OA19079A - Antibacterial compounds. - Google Patents

Abstract

The present invention relates to the following compounds wherein the integers are as defined in the description, and where the compounds may be useful as medicaments, for instance for use in the treatment of tuberculosis.

Description

ANTIBACTERJAL COMPOUNDS

I -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------The présent 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 interfering with ATP synthase in M. tuberculosis, with the inhibition of cytochrome &ci activity as the primary mode of action. Hence, primarily, such compounds are antitubercular agents.

BACKGROUND OF THE INVENTION

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infection with a world-wide distribution. Estimâtes from the World Health Organization indicate that more than 8 million people contract TB each year, 15 and 2 million people die ftom tuberculosis yearly. In the last decade, TB cases hâve 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 infections cause of adult mortality in the world. Complicating the TB 20 épidémie 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

Existîng approaches to treatment of tuberculosis ail involve the combination of multiple agents. For example, the regimen recommended by the U.S. Public Health Service is a combination of isoniazid, rifampicin and pyrazinamide for two months, followed by isoniazid and rifampicin alone for a further four months. These drugs are continued for a further seven months in patients infected with HIV. For patients infected with multi30 drug résistant strains of Ai tuberculosis, agents such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycioserine, ciprofoxacin and ofloxacin are added to the combination thérapies. There exists no single agent that is

I effective in the clinical treatment of tuberculosis, nor any combination of agents that offers the possibility of therapy of less than six months’ duration.

There is a high medical need for new drugs that improve current treatment by enabling i regimens that facilitate patient and provider compliance. Shorter regimens and those j that require less supervision are the best way to achieve this. Most of the benefit from

treatment cornes in the first 2 months, during the intensive, or bactericidal, phase when four drugs are given together; the bacterial burden is greatly reduced, and patients become noninfectious. The 4- to 6-month continuation, or sterilizing, phase is required to eliminate persisting bacilli and to minimize the risk of relapse. A potent sterilizing 5 drug that shortens treatment to 2 months or less would be extremely bénéficiai. Drugs that facilitate compliance by requiring less intensive supervision also are needed. Obviously, a compound that reduces both the total length of treatment and the frequency of drug administration would provide the greatest benefit.

Complicating the TB épidémie is the increasing incidence of multi-drug-resistant strains or MDR-TB. Up to four percent of ail cases worldwide are considered MDR-TB - those résistant to the most effective drugs of the four-drug standard, isoniazid and rifampin. MDR-TB is léthal when untreated and cannot be adequately treated through the standard therapy, so treatment requires up to 2 years of second-line drugs. These drugs are often toxîc, expensive and marginally effective. In the absence of an effective therapy, 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 drug with a new mechanism of action, which is likely to demonstrate activity against drug résistant, in particular MDR strains.

The term “drug résistant” as used hereinbefore or hereinafter is a term well understood by the person skilled in microbiology. A drug résistant Mycobacterium is a Mycobacterium which is no longer susceptible to at least one previously effective drug; which has developed the ability to withstand antibiotic attack by at least one previously 25 effective drug. A drug résistant strain may relay that ability to withstand to its progeny.

Said résistance 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 spécifie form of drug résistant tuberculosis due to a bacterium 30 résistant to at least isoniazid and rifampicin (with or without résistance to other drugs), which are at présent the two most powerful anti-TB drugs. Thus, whenever used hereinbefore or hereinafter “drug résistant” includes multi drug résistant.

Another factor in the control of the TB épidémie is the problem of latent TB. In spite of 35 décades of 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 épidémie of TB is fuelled by infection of HIV patients with TB and rise of multi-drug résistant TB strains (MDR-TB). The réactivation of latent TB is a high risk factor for disease development and accounts for 32% deaths in HIV infected individuals. To control TB épidémie, 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-γ. In case of HIV positive patients the only prophylactic treatment available for latent TB is two- three months regimens of rifampicin, pyrazinamide. The efficacy of the treatment régime is still not clear and furthermore the length ofthe treatments is an important constrain in resource-limited environments.

Hence there is a drastic need to identify new drugs, which can act as chemoprophylatic agents for individuals harboring latent TB bacilli.

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. In case of healthy individuals, most of the mycobacteria are killed in these environments but a small proportion of bacilli still survive and are thought to exist in a non-replicating, hypometabolic state and are tolérant to killing by anti-TB drugs like isoniazid. These bacilli can remain in the altered physiological environments even for individual’s lifetime without showing any clinical symptoms of disease. However, in 10% of the cases these latent bacilli may reactivate to cause disease. One of the hypothesis about development of these persistent bacteria is patho-physiological environment in human lésions namely, reduced oxygen tension, nutrient limitation, and acidic pH. These factors hâve been postulated to render these bacteria phenotypîcally tolérant to major anti-mycobacterial drugs.

In addition to the management of the TB épidémie, there is the emerging problem of résistance to first-line antibiotic agents. Some important examples include penicillinresistant Streptococcus pneumoniae, vancomycin-resistant enterococci, methicillinresistant Staphylococcus aureus, multi-resistant Salmonellae.

The conséquences of résistance to antibiotic agents are severe. Infections caused by résistant microbes fail to respond to treatment, resulting in prolonged illness and greater risk of death. Treatment failures also lead to longer periods of infectivity, which

increase the numbers of infected people moving in the community and thus exposing the general population to the risk of contracting a résistant strain infection.

Hospitals are a critical component of the antimicrobial résistance problem worldwide. The combination of highly susceptible patients, intensive and prolonged antimicrobial 5 use, and cross-infection has resulted in infections with highly résistant bacterial pathogens.

Self-medication with antimicrobiais is another major factor contributing to résistance. Self-medicated antimicrobiais may be unnecessary, are often inadequately dosed, or may not contain adéquate amounts of active drug.

Patient compliance with recommended treatment is another major problem. Patients forget to take médication, interrupt their treatment when they begin to feel better, or may be unable to afford a full course, thereby creating an idéal environment for 15 microbes to adapt rather than be killed.

Because of the emerging résistance to multiple antibiotics, physicians are confronted with infections for which there is no effective therapy. The morbidity, mortalïty, and fïnancial costs of such infections impose an increasing burden for health care Systems 20 worldwide.

Therefore, there is a high need for new compounds to treat bacterial infections, especially mycobacterial infections including drug résistant and latent mycobacterial infections, and also other bacterial infections especially those caused by résistant 25 bacterial strains.

Anti-infective compounds for treating tuberculosis hâve been disclosed in e.g.

international patent application WO 2011/113606. Such a document is concemed with compounds that would prevent M. tuberculosis multiplication inside the host macrophage and relates to compounds with a bicyclic core, imidazopyridines, which are linked (e.g. via an amido moiety) to e.g. an optionally substituted benzyl group.

International patent application WO 2014/015167 also discloses compounds that are disclosed as being of potential use in the treatment of tuberculosis. Such compounds 35 disclosed herein hâve a bicycle (a 5,5-fused bicycle) as an essential element, which is substituted by a linker group (e.g. an amido group), which itself may be attached to another bicycle or aromatic group. Such compounds in this document do not contain a sériés of more than three rings.

-5o

Journal article Nature Medicine, 19,1157-1160 (2013) by Pethe et al “Discovery of Q203, a potent clinical candidate for the treatment oftuberculosis” identifies a spécifie compound that was tested against M. tuberculosis. This compound Q203 is depicted 5 below.

This clinical candidates is also discussed in journal article, J. Médicinal Chemistry, 2014, 57 (12), pp5293-5305. It is stated to hâve activity against MDR tuberculosis, and hâve activity against the strain M. tuberculosis H37Rv at a MICso of 0.28 nM inside 10 macrophages. Positive control data (using known anti-TB compounds bedaquiline, isoniazid and moxifloxacin) are also reported. This document also suggests a mode of action, based on studies with mutants. It postulâtes that it acts by interfering with ATP synthase in M. tuberculosis, and that the inhibition of cytochrome bci activity is the primary mode of action. Cytochrome £>ci îs an essential component of the électron 15 transport chain required for ATP synthesis. It appeared that Q203 was highly active against both repli cating and non-replicating bacteria

International patent application WO 2015/014993 also discloses compounds as having activity against M. tuberculosis. International patent applications WO 2013/033070 20 and WO 2013/033167 disclose various compounds as kinase modulators.

The purpose of the présent invention is to provide compounds for use in the treatment of bacterial diseases, particularly those diseases caused by pathogenic bacteria such as Mycobacterium tuberculosis (including the latent disease and including drug résistant 25 M. tuberculosis strains). Such compounds may also be novel and may act by interfering with ATP synthase in M. tuberculosis, with the inhibition of cytochrome bc\ activity being considered the primary mode of action.

-6SUMMARY OF THE INVENTION

There is now provided a compound of formula (I) for use in the treatment of tuberculosis

wherein

R¹ represents Ci-6 alkyl or hydrogen;

L¹ represents a linker group -C(R^a)(R^b)- (or is not present);

Het represents a heteroaromatic linker group (which linker group may itself be optionally substituted by one or more substituents selected from fluoro, -O-R^c and Ci-6 alkyl, wherein the latter alkyl moiety is itself optionally substituted by one or more fluoro atoms);

R^a, R^b and R^c independently represent hydrogen or Ci-â alkyl (optionally substituted by one or more fluoro atoms);

X¹ represents -N(R²)(R³);

R² and R³:

(i) independently represent hydrogen or, preferably, Ci-β alkyl optionally substituted by one or more substituents selected from Q¹ and =0;

(ii) independently represent aryl or heteroaryl, each of which is optionally substituted by one or more substituents selected from Q²;

(iii) independently represent cycloalkyl or heterocycloalkyl, each of which is optionally substituted by one or more substituents selected from Q³ and =0;

or (iv) can be linked together to form:

a. a 3- to 8-membered ring optionally containing one to three heteroatoms (e.g. nitrogen, oxygen and/or sulfur), and which ring is optionally substituted by one or more substituents selected from Q⁴ and =0;

b. a “fused” bicyclic ring of the following type:

Q¹, Q², Q³, Q⁴ and Q⁵ each independently represent one or more substituents selected from halo, Ci-6 alkyl, -OCi-6 alkyl (which latter two alkyl moieties may themselves be optionally substituted by one or more halo, e.g. fluoro, atoms), aryl and heteroaryl (which latter two aromatic groups may themselves be optionally substituted by one or more substituents selected from halo, Ci-6 alkyl and -OCi-6 alkyl, which latter two alkyl moieties may themselves be substituted with one or more fluoro atoms);

ni and n2 independently represent 0 or 1 (hence, the X^a-containing ring may be 3-, 4or 5-membered, or (when m is 2), 6-membered);

X^a represents -C(R^al)(R^bl)_m- or -N(R^c1)-;

m represents 1 or 2;

each R^al and R^bl independently represents fluoro, hydrogen or Ci-6 alkyl;

R^cl represents hydrogen or Ci-6 alkyl;

X^b represents C(R^d), N, O (in which case L² is not présent) or C=O (in which case L² is also not présent);

R^d represents H, F or -OR^E (wherein R^e represents H or Ci-6 alkyl optionally substituted by one or more fluoro atoms);

q¹ represents -X^c-(CH2)_ni-X^d-; ni repesents 0,1 or 2;

q² represents -X^e-(CH2)_n2-X^f-;

n2 represents 0, 1 or 2, but wherein ni and n2 do not both represent 0;

X^e (which is attached to X^a) is either not present, or, when X^a represents CH, then X^e may represent -O-, -NH- or -S-;

X^d is either not present, or, when ni represents 2 or when X^e is not present, X^a represents C(R^C) and ni represents 1, then X^d may also represent -O-, -NH- or -S-; X^e and X^f independently are either not present, or may independently represent -O-, -NH- or -S-, provided that the aforementioned heteroatoms are not directly attached to 10 or a to another heteroatom;

q³ represents -X^Ë-(CH₂)_n3-X^h-;

q⁴ represents -X¹-(CH2)n4-X^j-;

n3 repesents 0, 1 or 2;

n4 represents 0,1 or 2, but wherein n3 and n4 do not both represent 0;

X^ë, X^h, X¹ and X·¹ independently are either not present, or may represent -O-, -NH- or -S-, provided that the aforementioned heteroatoms are not directly attached to or a to another heteroatom;

when X^b represents O or C=O, then L² is not present;

when X^b represents C(R^d) (e.g. CH) or N, then L² may represent hydrogen, halo, -OR^f, -C(O)-R^g, Ci-6 alkyl (optionally substituted by one or more halo, e.g. fluoro atoms) or an aromatic group (optionally substituted by one or more substituents selected from 25 halo, Ci-6 alkyl (itself optionally substituted by one or more substituents selected from fluoro, -CF3 and/or -SF5), -OCi-ealkyl (itself optionally substituted by one or more fluoro atoms), -O-phenyl (itself optionally substituted by halo, Ci-ealkyl, Ci-efluoroalkyl and/or -OCi-ealkyl) or-SFi);

R^f represents hydrogen, C1-6 alkyl (optionally substituted by one or more fluoro) or an aromatic group (itself optionally substituted by one or more substituents selected from halo, Ci-galkyl and -OCi-ealkyl, where the latter two alkyl moieties may themseleves be optionally substituted by one or more fluoro atoms);

R^Ë represents hydrogen or Ci-ealkyl (optionally substituted by one or more substituents selected from fluoro, or -OC1-3 alkyl, which latter moiety is also optionally substuituted by one or more fluoro atoms) or an aromatic group (optionally substituted by one or more substituents selected from halo, C1-6 alkyl or -OCi-ealkyl);

ring A is a 5-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom);

ring B is a 5- or 6-membered ring, which may be aromatic or non-aromatic, optionally containing one to four heteroatoms (preferably selected front nitrogen, oxygen and sulfur);

either ring A and/or ring B may be optionally substituted by one or more substituents 10 selected from: halo, Ci-6 alkyl (optionally substituted by one or more halo, e.g. fluoro atoms) and/or -OCi-ealkyl (itself optionally substituted by one or more fluoro atoms), or a pharmaceutically-acceptable sait thereof, which compounds may be referred to herein as “compounds of the invention”.

Pharmaceutically-acceptable 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 équivalents of an 20 appropriate acid or base, optionally in a solvent, or in a medium in which the sait 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 sait 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 sait 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 30 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, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,

5 benzenesulfonic, 72-10] uen es ul fonic, cyclamic, s alicylic, 72-am inosalicylic, pamo ic and the like acids.

For the purposes of this invention solvatés, prodrugs, N-oxides and stereoisomers of compounds of the invention are also included within the scope of the invention.

The term “prodrug” of a relevant compound of the invention includes any compound that, following oral or parentéral 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)). For the avoidance of doubt, the term “parentéral” administration includes ail 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 prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesîsing 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.

Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl dérivatives 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 (entgegen) and Z (zusammen) géométrie isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. Ail such isomers (e.g. if a compound of the invention incorporâtes 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. Ail tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention. The 35 term tautomer or tautomeric form refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a

proton, such as keto-enol and imine-enamine isomérisations. Valence tautomers include interconversions by réorganisation of some of the bonding électrons.

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 séparation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Altematively the desired optical isomers may be made by reaction 10 of the appropriate optically active starting materials under conditions which will not cause racémisation or épimérisation (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 derîvatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by séparation of the diastereomeric dérivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst ail under conditions known to the ski lied person.

AH stereoisomers (including but not limited to diastereoisomers, enantiomers and 20 atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention.

In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then ail stereoisomers are contemplated and included as the compounds 25 of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stéréo isomer is so specified and defined.

The compounds of the present invention may exist in unsolvated as well as solvated 30 forms with pharmaceutically acceptable solvents such as water, éthanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, but for the fact that one or more 3 5 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). Ail isotopes of any particular atom or element as specified herein are contemplated within the scope ofthe compounds ofthe 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 ²H, ³H, ⁿC, ¹³C, ¹⁴C , ¹³N, ¹⁵0,¹⁷0,¹⁸0,³²P, ³³P, ³⁵S, ¹⁸F, ³⁶C1, ^l23I, and ¹²⁵I. Certain isotopically-labeled compounds of the présent invention (e.g., those labeled with ³H 5 and ¹⁴C) are useful in compound and for substrate tissue distribution assays. Tritiated (³H) and carbon-14 (¹⁴C) isotopes are useful for their ease of préparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be 10 preferred in some circumstances. Positron emitting isotopes such as ¹⁵0,¹³N, ^HC and ¹⁸F are useful for positron émission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the présent invention can general ly be prepared by following procedures analogous to those disclosed in the Scheme 1 and/or in the Examples herein below, by substituting an isotopically labeled 15 reagent for a non-isotopically labeled reagent.

Unless otherwise specifïed, 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 20 cyclic (so forming a Cj-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 C2-_q alkenyl 25 or a C2-_q alkynyl group).

Cî-q cycloalkyl groups (where q is the upper limit of the range) that may be specifically mentioned 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 30 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.

The tenu “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, Equally, “aromatic or non-aromatic 5- or 6-membered rings” may be heterocyclic groups (as well as carbocyclic groups) that hâve 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 C2-_q heterocycloalkenyl (where q is the upper lîmit of the range) group. Ci-q heterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 15 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dîhydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and

1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including

1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]- heptanyl, 6-oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, nonaromatic pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trîthianyl), tropanyl and the like.

Substituents on 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 présent 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.

Aryl groups that may be mentioned include C6-20, such as C6.12 (e.g. Cê-io) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and hâve between 6 and 12 (e.g.

6 and 10) ring carbon atoms, in which at least one ring is aromatic. Ce-io 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. However, when aryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molécule via an aromatic ring. Most preferred aryl groups that may be mentioned herein are “phenyl”.

Unless otherwise specifîed, the term “heteroaryl” when used herein refers to an aromatic group containing one or more heteroatôm(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which hâve between 5 and 20 members (e.g. between 5 and 10) and 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). When the heteroaryl group is polycyclic the point of attachment may be via any atom including an atom of a non-aromatic ring. However, when heteroaryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest ofthe molécule via an aromatic ring. Heteroaryl groups that may be mentioned include 3,4-dihydro-l/ï-isoquinolinyl, 1,3-dihydroisoindolyl,

1,3-dihydroisoindolyl (e.g. 3,4-dihydro-177-isoquinolin-2-yl, l,3-dihydroisoindol-2-yl,

1.3- dihydroisoindol-2-yl; i.e. heteroaryl groups that are linked via a non-aromatic ring), or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro277-1,4-benzoxazinyl). benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[l,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), 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-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including

1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents on 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. Heteroaryl groups mentioned herein may be stated to be specifically monocyclic or bicyclic. When heteroaryl groups are polycyclic in which there is a non-aromatic ring present, then that non-aromatic ring 5 may be substituted by one or more =0 group. 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).

It may be specifically stated that the heteroaryl group is monocyclic or bicyclic. In the 10 case where it is specified that the heteroaryl is bicyclic, then it 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, 15 oxygen, nitrogen and sulfur.

When “aromatic” groups are referred to herein, they may be aryl or heteroaryl. When “aromatic linker groups” are referred to herein, they may be aryl or heteroaryl, as defined herein, any may be monocyclic or polycyclic (e.g. bicyclic) and attached to the 20 remainder of the molécule via any possible atoms of that linker group. However, it may specifically be mentioned that the linker group is a heteroaromatic linker group, in which case such a moiety is aromatic and has to contain at least one heteroatom.

For the avoidance of doubt, where it is stated herein that a group may be substituted by 25 one or more substituents (e.g. selected from Ci-6 alkyl), then those substituents (e.g.

alkyl groups) 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.

For the avoidance of doubt, where Q⁵ is mentioned herein, this represents one or more optional substituents on the bicycle to which it is attached, and such optional substituents may be situated on either (or both) rings of such bicycle (i.e. the N-containing 5-membered ring and/or the X^a-containing ring). ³⁵

Ail individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).

-16The skilled person will appreciate that 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.

Compounds of the invention that may be mentioned include in which: R² andR³:

(i) independently represent hydrogen or, preferably, Ci-6 alkyl optionally substituted by one or more substituents selected from Q¹ and =0;

(îi) independently represent aryl or heteroaryl, each of which is optionally substituted by one or more substituents selected from Q²;

(iii) independently represent cycloalkyl or heterocycloalkyl, each of which is optionally substituted by one or more substituents selected from Q³ and =0;

or (iv) can be linked together to form:

a. a 3- to 8-membered ring optionally containîng one to three heteroatoms (e.g. nitrogen, oxygen and/or sulfur), and which ring is optionally substituted by one or more substituents selected from Q⁴ and =0;

b. a “fused” bicyclic ring of the following type:

c. a “spiro” ring of the following type:

Hence, in an aspect, when R² and R³ are linked together to form a “fused” bicyclic ring, it is of the following type:

i.e. ni and n2 independently represent 1.

In two different aspects of the invention:

- ni and n2 both represent 1 ;

- ni and n2 both represent 0.

Certain (e.g. preferred) aspects of compounds of the invention include those in which: R^e represents hydrogen;

R^d represents hydrogen;

L¹ preferably represents a linker group as defined by -C(R^a)(R^b)-;

X^e (which is attached to X^a) is either not présent, or, when X^a represents CH, then X^e may also represent -O-;

X^d is either not présent, or, when ni represents 2 or when X^e is not présent, X^a represents C(R^C) and ni represents 1, then X^d may also represent -O-;

X^e and X^f independently are either not présent, or may independently represent -O-, provided that the aforementioned oxygen atom is not directly attached to or a to another heteroatom;

when X^e and/or X^d represent -O-, -NH- or -S-, it is understood that such heteroatoms 20 may not be attached directly (or a to) to another heteroatom.

More preferred compounds of the invention include those In which: '

R¹ represents hydrogen;

R^a and R^b independently represent hydrogen;

L¹ represents -CH2-;

when X¹ represents a heteroaromatic linker group (where the point of attachment may be via any atom of the ring System), then it in a major aspect of the invention:

- it is a bicyclic heteroaromatic linker group;

- it is a bicyclic heteroaromatic group linked to L¹ (or the amido moiety, when L¹ is not présent) via a carbocyclic aromatic moiety, so forming e.g.:

in which “het” (in the above instance) is a heteroaromatic 5- or 6-membered ring;

- a fused bicyclic ring System comprising a phenyl and/or a 5- or 6-membered monocyclic heteroaryl group (for instance forming a 9- or 10-membered heteroaromatic group, which consists of two separate rings fused with each other, in which each ring is 5- or 6-membered so forming a 6,6- or 6,5- or fused bicyclic ring), hence including groups such as those described below: -quinolylene (such as 2-quinolylene or 3-quinolylene), e.g.:

-quinoxalinyl (such as 2-quinolylene), e.g.:

- such heteroaromatic linker groups may be optionally substituted by one or more substituents as defined herein. In an aspect, the heteroaromatic linker group is not substituted or is only substituted (where possible) on a heteroatom (e.g. on a

nitrogen heteroatom) - in which case it remains unsubstituted on the carbon atoms. In an aspect, the points of attachment of the linker group are via distal atoms, for instance atoms that as far apart as possible (e.g. in a bicycle of 10 members, those atoms in a 2- and 6- position (or 3- and 7-position) but in another aspect, they are not necessarily the atoms the furthest apart (e.g. in a

10-membered bicycle, the atoms linked to the rest of the molécule has be the

3- and 6-atoms too).

When X¹ represents -N(R²)(R³), then:

(i) R² and R³ independently represent C1-3 alkyl (e.g. methyl or ethyl) optionally substituted byone or more (e.g. one) substituent(s) selected from Q¹;

(ii) R² and R³ are linked together to form:

a. a 4- to 6-membered ring optionally containing one further heteroatom (e.g. so formîng a piperidinyl, piperazinyl or azetidinyl ring), which is optionally (and, in an aspect, preferably) substituted by by one or more (e.g. one or two) substituents selected from Q⁴ (in one aspect, e.g. when Q⁴ represents an aromatic substituent, then there is only one Q⁴ substituent present; in another aspect, e.g. when Q⁴ represents a nonaromatic substituent, e.g. fluoro, then one or two Q⁴ substituents may be 20 present);

b. a fused bicyclic ring in which X^a represents -CH2- and which is optionally substituted (e.g. at the X^a position) by one or more (e.g. one) Q⁵ substituent(s);

c. a spiro ring system, in which X^b represents CH and L² is present and as defined herein.

Q¹ represents aryl (e.g. phenyl) optionally substituted by e.g. -OCi-jalkyl (itself optionally substituted by one or more fluoro atoms, so formîng e.g. a -OCF3 group);

Q⁴ represents aryl (e.g. phenyl) optionally substituted by e.g. -OCi-3alkyl (itself optionally substituted by one or more fluoro atoms, so formîng e.g. a -OCF3 group) or, in another aspect, Q⁴ represents fluoro (e.g. two fluoro atoms substituted atthe same carbon atom);

Q⁵ represents halo (e.g. fluoro);

X^e, X^d, X^e and X^f are independently not present;

ni and n2 independently represent 1;

X^Ê, X^h, X¹ and X¹ are independently not present;

n3 and n4 independently represent 1 ;

L² represents a fluoro substituent or, in another aspect, an aromatic group (e.g. aryl or phenyl) optionally substituted by one or more (e.g. one) substituent(s) e.g. selected from e.g. -OCi-3alkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -OCF3 group).

It is preferred that compounds of the invention comprise:

ring A, which is an aromatic ring containing at least one to three (e.g. one or two) heteroatoms, preferably contains at least one nitrogen atom;

ring B is more preferably also an aromatic ring (e.g. a 5- or especially a 6-membered 10 aromatic ring), preferably containing at least one nitrogen atom.

It is preferred that Ring A of the compounds of the invention are represented as follows:

Sub

Other preferred ring A moieties include:

Monocyclic heteroaryl groups that may be mentioned include 5- or 6-membered rings 20 containing one to four heteroatoms (preferably selected from nitrogen, oxygen and sulfur). It is preferred that Ring B of the compounds of the invention are represented as follows:

where “SUB” may be a relevant optional substituent (or more than when relevant substituent, where possible) on a carbon atom or, where possible, on a heteroatom e.g. on a NH, thus replacing the H.

Other preferred “Ring B” moieties include:

Preferred substituents (when present; e.g such optional substituents may be absent or there may be one) on ring B include C1-3 alkyl (e.g. methyl) or halo (e.g. bromo or, more preferably, chloro). Other preferred substituents on ring B include -OCi-6alkyl (e.g. -OCi-aalkyl, such as -OCH3).

Preferred substituents (when present; e.g such optional substituents may be absent or there may be one) on ring B include C1-3 alkyl (e.g. methyl) or halo (e.g. bromo or,

more preferably, chloro). Preferred substituents (when présent; preferably, there may be one or two substituents) on ring A include C1-3 alkyl (e.g. methyl or ethyl). When L² represents an aromatic group (e.g. phenyl or pyridyl) and such groups are substituted, preferred substituents include halo and especially -OC1-3 alkyl (e.g. -O-methyl), where 5 the latter is substituted by fluoro, so forming for example a -OCF3 group.

The combined ring Systems, i.e. Ring A and Ring B may be represented as follows:

Sub Sub

where “SUB” represents one or more possible substituents on the bicycle (i.e. on ring A and/or on ring B) and “Sub” represents a possible optional substituent on the N atom of the bicycle (unsubstituted in this context would mean “NH”).

Other combined ring A and ring B Systems that may be mentioned include the following:

Certain compounds of the invention are mentioned (e.g. hereinbefore) for use in the treatment of tuberculosis. Certain of such compounds mentioned herein may also be 5 novel per se. And certain of such compounds mentioned herein may be novel as medicaments/pharmaceuticals (or novel as a component of a pharmaceutical composition/formulation). Hence, in further aspects of the invention, there is provided the following compounds per se or following compounds for use as pharmaceuticals/medicaments (in the latter case such compounds may be components of a pharmaceutical composition/formulation):

(I) Compounds of formula (I) as hereinbefore defined and in which:

L¹ represents -CH2-;

Het represents a a bicyclic heteroaromatic group linked to L¹ (or the amido moiety, when L¹ is not présent) via a carbocyclic aromatic moiety, so forming e.g.:

in which “het” (in the above instance) is a heteroaromatic 5- or 6-membered ring;

when X¹ represents -N(R²)(R³), then:

(i) R² and R³ independentiy represent C1.3 alkyl (e.g. methyl or ethyl) optionally substituted by one or more (e.g. one) substituent(s)

-24Π selected from Q¹ (but wherein when both R² and R³ represent alkyl, then at least one is substituted by Q¹ in which Q¹ represents an optionally substituted aryl group as defined herein);

(ii) R² and R³ are linked together to form:

a. a 4- to 6-membered ring optionally containîng one further héteroatom (e.g. so forming a piperidinyl, piperazinyl or azetidïnyl ring), which is substituted by by one or two substituents selected from Q⁴ (in which at least one Q⁴ substituent is present that represents an optionally substituted aryl group as defined herein);

b. a fused bicyclic ring in which X^a represents -CH2- and which is optionally substituted (e.g. at the X^a position) by one or more (e.g. one) Q⁵ substituent(s);

c, a spiro ring system, in which X^b represents CH and L² is present and as defined herein;

when Q¹ represents aryl, then it is an optionally substituted as defined herein (e.g. by one or more substituents selected from -OCi-₃alkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -OCF3 group)); when Q⁴ represents aryl, then it is an optionally substituted phenyl as defined herein (e.g. by one or more substituents selected from -OCi-jalkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -OCF3 group));

when Q⁴ represents a non-aromatic substituent, then it may represent e.g. fluoro;

Q⁵ represents halo (e.g. fluoro);

X^e, X^d, X^e and X^f are independently not present;

ni and n2 independently represent 1 ; X^ë, X^h, X¹ and X^J are independently not present;

n3 and n4 independently represent 1 ;

L² represents an aromatic group (e.g. aryl or phenyl) optionally substituted by one or more (e.g. one) substituent(s) e.g. selected from e.g. -OCi-3alkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -OCF3 group);

ring A and ring B together represent a 8 or 9-membered bicyclic ring (ring

A is a 5-membered ring and ring B may be a 5 or 6-membered ring, in which both rings are preferably aromatic) containîng at least one nitrogen atom (and in a major embodiment, at least one nitogen atom that is common to both rings);

I ' ' .......’.....” ......’............ ...................

-25optional substituents on ring A and ring B are halo, C1-3 alkyl and -0Ci-3alkyl; and other integers are as defmed herein;

(II) Compounds as hereinbefore defmed (e.g. at (I) above) and further in which the X^b-containing rings are represented as defined herein or more particulary as follows:

(or any one of the above-mentioned représentations); and/or (III) Compounds as hereinbefore defmed (e.g. at (I) and/or (II) above) and further in which the ring A and ring B bicycles are represented as defined herein or more particulary as follows:

(or any one of the above-mentioned représentations).

In an embodiment (e.g. in aspect (I) mentioned above), R² and R³ may represent either (i) or (ii) mentioned herein. When R² and R³ represent (ii), then they may represent either a, b or c as defined in the sub-defïnitions (e.g. in aspect (I) above).

PHARMACOLOGY

The compounds according to the invention hâve 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 résistant 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 ôci activity being the primary mode of action. Cytochrome ôci is an essential component of the électron transport chain required for ATP synthesis.

Further, 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 médicament for the treatment of a bacterial infection including a mycobacterial infection.

Accordingly, in another aspect, 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.

The compounds of the present invention also show activity against résistant bacterial 30 strains.

Whenever used hereinbefore or hereinafter, that the compounds can treat a bacterial infection it is meant that the compounds can treat an infection with one or more bacterial strains.

The invention also relates to a composition comprising a pharmaceutically acceptable carrier and, as active ingrédient, a therapeutically effective amount of a compound according to the invention. The compounds according to the invention may be

formulated into varions pharmaceutical forms for administration purposes. As appropriate compositions there may be cited ail compositions usually employed for systemically administering drugs. To préparé the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition sait form, as the active ingrédient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms | depending on the form of préparation desired for administration. These pharmaceutical compositions are désirable in unitary dosage form suitable, in particular, for administration orally or by parentéral injection. For example, in preparing the compositions in oral dosage form, 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 préparations such as suspensions, syrups, élixirs, émulsions 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. For parentéral compositions, the carrier will usually comprise stérile water, at least in large part, though other ingrédients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in 20 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. Also included are solid form préparations which are intended to be converted, shortly before use, to liquid form préparations.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from O.l 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 30 more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, ail percentages being based on the total weight ofthe composition.

The pharmaceutical composition may additionally contain various other ingrédients known in the art, for example, a lubricant, stabilising agent, buffering agent, emulsifying agent, viscosity-regulating agent, surfactant, preservative, flavouring or colorant.

It is especially advantageous to formulate the aforementioned pharmaceutîcal compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrète units suitable as unitary dosages, each unit containing a predetermined quantity of active ingrédient calculated to produce the desired therapeutic effect in association with the required pharmaceutîcal carrier. Examples of such 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 10 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 admînistered at a daily dosage not exceeding 1 gram, e.g. in the range from 10 to 50 mg/kg body weight.

Given the fact that the compounds of formula (la) or Formula (lb) are active against bacterial infections, the présent compounds may be combined with other antibacterial agents in order to effectively combat bacterial infections.

Therefore, the présent invention also relates to a combination of (a) a compound 20 according to the invention, and (b) one or more other antibacterial agents.

The présent invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents, for use as a medicine.

The présent invention also relates to the use of a combination or pharmaceutîcal composition as defined directly above for the treatment of a bacterial infection.

A pharmaceutîcal composition comprising a pharmaceutically acceptable carrier and, as active ingrédient, a therapeutically effective amount of (a) a compound according to 30 the invention, and (b) one or more other antibacterial agents, is also comprised by the présent invention.

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 35 skilled in the art. Said ratio and the exact dosage and frequency of administration dépends 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 médication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is évident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the évaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the présent 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 préparation or they may be formulated in separate préparations so that they can be administered simultaneously, separately or sequentially. Thus, the présent invention also relates to a product containing (a) a compound according to the invention, and (b) one or more other antibacterial agents, as 15 a combined préparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.

The other antibacterial agents which may be combined with the compounds of the invention are for example antibacterial agents known in the art. For example, the 20 compounds of the invention may be combined with antibacterial agents known to interfère with the respiratory chain of Mycobacterium tuberculosis, including for example direct inhibitors ofthe ATP synthase (e.g, bedaquiline, bedaquiline fumarate or any other compounds that may hâve be disclosed in the prior art, e.g. compounds disclosed in W02004/011436), inhibitors of ndh2 (e.g. clofazimine) and inhibitors of 25 cytochrome bd. Additional mycobacterial agents which may be combined with the compounds of the invention are for example rifampicin (=rifampin); isoniazid;

pyrazinamide; amikacin; ethionamide; ethambutol; streptomycin; para-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thioacetazone; PA-824; delamanid; quinolones/fluoroquinolones such as for example moxifloxacin, gatifloxacin, ofloxacin, 30 ciprofloxacin, sparfloxacin; macrolides such as for example clarithromycin, amoxycillin with clavulanic acid; rifamycins; rifabutin; rifapentin; as well as others, which are currently being developed (but may not yet be on the market; see e.g. http://www.newtbdrugs.org/pipeline.php).

! ........

-30GENERAL PREPARATION

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.

EXPERIMENTAL PART

Compounds of formula I may be prepared in accordance with the techniques employed in the examples hereinafter (and those methods know by those skilled in the art), for example by using the following techniques.

Compounds of formula (I) may be prepared by:

(i) reaction of a compound of formula (II),

wherein the integers are as hereinbefore defined, or a suitable dérivative thereof, such as a carboxylic acid ester dérivative, with a compound of formula (III)

R¹

H N ,_llh

wherein the integers are as hereinbefore defined, under amide coupling reaction conditions, for example in the presence of a suitable coupling reagent (e.g.

I ,Γ-carbonyldîimidazole, jVjV’-dicyclohexylcarbodiimide, l-(3-dimethylaminopropyl)-

3-ethylcarbodiimide (or hydrochloride thereof) or ALV’-disuccinimidyl carbonate), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyridîne, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium teri-butoxide and/or lithium diisopropylamide (or variants thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridîne, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine). Altematively, the carboxylic acid

group of the compound of formula (IV) may first be converted under standard conditions to the corresponding acyl chloride (e.g. in the presence of POCI3, PCI5, SOCI2 or oxalyl chloride), which acyl chloride is then reacted with a compound of formula (V), for example under similar conditions to those mentioned above;

(ii) coupling of a compound of formula (IV),

wherein the integers are as hereînbefore defined, and LG² represents a suitable leaving group, such as iodo, bromo, chloro or a sulfonate group (for example a type of group that may be deployed for a coupling), with a compound of formula (V),

Χ^Η (V) wherein the integers are as hereînbefore defined, under standard conditions, for example optionally in the presence of an appropriate métal catalyst (or a sait or complex thereof) such as Pd(dba)2, Pd(OAc)2, Cu, Cu(OAc)2, Cul, N1CI2 or the like, with an optional additive such as Ph₃P, X-phos or the like, in the presence of an appropriate base (e.g. t-BuONa, or the like) in a suitable solvent (e.g. dioxane or the like) under reaction conditions known to those skilled in the art.

Other steps that may be mentioned include:

- nucleophilic aromatic substitution reactions

- other coupling reactions e.g. in which one compound contains a suitable leaving group such as one described hereînbefore with respect to LG² (and may particularly represent chloro, bromo or iodo), with another compound comprising a mutually compatible “leaving group” or another suitable group such as -B(OH)₂, -B(OR™)2 or -SNfR^j, in which each R™ independently represents a C1-6 alkyl group, or, in the case of-B(OR^W!C)2, the respective R™ groups may be linked together to form a 4- to 6-membered cyclic group, thereby forming e.g. a pinacolato boronate ester group (or may represent iodo, bromo or chloro, provided that the “leaving groups” are mutually compatible), and wherein the reaction may be performed in the presence of a suitable catalyst

-32Ο

System, e.g. a métal (or a sait or complex thereof) such as Pd, Cul, Pd/C, PdCh, Pd(OAc)2, Pd(Ph3P)2Cb, Pd(Ph3P)4, Pd₂(dba)3 and/or NiCl₂ (or the like) and a ligand such as PdCbfdppfj.DCM, t-BuaP, (CâHnjîP, PI13P or the like, in a suitabie solvent and under reaction conditions known to those skilled in the art.

It is évident that in the foregoing and in the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to méthodologies generally known in the art, such as extraction, crystallization and chromatography. It is further évident that reaction products that exist in more than one enantiomeric form, may be isolated from their mixture by known techniques, in particular préparative chromatography, such as préparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be obtained by Supercritical Fluid Chromatography (SCF).

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.

Svnthesis of Compound 1 and Compound 2

Synthesis of Intermediate T

F F

CAS [1147557-97-8]

PPh₃,l₂ imidazole, toluene reflux 1 h

__________CAS[1399301-27-2] trans-2-amino-cyclohexanol, NaHMDS, Nil₂, i-PrOH,

60°C, MW, 1 h, 90°C, MW, 1 h 120°C, MW, 5 h,

F F

HCOOH _/=, y~F

------* ^HN Λ) ( /)°

25°C,16h ^V

T

Préparation of intermediate R

Triphenylphosphine (1.89 g, 7.20 mmol), imidazole (735 mg, 10.8 mmol) and iodine (1.37 g, 5.40 mmol) were added to a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3] heptane-2-carboxylate (CAS [1147557-97-8], 768 mg, 3.60 mmol) in toluene (50 mL).

The resulting mixture was refluxed for 1 hour. The mixture was cooled to 25°C, washed with water (100 mL) and brine (50 mL). The separated organic layer was dried, filtered and the filtrate was concentrated under vacuum. The residue was purified by

flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate I/O to 1/1) to give intermediate R (1.20 g, yield: 93%).

Préparation of intermediate S

A mixture of 4-(Trifluoromethoxy)phenylboronic acid (CAS [139301-27-2], 510 mg, 2.48 mmol), trans-2-amino-cyclohexanol (23.0 mg, 0.200 mmol) and nickel iodine (62.5 mg, 0.200 mmol) in isopropanol (4 mL) was stirred at 25 °C for 30 minutes under nitrogen flow. NaHMDS (2.47 ml, 1 M in THF, 2.47 mmol) was added, and the mixture was stirred for 10 minutes under nitrogen flow. Intermediate R (400 mg,

1.24 mmol) in isopropanol (1 mL) was added and the mixture was stirred at 60°C under microwave for 1 hour, at 90 °C for 1 hour and at 120 °C for 5 hours. The mixture was diluted with dichloromethane (50 mL), washed with water (2x50 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 5/1) to give intermediate S (230 mg, yield: 52%).

Préparation of intermediate T

Intermediate S (220 mg, 0.616 mmol) was added to formic acid (5 mL) at 0 °C under nitrogen atmosphère. The mixture was stirred at 25°C for 5 hours. The mixture was concentrated under vacuum. The residue was dissolved into dichloromethane (20 mL). The solution was washed with saturated aqueous sodium carbonate solution (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give Intermediate T (150 mg, yield: 85%).

Synthesis of Compound 1 and Compound 2

K en ΓΗ ΓΜ mfliiY 1R h nn₃/ivic\jn, ιυ -v, lu n

CAS [78060-54-5] ^2^eu3-^reT1LJX·^{1 b n} 3

AY

X=N: Compound 1

X=C: Compound 2

Préparation of intermediate AY

A mixture of 2-chloro-6-quinolinecarbonitrile (CAS [78060-54-5], 14.7 mg, 0.078 mmol), Intermediate T (20.0 mg, 0.078 mmol) and potassium carbonate (21.6 mg, 0.156 mmol) in acetonitrile (5 mL) was refluxed for 16 hours. The solvent was evaporated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 1/1) to give intermediate AY (20.0 mg, 10 yield: 62.8%).

Préparation of intermediate AZ

A solution of intermediate AY (20.0 mg, 0.049 mmol) in NHa'MeOH (20 mL, 7 M NH3 in MeOH) was hydrogenated at 15 °C (15 psi) with Raney nickel (3 mg) as a catalyst for 16 hours. The catalyst was filtered off and the filtrate was concentrated under vacuum to give intermediate AZ (20.0 mg, yield: 91.84%).

Préparation of Compound 2

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS

[1216142-18-5], 9.79 mg, 0.044 mmol), HATU (21.7 mg, 0.057 mmol), DIEA (14.8 mg, 0.114 mmol) in CH2CI2 (10 mL) was stirred for 30 minutes at 25 °C. Intermediate AZ (20 mg, 0.048 mmol) was added to the mixture and the mixture was stirred for 2 hours at 25 °C. The mixture was concentrated under vacuum. The crude product was purified by high performance liquid chromatography over Gemini (eluent: 0.05% ammonia in water/methanol 35/65 to 5/95). The desired fractions were collected and concentrated to give Compound 2 (4.30 mg, 15.91%).

-351H NMR (400 MHz, CHLOROFORM-7) δ ppm 9.56 (s, 1 H) 7.84 (d, 7=8.80 Hz, 1 H)

7.74 (d, 7=8.56 Hz, 1 H) 7.59 (s, 1 H) 7.55 (d, 7=9.29 Hz, 2 H) 7.31 (d, 7=9.78 Hz,

H) 7.22 (d, 7=8.40 Hz, 2 H) 7.16 (d, 7=8.40 Hz, 2 H) 6.59 (d, 7=9.05 Hz, 1 H) 6.13 (br. s., 1 H) 4.79 (d, 7=5.62 Hz, 2 H) 4.33 (s, 2 H) 4.11 (s, 2 H) 3.50 (t, 7=8.68 Hz, 1 H)

2.97 (q, 7=7.42 Hz, 2 H) 2.65 - 2.76 (m, 2 H) 2.33 - 2.44 (m, 2 H) 1.38 (t, 7=7.58 Hz,

H)

Préparation of Intermediate L

O O

CAS 3002-24-2

NBS,NH₄OAc _; methyl t-butyl ether RT, 48 h

CAS [5428-89-7] EtOH, reflux, overnight

Préparation of intermediate J

NBS (45.1 g, 254 mmol) and NH4OAC (5.33 g, 69.2 mmol) were added to a solution of methyl-3-oxovalerate (CAS[30414-53-0], 30 g, 231 mmol) in methyl t-butylether (600 mL). The mixture was stirred at room température for 48 h. The mixture was fïltered and washed with H2O, dried over Na₂SO4 and fïltered. The filtrate was concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 20/1) to give intermediate J (20.0 g, yield: 35%).

Préparation of intermediate K

A solution of 5-Chloro-2-pyridinamine (CAS [5428-89-7], 12.0 g, 93.0 mmol) and intermediate J (25.0 g, 112 mmol) in éthanol (60 mL) was refluxed overnight. The mixture was concentrated under vacuum. The residue was dissolved into ethyl acetate (100 mL). The solution was washed with water (2x100 mL), brine (100 mL), dried over sodium sulfate, fïltered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 3/1) to give intermediate K (700 mg, yield: 3%).

-36o

Préparation of intermediate L

A mixture of intermediate K (700 mg, 2.10 mmol) and sodium hydroxide (252 mg,

6.30 mmol) in éthanol (2 ml) and H2O (2 mL) was stirred ovemight at room température. Water (20 mL) was added and the solution was acidified with 2 M aqueous hydrochloride to pH ~3. The solution was lyophilized to give crude intermediate L (2 g).

Préparation of Compound 1

Accordingly, Compound 1 was prepared in the same way as Compound 2 starting from intermediate L and intermediate AZ, yielding 0.037 g, 25%.

IH NMR (400 MHz, CHLOROFORMA) δ ppm 9.83 (d, >2.51 Hz, 1 H) 8.55 (d>2.51 Hz, 1 H) 7.83 (d, >8.78 Hz, 1 H) 7.75 (d, >8.53 Hz, 1 H) 7.55 (d, >9.20 Hz, 1 H) 7.53 (d, >6.80 Hz, 1 H) 7.22 (d, >8.80 Hz, 2 H) 7.15 (d, >8.40 Hz,

2 H) 6.58 (d, >8.78 Hz, 1 H) 6.26 (t, >5.27 Hz, 1 H) 4.77(d, >5.60 Hz, 2 H) 4.33 (s,

H) 4.11 (s, 2 H) 3.50 (quin, >8.85 Hz, 1 H) 3.01 (q, >7.53 Hz, 2H) 2.65 - 2.74 (m, 2

H) 2.33 - 2.43 (m, 2 H) 1.41 (t, >7.53 Hz, 3 H)

Further Examples

Synthesis of Compound 3

F F

pyridine, MW 150 »C, 30 min

Raney Ni, H₂ (50 psi) NH, in MeOH, MeOH intermediate A

CAS [78060-54-5] CAS [180160-91-2]

Préparation of intermediate A”

A mixture of 4-(4-(trifluoromethoxy)phenyl)piperidine (CAS [180160-91-2], 0.2 g,

0.710 mmol) and 2-chloroquinoline-6-carbonitrile (CAS [78060-54-5], 0.161 g,

0.852 mmol) inpyridine (5 mL) was stirred at 150 °C for 30 minutes under microwave. The mixture was evaporated to dryness and diluted with water, extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The

-37residue was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate- 8:1 to afford intermediate A”, 0.13 g, 46%.

Préparation of intermediate B”

To a solution of intermediate A” (0.13 g, 0.327 mmol) in MeOH (20 mL) was added Raney Nickel (65 mg) and ammonia 4M in MeOH (1 mL) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 25 °C for 10 hours. The suspension was filtered through a pad of Celite® was washed with MeOH (20 mL). The combined filtrâtes were concentrated to 10 dryness to give intermediate B”, 0.12 g, 92%.

Préparation of Compound 3

To a solution of intermediate B” (0.1 g, 0.2497 mmol) in DMF (10 mL) were added 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5],

0.067 g, 0.299 mmol), EDCI (0.072 g, 0.3747 mmol), HOBt (0.04 gg, 0.299 mmol) and trîethylamine (0.05 g, 0.498 mmol). The mixture was stirred at 80 °C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel chromatography eluted with dichloromethane: ethyl acetate=10: 1 to give Compound 3, 0.055 g, 36%.

’HNMR (400MHz, CHLOROFORM-d) δ = 9.54 (s, IH), 7.91 (d, 7=9.3 Hz, IH), 7.63 - 7.50 (m, 3H), 7.35 - 7.19 (m, 4H), 7.18 - 7.12 (m, 2H), 7.07 (d, 7=9.0 Hz, IH), 6.22 (br.s., IH), 4.85 - 4.63 (m, 4H), 3.17 - 3.07 (m, 2H), 2.98 (q, 7=7.4 Hz, 2H), 2.89 - 2.79 (m, IH), 2.01 (d, 7=12.5 Hz, 2H), 1.79 (dq, 7=3.8, 12.6 Hz, 2H), 1.39 (t, 7=7.5 Hz, 3H).

.

Synthesis of Compound 4 _F pyridine, Raney Ni, H_z (50psi) z—< VCl /—\ / ^r MW 150 °C, 30 min NH, in MeOH, MeOH

NC-Q N ₊ I--~ ^ ν··-Ζ^F --³--------’

CAS [76060-54-5] CAS [1554431-13-8] intermediate C

HATU, DIPEA Compound 4 intermediate D DMF, RT, 16 h

-38Préparation of intermediate C”

Accordingly, intermediate C” was prepared in the same way as intermediate A” starting from 2-chloroquinoline-6-carbonitrile CAS [78060-54-5] and 5-fluorooctahydrocyclopenta[c]pyrrole CAS [1554431-13-8] to give 0.15 g, 91%.

Préparation of intermediate D”

Accordingly, intermediate D” was prepared in the same way as intermediate B” starting from intermediate C” to give 0.15 g, 99%.

Préparation of Compound 4

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.07 g, 0.312 mmol), HATU (0.154 g, 0.405 mmol) and diisopropylethylamine (0.161 g, 1.25 mmol) in DMF (3 mL) was stirred at room température for

h. Intermediate D” (0.089 g, 0.312 mmol) was added and the solution was stirred at room température overnight. The solvent was evaporated under vacuum. The residue was purified by column chromatography over silica gel (eluent: CH2CI2/ methanol 10/1). The desired fractions were concentrated under vacuum to give Compound 4, 0.136 g, 87%.

¹HNMR (400 MHz, CHLOROFORM-d) δ =9.50 - 9.60 (m, 1 H) 7.80 - 7.87 (m, 1 H)

7.68 - 7.76 (m, 1 H) 7.49 - 7.60 (m, 3 H) 7.27 - 7.33 (m, 1 H) 6.71 - 6.78 (m, 1 H) 6.08

- 6.17 (m, 1 H) 5.18 - 5.35 (m, 1 H) 4.74 - 4.82 (m, 2 H) 3.74 - 3.85 (m, 2 H) 3.48 3.57 (m, 2 H) 3.02 - 3.13 (m, 2 H) 2.91 - 3.00 (m, 2 H) 2.25 - 2.40 (m, 2 H) 1.80 - 1.88 (m, 1 H) 1.70 - 1.78 (m, 1 H) 1.33 - 1.43 (m, 3 H)

Synthesis of Compound 5

CAS [78060-54-5] intermediate T

KjCOj, CH,CN. reflux. 16 h

intermediate E

Raney Ni, H- (50 psi)

NH₃inMeOH, MeOH

intermediate F

OH

HATU, DJPEA

DCM, RT

Compound 5

Préparation of intermediate E”

A mixture of 2-chloroquinoline-6-carbonitrile (CAS [78060-54-5], 0.015 g,

0.078 mmol), intermediate T (0.02 g, 0.078 mmol) and potassium carbonate (0.022 g,

0.156 mmol) in acetonitrile (5 mL) was refluxed for 16 hours. The solvent was evaporated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 1/1) to give intermediate E”, 0.02 g, 63%.

Préparation of intermediate F”

Accordingly, intermediate F” was prepared in the same way as intermediate B” starting from intermediate E” to give 0.02 g, 92%.

Préparation of Compound 5

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS

[1216142-18-5], 0.01 g, 0.044 mmol), HATU (0.022 g, 0.057 mmol), diisopropylethylamine (0.015 g, 0.114 mmol) in CH2CI2 (10 mL) was stirred for minutes at 25 °C. Intermediate F” (0.02 g, 0.048 mmol) was added to the mixture and the mixture was stirred for 2 hours at 25 °C. The mixture was concentrated under vacuum. The crude product was purified by high performance liquid chromatography 20 over Gemini (eluent: 0.05% ammonia/methanol 35/65 to 5/95). The desired fractions were collected and concentrated to give Compound 5, 0.0043 g, 16%.

1HNMR (400 MHz, CHLOROFORM-ri) δ ppm 9.56 (s, 1 H) 7.84 (d, >8.80 Hz, 1 H)

7.74 (d, >8.56 Hz, 1 H) 7.59 (s, 1 H) 7.55 (d, >9.29 Hz, 2 H) 7.31 (d, >9.78 Hz, 1 H)

7.22 (d, >8.40 Hz, 2 H) 7.16 (d,>8.40 Hz, 2 H) 6.59 (d, >9.05 Hz, 1 H) 6.13 (br. s., 25 1 H) 4.79 (d, >5.62 Hz, 2 H) 4.33 (s, 2 H) 4.11 (s, 2 H) 3.50 (t, >8.68 Hz, 1 H) 2.97 (q, >7.42 Hz, 2 H) 2.65 - 2.76 (m, 2 H) 2.33 - 2.44 (m, 2 H) 1.38 (t, >7.58 Hz, 3 H)

Synthesis of Compound 6

Compound 6

A solution of intermediate L (0.05 g, 0.222 mmol), HATU (110 mg, 0.289 mmol), diisopropylethylamine (0.075 g, 0.577 mmol) in CH2CI2 (10 mL) was stirred for 30 minutes at 25 °C. Intermediate F” (101 mg, 0.244 mmol) was added to the mixture and 5 the mixture was stirred for 2 hours at 25 °C. The mixture was concentrated under vacuum. The crude product was purified by high performance liquid chromatography over Gemini (eluent: 0.05% ammonia/methanol 20/80 to 5/95). The desired fractions were collected and concentrated to give Compound 6, 0.037 g, 25%.

1HNMR (400 MHz, CHLOROFORM-7) Ô ppm 9.83 (d, 7=2.51 Hz, 1 H) 8.55 (d,7=2.51 Hz, 1 H) 7.83 (d, 7=8.78 Hz, 1 H) 7.75 (d, 7=8.53 Hz, 1 H) 7.55 (d,

7=9.20 Hz, 1 H) 7.53 (d, 7=6.80 Hz, 1 H) 7.22 (d, 7=8.80 Hz, 2 H) 7.15 (d, 7=8.40 Hz,

H) 6.58 (d, 7=8.78 Hz, 1 H) 6.26 (t, 7=5.27 Hz, 1 H) 4.77(d, 7=5.60 Hz, 2 H) 4.33 (s,

H) 4.11 (s, 2 H) 3.50 (quin, 7=8.85 Hz, 1 H) 3.01 (q, 7=7.53 Hz, 2H) 2.65 - 2.74 (m, 2 H) 2.33 - 2.43 (m, 2 H) 1.41 (t, 7=7.53 Hz, 3 H)

Synthesis of Compound 7

CAS [77628-51-4] intermediate B

Compound 7

To a solution of intermediate B” (0.1 g, 0.2497 mmol) in CH2CI2 (15 mL) were added 6-methylimidazo[2,l-B][l,3]thiazole-5-carboxylic acid (CAS [77628-51-4], 0.059 g,

0.324 mmol), HATU (0.142 g, 0.374 mmol) and diisopropylethylamine (0.064 g,

0.498 mmol). The mixture was stirred at room température ovemight. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to dryness. The residue was purified by high performance liquid chromatography (Phenomenex Gemini

150x25mmxl0um, 25ml/min, mobile phase water (containing 0.1%

NHsTLOj/Acetonitrile, gradient from 45/55 to 25/85). The desired fraction was

-41collected and evaporated to remove off CH3CN in vacuum. The residue was lyophihzed to give Compound 7, 0.052 g, 37%.

’H NMR (400MHz, CHLOROFORM-d) δ = 8.31 (d, >4.5 Hz, 1H), 7.88 (d, >9.3 Hz, 1H), 7.72 (d, >8.8 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.27 - 7.23 (m, 2H), 7.19 - 7.13 (m, 2H), 7.06 (d, >9.3 Hz, 1H), 6.90 (d, >4.5 Hz, 1H), 6.03 (br. s„ 1H), 4.80 - 4.69 (m, 4H), 3.06 (dt, >2.3, 12.9 Hz, 2H), 2.84 (tt, >3.6, 12.2 Hz, 1H), 2.59 (s, 3H), 2.03 -

1.95 (m, 2H), 1.78 (dq, >4.3, 12.7 Hz, 2H).

Synthesis of Compound 8

Br nh₂

EtOH, 100°C,

12h

Interm ediate J CAS [5049-61 -6]

HCHO, NaBHjCN, AcOH, MeOH, RT, 10h

O

intermediate B N o

intermediate BL

H₂, HCIaq.,

PtO₂, MeOH,

RT, 10h

LiOH.H_zO,

MeOH, H₂O,

RT, 10h

O

intermediate BM

O

intermediate BO

O

intermediate BO

H₂N

O

HATU, DIPEA, DCM, RT intermediate B

o

Compound 8

Préparation of intermediate BL

A mixture of 2-aminopyrazine (CAS [5049-61-6], 12 g, 126.18 mmol) and intermediate J (39.6 g, 189.27 mmol) in EtOH (10 mL) was stirred at 100 °C for 12 h. The solvent was removed in vacuum. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=5/l~1 /1). The product fractions were collected and the solvent was evaporated to give intermediate BL, 2 g, 8%.

Préparation of intermediate BM

To a solution of intermediate BL (5 g, 24.36 mmol) in MeOH (20 mL) was added platine dioxide (500 mg) under N2, followed by addition a drop of con HCl. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 10 hours. The suspension was filtered through a pad of Celite® and the pad was washed with methanol (50 mL). The combined filtrâtes were concentrated to dryness to give intermediate BM, 5 g, 98%.

Préparation of intermediate BN

To a solution of intermediate BM (5 g, 23.89 mmol) in MeOH (75 mL) was added formaldéhyde aqueous solution (9.7 g, 119.47 mmol, 37%) at 0 °C, followed by addition sodium borocyanohydride (7.5 g, 119.47 mmol) and a drop of acetic acid (0.2 mL). Then the mixture was stirred at room température for ovemight. 10% NH4CI 15 solution (25 mL) was added dropwise. The mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over Na2SÛ4, filtered and the solvent was evaporated under vacuum. The residue was purified by column chromatography over silica gel (dichloromethane/methanol=15:l to 10:1) to give intermediate BN, 1.3 g, 24%.

Préparation of intermediate BQ

To a solution of intermediate BN (0.55 g, 2.46 mmol) in MeOH (25 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.52 g, 12.32 mmol). The mixture was stirred at room température for 10 h. The solvent was removed in vacuum to 25 dryness. The residue was purified by high performance liquid chromatography (DuraShell 150x25mmx5pm, 25ml/min, water (containing 0.05% HCI)/Acetonitrile from 100/0 to 70/30). The desired fraction was collected and evaporated to remove off acetonitrile in vacuum. The residue was lyophilized to give intermediate BO, 0.4 g, 78%.

Préparation of Compound 8

A solution of intermediate BO (0.03 g, 0.143 mmol), HATU (0.071 g, 0.186 mmol) and diisopropylethylamine (0.056 g, 0.430 mmol) in DMF (3 mL) was stirred at room température for Ih. Intermediate B” (0.058 g, 0.143 mmol) was added and the solution 35 was stirred at room température overnight. The solvent was evaporated under vacuum.

The residue was purified by high performance liquid chromatography over Waters Xbridge Prep OBD C18 100χ19πΗηχ5μπι (eluent: water (0.05% ammonia hydroxide

-43n v/v)-MeOH 25/75 to 5/95). The desired fractions were lyophilized under vacuum to give Compound 8, 0.045 g, 53%.

*H NMR (400 MHz, CHLOROFORMA) ppm 7.84 - 7.89 (m, 1 H) 7.68 - 7.73 (m, 1 H)

7.47 - 7.56 (m, 2 H) 7.21 - 7.25 (m, 2 H) 7.12 - 7.18 (m, 2 H) 7.02 - 7.07 (m, 1 H) 5.97

- 6.02 (m, 1 H) 4.69 (m, 4 H) 4.34 (m, 2 H) 3.65 (s, 2 H) 3.00 - 3.09 (m, 2 H) 2.78 2.82 (m, 2 H) 2.67 - 2.75 (m, 2 H) 2.45 - 2.50 (s, 3 H) 1.94 - 2.02 (m, 2 H) 1.71 - 1.83 (m, 3 H) 1.23 (m, 3 H)

Synthesis of Compound 9

pyridine,

MW 150 °C, 30 min

Raney Ni, H₂ (50 psi)

NH3 in MeOH, MeOH intermediate G¹¹

CAS [78060-54-5] CAS [187689-62-1]

F F

intermediate H¹'

HATU, DIPEA

DCM, RT, 2 h

F F

Compound 9

Préparation of intermediate G”

Accordingly, intermediate G” was prepared in the same way as intermediate A” starting 15 from2-chloroquinoline-6-carbonitrile (CAS [78060-54-5] and l-(4-Trifluoromethoxyphenyl)-piperazine CAS [187669-62-1] affording 0.15 g, 84%.

Préparation of intermediate H”

Accordingly, intermediate H” was prepared in the same way as intermediate B” starting 20 from intermediate G” affording 0.15 g, 96%.

Préparation of Compound 9

A solution of 6-methylimidazo[2,l-B][l,3]thiazole-5-carboxylic acid (CAS [7762851-4], 0.018 g, 0.1 mmol), HATU (0.049 g, 0.13 mmol) and diîsopropylethylamine (0.026 g, 0.20 mmol) in CH2CI2 (5 mL) was stirred at room température for Ih.

Intermediate H” (0.04 g, 0.1 mmol) was added and the solution was stirred at room température for 2 hours. The solution was washed with water (10 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was washed with methanol (3 mL). The precipitate was concentrated under vacuum to afford

Compound 9, 0.032 g, 57%

-44( )

1HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.26 - 8.37 (m, 1 H) 7.86 - 7.96 (m,

H) 7.70 - 7.78 (m, 1 H) 7.50 - 7.63 (m, 2 H) 7.11 - 7.20 (m, 2 H) 7.01 - 7.07 (m, 1 H) 6.92 - 7.00 (m, 2 H) 6.85 - 6.91 (m, 1 H) 5.97 - 6.07 (m, 1 H) 4.71 - 4.82 (m, 2 H) 3.83 - 3.99 (m, 4 H) 3.25 - 3.40 (m, 4 H) 2.54 - 2.66 (m, 3 H)

Synthesis of Compound 10

CAS [1529528-99-1] intermediate H

F F

Compound 10

A solution of intermediate H” (0.1 g, 0.249 mmol), 2-ethyl-5H,6H,7H,8H-imidazo[l,2-a]pyridine-3-carboxylic acid CAS [1529528-99-1], 0.107 g, 0.249 mmol), HATU (123 mg, 0.323 mmol) and diisoprpopylethylamine (96 mg, 0.746 mmol) in CH2CI2 (3 mL) was stirred at room température for 1 h. The solvent was evaporated under vacuum. The residue was purified by high performance liquid chromatography over

Phenomenex Gemini C18 250x21.2mmx5pm (eluent: water (0.05% ammonia hydroxide v/v)-MeOH 25/75 to 0/100). The desired fractions were lyophilized under vacuum to give Compound 10, 0.074 g, 52%.

¹HNMR (400 MHz, CHLOROFORM-ri) ppm 7.87 - 7.93 (m, 1 H) 7.69 - 7.75 (m, 1 H) 7.50 - 7.59 (m, 2 H) 7.10 - 7.18 (m, 2 H) 7.01 - 7.07 (m, 1 H) 6.92 - 6.98 (m, 2 H) 5.95

- 6.03 (m, 1 H) 4.66 - 4.74 (m, 2 H) 4.25 (m, 2 H) 3.86 - 3.96 (m, 4 H) 3.28 - 3.37 (m,

H) 2.83 - 2.91 (m, 2 H) 2.65 - 2.75 (m, 2 H) 1.85 - 2.00 (m, 4 H) 1.20 - 1.28 (m, 3 H)

Synthesis of Compound 11 ocf₃

F F

CAS [7Θ060-54-5] CAS [ 170015-09-3]

intermediate J

Préparation of intermediate I”

To a solution of 4-(Trifluoromethoxy)phenethylamine (CAS [170015-99-3], 0.5 g,

2.44 mmol) in DMF (30 mL) was aded 2-chloroquinoline-6-carbonitrile (CAS [7806054-5], 0.460 g, 2.44 mmol) and potassium carbonate (0.674,4.87 mmol). The mixture was stirred at 100 °C for 10 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mLx3). The organic layers were dried over sodium sulfate and concentrated in vacuum. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=5/l). The product fractions were collected and the solvent was evaporated to give intermediate I”, 0.2 g, 23%.

Préparation of intermediate J”

Sodium hydride (0.027 g, 0.67 mmol, 60% in minerai oil) was added to a mixture of intermediate I” (0.16 g, 0.45 mmol) in DMF (10 mL) at 0 °C under N2 atmosphère. The mixture was stirred at 0 °C for 30 minutes. Methyliodide (0.04 mL, 0.537 mmol) was

added to the mixture and stirred at 25 °C for 10 hours. The mixture was quenched with aq. NH4CI, diluted with water. The mixture was extracted with ethyl acetate (3x10 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography over silica gel (petroleum ether/ethyl acetate= 10/1-4/1). The product fractions were collected and the solvent was evaporated to give intermediate J”, 0.18 g, 84%.

Préparation of intermediate K”

To a solution of intermediate J” (0.18 g, 0.485 mmol) in ammonia 4M in methanol (10 mL) was added Raney Nickel (50 mg) under Ni. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 10 hours. The suspension was filtered through a pad of Celite® and the pad was washed with methanol (10 mL). The combined filtrâtes were concentrated în vacuum to give intermediate K”, 0.18 g, 99%.

Préparation of Compound 11

To a solution of 6-Methylimidazo[2,l-b][l,3]thiazole-5-carboxylic acid (CAS [7762851-4], 0.096 g, 0.53 mmol) in DMF (10 mL) was added intermediate K” (0.18 g, 0.48 mmol), HATU (23 7.02 mg, 0.62 mmol) and diisopropylethylamine (0.186 g,

1.44 mmol). The mixture was stirred at room température ovemight. The mixture was diluted with water (20 mL) and extracted with dichloromethane (10 mLx3). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by high performance liquid chromatography (Waters Xbridge Prep OBD C18 150χ30χ5μ, 25ml/min, mobile phase: water (containing 0.05%

NHî.FhOyacetonitrile, gradient from 52/58 to 22/78). The desired fraction was collected and evaporated to remove off acetonitrile in vacuum. The residue was lyophilized to give Compound 11, 0.091 g, 34%.

'H NMR (400MHz, CHLOROFORM-d) δ = 8.32 (d, .7=4.4 Hz, 1H), 7.83 (d, .7=9.3 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.59 - 7.50 (m, 2H), 7.31 - 7.27 (m, 2H), 7.14 (d, J=7.9 Hz,

2H), 6.89 (d, J=4.4 Hz, 1H), 6.82 (d, J=9.3 Hz, 1H), 6.01 (br. s„ 1H), 4.77 (d, 7=5.7

Hz, 2H), 3.90 (t, 7=7.5 Hz, 2H), 3.13 (s, 3H), 2.98 (t, 7=7.3 Hz, 2H), 2.59 (s, 3H).

-47Synthesis of Compound 12 ci.

Cul, BINOL, Cs₂C0. DMSO, 80°C ,15 h 'ΝΝΗ₂

0'

Cl

H inlermediate CD

CAS [211308-81-5]

Cl

NaH, Mel, DMF

intermediate CE

CAS [3002-24-2]

R

HO

B

HO

CAS[98-80-6]

HCOOH

AV °C, 16 h

HN

AW trans-2-amino-cyclohexanol, NaHMDS, Nil₂, i-PrOH, 60°C, MW, 1 h, 90°C, MW, 1 h 120°C, MW, 5 h,

K₂CO₃, DMSO, mW 120’C, 30 min

Raney Ni, H₂ NHjinMeOH, MeOH inlemnediale L

CAS [78060-54-5] intenmedfate AW

intemiediate N

Compound 12

Préparation of intermediate CD

A mixture of 5-chloro-3-iodopyridin-2-amine (CAS [211308-81-5], 4 g, 15.72 mmol),

2,4-Hexadione (CAS [3002-24-2], 4.50 g, 34.58 mmol), césium carbonate (5.12 g, 15.71 mmol), BINOL (900.20 mg, 3.14 mmol) and copper iodide (299.39 mg,

1.57 mmol) in DMSO (50 mL) was stirred for 15 hours under N2 flow. Brine and ethyl acetate were added to the mixture. The organic layer was separated, washed with brine, dried over MgSOi and filtered. The filtrate was concentrated. The crude product was purified by column chromatography over silica gel (eluent: ethyl acetate/hexane from 0 to 1/1). The desired fractions were collected and concentrated to give intermediate

CD, 2.5 g, 67%

Preparation of intermediate CE

Sodium hydride (0.354 g, 8.85 mmol) was added to a solution of intermediate CD (2.2 g, 7.38 mmol) in THF (40 mL) at 0 °C. After stirred for 30 minutes, methyl iodide 5 (1.26 g, 8.85 mmol) was added. The mixture was warmed up to 25 °C and stirred for hours. The mixture was poured into ice water. The mixture was extracted with ethyl acetate (50 mLx2). The organic layers were combined, washed with brine, dried over MgSÛ4 and filtered. The filtrate was concentrated. The crude product was purified by column chromatography over silica gel (cluent: ethyl acetate / petroleum ether from 10 0 to 1/3), The filtrate was concentrated to give intermediate CE, 1.6 g, 86%.

Préparation of intermediate AV

Intermediate AV was prepared in the same way as intermediate S, starting from intermediate R and Phenylboronic acid CAS [98-80-6], yielding 0.3 g, 62%.

Préparation of intermediate AW

Accordingly, intermediate AW was prepared in the same way as intermediate T, starting from intermediate AV, yielding 0.27 g, 99%.

Préparation of intermediate N”

Sodium hydroxide (0.225 g; 5.62 mmol) was added to a solution of intermediate CE (0.5 g; 1.88 mmol) in EtOH (7.5 mL) and H2O (7.5 mL) and the mixture was stirred at 70 °C for 48 h. The mixture was evaporated in vacuo to give a colorless oil which was azeotroped with toluene (twîce) to give 0.777 g of intermediate N” as white solid (quant).

Préparation of intermediate L”

A suspension of intermediate AW (0.169 g, 806 pmol), 2-chloroquinoline-6-carbonitrile (CAS [78060-54-5], 0.304 g, 1.61 mmol) and potassium carbonate (0.557 g, 30 4.03 mmol) in DMSO (3 mL) was heated to 120 °C using a single mode microwave (Biotage Initiator60) with a power output ranging from 0 to 400 W for 30 min [fixed hold time on]. The reaction was quenched with water and extracted with EtOAc (3x). The combined organic phases were washed with water (twice) and brine (3x), dried over MgSO4, filtered and evaporated to dryness. The crude was purified by préparative 35 LC (irregular silica 15-40 μηι, 12 g GraceResolv, dry loading (silica), mobile phase: heptane/EtOAc 90/10 to 70/30) to obtain 0.142 g of intermediate L” (54%).

Préparation of intermediate M”

A mixture of intermedediate L” (0.099 g, 0.304 mmol) and Ra-Ni (77.5 mg,

1.32 mmol) in ammonia 7M in Me OH (3.3 mL) was hydrogenated at room température under 2 bar overnight. The mixture was fïltered through a pad of celite® and rised with

EtOAc. The filtrate was evaporated until dryness to give 0.098 g of intermediate M” as a pale grey solid (98%).

Préparation of Compound 12

Diisopropylethylamine (0.12 mL, 0.706 mmol) and HATU (0.14 g, 0.367 mmol) were successively added to a solution of intermediate N” (0.074 g, 0.282 mmol) in DMF (7.8 mL). The resulting mixture was stirred at room température for 30 min, before the addition of intermediate M” (0.093 g, 0.282 mmol) and the mixture was stirred at room température overnight. The reaction mixture was diluted with EtOAc and washed with an aq. sat. NaHCOs solution (twice) and brine (twice). The organic phase was dried over MgSO4, fïltered and evaporated to dryness. The crude was purified by préparative LC (Irregular silica 15-40 pm, 14 g Grâce Resolv, dry loading (silica), mobile phase gradient: from Heptane/EtOAc 90/10 to 50/50) to obtain a solid which was triturated in Et₂O, fïltered and dried under vacuum to obtain 0.079 g of Compound 12 as white solid (51%).

Ή NMR (400 MHz, DMSO-tZ₆) δ ppm 8.34 (t, 7=5.8 Hz, 1 H) 8.27 (d, 7=2.0 Hz, 1 H) 8.21 (d, 7=2.0 Hz, 1 H) 7.99 (d, 7=9.1 Hz, 1 H) 7.62 (s, 1 H) 7.55 (s, 2 H) 7.17 - 7.34 (m, 5 H) 6.70 (d, 7=9.1 Hz, 1 H) 4.59 (d, 7=6.1 Hz, 2 H) 4.23 (s, 2 H) 4.01 (s, 2 H) 3.80 (s, 3 H) 3.34 - 3.50 (m, 1 H) 3.16 (q, 7=7.6 Hz, 2 H) 2.55 - 2.68 (m, 2 H) 2.27 - 2.44 (m, 2 H) 1.21 (t, 7=7.6 Hz, 3 H).

-50Synthesis of Compound 13

Compound 13

Préparation of intermediate O”

A suspension of intermediate AW (0.127 g, 750 pmol), 2-chloroquinoline-6carbonitrile (CAS [78060-54-5], 0.283 g, 1.50 mmol), and Potassium tert-butoxide (0.421 g, 3.75 mmol) in DMSO (2.8 mL) was heated to 120 °C using a single mode micro wave (Biotage InitiatorôO) with a power output ranging from 0 to 400 W for

30 min [fixed hold time on]. The reaction was quenched with water and extracted with

EtOAc (3x). The combined organic phases were washed with water (2x) and brine (3x), dried over MgSO4, fîltered and evaporated to dryness. The crude product was purified by préparative LC (irregular silica 15-40 pm, 24 g GraceResolv, dry loading (silica), mobile phase: heptane/EtOAc 90/10 to 50/50) to obtain 0.143 g of intermediate O” as yellow solid (67%).

Préparation of intermediate P”

A mixture of intermediate O” (0.141 g, 0.494 mmol) and Raney Nickel (0.126 g,

2.15 mmol) in ammonia 7M in MeOH (5.4 mL) was hydrogenated at room température under 2 bar overnight. The reaction mixture was fîltered over Celite®, rinsed with

EtOAc and evaporated to dryness to obtain 0.138 g of intermediate P” as white solid (97%).

Préparation of Compound 13

To a solution of intermediate N” (0.17 g, 0.653 mmol) and intermediate P” (0.156 g, 0.539 mmol) in DMF (18 mL) were added HATU (0.323 g, 0.849 mmol) and diisopropylethylamine (0.28 mL, 1.63 mmol) and the mixture was stirred atroom température ovemight. The reaction mixture was diluted with EtOAc and washed with an aq. sat. NaHCCh solution (twice) and brine (twice). The combined organic phases were dried over MgSO4, filtered and evaporated to dryness. The crude was purified by préparative LC (Irregular silica 15-40 pm, 24 g Grâce Resolv, dry loading (silica), mobile phase gradient: from Heptane/EtOAc 90/10 to 10/90) to obtain 0.167 g as a white solid which was triturated in Et2 O and EtOH, filtered and dried under vacuum to obtain 0.116 g of Compound 13 as a white solid (35%).

Ή NMR (400 MHz, DMSO-7₆) δ ppm 8.35 (t, 7=5.9 Hz, 1 H) 8.27 (s, 1 H) 8.21 (s,

H) 8.03 (d, 7=8.9 Hz, 1 H) 7.65 (s, 1 H) 7.58 (s, 2 H) 7.34 - 7.45 (m, 4 H) 7.24 - 7.29 (m, 1 H) 6.78 (d, 7=8.6 Hz, 1 H) 4.60 (d, 7=5.6 Hz, 2 H) 4.51 (t, 7=8.1 Hz, 2 H) 3.97 -

4.10 (m, 3 H) 3.81 (s, 3 H) 3.13 - 3.19 (m, 2 H) 1.21 (br t, 7=7.6 Hz, 3 H).

Synthesis of Compound 14

CAS [504-29-0]

CAS: [3240-34-4]

BF₃OEt>, THF °C to rt

intermediate CG

H_z (1 bar) HCl, PtO_z MeOH, rt

intermediate CH

LiOH-HzO

MeOH, H_ZO ’C

intermediate Cl

o

h₂i

F F

N )---ff 0 hlATU, ^DIPEA· ^DblF· ^RT intermediate Cl intermediate B

F F

Compound 14

Préparation of intermediate CG

A solution of 2-aminopyridine (CAS [504-29-0], 4.0 g; 42.5 mmol) in THF (220 mL) was cooled to 5 °C, before the addition of ethyl propionylacetate (CAS [4949-44-4],

6.1 mL; 42.5 mmol), lodobenzene Diacetate (CAS [3240-34-4], 13.7 g; 42.5 mmol) and BFa’OEti (556 pL; 2.13 mmol). The resulting mixture was allowed to warm to rt, then stirred at rt ovemight. The mixture was poured into saturated aqueous NaHCOs and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSCh, filtered and concentrated to give 18.8 g as an orange solid. The crude was taken-up in Et2Û, leading to précipitation. The precipitate was filtered to give 3.8 g of crude as an off-white solid (41%). The filtrate was purified by préparative LC (Regular silica 30 pm, 25 g, Iiquid loadîng (CH2CI2), mobile phase gradient: from

Heptane/EtOAc 100/0 to 50/50) to obtain 1.7 g of intermediate 30 as an off-white solid 15 which was taken-up in EtiO, the solid was filtered and dried under high vacuum to give

1.2 g of intermediate CG as a white solid (13%).

Préparation of intermediate CH

A solution of intermediate CG (1.2 g; 5.50 mmol) in MeOH (27 mL) was degassed by 20 N2 bubbling for 10 min before the addition of Platinum Oxide (125 mg; 0.55 mmol) and HCl (125 pL; 1.50 mmol). The resulting mixture was hydrogenated at rt under bar ovemight. EtOAc was added and the mixture was filtered through a pad of celite®, the filtrate was concentrated until dryness to give 1.4 g of intermediate CH as colourless oil (quant).

Préparation of intermediate CI

Lithium hydroxide monohydrate (170 mg; 4.05 mmol) was added to a solution of intermediate CH (300 mg; 1.35 mmol) in MeOH (3 mL) and H2O (158 pL). The resulting mixture was stirred at 50 °C for 48 h. The solvent was evaporated in vacuo

until dryness to give an off-white gum which was azeotroped with toluene (twice), then dried under high vacuum to give 0.353 g of intermediate CI as an off-white solid (used as such in the next step).

Préparation of Compound 14

Diisopropylethylamine (0.516 mL; 3.00 mmol) and HATU (0.593 g; 1.56 mmol) were added successively to a solution of intermediate CI (0.24 g; 1.20 mmol) in DMF (36 mL). The resulting mixture was stirred at room température for 30 min, before the addition of intermediate B” (0.481 g; 1.20 mmol) and the mixture was stirred at room température for 2 h. The reaction mixture was evaporated in vacuo until dryness then diluted with EtOAc and washed with brine (twice). The organic layer was dried over MgSO-i, filtered and evaporated to dryness. The crude was purified by préparative LC (Regular silica 30 pm, 12 g Interchim, dry loading (Celite®), mobile phase gradient: from Heptane/EtOAc/MeOH 90/8/2 to 50/40/10) to obtaîn 0.2 g as white solid. The solid was triturated in EtiO, filtered and dried under high vacuum to give 0.126 g of

Compound 14 as white solid (18%).

Ή NMR (400 MHz, DMSO-îZ₆) δ ppm 8.26 (t, >5.8 Hz, 1 H) 7.99 (d, >9.1 Hz, 1 H)

7.47 - 7.58 (m, 3 H) 7.40 (d, >7.8 Hz, 2 H) 7.28 (d, >9.1 Hz, 3 H) 4.70 (br d, >13.6 Hz, 2 H) 4.50 (d, >6.1 Hz, 2 H) 4.00 (t, >5.6 Hz, 2 H) 2.86 - 3.03 (m, 3 H)

2.70 (m, 2 H) 2.63 (m 2 H) 1.76 - 1.93 (m, 6 H) 1.59 - 1.70 (m, 2 H) 1.10 (t, >7.6 Hz,

H).

Synthesis of Compound 15 & Compound 16

intermediale Q, intermediate Q₂ intermediate R, intemiediate R₂

intermediate intermediate S₂

intermediate T, intermediate T₂

COQH

Compound 15 Compound 16

Préparation of intermediates Q”

To a solution of 3,4-dimaminobenzonitrile (CAS [17626-40-3], 1 g, 7.51 mmol) in MeOH (20 ml) was added ethylglyoxalate (6.81 ml, 34.35 mmol, 35%). After stirring ovemight at room température, the precipitate was collected and washed with methanol (10 ml) to give a mixture of intermediate Q”, 0.6 g, 47%.

Préparation of intermediates R”

Intermediate Q” (0.6 g, 3.5 mmol) was dîssolved in phosphoryl chloride (20 mL). The mixture was heated to reflux for about 2 h. The mixture was poured into water and basified with aqueous NaHCCh till pH = 8 and extracted with dichloromethane (30 mlx3). The organic layer was dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel chromatography eluted with petroleum ether: ethyl acetate= 10:1 to afford product as a mixture of intermediate R”, 0.6 g, 90%.

-55| C)

Préparation of intermediate S”

A mixture of intermediates R” (0.5 g, 2.65 mmol), N-Methyl-N-[4-(trifluoromethoxy) benzyl]amine (0.6 g, 2.91 mmol) and potassium carbonate (0.73 g, 5.3 mmol) in acetonitrile (30 mL) was stirred at 100 °C for 10 h. The mixture was evaporated to dryness and diluted with water (30 mL), extracted with ethyi acetate (50 mLx3). The organic layer was dried over NasSOi, filtered and concentrated. The residue was purified by silica gel chromatography eluted with petroleum ether: ethyi acetate= 8:1 to afford product as a mixture of intermediates S”, 0.6 g, 63%.

Préparation of intermediates T”

To a solution of intermediates S”(0.5 g, 1.4 mmol) in MeOH (50 mL) was added Raney Nickel (0.25 g) and ammonia in MeOH(10 mL, 4M) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 25 °C for 10 hours. The suspension was filtered through a pad of 15 Celite® was washed with MeOH (20 mL). The combined filtrâtes were concentrated to dryness. The residue was purified by high performance liquid chromatography (Phenomenex Synergî C18, 250x21.2mmx4pm, 25ml/min, water (containing 0.05% HCl)/Acetonîtrile gradient from 77/23 to 57/43). The desired fraction was collected and evaporated to remove off acetonitrile in vacuum. The residue was adjusted to pH =9 20 with aqueous NaHCOs solution (20 mL) and extracted with dichloromethane (3x50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuum to give intermediate Ti”, 0.1 g, 20% and T2”, 0.3 g, 59%.

Préparation of Compound 15

To a solution of intermediate Ti” (0.1 g, 0.276 mmol) in CH2CI2 (25 mL) was added chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.056 g, 0.251 mmol), HATU (0.124 g, 0.326 mmol) and diisopropylethylamine (0.084 g, 0.653 mmol). The mixture was stirred at room température ovemight. The reaction mixture was poured into water and extracted dichloromethane. The combined 30 organic layers were dried over NaaSCL and concentrated to dryness. The residue was purified by high performance liquid chromatography (Waters Xbrîdge Prep OBD Cl8 150χ30χ5μ, 20ml/min, water (containing 0.05% NHj.HiOj/Methanol gradient from 25/75 to 0/100). The desired fraction was collected and evaporated to remove off methanol in vacuum. The residue was lyophilized affording Compound 15, 0.054 g, 35 38%.

1HNMR (400MHz, CHLOROFORM-d) δ 9.57 (s, 1H), 8.50 (s, 1H), 7.86 (s, 1H), 7.75 - 7.68 (m, 1H), 7.63 (dd, J =1.5, 8.6 Hz, 1H), 7.56 (d, J =9.3 Hz, 1H), 7.36 - 7.29 (m,

3H), 7.18 (d, J =7.9 Hz, 2H), 6.21 (br. s., 1H), 4.97 (s, 2H), 4.86 (d, J =5.3 Hz, 2H),

3.28 (s, 3H), 3.01 (q, J =7.8 Hz, 2H), 1.42 (t, J =7.5 Hz, 3H).

Préparation of Compound 16

To a solution of intermediate T2” (0.15 g, 0.414 mmol) in CH2CI2 (25 mL) was added

6-chloro-2-ethylîmidazo[3,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.085 g, 0.376 mmol), HATU (0.186 g, 0.489 mmol) and diisopropylethylamine (0.126 g, 1.11 mmol). The mixture was stirred at room température overnight. The reaction mixture was poured into water and extracted dichloromethane. The combined organic layers were dried over Na2SÜ4 and concentrated to dryness. The residue was triturated with methanol (20 mL) and fïltered to afford Compound 16, 0.121 g, 56%. 1H NMR (400MHz, CHLOROFORM-d) δ 9.56 (d, J =1.3 Hz, 1H), 8.49 (s, 1H), 7.90 (d, J =8.4 Hz, 1H), 7.67 (s, 1H), 7.56 (d, J =9.5 Hz, 1H), 7.41 (dd, J =1.7, 8.5 Hz, 1H),

7.36 - 7.28 (m, 3H), 7.18 (d, J =8.2 Hz, 2H), 6.24 (br. s., 1H), 4.96 (s, 2H), 4.86 (d, J =5.7 Hz, 2H), 3.27 (s, 3H), 3.02 (q, J =7.5 Hz, 2H), 1.43 (t, J =7.6 Hz, 3H).

The following compounds were also prepared in accordance with the procedures described herein:

Compound 17

Compound 18 ci

3H), 7.18 (d, J =7.9 Hz, 2H), 6.21 (br. s., 1H), 4.97 (s, 2H), 4.86 (d, J =5.3 Hz, 2H),

3.28 (s, 3H), 3.01 (q, J =7.8 Hz, 2H), 1.42 (t, J =7.5 Hz, 3H).

Préparation of Compound 16

To a solution of intermediate T2” (0.15 g, 0.414 mmol) in CH2CI2 (25 mL) was added

6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.085 g, 0.376 mmol), HATU (0.186 g, 0.489 mmol) and diisopropylethylamine (0.126 g, 1.11 mmol). The mixture was stirred at room température ovemight. The reaction mixture was poured into water and extracted dichloromethane. The combîned organic layers were dried overNa2SC>4 and concentrated to dryness. The residue was triturated with methanol (20 mL) and filtered to afford Compound 16, 0.121 g, 56%. 1H NMR (400MHz, CHLOROFORM-d) δ 9.56 (d, J =1.3 Hz, 1H), 8.49 (s, 1H), 7.90 (d, J =8.4 Hz, 1H), 7.67 (s, 1H), 7.56 (d, J =9.5 Hz, 1H), 7.41 (dd, J =1.7, 8.5 Hz, 1H),

7.36 - 7.28 (m, 3H), 7.18 (d, J =8.2 Hz, 2H), 6.24 (br. s., 1H), 4.96 (s, 2H), 4.86 (d, J =5.7 Hz, 2H), 3.27 (s, 3H), 3.02 (q, J =7.5 Hz, 2H), 1.43 (t, J =7.6 Hz, 3H).

The following compounds were also prepared in accordance with the procedures described herein:

Compound 17

Compound 18 ci

Compound 19

Compound 20

Cl

Compound 21

Cl

Compound 22

Cl

Compound 23

Compound 24 o

Compound 25

Compound 26

Synthesis of Compound 27

K,CO,, DM F, ____ ^RT’ ^{48 h}

VnV ’ —^Ξ—COOEt -------.

nh₂

CAS [6295-87-0] CAS [4341-76-8]

THF/H₂O/MeOH, NaOH, 70°C intermediate U

COOH

intermediate V

Intermediate U”

Ethyl-2-butynoate (CAS [4341-76-8], 6.2 mL, 54.0 mmol) was added to a solution of 1-aminopyridinium iodide (CAS [6295-37-0], 10 g, 45 mmol) and potassium carbonate (7.5 g, 54 mmol) in DMF (100 mL). The resulting mixture was stirred at room température for 72 h. The mixture was evaporated to dryness and the residue was solubïlized in EtOAc and washed with brine (3x). The organic layer was dried over MgSC>4, fïltered and evaporated to dryness to give 5.1 g of intermediate U” as a brown solid (55%).

Intermediate V”

Intermeidate V” was prepared in accordance with the following procedure: aqueous sodium hydroxide 8M (e.g. about 164 mmol) is added to a solution of intermediate U” (e.g. about 32.1 mmol) in THF (e.g. about 39 mL) and methanol (e.g. about 39 mL). The resulting mixture may be stirred at e.g. 70 °C overnight. HCl (IM) may be added to the mixture untii pH~7-8. The resulting precipitate may be fïltered and dried under high vacuum to give intermediate V” as an off-white solid.

intermediate V intermediate H

F F

Compound 27

A solution of intermediate V” (0.1 g, 0.57 mmol), HATU (0.237 g, 0.62 mmol) and triethylamine (0.237 mL, 1.70 mmol) in DMF (7 mL) was stirred at room température for 30 min before the addition of intermediate H” (0.24 g, 0.60 mmol) in DMF (5 mL). The resulting mixture was stirred at room température for 2 h. The mixture was evaporated to dryness. The residue was solubilized in EtOAc and washed with an aq. solution of NaHCOî (1%) (2x), water and brine. The organic layer was dried over MgSO.i, filtered and evaporated to dryness. The crude product was purified by préparative LC (Regular SiOH 30 pm, 25 g Interchim, dry loading (Celite ®), mobile phase gradient DCM/MeOH from 100/0 to 95/5) to give 0.152 g of Compound 27 as a white solid (38%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.67 (d, J = 6.9 Hz, 1 H), 8.18 (t, J = 5.8 Hz,

H), 8.08 (d, J = 9.1 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.67 (s, 1 H), 7.59 (s, 2 H),

7.40 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 9.5 Hz, 1 H), 7.24 (d, J = 8.8 Hz, 2 H), 7.09 (d, J = 9.1 Hz, 2 H), 6.98 (t, J = 6.9 Hz, 1 H), 4.60 (d, J - 6.0 Hz, 2 H), 3.86 - 3.82 (m, 4 H),

3.33 - 3.30 (m, 4 H), 2.60 (s, 3 H)

Synthesis of Compound 28 /=\ fl K₂CO₃, DMF, /=\ Raney Ni, H₂ 2 bar z—< Cl _12œc z—G /)—N JS—CF, NH, in MeOH, MeOH ^NC“C=/“^{N + ην}\Λη —---- ^{N :}--CAS [78060-54-5] CAS [1212322-57-0] intermediate W o

Préparation of intermediate W”

A mixture of 2-chloroquinoline-6-carbonitrile ([78060-54-5], 0.464 g, 2.46 mmol), trans-6-(Trifluoromethyl)-3-azabicycIo[3.1.0]-hexane hydrochloride ([1212322-57-0], 0.6 g, 3.20 mmol) and potassium carbonate (1.02 g, 7.38 mmol) in DMF (19 mL) was heated to 120 °C overnight. The mixture was evaporated to dryness. The residue was 25 solubilized in EtOAc and washed with brine (2x), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by préparative LC (irregular

SiOH, 15-40 pm, 80 g, Grâce, dry loading (silica), mobile phase gradient

Heptane/EtOAc from 90/10 to 70/30) to give 0.3 g of intermediate W” as a white solid (40%).

Préparation of intermediate X”

Accordingly, intermediate X” was prepared in the same way as intermediate B”, starting from intermediate W”, and yielding 0.291 g, as a white powder, 97%.

Préparation of Compound 28

To a solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid ([121614210 18-5], 0.066 g, 0.288 mmol) in DCM (2.9 mL) and triethylamine (0.10 mL) were added

EDCI (0.083 g, 0.432 mmol) and HOBt (0.059 g, 0.434 mmol) and the mixture was stirred at room température for 30 min. Intermediate X” (0.094 g, 0.306 mmol) was added and the mixture was stirred at room température for 8 h, then heated to 80 °C for 5 h. The mixture was cooled to room température and washed with water (2x). The organic layer was dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 24 g, Grâce, dry loading (silica), mobile phase gradient Heptane/EtOAc from 90/10 to 10/90) to give 0.022 g of Compound 28 as white solid (15%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.09 (d, J = 1.6 Hz, 1 H), 8.54 (t, J = 6.0 Hz, 1

H), 8.01 (d, J = 9.1 Hz, 1 H), 7.69 - 7.64 (m, 2 H), 7.55 (s, 2 H), 7.46 (dd, J - 9.6, 2.0

Hz, 1 H), 6.88 (d, J = 9.1 Hz, 1 H), 4.62 (d, J = 5.7 Hz, 2 H), 3.94 (d, J = 10.7 Hz, 2 H), 3.54 (br d, J = 10.1 Hz, 2 H), 3.00 (q, J = 7.6 Hz, 2 H), 2.20 (br s, 2 H), 1.86 - 1.80 (m, 1 H), 1.25 (t, J - 7.6 Hz, 3 H).

Characterising Data Table__________________________________________________

Compound No	Meting Point (Kofler or DSC)	LCMS
Rt	UVArea%	MW exact	BPM1/ BPM2	LCMS Method
1		3.69	95.0	620.2	621.2	Method A
2		3.52	100.0	619.2	620.2	Method A

Further Characterising Data

Compound No	Meting Point (Kofler or DSC)	LCMS
Rt	UVArea%	MW exact	BPM1/ BPM2	LCMS Method
Cpd 3		3.3	95.0	607.2	608.1	Method D
Cpd 17		4.23	97.4	567.2	568.1	Method C

Compound No	Meting Point (Kofler or DSC)	LCMS
Rt	UVArea%	MW exact	BPM1/ BPM2	LCMS Method
Cpd 7		3.19	97.4	565.2	566.1	Method D
Cpd 18		3.29	97.7	567.2	568.1	Method D
Cpd 9		3.19	100.0	566.2	567.1	Method D
Cpd 19		3	99.3	525.1	526.1	Method D
Cpd 5 or Cpd 2		3.52	100.0	619.2	620.2	Method D
Cpd 16		3.8	100.0	568.2	569.1	Method D
Cpd 6 or Cpd 1		3.69	95.0	620.2	621.2	Method D
Cpd 15		3.86	100.0	568.2	569.1	Method D
Cpd 20		3.3	98.2	567.2	568.1	Method D
Cpd 21		3.82	97.1	620.2	621.3	Method D
Cpd 22		3.89	98.9	621.2	622.2	Method D
Cpd 23		3.74	94.4	548.2	549.2	Method D
Cpd 4		2.64	98.3	491.2	492.2	Method D
Cpd 8		3.01	99.8	592.3	593.2	Method D
Cpd 10		2.94	99.7	578.3	579.2	Method D
Cpd 24		2.48	95.1	483.2	484.1	Method D
Cpd 25		2.51	97.5	477.2	478.1	Method D
Cpd 11		5.54	98.4	539.2	540.1	Method E
Cpd 12	171.59°C/-59.2Jg-l, 25°Cto 350°C/10°Cmin/40pl Al	3.68	99.4	549.2	550.3/ 608.7 [M+CH3COO]-	Method B
Cpd 14	188.28°C/-72.04Jg-l, 25°Cto 350Τ/10ΈΓΤΐΙη/40μΙ Al	3.49	97.7	577.3	578.3/ 636.7 [M+CH3COO]-	Method B
Cpd 13	208.76°C/-94.35Jg-l, 25°Cto 350°C/10°Cmin/40pl Al	3.42	100.0	509.2	510.2/ 508.3	Method B
Cpd 26	207.61 °C / -95.26 J/g (DSC: 25°C to 350°C/10°Cmin/40 μΙ Al)	3.55	98.2	559.6	560.2/ 618.5 [M+CH3COO]·	Method B

Compound No	Meting Point (Kofler or DSC)	LCMS
Rt	UV Area %	MW exact	BPM1/ BPM2	LCMS Method
Cpd 27	217.14 °C/-83.66 J/g (DSC: 25°C to 350°C/10°Cmin/40 μΙ Al)	3.4	96	560.2	561.2/ 619.5 [M+CH3COO]·	Method B
Cpd 28	251.69 °C / -79.88 JgA-l, 25°C to 350°C/10°Cmin/40 μΙ Al (DSC: 25°C to 350°C/10°Cmin/40 M	3.3	98.8	513.2	514.2/ 512.3	Method B

Analytical methods

LCMS

The mass of some compounds was recorded with LCMS (liquid chromatography mass 5 spectrometry). The methods used are described below.

General procedure LCMS Methods A

The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in 10 the respective methods. If necessary, additional detectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time, etc) in order 15 to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental rétention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]⁺ (protonated molécule) and/or [M-H]’(deprotonated molécule). In case the 20 compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]⁺,

[M+HCOO], etc). For molécules with multiple isotopic patterns (Br, CL.), the reported value is the one obtained for the lowest isotope mass. Ail results were obtained with experimental uncertainties that are commonly associated with the method used.

Hereinafter, “MSD” Mass Sélective Detector, “DAD” Diode Array Detector.

Table: LCMS Method codes (Flow expressed in mL/min; column température (T) in °C; Run time in minutes).

Method code	Instrument	Column	Mobile phase	gradient	Flow	Run time
					50
	Agilent: 1100/1200 -DAD and MSD	Agilent: TC-C18 (5μπι, 2.1x50mm)	A: CF3COOH 0.1%in water, B: CF3COOH 0.05% in CHCN	90% A for 0.8min, to 20% A in 3.7min, held for 3min, backto 90% A in 2min.	0.8	10.5
50

When a compound is a mixture of isomers which give different peaks in the LCMS method, only the rétention time of the main component is given in the LCMS table.

Further Methods

General procedure

The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specifîed in 10 the respective methods. If necessary, additional detectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time...) in order to 15 obtain ions allôwing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental rétention times (Rt) and ions. If not specifîed differently in the table of data, the reported molecular ion corresponds to the [M+H]⁺ (protonated molécule) and/or [M-H]‘ (deprotonated molécule). In case the 20 compound was not directly ionizable the type of adduct is specifîed (i.e. [M+NH4J¹', [M+HCOO]', etc...). For molécules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. Ail results were obtained with experimental uncertainties that are commonly associated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “RT” room température, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector.

-65Table: LCMS Method codes (Flow expressed in mL/min; column température (T) in °C; Run time in minutes).

Method code	Instrument	Column	Mobile phase	gradient	Flow	Run time
Column T
Method B	Waters: Acquity UPLC®DAD and Quattro Micro™	Waters: BEH C18(1.7pm, 2.1x100 mm)	A: 95% CH3COONH4 7mM / 5% CHjCNjB: CH3CN	84.2% A for 0.49min, to 10.5% A in 2.18min, held for 1.94min, back to 84.2% A in 0.73min, held for 0.73min.	0.343	6.2
40
40

Hereinafter, “MSD” Mass Sélective Detector, “DAD” Diode Array Detector.

Table: LCMS Method codes (Flow expressed in mL/min; column température (T) in °C; Run time in minutes).

Method Code	Instrument	Column	Mobile phase	gradient	Flow	Run time
Column T
Method C	Agilent: 1100/1200 -DAD and MSD	Agilent: TC-C18 (5pm, 2.1x50mm)	A:CF3COOH 0.1% in water, BTUCOOH 0.05% in CH3CN	100% A for 1 min, to 40% A in 4min, toi5% A in 2.5min, back to 100% A in 2min.	0.8	10.5
50
Method D	Agilent: 1100/1200 -DAD and MSD	Agilent: TC-C18 (5pm, 21x50mm)	A:CF3COOH 0.1% in water, B:CF3COOH 0.05% in CH3CN	90% A for 0.8min, to 20% A in 3.7min, held for 3min, backto 90% A in 2min.	0.8	10.5
50
Method E	Agilent: 1100/1200 -DAD and MSD	Waters: XBridge™ ShieldRP18 (5μιη, 2.1x50mm)	ANHtOH 0.05% in water, BiCHaCN	100% A for 1min, to 40% A in 4min, held for 2.5min, back to 100% A in 2min.	0.8	10.5
40
50

Pharmacological examples

MIC détermination for testing compounds against M. tuberculosis. TEST1

Appropriate solutions of experimental and reference compounds were made in 96 well plates with 7H9 medium. Samples of Mycobacterium tuberculosis strain H37Rv were taken from cultures in logarithmic growth phase. These were first diluted to obtain an optical density of 0.3 at 600 nm wavelength and then diluted 1/100, resulting in an inoculum of approximately 5x10 exp5 colony forming units per well. Plates were incubated at 37°C in plastic bags to prevent évaporation. After 7 days, resazurin was added to ail wells. Two days later, fluorescence was measured on a Gemini EM Microplate Reader with 543 excitation and 590 nm émission wavelengths and MICso and/or pICso values (or the like, e.g. IC50, IC90, pICgo, etc) were (or may be) calculated.

TEST 2

Round-bottom, stérile 96-well plastic microtiter plates are filled with 100 μΐ of Middlebrook (lx) 7H9 broth medium. Subsequently, an extra 100 μ! medium is added to column 2. Stock solutions (200 x final test concentration) of compounds are added in 2 μΐ volumes to a sériés of duplicate wells in column 2 so as to allow évaluation of their effects on bacterial growth. Serial 2-fold dilutions are made directly in the microtiter plates from column 2 to 11 using a multipipette. Pipette tips are changed after every 3 dilutions to minimize pipetting errors with high hydrophobie compounds. Untreated control samples with (column 1) and without (column 12) inoculum are included in each microtiter plate. Approximately 10000 CFU per well of Mycobacterium tuberculosis (strain H37RV), in a volume of 100 μΐ in Middlebrook (lx) 7H9 broth medium, is added to the rows A to H, except column 12. The same volume of broth medium without inoculum is added to column 12 in row A to H. The cultures are incubated at 37°C for 7 days in a humidified atmosphère (incubator with open air valve and continuous ventilation). On day 7 the bacterial growth is checked visually.

The 90 % minimal inhibitory concentration (MIC90) is determined as the concentration 30 with no Visual bacterial growth.

TEST 3: Time kill assays

Bactericidal or bacteriostatic activity of the compounds can be determined in a time kill assay using the broth dilution method. In a time kill assay on Mycobacterium tuberculosis (strain H37RV), the starting inoculum of M. tuberculosis is 10⁶ CFU / ml in Middlebrook (lx) 7H9 broth. The antibacterial compounds are used at the concentration of 0.1 to 10 times the MIC90. 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 détermination of viable counts by serial dilution (10'¹ to 10‘⁶) in Middlebrook 7H9 medium and plating (100 μΐ) on Mîddlebrook 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 is commonly defined as 3-logio decrease in number of CFU per ml as compared to untreated inoculum. The potential carryover effect of the drugs is removed by serial dilutions and counting the colonies at highest dilution used for plating. ’

TEST 4 (see also test 1 above; in this test a different strain of Mycobacterium tuberculosis strain is employed)

Appropriate solutions of experimental and reference compounds were made in 96 well plates with 7H9 medium. Samples of Mycobacterium tuberculosis strain EH 4.0 (361.269) were taken from cultures in stationary growth phase. These were first diluted to obtain an optical density of 0.3 at 600 nm wavelength and then diluted 1/100, resulting in an inoculum of approximately 5x10 exp5 colony forming units per well. Plates were incubated at 37°C in plastic bags to prevent évaporation. After 7 days, resazurin was added to ail wells. Two days later, fluorescence was measured on a

Gemini EM Microplate Reader with 543 nm excitation and 590 nm émission wavelengths and MIC50 and/or pIC50 values (or the like, e.g. IC50, IC90, pIC90, etc) were (or may be) calculated. pICso values may be recorded below in pg/mL.

RESULTS

Compounds of the invention/examples, for example when tested in Test 1 or Test 2 decribed above, may typically hâve an IC90 value from 0.01 to 10 pg/ml. Compounds of the invention/examples, for example when tested in Test 1 or Test 2 described above, may typically hâve a pICso from 3 to 10 (e.g. from 4.0 to 9.0, such as from 5.0 to 8.0)

Compounds ofthe examples were tested in Test 1 described above (in section “Pharmacological Examples”) and the following results were obtained:

Biological Data Table

Compound No	plC50	plC50 *	plC50 **
1	6.87	6.88	6.96
2	6.17	6.16	6.23

* and ** dénoté repeated (2^nd and 3^rd) tests in the relevant assay; there may be some experimental déviation observed in the results

Further Biological Data

Compounds of the examples were tested in Test 4 described above (in section “Pharmacological Examples”) and the following results were obtained:

Compound No	pICso
Cpd 3	7.3
Cpd 17	7.1
Cpd 7	6.7
Cpd 18	6
Cpd 9	6.85
Cpd 19	6.55
Cpd 5 or Cpd 2	6.7
Cpd 16	6.2
Cpd 6 or Cpd 1	7.4
Cpd 15	6.2
Cpd 20	6.1
Cpd 21	<4.9

Compound No	plCS0
Cpd 22	<4.9
Cpd 23	<4.9
Cpd 4	7.5
Cpd 8	6.8
Cpd 10	6.9
Cpd 24	8.2
Cpd 25	6.75
Cpd 11	6.45
Cpd 12	<4.9
Cpd 14	6.7
Cpd 13	<4.9
Cpd 26	6.4
Cpd 27	6.1

Claims (18)

1. CLA1MS

   1. A compound of formula (I) for use in the treatment of tuberculosis

   wherein

   R¹ represents Ci-e alkyl or hydrogen;

   L¹ represents a linker group -C(R^a)(R^b)- (or is not present);

   10 Het represents a heteroaromatic linker group (which linker group may itself be optionally substituted by one or more substîtuents selected from fluoro, -O-R^c and Ci-6 alkyl, wherein the latter alkyl moiety îs itself optionally substituted by one or more fluoro atoms);

   15 R^a, R^b and R^c independently represent hydrogen or Ci-6 alkyl (optionally substituted by one or more fluoro atoms);

   X¹ represents -N(R²)(R³);

   R² and R³:

   20 (i) independently represent hydrogen or, preferably, Ci-6 alkyl optionally substituted by one or more substîtuents selected from Q¹ and =0;

   (ii) independently represent aryl or heteroaryl, each of which is optionally substituted by one or more substîtuents selected from Q²;

   (iii) independently represent cycloalkyl or heterocycloalkyl, each of which is

   25 optionally substituted by one or more substîtuents selected from Q³ and =0;

   or (iv) can be linked together to form:

   a. a 3- to 8-membered ring optionally containing one to three heteroatoms (e.g. nitrogen, oxygen and/or sulfur), and which ring is optionally

   30 substituted by one or more substîtuents selected from Q⁴ and =0;

   b. a “fused” bicyclic ring of the following type:

   c. a “spiro” ring of the following type:

   N----q¹

   5 Q¹, Q², Q³, Q⁴ and Q⁵ each independently represent one or more substituents selected from halo, Ci-6 alkyl, -OCi-6 alkyl (which latter two alkyl moieties may themselves be optionally substituted by one or more halo, e.g. fluoro, atoms), aryl and heteroaryl (which latter two aromatic groups may themselves be optionally substituted by one or more substituents selected from halo, Ci-6 alkyl and -OCi-6 alkyl, which latter two alkyl

   10 moieties may themselves be substituted with one or more fluoro atoms);

   ni and n2 independently represent 0 or 1;

   X^a represents -C(R^al)(R^bl)_m- or -N(R^C1)-;

   15 m represents 1 or 2;

   each R^al and R^bl independently represents fluoro, hydrogen or Ci-β alkyl;

   R^cl represents hydrogen or Ci-6 alkyl;

   X^b represents C(R^d), N, O (in which case L² is not présent) or C=O (in which case L² is 20 also not présent);

   R^d represents H, F or -OR^e (wherein R® represents H or Ci-6 alkyl optionally substituted by one or more fluoro atoms);

   25 q¹ represents -X^c-(CH2)ni-X^d-;

   ni repesents 0,1 or 2;

   q² represents -X^e-(CH2)n2-X^f-;

   n2 represents 0, 1 or 2, but wherein ni and n2 do not both represent 0;

   X^e (which is attached to X^a) is either not présent, or, when X^a represents CH, then X^e may represent -O-, -NH- or -S-;

   5 X^d is either not présent, or, when ni represents 2 or when X^e is not présent, X^a represents C(R^C) and ni represents 1, then X^d may also represent -O-, -NH- or -S-; X^e and X^f independently are either not présent, or may independently represent -O-, -NH- or -S-, provided that the aforementioned heteroatoms are not directly attached to or a to another heteroatom;

   q³ represents -X^Ê-(CH2)n3-X^h-;

   q⁴ represents -X¹-(CH2)n4-X·’-;

   n3 repesents 0, 1 or 2;

   n4 represents 0, 1 or 2, but wherein n3 and n4 do not both represent 0;

   X^s, X^b, X¹ and X< independently are either not présent, or may represent -O-, -NH- or -S-, provided that the aforementioned heteroatoms are not directly attached to or a to another heteroatom;

   20 when X^b represents O or C=O, then L² is not présent;

   when X^b represents C(R^d) (e.g. CH) or N, then L² may represent hydrogen, halo, -OR^f, -C(O)-R^ë, C i-6 alkyl (optionally substituted by one or more halo, e.g, fluoro atoms) or an aromatic group (optionally substituted by one or more substituents selected from halo, Ci-6 alkyl (itself optionally substituted by one or more substituents selected from 25 fluoro, -CF3 and/or -SF5), -OCi-éalkyl (itself optionally substituted by one or more fluoro atoms), -O-phenyl (itself optionally substituted by halo, Ci-ealkyl, Ci-éfluoroalkyl and/or -OCi-ealkyl) or-SFs);

   R^f represents hydrogen, Ci-6 alkyl (optionally substituted by one or more fluoro) or an 30 aromatic group (itself optionally substituted by one or more substituents selected from halo, Ci-6alkyl and -OCi-ealkyl, where the latter two alkyl moieties may themseleves be optionally substituted by one or more fluoro atoms);

   R^s represents hydrogen or Ci-6alkyl (optionally substituted by one or more substituents 35 selected from fluoro, or -OC1.3 alkyl, which latter moiety is also optionally substuituted by one or more fluoro atoms) or an aromatic group (optionally substituted by one or more substituents selected from halo, C1-6 alkyl or -OCi-6alkyl);

   ring A is a 5-membered aromatic ring containing at least one heteroatom (preferably containing at least one nitrogen atom);

   ring B is a 5- or 6-membered ring, which may be aromatic or non-aromatic, optionally 5 containing one to four heteroatoms (preferably selected from nitrogen, oxygen and sulfur);

   either ring A and/or ring B may be optionally substituted by one or more substituents selected from: halo, Ci-6 alkyl (optionally substituted by one or more halo, e.g. fluoro 10 atoms) and/or -OCi-r,alkyl (itself optionally substituted by one or more fluoro atoms), or a pharmaceutically-acceptable sait thereof.
2. 2. A compound for use as claimed in Claim 1, wherein:

   15 R¹ represents hydrogen;

   R^a and R^b independently represent hydrogen; and/or

   L¹ represents -CH2-.
3. 3. A compound for use as claimed in Claim 1 or Claim 2, wherein when X¹ represents a 20 heteroaromatic linker group that is a bicyclic heteroaromatic group linked to L¹ (or the amido moiety, when L¹ is not présent) via a carbocyclic aromatic moiety, so forming e.g.:

   in which “het” (in the above instance) is a heteroaromatic 5- or 6-membered 25 ring.
4. 4. A compound for use as claimed in Claim 3, wherein the linker group is a fused bicyclic ring system comprising a phenyl and/or a 5- or 6-membered monocyclic heteroaryl group (for instance forming a 9- or 10-membered heteroaromatic group,

   30 which consists of two separate rings fused with each other, in which each ring is 5- or 6-membered so forming a 6,6- or 6,5- or fused bicyclic ring), hence including groups such as those described below:

   -quinolylene (such as 2-quînolylene or 3-quinoIylene), e.g.:

   -quinoxalinyl (such as 2-quinolylene), e.g,:
5. 5. A compound for use as claimed in any of the preceding daims, wherein when X¹ represents -N(R²)(R³), then:

   (i) R² and R³ independently represent C1-3 alkyl (e.g. methyl or ethyl) optionally substituted by one or more (e.g. one) substituent(s) selected from Q¹;

   (ii) R² and R³ are linked together to form:

   a. a 4- to 6-membered ring optionally containing one further heteroatom (e.g. so forming a piperidinyl, piperazinyl or azetidinyl ring), which is optionally (and, in an aspect, preferably) substituted by Q⁴;

   b. a fused bicyclic ring in which X^a represents -CH2- and which is optionally substituted (e.g. at the X^a position) by one or more (e.g. one) Q⁵ substituent(s);

   c. a spiro ring system, in which X^b represents CH and L² is present and as defined herein.
6. 6. A compound for use as claimed in any of the preceding daims wherein: ring A is represented as follows:

   -75SUB——

   SUB——

   wherein “SUB” and “Sub” represent one or more possible substituents on the relevant atom (e.g, carbon or nitrogen atom).
7. 7. A compound for use as ciaimed in any one of the preceding claims, wherein the combined ring Systems, i.e. Ring A and Ring B may be represented as follows:

   Sub where “SUB” represents one or more possible substituents on the bicycle (i.e. on ring A and/or on ring B) and “Sub” represents a possible optional substituent on the N atom of 5 the bicycle (unsubstituted in this context would mean “NH”).
8. 8. A compound for use as claimed in any ofthe preceding daims, wherein: Q¹ represents aryl (e.g. phenyl) optionally substituted by -OCi-salkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -OCF3 group);

   10 Q⁴ represents aryl (e.g. phenyl) optionally substituted by -OCi-jalkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -OCF3 group); Q⁵ represents halo (e.g. fluoro);

   X^e, X^d, X^e and X^f are independently not présent;

   ni and n2 independently represent 1;

   15 X^g, X^h, X¹ and X^J are independently not présent;

   n3 and n4 independently represent 1; and/or

   L² represents an aromatic group (e.g. aryl or phenyl) optionally substituted by one or more (e.g. one) substituent(s) selected from -0Ci-3alkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -OCF3 group).
9. 9. A compound of formula (I) as defined in Claim 1 but wherein:

   L¹ represents -CH2-;

   Het represents a a bicyclic heteroaromatic group linked to L¹ (or the amido moiety, when L¹ is not présent) via a carbocyclic aromatic moiety, so forming e.g.:

   5 in which “het” (in the above instance) is a heteroaromatic 5- or 6-membered ring; when X¹ represents -N(R²)(R³), then:

   (i) R² and R³ independentiy represent C1-3 alkyl (e.g. methyl or ethyl) optionally substituted by one or more (e.g. one) substituent(s) selected from Q¹ (but wherein when both R² and R³ represent alkyl, then at least
10. 10 one îs substituted by Q¹ in which Q^f represents an optionally substituted aryl group as defined herein);

    (ii) R² and R³ are linked together to form:

    a. a 4- to 6-membered ring optionally containing one further heteroatom (e.g. so forming a piperidinyl, piperazinyl or

    15 azetidinyl ring), which is substituted by by one or two substituents selected from Q⁴ (in which at least one Q⁴ substituent is présent that represents an optionally substituted aryl group as defined herein);

    b. a fused bicyclic ring in which X^a represents -CH2- and which is

    20 optionally substituted (e.g. at the X^a position) by one or more (e.g. one) Q⁵ substituent(s);

    c. a spiro ring system, in which X^b represents CH and L² is présent and as defined herein;

    L² represents an aromatic group (e.g. aryl or phenyl) optionally substituted by one or 25 more (e.g. one) substituent(s) e.g. selected from e.g. -0Ci-3alkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g, a -OCF3 group);

    ring A and ring B together represent a 8 or 9-membered bicyclic ring (ring A is a

    5-membered ring and ring B may be a 5 or 6-membered ring, in which both rings are preferably aromatic) containing at least one nitrogen atom (and in a major embodiment, 30 at least one nitogen atom that is common to both rings);

    optional substituents on ring A and ring B are halo, C1-3 alkyl and -OC1-3 alkyl; and other integers are as defined herein.

    10. A compound as claimed in claim 9 wherein: when Q¹ represents aryl, then it is an optionally substituted as defined herein (e.g. by one or more substituents selected from -OCi-galkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -OCF3 group));

    5 when Q⁴ represents aryl, then it is an optionally substituted phenyl as defined herein (e.g. by one or more substituents selected from -OCi-salkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -OCF3 group)); when Q⁴ represents a non-aromatic substituent, then it may represent e.g. fluoro;

    Q⁵ represents halo (e.g. fluoro);

    10 X^e, X^d, X^e and X^f are independently not présent;

    ni and n2 independently represent 1;

    X^ë, X^h, X¹ and X? are independently not présent;

    n3 and n4 independently represent 1.

    15
11. 11. A compound as claimed in daim 9 or daim 10 wherein:

    the X^b-containing rings are represented as defined herein or more particulary as follows:

    (or any one ofthe above-mentioned représentations); and/or

    20 the ring A and ring B bicycles are represented as defined herein or more particulary as follows:

    (or any one of the above-mentioned représentations).
12. 12. A compound as defined in any of daims 9 to 11, for use as a pharmaceutical.
13. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingrédient, a therapeutically effective amount of a compound as defined in any one of daims 9-11.

    10
14. 14. Compound according to any one of daims 9-11 for use in the treatment of tuberculosis.
15. 15. Use of a compound as defined in any of daims 1 to 8 or use of a compound according to any one of daims 9 to 11 for the manufacture of a médicament for

    15 the treatment of tuberculosis.
16. 16. A combination of (a) a compound as defined in any of daims 1 to 8 or a compound according to any one of daims 9 to 11, and (b) one or more other

    20 anti-tuberculosis agent.
17. 17. A product containing (a) a compound as defined in any of daims 1 to 8 or a compound according to any one of daims 9 to 11, and (b) one or more other anti-tuberculosis agent, as a combined préparation for simultaneous, separate

    25 or sequential use in the treatment of a bacterial infection.
18. 18. A process for the préparation of a compound of formula (I) as defined in Claim 1, or according to any one of Claims 9-11, which process comprises:

    (i) reaction of a compound of formula (II),

    wherein the integers are as defined in Claim 1, or a suitable dérivative thereof, with a compound of formula (III)

    (III) wherein the integers are as defined in Claim 1 ;

    (ii) coupling of a compound of formula (IV),

    (IV) wherein the integers are as defined in Claim 1, and LG² represents a suitable leaving group, with a compound of formula (V),

    Χ^Η (V) wherein the integers are as defined in Claim 1.