one or two (e.g. one) of R a , R b , R c , R d and R e represents B 1 and the others represent hydrogen; and/or one or two (e.g. one) of R b .
  • R c and R d (preferably R c ) represents B 1 and the others represent hydrogen.
  • preferred compounds of the inventions include those in which: R b and one of R c or R d represent B 1 and the others represent hydrogen.
  • preferred compounds of the inventions include those in which: R b and R e represent B 1 and the others represent hydrogen.
  • preferred compounds of the inventions include those in which: R b and R d represent B 1 and the others represent hydrogen.
  • preferred compounds of the inventions include those in which: R b represent B 1 and the others represent hydrogen.
  • preferred compounds of the inventions include those in which: R c represent B 1 and the others represent hydrogen.
  • R e2 and R e4 independently represent hydrogen
  • R el , R e3 and R c:! each independently represent C 1.3 alkyl (e.g. methyl) substituted by one or more fluoro atoms.
  • yet further preferred compounds of the inventions include those in which:
  • B 1 represents a substituent selected from:
  • Ci -6 alkyl preferably C 1-3 alkyl, substituted by one or more fluoro atom; (iii) -OR el .
  • B 1 represents a substituent selected from halo (e.g. fluoro), C 1-3 alkyl (optionally substituted by one or more fluoro atom) and -OR el (in which R ei represents C 1-3 alkyl optionally substituted by one or more fluoro atom, so forming e.g. -OCH 3 or-OCFs).
  • B 1 is selected from fluoro, -CH 3, -0CH 3 , -CF 3 , -CHF2, -CH 2 CF3, -CH 2 CHF2, -CH 2 CH 2 CF 3 and -OCF3.
  • B 1 is selected from fluoro, -CH 3 , -CF 3 , -OCH 3 and -OCF3.
  • Z 1 represents:
  • ring C represents a 5-membered aromatic ring containing at least two heteroatoms, wherein at least one of said heteroatom is a nitrogen atom, and which ring is substituted by one or more substituents independently selected from R f ; one or two (e.g. one) of R b R c and R d (preferably R c ) represents B 1 and the others represent hydrogen;
  • R 1 and R h independently represent hydrogen or a substituent selected from B 1 ; each B 1 independently represents a substituent selected from:
  • R dl represents C 1 - 6 alkyl, preferably C 1-3 alkyl, optionally substituted by one or more fluoro atoms; and/or R el represent hydrogen or C 1 - 6 alkyl optionally substituted by one or more fluoro atoms.
  • the compounds according to the invention have surprisingly been shown to be suitable for the treatment of a bacterial infection including a mycobacterial infection, particularly those diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis (including the latent and drug resistant form thereof).
  • the present invention thus also relates to compounds of the invention as defined hereinabove, for use as a medicine, in particular for use as a medicine for the treatment of a bacterial infection including a mycobacterial infection.
  • Such compounds of the invention may act by interfering with ATP synthase in M. tuberculosis, with the inhibition of cytochrome bd activity being the primary mode of action.
  • cytochrome bd inhibition may have an effect in killing mycobacteria (and hence having an anti-tuberculosis effect directly).
  • cytochrome bd is not necessarily essential for aerobic growth, it may have the most pronounced effect in combination with another inhibitor of a target of the electron transport chain of mycobacteria.
  • Such compounds may be tested for cytochrome bd activity by testing in an enzymatic assay, and may also be tested for activity in the treatment of a bacterial infection (e.g.
  • mycobacterial infection by testing the kill kinetics, for example of such compounds alone or in combination (as mentioned herein, e.g. with one or more other inhibitor(s) of a (different) target of the electron transport chain of mycobacteria; such other different targets may be more implicated in aerobic growth).
  • Cytochrome bd is a component of the electron transport chain, and therefore may be implicated with ATP synthesis, for instance alone or especially with one or more other inhibitor(s) of a target of the electron transport chain of mycobacteria.
  • the present invention also relates to the use of a compound of the invention, as well as any of the pharmaceutical compositions thereof as described hereinafter for the manufacture of a medicament for the treatment of a bacterial infection including a mycobacterial infection (for instance when such compound of the invention is used in combination with another inhibitor of a target of the electron transport chain of mycobacteria).
  • the invention provides a method of treating a patient suffering from, or at risk of, a bacterial infection, including a mycobacterial infection, which comprises administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to the invention (for instance a therapeutically effective amount of a compound or pharmaceutical composition of the invention, in combination with one or more other inhibitor(s) of a target of the electron transport chain of mycobacteria).
  • the compounds of the present invention also show activity against resistant bacterial strains (for instance alone or in combination with another inhibitor of a target of the electron transport chain of mycobacteria).
  • the compounds can treat a bacterial infection (alone or in combination) it is meant that the compounds can treat an infection with one or more bacterial strains.
  • the invention also relates to a composition
  • a composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to the invention.
  • the compounds according to the invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the active ingredient(s), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • the pharmaceutical composition may additionally contain various other ingredients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
  • a lubricant for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • the daily dosage of the compound according to the invention will, of course, vary with the compound employed, the mode of administration, the treatment desired and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compound according to the invention is administered at a daily dosage not exceeding 1 gram, e.g. in the range from 10 to 50 mg/kg body weight.
  • the present compounds may be combined with other antibacterial agents in order to effectively combat bacterial infections.
  • compounds may be useful against bacterial infections, we mean that those compounds may have activity as such or those compounds may be effective in combination (as described herein, e.g. with one or more other inhibitors of the electron transport chain of mycobacteria) by enhancing activity or providing synergistic combinations, for example as may be described in the experimental hereinafter.
  • the present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents (e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenCi inhibitor).
  • one or more other antibacterial agents e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenCi inhibitor.
  • the present invention also relates to such a compound or combination, for use as a medicine.
  • the present invention also relates to the use of a combination or pharmaceutical composition as defined directly above for the treatment of a bacterial infection.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of (a) a compound according to the invention, and (b) one or more other antibacterial agents (e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor), is also comprised by the present invention.
  • one or more other antibacterial agents e.g. one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor
  • the weight ratio of (a) the compound according to the invention and (b) the other antibacterial agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other antibacterial agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • a particular weight ratio for the present compound of the invention and another antibacterial agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.
  • the compounds according to the invention and the one or more other antibacterial agents may be combined in a single preparation or they may be formulated in separate preparations so that they can be administered simultaneously, separately or sequentially.
  • the present invention also relates to a product containing (a) a compound according to the invention, and (b) one or more other antibacterial agents (e.g.
  • one or more other inhibitors of the electron transport chain of mycobacteria for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor), as a combined preparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.
  • a cytochrome be inhibitor for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor
  • antibacterial agents which may be combined with the compounds of the invention are for example antibacterial agents known in the art.
  • the compounds of the invention may be combined with antibacterial agents known to interfere with the respiratory chain of Mycobacterium tuberculosis, including for example direct inhibitors of the ATP synthase (e.g. bedaquiline, bedaquiline fumarate or any other compounds that may have be disclosed in the prior art, e.g. compounds disclosed in W02004/011436), inhibitors of ndh2 (e.g. clofazimine) and inhibitors of cytochrome bd.
  • direct inhibitors of the ATP synthase e.g. bedaquiline, bedaquiline fumarate or any other compounds that may have be disclosed in the prior art, e.g. compounds disclosed in W02004/011436
  • inhibitors of ndh2 e.g. clofazimine
  • inhibitors of cytochrome bd e.g. cytochrome bd.
  • compounds of the invention may be combined with one or more other inhibitors of the electron transport chain of mycobacteria, for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor.
  • a cytochrome be inhibitor for instance a cytochrome be inhibitor, an ATP synthase inhibitor, a NDH2 inhibitor and/or an inhibitor of the menaquinone synthesis pathway, such as a MenG inhibitor.
  • the compounds of the invention might act as cytochrome bd inhibitors, and hence target the electron transport chain of the mycobacteria (thereby blocking energy production of mycobacteria), the compounds of the invention (cytochrome bd inhibitors), combinations with one or more other inhibitors of the electron transport chain is thought to be a potentially effective way of providing an efficient regimen against mycobacteria. Even if the compounds of the invention (cytochrome bd inhibitors) alone might not be effective against mycobacteria, combining with one or more other such inhibitors may provide an effective regimen where the activity of one or more components of the combination is/are enhanced and/or such combinations act more effectively (e.g. synergistically).
  • the compounds according to the invention can generally be prepared by a succession of steps, each of which may be known to the skilled person or described herein.
  • reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as preparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be obtained by Supercritical Fluid Chromatography (SCF).
  • SCF Supercritical Fluid Chromatography
  • the starting materials and the intermediates are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.
  • reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art, such as extraction, crystallization and chromatography. It is further evident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular preparative chromatography, such as preparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be obtained by Supercritical Fluid Chromatography (SCF).
  • SCF Supercritical Fluid Chromatography
  • the starting materials and the intermediates are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.
  • compound AB-2 was prepared in the same way as compound AB-1 starting from AA-3 (0.452 mmol) and 4-Trifluoromethoxyphenylboronic acid (CAS [139301-27-2], 0.542 mmol), to give 0.106 g (54%) as a white solid.
  • compound AB-3 was prepared in the same way as compound AB-1 starting from AA-3 (0.845 mmol) and 3,4-difluorophenylboronic acid (CAS [168267- 41-2], 1.35 mmol) to give a beige solid, 0.093 g (28%).
  • compound AB-4 was prepared in the same way as compound AB-1 starting from AA-3 (1.41 mmol) and 4-methoxybenzeneboronic acid (CAS [5720-07- 0], 2.11 mmol) to give a pale beige powder, 0.528 g (98%).
  • compound AB-5 was prepared in the same way as compound AB-1 starting from AA-3 (1.41 mmol) and 3-fluoro-5-methylphenylboronic acid (CAS [850593-06-5], 2.11 mmol) to give a pale beige powder, 0.528 g (98%).
  • compound AB-6 was prepared in the same way as compound AB-1 starting from AA-3 (1.18 mmol) and 3-Fluoro-4-methylbenzeneboronic acid (CAS [168267-99-0], 1.77 mmol) to give a pale beige powder, 0.292 g (64%).
  • compound AB-7 was prepared in the same way as compound AB-1 starting from AA-3 (1.18 mmol) and 3-Fluoro-5-methoxyphenylboronic acid (CAS [609807-25-2], 1.77 mmol) to give a pale beige powder, 0.34 g (72%).
  • CAS [609807-25-2] 1.77 mmol
  • compound AB-8 was prepared in the same way as compound AB- 1 starting from AA-3 (1.18 mmol) and 3,5-dimethoxybenzeneboronic acid (CAS [192182-54-0], 2.11 mmol) to give a pale beige powder, 0.5 g (86%).
  • compound AB-9 was prepared in the same way as compound AB-1 starting from AA-3 (1.18 mmol) and 3-Fluoro-5-(trifluoromethyl)benzene boronic acid (CAS [159020-59-4], 1.77 mmol) to give a pale beige powder, 0.32 g (62%).
  • compound AB-10 was prepared in the same way as compound AB-1 starting from AA-3 (0.84 mmol) and 3-(Trifluoromethoxy)-benzeneboronic acid (CAS [179113-90-7], 1.27 mmol) to give a pale beige powder, 0.325 g (88%).
  • compound AB-11 was prepared in the same way as compound AB-1 starting from AA-3 (1.35 mmol) and [3-(2,2,2)-trifluoroethyl)phenyl]boronic acid (CAS [1620056-82-7], 2.03 mmol) to give a pale beige powder, 0.538 g (91%).
  • compound AB-12 was prepared in the same way as compound AB-1 starting from AA-3 (1.35 mmol) and 4-Fluoro-3-methoxybenzeneboronie acid (CAS [854778-31-7], 2.03 mmol) to give a pale beige powder, 0.16 g (29%).
  • FT was solubilized with Acetonitrile (2 mL) and extended with water (8 mL), the solution was freeze-dried overnight giving compound 57 as white foam, 0.022 g (5%).
  • reaction mixture was cooled to room temperature, diluted with water (25 mL), filtered through a glass frit to collect after rinsing with water (3 x 5 mL) a black solid. This was purified by flash chromatography on silica gel (25 g), DCM/Methanol 100/0 to 98/2 over 50 min) to afford an off-white solid. The solid was triturated with methanol (3 x 2 mL) and dried under high vacuum at 50°C (for 18 h) to afford AC-3 as a white solid, 0.107 g (50%).
  • Compound 7 was purified via chiral SFC (Stationary phase: CHIRALPAK AD-H 5 ⁇ m 250*30mm, Mobile phase: 60% CO2, 40% MeOH) affording 185 mg of compound 16 5 as white powder (41%) and 163 mg of compound 17 as white powder (36%).
  • the precipitate was filtered on a glass frit, washed with water and purified by flash chromatography over silica gel (cyclohexane/EtOAc from 100:0 to 0: 100) to afford AH-4 as a white solid (60 mg, 34%).
  • intermediate AE-3 (464 mg, 1.31 mmol), THF (4.5 mL) and water (4.5 mL) was added LiOH.H2O (110 mg, 2.62 mmol). The resulting mixture was stirred at room temperature for 6 h and then acidified with 1 M HC1 aqueous solution until pH- 1-2. The resulting precipitate was collected by filtration on a glass frit and washed with water, then dissolved in a CH2C12/MeOH mixture (9: 1), dried over Na 2 SO 4 , filtered and concentrated to dryness to afford intermediate AE-4 as a white solid (394 mg, 92%).
  • Trifluoromethoxyphenylboronic acid (CAS [139301-27-2], 1.81 g, 8,79 mmol) and 5 Potassium phosphatetribasic monohydrate (5.06 g, 22.0 mmol) in 1,4-dioxane (29.6 mL) and water (7.4 mL) was purged with nitrogen, 1,1'-
  • reaction mixture was cooled to room temperature and filtered on celite® and washed with a DCM/EtOH mixture (9: 1, 200 mL) to afford a yellow oil, 0.29 g. It was purified by flash chromatography over silica gel (DCM/MeOH from 100/0 to 95/5 over 40 min.). The desired fractions were concentrated under reduced pressure and the resulting solids were vacuum-dried at 60 °C for 20 h to afford compound 32 (0.084 g, 33%) as a yellow solid and compound 34 (0.044 g, 17%) as a yellowish solid.
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • SQL Single Quadrupole Detector
  • RT room temperature
  • BEH bridged ethylsiloxane/silica hybrid
  • HSS High Strength Silica
  • DAD Diode Array Detector
  • Melting points were determined by DSC on a Mettler-Toledo DSC1 instrument (using aluminum standard 40 pL pans with air as purge gas and a thermal gradient between - 10 °C and 350 °C) or on a melting point apparatus Buchi M-560, both applying indicated heating rates.
  • individual compounds of the invention/examples (or combinations containing such compounds, for instance cytochrome bd inhibitors of the invention/examples in combination with one or more other inhibitor(s) of a (different) target of the electron transport chain of mycobacteria, as described herein) may be tested.
  • combinations may be tested (e.g. combinations of test cytochrome bd compounds with known cytochrome be inhibitors, such as Q203 and Compound X).
  • CK- 2-63 is employed.
  • the compound Q203 (cytochrome bcl inhibitor) may be prepared in accordance with the procedures in J. Medicinal Chemistry, 2014, 57 (12), pp 5293-5305, as well as, in WO 2011/113606 (see Compound 289 “6-chloro-2-ethyl-/V-(4-(4-(4- (trifluoromethoxy)phenyl)piperidin-l-yl)benzyl)imidazo[l,2-a]pyridine-3- carboxamide”).
  • Compound X is 6-chloro-2-ethyl-/V-( ⁇ 4-[2-(trifluoromethanesulfonyl)-2- azaspiro[3.3]heptan-6-yl]phenyl ⁇ methyl)imidazo[ 1 ,2-a]pyridine-3-carboxamide, which is described as Compound 154 of WO 2017/001660 and may be prepared according to the procedures described therein.
  • CK-2-63 may be prepared in accordance with the procedures disclosed in WO 2017/103615 (see experimental and the disclosures therein, referring to WO 2012/2069856, where an experimental procedure is provided for “3-methyl-2-(4-(4- (trifluoromethoxy)phenoxy)phenyl)quinolin-4(lH)-one”).
  • Test compounds and reference compounds were dissolved in DMSO and 1 m ⁇ of solution was spotted per well in 96 well plates at 200x the final concentration. Column 1 and column 12 were left compound-free, and from column 2 to 11 compound concentration was diluted 3-fold. Frozen stocks of Mycobacterium tuberculosis strain EH4.0 expressing green-fluorescent protein (GFP) were previously prepared and titrated. To prepare the inoculum, 1 vial of frozen bacterial stock was thawed to room temperature and diluted to 5x10 exp5 colony forming units per ml in 7H9 broth. 200 m ⁇ of inoculum, which corresponds to 1x10 exp5 colony forming units, were transferred per well to the whole plate, except column 12.
  • GFP green-fluorescent protein
  • fluorescence was measured on a Gemini EM Microplate Reader with 543 excitation and 590 nm emission wavelengths and MIC50 and/or pICso values (or the like, e.g. IC50, IC90, rK3 ⁇ 4o, etc) were (or may be) calculated.
  • Time kill kinetics assays test 3 Bactericidal or bacteriostatic activity of the compounds can be determined in a time kill kinetic assay using the broth dilution method.
  • the starting inoculum of M. tuberculosis (strain H37Rv and H37Ra) is 10 6 CFU / ml in Middlebrook (lx) 7H9 broth.
  • the test compounds (cyt bd inhibitors) are tested in combination with a cyt be inhibitor (for example Q203 or Compound X) at the concentration ranging from 10- 30mM to 0.9-0.3mM respectively. Tubes receiving no antibacterial agent constitute the culture growth control.
  • the tubes containing the microorganism and the test compounds are incubated at 37 °C. After 0, 1, 4, 7, 14 and 21 days of incubation samples are removed for determination of viable counts by serial dilution (10° to 10 ⁇ 6 ) in Middlebrook 7H9 medium and plating (100 m ⁇ ) on Middlebrook 7H11 agar. The plates are incubated at 37 °C for 21 days and the number of colonies are determined. Killing curves can be constructed by plotting the logioCFU per ml versus time.
  • a bactericidal effect of a cytochrome be and cytochrome bd inhibitor is commonly defined as 2-log 10 decrease (decrease in CFU per ml) compared to Day 0.
  • the potential carryover effect of the drugs is limited by using 0.4% charcoal in the agar plates, and by serial dilutions and counting the colonies at highest dilution possible used for plating.
  • Phenotypic assay to determine the O2 consumption rate of Mycobacterium tuberculosis test 4 The aim of this assay is to evaluate the O2 consumption rate of Mycobacterium tuberculosis (Mtb) bacilli after inhibition of cyt be 1 and cyt bd, using extracellular flux technology. Inhibition of cyt bcl (e.g. using known inhibitors such as Q203 or Compound X) forces the bacillus to use the less energetically efficient terminal oxidase cyt bd. The inhibition of cyt bd will cause a significant decrease O2 consumption. A sustained decrease of O2 consumption under membrane potential disrupting conditions, via the addition of the uncoupler CCCP, will show to the efficacy of the cyt bd inhibitor.
  • Mtb Mycobacterium tuberculosis
  • OCR oxygen consumption rate
  • the Compound X (final concentration of 0.9 mM, Compound X), is used to inhibit cyt bcl and the cyt bd inhibitor, CK-2-63 (final concentration of 10 mM), is used as a positive control.
  • the uncoupler CCCP is used at a final concentration of 1 mM.
  • Phenotypic assay using a cytochrome be knock-out TB strain and MIC determination against M. tuberculosis ⁇ , test 5
  • Biological Data - Example A Compounds of the invention/examples (or combinations, e.g. compounds of the invention/examples in combination with one or more other inhibitors of a target of the electron transport chain), for example when tested in any of Tests 1 to 3, may display activity.
  • Biological Data - Example B Compounds of the invention/examples (or combinations, e.g. compounds of the invention/examples in combination with one or more other inhibitors of a target of the electron transport chain), for example when tested in any of Tests 1 to 3, may display activity.
  • Biological Data - Example B Compounds of the invention/examples (or combinations, e.g. compounds of the invention/examples in combination with one or more other inhibitors of a target of the electron transport chain), for example when tested in any of Tests 1 to 3, may display activity.
  • Biological Data - Example B Compounds of the invention/examples (or combinations, e.g. compounds of the invention/example
  • the compounds of the invention/examples may have advantages associated with in vitro potency, kill kinetics (i.e. bactericidal effect) in vitro, PK properties, food effect, safety/toxicity (including liver toxicity, coagulation, 5-LO oxygenase), metabolic stability, Ames II negativity, MNT negativity, aqueous based solubility (and ability to formulate) and/or cardiovascular effect e.g. on animals (e.g. anesthetized guinea pig).
  • the data below that was generated/calculated may be obtained using standard methods/assays, for instance that are available in the literature or which may be performed by a supplier (e.g. Microsomal Stability Assay - Cyprotex, Mitochondrial toxicity (Glu/Gal) assay - Cyprotex, as well as literature CYP cocktail inhibition assays).
  • compounds of the invention/examples may be found to be advantageous as no mitotoxicity alerts were observed (e.g. in the Glu/Gal assay).

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Abstract

La présente invention concerne les composés (I), les nombres entiers étant tels que définis dans la description, et lesdits composés pouvant être utiles en tant que médicaments, par exemple pour une utilisation dans le traitement de la tuberculose (par exemple en combinaison).
PCT/EP2022/059062 2021-04-07 2022-04-06 Composés antibactériens WO2022214519A1 (fr)

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Citations (7)

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