OA18504A - Antibacterial compounds. - Google Patents

Abstract

The present invention relates to the following compounds <img file="OA18504A_A0001.tif"/> 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

The présent invention relates to novel compounds. The invention also relates to such 5 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 5ci 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 Organîzation indicate that more than 8 million people contract TB each year, 15 and 2 million people die from 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 infectious cause of adult mortality în the world. Complicating the TB 20 épidémie is the rising tide of multl-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.

Existing approaches to treatment of tuberculosis ail involve the combination of multiple 25 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 isonïazid 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 multidrug résistant strains of M, tuberculosis, agents such as ethambutol, streptomycin, 30 kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofoxacin and ofloxacin are added to the combination thérapies. There exists no single agent that is 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 35 regimens that facilitate patient and provider compliance. Shorter regimens and those that require less supervision are the best way to achieve this. Most of the benefit from

-2treatment cornes ίη 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 drug that shortens treatment to 2 months or less would be extremely bénéficiai. Drugs that facilitate compliance by requîring 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 straîns or MDR-TB. Up to four percent of ail cases worldwide are considered MDR-TB - those résistant to the most effective drugs ofthe four-drug standard, isoniazîd 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 toxic, expensive and marginally effective. In the absence of an effective 15 therapy, infectious MDR-TB patients continue to spread the disease, producing new infections with MDR-TB straîns. There is a high medical need for a new drug with a new mechanism ofaction, which is likely to demonstrate activity against drug résistant, in particular MDR straîns.

The term “drug résistant” as used hereinbefore or hereinafter is a term well understood 20 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 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 25 its sensitivity to a single drug or to different drugs.

MDR tuberculosis îs a spécifie form of drug résistant tuberculosis due to a bacterium résistant to at least isoniazîd and rifampicin (with or without résistance to other drugs), which are at présent the two most powerfùl 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 décades of tuberculosis (TB) control programs, about 2 billion people are infected by

M. tuberculosis, though asymptomatically. About 10% ofthese 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 rîse of multî-drug résistant TB straîns (MDR-TB). The réactivation of latent TB is a high risk factor for disease development

-3and accounts for 32% deaths in HIV infected individuats. To control TB épidémie, the need is to discover new drugs that can kil! dormant or latent bacilli. The dormant TB can get reactivated to cause disease by several factors like suppression of host Îmmunity by use of immunosuppressive agents like antibodies against tumor necrosis 5 factor a or interferon-γ. In case of HIV positive patients the only prophy lactic treatment available for latent TB is two- three months regïmens of rifampicîn, pyrazinamide. The efticacy ofthe treatment régime is still not clear and furthermore the length ofthe treatments Is an important constraîn in resource-limited environments. Hence there îs a drastic need to identify new drugs, which can act as chemoprophylatic 10 agents for individuals harboring latent TB bacilli.

The tubercle bacilli enter healthy individuals by inhalation; they are phagocytosed by the alveolar macrophages ofthe 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 of6-8 weeks the host immune response cause 15 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-replicatîng, hypometabolîc state and are 20 tolérant to killing by anti-TB drugs like isoniazid. These bacilli can remain in the altered physiological environments even for individuars lifetime without showing any clinical symptoms ofdisease. However, în 10% ofthe 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, 25 reduced oxygen tension, nutrient limitation, and acldic pH. These factors hâve been postulated to render these bacteria phenotypically tolérant to major anti-mycobacterial drugs.

In addition to the management of the TB épidémie, there is the emerging problem of résistance to fïrst-line antibiotic agents. Some important examples include penicîllin30 résistant 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 ofdeath. 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 ofthe antîmîcrobïal résistance problem worldwide. The combination of highly susceptible patients, intensive and prolonged antimicrobial 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 ïs 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 creatîng an idéal environment for 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, mortality, and financial costs of such infections impose an increasing burden for health care Systems 15 worldwide.

Therefore, there îs 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 bacterial strains.

Anti-in fective 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 bîcyclic 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 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 30 sériés ofmore than three rings.

Journal article Nature Medicine, 19, 1157-1160 (2013) by Pethe et al “Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis” identifies a spécifie

-5compound that was tested against Ai. tuberculosis. This compound Q203 is depicted below.

This clinica! candidates is also discussed in journal article, J. Médicinal Chemistry,

2014,57 (12), pp 5293-5305. 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 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 10 interfering with ATP synthase in M. tuberculosis, and that the inhibition of cytochrome 6ci activity is the primary mode of action. Cytochrome ici is an essentia! component of the électron transport chain required for ATP synthesis. It appeared that Q203 was hîghly active against both replicating and non-replicating bacteria.

International patent application WO 2015/014993 also discloses compounds as having 15 activity against M. tuberculosis. International patent applications WO 2013/033070 and WO 2013/033167 disclose various compounds as kinase modulators.

The purpose ofthe présent invention is to provide compounds for use în the treatment of bacterial diseases, particularly those diseases caused by pathogenic bacteria such as Mycobacterium tuberculosis (including the latent disease and including drug résistant 20 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 àci activity beîng considered the primary mode of action.

-6SUMMARY OF THE INVENTION

There is now provided a compound of formula (1)

wherein

R¹ represents Ci-6 alkyl or hydrogen;

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

X* represents an optional aromatic linker group;

R* and R^b independently represent hydrogen or C i -6 alkyl (optionally substituted by one or more fluoro atoms);

X* represents C(R^e) or N;

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

R^c and R^d independently represent H or -OR^e (wherein R^e represents H or Cu alkyl optionally substituted by one or more fluoro atoms);

q¹ represents -X^c-(CH2)ni-X^d-;

ni repesents 0, I or2;

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^e represents CH, then X^e may represent -O-, -NH- or -S-;

X^d is either not present, or, when ni represents 2 or whenX^e is not presenU X* represents C(R^C) and ni represents 1, then X^d may also represent -O-, -NH- or-S-;

-7X^e and X* 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^B-(CH2)n3-X^h-;

q⁴ represents -X'-ÎCHîJm-X³-; n3 repesents 0, 1 or 2;

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

X⁸, X^h, X¹ and X³ independently are either not présent, or may represent -Ο-, -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 présent;

when X^b represents C(R^d) (e.g. CH) or N, then L² may represent hydrogen, halo, -OR^f, Ci^ 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-β alkyl (itself optionally substituted by one or more substituents selected from fluoro, -CF3 and/or -SFs), -OCwalkyl (itself optionally substituted by one or more fluoro atoms), -O-phenyl (itself optionally substituted by halo, Ci^alkyl, Cwfluoroalkyl and/or -OCwalkyl) or-SFj);

R^f represents hydrogen or Ci-6 alkyl (optionally substituted by one or more fluoro);

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 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^ alkyl (optionally substituted by one or more halo, e.g. fluoro atoms) and/or -OCwalkyl (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”.

In particular, in a major embodiment ofthe invention, the following compounds of formula (IA) are provided for use in the treatment of tuberculosis:

wherein

R* represents Ci-6 alkyl or hydrogen;

L* represents a linker group -C(R^a)(R^b)-;

X* represents an optional carbocyclic aromatic linker group (which linker group may itself be optionally substituted by one or more substituents selected from fluoro, -OH, 10 -OC i-6 alkyl and Ci-β alkyl, wherein the latter two alkyl moieties are themseleves optionally substituted by one or more fluoro atoms);

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

X^e represents C(R^C) or N;

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

R^c and R^d independently represent H, F or -OR^e (whereîn R^e represents H or Ci-β alkyl optionally substituted by one or more fluoro atoms), or, R^d and L² may be linked together to form a 4- to 6-membered cyclic group (i.e. a spiro-cycle), optionally containing one to three heteroatoms;

q¹ represents -X^c-(CH2)ni-X^d-;

ni repesentsO, 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*) is either not présent, or, when X^e represents CH, then X^e may represent -O-, -NH- or -S-;

X^d is either not présent, or, when η I represents 2 or when X^e is not présent, X* 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 aforementîoned heteroatoms are not directly attached to or a to another heteroatom;

q³ represents -X^g-(CH2)nj-X^h-;

q⁴ represents -X'-(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;

X⁸, X^h, X¹ and X^j independently are either not présent, or may represent -O-, -NH- or 15 -S-, provided that the aforementîoned heteroatoms are not directly attached to or a to another heteroatom;

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, 20 -C(O)-R⁸, Cu 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, C m alkyl (itself optionally substituted by one or more substituents selected from fluoro, -CFj and/or -SF5), -OCi^alkyl (itself optionally substituted by one or more fluoro atoms), -O-phenyl (itself optionally substituted by halo, Ciualkyl,

Ci-éfluoroalkyl and/or -OCiualkyl) or-SFj);

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

R⁸ represents hydrogen or Ci-6alkyl (optionally substituted by one or more substituents selected from fluoro, or-OCi-j alkyl, which latter moiety îs also optionally substuituted by one or more fluoro atoms) or an aromatic group (optionally substituted by one or 35 more substituents selected from halo, C1 alkyl or -OCi^alkyl);

-toring A may be attached to the requisite amide moiety (i.e. the -C(0)-N(R’)- moiety) via either one of two possible bonds represented by the dotted Unes, which bonds are linked to ring A at two different atoms (of that ring);

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 from nitrogen, oxygen and 10 sulfur);

either ring A and/or ring B may be optionally substituted by one or more substituents selected from: halo, Ci-6alkyl (optionally substituted by one or more halo, e.g. fluoro atoms) and/or -OCi^alkyl (itself optionally substituted by one or more fluoro atoms), 15 or a pharmaceutically-acceptable sait thereof, which compounds may also be referred to herein as “compounds of the invention”.

For instance, compounds of formula (IA) may as described above, may be such that the ring A is linked to the amide moiety via a spécifie ring atom, as depicted by compounds of formula (I) below:

This embodiment is essentially a graphical depiction of ring A being linked to the 25 requisite amido moiety via a bond represented by one of the dotted lines in formula (IA).

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 30 acid or a free base form of a compound of formula I with one or more équivalents of an

-11appropriate acid or base, optionally in a solvent, or in a medium în 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-toxîc acid addition sait forms that the compounds of formula (1) are able to form. These pharmaceutically acceptable acid 10 addition salts can convenîently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonïc, succinic (i.e. butanedîoic acid), maleic, fumarïc, malic, tartarîc, cîtric, methanesulfonic, ethanesulfonic, benzenesulfonîc,p-toluenesu!fonic, cyclamic, salicylic.p-aminosalicylic, pamoicand the like acids.

For the purposes of this invention solvatés, prodrugs, N-oxides and stereoisomers of 20 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 în an experimentally-detectable amount, and within a predetermined time 25 (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 30 groups présent on the compound în 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 synthesising the parent compound with a prodrug substituent. Prodrugs include compounds ofthe Invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group In a compound of the invention is bonded to any group that 35 may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.

-12Examples 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 ofthe invention may contain double bonds and may thus exist as E (entgegen) and Z (zusammeri) géométrie isomers about each individual double bond. Positional isomers may also be embraced by the compounds ofthe invention. Ail such ïsomers (e.g. if a compound of the invention incorporâtes a double bond or a fused ring, 10 the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope ofthe invention (e.g. single positional isomers and mixtures ofpositional isomers may be included within the scope ofthe invention).

Compounds ofthe invention may also exhibit tautomerism. Ail tautomeric forms (or 15 tautomers) and mixtures thereofare included within the scope ofthe invention. The 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 20 intereonversions by réorganisation of some of the bonding électrons.

Compounds ofthe 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 25 crystallisation. The various stereoisomers may be isolated by séparation of a racemic or other mixture ofthe compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Altematively the desired optical isomers may be made by reaction ofthe appropriate optically active starting materials under conditions which will not cause racémisation or épimérisation (i.e. a ‘chiral pool’ method), by réaction ofthe 30 appropriate starting material with a 'chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by séparation ofthe diastereomeric dérivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst ail under conditions known 35 to the skilled person.

-13AU stereoisomers (including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope ofthe invention.

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

The compounds ofthe présent invention may exist in unsolvated as wel! as solvated 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 présent invention also embraces isotopically-labeled compounds of the présent invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). Al! isotopes of any particular atom or element as specified herein are 20 contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphores, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, “C, ¹³C, ⁱ⁴C , ¹³N, ^lîO, ^l7O,¹⁸0,³²P, ³³P, ^3ÎS, ⁱ⁸F, ³ⁱCl, ^l23I, and ^|2JI. Certain isotopically-labeled compounds ofthe présent invention (e.g., those labeled with ³H and ^l4C) are usefu! in compound and for substrate tissue distribution assays. Tritiated (³H) and carbon-!4 (¹⁴C) isotopes are useful for their ease of préparation and detectability. Further, substitution with heavîer 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 preferred in some circumstances. Positron emitting isotopes such as ^lîO, ^l3N, ⁿC and ¹⁸F are useful for positron émission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds ofthe présent invention can generally be prepared by following procedures analogous to those disclosed in the description/Examples hereinbelow, by substituting an isotopically labeled reagent fora non-isotopically labeled reagent.

Unless otherwise specified, Ci-q alkyl groups (where q is the upper limit ofthe range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a

-14minimum of two or three, as appropriate) of carbon atoms, be branched-chaîn, and/or cyclic (so forming a Cî-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 Cî-q alkenyl or a Cî-q alkynyl group).

Cî-q cycloalkyl groups (where q is the upper limit ofthe range) that may be specifically 10 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 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 term “halo”, when used herein, preferably includes fluoro, chlore, 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 heterocycloalkenyl (where q is the upper limit ofthe range) group. Cî-q heterocycloalkyl groups that may be mentioned înclude 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dîhydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[22.1]heptanyl, 6-oxabicyclo18504

-15[3.2.1 Joctanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, non-aromatic pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as t ,2,3,4tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including t,3,5-trithianyl), 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 5- oxidised form. Heterocycloalkyl mentioned herein may be stated to be specifically monocyclic or bicyclic.

Aromatic groups may be aryl or heteroaryl. Aryl groups that may be mentioned include Ce-zo, such as Cô-iz (e.g. Cmo) 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-ιο aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl. The point of attachment ofaryl groups may be via any atom of the ring system. For example, when the aryl group is polycyclic the 20 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 specified, the term “heteroaryl when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which hâve between 5 and 20 members (e.g. between 5 and 10) and may be monocyclic, bicyclic or tricyclic, provided that at least one ofthe rings is aromatic (so forming, for example, a mono-, bi-, or tricyclic heteroaromatic group). When the heteroaryl group is polycyclic the point ofattachment may be via any atom including an atom ofa non-aromatic ring. However, when heteroaryl groups are polycyclic (e.g. bicyclic or tricyclic), they are preferably linked to the rest of the molécule via an aromatic ring. Heteroaryl groups that may be mentioned include 3,4-dihydro-t/7-isoquinolinyl, t,3-dihydroisoindotyl, t,3-dihydroisoindolyl (e.g. 3,4-dihydro-t//-isoquinolin-2-yl, t,3-dihydroisoindol-2-yl, t,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,

-16benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2//-l,4benzoxazïnyl), benzoxazolyl, benzomorpholinyl, benzoselenadtazolyl (including

2.1.3- benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[l,2-a]pyTÎdyl, indazolyh 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-oxadîazolyl,

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, tetrahydroïsoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquînolinyl), tetrahydroquînolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadîazolyl,

1,2,4-thiadiazolyl and 1,3,4-thîadiazolyl), thiazolyl, thiochromanyl, thîophenetyl, 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 în 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 présent as part of the ring system. Heteroaryl groups may also be in the N· or

5- oxîdised form. Heteroaryl groups mentioned herein may be stated to be specifically monocyclic or bicyclic. When heteroaryl groups are polycyclic in which there is a nonaromatic ring présent, then that non-aromatïc ring may be substituted by one or more =O 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 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 phosphores, silicon, boron and, preferably, 35 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

-17defined herein, are preferably monocyclic (but may be polycyclic) and attached to the remainder of the molécule via any possible atoms of that linker group. However, when, specifically carbocylic aromatic linker groups are referred to, then such aromatic groups may not contain a heteroatom, i.e. they may be aryl (but not heteroaryl).

For the avoidance of doubt, where it is stated herein that a group may be substituted by one or more substituents (e.g. selected from Ci-β alkyl), then those substituents (e.g. alkyl groups) are independent ofone another. That is, such groups may be substituted with the same substituent (e.g. same alkyl substituent) or different (e.g. alkyl) 10 substituents.

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 15 preferred features, or independently of them).

The skilled person will appréciât e that compounds ofthe invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufTiciently robust to survive isolation from e.g. a reaction 20 mixture to a useful degree of purity.

As mentioned hereinbefore, in a major embodiment ofthe invention the compounds of the invention are those in which:

L* represents a linker group -C(R)(R^b)-; and

X* represents an optional carbocyclic aromatic linker group; and the compound of formula (IA) represents a compound of formula (I).

Preferred compounds, or other aspects or embodiments, described herelnbelow may relate to such a major embodiment ofthe invention (in which case inconsistent définitions of L* or X¹ are redundant), where such définitions of L¹ and/or X¹ may be 30 taken in combination with one or more other features or aspects (e.g. those described hereinbelow, such as some preferred aspects described).

Preferred compounds ofthe invention include those in which:

when X represents CCR⁰), then it is preferably CH;

X* represents CH or N;

R^e preferably represents hydrogen;

R^c and R^d independently (and preferably) represent H;

L¹ preferably represents a linker group as defined by -C(R*)(R^b)- (for the major embodiment ofthe invention, this linker group is essential);

X¹ may not be présent, but preferably represents an aromatic linker group (for the major embodiment ofthe invention, this linker group, when présent, has to be a carbocyclic aromatic linker group);

X^e (which is attached to X^e) is either not présent, or, when X* 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* 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 may not be attached directly (or a to) to another heteroatom.

More preferred compounds ofthe invention include those în which:

R* represents hydrogen;

R* and R^b independently represent hydrogen;

L¹ represents -CHî-;

when X¹ represents an aromatic linker group (where the point of attachment may be via any atom ofthe ring system), that aromatic group may be carbocyclic or heterocyclic, so forming, for example, a phenyl, a 5- or 6-membered monocyclic heteroaryl group or a bicyclic aromatic group (such as a 8- or 10-membered aromatic group, which consists of two separate rings fused with each other, în whîch each ring is 5- or 6-membered so forming a 6,6-, 5,6- or 5,5-fused bicyclic ring), hence including groups such as phenyl, naphthyl (including fully aromatic naphthyl and 1,2,3,4-tetrahydronaphthyl) and the like, so forming e.g. în particular:

-phenylene- (especially a 1,4-phenylene), e.g.:

-quînolylene (such as 2-quinolylene), e.g..*

Such linker groups that X* may represent (e.g. phenylene) may be optionally substituted (e.g. by one or more substituents selected from fluoro, CH3, CF3, -OCH3 and -OCF3). In an embodiment such linker groups that X¹ may represent are unsubstituted.

In an embodiment (for instance, the major embodiment referred to above) of the invention, the following applîes:

X* represents an optional carbocyclic aromatic linker group, i.e. it may or may not be présent;

when X* is présent, then it represents a carbocyclic aromatic linker group, for example a phenyl group or a bicyclic (carbocyclic) aromatic linker group (in which at least one ofthe rings ofthe bicycle is aromatic), for instance such that the bicycle consists oftwo separate rings fused with each other, in which each ring is 5- or 6-membered so forming a 6,6-, 5,6- or 5,5-fused bicyclic ring), hence including groups such as phenyl, naphthyl (including fully aromatic naphthyl and 1,2,3,4-tetrahydronaphthyl) and the like, so forming e.g. in particular:

-phenylene- (especially a 1,4-phenylene), e.g.:

naphthylene, e.g.:

In an aspect ofthe invention, X¹, i.e. an aromatic linker group (in an embodiment, a carbocylic aromatic linker group, such as one defined above) is présent.

The spiro-cyclic moiety, i.e. the combined X* and X^b-containing ring may be represented as follows:

Other spiro-cyclic moieties that may be mentioned include the following:

Hence, it may be preferred that:

X* represents N or C(R^C) (e.g. CH);

X^b represents N, O, C(R^C) (e.g. CH) or C=0;

at least one of X^e and X^b represents N and the other represents C(R'), N or (in the case of X^b) O;

it is preferred that both X* and X^b do not represent CfR®);

X^e is not présent or represents -O-;

X^d is not présent;

X^e is not présent;

X^f is not présent;

-21X⁸, X^h, X¹ and X^ independently are not présent;

ni represents 0, 1 or 2;

n2 represents 1 or 2;

n3 represents 1 or 2;

n4 represents 1 or 2;

L? may represent hydrogen, halo (e.g. fluoro), -OR^f, or an aromatic group (optionally substituted by one or two (e.g. one) substituent(s) selected from -OCi^alkyl (itself optionally substituted by one or more fluoro atoms) or-SFs, or, altematively by halo, e.g. fluoro);

more specifically, L² may represent hydrogen, halo (e.g. fluoro), -OH, phenyt (optionally substituted by -OCF3, -SFj and/or altematively by -OCH3 or fluoro; in a further embodiment, other substituents that may be mentioned include -SCF3), pyrïdyl (e.g. 3-pyridyl, which is preferably unsubstituted or, altematively, 2- or 4-pyridyl, which is also preferably unsubstituted), triazolyl or thiazolyl;

altematively, other L² groups that may be mentioned include -OR^f, for instance in which R^f represents Ci^alkyl (e.g. methyl, -CH3) or an aryl group (e.g. phenyl) optionally substituted by C|.3alkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -CF3 group) or L² may represent -C(O)-R⁸, in which R⁸ represents hydrogen or C ualkyl (e.g. methyl; optionally substituted by fluoro so forming e.g. a -CF3 group) or phenyl (preferably unsubstituted); hence L² may also represent -C(O)H, -C(O)CH3, -C(O)CF3, -C(O)-phenyI, -OCH3 or -O-phenyl, i.e. phenoxy, which latter group may be substituted by a -CF3 moiety (or L² and R^d may be linked together to form a cyclic group). In a further embodiment, yet other L² groups that may addîtionally be mentioned (e.g. when attached to nitrogen, when X^b is N) include -S(O)2-Ci_6alkyl groups optionally substituted by one or more fluoro atoms (e.g. forming -S(O)2CF3).

In a further embodiment, X^b may also represent S, S(O) or, in a preferred embodiment, S(Oh.

It is further preferred that:

q* represents -CH₂-, -CH2-CH2-, -O-CH2- or (i.e. in the latter case, ni = 0, X^e is not présent and X^d is not présent);

q² represents -CH2- or -CH2-CH2-;

q³ represents -CH2- or -CH2-CH2-; q⁴ represents -CH2- or -CH2-CH2-.

It is preferred that compounds of the invention comprise:

ring A, which is an aromatic ring containîng 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 aromatic ring), preferably containîng 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 containîng 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

where “SUB” may be a relevant optîonal 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 présent; e.g such optîonal 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, chlore). Other preferred substituents on ring B include -OCî-ealkyl (e.g.-OC)-3alkyl, such as -OCH3).

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

-24include halo and especially-OCi-3 alkyl (e.g. -O-methyl), where the latter is substituted by fluoro, so forming for exemple a -OCF3 group.

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

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:

The combined ring A and ring B Systems that may be mentioned when ring A is attached to the amido moiety via the “central” atom of the 5-membered A ring include the following:

The following compounds of formula (IA) are preferred:

ring B ring A

-26wherein the întegers are as hereinbefore defined, and where, preferably:

ni, n2, n3 and n4 independently represent 1;

at least one of X^a and X^b represents N and the other represents CH or N.

Certain compounds ofthe invention are mentîoned (e.g. hereinbefore) for use in the treatment oftuberculosis. Certain ofsuch compounds mentîoned herein may also be 10 novel per se. And certain of such compounds mentîoned herein may be novel as medîcaments/pharmaceutîcals (or novel as a component of a pharmaceutical composition/formulation). Hence, în further aspects of the invention, there is provided the following compounds per se or following compounds for use as pharmaceuticals/medicaments (în the latter case such compounds may be components 15 ofa pharmaceutical composition/formulation):

(I) Compounds of formula (IB) as depicted below:

(B) wherein the întegers are as hereinbefore defined, and where, preferably:

ni, n2, n3 and n4 independently represent 1 ;

at least one of X^e and X^b represents N and the other represents CH or N;

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

L¹ represents-CH2-;

X¹ is not présent;

at least one of X‘ and X^b represents N and the other represents C(R^C), N or (in the case of X^b) O;

the X* and X^b-containing spiro-cycle 3- to 6-membered ring attached to a 4to 6-membered ring;

-27in one aspect L² represents an aromatic group (as defîned herein) optionally substituted as defîned herein, and/or, in another aspect L² represents ~OR^f in which R^f represents an aryl group (as defîned herein) optionally substituted as defîned herein;

when L² represents an (optionally substituted) aromatic group, it may be phenyl or a 5- or 6-membered heterocycüc group (e.g. containîng at least one nitrogen atom, so forming a pyridyl, thiazolyl or triazolyl ring; in a major embodiment the heterocyclîc group is a pyridyl), where the optional substituents are as defîned herein;

optional substituents on aromatic L² groups are selected from halo, Ct-ealkyl, -CF3, -OCt^alkyl and -OCF3;

when R^f represents an aryl group, then it is preferably phenyl optionally substituted by C1.3 alkyl, itself optionally substituted by fluoro);

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);

optional substituents on ring A and ring B are halo, C 1.3 alkyl and -OCi-3alkyl;

(III) Compounds of formula (IA) as hereînbefore defîned and in which:

L¹ represents -CH2-;

X* represents a carbocyclic aromatic linker group;

when X¹ represents a carbocyclic linker group it represents phenylene (e.g. a 1,4-phenylene) for instance:

at least one of X^a and X^b represents N and the other represents C(R^C), N or (in the caseofX^b)O;

the X and X^b-containing spiro-cycle 3- to 6-membered ring attached to a 4to 6-membered ring;

in one aspect L² represents an aromatic group (as defîned herein) optionally substituted as defîned herein, and/or, in another aspect L² represents -OR^f in which R^f represents an aryl group (as defîned herein) optionally substituted as defîned herein;

when L² represents an (optionally substituted) aromatic group, it may be phenyl or a 5- or 6-membered heterocyclic group (e.g. containing at least one nitrogen atom, so forming a pyridyl, thiazolyl or triazolyl ring; in a major embodiment the heterocyclic group is a pyridyl), where the optional 5 substituents are as defined herein;

optional substituents on aromatic L² groups are selected from halo, Cwalkyl, -CF3, -OC w alkyl and -OCF3;

when R^f represents an aryl group, then it is preferably phenyl optionally substituted by C1-3 alkyl, itself optionally substituted by fluoro);

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, 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;

(IV) Compounds as hereinbefore defined (e.g. at (I), (II) or (III) above) and further in which:

q¹ represents -CH2-, -CH2-CH2-, -O-CH2- or (i.e. in the latter case, ni = 0, X^e is not présent and X^d is not présent);

q² represents -CH 2- or -CH2-CH2-;

q³ represents -CH2- or -CH2-CH2-; q⁴ represents -CH 2- or -CH2-CH2-;

(V) Compounds as hereinbefore defined (e.g. at (I), (II), (III) or (IV) above) and further in which the X^e and X^b-contaîning rings are represented as defined herein or more partîculary as follows:

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

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

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 présent invention thus also relates to compounds ofthe 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 ici activity being the primary mode of action. Cytochrome ici is an essential component of the électron transport chain required for ATP synthesis.

Further, the présent invention also relates to the use ofa compound ofthe invention, as well as any ofthe 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 ofa compound or pharmaceutical composition according to the invention.

The compounds of the présent invention also show activity against résistant bacteria! 5 strains.

Whenever used hereînbefore or hereinafter, that the compounds can treat a bacteria! infection it is meant that the compounds can treat an infection with one or more bacteria! 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 various pharmaceutical forms for administration purposes. As 15 appropriate compositions there may be cited ail compositions usually employed for systemically administering drugs. To préparé the pharmaceutical compositions ofthis 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 20 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 în the case of 25 oral liquid préparations such as suspensions, syrups, élixirs, émulsions and solutions; or solid carriers such as starches, sugars, kaolin, dîluents, 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 30 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 în which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared în 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 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the active ingredient(s), and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, ail percentages being based on the total weight of the composition.

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

It is especially advantageous to formulate the aforementioned pharmaceutical compositions ln unit dosage form for ease of administration and uniformity of dosage.

Unît dosage form as used herein refers to physîcally discrète units suitable as unîtary dosages, each unit containing a predetermined quantity of active ingrédient calculated to produce the desired therapeutic effect în association with the required pharmaceutical 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 the compound employed, the mode of administration, the treatment desired and the mycobacterial disease indicated. However, in general, satisfactory results will be obtained when the compound according to the invention is administered at a daily dosage not exceeding 1 gram, e.g. in the range from 10 to 50 mg/kg body weight.

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. antîbacterial agents in order to effectively combat bacterial infections.

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

The présent invention also relates to a combination of (a) a compound according to the 35 invention, and (b) one or more other antîbacterial agents, for use as a medicine.

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

-32A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingrédient, a therapeutically effective amount of (a) a compound according to the invention, and (b) one or more other antibacterial agents, is also comprised by the 5 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 skilled în the art. Said ratio and the exact dosage and frequency of administration 10 dépends on the particular compound according to the invention and the other antibacterial agent(s) used, the particular condition being treated, the severity ofthe condition being treated, the âge, weight, gender, diet, time of administration and general physical condition ofthe particular patient, the mode ofadministration as well as other médication the individual may be taking, as is well known to those skilled in 15 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 ofthe physicien prescribing the compounds ofthe 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, 20 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 a combined preparation for simultaneous, separate or sequential use ln the treatment of a bacterial infection. .

The other antibacterial agents which may be combined with the compounds ofthe invention are for example antibacterial agents known in the art. For example, the 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 of the ATP synthase (e.g. bedaquiline, bedaquiline fumarate 35 or any other compounds that may hâve be disclosed in the prior art, e.g. compounds disclosed în WO2004/0I1436), inhibitors ofndh2 (e.g. clofazîmine) and inhibitors of cytochrome bd. Additional mycobacterial agents which may be combined with the compounds of the invention are for example rifampicîn (=rifampin); isoniazid;

-33pyrazinamide; amikacin; ethionamide; ethambutol; streptomycin; para-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thioacetazone; PA-824; delamanid; quinolones/fluoroquinolones such as for example moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin; macro!ides 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.newt bd rugs.org/Dipeline.Dhp).

GENERAL 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 exemples hereinafter (and those methods know by those skilled in the art), for example by using the following techniques.

Compounds of formula (I) or (IA) în which X^b represents N may be prepared by:

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

in which the integers are hereînbefore defined, with a compound of formula (III),

LG‘-L² (III) wherein L² is as hereînbefore defined (for instance when L² is not hydrogen, halo or linked to O or S), and LG¹ is a suitable leaving group such as chloro, bromo, iodo or a sulfonate group, which reaction may require spécifie conditions (e.g. nucleophilic aromatic substitution reaction conditions, such as described herein);

-34(h) reaction of a compound of formula (! V),

O

V-^0H

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

(V) wherein the integers are as hereinbefore defined, under amide coupling reaction conditions, for example in the presence ofa suitable coupling reagent (e.g. 1,1’carbonyldiimïdazole, A/JV’-dîcyclohexylcarbodiimide, l-(3-dimethylaminopropyl)3-ethylcarbodiimide (or hydrochloride thereof) or M/V’-disuccinimidyl carbonate), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrtdine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium /er/-butoxide and/or lithium diisopropylamide (or variants thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, 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 POCIj, PCI5, SOCb or oxalyl chloride), which acyl chloride is then reacted with a compound of formula (V), for example under similar conditions to those mentioned above;

(iii) coupling of a compound of formula (VI),

(VI) wherein the integers are as hereinbefore 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 (VI),

(VU) wherein the integers are as hereinbefore defined, under standard conditions, for exampie optionally în the presence of an appropriate métal catalyst (or a sait or complex thereof) such as Pd(dba)2, Pd(0Ac)2, Cu, Cu(OAc)2, Cul, NiCh or the like, with an optional additive such as PhjP, 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;

(iv) coupling of a compound of formula (VIII),

c
2
R	4
	—

wherein the integers are as hereinbefore defined, and LG³ represents a suitable leavîng group as described hereinbefore with respect to LG² (and may particularly represent chloro, bromo or iodo), with a compound of formula (IX),

LG⁴-!? (IX) wherein L² îs as hereinbefore defined (for instance when L² is not hydrogen, halo or linked to O or S), and LG⁴ is a suitable group such as -B(OH)2, -B(OR^WX)2 or _SN(R^ux)j, in which each R** independently represents a Ci^ alkyl group, or, in the case of-B(OR^UV)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 10 LG⁴ may represent iodo, bromo or chloro, provided that LG³ and LG⁴ are mutually compatible), and wherein the réaction may be performed in the presence of a suitable catalyst system, e.g. a métal (or a sait or complex thereof) such as Pd, Cul, Pd/C, PdCh, Pd(OAc)2, Pd(PhîP)2Cl2, Pd(PhîP)i, Pd?(dba)3 and/or NiCh (or the like) and a ligand such as PdCl2(dppf).DCM, t-BuîP, (CôHiQîP, PhjP or the like, in a suitable solvent and 15 under reaction conditions known to those skilled în 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 accottf ing to méthodologies generally known in the art, such as extraction, crystallization and 20 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 preparative HPLC, chiral chromatography. Individual diastereoisomers or individual enantiomers can also be obtained by Supercritical Fluid Chromatography (SCF).

The starting materials and the intermédiares are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known in the art.

Synthesis of Compound 1

NCCCHpPOCOEOj

LiHMDS, THF,-70 °C

A

Me_}SOI,t-BuOK DMSO

CAS [79099-07-3]

TFA/CH.Ct,

CAS [103962-05-6]

Pd(dba)j, Xphos, NaOtBu Dioxane, Il (TC,MW, 1 h

I

Compouid 1

Préparation of intermediate A

LiHMDS (50 mL, 1M in THF) was added to a mixture of N-tert-Butoxycarbonyl4-piperidone (CAS [79099-07-3], 8.86 g, 50.0 mmol) in THF (180 mL) at -70°C under Nî flow. The mixture was stirred for 10 minutes. Diethyl cyanomethyl phosphonate (9 g, 45.2 mmol) was added to the mixture at -70°C, The mixture was stirred for 1 hour. The mixture was quenched with NHjCI solution, extracted with ethyl acetate, washed ! 0 with brine, dried over MgSOi and filtered. The filtrate was concentrated to give A, 10.0 g, 90.0%.

Préparation of intermediate B

Me₃SOI (10.9 g, 49.5 mmol) was added slowly to a solution of t-BuOK (5.55 g,

49.5 mmol) in DMSO (60 mL). The mixture was stirred for 1.5 hours. A solution of A ( ! 0.0 g, 45.0 mmol) in DMSO (80 mL) was added to the mixture. The mixture was stirred 24 hours at 45°C. Saturated NH4CI solution was added to the mixture and stirred for 0.5 hours. The mixture was extracted with ethyl acetate. The organic layers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated to give

B, 10.0 g, 93%.

Préparation of intermediate C

To a solution of B (460 mg, 1.95 mmol) in MeOH (10 mL) was added CoCIî«6 H2O (463 mg, 1.95 mmol). The mixture was stirred at -IO°C for 10 min. NaBHi (368 mg,

9.74 mmol) was added above the mixture în portions. Then the mixture was stirred for another 1 h. IM HCl aqueous solution was added and the solid was dissolved. The aqueous phase was basified with aqueous ΝΗ3Ή2Ο till pH = 9 and extracted with ethyl acetate. The combined organic layers were dried over NaiSOj and concentrated in vacuum. The residue was triturated with an oxaiic acid solution in ethyl acetate and filtered to afford a white solid. The solid was basified with IN aqueous NaOH solution and extracted with dichloromethane. The combined organic layers were dried over NaîSOi and concentrated in vacuum to give C, 120 mg, 26%.

Préparation of intermediate D

HOBt (55.1 mg, 0.408 mmol), 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 91.7 mg, 0.408 mmol), DlEA(105 mg, 0.816 mmol) and EDCI'HCl ( 117 mg, 0.612 mmol) were added to a stirred solution of C ( 100 mg, 0.416 mmol) in DMF (10 mL). The mixture was stirred and heated at 60°C for 16 hours. The mixture was concentrated. The residue was dissolved in ethyl acetate.

The organic layer was washed with H2O, dried over MgSCh and filtered. The filtrate was concentrated to give D, (00 mg, 51%.

Préparation of intermediate E

TFA (5 mL) was added to a mixture of D (90 mg, 0.201 mmol) in CH2CI2 (5 mL) at

0°C. The mixture was stirred for 5 hours at room température. The mixture was concentrated under vacuum. The residue was dissolved in CH2CI2 and the mixture was adjust to pH=7 with NaHCOj solution. The organic layer was separated and concentrated. The crude product was purified by column chromatography over silica gel (eluent: ethyl acetate/petroleum ether from 0 to 1). The product fractions were collected and concentrated to give E, 70 mg, 90%.

Préparation of Compound 1

A solution of E (20 mg, 0.058 mmol), l-iodo-4-(trÎfluoromethoxy)benzene (CAS [103962-05-6], 16.7 mg, 0.058 mmol), Pd(dba)î (3.34 mg, 0.006 mmol), Xphos (4.57 mg, 0.009 mmol) and t-BuONa (22.3 mg, 0.232 mmol) in 1,4-dioxane (5 mL) was îrradiated under microwave at 110°C for 1 hour under N2. The mixture was concentrated under vacuum. The residue was purified by high performance liquid

-39chromatography over Gemini (eluent: NHj water/acetonitrile 30/70 to 70/30). The desired fractions were collected and concentrated to give Compound 1,19.3 mg, 64%. ‘H NMR (400 MHz, CDCb) δ ppm 9.47 (s, 1 H) 7.54(d, /=9.29 Hz, 1 H) 7.30 (dd, /=9.41,1.83 Hz, 1 H) 7.10 (d, /=8.80 Hz, 2 H) 6.91 (d, /=9.05 Hz, 2 H) 5.87 (br. s., 1

H) 3.51 - 3.60 (m, 2 H) 3.30 - 3.42 (m, 2 H) 3.08 -3.17 (m, 2 H) 3.02 (q, /=7.58 Hz, 2

H) 1.86· 1.94 (m, 1 H) 1.73- 1.82 (m, 1H) 1.64- 1.69(m, I H) 1.43 (t,/=7.58 Hz, 3

H) 1.36 (d,/=13.45 Hz, 1 H) 1.01 - 1.10 (m, 1 H) 0.70 (dd,/=8.44, 4.77 Hz, 1 H)

0.38(t, /=4.89 Hz, 1 H)

Synthesis of Compound 2

Intermediate R

OH b’

OH

CAS [126747-14-6] ^nc-O-<x>·^’

HCOOH rt, 12 h

CAS 1103962-05-61 . X-phos, Pd(dba)₂,t-BuONa, dioxane, MW. 100°C, 1 h

F F

O trans- 2-aminocycbhexanol, NaHMDS, N3₂, i-PrOH, 60°C. MW, 1 h, 90°C, MW, 1 h 120^eC, MW, 4 h,

RaneyNi, Hj (15 psi)

NHjhMeOH, RT, 16 h

CAS [1216142-18-5]

HATU.DŒA. CHjClj, 25°C, 2 h

I

Préparation of intermediate F

A mixture of intermediate R (364 mg, 2.47 mmol), trans-2-amino-cyclohexanol (28.5 mg, 0.248 mmol) and Nickel iodine (38.7 mg, 0.124 mmol) in i-PrOH (4 mL) was stirred at 25°C for 30 minutes under nitrogen flow. NaHMDS (2.48 mL, 1 M in

THF) was added, and the mixture was stirred for 10 minutes under nitrogen flow. A solution of 4-cyanophenylboronic acid (CAS [126747-14-6], 400 mg, 1.24 mmol) in iPrOH (4 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 4 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 F (300 mg, yield: 37%).

Préparation of intermediate G

A mixture of intermediate F (300 mg, 1.01 mmol) in formîc acid (5 mL) was stirred at room température for 12 hours. The mixture was concentrated and CH2CI2 (30 mL) was added to the mixture. The mixture was washed with Na2COj solution (20 mL). The organic layer was separated, dried over Na2SO₄ and filtered. The filtrate was concentrated to give intermediate G (150 mg, yield: 64%).

Préparation of intermediate H

A solution of intermediate G (100 mg, 0.504 mmol), l-iodo-4-(trifluoromethoxy) benzene (CAS [103962-05-6], 145 mg, 0.504 mmol), X-Phos (28.8 mg, 0.06 mmol), 20 Pd(dba)₂ (17.4 mg, 0.03 mmol) and t-BuONa (194 mg, 2.02 mmol) in dioxane (4 mL) was irradiated under microwave at 100°C for 1 hour under N2. The mixture was concentrated. The crude product was purified by column chromatography over silica gel (eluent: ethyl acetate / petroleum ether from 0 to 1/1). The desired fractions were collected and concentrated to give intermediate H (100 mg, yield: 55%).

Préparation of intermediate 1

A mixture of intermediate H (70.0 mg, 0.195 mmol) in NHj'MeOH (7M in methanol, 20 mL) was hydrogenated (15 psi) with Raney Nickel (7 mg) as catalyst at 25°C for 16 hours. After uptake of H2, the catalyst was filtered off and the filtrate was concentrated to give intermediate I (50.0 mg, yield: 71%).

Préparation of Compound 2

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxy!ic acid (CAS [1216142-18-5],22.5 mg, 0.100 mmol), HATU (49.4 mg, 0.130 mmol), D1EA (33.6 mg, 0.260 mmol) in CH2CI2 (20 mL) was stirred for 30 minutes at 25°C.

Intermediate I (40.0 mg, 0.110 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:

-410.05% ammonia in water/m éthanol 20/80 to 5/95). The desired fractions were collected and concentrated to give Compound 2 (9.80 mg, yield: 17%).

IH NMR (400 MHz, CDCb) δ = ppm 9.54 (s, 1 H) 7.55 (d, 7=9.26 Hz, 1 H) 7.27 - 7.37 (m, 3 H) 7.22 (d, 7=7.94 Hz, 2 H) 7.00 - 7.10 (m, 2 H) 6.40 (d, 7=8.82 Hz, 2 H) 6. H (br. s., 1 H) 4.68 (d, J=5.73 Hz, 2 H) 4.0! (s, 2 H) 3.80 (s, 2 H) 3.48 (q, 7=8.93 Hz, !

H) 2.98 (q, 7=7.50 Hz, 2 H) 2.59 - 2.71 (m, 2 H) 2.35 (td, 7=9.70,2.65Hz, 2 H) 1.36 1.47 (m, 3 H)

Synthesis of Compound 3

JQ NBS.NÎ^OAc methjlt-butyl ether CAS 3002-24-2 RT, 48 h

O O xA/oBr

J

CAS [3428-89-7]

EtOH, reftw, ovemçht

K

overnight l

I

HATU.D1EA, CHjCV 25 °C. 2 h

Compound 3

Préparation of intermediate J

NBS (45.1 g, 254 mmol) and NHiOAc (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 filtered and washed with HjO, dried over NajSCh and filtered. 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 ovemight. The

-42mixture was concentrated under vacuum. The residue was dissolved into ethyl acetate (J 00 mL). The solution was washed with water (2x100 mL), brine (100 mL), dried over sodium sulfate, filtered 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%).

Préparation of intermediate L

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

6.30 mmol) ïn 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 3

Accordingly, Compound 3 was prepared in the same way as Compound 2 starting from intermediate L and intermediate I, yielding 9.60 mg, yield: 8%.

IH NMR (400 MHz, CDCIj) δ ppm 9.84 (d, J=2.51 Hz, 1 H) 8.57 (d, J=2.76 Hz, 1 H)

7.30 - 7.35 (m, 2 H) 7.22 (d, J=8.03 Hz, 2 H) 7.06 (d, J=8.03 Hz, 2 H) 6.37 - 6.43 (m, 2 H) 6.14-6.20 (m, I H) 4.68 (d,J=5.77 Hz, 2 H) 4.01 (s, 2H) 3.80 (s, 2 H) 3.48 (q,

J=8.85 Hz, 1 H) 3.02 (q, J=7.53 Hz, 2 H) 2.61 - 2.70(m, 2 H) 2.31 - 2.40 (m, 2 H) 1.45 (t, J=7.53 Hz, 3 H)

SvntheaÎs of Compound 4

VOH νη₂ * fV EDCI.HCl HOBT, EtjN,

DCM,45°C,24hoin

CAS [I2I6I42-I8-5] CAS [39959-59-6]

CAS [103962-05-6]

Boc-ï/^NH

CAS [1041026-70-3]

X-phos, Pd/dba^.t-BuONa, ’dioxane.MW, JIOC, I h

HCOOH

25’C, 12 h ^HNX^N-O-^0>Lr

N

M

X-phos, Pd(dba)pt-BiiONa, dioxanc, MW, ! ΙΟΎ?, J h

Compound 4

Préparation of intermediate M

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [12161242-18-5], 1 g, 4.45 mmol), 4-lodobenzenemethanamtne (CAS [39959-59-6],

1.09 g, 4.67 mmol), EDCI*HC1 (1,28 g, 6.68 mmol), HOBT (0.601 g, 4.45 mmol) and triethylamine (1,24 mL, 9 mmol) în dichloromethane (8 mL) was stirred and heated at 45°C for 24 hours. The solution was cooled down to 15°C. The solid was collected by 10 filtration, washed with water and acetonitrile and the solid was dried (vacuum, 45 °C, hour) to give intermediate M, 1.2 g, 55%.

Préparation of intermediate N

A solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (CAS [1041026-7015 3], 500 mg, 2.52 mmol), l-iodo-4-(trifluoromethoxy)benzene (CAS [103962-05-6],

726 mg, 2.52 mmol), X-phos (240 mg, 0.504 mmol), Pd(dba)2 (145 mg, 0.252 mmol)

and t-BuONa (969 mg, 10.1 mmol) in dioxane (8 mL) was irradiated under microwave at 110°C for 1 hour under N2. Water was added to the mixture and the mixture was extracted with ethyl acetate (50 mL x 2). The organic layers were washed brine, dried over MgSÜ4 and filtered. The filtrate was concentrated. The crude product was purified 5 by column chromatography over silica gel (eluent: ethyl acetate/hexane from 0 to 1/5).

The desired fractions were collected and concentrated to give N, 500 mg, 50%.

Preparation of intermediate O

A mixture ofN (100 mg, 0.279 mmol) in HCOOH (5 mL) was stirred for 12 hours. The 10 mixture was concentrated and was used for the next step without further purification.

Préparation of Compound 4

A solution of intermediate O (72 mg, 0.279 mmol), intermediate M (123 mg, 0.279 mmol), X-Phos (26,6 mg, 0.056 mmol), Pd(dba)2 (16.0 mg, 0.028 mmol) and t-BuONa (107 mg, 1,12 mmol) in dioxane (8 mL) was irradiated under microwave at 110°C for 1 hour under N2. The mixture was concentrated. The crude product was purified by high performance liquid chromatography over Gemini (eluent: ammonia in water/acetonitrile 50/50 to 20/80). The desired fractions were collected and concentrated to give Compound 4,35.8 mg, 22%.

1H NMR (400 MHz, CDCh) Ô ppm = 9.53 (d, /=1.25 Hz, 1 H) 7.56 (d, /=9.79 Hz, 1 H) 7.31 (dd,J^=9.54,2.01 Hz, 1 H) 7.24 (s, 2 H) 7.08 (d, /=8.53 Hz, 2 H) 6.49 (d, /=8.53 Hz, 2 H) 6.42 (d, /=9.03 Hz, 2 H) 6.01 (br. s., 1 H) 4.59 (d, /=5.27 Hz, 2H) 4.04 (s, 4 H) 4.02 (s, 4 H) 2.96 (q, /=7.36 Hz, 2 H) 1.39 (t, /=7.53 Hz, 3 H)

-45Svnthesis of Compound 5

CAS [3058-39-7]

CN

I

X-phos, Pdfdba^.t-BuONa, dioxane, MW, 1 IO°C, 1 h

Compound 5

Préparation of intermediate P

A solution of intermediate O (100 mg, 0.387 mmol), 4-iodobenzonitrile (CAS [305839-7], 115 mg, 0.503 mmol), X-phos (22.0 mg, 46.2 mmol), Pd(dba)z (13.3 mg,

23.1 mmol) and t-BuONa (149 mg, 1.55 mmol) ïn dioxane (5 mL) was trradîated under microwave at 110°C for 1 hour under N2. The mixture was concentrated under vacuum. The crude product was purified by high performance liquid chromatography over Gemini (eluent: 0,05% ammonia tn water/methanol 30/70 to 5/95). The desired fractions were collected and concentrated to give intermediate P (60.0 mg, yield: 35%).

Préparation of intermediate O

Accordingly, intermediate Q was prepared as the same way as intermediate I starting from intermediate P, yîelding 60.0 mg, yield: 99%.

Préparation of Compound 5

A solution of intermediate L (28.3 mg, 0.125 mmol), HATU (61.8 mg, 0.162 mmol), D1EA (42.0 mg, 0.325 mmol) in DMF (5 mL) was stirred for 30 minutes at 25°C.

Intermediate Q (50.0 mg, 0.138 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 25/75 to 5/95). The desired fractions were collected and concentrated to give Compound 5 (10.3 mg, yield: 14%).

1H NMR (400 MHz, CDCh) δ = ppm 9.84 (d, J=2.51 Hz, 1 H) 8.56 (d, J=2.51 Hz,

I H) 7.25 (d, 7=8.53 Hz, 2 H) 7.08 (d, 7=8.78 Hz, 2H) 6.49 (d, 7=8.28 Hz, 2 H) 6.43 (d, 7=9.03 Hz, 2 H) 6.06 (s, 1 H) 4.59 (d, 7=5.27 Hz, 2 H) 4.05 (s, 4 H) 4.03 (s, 4 H) 2.99 (q, J=1A5 Hz, 2 H) 1.43 (t, 7=7.53 Hz, 3 H)

Synthesis of Compound 6

CAS [1529528-99-1]

Q

HATU. ΟΓΕΑ, DMF, 25°C,2h

Compound 6

Accordingly, Compound 6 was prepared in the same way as Compound 5 starting from 2-ethyl-5H,6H.7H,8H-îmidazo[l,2-a]pyridine-3-carboxy]ic acid CAS [152952899-1] and intermediate Q, yielding 153.90 mg, yield: 32%.

1H NMR (400 MHz, CDCh) δ ppm 7.21 (d, 7=8.28Hz, 2 H) 7.08 (d, 7=8.03 Hz, 2 H)

6.47 (d, 7=8.53 Hz, 2 H) 6.40-6.45 (m, 2 H) 5.83 (br. s., 1 H) 4.50 (d, 7=5.52 Hz, 2 H) 4.23 (t, 7=5.77 Hz, 2 H) 4.04 (s, 8 H) 2.86 (t, 7=6.40 Hz, 2 H) 2.68 (q. 7=7.53 Hz, 2 H) 1.83 - 2.01 (m, 4 H) 1.23 (1,7=7.53 Hz, 3H)

Synthesis of Compound 7 ^_°hOO-°^h

CAS [1147337-97-8]

PPhpIî iTiilajDk, toluene reflux 1 h

F F

CAS[ 1399301-27-2] tnms-2-anin>çyclohexanDl NalIMDS, NIj, 1-PiO», 60*C, MW, 1 h, 90°C, MW, 1 h 120°C, MW, 3 h,

HCOOH ®C, 16 h

-00-0°^

T

Intermediate M

X-phos, PdfdbaJj, t-BuONa dbxane, MW, 100°C, 1 h

Compound 7

Préparation of intermediate R

Triphenylphosphine (1.89 g, 7.20 mmol), imîdazole (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, 10 filtered and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 1/0 to 1/1) to give intermediate R (1.20 g, yield: 93%).

Préparation of intermediate S

A mixture of4-(Trifluoromethoxy)phenylboronic acid (CAS [139301-27-2], 510 mg,

2.48 mmol), trans-2-amîno-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 fiow. 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: petroieum 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%).

Préparation of Compound 7

A solution of intermediate T (110 mg, 0.428 mmol), Intermediate M (226 mg,

0.514 mmol), Pd(dba): (14.8 mg, 0.0260 mol), X-phos (20.4 mmol, 0.0430 mmol) and 20 sodium tert-butoxide (165 mg, 1,71 mmol) in 1,4-dîoxane (5 mL) was îrradiated under microwave at 100°C for 1 h under Nî atmosphère. Ethyl acetate (30 mL) was added and the mixture was washed with water (10 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: petroieum ether/ethyl 25 acetate 1/0 to 0/1) to give crude compound. It was further purified by high performance liquid chromatography over Phenomenex Gemini Cl8 200x25mmxl0pm (eluent: 0.5% ammonia in water/acetonitrile 80/20 to 14.5/85.5). The desired fractions were collected and lyophilized to give Compound 7 (84.60 mg, yield: 35%). .

*H NMR (400MHz, CDCh) δ = 9.52 (d, >1.8 Hz, 1H), 7.53 (d,>9.5 Hz, 1H), 7.29 30 (dd, >2.0,9.5 Hz, 1 H), 7.26 - 7.18 (m, 4H), 7.18 - 7.12 (m, 2H), 6.47 (d,>8.5 Hz,

2H), 5.99 (br.s., 1H), 4.58 (d, >5.3 Hz, 2H), 4.02 (s, 2H), 3.80 (s, 2H), 3.47 (q, >8.9 Hz, 1H), 2.94 (q, >7.5 Hz, 2H), 2.70 - 2.61 (m, 2H), 2.38 - 2.29 (m, 2H), 1.38 (t, >7.5 Hz, 3H)

-49Synthesis of Compound 8

F F ^hnCx>O-^0>Lf

T

CAS [3058-39-7]

X-phos, Pdfdba^.t-BuONa, dioxrne, MW, 110°C, 1 h ^nc-O-ⁿ0>O-O-®^î'^f

U

RaneyNlH^ISpsï)

NH_}MeOH,RT, 16h

IIATU, DIFA, DMF, 25°C, 2h ^ci'Çj;^^vOⁿX^O-^ocf·

Compound 8

Préparation of intermediate U

Accordingly, intermediate U was prepared in the same way as intermediate H, starting from intermediate T and 4-todobenzonttrile CAS [3058-39-7], yielding 120 mg, yield: 40%.

Préparation of intermediate V

Accordingly, intermediate V was prepared in the same way as intermediate I, starting from intermediate U yielding 120 mg, yield: 92%.

Préparation of Compound 8

A mixture of intermediate V (125 mg, 0.222 mmol), intermediate L (80.5 mg, 0.222 mmol), HATU (110 mg, 0.289 mmol) and DIEA (74.6 mg, 0.577 mmol) in dichloromethane (10 mL) was stirred at 25°C for 2 hours. Dichloromethane (50 mL) was added and the mixture was washed with water (50 mL) and brine (50 mL). The separated organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: ethyl acetate) to give crude product. The crude product was further purified by high performance liquid chromatography over Gemini 150x25 5μπι (eluent: 0.05%

-50ammomum water/ acetonitrile 21/79). The desired fractions were collected and lyophilized to give Compound 8 (36.6 mg, yield: 28%).

‘H NMR (400MHz, CDCh) δ = 9.83 (d,/=2.2 Hz, 1H), 8.55 (d, /=2.2 Hz, 1H), 7.25 7.08 (m, 6H), 6.46 (d, /=7.9 Hz, 2H), 6.06 (br. s., 1H), 4.58 (d, /=5.3 Hz, 2H), 4.02 (s, 2H), 3,81 (s, 2H), 3.47 (q,/=8.8 Hz, 1H), 2.98 (q, /=7.5 Hz, 2H), 2.73 - 2.59 (m, 2H), 2.41 - 2.27 (m, 2H), 1.42 (t,/=7.5 Hz, 3H).

Synthesis of Compound 9

CAS [3O58-39-7J «ooO iicrmedial AW

X-phos, Pd(dba),,t-BuONa, dioxane, MW, 11O°C, 1 h ^nc-0-oo-0 w

RaneyNÎ H₂ (I5psi) NHjMcOH, RT, 16h

Compound 9

Préparation of intermediate W

Accordingly, intermediate W was prepared in the same way as intermediate H starting from intermediate AW (120 mg, 0.693 mmol) and 4-îodobenzonitrile (CAS [305839-7], 238 mg, 1.04 mmol) yiedling 100 mg, 52%.

Preparation of intermediate X

Accordingly, intermediate X was prepared in the same way as intermediate 1 starting from intermediate W (100 mg, 0.364 mmol yielding 100 mg, 94%.

Preparation of Compound 9

A solution of intermediate L (50.0 mg, 0.222 mmol), HATU (110 mg, 0.289 mmol), DIEA (74.6 mg, 0.577 mmol) in DMF (5 mL) was stirred for 30 minutes at 25°C. Intermediate X (68.0 mg, 0.244 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: gradient 0.05% ammonia ln water/methanol from 25/75 to 5/95). The desired fractions were collected and concentrated to give Compound 9 (34.7 mg, yîeld: 31%).

1H NMR (400 MHz, CDC1₃) δ ppm 9.82 (d, J=2.51 Hz, 1 H) 8.55 (d, J=2.76 Hz, 1 H) 7.28 - 7.35 (m, 2 H) 7.18 - 7.23 (m, 5 H) 6.41 -6.50 (m, 2 H) 6.08 (t, J=5.02 Hz, 1 H) 4.58 (d, J=5.52 Hz, 2 H) 4.00 - 4.04(m, 2 H) 3.77 - 3.83 (m, 2 H) 3.42 - 3.53 (m, 1 H) 2.98 (q, J=7.36 Hz, 2 H) 2.62 - 2.69 (m, 2 H) 2.33 - 2.40 (m, 2 H) 1.37 - 1.46 (m, 3 H)

Synthesis of Compound 10 “'-O&

CAS 774-93-6

Pd/dppOjCl,, KOAc 'J'O F F

DMSO, 100°C, 16 h _Y

HCINalO,, THF,O^eCtoRT

trans-2-airmo-cyclûhcxanol, NaUMDS.NIj, kPiOII, 60*C, MW, 1 h, 90^eC, MW, 1 h, 120°C,MW,4h,

HCOOH

RT, 16h

n—Q-i ^C<S,WW71 Pd(dba)₂, X-phos, t-BuONa, ^tf dbxane, I I0°C, MW, 1 h ^AC

RancyNL llj (40 psi), NHjMeOU, RT, 16h

AD

O

HATU, DIEA.DMF, RT, 2 h

N

F S-F f t

F

Conpotnd 10

-52Préparation of intermediate Y

A mixture of4-bromophenylsulfur pentafluoridg (CAS [774-93-6] 4 g, 14,1 mmol), bis(pinacolato)iiiboron (CAS [73183-34-3], 4.30 g, 16.9 mmol), potassium acetate (2.80 g, 28.5 mmol) and Pd(dppf)2Cb (0.946 g, 1.29 mmol) in 1,4-dioxane (50 mL) was stirred at 100°C for 16 hours. Ethyl acetate (200 ml) was added and the mixture was washed with water (100 mL) and brine (100 mL). The separated 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 10/1) to give intermediate Y (4.60 g, yield: 89%).

Préparation of intermediate Z

Sodium periodate (3.49 g, 16.3 mmol) was added portionwise to a solution of intermediate Y (1.80 g, 5.45 mmol) in concentrated hydrochloride (5 mL) and THF (20 mL) at 0°C. The mixture was stirred at room température for 3 hours. Ethyl acetate (50 mL) was added and the mixture was washed with saturated aqueous sodium sulfite solution (2x20 mL). The separated organic layer was washed with water (20 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give Intermediate Z (1 g, yield: 72%).).

Préparation of intermediate AA

A mixture of intermediate Z (500 mg, 2.02 mmol), trans-3-amino-cyclohexanol (11.5 mg, 0.100 mmol) and nickel iodine (31.3 mg, 0.100 mmol) in isopropanol (7 ml) was stirred at room température for 30 minutes under nitrogen flow. NaHMDS (2.02 ml, 2.02 mmol, l M in THF) was added, and the mixture was stirred for

10 minutes under nitrogen flow. A solution of intermediate R (326 mg, 1.01 mmol) in isopropanol (3 ml) was added and the mixture was stirred at 60°C under microwave for I hour, at 90°C for l hour and at 120°C for 4 hours. The mixture was diluted with dichloromethane (50 ml), washed with water (50 mL) and brine (50 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 AA (170 mg, yield: 43%).

Préparation of intermediate AB

Accordingly, intermediate AB was prepared in the same way as intermediate G, starting from intermediate AA (170 mg, 0.426 mmol) yielding 100 mg, 78%.

Préparation of intermediate AC

Accordingly, intermediate AC was prepared in the same way as intermediate H, sarting from intermediate AB (80.0 mg, 0.267 mmol) and 4-iodobenzonitrile (CAS [305839-7J, 91.6 mg, 0.4 mmol) yîelding 90 mg, 71%.

Préparation of intermediate AD

Accordingly, intermediate AD was prepared în the same way as intermediate I, starting from intermediate AC (80.0 mg. 0.200 mmol) yîelding 80 mg, 99%.

Préparation of Compound 10

A mixture of 6-chloro-2-ethylimidazo[3,2-aJpyridine-3-carboxylic acid (CAS [ 1216142-18-5J.44.5 mg, 0.198 mmol), intermediate AD (80 mg, 0.198 mmol), HATU (97.9 mg, 0.257 mmol) and D!EA (76.8 mg, 0.594 mmol) in DMF (4 mL) was stirred at room température for 2 hours. The mixture was purified by high performance liquid chromatography over Waters Xbridge Prep OBD C18 ! 50x30 5μΜ (eluent: 0.05% ammonium water/methanol 15/85 to 5/95). The desired fractions were collected and lyophilized to give Compound 10 (36.6 mg, yield: 28%).

¹H NMR (400MHz, CDCb) δ = 9.52 (s, ! H), 7.69 (d, J=8.4 Hz, 2H), 7.54 (d, ^=9.3 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.23 (br. s., 3H), 6.47 (d, J=7.9 Hz, 2H), 5.99 (br.

s., 1H), 4.58 (d, J=4.4 Hz, 2H), 4.03 (s, 2H), 3.81 (s, 2H), 3.52 (quin, J=8.5 Hz, 1H),

2.94 (q, J=7.4 Hz, 2H), 2.69 (t, J=9.5 Hz, 2H), 2.36 (t, J=10.1 Hz, 2H), L38 (t, 7=7.3 Hz, 3H).

Synthesis of Compound 11

CAS [1692-2J-7]

-uKX>* R trans-2-amro-cyclo hexanol, NaHMDS, Ni ₂, FPiOH, 60X.MW, 1 h,90°C,MW, 1 h 120°C, MW, 4 K

P-OO-Q 11CC0.RT, 12 h

AE

CAS [3058-39-7]

X-phos,Pd(dba)₂,t-BuONa, dbxaiK, MW, 1 IO°C, 1 h

RancyNi, IL, (13psi)

NH₃MeOH,RT,16h

HATU, DIEA, DMF, 25”C,2h ^N

Compound II

Préparation of intermediate AE

A mixture of intermediate R (608 mg, 4.95 mmol), trans-2-amino-cyclohexanol (57.0 mg, 0.495 mmol) and Nib (77.3 mg, 0.248 mmol) tn i-PrOH (6 mL) was stirred at 25°C for 30 minutes under nitrogen flow. NaHMDS (908 mg, 4.95 mmol) was added, and the mixture was stirred for 10 minutes under nitrogen flow.

3-Pyridineboronic acid (CAS [1692-25-7], 800 mg. 2.48 mmol) in i-PrOH (4 mL) was added and the mixture was stirred at 60°C under microwave for I hour, at 90°C for

1 hour and at I20°C for 4 hours. The mixture was diluted with dichloromethane (50 mL). washed with water (50 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 I) to give intermediate AE (250 mg, yield: 37%).

Préparation of intermediate AF

Accordingly, intermediate AF was prepared in the same way as intermediate G, starting from intermediate AE (200 mg, 0.729 mmol) yielding 120 mg, 94%.

Préparation of intermediate AG

Accordingly, intermediate AG was prepared in the same way as intermediate AG, starting from intermediate AF (80.0 mg, 0.459 mmol) and 4-iodobenzonitrile (CAS [3058-39-7], 158 mg, 0.688 mmol) yielding 80.0 mg, 63%.

Préparation of intermediate AH

Accordingly, intermediate AH was prepared in the same way as intermediate I, starting from intermediate AG (70.0 mg, 0.254 mmol) yielding 70.0 mg, 99%.

Préparation of Compound 11

A solution of intermediate L (51.4 mg, 0.228 mmol), HATU (113 mg, 0.296 mmol), DIEA (76.6 mg, 0.593 mmol) in DMF (10 mL) was stirred for 30 minutes at 25°C. Intermediate AH (70.0 mg, 0.251 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:

gradient 0.05% ammonia in water/methano) from 30/70 to 5/95). The desired fractions were collected and concentrated to give Compound 11 (10.5 mg, yield: 9%).

IH NMR (400 MHz, CDCIj) δ ppm 9.83 (d, J=2.5I Hz, I H) 8.55 (d, J-2.76 Hz, 1 H) 8.42 - 8.49 (m, 2 H) 7.53 (d, J^=7.78 Hz, 1 H) 7.23 (d, J=8.53 Hz, 3 H) 6.47 (d, J^=8.53 Hz, 2 H) 6.06 (br. s., 1 H) 4.58 (d, J=5.21 Hz, 2 H) 4.04 (s, 2 H) 3.83 (s, 2 H) 3.50 (q,

J=8.72 Hz, 1 H) 2.99 (q, J=7.53 Hz, 2 H) 2.65 - 2.74 (m, 2 H) 2.33 - 2.43 (m, 2 H) 1.42 (t, J=1.53 Hz, 3 H) . Synthesis of Compound 12 and Compound 13 o

CAS [1131613-58- 5]

EDCIHCl HOBt DCM/THF. 18 h RT

CAS [1508720-12-4]

Compound 12

A solution of 6-ethyl-2-methylimidazo[2,l-b]thiazole-5-carboxylic acid (CAS [1131613-58-5], 40 mg, 0.19 mmol), (4-{2-azaspiro[3.3]heptan-2-yl}phenyl) methanamine (CAS [1508720-12-4], 46 mg, 0.23 mmol), EDCFHC1 (29 mg, 0.15 mmol), HOBt (26 mg, 0.19 mmol) and D1PEA (0.033 mL, 0.19 mmol) in

dichloromethane (1.3 mL) and THF (1.3 mL) was stirred at room température for 18h. The mixture was extended with silica and evaporated in vacuo. The residue was purified by préparative LC (regular SiOH 30 pm, 12 g Interchim, dry loading, mobile phase gradient: heptane/EtOAc from 70/30 to 50/50) to give after évaporation 41 mg of 5 Compound 12 as a white solid (55%).

'HNMR(500MHz, DMSO-î4) δ ppm 1.19 (t. >7.4 Hz, 2 H) 1.70 - l,86(m,2H) 2.15 (t, >7.6 Hz, 4 H) 2.42 (d, J= 1.3 Hz, 3 H) 2.84 (q, >7.6 Hz, 2 H) 3.72 (s, 4 H) 4.34 (d, >6.0 Hz, 2 H) 6.36 (d, >8.5 Hz, 2 H) 7.14 (d, >8.5 Hz, 2 H) 7.88 (d, >1.3 Hz, 1 H) 8.02 (br t, >6.0 Hz, I H).

Accordingly, Compound 13 was prepared as the same way as Compound 12 starting from 2-bromo-6-methylimidazo[2,3-b][l,3]thiazole-5-carboxy!ic acid CAS [8693315 04-2] and (4-{2-azaspiro[3.3]heptan-2-yl]phenyl)methanamine CAS [1508720-12-4], yielding 41 mg, 55%.

^lHNMR(500MHz,DMSO-i/₆)ôppm 1.19 (t, >7.4 Hz, 2 H) 1.70 - 1.86 (m, 2 H) 2.15 (t,>7.6 Hz, 4 H) 2.42 (d,>1.3 Hz, 3 H) 2.84 (q, >7.6 Hz, 2 H) 3.72 (s, 4 H) 4.34 (d, >6.0 Hz, 2 H) 6.36 (d, >8.5 Hz, 2 H) 7.14 (d, >8.5 Hz, 2 H) 7.88 (d, 20 >1.3 Hz, I H) 8.02 (brt, >6.0 Hz, I H).

Synthesis of Compound 14

CAS 1216142-18-5 +

CAS 1160246-99-0

HOBT, EDCt, EtjN, CIL, CL, °C, 16 h

HCl h dioxane, Ct^CL,

0-15’C, 12 h

F F _/-v y-^{p i}~O°

CAS [103962-05-6]

Pd(dba),, Xphos, NaOtBu, dioxane, H0°C, MW, f h

Compound 14

Préparation of intermediate Al

Triethylamine (0.096 mL, 0.690 mmol), tert-butyl 3-(aminomethyl)-2-oxa9-azaspiro[5.5]undecane-9-carboxylate (CAS [1160246-99-0], 100 mg, 0.352 mmol), HOBT (46.6 mg, 0.345 mmol) and EDCbHCI (99.3 mg, 0.518 mmol) were added to a solution of 6-chloro-2-ethylimidazo[3,2-a]pyrîdine-3-carboxylic acid (CAS [121614218-5], 77.5 mg, 0.345 mmol) in dichloromethane (2 mL) in tum. After stirred at 60°C 10 for 16 hours, ethyl acetate (20 mL) was added. The mixture was washed with water (2x20 mL) and brine (20 mL). The separated organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 1/1 to 0/1) to give intermediate AI (160 mg, Yield: 86%).

Préparation of intermediate AJ

Hydrochloride (2 mL, 8 mmol, 2 M in dioxane) was added to a solution of intermediate

AI (120 mg, 0.244 mmol) in dichloromethane (2 mL) at 0°C. After stirred at 15°C for hours, the solvent was evaporated under vacuum. The residue was dissolved into water (20 mL) and then basified with saturated aqueous sodium carbonate to pH ~ 10.

The solution was extracted with dichloromethane/methanol (10/1,2x20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and the filtrated was concentrated under vacuum to give intermediate AJ (50 mg, yield: 56%).

Préparation of Compound 14

A solution of intermediate AJ (30.0 mg, 0.0770 mmol), 1-iodo-4-(trifluoromethoxy) benzene (CAS [103962-05-6], 22.2 mg, 0.0770 mmol), Pd(dba)? (4.60 mg, 8.00 pmol, X-phos (7.63 mg, 16.0 gmol) and sodium tert-butoxide (29.6 mg, 0.308 mmol) ïn dîoxane (4 mL) was irradiated under microwave at 110°C for 1 h under N2 atmosphère. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, brine, dried over NaîSCh, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel (petroleum ether/ethyl acetate 10/1 to 0/1) to give crude compound. It was further purified by high performance liquid chromatography over Gemini C18 150x25mmxl0gl (eluent: 0.5% ammonia în water/acetonitrile 45/55 to 15/85). The desired fractions were collected and lyophilized to give Compound 14 (1.30 mg, yield: 3%).

’H NMR (400MHz, CDCh) δ = 9.50 (d,7=1.3 Hz, IH), 7.54 (d,7=9.5 Hz, IH), 7.29 (dd,7=2.1,9.4 Hz, lH),7.10(d,7=8.5Hz,2H),6.89(d,7=9.3Hz,2H),6.35(br.s., IH), 3.93 - 3.85 (m, 2H), 3.51 (br. s., IH), 3.30 (m, IH), 3.24 (d,7=11.3 Hz, IH), 3.21

- 3.07 (m, 4H), 3.03 (q,7=7.5 Hz, 2H), 1.94 - 1.85 (m, 2H), 1.79 (d,7=7.0 Hz, IH),

1.66 - 1.62 (m, IH), 1.61 - 1.59 (m, 2H), 1.50 - 1.47 (m, 2H), 1.44 (t,7=7.5 Hz, 3H)

Synthesis of Compound 15

Raney Ni, llj (15 psi)

MeOII/NH., 15 ’C H₂N r-χ -------- WX N-Boc

TOSMIC, t-BuONa, DME,t-BuOIl

AL

Pd(dba)j, X-phos, NaOtBu, 1,4-dioxane,

HO’C.MW

Compound 15

Préparation of intermediate AK

Sodium tert-butoxtde (481 mg, 5.01 mmol) tn dimethoxyethane (5 mL) and butanol (5 mL) was added to a solution of 7-Boc-7-azaspiro[3.5]nonan-2-one (CAS [20366169-2], 600 mg, 2.51 mmol) and Tosmïc (548 mg, 2.81 mmol) in dimethoxyethane (5 mL) under nitrogen atmosphère at 10 to 15°C over 1 hour. After stirring ofthe mixture at 20 °C for 12 hours, the reaction mixture was poured into ice water, and then extracted with ethyl acetate. The extract was washed with brine, dried, and evaporated. The residue was purified by column chromatography over silica gel (20% ethyl acetate-hexane) to give intermediate AK (50.0 mg, yield: 8%).

Préparation of intermediate AL

A solution of intermediate AK (50 mg, 0.200 mmol) in NHrMeOH (7 M in methanol, mL) was hydrogenated at 15°C (H2,15 psi) wtth Raney Nickel (25 mg) as a catalyst for 16 hours. The catalyst was filtered off and the filtrate was concentrated under vacuum to give intermediate AL (50.9 mg. Yield: 95%).

Préparation of intermediate AM

A solution of intermediate AL (44.9 mg, 0.200), 6-chloro-2-ethylimidazo[3,2-a] pyridîne-3-carboxylic acid (CAS [1216142-18-5], 50.9 mg, 0.200 mmol), HOBt (27.0 mg, 0.200 mmol), EDCI (57.5 mg, 0.300 mmol) and triethylamine (0.056 ml,

0.400 mmol) in DMF (2 ml) was stirred at 60°C for 16 hours. Ethyl acetate (20 mL) was added and the mixture was washed with brine, dried, filtered and the filtrate was concentrated. The residue was purified by column chromatography over silica gel (petroleum/ethyl acetate 1/1) to give intermediate AM (50.0 mg, yield: 51%).

Préparation of intermediate AN

Hydrochloride (1.00 mL, 4.00 mmol, 4 M in ethyl acetate) was added to a solution of Intermediate AM (50.0 mg, 0.108 mmol) in C at 0°C. The mixture was warmed up to 20°C and stirred for 16 hours. The mixture was neutralized with saturated sodium carbonate to pH -10 and diluted with ethyl acetate (10 mL). The organic layer was 15 washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by thin layer chromatography over silica gel (eluent: dichloromethane/methanol 10/1) to give intermediate AN (35.0 mg, yield: 81%).

Préparation of Compound 15

A solution of intermediate AN (15.0 mg, 0.0420 mmol), l-iodo-4-(trifluoromethoxy) benzene (CAS [103962-05-6], 12.1 mg, 0.042 mmol), Pd(dba)2 (3.66 mg, 6.37 pmol), X-phos (3.81 mg, 8.00 mmol) and sodium tert-butoxide (16.1 mg, 0.168 mmol) în 1,4-dioxane (2 mL) was îrradiated under microwave at 110°C for 60 min under N: atmosphère. The mixture was filtered and then the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 1/1) to give crude compound. It was further purified by high performance liquid chromatography over Gemini Cl8 150x25mmxl0gl (eluent: ammonia in water/acetonitrile 30/70 to 0/100). The desired fractions were collected and lyophilized to give Compound 15 (2.30 mg, yield: 10%).

Ή NMR (400MHz, CDCb) Ô = 9.47 (s, 1H), 7.54 (d, 7=9.5 Hz, 1H), 7.29 (dd, /=2.0, 9.5 Hz, 1 H), 7.08 (d, /=9.0 Hz, 2H), 6.89 (d, 7=9.0 Hz, 2H), 5.80 (br. s., 1 H), 3.57 (t, /=6.5 Hz, 2H), 3.17 - 3.09 (m, 2H), 3.09 - 3.03 (m, 2H), 3.00 (q, 7=7.5 Hz, 2H), 2.61 (td, /=8.3, 16.1 Hz, 1H), 2.11 -1.99 (m, 2H), 1.83 - 1.75 (m, 2H), 1.71 (d, /=5.5 Hz, 2H), 1.60 - 1.54 (m, 2H), 1.45 (t, J=1J Hz, 3H)

-61Synthesis of Compound 16, Compound 17, Compound 18 and Compound 19

HCOOH

CAS 1147557-97-8

DAST, CH,CL OH

Boc-N

RaneyNi «O-»»- = ,,,ΧΧ»-^A(? AR a wO^dast· QC «

2S. _Bot.<x>_F = H<xy_F Ù2Ï—. t-BuONa, Pd(dba),

CAS 1147557-97-8 AO AP X-pto.dbxane

Compound 16

Préparation of intermediate AO

DAST (0.507 mL. 3.84 mmol) was added dropwise to a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (CAS [63711570], 700 mg, 3.28 mmol) in dry dichloromethane (5 mL) under nitrogen atmosphère at 0°C. The mixture was slowly warmed up to 40°C and stirred ovemight. The resulting mixture was washed with water and brine. The organic layer was dried over magnésium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel to give intermediate AO (200 mg, yield: 27%).

Préparation of intermediate AP

A mixture of intermediate AO (200 mg, 0.929 mmol) in formic acid (5 mL) was stirred at 25°C for 16 hours. The mixture was concentrated under vacuum to give intermediate

AP (149 mg, yield: 100%).

-6210

Préparation of Compound 16

A solution of intermediate AP (59.4 mg, 0.369 mmol), intermediate M (195 mg, 0.443 mmol), Pd(dba)₂ (21.2 mg, 0.037 mmol), X-phos (35.2 mg, 0.074 mmol) and sodium tert-butoxide (177 mg, 1.85 mmol) in 1,4-dioxane (8 ml) was irradiated under microwave at 110°C for 60 min under N₂. Dichloromethane (50 mL) was added and the mixture was washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and the fiItrate was concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 1/0 to 0/1). The desired fractions were collected and concentrated. The residue was further purified by high performance liquid chromatography over Waters XbridgeCl8 150x20mmx5gm (eluent: 0.5% NHj water/methanol 35/65 to 5/95). The desired fractions were collected and lyophilized to give Compound 16 (33.30 mg, yield: 21%).

Ή NMR (400MHz, CDClj) δ = 9.52 (d, 7=1.5 Hz, 1H), 7.53 (d, J=9.5 Hz, 1H), 7.29 (dd, 7=2.1,9.4 Hz, 1H), 7.22 (d, 7=8.3 Hz, 2H), 6.43 (d, 7=8.3 Hz, 2H), 5.99 (br. s., 1 H), 5.10 - 4.85 (m, IH), 4.57 (d, 7=5.4 Hz, 2H), 3.87 (d, 7= 16.4 Hz, 4H), 2.94 (q, 7=7.6 Hz, 2H), 2.71 - 2.59 (m, 2H), 2.52 - 2.36 (m, 2H), 1.38 (t, 7=7.6 Hz, 3H).

Préparation of intermediate AO

A solution of intermediate AP (400 mg, 3.47 mmol), 4-iodobenzonitrile (1.19 g, 5.21 mmol), X-phos (199 mg, 0.42 mmol), Pd(dba)2 (120 mg, 0.208 mmol) and t-BuONa (1.34 g, 13.9 mmol) in dioxane (20 mL) was irradiated under microwave at 110 °C for 1 hour under N₂. The mixture was concentrated. The crude product was purified by column chromatography over silica gel (eluent: ethyl acetate / petroleum ether from 0 to 1/5). The desired fractions were collected and concentrated to give intermediate AQ (450 mg, yield: 60%).

Préparation of intermediate AR

H

A mixture of intermediate AQ (450 mg, 2.08 mmol) in NHj’MeOH (7M in methanol, mL) was hydrogenated (15 psi) with Raney Nickel (50 mg) as catalyst at 25°C for

-6316 hours. After uptake of H2, the catalyst was filtered off and the filtrate was concentrated to give intermediate AR (450 mg, yield: 98%).

Préparation of Compound 17

Cl.

Compound 17

Accordingly, Compound 17 was prepared as the same way as Compound 11, starting from intermediate AR and intermediate L, yielding 5.20 mg, yield: 3%.

1H NMR (400 MHz, CDCb) Ô ppm 9.82 (d, 7=2.51 Hz, 1 H) 8.55 (d, 7=2.51 Hz, 1 H) 7.21 (d, 7=8.28 Hz, 2 H) 6.43 (d, 7=8.53 Hz, 2 H) 6.05 (br. s., 1 H) 5.05-4.9 (m, 1 H) 4.57 (d, 7=5.52 Hz, 2 H) 3.89 (s, 2 H) 3.85 (s, 2 H) 2.98 (q, 7=7.53 Hz, 2 H) 2.61 - 2.69 (m, 2 H) 2.38 - 2.50(m, 2 H) 1.42 (t, .7=7.53 Hz, 3 H)

Préparation of Compound 18

Compound 18

Accordingly, Compound 18 was prepared as the same way as Compound 11, starting from intermediate AR and 6-ethyl-2-methylimidazo[2,l-b]thiazole-5-carboxylic acid CAS[1131613-58-5], yielding 41.8 mg, yield: 27%.

iH NMR (400 MHz, CDCb) δ ppm 7.99 (d, .7=1.26 Hz, 1 H) 7.20 (d, .7=8.28 Hz, 2 H) 6.40 - 6.45 (m, 2 H) 5.84 (br. s., 1 H) 5.05-4.9 (m, 1H) 4.54 (s, 2 H) 3.88 (s, 2 H) 3.84 (s, 2 H) 2.82 (q, 7=7.70 Hz, 2 H) 2.60 - 2.70 (m, 2 H) 2.37 - 2.52 (m, 5 H) 1.29 -1.36 (m, 3 H).

Préparation of Compound 19

Compound 19

Accordingly, Compound 19 was prepared as the same way as Compound 11, starting from intermediate AR and 2-ethyl-5H,6H,7H,8H-imidazo[l,2-a]pyridine-3-carboxylîc acid CAS [1529528-99-1], yielding 32.0 mg, yield: 21.5%.

1H NMR (400 MHz, CDCb) δ ppm 7.18 (d, J=8.28 Hz, 2 H) 6.41 (d, J=8.53 Hz, 2 H) 5.81 (br. s., 1 H) 4.86 - 5.10 (m, I H) 4.48 (d, J=5.52 Hz, 2 H) 4.22 (t, J=5.90 Hz, 2 H) 3.88 (s, 2 H) 3.84 (s, 2 H) 2.85 (t, J=6.40 Hz, 2H) 2.60 - 2.70 (m, 4 H) 2.37 - 2.51 (m, 2 H) 1.83 - 1.99 (m, 4 H) 1.22 (t, J=7.65 Hz, 3 H)

Synthesis of Compound 20 and Compound 21

CAS [1181816-12-3]

TF AH N' pW, KjCOj, DMSO l2(FC,30mh

NC

AT

AS

COjH

OH

Compound 20

DMP, DCM

RT, 18h

Compound 21

Préparation of intermediate AS

TFA (1.6 mL, 21 mmol) was added to a solution of fert-butyl 6-oxo-2-azaspiro[3.3] heptane-2-carboxylate (CAS [1181816-12*5], 0.3 g, 1.4 mmol) in dichloromethane (9.8 mL) and the mixture was stirred at room temperature for 18h. The réaction mixture 5 was evaporated under vacuum, and coevaporated twice with toluene to afford 320 mg of Intermediate AS as a colorless oil (100%).

Preparation of intermediate AT

A solution of intermediate AS (0.34 g, 1.5 mmol), 4-fluorobenzonitrile (CAS [119410 02-1], 0.37 g, 3.0 mmol) and K2COJ (0.62 g, 4.5 mmol) in DMSO (5.4 mL) was heated at 120°C using a single mode microwave (Biotage initiatorÔO) with a power output ranging from 0 to 400 W for 30 min. Brine and EtOAc were added. The organic layer was extracted, dried over MgSO4, filtered and evaporated. Purification of the residue was carried out by préparative LC (Interchim, 12 g, 30pm, Heptane/EtOAc 90/10).

Pure fractions were collected and evaporated to give 60 mg of intermediate AT as a white solid (19%).

Preparation of intermediate AU

A solution of intermediate AT (60 mg, 0.28 mmol) in dry THF (1.1 mL) was added dropwise to a mixture of L1AIH4 (64 mg, 1.7 mmol) in dry THF (1.2 mL) at 0°C. The mixture was slowly let corne back to room temperature and stirred ovemight. Water (0.24 mL) then dichloromethane (30 mL) were added very slowly and stirred for min. MgSCL was added, the insoluble was filtered on a pad of celite, and the filtrate was evaporated until dryness to give 57 mg of intermediate AU as a white solid (92%).

Preparation of Compound 20

A solution of 6-ethyl-2-methylimidazo[2,l-b]thiazole-5-carboxylic acid (CAS [1131613-58-5], 46 mg, 0.22 mmol), intermediate AU (57 mg, 0.26 mmol), EDCPHCI (34 mg, 0.22 mmol), HOBt (29 mg, 0.22 mmol) and DIPEA (0.038 mL, 0.22 mmol) in dichloromethane (1.5 mL) and THF (1.5 mL) was stirred at room temperature for 18h.

The mixture was extended with silica and evaporated in vacuo. The residue was purified by préparative LC (regular SiOH 30 pm, 12 g, dry loading, mobile phase gradient: DCM/MeOH from 99/1 to 96/4) to give after évaporation, trituration ïn Et2Û and a second évaporation, 53 mg of Compound 20 as a beige solid (59%).

^lH NMR (400 MHz, DMSO-ifc) δ ppm 1.19 (t, /=7.6 Hz, 3 H) 1.89 - 2.02 (m, 2 H)

2.38 - 2.45 (m, 2H) 2.41 (s, 3 H) 2.83 (q, /=7.6 Hz, 2 H) 3.67 (s, 2 H) 3.72 (s, 2 H) 3.90

- 4.08 (m, 1 H) 4.34 (d, /=5.6 Hz, 2 H) 5.01 (d, /=6.6 Hz, 1 H) 6.34 (d, /=8.6 Hz, 2 H)

7.13 (d,/=8.1 Hz, 2 H) 7.87 (d,/=1.0 Hz, 1 H) 7.99 (1,/=6.1 Hz, 1 H).

Préparation of Compound 21

Under nitrogen, DMP (15%) in dichloromethane (0.20 mL, 94 pmol) was added to a solution of Compound 20 (35 mg, 85 pmol) in dichloromethane (2.7 mL) and the mixture was stirred at room température for 72h. The mixture was extended with silica and evaporated in vacuo. The residue was purified by préparative LC (regular SiOH 30 pm, 12 g, dry loading, mobile phase gradient: DCM/MeOH from 99/1 to 97/3) to give after évaporation, trituration în EtîO and évaporation, 18 mg of a beige solid. This solid was purified via Reverse phase (Statîonary phase: X-Bridge-C18 5pm

30* 150mm, Mobile phase: Gradient from 75% aq. NH4HCO3 (0.5%), 25% MeCN to

35% aq. NH4HCO3 (0.5%), 65% MeCN) to give 5 mg of Compound 21 as a beige solid (14%).

'H NMR (400 MHz, DMSO-rfc) δ ppm 1.19 (t, 7=7.6 Hz, 3 H) 2.41 (s, 3 H) 2.84 (q, 7=7.6 Hz, 2 H) 3.32 (s, 4 H) 3.95 (s, 4 H) 4.35 (d, 7=5.6 Hz, 2 H) 6.43 (d, 7=8.1 Hz, 15 2 H) 7.17 (d, 7=8.6 Hz, 2 H) 7.88 (s, 1 H) 8.02 (1,7=5.6 Hz, 1 H).

Synthesis of Compound 23 and Compound 22

HO t B

HO

CAS[98-80-6]

HCOOH °C, 16 h

AW trans-2-amino-cycbhexanot NaHMDS.Nïj, i-PtOH, 60°C, MW, 1 K 90°C, MW, 1 h !20°C, MW, 5 h.

M

X-phos, Pd(dba)_:, t-BuONa dbxane, MW, 1ÔO°C, I h

R“H: Compound 23

R-Ct Compound 22

Préparation of intermediate AV

Accordingly, 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%.

-67Preparation 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 Compound 22 and Compound 23

Accordingly, Compound 22 was prepared in the same way as Compound 7 starting from intermediate AW and intermediate M. Yielding Compound 22,0.031 g, 16% and Compound 23, as by product, 0.0071 g, 13%.

Compound 22 ΉNMR (400MHz, CHLOROFORM-d) δ = 9.53 (d, 7=2.0 Hz, IH), 7.57 - 7.49 (m, IH), 7.28 (d, 7=2.3 Hz, 3H), 7.24 (s, IH), 7.23 - 7.17 (m, 4H), 6.47 (d, 7=8.3 Hz, 2H), 5.98 (br. s., IH), 4.58 (d, J=5.5 Hz, 2H), 4.02 (s, 2H), 3.81 (s, 2H), 3.48 (quin, 7=8.9 Hz, 1 H), 2.94 (q, J=7.5 Hz, 2H), 2.69 - 2.60 (m, 2H), 2.41 - 2.32 (m, 2H), 1.38 (t, 7-7.7 Hz, 3 H).

Compound 23 ‘H NMR (400 MHz, CHLOROFORM-7) δ ppm 9.40 (d, 7=7.28 Hz, 1 H) 7.60 (d, 7=9.03 Hz, 1 H) 7.34 - 7.31 (m, 3 H) 7.29 - 7.20 (m, 5 H) 6.88 - 6.95 (m, 1 H) 6.47 (d, 7=8.28 Hz, 2 H) 5.97 (br. s., 1 H) 4.59 (d, 7=5.27 Hz, 2 H) 4.02 (s, 2 H) 3.81 (s, 2 H) 3.38-3.54 (m, 1 H) 2.96 (q, 7=7.61 Hz, 2 H) 2.59 - 2.74 (m, 2 H) 2.31 2.42 (m, 2 H) 1.39 (t, 7=7.53 Hz, 3 H)

Synthesis of Compound 24

CAS [77628-31-4]

HATU, D1EA, CiLCln

AX ^Hf00^-O°^pFl jiteirnediate T

X-phos, Pd(dba)_:, t-BuONa dbxane, MW, 100°C, 1 h

Compound 24

Préparation of intermediate AX

A mixture of 6-methylimidazo[2,l-B][l,3]thiazole-5-carboxylic acid (CAS [77628-514], 200 mg, 1.10 mmol), 4-iodobenzenemethanamine (CAS [39959-59-6], 256 mg,

1.10 mmol), HATU (544 mg, 1.43 mmol), and diisopropylethylamîne (425 mg,

3.29 mmol) in dichloromethane (5 m!) was stirred at 25 °C for 2 hours. The mixture was diluted with dichloromethane (100 ml). The solution was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent:

petroleum ether/ethyl acetate 0/1 ) to give intermediate AX (220 mg, yield: 47.3%).

Préparation of Compound 24

Accordingly, Compound 24 was prepared in the same way as Compound 7 starting from intermediate AX and intermediate T, yielding 0.029g, 17%.

^lH NMR (400MHz, CHLOROFORM-d) δ ppm 8.29 (d, 7=4.5 Hz, 1H), 7.24 - 7.18 (m, 4H), 7.18 - 7.13 (m, 2H), 6.88 (d, 7=4.5 Hz, 1H), 6.46 (d, 7=8.5 Hz, 2H), 5.85 (br. s., 1H), 4.56 (d, 7=5.5 Hz, 2H), 4.02 (s, 2H), 3.80 (s, 2H), 3.47 (quin, 7=8.9 Hz, 1H), 2.70 - 2.61 (m, 2H), 2.56 (s, 3H), 2.38 - 2.29 (m, 2H)

Synthesis of Compound 25 and Compound 26

CAS [78060-54-5] hermediateT

K₂COj, CHjCN, reflux, 16 h

RancyNi, H₂ (15 psi) NHj/McOH, 15 C, 16 h

O

HATU, DIEA, CHjClj

X*N:Compoinl 25

X=€: Compoind 26

Préparation of intermediate AY

A mixture of2-chloro-6-quino!Înecarbonitri!e (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 retluxed 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/!) to give intermediate AY (20.0 mg, yield: 62.8%).

Préparation of intermediate AZ

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

Préparation of Compound 26

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridîne-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 în water/methanol 35/65 to 5/95). The desired fractions were collected and concentrated to give Compound 26 (4.30 mg, 15.91%).

IH 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, I 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, I 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, 3 H)

Préparation of Compound 25

Accordingly, Compound 25 was prepared in the same way as Compound 26 starting from intermediate L and intermediate AZ, yîelding 0.037 g, 25%.

1H NMR (400 MHz, CHLOROFORM-7) Ô ppm 9.83 (d, 7=2.51 Hz, 1 H) 8.55 (d,7=2.51 Hz, I H) 7.83 (d, 7=8.78 Hz, 1 H) 7.75 (d, 7=8.53 Hz, I 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, 2 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, 2 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)

The following comounds were also prepared în accordance with the procedures 35 described herein:

Compound No	Structure
27	-cxp
28
29	Q o f f
30	UK
31
32

Compound No	Structure
33	03^7
34
35
36	yzO-<X>-O3i OP 1
37

Compound No	Structure
38	CL jOT Tf
39
40	. r·^'
41	. <ού· 'QtA'Vj
42	&
43	y vx>CK}y 1

Compound No	Structure
44	U
45	π Γχ¥·
46	y^OO^O^y -COy F F
47	X--\NZ r 1
48
49	^.>o.cry

Compound No	Structure
50
51
52	y.^X2X>y, Qj~/ ’ ' \
53	\ £Τ°Ύ~: F
54	xY tu.

Compound No	Structure
55

Synthesis of Compound 56

HATU, DIPEA, DMF, RT, 16h

CAS [1352395-28-8]

Intermediate I

Compound 56

To a solution of 5-methoxy-2-methylpyrazolo[l,5-a]pyridine-3-carboxylic acîd (CAS [1352395-28-8], 0.055 g mg, 0.26 mmol) in DMF (5 mL) was added intermediate I (0.08 g, 0.22 mmol), HATU (0.1 g, 0.26 mmol) and diisopropylethylamïne (0.085 g, 0.66 mmol). The mixture was stirred at room température ovemight. The solvent was removed in vacuum to dryness. The residue was purified by high performance liquid chromatography (Waters Xbridge Prep OBD C18 150χ30χ5μ, 25mL/min, gradient water (containing 0.05% NH3.H20)/Acetonitrtle from 85/15 to 55/45). The desired fraction was collected and evaporated to remove off acetonitrile in vacuum. The residue was lyophilized to give Compound 56,0.027 g, 21%.

^lH NMR (400MHz, CDCh) 6 = 8.19 (d, J=7.5 Hz, 1 H), 7.57 (d, J=2.2 Hz, 1 H), 7.34 (d, J=7.5 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.54 (dd, J=2.4,

7.3 Hz, 1 H), 6.40 (d, J=8.8 Hz, 2H), 5.96 (br. s., IH), 4.67 (d, .7=5.3 Hz, 2H), 4.01 (s,

2H), 3.91 (s, 3H), 3.80 (s, 2H), 3.51 - 3.44 (m, IH), 2.70 - 2.56 (m, 5H), 2.41 - 2.30 (m, 2H).

Synthesis of Compound 57

Intermediate Q

HATU, DIPEA.

DMF,RT,16h

CAS [1332395-28-8]

Accordingly, Compound 57 was prepared în the same way as Compound 56 starting from 5-methoxy-2-methylpyrazolo[l,5-a]pyridine-3-carboxylic acid CAS [135239528-8], and intermediate Q, yielding 0.027 g, 21%.

IH NMR (400MHz, CDCh) δ = 8.18 (d, J-7.5 Hz. IH), 7.57 (d, J=2.6 Hz, IH), 7.25 (br. s., 2H), 7.09 (d^=8.8 Hz, 2H), 6.53 (dd, .7=2.6,7.5 Hz, IH), 6.49 (d, J-8.4 Hz, 2H), 6.43 (d, ,7=8.8 Hz, 2H), 5.86 (br. s., IH), 4.59 (d^=5.3 Hz, 2H), 4.04 (s, 8H), 3.91 10 (s, 3H), 2.58 (s, 3H)

Synthesis of Compound 58 o O

A⁷»'

Br

EtOH, 100*0,

12h

Intermediate BA

LjOH.HjO, MeOH, Η,Ο, RT, lOh

Intermediate J CAS [33332-29-5]

X—OH Intermediate Q

HATUJ3IEA.CHjClj.RT.2h

V-nH------Intermediate BB

ⁿXⁿ-O“°^^f

Compowd 58

Préparation of intermediate B A

A mixture of 2-Amino-5-chloropyrazine (CAS [33332-29-5], 6 g, 46.31 mmol) and intermediate J ([4.52 g, 69.47 mmol) in EtOH (10 mL) was stirred at 100°C for 12 h.

-77The solvent was removed in vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=5/l). The product fractions were collected and the solvent was evaporated to give intermediate BA, 0.81 g, 7%.

Préparation of intermediate BB

To a solution of intermediate B A (0.8 g, 3.34 mmol) in MeOH (30 mL) and water (6 mL) was added lithium hydroxide monohydrate (0.7 g, 16.69 mmol). The mixture was stirred at room température for 10 h. The solvent was removed în vacuum. The mixture was acidified with aqueous HCl 2N (5 mL) to pH=3~4. The resulting white précipitâtes were filtered, and washed with water (20 mL) to afford intermediate BB, 0.65 g, 86%.

Préparation of Compound 58

Accordingly, Compound 58 was prepared in the same way as Compound 56 starting from intermediate BB and intermediate Q, yielding 0.05 g, 29%.

1H NMR (400MHz, CDCb) δ = 9.41 (s, 1H), 8.90 (s, 1H), 7.24 (d, /=7.9Hz, 2H), 7.08 (d, /=8.4 Hz, 2H), 6.49 (d, /=8.4 Hz, 2H), 6.42 (d, /=8.8 Hz, 2H), 6.10(br. s., 1H), 4.60 (d, /=5.3 Hz, 2H), 4.04 (d, /=3.5 Hz, 8H), 3.00 (q, /=7.5 Hz, 2H), 1.42 (t, /=7.5 Hz, 3H)

Synthesis of Compound 59

CAS P0366J-W-2]

NaBH₄, MeOH,

RT. I6h

intermediate BC

IICVBOAe. DCM. RT. I6h

intermediate BD

CijCOpCuI, UProlme, DMSO, 9œC.l6h

intermediate BE

ΜιΟ,Β,Ν. DCM. RT, I6h

intermediate BF

NaCN.TBABr, DMF. 120°C, lOh

intermediate BO

Raney Ni, Hj (15pii)

NHjMeOURT, J6h

/OO¹ mtermediate BH

Compound 59

Préparation of intermediate BC

Sodium borohydride (2.13 g, 56.41 mmol) was added to a solution of 7-Boc-7azaspiro[3.5]nonan-2-one (CAS [203661-69-2], 2.5 g, 10.45 mmol) in MeOH (30 mL). The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under vacuum. The residue was diluted with ethyl acetate (50 mL), washed with water (2x50 mL) and brine (50 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give intermediate BC, 2.5 g, 99%.

Préparation of intermediate BD

A solution HCl 4M in EtOAc (5.18 mL, 20.72 mmol) was added to a solution of intermediate BC (2.5 g, 10.36 mmo) in CH2CI2 (100 mL) at 0°C. The solution was stirred at room temperature ovemight. The solvent was concentrated under vacuum afïbrding intermediate BD as an hydrochloride sait, 1.84 g, 100%.

Preparation of intermediate BE

To a solution of l-iodo-4-(trifluoromethoxy)benzene (CAS [103962-05-6], 4.48 g, 15.54 mmol) in DMSO (50mL) was added intermediate BD (1.84 g, 10.36 mmol), césium carbonate (8.44 g, 25.9 mmol), L-Proline (0.48 g, 4.14 mmol) and copper iodtde (0.39 g, 2.07 mmol). The mixture was heated at 90 °C for 18 h under argon atmosphère. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mLx3). The organic layer was washed with brine (50 mL), dried over NajSOj, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=4/l) to give intermediate BE, 1.5 g, 48%.

Preparation of intermediate BF

Methanesulfonyl chloride (0.77 mL, 9.96 mmol) was added to a solution of intermediate BE (1.5 g, 4.98 mmol) and triethylamine (2.78 mL, 19.91 mmol) in CH2CI2 (20mL). The reaction solution was stirred at room temperature ovemight. The mixture was washed with water (100 mL) and concentrated under vacuum. The residue

was purified by column chromatography over silica gel (petroleum ether/ ethyl acetate 4/1). Pure fractions were collected and evaporated to give intermediate BF, 1.6 g, 85%.

Préparation of intermediate BG

A mixture of intermediate BF (1.6 g, 4.22 mmol), sodium cyanide (0.83 g, 16.87 mmol) and tetrabutylammonium bromide (0.82 g, 2.53 mmol) in DMF (30 mL) was stirred at 120 °C for 10 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mLx3). The organic layers were washed with brine (200 mL), dried over NaiSCh, filtered and concentrated in vacuum. The residue was purified by column chromatography over scilica gel (petroleum ether/ethyl acetate 4/1). The product fractions were collected and the solvent was evaporated affording intermediate BG,

1.3 g, 99%.

Préparation of intermediate BH

A mixture of intermediate BG (1.3 g, 4.19 mmol) in NHj'MeOH (7M in methanol, 20 mL) was hydrogenated (15 psi) with Raney Nickel (1 g) as catalyst at 25°C for hours. After uptake of IL, the catalyst was filtered off and the filtrate was concentrated to give intermediate BH, 1.3 g, 99%.

Préparation of Compound 59

Accordingly, Compound 59 was prepared in the same way as Compound 56 starting from 5-methoxy-2-methylpyrazolo[l,5-a]pyridine-3-carboxylic acid CAS [135239528-8] and intermediate BH, yielding 0.048 g, 36%.

lHNMR(400MHz,CDClj)ô = 8.18(d,J=7.5Hz, 1 H), 7.54 (d,J=2.6Hz, 1 H), 7.08 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 6.53 (dd, J=2.6, 7.5 Hz, 1 H), 5.66 (br. s.,

1H), 3.90 (s, 3H), 3.53 (U=6.4 Hz, 2H), 3.16 - 3.09 (m, 2H), 3.08 - 3.02 (m, 2H), 2.63 - 2.60 (m, 3H), 2.04 (010.4 Hz, 2H), 1.81 - 1.75 (m, 2H), 1.72 - 1.66 (m, 2H), 1.62 (br. s, 2H) ·

Synthesis of Compound 60

Compound 60

-80Accordingly, Compound 60 was prepared in the same way as Compound 59 starting from intermediate L and intermediate BH, yielding 0.075 g, 45%.

^lH NMR (400MHz, CDCh) 5 = 9.79 (d, J=2.2 Hz, 1 H), 8.56 (d, >2.2 Hz, 1 H), 7.09 (d,>8.8 Hz, 2H), 6.89 (d,J=8.8 Hz, 2H), 5.86 (br. s., 1H), 3.57 (t, J=6A Hz, 2H), 3.17 - 3.11 (m, 2H), 3.10 - 3.00 (m, 4H), 2.61 (td,>8.0,16.2 Hz, 1H), 2.11 - 2.01 (m, 2H), 1.83 -1.77 (m,2H), 1.75 - 1.68 (m, 2H), 1.64 (m,2H), 1.49 (t, >7.5 Hz,3H).

Synthesis of Compound 61

Compound 61

Accordîngly, Compound 61 was prepared in the same way as Compound 59 starting from 2-ethyl-5H,6H,7H,8H-imidazo[l,2-a]pyridine-3-carboxylic acid CAS [152952899-1] and intermediate BH, yielding 0.082 g, 65%.

Ή NMR (400MHz, CDCh) δ = 7.09 (d, >8.5 Hz, 2H), 6.96 - 6.85 (m, 2H), 5.64 (br. s., 1H), 4.20 (t, >5.9 Hz, 2H), 3.47 (dd, >5.8, 7.3 Hz, 2H), 3.16 - 3.09 (m, 2H), 3.08 3.02 (m, 2H), 2.86 (t, >6.3 Hz, 2H), 2.73 (q, >7.6 Hz, 2H), 2.55 (td, >7.9,16.0 Hz, 1H), 2.05- 1.98 (m, 2H), 1.97- 1.85 (m, 4H), 1.82-1.74 (m, 2H), 1.71 - 1.67 (m,2H), 1,61 - 1.52 (m,2H), 1.30 (t, >7.7 Hz, 3 H).

Synthesis of Compound 62

CAS [681508-68-9]

Dwthylcyanorrrthylphosphonale,

UHMDS.THF,-78°C!h

mtennediaie Bl tranethybuironnnim ndide, lB«OK,DMSQ,45°C,24h

Raney Ni, Hj (15p>t)

NU,MeOH,RT, I6h

HATU, DIPEA, DMF.RT, I»

mtennediate BK mtermrdiate BJ

Préparation of intermediate Βί

LiHMDS (19.27 mL, 19.27 mmol) was added to a mixture of Diethylcyanomethy] phosphonate (3.41 g, 19.27 mmol) in THF (180 mL) at -70 °C under Ni flow. The mixture was stirred for 10 minutes. 1-[4-(trifiuoromcthoxy)phenyl]-4-piperidinone (CAS [681508-68-9], 4.5 g, 17.36 mmol) was added to the mixture at -78°C. The 10 mixture was stirred for t hour at -78°C. The mixture was quenched with NH4CI solution, extracted with ethyl acetate (300 mL), washed with brine (200 mL), dried over MgSO< and filtered. The filtrate was concentrated. The crude product was purified by column chromatography over silica gel (ethyl acetate/petroleum ether from 0 to 1/3). The desired fractions were collected and concentrated to give intermediate Bl, 7.8 g, 15 72%.

Préparation of intermediate BJ

Trimethylsulfoxonium iodide (5.83 g, 26.5 mmol) was added slowly to a solution of potassium Zeri-butoxide (2.97 g, 26.5 mmol) in DMSO (50 mL). The mixture was stirred for 1.5 hours at room température. A solution of intermediate BI (6.8 g,

24.09 mmol) in DMSO (50 mL) was added to the mixture. The mixture was stirred hours at 45 °C. Saturated NH4CI solution was added to the mixture and stirred for 0.5 hours. The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (70 mL), dried over MgSCh and filtered. The filtrate was concentrated. The crude product was purified by column chromatography over silica gel (ethyl acetate/petroleum ether from 0 to 1/3). The desired fractions were collected and concentrated to give intermediate BJ, 4.5 g, 63%.

Préparation of intermediate BK

Accordingly intermediate BK was prepared by the same way as intermediate BH, starting from intermediate BJ aflording, 0.18 g,

Préparation of Compound 62

Accordingly, Compound 62 was prepared in the same way as Compound 56 starting from 5-methoxy-2-methy!pyrazolo[l,5-a]pyridine-3-carboxylic acid CAS [135239520 28-8] and intermediate BK, yielding 0.04 g, 9%.

1H NMR (400MHz, CDCb) δ = 8.18(d,>7.1 Hz, 1 H), 7.53 (d, >2.2 Hz, 1 H), 7.10 (d,>8.8 Hz, 2H), 6.91 (d,>9.3 Hz, 2H), 6.52 (dd,>2.4,7.3 Hz, 1H), 5.73 (br. s.,

1H), 3.89 (s, 3H), 3.60 - 3.48 (m, 2H), 3.34 (t, >13.0 Hz, 2H), 3.17 - 3.09 (m, 2H), 2.63 (s, 3 H), 1.93 - 1.84 (m, 1H), 1.80- 1.73 (m, 1H), 1.66- 1.58 (m, 1H), 1.42-1.34 (m, 1H), 1.10-1.00 (m, 1 H), 0.67 (dd, >4.6, 8.2 Hz, I H), 0.36 (t, >4.9 Hz, 1 H)

Synthesis of Compound 63

Compound 63

Accordingly, Compound 63 was prepared in the same way as Compound 62 starting from intermediate L and intermediate BK, yielding 0.019 g, 16%.

1H NMR (400 MHz, CDCb) δ ppm 9.78 (d>2.76 Hz, 1 H) 8.56 (d, >2.76 Hz, 1 H)

7.11 (d, >8.28Hz, 2 H) 6.86 - 6.96 (m, 2 H) 5.92 (br. s., 1 H) 3.57 (dd>7.65, 5.40 Hz,

H) 3.30 - 3.43 (m, 2 H) 3.09 - 3.17 (m,2 H) 3.06 (q, 7=7.53 Hz, 2 H) 1.90 (ddd, 7=12.92, 9.16,3.26 Hz, 1 H) 1.74 -1.83 (m, 1 H) 1.63 (br. s., 1 H) 1.47(t, 7=7.65 Hz,

H) 1.30 -1.41 (m, 1 H) 0.99 -1 JO (m, IH) 0.71 (dd,7=8.28,4.77 Hz, 1 H) 0.38 (t, 7=5.02 Hz, 1 H)

Svnthesis of Compound 64

Compound 64 to

Accordingly, Compound 64 was prepared in the same way as Compound 62 starting from 6-ethyl-2-melhylimïdazo[2J-b]thîazole-5-carboxylic acid CAS [1131613-58-5], and intermediate BK, yieldîng 0.048 g, 32%.

IH NMR (400 MHz, CDCIj) δ ppm 7.95 (d, 7=1.51 Hz, 1 H) 7.10 (d,7=8.53 Hz, 2 H) 6.91 (d,7=8.53 Hz 2 H) 5.72 (br. s., IH) 3.45 - 3.58 (m, 2 H) 3.34 (t, 7=13.05 Hz, 2 H) 3.07 - 3.18 (m, 2H) 2.89 (q, 7=7.53 Hz, 2 H) 2.43 (d, 7=1.51 Hz, 3 H) 1.82 - 1.93 (mj H) 1.69- 1.80 (m, 1 H) 1.63 (br. s., 1 H) 1.38 (t, 7=7.65 Hz, 3 H) 1.30 (t,

7=7.65 Hz, 1 H) 0.97 - 1.07 (m, 1 H) 0.68 (dd, 7=8.91,4.39Hz, 1 H) 0.35 (t, 7=4.89 Hz, IH)

Svnthesis of Compound 65

CAS [1529528-99-1]

A solution of 2-ethyl-5H,6H,7H,8H-imidazo[l,2-a]pyridine-3-carboxylic acid (CAS [1529528-99-1], 0.18 g, 0.41 mmol), HATU (0.204 g, 0.54 mmol), diisopropylethylamine (0.139 g, 1.08 mmol) in DMF (5 mL) was stirred for 30 minutes

Compound 65

-84at 25 °C. Intermediate I (0.15 g, 0.41 mmol) was added to the mixture and the mixture was stirred for 2 hours at 25 °C. The crude product was purified by high performance liquid chromatography over Waters Xbridge Prep OBD (eluent: 0.05% ammonia water/acetonitrile 25/75 to 5/95).The desired fractions were collected and lyophilized to give Compound 65 0.035 g, 29%.

1H NMR (400 MHz, CDCb) δ ppm 7.27 - 7.31 (m, 2 H) 7.19 (d, /=8.03 Hz, 2 H)7.06 (d, /=8.28 Hz, 2 H) 6.37 - 6.42 (m, 2 H) 5.92 (br. s., 1 H) 4.58 (d, /=5.77 Hz, 2 H) 4.23 (t, /=5.77 Hz, 2 H) 4.01 (s, 2 H) 3.79 (s, 2 H) 3.47 (quin, /=8.72 Hz, I H) 2.86 (t, /=6.40 Hz, 2 H)2.71 (q, /=7.70 Hz, 2 H) 2.61 - 2.68 (m, 2 H) 2.31 - 2.39 (m, 2 H) 1.83 - 2.00 (m, 4 H) 1.25 (t, /=7.65 Hz, 3 H)

Svnthcsh of Compound 66

ttennedtate L

HATU, DIPEA, DMF, RT, 2 h intermediate AD

Compound 66

A mixture of intermediate L (0.011 g, 0.049 mmol), intermediate AD (0.02 g, 0.049 mmol), HATU (0.024 g, 0.063 mmol), and diisopropylethylamine (0.032 g, 0.245 mmol) În dichloromethane (1 mL) was stirred at room température for 2 hours. The mixture was concentrated under vacuum. Ethyl acetate (20 mL) was added and the mixture was washed with water (2x20 mL) and brine (20 mL). The separated organic layer was dried over magnésium sulfate, filtered and concentrated under vacuum. The residue was purified by high performance liquid chromatography over Phenomenex Gemini C18 250x2 L2mmx5pm (eluent: water (0.05% ammonia hydroxide v/v)/methanol 25/75 to 5/95). The desired fractions were collected and lyophilized to give Compound 66,0.011 g, 37%.

Synthesis of Compound 67

Intermediate I

CAS [1131613-58-5]

A mixture of6-ethyl-2-methylimidazo[2,l-b]thiazole-5-carboxylic acid (CAS [1131613-58-5], 0.038 g, 0.18 mmol), HATU (0.082 g, 0.22 mmol), and diîsopropylethylamine (0.056 g, 0.43 mmol) in DMF (20 mL) was stirred for 30 minutes at 25 °C. Intermediate 1 (0.06 g, 0.17 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 Phenomenex Gemini (water(0.05%HCl)/ACN 60/40 to 30/70).The desired fractions were collected and lyophîlized to give Compound 67,0.036 g, 33%. ^lH NMR (400MHz, CHLOROFORM-d) δ = 7.98 (s, IH), 7.28 (d, /=7.5 Hz, 2H), 7.18 (d, /=7.9 Hz, 2H), 7.04 (d, /=8.8 Hz, 2H), 6.38 (d, /=8.8 Hz, 2H), 5.96 (br. s., 1 H),

4.62 (d, /=5.7 Hz, 2H), 3.99 (s, 2H), 3.77 (s, 2H), 3.45 (quin,/=8.8 Hz, IH), 2.84 (q, /=7.5 Hz, 2H), 2.67 - 2.59 (m, 2H), 2.47 - 2.38 (m, 3H), 2.36 - 2.29 (m, 2H), 1.40 1.29 (m,3H)

Synthesis of Compound 68

2o Compound 68

Diîsopropylethylamine (0.512 mL; 2.98 mmol) and HATU (0.588 g; 1.55 mmol) were added successively to a solution of6-ethyl-2-methylîmidazo[2,l-b]thiazo!e5-carboxylic acid (CAS [1131613-58-5], 0.25g, 1.19 mmol) in DMF (30 mL). The resulting mixture was stirred at room température for 30 min, before the addition of

86intermediate Q (0.432 g, 1.19 mmol) and the mixture was stirred at room température for 4 h. The reaction mixture was evaporated in vacuo until dryness, diluted with EtOAc and washed with brine (twice). The organic layer was dried over MgSO-i, filtered and evaporated to give l.l g as brown oil. The crude product was purified by 5 préparative LC (Regular SiOH 30 pm, 40 g Interchim, dry loading (celite®), mobile phase gradient: from CHîCh/MeOH 100:0 to 95:5) to obtain 0.203 g as an off-white foam which was triturated in EtîO, filtered and dried under high vacuum to give 0.151 g of Compound 68 as an off-white solid (23%).

'H NMR (400 MHz, DMSO-de) δ ppm 8.02 (t, 7= 5.8 Hz, 1 H), 7.87 (d, J= 1.5 Hz, 10 1 H), 7.16 (dd, 7= 8.6,3.5 Hz, 4 H), 6.49 (d, 7= 8.0 Hz, 2 H), 6,42 (d, 7= 8.6 Hz, 2

H), 4.35 (d, J = 6.1 Hz, 2 H), 3.94 (s, 4 H) 4.00 (s, 4 H), 2.84 (q, 7= 7.4 Hz, 2 H), 2.41 (d, 7= 1.5 Hz, 3 H), 1.19 (t, 7= 7.6 Hz, 3 H).

Synthesis of Compound 69, Compound 70 and Compound 71

lntcmKdiateJ CAS [5049-61-6] intennediate BL

Hj.HOaq.

PlOj.McOtt, RT.IOh

O

HCHO, NaBILjCN. AcOH MeOH. RT.IOh intermediâte BM

O

(itermediate BN üOHHjO. MeOHHjO, RT.IOh

mtermedute BO

Préparation of intermediate BL

A mixture of 2-aminopyrazine (CAS [5049-61-6], 12 g, 126.18 mmol) and intermediate 20 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-l/l). 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 Nj, followed by addition a drop of con HCl. The suspension was degassed under vacuum and purged with Hî several times. The mixture 5 was stirred under Hi (15 psi) at 25 °C for 10 hours. The suspension was filtered through a pad of Celîte® 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% NHjCI solution (25 mL) was added dropwise. The mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over NaiSO-i, filtered and the solvent was evaporated under vacuum. The residue was purified by column chromatography over sîlîca gel (dichloromethane/methanol=l5: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 dryness. The residue was purified by high performance liquid chromatography (DuraShell 150x25mmx5gm, 25ml/min, water (containing 0.05% HCl)/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 69

A solution of intermediate BO (0.04 g, 0.19 mmol), HATU (0.095 g, 0.25 mmol), diisopropylethylamine (0.064 g, 0.5 mmol) in DMF (5 mL) was stirred for 30 minutes

-88at 25 °C. Intermediate I (0.069 g, 0.19 mmol) was added to the mixture and the mixture was stirred for 2 hours at 25 °C. The crude product was purified by high performance liquid chromatography over Waters Xbridge Prep OBD (eluent: 0.05% ammonia water/acetonitrile from 50/50 to 20/80). The desired fractions were collected and lyophilized to give Compound 69,0.053 g, 50%

IH NMR (400 MHz, CDCb) 6 ppm 7.27 - 7.31 (m, 2 H) 7.17 - 7.22(m, 2 H) 7.06 (d, 7=8.28 Hz, 2 H) 6.37 - 6.42 (m, 2 H) 5.94 (br. s., 1 H) 4.58 (d, 7=5.52 Hz, 2 H) 4.32 (t, 7=5.65 Hz, 2 H) 4.01 (s, 2 H) 3.79 (s, 2 H) 3.65 (s, 2 H)3.39 - 3.53 (m, 1 H) 2.80 (t, 7=5.65 Hz, 2 H) 2.72 (q, 7=7.70 Hz, 2 H) 2.61 -2.68 (m, 2 H) 2.47 (s, 3 H) 2.29 - 2.40 (m, 2 H) 1.26 (ζ 7=7.53 Hz, 3 H)

Préparation of Compound 70

Accordingly, Compound 70 was prepared in the same way as Compound 69 starting from intermediate BO and intermediate Q affording 0.06 g, 50%.

‘H NMR (400MHz, CDCb) δ = 7.21 (d, 7=8.3 Hz, 2H), 7.09 (d, 7=8.3 Hz, 2H), 6.45 (dd, 7=8.5,17.8 Hz, 4H), 5.85 (br. s., 1H), 4.50 (d, 7=5.5 Hz, 2H), 4.32 (t, 7=5.4 Hz, 2H), 4.04 (s, 8H), 3.65 (s, 2H), 2.80 (t, 7=5.6 Hz, 2H), 2.70 (q, 7=7.4 Hz, 2H), 2.48 (s, 20 3H), 1.24 (t, 7=7.5 Hz, 3H).

Préparation of Compound 71

Accordingly, Compound 71 was prepared in the same way as Compound 69 starting from intermediate BO and intermediate V affording 0.035 g, 38%.

1H NMR (400 MHz, CDCb) δ ppm 7.10 - 7.23 (m, 6 H) 6.45 (d, 7=7.94 Hz,2 H) 5.83 (br. s., 1 H) 4.48 (d, 7=5.29 Hz, 2 H) 4.32 (t, 7=5.51 Hz, 2 H) 4.01 (s, 2 H) 3.80(s, 2 H)

-893.64 (s, 2 H) 3.43 - 3.50 (m, I H) 2.79 (t, .7=5.51 Hz, 2 H) 2.67 (dt, /=15.33, 7.99Hz,

H) 2.47 (s, 3 H) 2.28 - 2.39 (m, 2 H) 1.23 (t, /=7.50 Hz, 3 H)

Synthesis of Compound 72, Compound 73 and Compound 74

CAS [402-45-9]

PPh), DIAD, toluene, RT, 16h

riermediatc BP

HCOOH, RT, I2h \ °>00-^OH

CAS [1147557-97-8]

I6h

-39-7] iiermediate DQ ntennedûte BR

Pdjfdba),, tBuONa, BINAP, EtjN, toluene, UO’Cjeh

tfermediate BS

Uct-COOH. DIPEA. HATU, DMF, RT _He?

Prenaration of intermediate BP

DIAD (1.40 g, 6.92 mmol) in toluene (10 mL) was added to a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (CAS [1147557-97-8], 1.2 g, 5.63 mmol), 4-(trifluoromethyl)phenol (CAS [402-45-9], 1.10 g, 6.75 mmol), and trîphenylphosphine (2.31 g, 8.80 mmol) in toluene (40 mL) at 0 °C under N2 flow. The mixture was stirred ovemight at room temperature. The mixture was concentrated. The crude product was purified by column chromatography over silica gel (petroleum ether/ethyl acetate from 1/0 to 3/1). The desired fraction was collected and concentrated to give intermediate BP, 2 g, 99%.

Preparation of intermediate BQ

A mixture of intermediate BP (2 g, 5.60 mmol) in formic acid (10 mL) was stirred for 12 hours. The mixture was concentrated to give intermediate BQ, 1.4 g, 97%.

Préparation of intermediate BR

A solution of intermediate BQ (1.4 g, 5.44 mmol), 4-iodobenzonitriIe (CAS [305839-7], 0.99 g, 5.44 mmol), BINAP (0.203 g, 0.33 mmol), Pd₂(dba)j (0.1 g, 0.11 mmol), sodium terr-butoxide (1.57 g, 16.33 mmol) and triethylamine (0.38 mL) in toluene (50 5 mL) was stirred ovemight at 110°C under N₂ flow. The mixture was concentrated. The residue was dissolved in CH₂C!₂ (100 mL) and water(100 mL). The organic layer was washed with brine (100 mL), dried over MgSO₄ and filtered. The filtrate was concentrated. The crude product was purified by column chromatography over silica gel (ethyl acetate / petroleum ether from 0 to 1/5). The desired fractions were collected 10 and concentrated to give intermediate BR, 1.8 g, 92%.

Préparation of intermediate BS

A mixture of intermediate BR (0.2 g, 0.56 mmol) in ammonia 7N in methanol (20 mL) was hydrogenated with Raney Nickel (20 mg) as catalyst at 25 °C (15 Psi) for 16 hours.

After uptake of H₂, the catalyst was filtered off and the filtrate was concentrated to give intermediate BS, 0.2 g, 99%.

Préparation of Compound 73

Compound 73

A solution of intermediate L (0.112 g, 0.25 mmol), HATU (0.122 g, 0.32 mmol), diisopropylethylamine (0.083 g, 0.65 mmol) in DMF (10 mL) was stirred for 30 minutes at 25 °C. Intermediate BS (0.09 g, 0.25 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 Phenomenex Gemini (eluent: 0.05% ammonia water/acetonitrile 35/65 to 5/95).The desired fractions were collected and lyophîlîzed to give Compound 73 , 0.016 g, 11%.

IH NMR (400 MHz, CDCIj) δ ppm 9.83 (d,7=2.65 Hz, 1 H) 8.47 - 8.60(m, 1 H) 7.53 (d, 7=8.38 Hz, 2 H) 7.22 (d, 7=7.94 Hz, 2 H) 6.86 (d, 7=8.38 Hz, 2 H)6.45 (d, 7=8.38

Hz, 2 H) 6.05 (br. s., 1 H) 4.63 - 4.71 (m, 1 H) 4.58 (d, 7=5.29 Hz, 2H) 3.95 (s, 2 H)

3.90 (s, 2 H) 2.98 (q, 7=7.50 Hz, 2 H) 2.76 - 2.84 (m, 2 H) 2.39 -2.47 (m, 2 H) 1.42 (t,

7=7.50 Hz, 3 H)

Préparation of Compound 72

Compound 72

Accordingly, Compound 72 was prepared in the same way as Compound 73 starting from 6-ch!oro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid CAS [1216142-18-5] and intermediate BS affording 0.035 g, 28%.

1H NMR (400 MHz, CDCb) S ppm 9.52 (s, 1 H) 7.53 (d, /=8.38 Hz, 3 H)729 (dd, /=9.48, 1.98 Hz, 1 H) 7.23 (d, /=8.38 Hz, 2 H) 6.86 (d,/=8.82 Hz, 2 H) 6.46 (d^=8.38 10 Hz, 2 H) 5.99 (br. s.. 1 H) 4.64 - 4.70 (m, 1 H) 4.58 (d, /=5.29 Hz, 2 H) 3.95 (s, 2H)

3.90 (s, 2 H) 2.94 (q, /=7.50 Hz, 2 H) 2.80 (ddd, /=10.47, 6.95,2.87 Hz, 2 H) 2.43(ddd, /=10.25,6.73, 3.31 Hz, 2 H) 1.38 (t,/=7.50 Hz, 3 H)

Préparation of Compound 74

Compound 74

Accordingly, Compound 74 was prepared În the same way as Compound 73 starting from intermediate BO and intermediate BS affording 0.064 g. 70%.

Synthesis of Compound 75

NaOtBu, Pd(OAc)₂, Xantphos, dioxane, IOO°C,2h

TFA, CILClj, RT, 20 mn

CAS (885270-86-0] CAS [407-14-7] ntermediate BT ^bOl

CAS [623-00-7]

tiermedate BV

NHj 7M h MeOH, RarryNi, IL, 2bar, Ih

OO-CW ntermediate BU

NaOtBu, Pd(OAc)₂, Xantphos, dioxane, 100°Q2h

ntermediate BW

DMF.RT, I6h, then50°C, 2 h

Compouid 75

Préparation of intermediate BT

In a Shlenck reactor, a solution of 6-Boc-2,6-diazaspîro[3.4]octane (CAS [885270-860], 0.5g, 2.36 mmol), l-Bromo-4-(trifluoromethoxy)benzene (CAS [407-14-7], 525 pL, 3.53 mmol) and sodium rerbutoxide (0.453 g, 4.71 mmol) >n 1,4-dîoxane (25 mL) was purged with Nî. Then Palladium (II) acetate (52.9 mg, 0.236 mmol) and Xantphos (0.136 g, 0.236 mmol) were added, the mixture was purged again with Nî and stirred at 10 IOO°C for 2h. The mixture was combined filtered on a pad ofCelite®. The cake was washed with EtOAc and the fitlrate was evaporated în vacuo to give 1.2 g as a brown solid. The residue was purified by préparative LC (irregular SiOH, 15-40 pm, 50 g, Merck, dry loading (Celite®), mobile phase gradient: from Heptane/EtOAc from 95/5 to 60/40) to give 0.756 g of intermediate BT as off-white solid (80%).

Préparation of intermediate BU

To a solution of intermediate BT (0.706 g, 1.90 mmo!) in CHîCh (20 mL) was added trifluoroacetic acid (7.25 mL, 94.7 mmol) (réaction mixture tum brown) and the mixture was stirred at room température for 20 min. The mixture was poured into a sat.

solution of NaHCOj. The layers were separated and the aqueous layer was extracted

with CH2CI2. The combined organic layers were dried over MgSCh, filtered offand evaporated in vacuo to give brown oil whîch was triturated in Et2O and filtered off to give 0.519 g of intermediate BU as a off-white powder (98%).

Préparation of intermediate BV

In a scealed tube, a solution of intermediate BU (0.5 g, 1.84 mmol), 4Bromobenzonitrile (CAS [623-00-7], 0.5 g, 2.76 mmol) and sodium Zerbutoxide (0.53 g, 5.51 mmol) in 1,4-dioxane (20 mL) was purged withN2. Then Palladium (II) acetate (0.041 g, 0.184 mmol) and Xantphos (0.106 g, 0.184 mmol) were added, the 10 mixture was purged again with N2 and stirred at 100°C for 3h. The mixture was cooled down to room température, filtered on a pad of Celite® and the cake was washed with EtOAc. The filtrate was evaporated in vacuo to give a brown oil. The residue was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g, Grâce, dry loading (Celite®), mobile phase gradient: from Heptane/EtOAc from 95/5 to 50/50) to give 15 0.429 g of a yellowoil (which crystalized on standing). The oil was purified by Reverse phase (Stationary phase: YMC-actus Triart-CI8 lOpm 30x150mm, Mobile phase: Gradient from (aq. NH4HCO3 0.2%)/CAN from 50/50 to 0/100) to give 0.328 g of intermediate BV as a yellow solid (48%).

Préparation of intermediate BW

In an autoclave, to a solution of intermediate BV (0.28 g, 0.75 mmol) in Ammonia 7M în methanol (7.8 mL) was added Raney Nickel and the mixture was hydrogenated at room température under 2 bar for lh. The mixture was filtered on a pad of Celite® and the cake was washed with MeOH. The filtrate was evaporated in vacuo to give a black 25 solid which was solubilized in EtOAc, filtered off and the filtrate was evaporated to provide 0.244 g of intermediate BW as a white solid (86%).

Préparation of Compound 75

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.155 g, 0.647 mmol), intermediate BW (0.244 g, 0.647 mmol),

HATU (0.271 g, 0.712 mmol) and diisopropylethylamine (0.286 mL, 1.68 mmol) in DMF (6.5 mL) was stirred at room température ovemight. The mixture was heated at 50°C for 2h. The mixture was cooled down to room température and evaporated in vacuo to give 980 mg of black oil. The residue was purified by préparative LC (irregular SiOH, 15-40 pm, 50 g, Merck, dry loading (Celite®), mobile phase gradient:

from Heptane/EtOAc from 95/5 to 50/50) to give 0.254 g of resiude as a yellow solid.

The residue was purified by reverse phase (spherical Cl8,25 pm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient (aq. NH4HCO3 0.2%)/MeCN from 30/70

-94to 0/100) to give a white solid which was triturated in pentane, filtered off and evaporated under vacuum (50 °C, 16 h) affording 0.156 g of compound 75 as a white solid (41%).

’H NMR (400 MHz, DMSO-7,) δ ppm 9.06 (s, 1 H), 8.35 (br t, J= 5.8 Hz, 1 H), 7.65 (d, 7= 9.6 Hz, 1 H), 7.44 (dd, 7= 9.6,2.0 Hz, 1 H), 7.20 (brd, 7=8.1 Hz, 2 H), 7.16 (br d, 7= 8.6 Hz, 2 H), 6.53 (br d, 7= 8.6 Hz, 2 H), 6.49 (br d, 7= 8.6 Hz, 2 H), 4.40 (d, 7= 6.1 Hz, 2 H), 3.82 (s, 4 H), 3.46 (s, 2 H), 3.25 - 3.29 (m, 2 H), 2.96 (q, 7= 7.4 Hz, 2 H), 2.23 (t, 7= 6.8 Hz, 2 H), 1.25 (t, 7= 7.6 Hz, 3 H)

Synthesis of Compound 76

NC.

CAS [β23-00-η CAS [B85270-S8-0]

NaOtBu, Pd|OAc)₂, Xantphoa, dioxine, _u. 1M*C-2h _r ^C‘

Br,

NaOtBu, Pd(OAc),, Xantphoa, dioxine, 100*0,2h

Intermediate BZ

Cl

OCF,

OH

HATU, DIP EA,

DMF. 50*C. 2h.

OCF,

OCF,

Intermediate CA

Compound 76

Préparation of intermediate BX

Accordingly, intermediate BX was prepared in the same way as intermediate BT starting from 6-Boc-2,6-dîazaspiro[3.4]octane CAS [885270-86-0] and 4-bromobenzonîtrile CAS [623-00-7] affording 0.673 g, 84%.

-95Préparation of intermediate BY

Accordingly, intermediate BY was prepared in the same way as intermediate BU starting from intermediate BX affording 0.312 g, 80%.

Préparation of intermediate BZ

Accordingly, intermediate BZ was prepared in the same way as intermediate BV starting from intermediate BY and l-bromo-4-(trinuoromethoxy)benzene CAS [407-14-7] affording 0.369 g, 73%.

Préparation of intermediate CA

Accordingly, intermediate CA was prepared in the same way as intermediate BW starting from intermediate BZ affording 0.2 g, 56%.

Préparation of Compound 76

Accordingly, Compound 76 was prepared in the same way as Compound 75 starting from 6-chIoro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid CAS [1216142-18-5] and intermediate CA affording 0.078 g, 30%.

’H NMR (500 MHz, DMSO-tfc) δ ppm 9.07 (s, 1 H), 8.41 (t, 7= 6.2 Hz, 1 H), 7.67 (d, 7= 9.5 Hz, 1 H), 7.46 (dd, J= 9.6,1.7 Hz, 1 H), 7.21 (m, 7= 8.2 Hz, 2 H), 7.15(brd,7 = 8.8 Hz, 2 H), 6.57 (d, 7= 9.1 Hz, 2 H), 6.46 (m, 7= 8.2 Hz, 2 H), 4.42 (d, 7=5.6 Hz,

H), 3,79 (s, 4 H), 3.47 (s, 2 H), 3.30 - 3.33 (m, 2 H), 2,97 (q,7= 7.4 Hz, 2 H), 2.24 (t, 7= 7.0 Hz, 2 H), 1.26 (t, 7= 7.4 Hz, 3 H)

Svnthesis of Compound 77 25

Intermediate M intermediate AF

Pd(dba)j, Xpho·, t-8uONa

Dloxan», 100 »C,MW.1 h

Compound 77

A solution of intermediate AF (0.1 g, 0.574 mmol), intermediate M (0.28 g,

0.631 mmol), X-phos (0.033 g, 0.069 mmol), Pd(dba)z (0.02 g, 0.034 mmol) and sodium rerr-butoxide (0.221 g, 2.30 mmol) in dioxane (4 mL) was irradiated under microwave at 100 °C for 1 hour underN2. The mixture was concentrated. The crude product was purified by high performance liquid chromatography over Gemini (eluent:

NHj water/acetonitrile 45/55 to 45/55). The desired fractions were collected and concentrated to give Compound 77,0.0076 g, 3%.

1H NMR (400 MHz, CHLOROFORM-c/) δ ppm 9.53 (d, J=1.25 Hz, 1 H) 8.47 (s, 2H) 7.50 - 7.56 (m, 2 H) 7.30 (d, J=2.01 Hz, 1 H) 7.28 (d, J=2.01 Hz, ! H) 7.25 (s, IH) 7.23 (s, 1 H) 6.47 (d, J=8.53 Hz, 2 H) 5.99 (s, 1 H) 4.59 (d, J=5.27 Hz, 2 H) 4.04(s, 2 H) 3.83 (s, 2 H) 3.50 (t, J=8.78 Hz, 1 H) 2.95 (q, J=7.53 Hz, 2 H) 2.63 - 2.75(m, 2 H) 2.30

- 2.44 (m, 2 H) 1 .39 (t, J=7.65 Hz, 3 H)

Synthesis of Compound 78 t-BuON», Pdj(dbi)3 B1NAP,tolu«n· Rinty NI, Hj (15 p»l) .Mg

CAS [62340-7] CAS [1354963-09-6] Intermediate CB Intermediate CC

HATU, DIEA, DMF Compound 78

Préparation of intermediate CB

A solution of 2-fluoro-6-azaspiro[3.3]heptane (CAS [1354953-09-5], 0.8 g,

6.95 mmol), 4-bromobenzonitrile (CAS [623-00-7], 1,265 g, 6.95 mmol), BINAP (0.26 g, 0.42 mmol), Pd2(dba)3 (0.127 g, 0.14 mmol), sodium rert-butoxide (2 g, 20.84 mmol) and triethylamine (0.48 mL) in toluene (50 mL) was stirred ovemight at 110 °C under

N2 flow. The mixture was concentrated. The residue was dissolved in CH2CI2 (300 mL) and water (150 mL).The organic layer was washed with brine (150 mL), dried over magnésium sulfate and filtered. The filtrate was concentrated. The crude product was purified by column chromatography over silica gel (eluent: ethyl acetate / petroleum ether from 0 to 1/5). The desired fractions were collected and concentrated to give 20 intermediate CB, 1 g, 66%.

Préparation of intermediate CC

A mixture of intermediate CB (0.45 g, 2.08 mmol) în ammonia 7M in MeOH (20 mL) was hydrogenated with Raney Nickel (40 mg) as catalyst at 25 °C (H2,15 Psi) for 16 hours. After uptake of H2, the catalyst was filtered off and the filtrate was concentrated to give intermediate CC, 0.45 g, 98%.

Préparation of Compound 78

A solution of întermediate BO (0.048 g, 0.23 mmol), HATU (0.112 g, 0.3 mmol), diisopropylethylamine (0.076 g, 059 mmol) in DMF (10 mL) was stirred for 30 minutes

-97at 25 °C. Intermediate CC (0.05 g, 0.23 mmol) was added to the mixture and the mixture was stirred for 2 hours at 25 °C. The crude product was purified by high performance liquid chromatography over Phenomenex Gemini (eluent: 0.05% ammonia water/methanol 30/70 to 0/100).The desired fractions were collected and lyophilizedto give Compound 78,0.0134 g, 14%.

IH NMR (400 MHz, CHLOROFORM-i/) δ ppm 7.18 (d,.7=8.53 Hz, 2 H) 6.38 - 6.45 (m, 2 H) 5.83 (br. s., I H) 4.86 - 5.09 (m, 1 H) 4.48 (d, .7=5.52 Hz, 2 H) 4.31 (t, .7=5.65 Hz, 2 H) 3.88 (s, 2 H) 3.84 (s, 2 H) 3.64 (s, 2 H) 2.79 (t, .7=5.52 Hz, 2 H) 2.67 - 2.71 (m, 2 H) 2.60 -2.67 (m, 2 H) 2.38 - 2.50 (m, 5 H) 1.22 (t, J=7.53 Hz, 3 H)

Synthesis of Compound 79

o^x *

H,

CAS P11308-81 -8] CAS P002-24-2]

Cul, ΒΙΝΟί,ϋΕ,ΟΟ,,

DM30,80*0,18 h ,

NiOH, H,O, 80*C, 18h

tntornwdlata CF

Intormodlata CD tnta rnwdiat· CE

Compound 79

HATU, DIEA, DMF, RT

Préparation of intermediate CD

A mixture of5-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 iodîde (299.39 mg,

1.57 mmol) in DMSO (50 mL) was stirred for 15 hours under Nî flow. Brine and ethyl acetate were added to the mixture. The organic layer was separated, washed with brine, 20 dried over MgSCh 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%

Préparation 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 iodîde (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

MgSO< and filtered. The filtrate was concentrated. The crude product was purified by column chromatography over silica gel (eluent: ethyl acetate / petroleum ether from 0 to 1/3). The filtrate was concentrated to give intermediate CE, 1.6 g, 86%.

Préparation of intermediate CF

A mixture of intermediate CE (1.6 g, 6.33 mmol) în sodium hydroxide aqueous (5 g, 62.51 mmol, 50% in HîO) solution was stirred ovemight at 80 °C. Thin layer chromatography (eluent: ethyl acetate / petroleum ether =1/3) showed starting material was consumed. The mixture was concentrated. The mixture was extracted with methyl tert-butyl ether (25 mLx2). The water layers were extracted with solution (ethyl acetate / petroleum ether = 1/3) (2x50 mL). The water layers were adjusted with 1 N HCl until pH was 4. The residue was filtered and concentrated to give intermediate CF, 1.3 g, 86%.

Préparation of Compound 79

A solution of intermediate CF (0.06 g, 0.25 mmol), HATU (0.123 g, 0.33 mmol), diisopropylethylamine (0.08 g, 0.62 mmol) in DMF (10 mL) was stirred for 30 minutes at 25 °C. Intermediate Q (0.1 g, 0.28 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/methanol 40/60 to 10/90). The desired fractions were collected and concentrated to give Compound 79, 0.052 g, 36%.

1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 8.22 (d,>1.76 Hz, 1 H) 7.91 (d^=l.76 Hz, 1 H) 7.28 (s, 2 H) 7.08 (d,>8.82 Hz, 2 H) 6.49 (d,>8.38 Hz, 2 H)

6.42(d, >8.82 Hz, 2 H) 5.89 (br. s., 1 H) 4.59 (d, >5.29 Hz, 2 H) 4.04 (d, >2.21 Hz,

7H) 3.83 (s, 3 H) 3.21 (q,>7.50 Hz, 2 H) 1.33 (t, >7.72 Hz, 3 H)

Synthesis of Compound 80

-99A solution of 5-chloro-2-ethyl-l-methylindole-3-carboxylic acîd (CAS [1784796-04-8], 0.131 g, 0.55 mmol), HATU (0.272 g, 0.72 mmol), diîsopropylethylamine (0.185 g, 1.43 mmol) in DMF (10 mL) was stirred for 30 minutes at 25 °C. Intermediate Q (0.1 g, 0.28 mmol) was added to the mixture and the mixture was stirred for 2 hours at

25 °C. The mixture was concentrated under vacuum. The residue was purified by high performance liquid chromatography over Waters Xbridge Prep OBD Cl8 Ι50χ30χ5μ (eluent: NH3 water/acetonitrile from 70/65 to 40/95). The desired fractions were collected and lyophilized to give Compound 80,0.0423 g, 13%.

1HNMR (400 MHz, CHLOROFORM-d) δ ppm 7.62 (d,>1.76 Hz, 1 H) 7.28(d, >8.53 Hz, 2 H) 7.22 - 7.25 (m, 1 H) 7.14 - 7.19 (m, 1 H) 7.08 (d, >8.78Hz, 2 H) 6.49 (d, >8.53 Hz, 2 H) 6.42 (d, >9.03 Hz, 2 H) 6.01 (br. s., I H)4.61 (d, >5.52 Hz, 2 H) 4.04 (s, 8 H) 3.72 (s, 3 H) 3.19 (q, >7.19 Hz, 2 H)1.30 (t, >7.53 Hz, 3 H)

Synthesis of Compound 81

Intermediate M

CAS [1283178-15-91

Pd(dba)_2> Xphos, t-BuOftt Dloxana. 100 «C,MW,1h

F

Compound 81

A solution of intermediate M (0.1 g, 0.23 mmol), 2-fluoro-7-aza-spîro[3.5]nonane (CAS [I263I78-15-9], 0.049 g, 0.23 mmol), X-phos (0.0105 g, 0.022 mmol), Pd(dba)z (0.0065 g, 0.011 mmol) and sodium tert-butoxide (0.055 g, 0.57 mmol) in dioxane (3 mL) was irradiated under mîcrowave at 100 °C for I hour under N2. The mixture was concentrated. The crude product was purified by high performance liquid chromatography over Gemini (Cl8 150x25mmxl0p, 25mL/min, eluent: NH3 water/acetonitrile 45/55 to 45/55). The desired fractions were collected and concentrated to give Compound 81, 0.0073 g, 7%. · ¹H NMR (400MHz, CDCb) δ 9.53 (d, 7=1.5 Hz, 1H), 7.54 (d, 7=9.5 Hz, 1H), 7.33 7.26 (m, 3H), 6.95 (d, 7=8.6 Hz, 2H), 6.02 (br. s., 1H), 5.86 (tdd, 7=7.4,10.0,17.1 Hz, 1H), 5.20 - 5.08 (m, 2H), 4.61 (d, 7=5.5 Hz, 2H), 3.50 (d, 7=12.3 Hz, 2H), 3.10 (dt,7 =2.4,12.2 Hz, 2H), 2.96 (q, 7=7.5 Hz, 2H), 2.47 - 2.34 (m, 2H), 1.99 - 1.63 (m, 4H),

1.39 (t, 7=7.5 Hz, 3H)

-100-

Synthesis of Compound 82
	0 0 * \/kA0---X. —	t OAc O-L CAS [3240-344] BFjOCtj.THF	- oP
CAS [504-29-0]		î°Ctort	«itermedixte CO

«,(>·-) /— ΗΟ,ΡιΟ, V~O MeOH,rt /	LiOH-lljO MeOH, HjO 70’C	°k,0U oP
mtetmediate CH		Mtetmediate CI
CAS [4949444]	F F
HATU, OŒA.ONIF.RT	F F y·’ 0 V	o£- Compound 82

Préparation of intermediate CG .

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

6.1 mL; 42.5 mmol), Iodobenzene Diacetate (CAS [3240-34-4], 13.7 g; 42.5 mmol) and BF3*0Etî (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 NaHCCh and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give 18.8 g as an orange solid. The crude was taken-up in EtîO, 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, liquid loading (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 EtîO, 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

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

-1011 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 oîl (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 HîO (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 (twîce), 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 82

Diîsopropylethylamine (0.232 mL; 1.35 mmol) and HATU (0.267 g; 0.70 mmol) were added successively to a solution of intermediate CI (0.108 g; 0.54 mmol) in DMF (10 mL). The resulting mixture was stirred at room température for 30 min, before the addition of intermediate V (0.196 g; 0.54 mmol) in DMF (7 mL). The mixture was stirred at room température for 4 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 MgSCh, filtered and evaporated to dryness to give 585 mg as a brown oîl which was purified by préparative LC (Regular silica 30 pm, 12 g, dry loading (Celite®), mobile phase gradient Heptane/EtOAc/MeOH from 90/8/2 to 50/40/10) to obtain 0.131 g as an off-white solid. The solid was triturated in EtiO, filtered and dried under high vacuum to give 97 mg of Compound 82 as a white solid (33% over 2 steps). Ή NMR (400 MHz, DMSO-/,) δ ppm 8.08 (t,/=6.1 Hz, 1 H) 7.35 (d,/=8.6 Hz, 2 H) 7.29 (d,/=8.I Hz, 2 H) 7.11 (d,/=8.6 Hz, 2 H) 6.39 (d,/=8.1 Hz, 2 H) 4.28 (d,/=6.1 Hz, 2 H) 3.96 (t, J=5.6 Hz, 2 H) 3.91 (s, 2 H) 3.70 (s, 2 H) 3.47 (quint, /=8.8 Hz, 1 H) 2.66 - 2.72 (m, 2 H) 2.52 - 2.62.(m, 4 H) 2.26 - 2.34 (m, 2 H) 1.74 - 1.87 (m, 4 H) 1.08 (t,/=7.3 Hz, 3 H)

Synthesis of Compound 83

N‘

Compound 83

Diisopropylethylamine (0.31 mL, 1.78 mmol) and HATU (0.353 g, 0.927 mmol) were successïvely added to a solution of 6-Ethyl-2-methyIimidazo[2,1 -b]thiazole5-carboxylic acid (CAS [1131613-58-5], 0.15 g, 0.713 mmol) in DMF (20 mL). The resulting mixture was stirred at room température for 30 min, before the addition of intermediate V (259 mg, 0.713 mmol) and the mixture was stirred at room température ovemight. The reaction mixture was diluted with EtOAc and washed with an aq. sat. NaHCOj solution (twice) and brine (twice). The combined organic phases were dried over MgSOj, filtered and evaporated to dryness. The crude was purified by préparative LC (lrregular silica 15-40 pm, 12 g, dry loading (silica), mobile phase gradient: from

Heptane/EtOAc 90/10 to 50/50) and the obtained solid was triturated in pentane, filtered and dried under vacuo at 45 °C to obtain 0.167 g of Compound 83 as white solid (42%).

'H NMR (400 MHz, DMSCMs) δ ppm 8.01 (t,>5.8 Hz, 1 H) 7.87 (s, 1 H) 7.36 (d, >8.6 Hz, 2 H) 7.28 (d, >8.6 Hz, 2 H) 7.15 (d, >8.1 Hz, 2 H) 6.40 (d,>8.6 Hz, 2 H)

4.35 (d, >5.6 Hz, 2 H) 3.91 (s, 2 H) 3.70 (s, 2 H) 3.47 (br t, >8.6 Hz, 1 H) 2.84 (q, >7.2 Hz, 2 H) 2.55 - 2.62 (m, 2 H) 2.41 (s, 3 H) 2.25 - 2.35 (m, 2 H) 1.19 (t, >7.58 Hz, 3 H).

Synthesis of Compound 84 and Compound 85

K ,00,, DMSO, Raney ΝΙ,Η,ΐ bar

Intarmcdlate CK / O

Intermediate CJ

CAS [1194-02-11

HATU, D1EA, DMF

CAS [1β387β1-19-β[

Compound 84

Pd/C, H,3b«r. V-N

Compound 85

Préparation of intermediate CJ

A suspension of 6-methoxy-2-azaspiro[3.3]heptane hydrochloride (CAS [1638761-199], 0.47 g, 2.36 mmol), 4-Fluorobenzonitrile (CAS [1194-02-1], 0.576 g, 4.71 mmol) and potassium carbonate (0.976 g, 7.07 mmol) in DMSO (11 mL) was heated at 120 °C using a single mode microwave (Biotage lnitiator60) with a power output ranging from to 400 W for 30 min [fixed hold time]. The reaction mixture was evaporated în a

Genevac apparatus and purified by préparative LC (irregular silica, 15-40 pm, 50 g, dry loading (Celite®), mobile phase gradient Heptane/EtOAc from 95/5 to 70/30) to give

0.361 g of intermediate CJ as a white solid (67%).

Preparation of intermediate CK

In an autoclave, Raney Nickel (0.8 g, 13.6 mmol) was added to a solution of intermediate CJ (0.713 g, 3.12 mmol) in ammonia 7N in MeOH (15 mL) and the mixture was stirred at room temperature under 3 bar of H2 ovemight. The mixture was 5 filtered over Celite* and evaporated in vacuo to give 0.717 g of intermediate CK as a blue oil (99%).

Préparation of Compound 84

Diisopropylethylamine (0.461 mL, 2.71 mmol) and HATU (436 mg, 1.15 mmol) were 10 added successively to a solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine3-carboxylic acid (CAS [1216142-18-5], 0.25 g, 1.04 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 30 min., then a solution of intermediate CK (0.242 g, 1.04 mmol) in DMF (5 mL) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated in vacuo until 15 dryness. The crude product was purified by préparative LC (irregular silica, 15-40 pm,

120 g, dry loading (silica), mobile phase gradient: from DCM 100%, MeOH 0% to DCM 90%, MeOH 10% in 20 CV) to give 0.5 g of an orange solid, which was successively triturated in Et20, Et2O/EtOH (9:1), iPnO and EtOH to give 0.317 g of Compound 84 as a slightly orange solid (69%).

Ή NMR (400 MHz, DMSO-/,) δ ppm 9.05 (d, J= 1.5 Hz, 1 H), 8.37 (t, J= 5.8 Hz,

H), 7.65 (d, J= 9.6 Hz, I H), 7.44 (dd,/= 9.6,2.0 Hz, 1 H), 7.17 (d, J= 8.6 Hz,

H), 6.37 (d, J= 8.6 Hz, 2 H), 4.39 (d,/= 6.1 Hz, 2 H), 3.75 (s, 2 H), 3.81 - 3.74 (m, I H), 3.70 (s, 2 H), 3.11 (s, 3 H), 2.95 (q, /= 7.4 Hz, 2 H), 2.47 - 2.41 (m, 2 H), 2.02 (ddd, /= 10.0,7.0, 2.8 Hz, 2 H), 1.27 - 121 (m, 3 H)

Preparation of Compound 85

A solution of Compound 84 (0.08 g; 114 mmol) in MeOH (3.5 mL) was degassed by N2 bubblîng for 5 min before the addition ofPd/C (0.0032 g; 3.01 pmol). The resulting mixture was hydrogenated at room temperature under 3 bar ovemight. The mixture was 30 filtered through a pad of celite®, and the filtrate was evaporated under vacuum to dryness. The crude was purified by préparative LC (Regular silica 15-40 pm, 12 g, dry loading (Celite®), mobile phase gradient: from CHîClî/MeOH 100/0 to 95/5) to obtain 0.057 g of a solid which was triturated in heptane, filtered and dried under high vacuum at 50 °C during 72 h to give 0.043 g of Compound 85 as white solid (58%).

Ή NMR (500 MHz, DMSO-/) δ ppm 8.19 (br s, 1 H) 7.10 (d, /=8.2 Hz, 2 H) 6.36 (d, /=8.2 Hz, 2 H) 4.28 (d, /=5.9 Hz, 2 H) 3.98 (br t, /=5.5 Hz, 2 H) 3.73 - 3.79 (m, 3 H) 3.70 (s, 2 H) 3.12 (s, 3 H) 2.72 (br t, /=5.9 Hz, 2 H) 2.58 - 2.65 (m, 2 H) 2.41 - 2.48 (m,

-1042 H) 2.03 (m, 2 H) 1.85 (br d, 7=4.7 Hz, 2 H) 1.79 (br d, 7=5.4 Hz, 2 H) 1.09 (t, 7=7.6 Hz, 3 H).

Synthesis of Compound 86 et

Compound 66

Di isopropyl ethy lamine (0.293 mL, 1.73 mmol) and HATU (0.402 g, 1,06 mmol) were added successîvely to a solution of intermediate L (0.2 g, 0.704 mmol) in DMF (5 mL). The resulting mixture was stirred at room température for 30 min., then a solution of intermediate CK (0.135 g, 0.581 mmol) in DMF (2.3 mL) was added and the mixture was stirred at room température for 1 h. The reaction mixture was evaporated in vacuo until dryness to give 0.96 g as brown oil. The crude product was purified by préparative LC (Irregular silica 15-40 pm, 40 g, dry loading (Celite*), mobile phase gradient: from DCM 99.5%, MeOH/aq.Nty (95:5) 0.5% to DCM 94%, MeOH/aq.NHj (95:5) 6%) to obtain 0.516 g as an orange gum. The product was purified by Reverse phase (spherical C18 silica, 25 pm, 120 g YMC-ODS-25, dry loading (Celite*), mobile phase gradient: from 60% aq. (NH4HCO3 0.2%), 40% MeCN to 20% aq. (NH4HCO3 0.2%), 80% MeCN) to give 0.164 g of a pale yellow solid which was triturated in EtjO, filtered and dried under high vacuum to afford 0.085 g of Compound 86 as a white solid (27%).

^lH NMR (400 MHz, DMSO-7₆) δ ppm 9.38 (d, 7= 2.5 Hz, 1 H), 8.67 (d, 7= 2.5 Hz,

H), 8.47 (t, 7= 5.8 Hz, I H), 7.18 (d, 7= 8.6 Hz, 2 H), 6.37 (d, 7= 8.1 Hz, 2 H), 4.40 (d, 7= 5.6 Hz, 2 H), 3.79 - 3.69 (m, 5 H), 3.11 (s, 3 H), 2.99 (q, 7= 7.6 Hz, 2 H), 2.46 2.39 (m, 2 H), 2.06 - 1.97 (m, 2 H), 1.26 (ζ 7= 7.6 Hz, 3 H)

-105Synthesis of Compound 87

Intermediate R

CAS [2357-52-0]

IPrMgCLLiCI, COCIJ.THF, 0*CtoRT

XVn^-Q-OH TMSCl»feOH.RT

Intermediate CL

intermediate CM »-Q-f

CAS [119442-1] KjCOj.DMSO, pW120*C

Raney NI, H₂ 3 bar NH/MeOH

Intermediate CN °*-OH

HATU, DIEA, DMF

Intermediate CO

Compound 87

Préparation of intermediate CL

In a flame-dried round-bottom flask under N2, a solution of /PrMgCl.LiCl 1.3 M (7.14 mL, 9.28 mmol) was added to a solution of 4-Bromo-2-fluoroanisole (CAS [2357-520], 1.90 g, 9.28 mmol) in anhydrous THF (30 mL) at room température. The solution was stirred at room température for 5 h under a stream of N2, then added dropwise (ca. 15 min.) to a solution of intermediate R (1.00 g, 3.09 mmol), Nl,NI,N2,N2-tetramethylcyclohexane-l,2-diamine (CAS [38383-49-2], 0.063 g, 0.37 mmol)and Cobalt II chloride (0.04 g, 0.3 [ mmol) in anhydrous THF (30 mL) under N2, at 0 °C. The resulting mixture was stirred at room température over week-end, hydrolyzed with aq.

NH4CI10% (40 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic phases were dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by préparative LC (irregular silica, 15-40 pm, 220 g, dry loading (silica), mobile phase gradient: from Heptane/EtOAc from 90/10 to 60/40) to give 0.619 g of intermediate CL as white solid (62%).

Préparation of intermediate CM

Trimethylsilyl chloride (1.21 mL, 9.60 mmol) was added dropwise to a solution of intermediate CL (0.615 g, 1.91 mmol) in anhydrous methanol (20 mL) under N2. The

-106reaction mixture was stirred at room température ovemight and then evaporated to dryness to give 0.447 g of intermediate CM as a white solid (91%).

Préparation of intermediate CN

A mixture of intermediate CM (0.425 g, 1.65 mmol), 4-Fluorobenzonîtrile (CAS [119402-1], 0.3 g, 2.47 mmol) and potassium carbonate (0.912 g, 6.60 mmol) in anhydrous DMSO (10 mL) was heated at 120 °C using a single mode microwave (Biotage InitiatorôO) with a power output ranging from 0 to 400 W for 1 h [fixed hold time]. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (2x50 mL). The combined organic phases were washed with water (2 x 50 mL) and brine (2 x 50 mL), dried over MgSCh, filtered and evaporated to dryness. The crude product was purified by préparative LC (irregular silica, 15-40 pm, 120 g, dry loading (silica), mobile phase gradient: from Heptane/EtOAc from 90/10 to 40/60) to give 0.349 g of intermediate CN as a white solid (65%).

Préparation of intermediate CO

In an autoclave, a mixture of intermediate CN (0,34 g, 1.06 mmol), and Raney Nickel (0.269 g, 4.58 mmol) in ammonia 7N în MeOH (11 mL) was stirred at room température under 3 bar of Hî ovemight. The reaction mixture was then filtered through a pad of Celite® and evaporated to dryness to give 0.3 g of intermediate CO as ofT-white solid (87%).

Préparation of Compound 87

Diisopropylethylamîne (0.19 mL, 1.09 mmol) and HATU (0.175 g, 0.46 mmol) were added successîvely to a solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.1 g, 0.42 mmol) în DMF (7 mL). The resulting mixture was stirred at room température for 1 h, then intermediate CO (0.15 g, 0.46 mmol) was added and the mixture was stirred at room température for 2 h. The reaction mixture was evaporated în vacuo until dryness. The crude product was purified by préparative LC (irregular silica, 15-40 pm, 40 g, liquid loading, mobile phase gradient DCM/MeOH from 100/0 to 95/5) to give a yellow solid. That solid was triturated in Et;O to give 0.132 g of a yellow solid which was dissolved in EtOH and evaporated to dryness to give 0.123 g of Compound 87 as a slightly yellow solid (55%). Ή NMR (500 MHz, DMSO-tfe) δ ppm 9.05 (s, 1 H), 8.39 (br t, J= 5.7 Hz, 1 H), 7.66 (d, J= 9.5 Hz, 1 H), 7.45 (br d, 9.5 Hz, 1 H), 7.19 (d, J= 8.2 Hz, 2 H), 7.13 - 7.04 (m, 2 H), 6.99 (brd, J= 8.5 Hz, ! H), 6.41 (d, 8.2 Hz, 2 H), 4.40 (brd, J= 5.7 Hz,

H), 3.90 (s, 2 H), 3.80 (s, 3 H), 3.70 (s, 2 H), 3.40 - 3.33 (m, 1 H), 2.96 (q, J= 7.4 Hz,

H), 2.28 - 2.23 (m, 2 H), 1.25 (t, J = 7.4 Hz, 3 H)

-107Synthesis of Compound 88

F

Diisopropylethy lamine (0.171 mL, 1.01 mmol) and HATU (0.162 g, 0.43 mmol) were added successively to a solution of intermediate L (0.11 g, 0.39 mmol) in DMF (4 mL). The resulting mixture was stirred at room température for 45 min., then a solution of intermediate 38 (0.139 g, 0.43 mmol) in DMF (2 mL) was added and the mixture was stirred at room température for 1 h. The reaction mixture was evaporated ln vacuo until dryness. The crude product was purified by préparative LC (irregular silica, 15-40 pm, 40 g. Grâce, liquid loading, mobile phase gradient DCM/MeOH from 100/0 to 90/10) to give a brownîsh solid which was triturated in EtiO and dried under high vacuum at 50 °C ovemight to give 0.098 g of a yellowish solid. This solid was dissolved in éthanol and evaporated to dryness to give a yellowish solid which was triturated in iPnO to give 0.091 g of Compound 88 as a white solid (44%).

*H NMR (400 MHz, DMSO-îA) δ ppm 9.39 (s, 1 H), 8.67 (s, ! H), 8.47 (br s, 1 H), 7.19 (d, J= 8.1 Hz, 2 H), 7.13 - 7.03 (m, 2 H), 7.02 - 6.96 (m, 1 H), 6.40 (d, J= 8.1 Hz, 2 H), 4.41 (br d, 5.6 Hz, 2 H), 3.90 (s, 2 H), 3.80 (s, 3 H), 3.69 (s, 2 H), 3.41 - 3.33 (m, 1 H), 3.00 (q, J = 7.2 Hz, 2 H), 2.27-2.2! (m, 2 H), 1.26 (b rt, J = 7.6 Hz,3 H)

TMSCI, MeOH, RT

Synthesis of Compound 89

KHMDS.NUj, IPrOH, 90*C

Intermediate CP

Intermediate R CAS [1962-15-5] ^H00~0

Intermediate CQ

CAS [1194-02-1]

K₂CO₃,DMSO, pW120'C

Raney NI, H_z 3 bar

Intermediate CR _HiNK><x>-O

Intermediate CS

Préparation of intermediate CP

A solution of Pyridine-4-boronic acid (CAS [1692-15-5], 0.571 g, 4.64 mmol),

Potassium bis(trimethylsilyl)amide (1,14 g, 6.19 mmol), Nickel II iodide (0.097 g,

0.31 mmol) and trans-2-Aminocyclohexanol hydrochloride (CAS [5456-63-3], 0.036 g, 0.31 mmol) in iPrOH (20 mL) was stirred under Nî for 5 min. at room température. Then, intermediate R (1.00 g, 3.09 mmol) was added and the reaction mixture was heated at 90 °C for 20 h. The reaction mixture was hydrolyzed with water (50 mL) and extracted with ethyl acetate (2x50 mL). The organic phases were combined and washed with brine (50 mL), dried over MgSO-i and evaporated to dryness. The crude product was purified by préparative LC (irregular silica, 15-40 pm, 120 g, liquid loading, mobile phase gradient DCM/MeOH from 95/5 to 90/10) to give 0.251 g of intermediate 39 as a white solid (30%).

Préparation of intermediate CO

Trimethylsîlyl chloride (0.52 mL, 4.15 mmol) was added dropwise to a solution of intermediate CP (0.227 g, 0.83 mmol) in anhydrous methanol (10 mL) under N?. The reaction mixture was stirred at room température ovemight and then evaporated to dryness to give 0.194 g of intermediate CQ as a white solid (quant.), used as such în the next step.

-109Préparation of intermediate CR

A mixture of intermediate CQ (0.179 g), 4-Fluorobenzonîtrile (CAS [1194-02-1], 0.206 g, 1.70 mmol) and potassium carbonate (0.587 g, 4.25 mmol) in anhydrous

DMSO (5.5 mL) was heated at 120 °C using a single mode microwave (Biotage InitiatorôO) with a power output ranging from 0 to 400 W for 1 h [fixed hold time], The reaction mixture was quenched with water and extracted with ethyl acetate (twice). The combined organic phases were washed with water (twice) and brine (twice), dried over MgSOj, filtered and evaporated to dryness. The crude product was purified by ! 0 preparative LC (irregular silica, 15-40 pm, 40 g, liquid loading, mobile phase gradient

DCM/MeOH from 100/0 to 95/5) to give 0.095 g of intermediate CR as a white solid (41%).

Préparation of intermediate CS

A mixture of intermediate CR (0.095 g, 0.35 mmol), and Raney Nickel 0.088 g, 1.5 mmol) in ammonia 7N in MeOH (4 mL) was stirred at room température under 3 bar of H2 ovemïght. The reaction mixture was then filtered through a pad of Celite® and evaporated until dryness to give 0.078 g of intermediate CS as a white solid (81%).

Préparation of Compound 89

Diisopropylethylamïne (0.118 mL, 0.69 mmol) and HATU (0.112 g, 0.29 mmol) were added successively to a solution of 6-chloro-2-ethylimidazo[3.2-a]pyridine3-carboxylic acid (CAS [1216142-18-5], 0.064 g, 0.27 mmol) in DMF (3 mL). The resulting mixture was stirred at room température for 45 min., then a solution of intermediate CS (0.078 g, 0.28 mmol) in DMF (2 mL) was added and the mixture was stirred at room température for 1 h. The reaction mixture was evaporated in vacuo until dryness. The crude product was purified by preparative LC (irregular silica, 15-40 pm, 40 g, liquid loading, mobile phase gradient DCM/MeOH from 100/0 to 90/10) to give a sticky solid. This solid was triturated in EtzO, then dissolved in DCM and washed twice with water, dried over MgSO<, filtered and evaporated to dryness to give 0.072 g of a white solid. That solid was dissolved in éthanol and evaporated to dryness, then successively triturated in Et;O and iPnO/EtOH (9:1). The resulting solid was purified by preparative LC (spherical Cl 8 silica, 25 pm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient: 0.2% aq. (NH4HCO3) / MeCN from 30:70 to 0:100 in

6 CV) and finally triturated in EtiO to give 0.032 g of Compound 89 as a white solid (25%).

'H NMR (400 MHz, DMSO-î/ô) δ ppm 9.06 (s, 1 H), 8.47 (br d, J= 5.6 Hz, 2 H), 8.37 (br t, 5.6 Hz, 1 H), 7.66 (d, J= 9.6 Hz, I H), 7.44 (br d, J= 9.6 Hz, 1 H), 7.25 (d, J

-110= 4.8 Hz, 2 H), 7.19 (d, J =8.0 Hz, 2 H), 6.41 (brd,J=8.1 Hz, 2 H), 4.41 (brd,J=

5.6 Hz, 2 H), 3.92 (s, 2 H), 3.71 (s, 2 H), 3.48 - 3.43 (m, 1 H), 2.96 (q, J= 7.6 Hz, 2 H),

2.62 - 2.57 (m, 2 H), 2.35 - 2.29 (m, 2 H), 1.25 (br t, J= 7.3 Hz, 3 H)

Synthesis of Compound 90

CAS [1M1026-71-4]

Br NaOtBu, Xanphos,

Yl Pd(QAc)_r dioxane, 100*C

CAS [623-00-7] intermediate CT

Raney NI, EtjN, Ac_tO, ₀ H, 3 bar ^HC00H’?^T NC-θ-Ν^ΝΗ DCM.OTO» _NC-£J>-_N^N-^ NH^eOH

Intermediate CU Intermediate CV

Préparation of intermediate CT

A solution of 2-Boc-2,6-diazaspiro[3.3]heptane oxalate (CAS [1041026-71-4], 2.0 g,

6.73 mmol), 4-Bromobenzonitrile (CAS [623-00-7], 1.84 g, 10.1 mmol) and sodium /er-butoxide (2.59 g, 26.9 mmol) in 1,4-dioxane (70 mL) was degassed. Then, palladium acetate (0.151 g, 0.673 mmol) and Xantphos (0.389 g, 0.673 mmol) were added, the mixture was purged again with Nî and stirred at 100 °C for 3 h. The mixture was cooled down to room température and filtered on a pad of Celite®. The cake was washed with EtOAc and the filtrate was evaporated in vacuo. The crude product was purified by préparative LC (irregular silica, 15-40 gm, 120 g, dry loading (Celite®), mobile phase gradient Heptane/EtOAc from 95/5 to 60/40) to give 0.919 g of intermediate CT as a white solid (48%).

-111Préparation of intermediate CU

A mixture of intermediate CT (0.5 g, 1.67 mmol) in formic acid (5 mL) was stirred at room température for 16 h. The mixture was evaporated in vacuo to give 0.526 g of intermediate 44 as an orange gum which crystallîzed on standing (quant.).

Préparation of intermediate CV

To a solution of intermediate CU (0.25 mg, 0.715 mmol) and triethylamîne (0.5 mL,

3.60 mmol) in DCM (7.5 mL) at 0 °C was added acetic anhydride (0.075 mL,

0.79 mmol) and the mixture was stirred at 0 °C for 2 h. The mixture was diluted with

DCM and washed with water. The organic layer was dried over MgSOj, filtered off and evaporated in vacuo. The crude product was purified by préparative LC (irregular silica, 15-40 pm, 24 g, liquid loading (DCM), mobile phase gradient DCM/MeOH from 99/1 to 94/6) to give 0.167 g of intermediate CV as a white solid (97%).

Préparation of intermediate CW

In an autoclave, to a solution of intermediate CV (0.167 g, 0.69 mmol) in ammonia 7N în MeOH (4 mL) was added Raney Nickel 0.2 g, 3.4 mmol) and the mixture was stirred at room température under 3 bar of H₂ for 2 h. The mixture was filtered off and evaporated in vacuo to give 0.153 g of intermediate CW as a white solid (90%).

Préparation of Compound 90

Triethylamîne (0.29 mL, 2.09 mmol) and HATU (0.285 g, 0.75 mmol) were added successively to a solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.163 g, 0.68 mmol) in DMF (4 mL). The resulting mixture was stirred at room température for 30 min., then a solution of intermediate CW (0.178 g,

0.726 mmol) in DMF (3 mL) was added and the mixture was stirred at room température for 3 h. The reaction mixture was evaporated in vacuo until dryness to give 0.717 g as a pale yellow solid. The crude product was purified by préparative LC (Irregular silica 15-40 pm, 50 g, dry loading (Celite®), mobile phase gradient

DCM/MeOH from 99/1% to 95/5) to obtain 0.351 g as a yellow gum. The product was purified by Reverse phase (Stationary phase: YMC-actusTriart-C18 lOpm 30x150mm,

Mobile phase: Gradient from 70% aq. (NH4HCO3 0.2%), 30% MeCN to 100% MeCN) to give 0.234 g of a white solid which was triturated in EtiO, filtered and dried under high vacuum to afford 0.222 g of Compound 90 as a white solid (72%).

Ή NMR (400 MHz, DMSO-7,) δ ppm 9.06 (s, 1 H), 8.41 (br s, 1 H), 7.67 (d, J= 9.5

Hz, 1 H), 7.46 (d, J= 9.0 Hz, 1 H), 7.20 (d, J= 8.2 Hz, 2 H), 6.43 (d, J= 8.2 Hz, 2 H),

4.41 (br d, J= 5.0 Hz, 2 H), 4.28 (s, 2 H), 4.00 (s, 2 H), 3.91 (s, 4 H), 2.96 (q, J= 7.4

Hz, 2 H), 1.75 (s, 3 H), 1.25 (t, J= 7.6 Hz, 3 H)

Synthesis of Compound 91

NC

H

Et^N, PhCOCI, DCM,0'C

Riney NI,

NH^MeOH

Intarnwdlata CU

Préparation of intermediate CX

To a solution of intermediate CU (0.25 g, 0.715 mmol) and triethylamine (0.50 mL,

3.60 mmol) in DCM (7.5 mL) at 0 °C was added benzoyl chloride (0.09 mL, 0.78 mmol) and the mixture was stirred at 0 °C for 2 h. The mixture was diluted with DCM and washed with water. The organic layer was dried over MgSCh, filtered off and evaporated în vacuo. The crude product was purified by préparative LC (irregular silica, 15-40 pm, 24 g, Grâce, liquid loading (DCM), mobile phase gradient: from DCM 99%, MeOH 1% to DCM 96%, MeOH 4%) to give 0.128 g of intermediate CX as a white solid (59%).

Préparation of intermediate CY

In an autoclave, to a solution of intermediate CX (0.128 g, 0.422 mmol) in ammonia 7N in MeOH (2.4 mL) was added Raney Nickel (0.12 g, 2.1 mmol) and the mixture was stirred at room température under 3 bar for 2 h. The mixture was filtered off and evaporated in vacuo to give 0.108 g of intermediate CY as a colourless oil which 20 crystallized on standing (83%).

Préparation of Compound 91

Diisopropylethylamine (0.168 mL, 0.99 mmol) and HATU (0.168 g, 0.44 mmol) were added successively to a solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carbo25 xylic acid (CAS [1216142-18-5], 0.09 g, 0.38 mmol) in DMF (2.5 mL). The resulting mixture was stirred at room température for 30 min., then a solution of intermediate CY (0.13 g, 0.42 mmol) in DMF (1.7 mL) was added and the mixture was stirred at room température for 3 h. The reaction mixture was evaporated in vacuo until dryness to give

0.52 g as an orange gum. The crude product was purified by préparative LC (Irregular silica 15-40 pm, 40 g, dry loading (Celite®), mobile phase gradient DCM/MeOH from

-11399/1 to 94/6) to obtain 0.137 g as a yellow gum. The product was purified by Reverse phase (Stationary phase: YMC-actus Triart-C18 10pm 30x150mm, Mobile phase: Gradient from 60% aq. (NH4HCO3 0.2%), 40% MeCN to 100% MeCN) to give 0.109 g of a colorless oil which was triturated in EtîO, filtered and dried under high vacuum to afford 0.095 g of Compound 91 as a white solid (49%).

‘H NMR (500 MHz, DMSO-î/₆) δ ppm 9.06 (s, 1 H), 8.40 (br t, J= 5.8 Hz, 1 H), 7.68 7.62 (m, 3 H), 7.54 - 7.44 (m, 4 H), 7.20 (d, J= 8.2 Hz, 2 H), 6.43 (d, J= 8.5 Hz, 2 H), 4.49 (s, 2 H), 4.41 (d, 5.7 Hz, 2 H), 4.24 (s, 2 H), 3.99 - 3.90 (br q, 4 H), 2.96 (q, J = 7.4 Hz, 2 H), 1.25 (t, J= 7.4 Hz, 3 H)

Synthesis of Compound 92

Intermediate F

Intermediate CZ

HATU, DIPEA, DMF

Intermediate DA

Me.SICI, ci MeOH, RT

Intermediate DB

Compound 92

Préparation of intermediate CZ

In an autoclave, to a solution of intermediate F (1.57 g, 5.26 mmol) in ammonia 7M in MeOH (50 mL) was added Raney Nickel (1.4 g, 23.9 mmol) and the mixture was hydrogenated at room température under 3 bar over the weekend (after 3h, ail hydrogen was consumed. The autoclave was refilled to 3 bar of Hi). The mixture was filtered off and evaporated in vacuo. The residual grey gum was solubilîzed in EtOAc, stirred with

SilîaMetS(R) Imidazole (1 eq. w/w) for 1 h then filtered over a pad of Celite®. The filtrate was evaporated în vacuo to afford 1.29 g of intermediate CZ as a white solid.

Préparation of intermediate DA

To a solution of 6-chloro-2'ethylimidazo[3,2-a]pyridine-3-carboxy!ic acid (CAS

-114[1216142-18-5], 0,4 g, 1.67 mmol) in diisopropylethylamine (0.74 mL, 4.35 mmol) and DMF (15 mL) was added HATU (0.7 g, 1.84 mmol) and the mixture was stirred at room température for 20 min. Intermediate CZ (505 mg, 1.67 mmol) was added then the mixture was stirred at room température for 1 h. The mixture was evaporated in vacuo to give a brown gum. The residue was purified by préparative LC (irregular SÎOH, 15-40 pm, 50 g, dry loading (Celite*), Heptane/EtOAc/MeOH (9:1) from 85/15 to 35/65) to give 0.784g of intermediate DA as a white solid (92%).

Préparation of intermediate PB

To a solution of intermediate DA (0.784 g, 1.54 mmol) in MeOH (16 mL) was added Chlorotrimethylsilane (1 mL, 7.92 mmol) and the mixture was stirred at room température for 16h. The mixture was evaporated în vacuo to afford 0.79 g of intermediate DA as pale yellow foam (crude used as such in next step).

Préparation of Compound 92

Trifluoroacetïc anhydride (0.235 mL, 1.69 mmol) was added at 0 °C to a solution of intermediate DB (0.79 g, 80%, 1.54 mmol) and triethylamine (1.1 mL, 7.91 mmol) în DCM (9 mL). The reaction mixture was stirred at 0 ^qC for 1 h then, at room température for 1 h. The reaction mixture was quenched with NaHCOj sat. and extracted with DCM (twice). The organic layer was dried over MgSO-», filtered off then evaporated în vacuo 0.75 g of an off-white foam. The residue was purified by préparative LC (irregular SiOH, 15-40 pm, 50 g, dry loading (Celite®), Heptane/EtOAc/MeOH (9:1) from 90/10 to 60/40) to give 0.643 g of a white foam.

The reisude was purified by reverse phase (spherical Cl8,25 pm, 120 g YMC-ODS25 25, dry loading (Celite®), mobile phase gradient: from 35% aq.(NH4HCO3 0.2%), 65%

MeCN to 100% MeCN) and clean fractions were directly freeze-dried. The fluffy solid was solubilized in MeCN then evaporated under vacuum to give a colorless oil. This oil was triturated in Et2Û and evaporated under vacuum to afford 0.593 g of Compound 92 as a white solid (76% over 2 steps).

*H NMR (400 MHz, DMSO-dô) δ ppm 9.07 (d, J =2.0 Hz, 1 H), 8.46 (brt, J= 5.8 Hz,

H), 7.66 (d, J= 9.6 Hz, 1 H), 7.45 (dd, J= 9.1,2.0 Hz, 1 H), 7.30 (d, J= 8.1 Hz,

H), 7.20 (d, J= 8.1 Hz, 2 H), 4.56 (s, 1 H), 4.49 (d, J= 5.6 Hz, 2 H), 4.33 (s, 1 H), 4.23 (s, 1 H), 4.01 (s, 1 H), 3.41 - 3.33 (m, 1 H), 2.99 (q, J= 7.6 Hz, 2 H), 2.68 - 2.55 (m, 2 H), 2.33 - 2.25 (m, 2 H), 1.26 (t, J= 7.6 Hz, 4 H)

-115Synthesis of Compound 93

Q

HATU.DIEA, DMF, RT

Intermediate L

Cl.

F F

H

Compound 93

A solution of intermediate L (0.085 g, 0.299 mmol) and HATU (0.17 g, 0.447 mmol) in diisopropyiethyiamine (0.13 mL, 0.764 mmol) and DMF (2 mL) was stirred at room temperature for 30min. Then, intermediate Q (0.085 g, 0.304 mmo!) in DMF (1.4 mL) was added and the mixture was stirred at room temperature for 3 h. The mixture was evaporated in vacuo to give 0.543 g of a brown gum. The residue was purified by préparative LC (irregular SiOH, 15-40 pm, 30 g, dry loading (Celite*),

Heptane/EtOAc/MeOH (9:1) from 90/10 to 45/55) to give 0.088 g of a yellow gum (which crystallized on standing). The reisude was triturated in Et2O/EtOH (9:1), filtered off and dried under vacuum (50 °C, 16 h) to give 0.064 g of Compound 93 as a pale yellow solid (36%).

*H NMR (400 MHz, DMSO-/) δ ppm 9.38 (s, 1 H), 8.67 (s, 1 H), 8.51 (t, J= 5.6 Hz, 1

H), 7.21 - 7.15 (m, 4 H), 6.68 (br t, 7.1 Hz, 1 H), 6.44 (br d, 8.1 Hz, 4 H), 4.41 (br d, J= 5.6 Hz, 2 H), 3.95 (br s, 8 H), 3.00 (q, J= 7.6 Hz, 2 H), 1.26 (t, 7.6 Hz, 3 H).

Synthesis of Compound 94

Intermediate G

NaOtBu, Pd(OAc)_r Xabtphos, dioxane, t00*C, 2h

Intermediate DD

Raney Νζ H, 3 bar ΝΗ,/MeOH

Preparation of intermediate PC

Accordingly, intermediate DC was prepared in the same way as intermediate BV starting from intermediate G (0.315 g, 1.34 mmol) and bromobenzene affording 0.245 g, 66%.

-116Préparation of intermediate DD

Accordingly, intermediate DD was prepared in the same way as intermediate CZ starting from intermediate DC (0.14 g, 0.51 mmol) to give 0.135 g, 83%.

Préparation of Compound 94

A solution of intermediate L (0.135 g, 0.475 mmol) and HATU (0.27 g, 0.71 mmol) in diisopropylethylamine (200 pL, 1.18 mmol) and DMF (2.5 mL) was stirred at room température for 30min. Then, intermediate 52 (0.135 g, 0.485 mmol) în DMF (2.5 mL) was added and the mixture was stirred at room température for 3h. The mixture was evaporated in vacuo to give 0.848 g ofa brown oil. The residue was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g, dry loading (Celite®), Heptane/EtOAc/MeOH (9:1) from 80/20 to 35/65) to give 0.159 g of a pale yellow solid. The solid was triturated in EtîO/EtOH (9:1), filtered off and dried under vacuum (50 °C, 16 h) to give 0.118 g of a white solid. This solid was purified by Reverse phase (Stationary phase: YMC-actus Triart-C18 lOpm 30x150mm, Mobile phase: Gradient from 40% aq.(NH4HCOj 0.2%), 60% ACN to 100% ACN) then dried under vacuum (60 °C, 16 h) to give 0.076 g of Compound 94 as a white solid (29%).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.40 (d, J = 3.0 Hz, 1 H), 8.68 (d, J = 2.5 Hz, 1 20 H), 8.57 (t, J = 5.8 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.15 (t,

J = 7.8 Hz, 2 H), 6.65 (t, J = 7.3 Hz, 1 H), 6.41 (d, J = 7.6 Hz, 2 H), 4.51 (d, J = 5.6 Hz, 2 H), 3.93 (s, 2 H), 3.71 (s, 2 H), 3.42 (quin, J = 8.7 Hz, I H), 3.03 (q, J = 7.6 Hz, 2 H),

2.61 - 2.54 (m, 2 H), 2.34 - 2.23 (m, 2 H), 1.28 (t, J = 7.6 Hz, 3 H).

-117Synthesis of Compound 95 and Compound 96

1,3-propanediol, zirconium chloride, θ ethyk>rthofonrate,OCM

Me.SICI, MeOH, RT

CAS [1147557-97-8] Intermediate DE •000 intermediate DF

E^N, DIPEA, DMF xc-Q-f

K_tC0,,DMS0, pW12(rC,1h

-Ooo0 intermediate DO _Cl ⁰ -0^000

Compound 95

Raney NI, H_t 3 bar NH^MeOH „^-0-000

Intermediate OH

PTSA, Η,Ο, ecetone Cl

Compound 9o

Préparation of intermediate DE

A solution of 2-Boc-2-azaspiro[3.3]heptan-6-one (CAS [1181816-12-5], 0.5 g,

2.37 mmol), 1,3-propanediol (0.26 mL, 3.55 mmol), ethylorthoformate (0.39 mL,

2.37 mmol) and zirconium chloride (0.028 g, 0.118 mmoi) în anhydrous DCM (10 mL) was stirred under N2 for 2 h at room température. After 2h, 025 eq of ethylorthoformate (0.099 mL, 0.59 mmol) and 0.5 eq. of 1,3-propanediol (0.09 mL,

1.18 mmol) were added.

After 5 h: the reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL). The organic phase was washed with water, dried over MgSCh, filtered and evaporated to dryness to give 0.633 g of intermediate DE as a colorless oïl.

Préparation of intermediate DF

Accordingly, intermediate DF was prepared in the same way as intermediate DB, starting from intermediate DE (0.63 g, 2.35 mmol) affordingO.431 g, 2.1 mmol as an hydrochloride sait.

Préparation of intermediate DG

A mixture of intermediate DF (0.426 g, 2.07 mmol), 4-Fluorobenzonitrile (0.376 g,

3.11 mmol) and potassium carbonate (0.859g, 6.21 mmol) in anhydrous DMSO (12 mL) was heated at 120 °C using a single mode microwave (Biotage initiatorôO)

-118with a power output ranging from 0 to 400 W for Ih [fixed hold time]. The réaction mixture was quenched with water (30 mL), extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with water (2 x 30 mL) and brine (2 x 20 mL), dried over MgSO.», filtered and evaporated to dryness to give a green soüd. The residue was purified by préparative LC (irregular SiOH, 15-40 pm, 80 g, Grâce, dry loadïng (Silica), Heptane/EtOAc from 90/10 to 50/50) to give 0.369 g of intermediate DG as white solid (66%).

Préparation of intermediate DH

Accordingly, intermediate DH was prepared in the same way as intermediate CZ starting from intermediate DG (0.334 g, 1.24 mmol) to give 0.297 g, 88%.

Préparation of Compound 95

A solution of 6-chloro-2-ethylimidazo[3,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.225 g, 0.939 mmol) and HATU (0.39 g, 1.03 mmol) in triethylamîne (0.39 mL, 2.81 mmol) and DMF (6 mL) was stirred at room température for 30 min. Then, intermediate DH (0.27 g, 0.984 mmol) in DMF (5 mL) was added and the mixture was stirred at room température for 3 hours. The mixture was evaporated În vacuo to give 1.22 g of an orange gum. The residue was purified by préparative LC (irregular SiOH, 15-40 pm, 50 g, merck, dry loading (Celîte®), Heptane/EtOAc/MeOH (9:1) from 90/10 to 45/55) to give 0.483 g as a white foam (96%).

mg ofthe residue was solubîlîzed în MeCN, washed with pentane (twice) and evaporated în vacuo. The residual colorless oil was triturated in Et2Ü, filtered offand dried under high vacuum (50 °C, 16 h) to afford 43 mg of Compound 95 as a white solid.

^lH NMR (400 MHz, DMSO-ifc) δ ppm 9.05 (s, 1 H), 8.37 (t, J = 5.8 Hz, 1 H), 7.65 (d, ./=9.6 Hz, 1 H), 7.44 (dd, J= 9.6,2.0 Hz, 1 H), 7.17 (d, J=8.1 Hz, 2 H), 6.39 (d, J 8.6 Hz, 2 H), 4.40 (d, J=. 6.1 Hz, 2 H), 3.77 - 3.72 (m, 8 H), 2.95 (q, J= 7.6 Hz, 2 H), 2.39 (s, 4 H), 1.60 - 1.55 (m, 2 H), 1.24 (t, J= 7.6 Hz, 3 H)

Préparation of Compound 96

A solution of Compound 95 (0.35 g, 0.673 mmol) and para-toluenesulfonic acid (0.013 g, 0.0673 mmol) in acetone (7.5 mL)and water (1.8 mL) was heated at 100 °C using a single mode microwave (Biotage initiator60) with a power output ranging from

0 to 400 W for 2 h [fixed hold time]. Themixture was heated again at 100 °C using a single mode microwave (Biotage ÎnîtîatorôO) with a power output ranging from 0 to

400 W for 2 h [fixed hold time]. The mixture was diluted with EtOAc, washed with aq.

NaHCOî sat., brine, dried over MgSOj, filtered off and evaporated in vacuo to afford

-1190.301 g of a yellow solid. The residue was purified by préparative LC (irregular SiOH, 15-40 pm, 24 g, Grâce, dry loading (Celite®), Heptane/EtOAc/MeOH (9:1) from 80/20 to 40/60) to give 0.275 g of an off-white solid. The solid was triturated în EtjO (3 times) then in EtîO/EtOH (9:1, twice) and filtered off to afford 0.256 g a white solid. The solid was purified by préparative LC (irregular SiOH, 15-40 pm, 24 g, Grâce, dry loading (Celite®), Heptane/EtOAc/MeOH (9:1) from 90/10 to 50/50) and clean fractions were directly combined to give 0.151 g of a white solid. The solid was purified by reverse phase (spherical C18,25 pm, 40 g YMC-ODS-25, dry loading (Celite), mobile phase gradient: from 75% aq.(NH4HCOj 0.2%), 25% MeCN to 35% aq.(NHiHCO3 0.2%), 65% MeCN) and clean fractions were freeze-dried to afford 0.045 g of Compound 96 a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (d, J = 2.0 Hz, 1 H), 8.39 (br s, 1 H), 7.66 (d, J = 9.6 Hz, 1 H), 7.44 (dd, J = 9.6,2.0 Hz, l H), 7.20 (d, J = 8.08 Hz, 2 H), 6.45 (d, J = 8.59 Hz, 2 H), 4.41 (br d, J = 4.6 Hz, 2 H), 3.96 (s, 4 H), 3.35-3.29 (m, 4 H), 2.96 (q, J = 7.6 Hz, 2 H), 1.25 (t, J = 7.6 Hz, 3 H)

The Following Compounds were also prepared in accordance with the procedures herein:

Compound No	Structure
97	F F
98
99

-120-

-122-

-123-

Compound No	Structure
120
121
122
123
124
125

-124-

Compound No	Structure
126	yoOOO° ^,Λ=ν
127
128
129	. O<o O

Synthesis of Compound 117. Compound 130 & Compound 131

CAS (1147557-974J

MuoropyrWlM, S^toetFluw, KF, AflOTT, TMSCF, BOAs, AT xJ-OO-»’.

Intormodlit» DI

TMsa, ΜαΟΗ,ΑΤ «<X>-^oeF>

Intomwdlit· DJ

RanayNI, H,lb«r NH/HaOH

brttrmodiif· DL

Intornwdlat· DK

. y.

B.N, HATU, DMF kjCV/

-> Compound 117

-125Préparation of intermediate Dî

A suspension of siîver triflate (3.6 g, 14.1 mmol), Selectfluor® (2.49 g, 7.03 mmol), potassium fluoride (1.09 g, 18.8 mmo!) and 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (CAS [1147557-97-8], 1.00 g, 4.69 mmol) was purged with N2. Then, EtOAc (24 mL), 2-fluoropyridïne (1.21 mL, 14.1 mmol) and trifluoromethyltrimethyîsilane

2M în THF (7.03 mL, 14.1 mmol) were added, the mixture was purged again and the resulting mixture was stirred at room température for 3 days. The reaction mixture was then filtered on Celite® and evaporated to dryness. The crude product was purified by preparative LC (irregular silica, 15-40 pm, 50 g, Merck, dry loading (Celite®), mobile 10 phase gradient: Heptane/EtOAc from 90/10 to 50/50) to give 0.64 g of intermediate DI as a white crystals (49%).

Préparation of intermediate DJ

Chlorotrimethylsilane (0.9 mL, 7.12 mmol) was added to a solution of intermediate DI (0.4 g, 1.42 mmol) in anhydrous methanol (9 mL) and the mixture was stirred at room température ovemîght. The mixture was evaporated in vacuo to give 0.308 g of intermediate DJ as a pale pink gum which crystallized on standing (quant.).

Préparation of intermediate DK

A suspension of intermediate DJ (0.308 g, 1.42 mmol), 4-Fluorobenzonitrile ( CAS [1194-02-1], 0.346 g, 2.83 mmol) and potassium carbonate (0.782 g, 5.66 mmol) în DMSO (7 mL) was heated at 120 °C using a single mode microwave (Biotage InitiatorôO) with a power output ranging from 0 to 400 W for 30 min [fixed hold time]. The mixture was diluted in EtOAc, washed with water (3x), brine (3x), dried over

MgSO.t, filtered ofî and evaporated. The crude product was purified by preparative LC (irregular silica, 15-40 pm, 24 g, Grâce, dry loading (Celite®), mobile phase gradient: Heptane/EtOAc from 95/5 to 60/40) to give 0.101 g of intermediate DK as a white solid (25%).

Préparation of intermediate DL ln an autoclave, to a solution of intermediate DK (0.101 g, 0.36 mmol) in ammonia 7N in MeOH (1.8 mL) was added Raney Nickel (-Ό. I g, 1.7 mmol) and the mixture was stirred at room température under 3 bar of H2 for 2 hours. The mixture was filtered off and evaporated in vacuo. The filtrate was taken-up in EtOAc and filtered on a pad of

Celite®. The filtrate was evaporated in vacuo to give 0.09 g of intermediate DL as a coîorless oil (87%).

-12610

Préparation of Compound 117

Diisopropylethylamine (0.132 mL, 0.78 mmol) and HATU (125 mg, 0.33 mmol) were added successively to a solution of 6-chloro-2-ethylimidazo[l,2-a]pyridine-3-carboxyltc acid (CAS [1216142-18-5], 0.072 g, 0.30 mmol) in DMF (2 mL). The resulting mixture was stirred at room température for 30 min., then a solution of intermediate DL (0.09 g, 0.31 mmol) in DMF (1 mL) was added and the mixture was stirred at room température for 1 h. The reaction mixture was evaporated in vacuo until dryness to give 0.26 g as brown oil. The crude product was purified by préparative LC (Irregular silica 15-40 pm, 12 g Grâce, dry loading (Celite®), mobile phase gradient Heptane/EtOAc/MeOH (9:1) from 90/10 to 50/50) to obtain 0.126 g as a yellow solid. The product was purified by Reverse phase (spherical Cl8,25 pm, 120 g YMC-ODS25, dry loading (Celite®), mobile phase gradient: from 30% aq. (NH4HCOJ 0.2%), 70% MeCN to 100% MeCN) to give 0.107 g of a white solid which was triturated in Et₂O, filtered and dried under high vacuum to afford 0.085 g of Compound 117 as a white solid (57%).

IH NMR (400 MHz, DMSO-d6) δ ppm 9.05 (s, 1 H), 8.37 (t, J = 5.6 Hz, 1 H), 7.65 (d, J = 9.6 Hz, 1 H), 7.44 (dd, J = 9.6,1.5 Hz, I H), 7.18 (d, J = 8.6 Hz, 2 H), 6.38 (d, J =

8.6 Hz, 2 H), 4.79 (m, J = 7.1 Hz, 1 H), 4.40 (d, J = 5.6 Hz, 2 H), 3.78 (d, J = 11.6 Hz, 4 H), 2.95 (q, J = 7.6 Hz, 2 H), 2.68 - 2.55 (m, 2 H), 2.45 - 2.38 (m, 2 H), 1.24 (t, J =

7.6 Hz, 3 H)

Préparation of Compound 130

Compound 130 was prepared in the same way as Compound 117, starting from intermediate CI and intermediate DL. The crude product was purified by préparative LC (Regular SiOH 30 pm, 12 g Interchim, dry loading (Celite®), mobile phase gradient Heptane/EtOAc/MeOH from 70:25:5 to 40:50:10) to give 0.099 g of Compound 130 as an off-white solid (31%).

IH NMR (500 MHz, DMSO-d6) δ ppm 8.09 (t, J = 6.0 Hz, 1 H), 7.11 (d, J = 8.5 Hz, 2 H), 6.36 (d, J = 8.5 Hz, 2 H), 4.79 (quint., J = 7.3 Hz, I H), 4.28 (d, J = 6.0 Hz, 2 H), 3.96 (t, J = 5.8 Hz, 2 H), 3.78 (s, 2 H), 3.75 (s, 2 H), 2.70 - 2.63 (m, 4 H), 2.58 (q, J = 7.6 Hz, 2 H), 2.47 - 2.39 (m, 2 H), 1.86 - I.75 (m, 4 H), 1.08 (t, J = 7.6 Hz, 3 H)

-127-

Préparation of Compound 131

To a solution of intermediate L (250 mg, 1.03 mmol) in triethylamine (0.4 mL, 2.88 mmol) and DCM (8.5 mL) were added EDCI (300 mg, 1.57 mmol) and HOBt (210 mg, 1.55 mmol) and the mixture was stirred at room température for 30 min.

Intermediate DL (312 mg, 1,09 mmol) in DCM (2 mL) was added and the mixture was stirred at room température for 16 h. The mixture was then washed with water (2x) and brine. The organic layer was dried over MgSO<, filtered, and evaporated to dryness. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g,

Grâce, dry loading (Celite®), mobile phase gradient Heptane/EtOAc from 80/20 to 20/80) to give a pale yellow solid, which was triturated in éthanol and filtered off to afford 0.248 g of Compound 131 as a white solid (49%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.38 (d, J = 2.5 Hz, 1 H), 8.67 (d, J = 2.8 Hz,

H), 8.49 (t, J = 5.8 Hz, 1 H), 7.19 (d, J = 8.2 Hz, 2 H), 6.38 (d, J = 8.5 Hz, 2 H), 4.79 (quin, J = 7.1 Hz, 1 H), 4.40 (br d, J = 5.7 Hz, 2 H), 3.7 (s, 2 H), 3.76 (s, 2 H), 2.99 (q, J = 7.4 Hz, 2 H), 2.67 - 2.63 (m, 2 H), 2.43 - 2.39 (m, 2 H), 1.26 (t, J = 7.6 Hz, 3 H)

Synthesis of Compound 132

Κ,ΟΟ,ΟΜΟ,

IntarmadlataDM

Rinty NI, H, 3 bar NHJMeQH

Intarmedlata ON

-^F<?

Intarmadlit» Q

Compoind132

HATU, D1PEA, DMF

Préparation of intermediate DM

A suspension of intermediate G (0.238 g, 1.01 mmol), 2-fluoropyrazîne (0.123 mL,

1.52 mmol) and potassium carbonate (420 mg, 3.04 mmol) in DMSO (6.2 mL) was heated at 120 °C using a single mode microwave (Biotage Înitiator60) with a power output ranging from 0 to 400 W for 1 h [fixed hold time]. The reaction mixture was evaporated in Genevac and purified by préparative LC (irregular SiOH, 15-40 pm, 40

-12810 g, Merck, dry loading (silica), mobile phase gradient from DCM/MeOH from 100/0 to 90/10) to give 0.194 g of intermediate DM as a yellow solid (69%).

Préparation of intermediate DN

Accordingly, intermediate DN was prepared in the same was as intermediate DL starting from intermediate DM, yîelding 0.169 g, 88%.

Préparation of Compound 132 Diisopropylethylamine (0.24 mL, 1.41 mmol) and HATU (0.227 g, 0.60 mmol) were added successively to a solution of 6-chloro-2-ethylimidazo[l,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.125 g, 0.54 mmol) in DMF (3.2 mL). The resulting mixture was stirred at room température for 1 h, then a solution of intermediate DN (0.152 g, 0.54 mmol) in DMF (3.2 mL) was added and the mixture was stirred at room température for 1 h. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM and washed with NaHCOj 1% (2x), water (2x) and brine, dried over MgSOi, filtered and evaporated to dryness. The crude product was purified by préparative LC (inegular SiOH, 15-40 pm, 40 g, Grâce, dry loading (Silica), mobile phase gradient DCM/MeOH from 100/0 to 90/10) to give a brown solid, which was triturated ïn Et₂O to afford 0.121 g of Compound 132 as an off-white solid (46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (s, 1 H), 8.48 (t, J = 5.8 Hz, 1 H), 8.02 (s,

H), 7.85 (s, 1 H), 7.82 (d, J = 2.8 Hz, 1 H), 7.67 (d, J = 9.6 Hz, 1 H), 7.46 (dd, J = 9.6, 2.0 Hz, 1 H), 7.31 (d, J = 7.6 Hz, 2 H), 7.23 (d, J = 8.1 Hz, 2 H), 4.50 (d, J = 6.1 Hz,

H), 4.17 (s, 2 H), 3.96 (s, 2 H), 3.42 (quin, J = 8.9 Hz, 1 H), 2.99 (q, J = 7.6 Hz, 2 H), 2.63 - 2.57 (m, 2 H), 2.33 - 2.27 (m, 2 H), 1.27 (t, J = 7.6 Hz, 3 H)

Synthesis of Compound 125 & Compound 133

NCIntermediate DO (ntermediate DP

CAS [823-00-7] CAS [1253181-92-5]

-129Préparation of intermediate DO

A solution of 2,2-difluoro-7-azaspiro[3.5]nonane hydrochloride (CAS [1263181-82-5], 0.3g, 1.52 mmol), 4-Bromobenzonitrile (0.414 g, 2.28 mmol) and sodium terbutoxide (0.583 g, 6.07 mmol) in 1,4-dioxane (16 mL) was degassed under Nî. Then, Palladium

II acetate (0.034 g, 0.152 mmol) and Xantphos (0.088 g, 0.152 mmol) were added, the mixture was purged agaîn with Nî and heated to 120 ^qC ovemight. The mixture was cooled to room température and filtered over a pad of Celite®. The cake was washed with EtOAc and the filtrate was evaporated in vacuo. The crude was purified by préparative LC (irregular SiOH, 15-40 pm, 24 g. Grâce, dry loading (SiOH), mobile phase gradient Heptane/EtOAc from 90/10 to 50/50 to obtain 0.343 g of intermediate DO as yellow solid (86%).

Préparation of intermediate DP

Accordîngly, intermediate DP was prepared in the same was as intermediate DL starting from intermediate DO, yield in g 0.312 g, 90%.

Préparation of Compound 125 Diisopropylethylamine (0.21 mL, 1.20 mmol) and HATU (238 mg, 0.625 mmol) were added successively to a solution of 6-ch!oro-2-ethylimidazo[I,2-a]pyridine-3-carbo- .

xylic acid (CAS [1216142-18-5], 0.1 II g, 0.481 mmol) in DMF (13 mL). The resulting mixture was stirred at room température for 30 min, before the addition of intermediate DP (0.128 g, 0.481 mmol) and the mixture was stirred at room température for I h. The reaction mixture was diluted with EtOAc and washed with an aq. sat. NaHCOj solution (twice) and brine (twice). The organic phase was dried over MgSO-i, filtered and evaporated to dryness to give 0.269 g. The crude was purified by préparative LC (Irregular SiOH 15-40 pm, 40 g Grâce Resolv, dry loading (SiOH), mobile phase gradient: Heptane/EtOAc from 90/10 to 50/50) to obtain 0.199 g as white brown solid. The residue was dissolved in EtOAc and washed with 1% aq. NaHCOj (2x), water and brine (2x), dried over MgSO-i, filtered and evaporated to obtain 0,183 g. It was triturated in ÏPnO, filtered and dried to obtain 0.146 g as white solid. It was dissolved in EtOH and evaporated to dryness (3x) and dried under vacuo ovemight to obtain 0.144 g of Compound 125 as white solid (63%).

IH NMR (400 MHz, DMSO-d6) δ ppm 9.06 (d, J = 1.5 Hz, I H), 8.40 (t, J = 5.8 Hz, I H), 7.66 (d, J = 9.6 Hz, 1 H), 7.45 (dd, J = 9.3,2.3 Hz, 1 H), 7.21 (d, J = 8.6 Hz, 2 H),

6.92 (d, J = 8.6 Hz, 2 H), 4.42 (d, J = 6.1 Hz, 2 H), 3.10 - 3.07 (m, 4 H), 2.96 (q, J =

7.6 Hz, 2 H), 2.39 (t, J = 13.1 Hz, 4 H), 1.70 - 1.67 (m, 4 H), 1.25 (t, J = 7.6 Hz, 3 H)

-130Preparation of Compound 133

Compound 133 was prepared in the same way as Compound 125, starting from intermediate L and intermediate DP. The crude product was purified by préparative LCs (Irregular SiOH 15-40 pm, 40 g Grâce, dry loading (silica), mobile phase gradient Heptane/(AcOEt/MeOH 9/1) from 90/10 to 60/40; then spherical CI8 25 pm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient: 0.2% aq. NHiHCOî/MeCN from 65/35 to 25/75) to give 0.083 g of Compound 133 as a white solid (36%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.39 (d, J = 2.5 Hz, 1 H), 8.67 (d, J = 2.5 Hz, 1 H), 8.51 (t, J = 5.7 Hz, 1 H), 7.21 (d, J = 8.5 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 4.42 (d, J = 5.7 Hz, 2 H), 3.10 - 3.06 (m, 4 H), 3.00 (q, J = 7.4 Hz, 2 H), 2.39 (t, J = 13.5 Hz, 4H), 1.71 -1.67 (m, 4 H), 1.26 (t, J = 7.4 Hz, 3 H)

Synthesis of Compound 134

Pd(OAc)₂, Xantphoe, NaOtBu, dioxane, 100*C

intermediate DQ

NHj/MbOH Raney Ni, Hj3bar intermediate G

Compound 134 intermediate DR

Préparation of intermediate DO

Palladium acetate (0.107 g, 117 pmol) and Xantphos (0.182 g, 293 pmol) were added to a mixture of intermediate G (0.55 g, 2.34 mmol), 5-bromopyrimidine (0.373 g, 2.34 mmol) and sodium t-butoxide (0.676 g, 7.03 mmol) in 1,4-dioxane (8.3 mL). The atmosphère was evacuated and backfilled with N2. The reaction mixture was heated at 100 °C for 5h. After cooling to room température, the reaction mixture was diluted with AcOEt and DCM and filtered over a pad of Celite®. The filtrate was evaporated to

dryness. The crude mixture was purified by préparative LC (trregular SiOH, 15-40 pm, 120 g, Grâce, dry loading (silica), mobile phase gradient DCM/MeOH from 100/0 to 95/5) to give 0.306 g of intermediate DQ as a yellow solid (47%).

Préparation of intermediate DR

Accordingly, intermediate DR was prepared in the same was as intermediate DL starting from intermediate DQ, yielding 0.298 g, 96% as a yellow solid.

Preparation of Compound 134

Compound 134 was prepared in the same way as Compound 132, starting from 6-chloro-2-ethylimidazo[l,2-a]pyridine-3-carboxylic acid CAS [1216142-18-5] and intermediate DR. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 80 g. Grâce, dry loading (silica), mobile phase gradient DCM/MeOH from 15 100/0 to 90/10) to give 0.268 g of Compound 134 as a white solid (56%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.08 (s, t H), 8.53 (s, 1H), 8.48 (t, J = 5.6 Hz,

H), 8.03 (s, 2 H), 7.68 (d, J = 9.5 Hz, t H), 7.47 (dd, J = 9.5,1.9 Hz, 1 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.23 (d, J = 7.88 Hz, 2 H), 4.51 (d, J = 5.6 Hz, 2 H), 4.09 (s, 2 H), 3.88 (s,

H), 3.46 - 3.36 (m, 1 H), 3.00 (q, J = 7.6 Hz, 2 H), 2.62 - 2.58 (m, 2 H), 2.33 - 2.28 (m, 2 H), 1.29-1.24 (t, J = 7.6 Hz, 3 H)

-132Synthesis of Compound 135 & Compound 136

FSOjCFjCOjH CAS [1717-59-5], Cul.ACN,50‘C

V<XW

Intermediate DS

TMSCI. MeOH. RT ^nc“Q-^f

KjCO,. OMSO.

HI0^-OCF₂H ^^12Ο'°. ¹l ^nc-^XX>-^ocf2^h

ΝΗ,/ΜβΟΗ RaneyN, H, 5 bar

Intermediate OT

intermediate DV intermediate DU

Compound 135

OCFjH

Préparation of intermediate DS

A solution of 2,2-Difluoro-2-(fluorosuifonyl)acetic acid (CAS [1717-59-5], 1.25 g, 7.03 mmol) in Acetonitrile (6 mL) was added over 1 h30 to a solution of tert-Butyl 6hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (CAS [1147557-97-8], 1.00 g, 4.69 mmol) and copper iodide (0.179 g, 0.94 mmol) in acetonitrile (12 mL) at 50 °C under Nî. The reaction mixture was further stirred at 50 °C for 30 min, then 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 100/0 to 70/30) to give 0.788 g of intermediate DS as a white solid (64%).

Préparation of intermediate DT ·

Accordingly, intermediate DT was prepared in the same way as intermediate DJ starting from intermediate DS yielding 0.563 g, quantitative, as a colorless oil, used as such.

Préparation of intermediate DU

Accordingly, intermediate DU was prepared in the same way as intermediate DK starting from intermediate DT yielding 0.445 g, 60% as a white solid.

-133-

Préparation of intermediate DV

Accordingly, intermediate DV was prepared in the same was as intermediate DL starting from intermediate DU yielding 0.433 g, 96% as a colorless oil.

Préparation of Compound 135

Compound 135 was prepared in the same way as Compound 132, starting from 6chloro-2-ethylimidazo[l,2-a]pyridine-3-carboxylic acid CAS [1216142-18-51 and intermediate DV. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 80 g, Grâce, dry loading (silica), mobile phase gradient: from DCM 100%, 10 MeOH 0% to DCM 95%, MeOH 5% to gîve 0.176 g of Compound 135 as a white solid (53%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.05 (s, I H), 8.38 (brt, J = 5.8 Hz, 1 H), 7.66 (d, J = 9.5 Hz, 1 H), 7.45 (dd, J = 9.5,1.9 Hz, I H), 7.18 (d, J « 8.2 Hz, 2 H), 6.62 (t, J = 76 Hz, 1 H), 6.38 (d, J = 8.5 Hz, 2 H), 4.54 (quin, J = 7.2 Hz, 1 H), 4.40 (d, J = 6.0

Hz, 2 H), 3.78 (s, 2 H), 3.74 (s, 2 H), 2.95 (q, J = 7.6 Hz, 2 H), 2.59 - 2.55 (m, 2 H),

2.30 - 2.26 (m, 2 H), 2.28, 1.24 (t, J = 7.4 Hz, 3 H)

Préparation of Compound 136

Compound 136 was prepared în the same way as Compound 135, starting from intermediate L and intermediate DV. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 80 g, Grâce, dry loading (silica), mobile phase gradient DCM/MeOH from 100/0 to 90/10) to give 0.127 g of Compound 136 as a white solid 25 (38%).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.38 (d, J = 2.5 Hz, I H), 8.67 (d, J = 2.5 Hz, 1

H), 8.48 (t, J = 5.8 Hz, 1 H), 7.18 (d, J = 8.6 Hz, 2 H), 6.62 (t, J = 76 Hz, 1 H), 6.37 (t, J = 8.4 Hz, 2 H), 4.54 (t, J = 7.1 Hz, 1 H), 4.40 (d, J = 6.1 Hz, 2 H), 3.78 (s, 2 H), 3.74 (s, 2 H), 2.99 (q, J = 7.4 Hz, 2 H), 2.59 - 2.54 (m, 2 H), 2.30 - 2.25 (m, 2 H), 1.26 (t, J = 30 7.6 Hz, 3 H)

-134-

Synthesis of Compound 137 '-Q-OC 'Ό_ο„,„

Pd(OAc)j, Xantphos. NaOtBu, dioxane. 100*0 ^kc-Q-OCⁿ-O-° CFjH

ΝΗ,/ΜεΟΗ Raney M, H, 3 bar

Intermediate G

CAS [5905-69-1)

Intermediate DW

Compound 137

Intermediate DX

Préparation of intermediate DW

Accordingly, intermediate DW was prepared in the same way as intermediate DQ starting from intermediate G and 4-bromodifluoromethoxybenzene CAS [5905-69-1], yielding 0.13 gas a white solid (30%).

Préparation of intermediate DX

Accordingly, intermediate DX was prepared in the same way as intermediate DR starting from intermediate DW yielding 0.264 g as a white solid (90%).

Préparation of Compound 137

Compound 137 was prepared in the same way as Compound 132, starting from 615 chloro-2-ethyiimidazo[l,2-a]pyridine-3-carboxylic acid CAS [1216142-18-5] and intermediate DX. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g, Grâce, dry loading (silica), mobile phase gradient DCM/MeOH from 100/0 to 90/10) to give 0.132 g of Compound 137 as a white solid (69%).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (d, J = 1.5 Hz, I H), 8.47 (t, J = 6.1 Hz, 1

H), 7.67 (d, J = 9.6 Hz, 1 H), 7.46 (dd, J = 9.6,2.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H),

7.22 (d, J = 8.0 Hz, 2 H), 6.98 (t, J = 76 Hz, 1 H), 6.98 (d, J = 7.9 Hz, 2 H), 6.43 (d, J = 7.9 Hz, 2 H), 4.50 (d, J = 5.6 Hz, 2 H), 3.92 (s, 2 H), 3.71 (s, 2 H), 3.46 - 3.36 (m, I H), 2.99 (q, J = 7.6 Hz, 2 H), 2.59 - 2.54 (m, 2 H), 2.30 - 2.25 (m, 2 H), 121 (t, J = 7.6 Hz, 3 H)

-135-

Synthesis of Compound 138 & Compound 139

NHj

-COOEt

KjCO,. DNF,

RT, 48 h

TMF/HjO/MeOH. NaOH, 70*C

CAS (6205-87-0) CAS [55314-57-3]

COOEt

CçL·

Intermedlale DY

	η,,τ-Ο-ΟΟ-Ο-0·
COOH Op·	intermediate t EDCl ΗΟΒΤ, EtjN, DCM. RT

intermediate DZ

Pd/C, H, 1 atm, EtOH, 60*C

Compound 139

Préparation of intermediate DY

Ethyl 2-pentynoate (18 mL, 135 mmol) was added to a solution of l-aminopyridinium iodîde (25 g, 113 mmol) and potassium carbonate (19 g, 135 mmol) in DMF (250 mL). The resulting mixture was stirred at room température for 48 h and evaporated to dryness. The residue was solubilized in EtOAc and washed with brine (3x). The organic layer was dried over MgSQi, filtered and evaporated to dryness to give 14.5 g 10 of a brown solid, which was triturated successively in EtzO, and MeCN and filtered to give 8.1 g of intermediate DY as an off-white solid. The filtrate was evaporated to dryness and purified by préparative LC (Regular SiOH 30 pm, 120 g lnterchim, dry loading (Celite®), mobile phase gradient Heptane/EtOAc from 100/0 to 70/30) to give additional 1.2 g of intermediate 73 as a white solid (global yield: 38%).

·

Préparation of intermediate DZ

Aqueous sodium hydroxide 8M (20 mL, 164 mmol) was added to a solution of intermediate DY (7 g, 32.1 mmol) in THF (39 mL) and methanol (39 mL). The resulting mixture was stirred at 70 °C ovemight. HCl (IM) was added to the mixture 20 until pH~7-8. The resulting precipitate was filtered and dried under high vacuum to give 5.3 g of intermediate DZ as an off-white solid (87%).

-136Préparation of Compound 138

To a solution of intermediate DY (0.1 g, 0.52 mmol)andtriethy!amine(0.188 mL, 1.36 mmol) in DCM (6 mL) were added EDCI (0.152 g, 0.78 mmol) and HOBt (0.108 g, 0.78 mmol). The resulting mixture was stirred at room température for 30 min before the addition of Intermediate I (0.202 g, 0.56 mmol), then stirred at room température for 4 h. The reaction mixture was washed with water (2x). The organic layer was dried over MgSCh, filtered and evaporated to dryness. The crude product was purified by préparative LCs (Regular SiOH 30 pm, 25 g Interchim, dry loading (Ceüte®), mobile phase: Heptane/AcOEt/MeOH 100:35:5; then spherical C18 25 pm, 40 g YMC-ODS10 25, liquid loading (MeOH/MeCN), mobile phase gradient: 0.2% aq. NHiHCOj/MeCN from 50:50 to 0:100 then 100% MeCN) to give a white solid, further triturated în Et 2 O to give 0.145 g of Compound 138 as a white solid (52%).

1H NMR (500 MHz, DMSO-d6) 5 ppm 8.68 (d, J = 6.9 Hz, 1 H), 8.18 (t, J = 6.0 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.40 - 7.36 (m, 1 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 7.9 Hz, 2 H), 7.14 (d, J = 8.5 Hz, 2 H), 6.95 (td, J = 6.9,1.3 Hz, 1 H), 6.45 (d, J = 7.8

Hz, 2 H), 4.45 (d, J = 6.0 Hz, 2 H), 3.96 (s, 2 H), 3.75 (s, 2 H), 3.45 - 3.35 (m, 1 H), 3.01 (q, J = 7.6 Hz, 2 H), 2.59 - 2.55 (m, 2 H), 2.31 - 2.25 (m, 2 H), 1.25 (t, J = 7.6 Hz, 3 H)

Préparation of Compound 139

Compound 138 (0.1 g, 0.187 mmol) was dissolved in éthanol (1.3 mL) and treated with Pd/C 10% ( 10 mg). The reaction was stirred under Hj at atmospheric pressure at 60 °C for 16 h. The reaction mixture was filtered over Celite® and rinsed with EtOAc. The solvent was removed under reduced pressure. 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 70/30 to 10/90) and to give 0.065 g of Compound 139 as white solid (65%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.69 (br t, J = 6.0 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 2 H), 729 (d, J = 8.5 Hz, 2 H), 7.10 (d, J = 8.2 Hz, 2 H), 6.38 (d, J = 8.2 Hz, 2 H), 4.26 (d, J = 5.7 Hz, 2 H), 3.96 (br t, J = 5.8 Hz, 2 H), 3.91 (s, 2 H), 3.69 (s, 2 H), 3.50 - 3.43 (m, 1 H), 2.84 (br t, J = 6.1 Hz, 2 H), 2.67 (q, J = 7.5 Hz, 2 H), 2.60 - 2.56 (m, 2 H), 2.31 - 2.27 (m, 2 H), 1.93-1.88 (m, 2 H), 1.76-1.72 (m, 2 H), 1.09 (t, J = 7.6 Hz, 3 H)

Synthesis of Compound 140, Compound 141 & Compound 142

KjCOj.DhF,

-S-COOEI ^RT ₁ ^4ah—».

COOEt THFMjOAfcOH.

£ N*0H,7Q*C

COOH

Hwnwdtat· EB

MannedlMEA

CAS [1180247-15-J]

DPEAHATU.DKF.RT

CAS [8295-87-0] CAS [4341-78-8]

IntermedUt* EC

HCl CPIÆ. MaOKrt

^bXl ν'OCF,

PdtOAc),, XmtphM. NaDtBu, do»», 100*C

Compound 140

Préparation of intermediate EA

Ethyi-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 mmoi) 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 solubilizcd in EtOAc and washed with brine (3x). The organic layer was dried over

MgSOj, filtered and evaporated to dryness to give 5.1 g of intermediate EA as a brown solid (55%).

Préparation of intermediate EB

Accordingly, intermediate EB was prepared in the same way as intermediate DZ starting from intermediate EA yielding 3.7 g as an off-white solid, 84%.

Préparation of intermediate EC

A solution of intermediate EB (0.2 g, 1.14 mmol), HATU (0.475 g, 1.25 mmol) and diîsopropylethylamine (0.47 mL, 3.41 mmol) in DMF (15 mL) was stirred at room 20 température for 30 min before the addition of tert-butyl 2-(amînomethyl)-7-azaspiro[3.5]nonane-7-carboxylate (CAS [1160247-15-3], 0.303g, 1.19 mmol) in DMF (5 mL). The resulting mixture was stirred at room température for 2 h. The mixture was evaporated to dryness and the residue wàs solubilized in EtOAc and washed with an aqueous solution of NaHCOj 1% (2x), water (2x) and brine (2x). The organic layer was 25 dried over MgSO-i, filtered and evaporated to dryness. The crude product was purified by preparative LCs (Regular SiOH 30 pm, 12 g Interchim, dry loading (Celite®), mobile phase gradient: from Heptane/EtOAc/MeOH 100:0:0 to 70:25:5; then spherical CI8 25 pm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient: 0.2%

-138-

aq. NH-iHCOj/MeOH from 50:50 to 10:90 then 0.2% aq. httLHCOj/MeOH 10:90) to give 0.318 g of intermediate EC as a colorless oi! (68%).

Préparation of intermediate ED

HCl 3M in CPME (0.77 mL, 2.31 mmol) was added to a solution of intermediate EC (0.318 g, 0.77 mmol) în methanol (6 mL) at 0 °C. The resulting mixture was allowed to warm to room température ovemight. Additional HCl 3M in CPME (0.51 mL,

1.54 mmol) was added at 0 °C and the mixture was allowed to warm to room température ovemight. The mixture was evaporated to dryness to give 0.306 g of intermediate ED as a white solid (quant.).

Préparation of Compound 140

A mixture of intermediate ED (0.26 g, 0.745 mmol), 4-bromotrifluoromethoxybenzene (0.166 mL, 1.12 mmol) and sodium t-butoxide (0.286 g, 2.98 mmol) in 1,4-dioxane (10 mL) was degassed by Nî bubbling for 10 min before the addition of palladium acetate (0.016 g, 75 pmol) and Xantphos (0.043 g, 75 pmol). The resulting mixture was stirred at 100 °C ovemight, then cooled to room température and filtered through a pad of Celite®. The cake was washed with EtOAc and the filtrate was evaporated to dryness. The residue was solubilized in EtOAc and washed with brine (2x). The organic layer was dried over MgSCh, filtered and concentrated to dryness. The crude product was purified by préparative LCs (ïrregular SiOH 15-40 pm, 10 g Biotage, liquid loading (DCM), mobile phase gradient; from Heptane/EtOAc/MeOH 80:17:3 to 60:35:5; then spherical C18 25 pm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient: 0.2% aq. NH-^HCOj/MeCN from 70:30 to 0:100 in 10 CV, then 5 CV at 0.2% aq. NHJICCh/MeCN 0:100) to give 0.062 g of Compound 140 as a white solid (18%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.64 (d, J = 6.6 Hz, 1 H), 7.84 (d, J = 8.8 Hz,

H), 7.60 (t, J = 5.7 Hz, 1 H), 7.37 (td, J = 7.9,1.0 Hz, 1 H), 7.15 (d, J = 8.8 Hz, 2 H), 7.00 - 6.93 (m, 3 H), 3.37 - 3.30 (m, 2 H), 3.17 - 3.12 (m, 2 H), 3.07 - 3.05 (m, 2 H),

2.58 - 2.50 (m, 1 H), 2.54 (s, 3 H), 1.93 - 1.88 (m, 2 H), 1.69 - 1.65 (m, 2 H), 1.63 -

1.54 (m,4H)

Préparation of Compound 141

-139Compound 141 was prepared in the same way as Compound 140, starting from intermediate EB and intermediate I. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g. Grâce, dry loading (silica), mobile phase gradient Heptane/EtOAc from 70/30 to 10/90) to give 0.056 g of Compound 141 as a white solid (43%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.65 (d, J = 6.9 Hz, 1 H), 8.08 (t, J = 6.0 Hz,

H), 7.91 (d, J = 9.1 Hz, 1 H), 7.40 - 7.37 (m, 1 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 7.9 Hz, 2 H), 7.14 (d, J = 8.5 Hz, 2 H), 6.97-6.95 (m, 1 H), 6.45 (d, J = 8.8 Hz, 2 H), 4.46 (d, J = 5.7 Hz, 2 H), 3.96 (s, 2 H), 3.75 (s, 2 H), 3.41 (quin, J = 8.8 Hz, ! H), 2.60 -

2.55 (m, 2 H), 2.57 (s, 3 H), 2.30 - 2.26 (m, 2 H)

Préparation of Compound 142

Compound 142 was prepared in the same way as Compound 140, starting from intermediate EB and intermediate Q. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g. Grâce, dry loading (silica), mobile phase gradient Heptane/EtOAc from 70/30 to 10/90) and yîelding 0.165 g of Compound 142 as a white solid (62%).

! H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (d, J = 6.6 Hz, ! H), 7.98 (t, J = 5.8 Hz,

H), 7.88 (d, J = 9.1 Hz, 1 H), 7.39 - 7.35 (m, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 8.0 Hz, 2 H), 6.97-6.93 (m, 1 H), 6.49 (d, J = 8.6 Hz, 2 H), 6.43 (d, J = 8.6 Hz, 2 H), 4.37 (d, J = 5.6 Hz, 2 H), 4.00 (s, 4 H), 3.95 (s, 4 H), 2.55 (s, 3 H)

Préparation of Compound 143

Compound 143 was prepared in the same way as Compound 140, starting from intermediate EB and intermediate CC. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g, Grâce, dry loading (silica), mobile phase gradient

-140Heptane/EtOAc from 70/30 to 10/90) to give 0.252 g of Compound 143 as a white solid (74%).

1H NMR (500 MHz, DMSO-d6) δ ppm 8.64 (d, J - 6.6 Hz, 1 H), 7.98 (br t, J = 5.8 Hz,

H), 7.87 (d, J = 8.8 Hz, 1 H), 7.39 - 7.35 (m, 1 H), 7.17 (d, J = 8.5 Hz, 2 H), 6.96-6.93 (m 1 H), 6.37 (d, J = 8.5 Hz, 2 H), 5.01 (dquin, J = 56,6.5 Hz, 1 H), 4.35 (d, J = 6.0 Hz,

H), 3.76 (s, 2H), 3.74 (s, 2 H), 2.61 - 2.58 (m, 2 H), 2.54 (s, 3 H), 2.39 - 2.30 (m, 2 H)

Synthesis of Compound 144 & Compound 145

COOH

QQ · „_1N^0-oc^,0^,cf‘

EDCL HOBT. EtjN, DCM. RT

CF,

QP

Compound 144

Intennedlate DZ

IrrtermatSateQ

PtVC, H, 3 bar, EtOH, RT

N Compound 145

Préparation of Compound 144

Compound 144 was prepared in the same way as Compound 138, starting from intermediate DZ and intermediate Q. The crude product was purified by préparative LC (irregular SÎOH, 15-40 gm, 40 g, Grâce, dry loading (silica), mobile phase gradient 15 Heptane/EtOAc from 70/30 to 10/90) to give 0.128 g of Compound 144 as a white solid (51%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (d, J = 7.1 Hz, 1 H), 8.06 (t, J = 5.8 Hz,

H), 7.84 (d, J = 9.1 Hz, 1 H), 7.38 - 7.34 (m, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 6.95-6.92 (m, 1 H), 6.49 (d, J = 9.1 Hz, 2 H), 6.43 (d, J = 8.1 Hz, 2 H),

4.37 (d, J = 6.1 Hz, 2 H), 4.00 (s, 4 H), 3.95 (s, 4 H), 2.99 (q, J = 7.6 Hz, 2 H), 1.24 (t, J = 7.6 Hz, 3 H)

Préparation of Compound 145

Compound 144 (0.32 g, 0.56 mmol) was dissolved in éthanol (5 mL) and treated with

Pd/C 10% (0.064 g, 0.060 mmol). The reaction mixture was stirred under 3 bar of Hî at room température for 3 days, then filtered over a pad of Celite® and evaporated to dryness. The crude product was purified by préparative LCs (irregular SiOH, 15-40 gm, 24 g, Grâce, liquid loading (DCM), mobile phase gradient Heptane/(EtOAc /MeOH) (9:1) from 90/0 to 20/80; then spherical Cl8, 25 gm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient: from 50% (aq. NHiHCOj 0.2%), 50% MeCN

-141to 100% MeCN then MeCN 100%) to give 0.184 g of Compound 145 as a white solid (56%).

1H NMR (500 MHz, DMSO-d6) δ ppm 7.69 (t, J = 5.8 Hz, 1 H), 7.16 (d, J = 8.2 Hz, 2 H), 7.12 (d, J = 8.2 Hz, 2 H), 6.49 (d, J = 8.8 Hz, 2 H), 6.41 (d, J = 8.5 Hz, 2 H), 4.27 (d, J = 5.7 Hz, 2 H), 4.0 (s, 4 H), 3.99 - 3.94 (m, 2 H), 3.94 (s, 4 H), 2.85 (t, J = 6.3

Hz, 2 H), 2.67 (q, J = 7.6 Hz, 2 H), 1.94 - 1.88 (m, 2 H), 1.77 - 1.72 (m, 2 H), 1.09 (t, J = 7.4 Hz, 3 H)

Synthesis of Compound 146 & Compound 147

LWhDS.CjCI,, THF.-WC loRT

Msrtnedat· D V

COOEt

Hannedal· EE

NaOH 7trc.

ΤΗΓΜ,ΟΜβΟΗ

COOH COOH * Mp^

Hamwdat· EF HermadUt» EG .,'ΟοοΌ'·

Hamadat· I

EDCl HOBT, Et,N, DCM. RT

Préparation of intermediate EE

LiHMDS 1.5 M (2.64 mL, 3.96 mmol) was added dropwise to a stirred solution of intermediate DY (0.721 g, 3.30 mmol) in THF (10 mL) at -70 °C under Nî. The reaction was stirred at -70 °C for 2 h, then hexachloroethane (0.938 g, 3.96 mmol) in THF (2 mL) was added dropwise. The reaction was allowed to stir at room temperature for 4 h and quenched with water and saturated aqueous NH4CI. The aqueous phase was extracted with EtOAc. The organic phase was dried over MgSO4, filtered and evaporated to dryness to give 0.913 g of intermediate EE (quant.), used as such în the next step.

Préparation of intermediate EF/EG

Sodium hydroxide 8M (2.05 mL, 16.4 mmol) was added to a solution of intermediate 25 EE (813 mg, 3.22 mmol) in THF (3.9 mL) and MeOH (3.9 mL), the resulting mixture was stirred at 70 °C ovemight. HCl (1 M) was added to the mixture until pH 1. The resulting precipitate was filtered and dried under high vacuum at 50 °C to give 0.612 g of a mixture of intermediate EF and EG, used as such în the next step.

Cotnpoixid 149

Compoxid t47

-142Préparation of Compound 146 & Compound 147

Compounds 146 and 147 were prepared in the same way as Compound 138, starting from mixture of intermediate EF/EG and intermediate 1. The crude products were purified by préparative LC (irregular SiOH, 15-40 pm, 24 g, Grâce, dry loading (silica), 5 mobile phase gradient Heptane/EtOAc from 70/30 to 10/90) to give 0.128 g (61%) of

Compound 146 and 0.037 g (17%) of Compound 147, both as white solids.

Compound 146

IH NMR (400 MHz, DMSO-d6) δ ppm 8.36 (t, J = 5.8 Hz, 1 H), 7.87 (d, J = 8.6 Hz, I

H), 7.42 - 7.38 (m, 1 H), 7.31 - 7.26 (m, 3 H), 7.21 (d, J = 8.1 Hz, 2 H), 7.14 (d, J = 8.6 10 Hz, 2 H), 6.45 (d, J = 9.1 Hz, 2 H), 4.46 (d, J = 5.6 Hz, 2 H), 3.96 (s, 2 H), 3.75 (s, 2

H), 3.43 - 3.38 (m, I H), 3.04 (q, J = 7.6 Hz, 2 H), 2.60 - 2.54 (m, 2 H), 2.31 - 2.25 (m, 2 H), 126 (t, J = 7.3 Hz, 3 H)

Compound 147

IH NMR (400 MHz, DMSO-d6) δ ppm 8.14 (t, J = 6.1 Hz, I H), 7.47 (d, J = 8.4 Hz, 1

H), 7.40 - 7.36 (m, I H), 7.29 (d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.14 (d, J =

8.1 Hz, 2 H), 6.46 - 6.44 (m, 3 H), 4.44 (d, J = 5.6 Hz, 2 H), 4.09 (s, 3 H), 3.96 (s, 2 H), 3.75 (s, 2 H), 3.46 - 3.38 (m, I H), 3.00 (q, J = 7.4 Hz, 2 H), 2.60 - 2.54 (m, 2 H), 2.31 2.25 (m, 2 H), 1.23 (t, J = 7.6 Hz, 3 H)

Synthesis of Compound 148

CAS [1181816-12-5]

DAST. DCM (TCtoRT

intermediate EH

TMSCI, KteOH, RT «KXX .HCl intermediate El

NC-^^-F

W.DM50. /=\ aa^F

UW 120*C, 11 ^NC intermediate EJ

ΝΗ,/MeOH Raney Ni, H,5bar

Intermediate EK

O

EtjN, HATU, DIVF

Cl

Compound 148

-143Préparation of întermediate EH

To a solution of tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (CAS [1181816-12-5], 1 g, 4.73 mmol) în dry DCM (50 mL) at 0 °C was added DAST (1.86 mL, 14.2 mmol), then the mixture was warmed to room température and stirred 5 for 16 h. Additional DAST (0.62 mL, I eq., 4.73 mmol) was added, then the mixture was stirred at room température for 3 h. The mixture was quenched with sat. NaHCOj, then stirred for 10 min. The layers were separated and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over MgSOj, filtered off and evaporated to dryness to give 1.02 g of intermediate EH as a yellow solid (76%).

Préparation of intermediate El

Accordingly, intermediate 83 was prepared in the same way as întermediate DJ starting from intermediate EH yielding 0.764 g as a beige solid

Préparation of intermediate EJ

Accordingly, intermediate EJ was prepared in the same way as intermediate DK and 4-fluorobenzonïtrile starting from intermediate El yielding 0.608 g as a white solid, 74%

Préparation of intermediate EK

Accordingly, intermediate EK was prepared în the same way as intermediate DL starting from intermediate EJ yielding 0.559 g as a blue solid, 74%

Préparation of Compound 148

Compound 148 was prepared în the same way as Compound 117 (using triethylamine instead of DIPEA), starting from intermediate L and intermediate EK. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g. Grâce, dry loading (Ceüte®), mobile phase gradient Heptane/(EtOAc /MeOH) (9:1) from 85/15 to 40/60) to give 0.285 g of Compound 148 as a white solid (70%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.38 (d, J = 2.5 Hz, 1 H), 8.67 (d, J = 2.5 Hz, I

H), 8.50 (t, J = 5.8 Hz, 1 H), 7.19 (d, J = 8.2 Hz, 2 H), 6.42 (d, J = 8.2 Hz, 2 H), 4.41 (d, J = 5.7 Hz, 2 H), 3.85 (s, 4 H), 2.99 (q, J = 7.5 Hz, 2 H), 2.84 (t, J = 12.6 Hz, 4 H). 1.26 (t, J = 7.6 Hz, 3 H)

144

Synthesis of Compound 149

F

N

Br ·

ÎPrfctjCI uci,

CAS [38383-49-2], CoCI,. THF.

0*C to RT

F

N

Intermediate EL

TMSCI.

CAS [105942-08-3]

Intermediate R

Intennediata EM

Xl >^OCF|

PcKOAc),. Xantphoe,

NeOtBu. dioxane, 10CTC

OCF,

NH^MaOH RaneyN, H, S bar „,_nAxx>O—

Intermediate EN

Intermediate E0 °-.0H

LN, EDCl HO B T, DCM

Et,N, EDCl,

Compound 149

Préparation of intermediate EL iPrMgCl.LÎCl 1.3 M (7.14 mL, 9.28 mmol) was added to a solution of 2-fluoro4-bromobenzonitrîle in anhydrous THF (25 mL) at 0 °C under Nz. The resulting solution was stirred at 0 °C for 4h under a stream of N2, before being cannulated (ca. 30 min) to a solution of intermediate R andNl,Nl,N2,N2-tetramethylcyclohexane-l,

2-diamine (CAS [38383-49-2], 0.063 g, 0.37 mmol) and CoCh (0.04 g, 0.31 mmol) în 10 anhydrous THF (25 mL) under Nî, at 0 °C. The resulting mixture was stirred at room température for 18h, then quenched with water. EtOAc was added, the aqueous layer was separated and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO4, filtered off and evaporated to dryness. The crude mixture was purified by préparative LCs (regular SÎOH, 30 pm, 80 g, Interchim, dry 15 loading (Celite®), mobile phase gradient Heptane/EtOAc from 95/5 to 60/40; then spherical Cl8,25 pm, 120 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient: from 20% (aq. NH4HCO3 0.2%), 80% MeCN to 100% MeCN) to give 0.933-g of intermediate EL as a white solid, 95%.

Préparation of intermediate EM

Accordingly, intermediate EM was prepared in the same way as intermediate DJ starting from intermediate EL yielding 0.608 g as a white solid, 74%

Préparation of intermediate EN

Accordingly, intermediate EN was prepared in the same way as intermediate DW starting from intermediate EM and 4-bromotrifluoromethoxybenzene, yielding 0.478 g as a white solid, 44%.

Préparation of intermediate EQ

Accordingly, intermediate EO was prepared in the same way as intermediate DL starting from intermediate EN yielding 0.18 g as a blue solid, 89%

Préparation of Compound 149

Compound 149 was prepared in the same way as Compound 131, starting from 6-chloro-2-ethylimidazo[l,2-a]pyridîne-3-carboxylic acid CAS [1216142-18-5], and intermediate EO. The crude product was purified by préparative LCs (irregular SiOH, 15—40 pm, 24 g. Grâce, dry loading (Celite®), mobile phase gradient Heptane/(EtOAc /MeOH) (9:1) from 95/5 to 50/50; then spherical Cl8,25 pm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient: from 50% (aq. NH4HCO3 0.2%), 50% MeCN to 100% MeCN then 100% MeCN) to give 0.148 g of Compound 149 as a white solid (41%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.06 (d, J = 1.6 Hz, 1 H), 8.46 (t, J = 5.7 Hz,

1 H), 7.67 (d, J = 9.5 Hz, 1 H), 7.46 (dd, J = 9.5,2.2 Hz, 1 H), 7.36 (t, J = 7.9 Hz, 1 H),

7.15 - 7.06 (m, 4 H), 6.45 (d, J = 7.8 Hz, 2 H), 4.54 (br d, J = 5.7 Hz, 2 H), 3.96 (s.

H), 3.75 (s, 2 H), 3.44 (quin, J = 8.8 Hz, I H), 2.98 (q, J = 7.6 Hz, 2 H), 2.59 - 2.55 (m, 2 H), 2.32 - 2.28 (m, 2 H), 1.26 (t, J = 7.6 Hz, 3 H)

-146Synthesis of Compound 150

PrM)CI UCI, Fe(acac),, TNEDA. THF. 0*C to RT ^c-O^X-(v tmsci, _/

MKMRL NC-θ—(X>H

CAS [133059-44-«] htermedrteR

Intermedlote EP

Irtermedlite EQ ‘'O.

^^OCFj

Pd(OAc),. Xantpho*.

NuOiflu, dioxana. 100*0

NH/bteOH RaneyNi, CF, M¹»·· _ lnterme<S»teER „,»K^oc^N-O-°^c'ⁱ

Intermediite ES

ΕΙ,Ν, EDCt, HOBT. DCM

Compound 150

Préparation of intermediate EP iPrMgCl.LiCl 1.3 M (10.5 mL, 13.7 mmol) was added to a solution of4-bromo-

3-fluorobenzonitrile (1.39 g, 6.96 mmol) in anhydrous THF (8 mL) at 0 °C under N2. The resulting solution was stirred at 0 °C for 4 h under a stream of N2. This solution was added dropwise over lh to a solution of intermediate R (0.75 g, 2.32 mmol), Fe(acac)j (0.082 g, 0.23 mmol) and TMEDA (0.84 mL, 5.57 mmol) in anhydrous THF 10 (15 mL) under N2, at 0 °C. The resulting mixture was stirred at room température for

18h, then quenched with NHiCl. EtOAc and water were added, the aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude mixture was purified by préparative LC (irregular SiOH, 15-40 pm, 50 g, Merck, dry loading (Celite®), mobile phase gradient Heptane/EtOAc from 100/0 to 65/35) to give 0.391 g of intermediate EP as a yellow solid (53%).

Préparation of intermediate EQ

Accordingly, intermediate EQ was prepared in the same way as intermediate EM starting from intermediate EP yielding 0.325 g as a green gum, quant.

Préparation of intermediate ER

Accordingly, intermediate ER was prepared in the same way as intermediate EN starting from intermediate EQand 4-bromotrifluoromethoxybenzene, yielding 0.385 g as a white solid, 81%.

Préparation of intermediate ES

Accordingly, intermediate ES was prepared in the same way as intermediate EO starting from intermediate ER yielding 0.229 g as a grey solid, 59%

Préparation of Compound 150

Compound 150 was prepared in the same way as Compound 149, starting from 6chloro-2-ethylimidazo[l,2-a]pyridine-3-carboxylic acîd CAS [1216142-18-5] and intermediate ES. The crude product was purified by préparative LC (irregular SiOH, 15-40 gm, 24 g, Grâce, dry loading (Celite®), mobile phase gradient Heptane/(EtOAc /MeOH) (9:1) from 95/5 to 50/50) to give 0.289 g of Compound 150 as a white solid (84%).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (s, 1 H), 8.48 (t, J = 5.8 Hz, 1 H), 7.67 (d, J = 9.6 Hz, 1 H), 7.46 (dd, J = 9.6,2.0 Hz, 1 H), 7.33 (t, J = 7.9 Hz, 1 H), 7.19 - 7.11 (m, 4 H), 6.45 (d, J = 8.6 Hz, 2 H), 4.51 (br d, J = 5.6 Hz, 2 H), 3.98 (s, 2 H), 3.75 (s,

2 H), 3.57 (quin, J = 8.8 Hz, l H), 3.00 (q, J = 7.4 Hz, 2 H), 2.61 - 2.56 (m, 2 H), 2.37 2.31 (m, 2 H), 1.27 (t, J = 7.6 Hz, 3 H)

Synthesis of Compound 151

Pd(OAc),. Xantpbos.

<=-000 · XV^F· no-Q-OCn-O-⁸·

UAIH,, Εί,Ο, reflux

Intermediate G

CAS [333-47-1]

Intermediate ET

O ny ,„.-0-000- ‘tïp ^α

Intermediate EU HATU. _{DPEA DM}r

Préparation of intermediate ET

Accordingly, intermediate ET was prepared in the same way as intermediate DQ starting from intermediate G and l-Bromo-4-(Trifluoromethylthio)Benzene CAS [333-47-1] yielding 0.37 g as a reddish solid. 60%.

Préparation of intermediate EU

Intermediate ET (0.32 g, 0.855 mmol) was added portionwise to a suspension of

LÎA1H4 (0.04 g, 1.05 mmol) in dry EtiO (8 mL) at 0 °C under N2. The mixture was warmed to room température then refluxed for 3 h, and evaporated to dryness. The residue was taken-up in MeOH and filtered over a pad of Celite®. The cake was

-148washed with MeOH and the filtrate was evaporated to dryness to give 0.328 g of intermediate EU as a pale yellow solid (quant.).

Préparation of Compound 151

Compound 151 was prepared in the same way as Compound 150, starting from 6chloro-2-ethylimidazo[l,2-a]pyridine-3-carboxylic acid CAS [1216142-18-5] and intermediate EU. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 30 g, Merck, dry loading (Celite®), mobile phase gradient Heptane/EtOAc from 90/10to 10/90)to give 0.189 g ofCompound 151 as awhite solid (41%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.08 (s, 1 H), 8.47 (t, J = 5.7 Hz, 1 H), 7.67 (d,

J = 9.5 Hz, I H), 7.49 - 7.41 (m, 3 H), 7.32 (d, J = 7.9 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 6.48 (d, J = 8.5 Hz, 2 H), 4.50 (br d, J = 5.7 Hz, 2 H), 4.05 (s, 2 H), 3.83 (s, 2 H), 3.32 (quin, J = 8.8 Hz, 1 H), 2.99 (q, J = 7.6 Hz, 2 H), 2.66 - 2.62 (m, 2 H), 2.33 - 2.27 (m, 2 H), 1.27 (t, J = 7.6 Hz, 3 H)

Svnthesis of Compound 152

	•“CL ·	DIAD.PPn,. Q V/ TMSCl PliMa, tTCloRT , MaOH.RT ) 0	• hnOO-°	Ύι P<KOAe]r Xantphoa. NaOfflu, dtoxana. 10CC
CAS [1147557-07-8]	CAS [371-41-5]	f HarmadalaEV	Ιπ1μγπ·Λ·Ι· EW

ι*φι*0Η RarwyM. H, 7 bar

%OH °

EDCLHOBT.EtjN,

Compound 152 DCM50-C

Préparation of intermediate EV

A solution of DIAD (0.74 mL, 3.75 mmol) in toluene (5 mL) was added to a solution of 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (CAS [1147557-97-8], 0.8 g, 3.75 mmol),

4-fluorophenol (0.421 g, 3.75 mmol) and triphenylphosphine (1.48 g, 5.63 mmol) in toluene (35 mL) at 0 °C under N2. The reaction mixture was then allowed to warm up to room température slowly ovemight. Additional 4-fluorophenol (0.21 g, 1.88 mmol) was added and the reaction was stirred further at room température for 3d. The reaction mixture was evaporated to dryness, then dissolved in a minimum of diethyl ether and cooled to 0 °C. A large excess of heptane was added and the resulting mixture was evaporated under vacuum which induced the précipitation of PPhjO, which was filtered off and washed with diethyl ether. The filtrate was evaporated to dryness and purified by préparative LC (irregular SiOH, 15-40 pm, 40 g, Grâce, dry loading (silica), mobile

phase gradient: Heptane/EtOAc from 90/10 to 50/50) to give 1.07 g of intermediate EV as a yellow solid (not obtained pure but engaged as such in the next step).

Préparation of intermediate EW

A solution of intermediate EV (0.945 g, 3.08 mmol) and chlorotrimethylsilane (1.95 mL, I5.4mmol) inanhydrousmethanol(31 ml) was stirred under N₂ ovemight. The reaction mixture was then evaporated to dryness and the residue triturated in Et₂O, filtered and dried to give 0.543 g of intermediate EW as beige solid (85%).

Préparation of intermediate EX

A mixture of intermediate EW (0.393g, 1.90 mmol), 4-bromobenzonitrile (0.518 g, 2.84 mmol) and sodium t-butoxîde (0.729 g, 7.59 mmol) in 1,4-dioxane (20 mL) was degassed under N₂. Then, palladium acetate (0.043 g, 0.190 mmol) and Xantphos (0.11 g, 0.190 mmol) were added, the mixture was purged again with N₂ and heated to 15 120 °C ovemight. The mixture was cooled to room température and filtered over a pad of Celite®. The cake was washed with EtOAc and the filtrate was 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 50/50) to give 0.24 g of intermediate EX as yellow solid (41%).

Préparation of intermediate EY

Accordingly, intermediate EY was prepared in the same way as intermediate ES starting from intermediate EX yîelding 0.304 g as a white solid, 97%

Préparation of Compound 152

Compound 152 was prepared in the same way as Compound 131 (heating 50 °C), starting from intermediate L and intermediate EY. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g Grâce, dry loading (silica), mobile phase gradient Heptane/EtOAc from 90/10 to 10/90) to give 0.157 g of Compound 152 30 as a yellow solid (67%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.38 (d, J = 2.5 Hz, 1 H), 8.67 (d, J = 2.8 Hz, 1 H), 8.49 (t, J = 5.8 Hz, 1 H), 7.19 (d, J = 8.2 Hz, 2 H), 7.10 (t, J = 8.8 Hz, 2 H), 6.86 (dd, J = 9.1,4.4 Hz, 2 H), 6.39 (d, J = 8.2 Hz, 2 H), 4.63 (quin, J = 6.9 Hz, 1 H), 4.40 (d, J = 6.0 Hz, 2 H), 3.84 (s, 2 H), 3.76 (s, 2 H), 2.99 (q, J = 7.5 Hz, 2 H), 2.75-2.72 (m, 35 2 H), 2.26-2.22 (m, 2 H), 1.26 (t, J = 7.6 Hz, 3 H)

-150Synthesis of Compound 153

CAS (1147557-97-8]

TMSCF,. KF, SelectFluor.AgOTf, i-fluoropyrtdira

Intermediate EZ

HClklCPIÆ KteOH, RT

Intermediate FA ^FO-_ra

KjCO,.

DMSO, 120*C

N

Intermediate FB

WÇMeOH

Raney M, 5 H, 3 bar

Intarmetlate FC

EPCI HOBT, Et, N. DCM, RT

Préparation of intermediate EZ

Silver triflate (4.79 g, 18.6 mmol), Selectfluor (3.30 g, 9.32 mmol), potassium fluoride (1.44 g, 24.9 mmol) and tert-Butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (CAS [240401-28-9], 1.50 g, 6.22 mmol) were dissolved in ethyl acetate (33 mL). 2-fluoropyridine (1.60 mL) and trifluoromethyltrimethylsilane 2M (9.32 mL, 18.6 mmol) were added under Nî and the resulting mixture was stirred at room température for 40 h. The reaction mixture was then filtered over Celite® and evaporated to dryness. The crude mixture was purified by préparative LC (irregular SiOH, 15-40 pm, 120 g, Grâce, dry loading (Silica), mobile phase gradient: from Heptane/EtOAc from 90/10 to 80/20) to give 0.855 g of intermediate EZ as white solid (44%).

Préparation of intermediate FA

Intermediate EZ (0.853 g, 2.76 mmol) was dissolved in methanol (21 mL) and treated with HCl 3M in CPME (4.6 mL, 13.8 mmol) at 0 °C. The reaction was then stirred at room température ovemight. The solvent was removed under reduced pressure to give 20 0.674 g of intermediate FA as white solid (99%).

Préparation of intermediate FB

A suspension of intermediate FA (0.67 g, 3.21 mmol), 4-fluorobenzonitrile (0.79 g, 6.45 mmol) and potassium carbonate (3.53 g, 25.5 mmol) in DMSO (32 mL) was heated at 120 °C ovemight. The reaction was quenched with water and extracted with EtOAc (3x). The combined organic phases were washed with water (3x) and brine (2x), dried over MgSOj, filtered and evaporated to dryness. The crude product was purified by préparative LC (irregular SiOH 15-40 pm, 40 g Grâce, dry loading (silica), mobile

phase gradient Heptane/EtOAc from 90/10 to 70/30) to give 0.747 g of intermediate FB as white solid (70%).

Préparation of intermediate FC

Accordingly, intermediate FC was prepared in the same way as intermediate ES starting from intermediate FB yieiding 0.241 g as a white solid, 95%

Préparation of Compound 153

Compound 153 was prepared in the same way as Compound 152, starting from intermediate L and intermediate 103. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g, Grâce, dry loading (silica), mobile phase gradient Heptane/EtOAc from 90/10 to 10/90) to give 0.222 g of Compound 153 as a yellow solid (59%).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.39 (d, J = 2.8 Hz, 1 H), 8.67 (d, J = 2.5 Hz,

1 H), 8.50 (t, J = 5.8 Hz, 1 H), 7.21 (d, J = 8.5 Hz, 2 H), 6.90 (d, J = 8.5 Hz, 2 H), 4.89 (quin, J = 7.2 Hz, 1 H), 4.42 (d, J = 5.7 Hz, 2 H), 3.09 - 3.07 (m, 2 H), 3.04 - 3.02 (m, 2 H), 3.00 (q, J = 7.5 Hz, 2 H), 2.36 - 2.32 (m, 2 H), 1.98 - 1.94 (m, 2 H), 1.66 - 1.64 (m, 4 H), 1.27 (t, J = 7.4 Hz, 3 H)

Synthesis of Compound 154

NH/*OH R*wyM, H, 3Mr

HermedMeFE

Hermedtat· FO

EDCI. HOBT, Et,M DCM, RT

TMSCI MOH.RT « W-O-OO

Cip ~

MannedMf FF

TT,Ο, ΕΙ,Ν. DWP.DCMtrç

Compouid 134

Préparation of intermediate FD

Accordingly, intermediate FD was prepared in the same way as intermediate ES 25 starting from intermediate F yieiding 1.29 g as a white solid, 81%

Préparation of intermediate FE

To a solution of 6-chloro-2-ethy!imidazo[l,2-a]pyridine-3-carboxylic acid (CAS [1216142-18-5], 0.117 g, 0.504 mmol) in DCM (5.1 mL) and triethylamine (0.18 mL) were added EDCI (145 mg, 0.756 mmol) and HOBt (103 mg, 0.760 mmol) and the

mixture was stirred at room température for 30 min. Intermediate FD (0.162 g, 0.536 mmol) was added and the mixture was stirred at room température for 4 h. The mixture was washed with water (2x). The organic layer was dried over MgSOj, filtered and evaporated to dryness to give 0.293 g of intermediate FE as colourless oil (quant.), 5 used as such in the next step.

Préparation of intermediate FF

To a solution of intermediate FE (0.291 g, 0.572 mmol) in methanol (5.9 mL) was added trimethylchlorosilane (0.37 mL, 2.94 mmol) and the mixture was stirred at room température for 16 h. The mixture was evaporated to dryness to give 0.304 g of intermediate FF as a pale yellow foam (quant.).

Préparation of Compound 154

Trifluoromethanesulfonic anhydride (0.12 mL, 0.696 mmol) was added to a solution of intermediate FF (155 mg, 0.348 mmol) and DMAP (2.13 mg, 17.4 pmol) in triethylamine (0.39 mL, 2.78 mmol) and DCM (5.3 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 6 h. Water was added and the organic layer was washed with water, dried over MgSQ», filtered and evaporated to dryness. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g. Grâce, dry loading (silica), 20 mobile phase gradient Heptane/EtOAc from 90/10 to 10/90) to obtain 186 mg of a pale yellow solid, which was triturated în heptane and purified by préparative LC (spherical C18 25 pm, 40 g YMC-ODS-25, dry loading (Celite®), mobile phase gradient: 0.2% aq. NHiHCOj/MeCN from 90/10 to 0/100) to give 0.112 g of Compound 154 as a white solid (59%).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (s, 1 H), 8.47 (br s, 1 H), 7.67 (d, J =

8.1 Hz, 1 H), 7.46 (br d, J = 9.1 Hz, 1 H), 730 (br d, J = 8.1 Hz, 2 H), 720 (br d, J = 7.6 Hz, 2 H), 4.49 (br d, J = 5.1 Hz, 2 H), 4.41 (s, 2 H), 4.18 (s, 2 H), 3.39-3.31 (m, 1 H), 2.98 (q, J = 7.4 Hz, 2 H), 2.63 - 2.58 (m, 2 H), 2.34-2.29 (m, 2 H), 126 (br t, J =

7.3 Hz, 3 H)

-153Synthesis of Compound 155 & Compound 156

NHytfeOH Raney M, H, 5 bar intecmedata FG

Η,Ν^Ο-ΟΟ'*

EDCL HOBT, Et, N, DCM RT

CAS 11263182-09-7]

Pd/C, H, S bar,

MeOH RT

Intermedate FH

Préparation of intermediate FG

Accordingly, intermediate FG was prepared in the same way as intermediate DK starting from 2-Thia-6-azaspiro[3.3]heptane 2,2-dioxide CAS [1263182-09-7] and 4-fluorobenzonitrile, yielding 0.206 g as a white solid, 51%

Préparation of intermediate FH

Accordingly, intermediate FH was prepared in the same way as intermediate ES starting from intermediate FG yielding 0.208 g as a white solid, 93%

Préparation of Compound 155

Compound 155 was prepared in the same way as Compound 153, starting from

6-chloro-2-ethylimîdazo[l,2-a]pyridine-3-carboxylic acid CAS [1216142-18-5] and intermediate FH. The crude product was purified by préparative LC (îrregular SiOH, 15-40 pm, 24 g, Grâce, dry loading (silica), mobile phase gradient Heptane/EtOAc from 90/10 to 10/90) and yielding 0.252 g of Compound 155 as a white solid (69%). IHNMR(400 MHz, DMSO-d6) δppm 9.05 (s, 1 H), 8.40(brs, I H), 7.66(d, J = 8.6

Hz, .1 H), 7.45 (d, J = 9.6 Hz, 1 H), 7.21 (d, J = 7.1 Hz, 2 H), 6.46 (d, J = 8.1 Hz, 1 H), 4.47 (d, J = 1.5 Hz, 4 H), 4.41 (br s, 2 H), 3.99 (s, 4 H), 2.96 (q, J = 7.4 Hz, 2 H), 1.25 (t, J = 7.4 Hz, 3 H)

Préparation of Compound 156

A solution of Compound 155 (0.117 g, 255 pmol) in methanol (5.6 mL) was degassed by Nî bubbling for 5 min before the addition of Pd/C 10% (8.99 mg, 8.44 pmol). The resulting mixture was stirred at room température under 5 bar of Hî ovemight. The mixture was filtered through a pad of Celite®, rinsed with EtOAc and evaporated to dryness. The crude product was purified by préparative LC (Regular SiOH 15-40 pm,

-15424 g Grâce, dry loading (stltca), mobile phase gradient Heptane/EtOAc from 70Z30 to 0/100 then MeOH 100%) to give 0.095 g of Compound 156 as white solid (69%).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.10 (br t, J = 5.6 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 2 H), 6.44 (d, J = 8.1 Hz, 2 H), 4.46 (s, 4 H), 4.29 (br d, J = 6.1 Hz, 2 H), 3.98 (s, 4 H), 3.97 - 3.94 (m, 2 H), 2.71 - 2.68 (m, 2 H), 2.58 (q, J = 7.4 Hz, 2 H), 1.83-1.78 (m, 4 H), 1.08 (t, J = 7.6 Hz, 3 H)

Synthesis of Compound 157

CAS [21717-95-3]

PhKOAc),.

BFj.OEtj.

MbTHF, 5*C to

COOE1

ΕΙΟΗΉ,Ο NaOH. RT

COOH

9P intennediate Fl

Intermediate FJ

intennediate I

EDCL HO8T. Et,N, DCM RT

CFj

Compound 157

Préparation of intermediate FI

A solution of 2-amino-3-fluoropyridine (CAS [21717-95-3], 0.2 g, 1.78 mmo) in MeTHF (9 mL) was cooled down to 5 °C. Ethyl 3-oxovalerateethyl 3-oxovalerate (0.50 mL, 3.53 mmol), iodobenzene diacetate (0.578 g, 1.79 mmol) and boron trifluoride etherate (0.024 mL, 0.089 mmol) were added successively. The solution was stirred at the 5 °C for 2 h and then warmed to room température ovemight. EtOAc and saturated aqueous NaHCOj were added. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO-i, filtered and evaporated to dryness. The crude mixture was purified by préparative LC (irregular SiOH, 15-40 pm, 120 g, Grâce, liquid loading (DCM), mobile phase gradient Heptane/EtOAc from 90/10 to 70/30) to give 0.274 g of intennediate FI as white solid (65%).

Préparation of intennediate FJ

To a solution of intennediate FI (0.172 g, 0.73 mmol) În water (2.4 mL) and éthanol (2.4 mL) was added sodium hydroxide (0.088 g, 2.19 mmol) and the mixture was stirred at room température ovemight. The mixture was acidified to pH 3 with HCl

(3N). EtOH was evaporated and the residue was basified with KOH solution. The resulting white precipitate was collected by filtration and acidified with HCl (IM) to pH I and the white solid was filtered and dried to give 0.119 g of intermediate FJ as a white solid (79%).

Préparation of Compound 157

Compound 157 was prepared in the same way as Compound 131, starting from intermediate FJ and intermediate I. The crude product was purified by préparative LC (irregular SiOH, 15-40 pm, 40 g, Grâce, dry loading (silica), mobile phase gradient 10 Heptane/EtOAc from 90/10 to 10/90) to give 0.091 g of JNJ-65053092-AAA as a white solid (42%).

IH NMR (500 MHz, DMSO-d6) δ ppm 8.76 (d, J « 6.9 Hz, 1 H), 8.56 (br t, J = 5.7 Hz,

H), 7.32 - 7.27 (m, 3 H). 7.22 (d, J = 8.2 Hz, 2 H), 7.14 (d, J = 8.5 Hz, 2 H), 7.00 6.96 (m, 1 H), 6.45 (d, J = 9.1 Hz, 2 H), 4.50 (d, J = 6.0 Hz, 2 H), 3.96 (s, 2 H), 3.75 (s,

2 H), 3.45-3.38 (m, I H), 2.99 (q, J = 7.6 Hz, 2 H), 2.60 - 2.55 (m, 2 H), 2.30 - 2.26 (m,

H), 1.27 (t, J = 7.6 Hz, 3 H)

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

Compound 158

Compound 159

-156Compound 160

Compound 162

Compound 163

Compound 164

Compound 165

Compound 166

Compound 167

Compound 168

Characterising Data Table

Compound No	Melting Point (Kotler or DSC)	LCMS
Rt	uv Area %	MW eia et	BPM1/ BPM2	LCMS Method
l		3.21	97.9	506.2	507.1	Method A
17		3.18	983	4272	428.1	Method A
2		4.40	96.9	568.2	569.1	Method A
3		4.88	993	569.2	570.1	MethodA
23		339	94.2	450.2	4512	Method A
22		3.72	99.6	484.2	485.1	MethodA
5		4.45	993	570.2	571.1	MethodA
9		4.08	97.0	485.2	486.1	MethodA
7		3.96	100.0	568.2	569.1	MethodA
15		4.41	100.0	520.2	5212	MethodB
4		4.10	98.1	569.2	570.1	MethodA
12	25°C to 300°C/10°Cmin/40p 1A1	333	98.7	394.2	395.4/ 393.1	MethodC
25		3.69	95.0	620.2	621.2	MethodA
6		3.64	99.4	5393	5402	MethodA
8		4.49	97.7	569.2	570.1	Afethod A
10		4.16	92.1	610.2	611.1	MethodA
18		5.10	99.1	4122	413.1	Afethod A
24		3.96	963	5262	527.1	Afethod A
13	13137’C/ -58.88 J/g 25’Cto 350°C/10°Crnin/40p! Al	3.43	98.8	444.1	445/ 442.9	Afethod C

-159-

Compound No	Melting Point (Kofler or DSC)	LCMS
Rt	ÜV Area %	MW eia et	BPM1/ BPM2	LCMS Method
16		4.12	98.4	426.2	427.2	Method B
26		3.52	100.0	619.2	620.2	Method A
19		2.52	99.6	396.2	397.1	Method A
II		2.52	97.1	486.2	487.1	Method A
21		2.58	96.7	410.2	409/ 407	Method C
14		3.29	100.0	550.2	551.2	Method A
27	136 °C (Kofler)	2.47	92.7	396.2	397.1/ 395	AfethodC
28		2.44	95.5	485.2	486.1	Method A
29		4.45	98.2	534.2	535.1	Method B
30	160 °C (Kofler)	228	99.4	368.1	369/ 367	MethodC
31		2.39	97.7	406.2	4072	Method A

Further Characterising data

Compound No	Melting Point (Kofler or DSC)	LCMS
Rt	UVArea ·/.	MW (theor)	BPM1/ BPM2	LCMS Method
28		3.78	96.6	5972	598.1	METHOD D
14		3.29	100.0	5502	5512	METHOD D
15		4.41	100.0	5202	5212	METHOD E
1		3.21	97.9	506.2	507.1	METHOD D
7		3.96	100.0	568.2	569.1	METHOD D
29		4.45	982	5342	535.1	METHODE
81		3.79	100.0	454.2	455.1	METHODE
16		3.01	99.7	4262	427.1	METHOD D
4	184.57 °C/-35.49J/g 25°Cto 350°C/IOeCmin/40pi Al	3.72	98.73	569.18	570.2/ 568.6	METHOD F
24		3.96	96.3	5262	527.1	METHOD D
23		3.39	942	4502	451.2	METHOD D
26		3.52	100.0	6192	620.2	METHOD D
22		3.72	99.6	484.2	485.1	METHOD D

-160-

Compound No	Melting Point (Kofler or DSC)	LCMS
Rt	UVArea %	MW (theor)	BPM1/ BPM2	LCMS Method
2		4.40	96.9	568.2	569.1	METHOD D
3		4.61	97.6	569.2	570.1	METHOD D
77		2.44	95.47	485.2	486.1	METHOD D
8		4.49	97.71	569.2	570.1	METHOD D
9		4.08	97.02	4852	486.1	METHODD
13	131-37 C/-58.88 J/g 25°Cto 350°C/10°Cmin/40pi Al	3.43	98.8	444.1	445/ 442.9	METHOD F
12	see curve 25°C to 300°C/l0oCmin/40p 1A1	3.33	98.7	394.2	395.4/ 393.1	METHOD F
5	242.43 eC/-52.69 J/g 25°Cto 350oC/l0°Cmin/40pl Al	3.56	98.2	5702	571.3/ 569.5	METHOD F
30	160 eC (Kofler)	2.11	98.2	368.1	369/ 367	METHOD F
20	see curve 25°C to 300eC/10°Cmin/40p 1A1	2.38	99.4	4102	411.1/ 409.1	METHOD F
27	136 eC (Kofler)	2.47	92.7	396.2	397.1/ 395	METHOD F
21		2.77	99.3	408.2	409.1	METHOD G
il		2.52	97.06	486.1	487.1	METHOD D
18		5.1	99.14	4122	413.1	METHOD H
10		4.16, 4.22	92.14, 4.77	6102	611.1,611.1	METHOD D
17		3.18	98.34	4272	428.1	METHOD D
19		2.52	99.61	3962	397.1	METHOD D
6		3.64	99.4	539.3	540.2	METHOD D
31		2.39	97.7	4062	407.2	METHOD D
66		4.41	97.7	6112	612.1	METHOD D
80		4.93	100.0	5822	583.1	METHOD D
32		3.48	99.5	5062	507.1	METHOD D
79		4.86	98.7	5832	584.1	METHOD D
34		3.52	96.45	4062	4072	METHOD E
35		4.59	98.76	510.2	511.2	METHOD D

-161-

Compound No	Melting Point (Kofler or DSQ	LCMS
Rt	UV Area %	MW (theor)	BPMI/ BPM2	LCMS Method
68	180.57 °C/-42.6 IJ/g 25eC to 350°C/l0°Cmin/40pl Al	3.62	99.3	555.2	556.2/ 554.5	METHOD F
64		3.4	98.1	492.2	493.1	METHOD D
39		4.27	98.46	519.2	520	METHOD D
40		3.72	97.68	447.2	448.1	METHOD D
38		4.03	97.72	520.2	521.1	METHOD D
41		2.77	98.27	4913	492.2	METHOD D
70		3.53	99.43	554.3	555.2	METHOD D
43		4.02	99.14	535.0	535.1	METHOD D
44		3.91	97.85	461.2	462.1	METHOD D
78		3.53	99.32	411.2	412.2	METHOD E
48		3.03	99,74	476.2	477.2	METHOD D
49		2.93	97.41	486.2	487.2	METHOD D
61		3	98.65	490.3	491.2	METHOD D
46		2.83	95.62	505.3	506.2	METHOD D
47		3.71	95	549.2	5502	METHOD D
51		3.67	98.3	549.6	550.1	METHOD D
53		2.92	100.0	486.2	4872	METHOD D
52		3.11	93.0	500.2	5012	METHOD D
65		3.95	96.8	538.3	5392	METHOD D
69		3.79	98.8	553.3	554.2	METHOD D
33		3.43	98.0	447.2	448,1	METHOD D
63		5.51	95.4	507.2	508.1	METHOD H
60		3.55	100.0	521.2	522.1	METHOD D
71		3.55	100.0	553.3	5542	METHOD D
36		3.62	99.5	548.2	5492	METHOD D
37		4.35	98.4	509.2	5102	METHOD D
42		4.28	99.9	510.2	5112	METHOD D
45		4.16	98.8	5092	510.1	METHOD D
50		2.87	98.8	500.2	501.2	METHOD D
54		3.70	99.1	507.2	508.1	METHOD D
55		2.90	99.2	486.2	487.1	METHOD D
97		4.40	99.9	549.2	550.2	METHOD D

-162-

Compound No	Meltlng Point (Kofler or DSC)	LCMS
Rt	UV Are» %	MW (theor)	BPM1/ BPM2	LCMS Method
98		4.47	99.9	549.2	550.2	METHOD D
99		2.85	100.0	486.2	487.2	METHOD D
100		5.57	100.0	461.2	462.2	METHOD H
101		3.70	100.0	522.0	522.1	METHOD D
102		4.90	100.0	549.2	550.2	METHOD D
103		4.97	100.0	549.2	550.2	METHOD D
HM		3.61	99,4	548.2	549.2	METHOD D
105		3.78	100.0	5012	502.2	METHOD D
106		3.77	98.67	487.2	488.1	METHOD D
107		3.75	100.0	501.2	5022	METHOD D
108		3.80	98.6	487.2	488.1	METHOD D
109		3.95	96.4	500.2	501.2	METHOD E
58		4,47	98.9	570.2	571.1	METHOD D
67		4.39	98.9	554.2	555.1	METHOD D
110		5.61	99.0	506.2	507.1	METHOD H
72		4.16	99.5	568.2	569.1	METHOD O
111		2.87	97.8	500.2	501.2	METHOD G
73		3.61, 3.68	91.65,733	569.2	570.1	METHOD î
74		5.43	99.9	553.3	554.2	METHOD H
112		3.74	98.9	548.2	549.2	METHOD G
113		5.18	99.1	520.2	521.1	METHOD J
56		4.86	96.5	550.2	551.2	METHOD G
57		4.47	96.8	551.2	552.1	METHOD O
59		3.67	95.3	502.2	503.1	METHOD G
114		5.40	99.1	581.2	582.1	METHOD G
115		5.07	98.0	509.2	510.2	METHOD G
76	136.04’C/-55.97 J/g 25°C to 350’C/10eCmin/40pl Al	3.88	96.9	583.2	5843/ 582.7	METHOD F
75	i83.86 ’C/-50.09 J/g 25°C to 3OO’C/lO°Cmin/4Op 1A1	3.89	100.0	583.2	5843/ 582.6	METHOD F

-163-

Compound No	Melting Point (Kofier or DSQ	LCMS
Rt	UVArea %	MW (theor)	BPM1/ BPM2	LCMS Method
92	80.75 ’C/-33.76 J/g 25’C to 350°C/I0°Cmin/40ul Al	3.16	100	504.2	505.1/ 503.5	METHOD F
116		2.86	99.8	436.2	437.1	METHOD G
84	137.48’C/-87.44 J/g 25’C to 350°C/10’Cmin/40gl Al	3.06	100.0	438.2	439.1/ 437.4	METHOD F
87	190.35’C/-55.85 J/g 25’C to 250°C/I0°Cmin-W IAI	3.61	100.0	532.2	5333/ 531.6	METHOD F
88	156.54’C/-49.74 J/g 25’C to 350’C/10°Cmin/40pl Al	3.44	97.2	533.2	5343/ 532.4	METHOD F
86	127.22’C/-63.46 J/g 25’Cto 350’C/10°Cmin/40pl Al	2.85	96.4	439.2	440.1/ 4383	METHOD F
83	108.84’C/-49.64 J/g 25’Cto 350°C/10°Cmin/40pl Al	3.86	100.0	554.2	555.2/ 613.6 [M+CHjCOOl-	METHOD F
82	190.78 ’C/-5834 J/g 25’Cto 350°C/10°Cmin/40pl Al	3.54	96.8	5383	539.4/ 597.6 (M+CHiCOOl-	METHOD F
117	167.85 ’C/-8732 J/g 25’Cto 350°C/10°Ctnin/40gl Al	3.48	100.0	492.2	493.1/ 491.4	METHOD F
89	192.86 ’C/-45.19 J/g 25’Cto 220’C/10oCmin/40pl Al	3.02	100.0	485.2	486.2/ 484.4	METHOD F
85	147.41’C/-31.45 J/g	2.52	99.5	4083	409.2/ 4673 [M+CHjCOO]-	METHOD F
90	237.63 ’C/-116.22 J/g 25’C to 300°C/|0’Cmin/40p IAI	230	100.0	451.2	452.5/ 450.2	METHODK

-164-

Compound No	Mettlng Point (Kofier orDSC)	LCMS
Rt	UV Area %	MW (theor)	BPM1/ BPM2	LCMS Method
91	204.21 eC/-81.42 J/g 25°C to 300°C/t0°Cmin/40p 1AI	2.72	100.0	513.2	514.5/ 5123	METHOD K
93	182.04 eC ! -67 J1 J/g 25°Cto 300°C/|0°Cmin/40n IAI	3.19	98.32	486.2	487.5/ 485.3	METHOD K
118	20134 eC/-67.10 JgA-l 25°Cto 350oC/l0°Cmin/40p IAI	2.39	94.45	398.1	399.4/ 3972	METHOD K
119	147.85 eC/-5131 J/g 25°Cto 350°C/10°Cmin/40u IAI	3	100	485.2	486.4/ 4843	METHOD K
120	139.57 eC/-113.34 J/g 25°C to 350°C/10°Cmin/40p IAI	3.02	100	485.2	486.5/ 484.2	METHOD K
94	168.80 °C/-55.36 J/g 25°Cto 350°C/10°Cmin/40p IAI	3.61	99.27	485.2	486.1/ 484.3	METHOD F
95	154.23 ’C/-78.85 J/g 25°C to 350°C/10°Cmin/40p IAI	2.84	100	480.2	481.4/ 497.2	METHODK
121	241.08 °C/-75.05 J/g 25°C to 350°C/)0°Cmin/40u IA)	2.65	96.76	4872	488.1/ 4863	METHOD F
122	16123 °C/-54.16 J/g 25°Cto 350Ό10°Οηίη/40μ IAI	2.92	96.6	486.2	487.1/ 485.4	METHOD F
96	182.82 °C/ -91.28 J/g 25°Cto 300eC/IO°Cmtn/40g IAI	2.62	100	4222	423.5/ 421.2	METHOD K
Cpd 123	166.63 ’C/-55.15 J/g, 25*Cto 300*Ç/10*Cmin/40gl Al (DSC: 25*Cto 300’C/10’Cmin/40g IAI)	2.58	97.1	475.2	476.2/ 474.3	METHOD F

-165-

Compound No	Melting Point (Kofler or DSC)	LCMS
Rt	UV Area %	MW (thenr)	BPM1Z BPM2	LCMS Method
Cpd 124	135.97’C/-75.64 J/g, 25Cto 300*C/10*Cmin/40pl Al (DSC: 25Cto 300*C/10*Cmin/40p IAI)	3.02	100.0	491.2	492.4/ 490.3	METHOD K
Cpd 125	146.77 *C/-81.28 JgA1,25’Cto 350*C/10*Cmin/40pl Al (DSC: 25*Cto 3S0*C/10*Cmln/40pl Al)	3.35	100.0	472.2	473.1/ 471.3	METHOD F
Cpd 126	187.49 ’C/-68.56 J/g; 289.39 ’C/+284.49 J/g (DSC 25*C to 300’C/10’Cmin/40p IAI)	2.59	99.3	423.1	424/ 482.2 [M+CHjCOO]-	METHOD F
Cpd 127	201.15 C/-111.61 J/g (DSC: 25*C to 300*C/10*Cmin/40p IAI)	3.39	98.7	436.2	437.1/ 495.3 [M+CHjCOO]-	METHOD F
Cpd 128	160.59 *C/-94.05 J/g (DSC: 25*C to 300C/10*Cmln/40p IAI)	2.97	100.0	505.2	506.1/ 504.3	METHOD F
Cpd 129	188.46 C/-42.53 J/g (DSC: 25*C to 350'C/10’Cmin/40pl Al)	2.68	90.7	414.1	414.9/ 413.1	METHOD F
Cpd 158	101.95 ’C/-40.87 J/g (D5C:25Cto 350*C/10*Cmin/40pl Al)	2.93	100.0	488.2	489.1/ 487.4	METHOD F
Cpd 152	see curve (DSC: 25*C to 350*C/10*Cmin/40pi Al)	3.41	98.5	519.2	520.1/ 518.4	METHOD F
Cpd 148	158.14 *C/-65.57 J/g (DSC 25’C to 350C/10*Cmln/40pl Al)	3	100.0	445.1	446/ 444.3	METHOD F
Cpd 133	84.29 ’C/-42.38 JgA-l (DSC: 25*Cto 350C/10*Cmln/40pl Al)	3.18	100.0	473.2	474.1/ 472.3	METHOD F

-166-

Compound No	Melting Point (Kofler or DSC)	LCMS
Rt	UV Area %	MW (theor)	BPM1/ BPM2	LCMS Method
Cpd 159	177.08’C/-85.31 J/g (DSC: 25’Cto 350’C/10’Cmln/40pt Al)	3.76	100.0	576,2	575.4/ 577.2	METHOD F
Cpd 141	158.48 ’C/-115.36 JgA-l (DSC: 25’Cto 350’C/10’Cmin/40pl Al)	3.64	98.9	520.2	521.2/ 579.5 [M+CHjCOO]-	METHOD F
Cpd 142	193.19’C/-79.28 JgA1(DSC: 25’Cto 350’C/10’Cmln/40pl Al)	3.4	100.0	521.2	522.2/ 580.5 [M+CHjCOO]-	METHOD F
Cpd 131	172.76’C/-68.86 J/g (DSC: 25’Cto 350’C/10’Cmin/40pl Al)	3.31	100.0	493.1	494,1/ 492.3	METHOD F
Cpd 144	135.80’C/-64.11 JgA1 (DSC: 25’Cto 350’C/10’Cmin/40pl Al)	3.51	97.8	535.2	536.2/ 594.5 [M+CHjCOO]-	METHOD F
Cpd 138	105.98’C/-50.26 J/g (DSC 25’Cto 350’Ç/10’Cmln/40pl Al)	3.75	98.5	534.2	535.2/ 593.5 [M+CHjCOO]-	METHOD F
Cpd 130	169.56 ’C/-68.85 J/g (DSC: 25’Cto 350’Ç/10’Cmin/40pl Al)	2.91	100.0	462.2	463.5/ 521.3 [M+CHjCOO]-	METHODK
Cpd 134	188.07 ’C/ -99.63 J/g (DSC: 25’Cto 350’C/10’Cmln/40pl Al)	2.89	100.0	486.2	487.2/ 485.5	METHOD F
Cpd 160	166.29 ’C/-77.23 J/g (DSC: 25’Cto 350’C/10’Cmln/40pl Al)	3.52	100.0	562.2	563.4/ 621.4 [M+CHjCOO]-	METHOD K
Cpd 143	130.31’Ç/-8 3.46 JgA-l (DSC: 25’Cto 350’C/10’Cmln/40pl Al)	2.73	97.9	378.2	379/ 437.3	METHOD F
Cpd 153	150.61 ’C / -64.88 JgA1 (DSC: 25’Cto 350’C/10’Cmln/40pl Al)	3.5	98.7	521.2	522.2/ 520.5	METHOD F

-167-

Compound No	Melting Point (Kofler or DSC)	LCMS
Rt	UVArea %	MW (theor)	BPMl/ BPM2	LCMS Method
Cpd 161	126.57 ’C/-47.92 J/g (DSC: 25*Cto 350’C/10’Cmin/40pl Al)	3.61	100.0	534.2	535.5/ 593.3 [M+CHjCOOJ-	METHOD K
Cpd 162	238.06’C /-64.81 J/g (DSC: 25’Cto 350*C/10*Cmln/40pl Al)	3.27	100.0	563.2	564.5/ 622.4 [M+CHaCOOJ-	METHOD K
Cpd 132	149.46’C /-64.76 J/g (DSC: 25’Cto 350*C/10‘Cmin/40pl Al)	2.99	100.0	486.2	487.1/ 485.4	METHOD F
Cpd 163	142.39 ’C/-61.91 J/g (DSC: 25’Cto 350*C/10*Cmin/40pl Al)	3.37	100.0	408.2	409.4/ 407.4	METHOD K
Cpd 149	141.92 ’C/ -60.55 J/g (DSC: 25’Cto 350*C/10*Cmln/40pl Al)	3.98	100.0	586.2	587.4/ 585.3	METHOD K
Cpd 164	165.12 ’C/ -58.86 J/g (DSC: 25’Cto 350’C/10’Cmin/40pl Al)	3.52	100.0	492.15	493.5/ 491.2	METHOD K
Cpd 157	144.55’C/-60.51 JgA1 (DSC: 25’Cto 350’C/10’Cmln/40pl Al)	3.67	99.5	552.2	553.5/ 551.4	METHOD K
Cpd 139	135.21’C/-62.94 JgA1 (DSC: 25’Cto 350*C/10’Cmin/40pl Al) .	3.62	100.0	538.3	539.5/ 597.5 [M+CHjCOO]-	METHOD F
Cpd 165	150.69 ’C/-73.99 J/g (DSC: 25*C to 350’C/10’Cmln/40pl Al)	3.4	100.0	458.2	459.2/ 4S7.3	METHOD F
Cpd 150	144.49 ’C/-43.61 J/g (DSC: 25*Cto 350’C/10’Cmin/40pl Al)	4.03	97.0	586.2	587.3/ 585.4	METHOD F
Cpd 146	119.23 ’C/-38.89 JgA1 (DSC; 25’Cto 350’C/10’Cmln/40pl Al)	3.88	100.0	568.2	569.5/ 627.4 [M+CHjCOO]·	METHOD K

-168-

Compound No	Melting Point (Kotler or DSC)	LCMS
Rt	UV Area %	MW (theor)	BPM1/ BPM2	LCMS Method
Cpd 147	151.74’C/-63.26 JgA1 (DSC: 25’Cto 350’C/10’Cmln/40pl Al)	3.66	100.0	564.2	565.4/ 623.5 [M+CHiCOOl-	METHOD F
Cpd 140	121.52’C/-62.48 J/g (DSC: 25’C to 350’C/10*Cmin/40pl Al)	3.45	99.4	472.2	473.2/ 531.6 [M+CHjCOO]-	METHOD F
Cpd 154	132.95 ’C/-79.92 JgA1(DSC: 25*Cto 350’C/10*Cmln/40pl Al)	3.25	100.0	540.1	541.5/ 539.3	METHOD K
Cpd 155	232.10 ’C/-88.86 JgA1 (DSC: 25’Cto 350*C/10’Cmin/40pl Al)	2.44	100.0	458.1	459.5/ 457.2	METHOD K
Cpd 166	156.21’C/-30.90 J/g (DSC: 25’Cto 350’C/10’Cmln/40pl Al)	5.22	100.0	535.2	536.3/ 594.4 [M+ClhCOO]-	METHOD F
Cpd 145	198.95 ’C/ -102.61 J/g (DSC: 25’Cto 350*C/10’Cmln/40pl Al)	3.42	100.0	539.3	540.4/ 598.7 [M+CHjCOOJ-	METHOD F
Cpd 167	164.95 ’C /-78.44 JgA1 (DSC; 25’Cto 350’C/10’Cmln/40pl Al)	3.66	98.0	538.3	539.4/ 597.6 [M+CHjCOO]·	METHOD F
Cpd 156	202.90’C/-47.56 JgA1 (DSC: 25’Cto 350’C/10’Cmin/40pl • Al)	2.13	100.0	428.2	429.2/ 427.4	METHOD F
Cpd 136	163.21’C/-60.16 J/g (DSC: 25’Cto 350’C/10’Cmln/40pl Al)	3.05	99.4	475.16	476.2/ 474.4	METHOD F
Cpd 151	164.83 ’C/-27.18 J/g (DSC: 25’Cto 350’C/10’Cmln/40pl Al)	4.32	98.9	584.2	585.3/ 583.5	METHOD F
Cpd 135	148.28 ’C/-63.15 J/g (DSC: 25’Cto 350’C/10’Cmln/40pl Ai)	3.22	98.8	474.16	475.2/ 473.4	METHOD F

-169-

Compound No	Melting Point (Kofler or DSC)	LCMS
Rt	UVArea %	MW (theor)	BPM1/ BPM2	LCMS Method
Cpd 137	201.30 ’C/-41.79 J/g (DSC:25*Cto 350’C/10’Cmin/40p! Al)	3.65	98.9	550.2	551.3/ 549.5	METHOD F
Cpd 158	183.37’C /-57.51 J/g (DSC: 25*C to 350*C/10’Cmin/40p! Al)	2.33	100.0	424.2	425.1/ 423.1	METHOD F

Analvtical methods

LCMS

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

General procedure Method C

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 în 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 monoîsotopic 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 isotopîc 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.

Hereinaftcr, “SQD” means Single Quadrupole Detector, “RT” room température, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “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 Ί
Method C	Waters: Acquit} UPLC®-DAD and Quattro Micro™	Waters: BEH C18(1.7gm, 2.1x100mm)	A: 95% CHjCOONHi 7mM/5% CHjCN,B: CHjCN	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

General procedure LCMS Methods A and B

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 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, (t Is within the knowledge ofthe skilled person to set the tune parameters (e.g. scanning range, dwell time, etc) in order to obtain ions allowing the identification ofthe 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), ln case the compound was not directly ïonizable the type of adduct is specified (i.e. [M+NH4]⁺, [M+HCOO]', etc). For molécules with multiple isotopic patterns (Br, Cl..), the reported 20 value is the one obtained for the lowest isotope mass. Ail results were obtained with experimental uncertaintîes 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).

-171-

Method code	Instrument	Column	Mobile phase	gradient	Flow	Run time
Al/rriB	Agilent: 1100/120 0-DAD and MSD	Agilent: TC-C18 (5pm, 2.1x50mm)	A: CFjCOOH 0.1% in water, B: CFjCOOH 0.05% in CHCN	100% A for 1min, to 40% A in 4mîn. toi5% A in 2.5min, back to 100% A în 2min.	0.8	10. 5
50
MfrdA	Agilent: 1100/120 0-DAD and MSD	Agilent: TC-C18 (5gm, 2.1x50mm)	A: CFjCOOH 0.1% in water. B: CFjCOOH 0.05% in CHsCN	90% A for 0.8min, to 20% A in 3.7min, heid for 3min, back to 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.

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 specified în the respective methods. ifnecessary, 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 ofthe skilled person to set the tune parameters (e.g. scanning range, dwell time...) în order to obtain ions allowîng the identification ofthe compound’s nominal monoîsotopîc 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 compound was not directly ionîzable the type ofadduct is specified (i.e. [M+NH.t]⁺, [M+HCOO]’, etc...). For molécules with multiple îsotopic 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” Hîgh Strength Silica, “DAD” Diode Array Detector.

-172Table: 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 F	Waters: Acquity UPLC*DAD and Quattro Micro™	Waters: BEHCI8 (1.7pm, 2.1x100 mm)	A: 95% CHjCOONlL 7mM/5% CHjCN,B: CHjCN	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
Method K	Waters: Acquity® H-Class DAD and SQD2™	Waters: BEHC18 (1.7pm, 2.1x100 mm)	A: 95% CHjCOON H(7mM/ 5%CH£N, B: CHjCN	84.2% A to 10.5% A in 2.18 min, held for 1.96 min, back to 84.2% A in 0.73 mïn, held for 0.73 min.	0.343	6.1
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
Ntftd E	Agilent: 1100/120 0-DAD and MSD	Agilent: TC-C18 (5pm, 2.1x5ftnm)	A: CFjCOOH 0.1% in water, B: CFjCOOH 0.05% in CHjCN	100% A for 1min, to40% A in 4min, toi 5% A in 2.5min, backto 100% A in 2min.	0.8	10.5
50
Mtal D	Agilent: 1100/120 0-DAD and MSD	Agilent: TC-C18 (5pm, 2.1x5frnm)	A: CFjCOOH 0.1%in water, B: CFjCOOH 0.05% in CHjCN	90% A for 0.8min, to 20% A in 3.7min, held for 3min, back to 90% A in 2min.	0.8	10.5
50

-173-

Method Code	Instrument	Column	Mobile phase	gradient	Flow	Run time
Column T
Nhhod H	Agilent: 1100/120 0-DAD and MSD	Waters: XBridge™ Shield RP 18 (5pm, 2.1x50mm)	AiNILOH 0.05% in water, B: CHjCN	100% A for 1 mîn, to 40% A in 4min, held for 2.5min, backto 100% A in 2min.	0.8	10.5
40
Nfcthod G	Agilent: 1200DAD and MSD611 0	Phenomene x: LunaCI8(5pm, 2 x50mm)	A: CFjCOOH 0.l%in water, B: CFjCOOH 0.05% in CHjCN	90% A for 0.8min, to 20% A in 3.7min, held for 3min, back to 90% A in 2min.	0.8	10
50
Nfcthod I	Agilent: 1200DAD and MSD6H 0	Phenomene x:LunaCI8(5pm, 2x5 0mm)	A: CFjCOOH 0.l%in water, B: CFjCOOH 0.05% in CHïCN	70% A for 0.8min, to 10% A in 3.7min, held for 3min, back to 70% A in 2min.	0.8	10
50
Nfcthod J	Agilent: 1200DAD and MSD611 0	Phenomene x:LunaC18(5pm, 2 x50mm)	A: CFjCOOH 0.l%in water, B: CFjCOOH 0.05% in CHjCN	100% A for Imin, to 40% A in 4min, to 15% A in 2.5min, back to 100% A in 2min.	0.8	10

Pharmacologica! Examples

MTC 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 ofMycobacterium tuberculosis strain H37Rv were taken from cultures in logarithmïc growth phase. These were first diluted to obtain an optical density of0.3 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, plCw, etc) were (or may be) calculated.

TEST 2

Round-bottom, stérile 96-well plastic microtiter plates are filled with 100 μΐ of Middlebrook (1 x) 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 5 2 μΙ 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 mînimize pipetting errors with high hydrophobie compounds. Untreated control samples with (column 1) and without (column 12) inoculum are included in 10 each microtiter plate. Approximately 10000 CFU per well ofMycobacterium 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 încubated at 37°C for 7 days in a humidified atmosphère (incubator with open air valve 15 and continuous ventilation). On day 7 the bacterial growth is checked visually.

The 90 % minimal inhibitory concentration (MIC90) is determined as the concentration 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 ofM. tuberculosis is 10^s CFU / ml in Middlebrook (lx) 7H9 broth. The antibacterial compounds are used at the concentration of0.1 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 încubated 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‘* to 10*) in Middlebrook 7H9 medium and plating (100 μΙ) on Middlebrook 7H11 agar. The plates are încubated 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 potentiel carryover effect of the drugs îs 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)

-175Appropriate 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 în 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 inventîon/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 15 ofthe invention/examples, for example when tested in Test 1 or Test 2 described above, may typically hâve a plCso 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 I described above (in section “Pharmacological Examples”) and the following results were obtained:

Biological Data Table

Compound No	plC50	p1C50*	plC5O··
1	8.03	7.88
17	7.82	6.5	6.33
2	7.79	7.83	7.93
3	7.59	7.58	7.59
23	7.32	7.35	7.35
22	7.26	7.18	7.24
5	7.16	7.13	7.13
9	7.08	7.14	7.27
7	7	7.12	7.1
15	6.99	7.02
4	6.92
12	6.89	7.15	6.97

Compound No	plC50	pICSO·	pICSO ··
25	6.87	6.88	6.96
6	6.85	6.99	6.89
8	6.83	6.73	6.77
10	6.83	6.85	6.97
18	6.72	6.91	6.9
24	6.7	6.56	6.94
13	6.57	6.59	6.58
16	6.55	6.61
26	6.17	6.16	6.23
19	6.1	5.94	5.97
11	5.73	5.52	5.92
21	5.61	5.98	5.86

Compound No	pICSO	plC50·	plC50 *·
14	5.55	5.53
27	5.39	5.38	5.54
28	5.22	5.12	5.13

Compound No	pICSO	plCSO·	plC50 ··
29	5.1	5.17	5.15
30	5.05	<4.9	4.96
31	<4.9	<4.9	<4.9

* and ** dénoté repeated (2™* and 3^rd) tests în 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	plCso
28	8.5
14	6.4
15	6.8
1	7.0
7	7.8
29	5.1
81	8.3
16	8.0
4	83
24	6.6
23	7.5
26	6.4
22	7,9
2	73
3	83
77	6.1
8	73
9	7.9
13	7.5
12	7.5
5	7.5
30	5.1

Compound No	plCso
20	6.5
27	6.4
21	7.0
11	6.1
18	7.5
10	7.5
17	7.4
19	5.9
6	7.6
31	<4.9
66	8.1
80	<4.9
32	7.4
79	<4.9
34	<4.9
35	5.1
68	7.2
64	7.0
39	<4.9
40	<4.9
38	<4.9
41	5.1

Compound No	plCso
70	6.5
43	<4.9
44	5.1
78	5.6
48	5.2
49	<4.9
61	6.2
46	5.1
47	52
51	52
53	<4.9
52	5.1
65	8.0
69	7.5
33	<4.9
63	6.5
60	7.0
71	6.5
36	5.1
37	5.4
42	5.0
45	5.1

-177-

Compound No	pICso
50	<4.9
54	5.1
55	<4.9
97	<4.9
98	<4.9
99	<4.9
100	<4.9
101	5.8
102	5.4
103	5.1
104	<4.9
105	<4.9
106	<4.9
107	<4.9
108	<4.9
109	<4.9
58	7.0
67	8.0
110	<4.9
72	8.0

Compound No	pICso
111	<4.9
73	6.7
74	7.2
112	5.5
113	<4.9
56	8.2
57	8.1
59	6.5
114	4.9
115	5.5
76	7.6
75	7.8
92	6.6
116	6.5
84	7.0
87	6.6
88	6.6
86	6.8
83	7.0
82	7.2

Compound No	pICso
117	7.7
89	5.2
85	6.0
90	4.9
91	5.0
93	6.9
118	4.9
119	6.2
120	5.0
94	7.1
95	6.8
121	5.6
122	6.1
96	6.9
124	7.1/7.2
126	5/4.9
127	6.9/7.0
128	7.5
129	6.4/6.5

Compound No	pICso
123	5.8
125	8.7
158	6.4
152	7.8
148	7.8
133	8.7
159	7.4
141	7.5
142	6.9
131	8.3

Compound No	plC»
144	7.1
138	7.4
130	7.8
134	8.2
160	7.5
143	6.4
153	8.7
161	5.6
162	5.1
132	5.1

Compound No	pICso
163	5.1
149	8.7
164	5.1
157	5.1
139	5.1
165	5.1
150	8.7
146	6.5
147	5.9
140	5.8

-178-

Claims (20)

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

R¹ represents alkyl or hydrogen;

L* represents a linker group -C(R^B)(R^b)-;

X¹ represents an optional carbocyclic aromatic linker group (which linker group may itself be optionally substituted by one or more substituents selected from fluoro, -OH, -OC|-6 alkyl and Ci_6 alkyl, wherein the latter two alkyl moieties are themseleves optionally substituted by one or more fluoro atoms);

R‘ and R^b independently represent hydrogen or C|_6 alkyl (optionally substituted by one 15 or more fluoro atoms);

X represents C(R^C) or N;

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^c and R^d independently represent H, F or -OR^e (wherein R^e represents H or C|_6 alkyl optionally substituted by one or more fluoro atoms), or, R^d and L² may be linked together to form a 4- to 6-membered cyclic group (i.e. a spiro-cycle), optionally containing one to three heteroatoms;

q¹ represents -X^c-(CH₂)_ni-X^d-;

ni repesents 0, 1 or 2;

q² represents -X^c-(CH2)_n2-X^r-;

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

-179X^e (which is attached to X*) is either not présent, or, when X^a represents CH, then X^e may represent -O-, -N H- or -S-;

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

5 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 -X⁸-(CH₂)_n3-X^h-;

10 q⁴ represents -X’-iCHj^-X³-;

n3 repesents 0, 1 or 2;

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

X⁸, X^h, X¹ and X^ independently are either not présent, or may represent -O-, -NH- or 15 -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 présent;

when X^b represents C(R) or N, then L² may represent hydrogen, halo, -OR^f, -C(O)-R⁸, 20 Cialkyl (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^ alkyl (itself optionally substituted by one or more substituents selected from fluoro, -CF₃ and/or -SFj), -OCi^alkyl (itself optionally substituted by one or more fluoro atoms), -O-phenyl (itself optionally substituted by halo, C| .«alkyl, Cj^fluoroalkyl and/or 25 -OCj^alkyl) or -SF5); or, when attached to nitrogen, i.e. when X^b is N, L² represents

-S(O)₂-Ci^alkyl optionally substituted by one or more fluoro atoms (e.g. forming -S(O)₂CF₃);

R^f represents hydrogen, 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^alkyl and -OCi^alkyl, where the latter two alkyl moieties may themseleves be optionally substituted by one or more fluoro atoms);

R⁸ represents hydrogen or Ci.«alkyl (optionally substituted by one or more substituents

35 selected from fluoro, or -OCi.₃ alkyl, which latter moiety îs also optionally substuituted by one or more fluoro atoms) or an aromatic group (optionally substituted by one or more substituents selected from halo, C|.« alkyl or -OCj^alkyl);

-180« t I a « i

ring A may be attached to the requisite amide moiety (i.e. the -C(O)-N(R*)- moiety) via either one of two possible bonds represented by the dotted lines, which bonds are lînked to ring A at two different atoms (of that ring);

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 from nitrogen, oxygen and sulfur);

either ring A and/or ring B may be optionally substituted by one or more substituents selected from: halo, Cm alkyl (optionally substituted by one or more halo, e.g. fluoro atoms) and/or -OCmalkyl (itself optionally substituted by one or more fluoro atoms), or a pharmaceutically-acceptable sait thereof.

2. A compound for use as claimed in Claim 1, wherein:

R¹ represents hydrogen;

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

L¹ represents -CH2-.

3. A compound for use as claimed in Claim 1 or Claim 2, wherein X¹ represents a carbocyclic aromatic linker group that is:

-phenylene- (especially a 1,4-phenylene), e.g.:

naphthylene, e.g.:

-181-quînolylene (such as 2-quinolylene), e.g.:

kP in which such lînker groups are optionally substituted (e.g. by one or more substituents selected from fluoro, CHj, CF3, -OCH3 and -OCF3).

4. A compound for use as claimed in any of the preceding claims, wherein the spirocyclic moiety, i.e. the combined X and X^b-containing ring may be represented as follows:

-182-

5. A compound for use as claimed in any of the preceding claims wherein:

ring A is represented as follows:

ring B is represented as follows:

wherein “SUB” and “Sub” represent one or more possible substituents on the relevant

5 atom (e.g. carbon or nitrogen atom).

6. A compound for use as claimed in any one of the preceding claims, whereîn the combined ring Systems, i.e. Ring A and Ring B may be represented as follows:

-184- «

-185- 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”).

7. A compound for use as claimed in any one of the preceding claims, wherein:

X^a represents N or C(R^C) (e.g. CH);

X^b represents N, O, C(R^c) (e.g. CH) or C=O;

at least one of X“ and X^b represents N and the other represents C(R^C), N or (in the case of X^b) O;

both X and X^b do not represent C(R');

X^e is not présent or represents -O-;

X^d is not présent;

X^e is not présent;

X^f îs not présent;

X®, X^h, X¹ and X^j independently are not présent;

ni represents 0, 1 or 2;

n2 represents 1 or 2;

n3 represents 1 or 2;

-186n4 represents 1 or 2;

q¹ represents -CH2-, -CH2-CH2-, -O-CH2- or (i.e. în the latter case, ni = 0, X^e is not présent and X^d is not présent);

q² represents -CJI2- or -CH2-CH2-;

q³ represents -CH2- or -CH2-CH2-; and/or q⁴ represents -CII2- or -CH2-CH2-.

8. A compound for use as claimed in any one of the preceding claims, wherein L² represents hydrogen, halo (e.g. fluoro), -OR^f, -C(O)R^g, or an aromatic group (optionally substituted by one or two (e.g. one) substituent(s) selected from -OCi^alkyl (itself optionally substituted by one or more fluoro atoms) or -SF5, or, altemativeïy by halo, e.g. fluoro).

9. A compound for use as claimed in any one of the preceding claims, wherein R^f represents Ci^alkyl or an aryl group optionally substituted by Ci^alkyl (itself optionally substituted by one or more fluoro atoms, so forming e.g. a -CF3 group) and/or R^e represents Ci_3alkyl (optionally substituted by fluoro) or phenyl.

10. A compound of formula (IA) as defined in Claim lbut wherein:

L¹ represents -CH2-;

X* is not présent or X* represents a carbocyctic aromatic linker group;

when X¹ represents a carbocyclic linker group it represents phenylene (e.g. a 1,4phenylene) for instance:

at least one of X^a and X^b represents N and the other represents C(R^C), N or (in the case ofX^b) O;

the X^e and X^b-containing spiro-cycle 3- to 6-membered ring attached to a 4- to 6membered ring;

in one aspect L² represents an aromatic group (as defined herein) optionally substituted as defined herein, and/or, in another aspect L² represents -OR^f in which R^f represents an aryl group (as defined herein) optionally substituted as defined herein;

when L² represents an (optionally substituted) aromatic group, it may be phenyl or a 5or 6-membered heterocyclic group (e.g. containing at least one nitrogen atom, so forming a pyridyt, thiazolyl or trîazolyt ring; in a major embodiment the heterocyclic group is a pyridyl), where the optional substituents are as defined herein;

-187optional substituents on aromatic L² groups are selected from halo, alkyl, -CF3, OCi_6 alkyl and -OCF3;

when R^r represents an aryl group, then it is preferably phenyl optîonally substituted by Cu alkyl, itself optîonally substituted by fluoro);

ring A and ring B together represent a 8 or 9-membered bicyclic ring (ring A is a 5membered 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, at least one nîtogen atom that is common to both rings);

optional substituents on ring A and ring B are halo, C1.3 alkyl and -OC1.3 alkyl, or a pharmaceutically-acceptable sait thereof.

11. A compound as claimed in Claim 10 wherein:

q¹ represents -CH2-, -CH2-CH2-, -O-CH2- or (i.e. in the latter case, ni = 0, X^e is not présent and X^d is not présent);

q² represents -CH2- or -CH2-CH2-;

q³ represents -CH2- or -CH2-CH2-;

q⁴ represents -CH2- or -CH2-CH2-.

12. A compound of formula (IB) as depîcted below:

the integers are as hereinbefore defined, and where, preferably:

ni, n2, n3 and n4 independentiy represent 1;

at least one of X* and X^b represents N and the other represents CH or N;

13. A compound of formula (I)

-188- wherein

5 R¹ represents hydrogen;

L¹ represents-CH₂-;

X* represents a carbocyclic aromatic linker group that is: -phenylene- (especially a 1,4-phenylene), e.g.: the spiro-cyclic moiety, i.e. the combined X* and X^b-containing ring may be represented as follows:

Hzi y

15 L² represents -S(O)₂-C)^alkyl optionally substituted by one or more fluoro atoms (e.g. forming

-S(O)₂CF₃);

ring A is a 5-membered aromatic ring containing at least one heteroatom (preferably 20 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 from nitrogen, oxygen and sulfur);

I

-189wherein the combined ring Systems, i.e. Ring A and Ring B may be represented as follows:

optional substituents on ring A and ring B are halo, C|.j alkyl and -OC|.j alkyl, or a pharmaceutically-acceptable sait thereof.

14. A compound as defined in any one of claims 10 to 13, for use as a pharmaceutical.

15. 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 claims 10-13.

16. Compound according to any one of claims 10-13 for use in the treatment of tuberculosis.

17. Use of a compound according to any one of claims 1 to 13 for the manufacture of a médicament for the treatment of tuberculosis.

18. A combination of (a) a compound according to any one of claims 1 to 13, and (b) one or more other anti-tuberculosis agent.

19. A product containing (a) a compound according to any one of claims 1 to 13, and (b) one or more other anti-tuberculosis agent, as a combined préparation for simultaneous, separate or sequential use in the treatment of a bacterial infection.

20. A process for the préparation of a compound of formula (IA) as claimed in Claim 1, or Claims 10-13, which process comprises:

(i) reaction of a compound of formula (Π), in which the întegers are defined in Claim 1, with a compound of formula (III),

LG'-L² (III) wherein L² îs as defined in Claim 1 (but when L² is not hydrogen, halo or linked to O 5 or S), and LG* is a suitable leaving group;

(ii) reaction of a compound of formula (IV), (IV) wherein the întegers are as defined in Claim 1, or a suitable dérivative thereof, such as a carboxylic acid ester dérivative, with a compound of formula (V) (V)

-191wherein the integers are as hereinbefore defined, under amide coupling reaction conditions;

(iii) coupling of a compound of formula (VI), (VI)

5 wherein the integers are as defined in Claim 1, and LG² represents a suitable leaving group, with a compound of formula (VI), (VII) wherein the integers are as defined in Claim 1;

(iv) coupling of a compound of formula (VIII), wherein the integers are as defined in Claim 1, and LG³ represents a suitable leaving group as described above with respect to LG² (and may particularly represent chloro, bromo or iodo), with a compound of formula (IX), lg⁴-l² (IX)

-192wherein L² is as defined in Claim 1 (but when L² is not hydrogen, halo or linked to 0 or S), and LG⁴ is a suitable group.